indian journal of ijpp practical pediatrics

2008; 10(2) : 91

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IJPPINDIAN JOURNAL OFPRACTICAL PEDIATRICS

••••• IJPP is a quarterly subscription journal of the Indian Academy of Pediatricscommitted to presenting practical pediatric issues and managementupdates in a simple and clear manner

••••• Indexed in Excerpta Medica, CABI Publishing.

Vol.10 No.2 APR.-JUN.2008

Dr. K.Nedunchelian Dr. S. ThangaveluEditor-in-Chief Executive Editor

CONTENTS

FROM THE EDITOR'S DESK 93

TOPIC OF INTEREST - HEMATOLOGY

Hematinics in Children 96

- Naithani R, Saxena R

Challenges in the management of febrile neutropenia in children 106- Arora B, Kurkure P, Purvish Parikh

Disseminated intravascular coagulation 115

- Satyendra Kateeva, Anupam Sachdev, Yadav SP

Thrombotic disorders in children 132

- Nitin K. Shah

Chronic immune thrombocytopenic purpura in children 138

- Lalitha Kailas, Abhilash TG

Hemophagocytic lymphohistiocytosis 143

- Revathi Raj

Prenatal diagnosis of hematological conditions 148

- Sujatha Jagadeesh, Lathaa Bhat

Journal Office and address for communications: Dr. K.Nedunchelian, Editor-in-Chief, Indian Journal ofPractical Pediatrics, 1A, Block II, Krsna Apartments, 50, Halls Road, Egmore, Chennai - 600 008. Tamil Nadu,India. Tel.No. : 044-28190032 E.mail : [email protected]

Indian Journal of Practical Pediatrics 2008; 10(2) : 92

Published on behalf of the Indian Academy of Pediatrics by Dr.K.Nedunchelian, Editor-in-Chief,Indian Journal of Practical Pediatrics from 1A, Block II, Krsna Apartments, 50, Halls Road, Egmore,Chennai - 600 008. Tamil Nadu, India and printed by Mr. D. Ramanathan, at Alamu Printing Works,9, Iyyah Street, Royapettah, Chennai - 600 014.

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FOR YOUR KIND ATTENTION

* The views expressed by the authors do not necessarily reflect those of the sponsor orpublisher. Although every care has been taken to ensure technical accuracy, no responsibility isaccepted for errors or omissions.

* The claims of the manufacturers and efficacy of the products advertised in the journal are theresponsibility of the advertiser. The journal does not own any responsibility for the guarantee of theproducts advertised.

* Part or whole of the material published in this issue may be reproduced withthe note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission.

- Editorial Board

CARDIOLOGYAcute myocarditis 155

- Shakuntala Prabhu, Sumitra Venkatesh

SKELETAL DISORDERSA clinical approach to skeletal dysplasia 164- Elizabeth KE, Binoy Thomas

DERMATOLOGYUrticaria in children and the role of antihistamines in pruritus 174

- Jayakar Thomas

RADIOLOGIST TALKS TO YOUSeizures and epilepsy - Role of radiological investigations 180- Vijayalakshmi G, Elavarasu E, Vijayalakshmi M, Venkatesan MD

CASE STUDY 183

McCune Albright Syndrome

- Chitra Ayyappan, Arun Prasath TS, Meikandan D, Vasanthakumari ML

BOOK REVIEW 179

NEWS AND NOTES 114,131,142,147,154,163,173,182

2008; 10(2) : 93

FROM THE EDITOR’S DESK

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The present issue of IJPP is dedicated totopics in “Hematology”. Hematology hasemerged as a highly developed super specialtyin all aspects, including molecular genetics.

All the components in blood are essentialto maintain the health of an individual. Bloodcomponents in single or in combination can beaffected either primarily or secondarily leadingon to disease status. For example congenital redcell aplasia which is a primary disorder andanemia of chronic renal failure which is asecondary problem affecting red blood cell.Bleeding disorder can be primary or secondarydue to disseminated intravascular coagulation.

There are many hematological disorderswhich are of great interest to practicingpediatricians. As it is impossible to cover allthose in a single issue of the journal, mostcommon and interesting conditions are coveredin this issue. There are many conditions likeanemia which can be managed by a generalpediatrician himself, if he is equipped with thebasic knowledge and simple laboratory support.The most frequent hematological disorders whichare faced by a practicing pediatrician are due toderangements in RBC and hemoglobin. It is socommon that it gives an impression that the entirehematology revolves around anemia and nothingelse. Most common cause of anemia indeveloping countries is nutritional deficiencyinvolving many micro nutrients. Thesemicronutrients are misused many times andunder used on a few occasions. The article“Hematinics” in this issue will demystify thedoubts in the minds of practicing pediatricians.

Next to RBCs, WBCs can be considered asan important cellular component of blood.Among them neutrophils play a vital role bytackling the micro organisms which enter the

body. Neutropenia or defective function ofneutrophils makes the individual more prone forinfection and a severe infection by itself can leadon to neutropenia. The management ofneutropenia is a challenging one. A clear cut ideaon how to manage these children efficiently isgiven in this issue.

Coagulation is a fascinating area inhematology in view of its unique cascade.A systematic approach will lead on to a correctdiagnosis when coagulation disorder is suspected.This issue covers the pathophysiology in DIVCas well as how to approach a child withthrombotic disorders.

One other important cause of bleedingdiathesis is thrombocytopenia. Idiopathicthrombocytopenic purpura if it runs a chroniccourse, is a problem to both the parents andphysicians. A brief article on the approach to thesame will be an eye opener to our readers.

Hemophagocytic syndrome, anotherinteresting condition which is under diagnosedis dealt with briefly in this issue.

Approach to hematological conditionswhich can be diagnosed prenatally is also coveredin this issue.

Articles on acute myocarditis and skeletaldysplasias attempt to give an overview on theseconditions. Use of radiological investigations forevaluation of seizures is covered in this issue.

Urticaria is dealt with in this issue underdermatology series. A case study on McCuneAlbright syndrome illustrates the importantclinical aspects of the condition. We hope youwill find this issue to be practical and useful.

Dr. K. Nedunchelian,Editor-in-Chief


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2008; 10(2) : 95

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Article should be informative covering the recent and practical aspects in that field. Main articles can be in1500 – 2000 words with 12 – 15 recent references and abstract not exceeding 100 words.

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HEMATINICS IN CHILDREN

* Naithani R** Saxena R

Abstract : Iron deficiency anemia is verycommon in children and is usually secondary todietary deficiency and worm infestation. Correctchoice of hematinics is important as most ironpreparations cause gastric irritation andstaining of teeth leading to poor compliance.Thediscussion below will clarify all queries relatedto ideal choice of hematinics .

Keywords : Iron Deficiency, Children,Hematinics

Nutritional anemia is a major public healthproblem in India. The prevalence of anemia under15 years is 50-70%. Predominant cause of theseanemias is nutritional in this age group and henceis easily amenable to supplementation of thedeficient factor. Diet, however needs to bemodified in these children to prevent relapses ofanemia.

Iron deficiency

Iron deficiency is the most commonpreventable nutritional deficiency in the world,especially among infants and young children.Anemia secondary to iron deficiency is linkedwith depressed mental and motor developmentduring infancy and early childhood. It may bereversible if detected and treated adequately. Iron

deficiency anemia (IDA) during childhood alsoresults in decreased physical activity anddecreased interaction with the environment.Learning capability and school achievements areadversely affected in presence of severe andpersistent IDA.1-6

Magnitude of problem

Prevalence of IDA among children under5 years of age has been estimated to be 75% inIndia.2-4,6-8 The 1998-99 National Family HealthSurvey-2 (NFHS-2) in India documented aprevalence of IDA as 75% among childrenbetween 6-35 months of age.

Causes

Although malabsorption and bleeding aredescribed as causes of iron deficiency, theoverwhelming cause is dietary in origin. The mainreason for this high rate is the undue reliance onfresh unmodified cows’ milk and non-ironcontaining convenience foods. Much of this isthe result of late or inappropriate weaning. It hasbeen shown that iron intake is low in the firstfour years of life. Iron intake is lowest in familieswith lower income and in poorer areas. Presenceof worm infestation, hookworm or mixedinfections, serve as a major cause of blood loss.Poor hygienic habits result in recurrentgastrointestinal infection. Recurrent episodes ofdiarrhea and amoebic dysentery increase the riskof development of IDA. A term baby is born withsufficient iron stores for 6–8 months. Assumingthat the mother has sufficient iron stores and thechild is on breast milk which has got a higherbioavailability of iron, though the iron content islow, if appropriate weaning has taken place at

HEMATOLOGY

* Senior Resident** Professor and Head

Department of HematologyAIIMS, New Delhi.

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6 months of age, with iron containing weaningfoods, significant iron deficiency should notoccur.1-12 In chronic inflammatory disease,absorption of iron appears to be reduced whichwould limit the growth of microbes in chronicinfections.13 Recently an acute phase proteinhepcidin has been identified, which plays a majorrole in iron absorption. Hepcidin over expressionin the liver leads to decreased iron uptake by theduodenum.14 Most of the iron that is absorbed isdirected into the RES while only minor amountsmay reach the sites of erythropoiesis.

Clinical consequence

It was earlier believed that the clinicalsymptoms of anemia (such as fatigue, headache,dizziness, shortness of breath or tachycardia)occur only when the hemoglobin level droppedabruptly. Asymptomatic anemia presents withimpairments in physical condition, quality of life,and cognitive function which may beunrecognized by both patients and even by theirdoctors. The adaptation to chronic anemia is infact adaptation to lower quality of life.15 Fatigueis associated with significant physical, emotional,psychological and social consequences, withvirtually every aspect of daily life beingaffected.16 Surprisingly, over the range 8-14g/dL,the largest improvement in quality of lifeoccurred when hemoglobin levels increased from11 to 13 g/dL.17 In addition, children who areiron deficient tend to be shorter than non-irondeficient children and there is some evidence thatthey may be more prone to infections, althoughthis remains speculative.18

Children learn from play and interactionand iron deficient children are always tired andclingy and do not interact with other children.In addition, they have a short attention span,unhappiness, and increased fearfulness.However, these changes have been attributedto “social isolation” rather than secondary toIDA.5,19,20

Treatment of IDA

The objectives of therapy in IDA are i) To restorethe hemoglobin to normal ii) replenish thedepleted iron stores iii) treat etiologic factorsand prevent their recurrence.

Oral iron supplements should be started assoon as a diagnosis of IDA is established. Thestandard dose is 3 mg/kg of elemental iron perday up to a maximum of 180 mg/day.Higher doses (6mg/kg body weight) werepreviously used; but were associated with morefrequent gastrointestinal side effects. Single dailydoses are as effective, but 2-3 divided doses arebetter tolerated by children. Ideally, oral ironshould be given at least half an hour before ameal to ensure maximal absorption. It can alsobe given 1-2 hours after meals. Oral iron therapymust continue for a period of at least four monthsto replenish depleted iron stores, if an adequateresponse to therapy is seen. Stoppage of iron,once anemia is corrected, is the most frequentcause for recurrence of IDA.8

Dramatic improvement in sense of well-being is usually observed within first 12-24 hoursof starting therapy. An increase in reticulocytecount is observed in 48-72 hours and peaks in5-7 days. The height of response is inverselyproportional to the severity of anemia. Thehemoglobin level rises at an average rate of0.15 g/dl per day, usually commencing about oneweek after the institution of therapy. The rate ofregeneration is most marked in early stages.

Choice of iron preparations8, 21

i) Ferrous sulphate tablets are available intwo forms: a) Routinely available tablet has333mg of ferrous sulphate (adult) with elementaliron of 100mg and 66mg (Pediatric) with 20mgelemental iron and b) The exsiccated form offerrous sulphate is used in the MCH programme.The total strength of ferrous sulphate is 200 mg.The content of elemental iron remains 60 mg per

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tablet. Pediatric iron tablets of 100 mg withelemental iron content of 20 mg are also availablein MCH programme.

Since various commercial preparations containelemental iron ranging from 25mg/ml to250mg/5ml, lack of awarness often results in overdosage. There are several iron / hemoglobin /vitamin cocktails which are expensive andcontain sub optimal amounts of elemental iron.

Various salts have been used. Ferroussulphate is used most frequently, is leastexpensive and causes few side effects ifadministered in appropriate doses. Ferric-hydroxide polymaltose complex, a recentlyintroduced salt in the market, has fewergastrointestinal side effects. As maximum ironabsorption occurs in the duodenum and proximaljejunum, enteric-coated tablets should not beused. Nausea, vomiting, abdominal discomfort,diarrhea and constipation occur in some patients.These side effects are dose related and can beminimized by adhering to standard doses, gradualhiking up of dose and administration of iron withor after meals.21

Oral iron preparations

Tables 1 and 2 show elemental iron contentof various iron salts and different ironpreparations. All ferrous compounds are oxidizedin the lumen of the gut or within the mucosa withrelease of activated hydroxyl radicals, which willattack the gut wall and produce a range ofgastrointestinal symptoms and discomfort.13,22

Enteric coated ferrous formulations attempt toavoid this by minimizing iron release in thestomach but the absorbtion of iron may becompromised. The newer non-ionic ironpolymaltose has been shown to have no oxidativepotency on lipoproteins in healthy subjects and abetter compliance than ferrous sulphate but dataon efficacy are lacking.23 Haem iron polypeptidehas an advantage of alternative absorption

pathways. This product is thought to haveimproved bioavailability24 and promises lowerside effects.

Table 1. Iron compounds andelemental iron content

Iron % ElementalPreparation iron

Ferrous sulfate 20Exsiccated ferrous sulfate 30Ferrous fumarate 33Ferrous succinate 23Ferrous carbonate 16Ferrous lactate 19Ferrous gluconate 12Ferric ammonium citrate 18Ferrous glycine sulfate 18

Table 2: Iron preparations andelemental iron content

Iron Preparation Elemental iron(per tab/capor per 5 ml)

Fersolate Tab 66 mgTonoferon syrup 250 mgTonoferon pediatric syrup 80 mgTonoferon drops 25 mg/mlFefol Z, Fesovit, Dexorange,Hepatoglobine 30 mgLivogen hemtonic 42 mgAutrin 113 mgVitcofol syrup, Hemsi syrup,Fesovit syrup 33 mgJectofer injection 50 mg/mlImferon injection 50 mg/ml

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a) Ferrous salts: All dietary iron has to bereduced to ferrous form to enter the mucosal cells.Hence bivalent iron salts like ferrous sulfate,fumarate, gluconate, succinate, glutamate andlactate have been preferred over ferric saltpreparations. In addition, these salts are amongstthe cheapest preparations of iron availablefor medicinal use. Ferrous sulfate (FS)(20 % elemental iron) is commonly used in tabletpreparations. However, liquid formulations of thesalt are only available as elixirs in sorbitol baseas syrup preparations are unstable (the salt iseasily oxidizable in moist environment) whichnegates the cost advantage. Ferrous fumarate (FF)(33% elemental iron) has a similar efficacy andgastrointestinal tolerance to ferrous sulphate. FFsalt is moderately soluble in water,environmentally more stable and is tasteless.These salts have uniformly good bioavailability.However, the bioavailability decreases markedlyin the presence of dietary inhibitors like phytates,tannic acid, etc. They cannot be added to otherfoods/milk/fortified formulas for the samereason25. Teeth are known to be stained withliquid preparations if the drops are not placedcarefully at the back of the tongue21. The bio-availability of iron from ferric salts is 3 to 4 timesless than that of ferrous sulphate. Ferricammonium citrate (18% elemental iron) is themost commonly used of these salts.

b) Iron amino-acid chelates: Iron amino-acidchelates are conjugates of the ferrous or ferricion with amino-acids. They have no effect on thecolor or taste of food products and have highbioavailability in the presence of dietaryinhibitors. It is hypothesised that the chelatesprevent iron from binding to inhibitors in foodor precipitating as insoluble ferric hydroxide inthe pH of the small intestine. Comparison offerrous sulphate with ferrous bisglycinate ininfants of 6 to 36 months of age showedequivalent rise in hemoglobin in the two groups.26

However, the group receiving ferrous

bisglycinate had a higher rise in serum ferritin.Also, a lesser incidence of side effects wasobserved in this group. Ferrous glycine sulphate(FGS) is the only salt of this group available inIndia.

c) Iron polymaltose complex: Iron polymaltosecomplex contains non-ionic iron and polymaltosein a stable complex. Its absorption is not affectedby food or milk. These salts are better absorbedand have lesser side effects. They are expensiveand improvement in hemoglobin level is not asexpected compared with other ironpreparations21.

Packed red cell transfusions

Red-cell transfusions should not berecommended routinely in IDA. Transfusions areindicated only if there is evidence of impendingor overt cardiovascular decompensation. Ifpatient is in congestive cardiac failure, a partialexchange transfusion may be required.

General measures

Deworming at initial diagnosis and thenperiodically at 3-6 monthly intervals helps inimproving the iron status. Children should beencouraged to wear shoes while going to thefields to prevent infestation with the infectiveform of hookworm larvae. Table 3 shows thevarious sources of iron and Table 4 shows factorsaffecting iron absorption.

Failure of response

Failure to attain adequate response totherapy in 2-3 weeks is designated as failure torespond. Poor compliance and inadequate dosesare the most important causes of failure torespond to iron supplements, if the diagnosis ofIDA is correct. Usually stools turn black on ironsupplements and this can be used as an easymeasure to detect poor compliance. Certainpreparations containing ferric hydroxide

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polymaltose complex have been associated withpoor response, even when given in adequatedoses. Associated folic acid deficiency alsohinders response to iron therapy. If all thesecauses have been ruled out, one must think ofmalabsorption and chronic blood loss. Celiacdisease may present with nonresponsive IDA.Other features of malabsorption may be subtleor altogether absent. Serological tests andduodenal biopsy may clinch the diagnosis.Chronic blood loss from gastrointestinal tract andlungs is another major cause of nonresponsiveIDA.6,8

Prevention of IDA

1) Diet: Daily iron requirement in first year oflife is 5-7 mg. Preterm and low birth weightinfants with low iron stores should receive10-15 mg iron per day. In childhood, 10 mgelemental iron is required per day with increasedrequirements during pubertal spurt. Tables 3 and4 show the diet sources and different factorsaffecting its absorption.

2) Complementary foods: To improve thenutritional value of home-based complementaryfoods, “micronutrient Sprinkles” in a powderform were developed as a home-fortificationstrategy for improving the nutritional quality ofhome-based complementary foods. Theformulations of these sprinkles containmicroencapsulated ferrous fumarate along withother micronutrients such as zinc, vitamins A, Cand D or folic acid. Sprinkles are packed insingle-dose-sachets. Entire contents of one sachetneed to be sprinkled daily onto any semi-solidfood for infants. The iron in sprinkles isencapsulated with a thin coating of a vegetable-based hydrogenated lipid that prevents the ironfrom oxidizing the food so as not to change thecolor, texture or taste of the food to whichSprinkles are added. The consumption of60 sprinkles sachets (each containing 12.5 mg ofelemental iron) over at least 2 months should beadequate for repletion and to maintain sufficientiron stores and normal hemoglobin levels inyoung children.2,27,28

Table 3. Sources of dietary iron10

Chemical form and Sourcetype of ironHaem iron - Meat, fish, poultry and blood products

- 10-15% of iron intake in industrialized countries.- Less than 10% of total intake in developing countries.- Bioavailability high: absorption 20-30%

Non-haem iron – Food iron - Cereals, tubers, vegetables and pulses.- Bioavailability determined by the presence of enhancing

and inhibiting factors consumed in the same meal- Contamination iron Soil, dust, water, iron pots, etc.

- Bioavailability usually low.- Fortification iron - Various iron compounds used

- varying potential bioavailability- bioavailability of soluble fraction determined by

composition of meal.

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3) Food fortification: Iron fortification involvesthe addition of iron, usually with folic acid, to anappropriate food vehicle that is made availableto the population at large. In developed countries,cereal flour is the most common food vehicle butother foods, such as noodles, rice, and varioussauces, have also been used. Iron supple-mentation has a major impact on populationhealth. Iron supplementation would avert almost2.5 million disability adjusted life years (DALYs)in the Southeast Asian sub region. On the otherhand, fortification is less costly thansupplementation of any iron preparation.Consumption of fortified foods is generallylimited to the middle- and high-income groupswho are not always at greatest risk ofmicronutrient deficiencies. Key factors in theselection of the right food vehicle include thatthe vehicle must be consumed regularly and inpredictable amounts, and must be affordable bythe target population. It must be processed in largecentral mills so that quality control can beeffectively implemented. The fortified foodshould not undergo changes in color, taste, orappearance as a result of the addition of thesemicronutrients. Stability and bioavailability ofthe micronutrients added to the food must remainhigh under standard under local conditions ofstorage and use. Other fortificants have beensuggested, such as ferrous fumarate or ferroussulfate, which are more costly but also morebioavailable.29,30

The recent WHO/UNICEF review ofcomplementary foods in developing countriesconcluded that iron requirements may be difficultto meet from non-fortified complementary foods,especially if animal products are not widelyconsumed.2,29-31 In addition, prolonged exclusivebreastfeeding, delayed introduction of weaningfoods (which are often of poor quality) andfeeding of small amounts of foods to infants areresponsible for higher prevalence of irondeficiency.

Though iron deficiency anemia has beenrecognized as a major public health problemamong children in India, low priority has beengiven for its prevention and control. In 1998-99,for example, the National Anemia ControlProgram reached fewer than 28% of Indianchildren 1-5 years of age.2,32 Combination of lowcoverage and poor adherence to the interventionand poor quality of iron preparations were themajor reason for failure of programme.Prevalence of IDA remains high among youngchildren in India even after the implementationof the National Anemia Control Program.Technical disadvantages associated with the useof liquid iron preparations are limited shelf life

Table 4. Major determinants of ironabsorption9

Dietary factors

(1) Haem iron is better absorbed(2) Factors that enhance non-haem iron

absorption:- Ascorbic acid (vitamin C)- Meat, poultry, fish and other seafood- Low pH (e.g., lactic acid)- Histidine, cystine, lysine

(3) Factors that inhibit non-haem ironabsorption:

- Calcium- Phytates- Tannins in tea and coffee specially

after food

Host Factors

(1) Iron Status(2) Health Status

- Infections- Chronic diarrhea- Short bowel

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and expensive transportation costs due to theweight of the bottles. National Institute ofNutrition, Hyderabad successfully fortified saltwith iron (ferrous sulphate 3.2g, sodium acidsulfate 5.0g and orthophosphoric acid 3.2g in onekg of common salt). Multiple studies have beenconducted showing that iron fortified saltsuccessfully prevented the development of IDAand was also able to correct mild IDA.33 Sinceiodine deficiency is also common, salt was alsofortified with iodine. Iron fortified salt needs tobe utilized throughout the country as prophylaxisand control of IDA.

Current WHO and UNICEF guidelinesrecommend that interventions for the preventionand the control of iron deficiency should followan integrated, long-term approach. IDA must beaddressed by a multidisciplinary approach,including the following elements: 1) increasediron intake (i.e., iron-rich diets, increasing ironabsorption, and iron and folate supplements,fortification of wheat flour and othercomplementary foods with iron and othermicronutrients, where appropriate); 2) infectioncontrol (i.e., public health measures to controlhookworm infestations, malaria, andschistosomiasis); 3) improved nutritional status(i.e., control of major nutrient deficiencies, dietdiversification, and infection prevention).29

VITAMIN B12 AND FOLATEDEFICIENCY

Megaloblastic anemia (MA) is the most commonresult of deficiency of these vitamins. Other lesscommon manifestations in children includeneuro-developmental effects and abnormalmovements. Neural tube defects result fromdeficiency in mothers during pregnancy.1,2 Thecommonest age is 3-18 months with maximumnumber of cases being in 9-12 months.1 Thesechildren are generally exclusively breast-fed bymothers who are undernourished and have poorblood levels of folate and cobalamin.2

Prevalence of megaloblastic anemia

The increase in prevalence of MA is alsosupported by observation that MA accounts formaximum/ a large number of cases ofpancytopenia in many Indian series.3-5 Estimationof serum levels are required to be certain of thedeficient micronutrient. Sarode et al5 reportedB12 deficiency in nearly 85% cases withmegaloblastic anemia. Chandra et al6 observedfolate deficiency in 50%, cobalamin deficiencyin 62% and combined deficiency of bothcobalamin and folate in 30%. Gomber et al. foundeven lower prevalence of folate deficiency in astudy on preschool children from Delhi.7

Etiology

In India, most cases of MA are caused bynutritional deficiency of folate, B12 or both.Pernicious anemia due to intrinsic factordeficiency, malabsorption resulting in folatedeficiency (celiac disease) and certain inbornerrors of metabolism eg. methylmalonic aciduria(B12 deficiency) and methylene tetrahydrofolatereductase deficiency (folate) account for minorityof cases.

Nutritional deficiency is far more commonin vegetarian than in non-vegetarian families.8

B12 deficiency seen in infants and young childrenhas been particularly related to maternaldeficiency which results in poor body stores atthe time of birth. These infants who areexclusively/ predominantly breastfed forprolonged period tend to develop B12 deficiencyas the breast milk content of B12 in these mothersis far below normal. Chandra et al havedocumented a good co-relation between serumlevels of the mothers and their suckling infantsand young children.6 From the developedcountries, cases of MA are being reported amonginfants born to vegetarian mothers.8,10

Giardia infection has been demonstrated tocause folate malabsorption. H.pylori infection has

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been incriminated to cause B12 malabsorptionamong adults.11

Clinical consequences

Symptoms of anemia such as fatigue,headache, dizziness, shortness of breath, ortachycardia may occur. Most cases tend to bemoderately or severely malnourished.

Some features peculiar to MA includehyperpigmentation of knuckles and terminalphalanges and mild enlargement of liver andspleen. Petechial and other hemorrhagicmanifestations have been reported in upto25% cases. Presence of bleeding with severeanemia makes them clinically indistinguishablefrom aplastic anemia.6,11,12

Some cases of MA exhibit developmentalretardation/ regression in association with severeanemia. The infantile tremors syndrome caseshave macrocytic anemia and developmentalregression in addition to tremors. Occurrence ofabnormal movements in association withhypotonia, psychomotor retardation, apathy andfailure to thrive is being reported.16,17 Impairmentof cognitive function is also described in childrenand adolescents with B12 deficiency even inabsence of anemia.18

Treatment

Like any other deficiency state replacementtherapy is required. Anemia and other cytopeniasrespond to administration of very small doses ofdrugs. However, since folate is available as a5 mg tablet and its over dose is not associatedwith adverse effects; 5 mg daily dose has beenused.

For B12 deficiency, parenteral administrationof B12 is usually recommended. A dose of 10 µgcyanocobalamine (CNCbl) subcutaneous daily issufficient to correct metabolic abnormalities likeincreased LDH and iron levels and in increasingthe reticulocyte counts with maximum count

attained on 5-7 days. For smaller children thedose of CNCbl is 0.2 µg/kg. It acts as atherapeutic test of vit B12 deficiency. This doesnot restore the plasma methylmalonic acid andtotal homocysteine levels to normal. Dementiaand depression may improve rapidly with therapywhile other neurologic abnormalities usuallyshow slow improvement over 6 months and maynot improve at all. Decrease in MCV,reticulocytosis, and improvement in platelet andneutrophil counts are observed within few days.Subsequently 1000 µg CNCbl daily for 7 daysfollowed by 100 µg weekly for 1 month isrequired. Six to eight weeks treatment is usuallydescribed as sufficient.19

In pernicious anemia 1000 µg ofhydroxycobalamine (OHCbl) every 3 months or1000 µg daily for 1-2 weeks every 6-12 monthsis given. A small number of children may developantibodies against OHCbl. In children withinherited defects of cobalamine metabolismhigher doses of OHCbl i.e 1000 µg OHCbl2-3 times every week is required.19

Chandra et al20 observed development oftremors in 6 out of 51 cases within few hours ofadministration of 1000 µg dose. However, thesetremors and other neurological signs have beenself-limiting but their appearance may influencethe compliance. They recommend a dose of250 µg in infants and 500 µg in older children.Sudden increase in the levels of neurotransmittershas been offered as the plausible explanation forthis neurological phenomenon.9

They also noticed that some cases havedeveloped thrombocytosis which resulted instroke in one patient.20 Hence careful monitoringof blood counts is required during treatment.

Deficiency of other micronutrients

Usually the children presenting with dietaryiron deficiency or vitamin B12 or folic aciddeficiency also have other micronutrient

13


deficiencies as diet is likely to be deficient inother micronutrients also. A holistic approach isrequired in treatment of these children.

Points to Remember

• Iron deficiency is the most commonpreventable nutritional deficiency in theworld, especially among infants and youngchildren.

• Prevalence of IDA among children under5 years of age has been estimated to be 75%in India.

• Oral iron supplements should be started assoon as a diagnosis of IDA is established.

• The standard dose is 3 mg/kg ofelemental iron per day up to a maximumof 180 mg/day.

• Ferrous sulphate is used most frequently,is least expensive and causes few sideeffects if administered in appropriate doses.

• Failure to attain the adequate response totherapy in 2-3 weeks is designated as failureto respond.

• Poor compliance and inadequate doses arethe most important causes of failure torespond to iron supplements, if thediagnosis of IDA is correct.

• Chronic blood loss from gastrointestinaltract and lungs is a major cause ofnonresponsive IDA

References

1) McGregor GS, Ani C. A review of studies onthe effect of iron deficiency on cognitivedevelopment in children. J Nutr 2001; 131:649S-668S.

2) Zlotkin SH, Christofides AL, Ziauddin HyderSM, Schauer CS, Tondeur MC, Sharieff W.Controlling iron deficiency anemia through theuse of home-fortified complementary foods.Indian J Pediatr 2004; 71:1015-1019.

3) Pathak P, Kapil U, Kapoor S, et al. Prevalenceof multiple micronutrient deficiencies amongstpregnant women in a rural area of Haryana.Indian J Pediatr 2004; 71:1007-I014.

4) Choudhry VP, Kashyap R. Nutritional anemia,aetiopathogenesis, diagnosis and management.J Int Med 1995; 10:57.

5) Harris R J. Nutrition in the 21st century: whatis going wrong? Archi Dis Child 2004; 89:154-158.

6) Choudhry VP. Hematological Disorders. In:Ghai Essential Pediatrics. 5th ed. Ghai OP,Gupta P, Paul VK (Eds). New Delhi, Interprint,2000; pp 87-91.

7) Iron absorption and its implications on strategiesto control iron deficiency anemia. ICMRBulletin Feb 2000:15-20.

8) Marwaha RK. Iron deficiency anemia andbeyond perspectives for the practicingpediatrician. PHO Bulletin 2003; 16: 3-5.

9) DeMaeye EM, Dallman P, Gurney JM, HallbergL, Sood SK, Srikantia SG. Preventing andcontrolling iron deficiency anemia throughprimary health care. A guide for healthadministrators and programme managers.WHO, Geneva, 1989.

10) Schauer C, Zlotkin S. Home fortification withmicronutrient sprinkles-a new approach for theprevention and treatment of nutritional anemias.Pediatr Chil Health 2003; 8: 87-90.

11) Choudhry P, Dubey AP. Iron deficiency andanemia. Nutrisearch 2002; 9:2-3.

12) Mitchell A, Guyatt G, Singer J, et al. Qualityof life in patients with inflammatory boweldisease. J Clin Gastroenterol 1988; 10:306–310.

13) Demetri GD, Kris M, Wade J, et al. Quality-of-life benefit in chemotherapy patients treatedwith epoetin alfa is independent of diseaseresponse or tumor type: results from aprospective community oncology study. ProcritStudy Group. J Clin Oncol 1998; 16:3412–3425.

14) Crawford J, Cella D, Cleeland CS, et al.Relationship between changes in hemoglobinlevel and quality of life during chemotherapy

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in anemic cancer patients receiving epoetin alfatherapy. Cancer 2002; 95:888–895.

15) Jason J , Archibald LK, Nwanyanwu OC, et al.The effects of iron deficiency on lymphocytecytokine production and activation:preservation of hepatic iron but not at all cost.Clin Exp Immunol 2001; 126:466–473.

16) Lozoff B, Brittenham GM. Behavioralalterations in iron deficiency. Haem Oncol ClinN Am 1987; 1:449–464.

17) Lozoff B, Klein NK, Nelson EC, et al. Behaviorof infants with iron-deficiency anemia. ChildDev 1998; 69:24–36.

18) National Family Health Survey-2 (NFHS-2)-India 1998-99. Key findings: Anemia amongwomen and children. Mumbai, InternationalInstitute for Population Sciences, 2000;pp271-273.

19) Gomber S, Bhawna, Madan N, Lal A, Kela K.Prevalence and etiology of nutritional anemiaamong school children of urban slums. Indian JMed Res 2003; 118: 167-171.

20) Verma M, Chhatwal J, Kaur G. Prevalence ofanemia among school children of Punjab. IndPediatr 1998; 35: 1181-1186.

21) Nagpal J, Choudhury P. Iron Formulations inPediatric Practice. Indian Pediatr 2004; 41:807-815.

22) Gasche C, Lomer M C E, Cavill I, Weiss G.Iron, anaemia, and inflammatory boweldiseases. Gut 2004; 53:1190-1197.

23) Millar AD, Rampton DS, Blake DR. Effects ofiron and iron chelation in vitro on mucosaloxidant activity in ulcerative colitis. AlimentPharmacol Ther 2000; 14:1163–1168.

24) Ganz T. Hepcidin, a key regulator of ironmetabolism and mediator of anemia ofinflammation. Blood 2003; 102:783–788.

25) Jacobs P, Wood L, Bird AR. Erythrocytes: bettertolerance of iron polymaltose complexcompared with ferrous sulphate in the treatmentof anaemia. Hematology 2000; 5:77–83.

26) Seligman PA, Moore GM, Schleicher RB.Clinical studies of HIP: an oral heme-ironproduct. Nutr Res 2000; 20:1279–86.

27) Hallberg L, Ryttinger L, Solvell L. Side Effectsof oral iron therapy. A double blind study ofdifferent iron compounds in tablet form. ActaMed Scand Suppl. 1966; 459: 3-10.

28) Pineda O, Ashmead HD. Effectiveness oftreatment of iron-deficiency anemia in infantsand young children with ferrous bis-glycinatechelate. Nutrition 2001: 17; 381-384.

29) Zlotkin S, Arthur P, Schauer C, Antwi KY,Yeung G, Piekarz A. Home-fortification withiron and zinc sprinkles or iron sprinkles alonesuccessfully treats anemia in infants and youngchildren. J Nutr 2003; 133: 1075-1080.

30) Christofides A, Zlotkin S, Schauer C. Impactof micronutrient sprinkles for the treatment andprevention of iron deficiency in Canadian firstnations and Inuit infants 4-18 months old.FASEB J 2003; 17A; S1102.

31) Baltussen R, Knai C, Sharan M. IronFortification and Iron Supplementation areCost-Effective Interventions to Reduce IronDeficiency in Four Subregions of the World.J Nutr 2004; 134:2678-2684.

32) Hurrell R, Bothwell T, Cook JD, et al.SUSTAIN Task Force. The usefulness ofelemental iron for cereal flour fortification: aSUSTAIN Task Force report. Sharing UnitedStates Technology to Aid in the Improvementof Nutrition. Nutr Rev 60:391-406.

33) Villar J, Merialdi M, Gulmezoglu AM, et al.Nutritional interventions during pregnancy forthe prevention or treatment of maternalmorbidity and preterm delivery: an overviewof randomized controlled trials. J Nutr2003;133:1606S-1625S.

34) Proceedings from the national workshop onmethodologies for assessment of vitamin Adeficiency, iron deficiency anemia and iodinedeficiency disorders, New Delhi, All IndiaInstitute of Medical Sciences, India, September13-15, 2004.

35) Nair KM, Brahmam GNV, Rangnathan S,Vijayraghavan K, Sivakumar B, KrishnaswamyK. Impact evaluation of iron & iodine fortifiedsalt. Indian J Med Res 1998 (108): 203-211.

15


CHALLENGES IN THEMANAGEMENT OFFEBRILE NEUTROPENIAIN CHILDREN

* Arora B ** Kurkure P

*** Purvish Parikh

Abstract: Managing febrile neutropenia inchildren is a challenge. Although, improvedunderstanding of risk factors and betterdiagnostic as well as therapeutic options haveimproved the outcome of febrile neutropenia,newer emerging risk factors, changingepidemiology of infections and increasingbacterial resistance continue to pose seriouschallenges. The present focus is to develop new,effective antimicrobials for resistant pathogens,refine the existing risk-stratification models toreliably identify patients for outpatient treatmentand employ novel nonculture-based tools toreplace empirical therapy with pathogen-directed, preemptive therapy. Existing challengesand possible strategies in the management offebrile neutropenia in children are discussed.

Key words: Febrile neutropenia, Children,Challenges

Fever in a neutropenic patient is the mostcommon oncologic emergency and demands

HEMATOLOGY

urgent medical intervention. It occurs in10-15% of patients with solid tumors and inmore than 80% of patients with hematologicalmalignancies. It is associated with a mortalityrate of 5-10%. Managing infections inneutropenic patients is a dynamic process. Onone hand, there is an improved understanding ofrisk factors and a greater availability of diagnosticand treatment options. On the otherhand newerrisk factors are emerging, epidemiology ofinfections are constantly changing, bacterialresistance is increasing and with intensificationof chemotherapy, the immunosupressed hosts areincreasing in number. Hence, infection in theimmunocompromised host continues to poseserious challenges1. The Infectious DiseasesSociety of America (IDSA) has establishedguidelines for the treatment of febrile neutropenicpatients. However, these guidelines fail to addressthe specific needs of pediatric patients1. Existingchallenges in the management of febrileneutropenia and strategies to overcome them inpediatric cancer patients are presented.

Febrile neutropenia and itsimportance

Febric neutropenia is defined as development offever in a neutropenic patient.

Fever is defined as a single oral temperaturemeasurement of more than 38.3°C (101°F) oraxillary temperature of more than 37.5°C, in theabsence of obvious environmental causes.Neutropenia is defined as neutrophil counts ofless than 500 cells/mm3 or a count of less than1000 cells/mm3 with a predicted decrease to lessthan 500 cells/mm3 in the immediate future1.

* Associate Professor** Professor and IC Pediatric Oncology

*** Professor and HeadDepartment of Medical Oncology,Tata Memorial Hospital,Parel, Mumbai - 400 012.

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Bodey and colleagues demonstrated thatthe risk of infection clearly increased whenabsolute neutrophil count (ANC) dropped below1000/mm3, with a marked increase when theANC was below 500/mm3. This study laid thefoundation of contemporary therapeuticparadigms in the management of febrileneutropenia2. In addition to the absence ofgranulocytes; the disruption of the integumentary,mucosal and mucociliary barriers and inherentmicrobial flora shifts as well as antimicrobialusage predispose the neutropenic patient toinfections. It is noteworthy that the signs andsymptoms of infection are often absent or mutedin the presence of neutropenia with feverremaining the only consistent early sign.Approximately 48 to 60% patients who becomefebrile have an established or occult infection.Common sites of infection are the alimentarytract (i.e., mouth, pharynx, esophagus, large andsmall bowel and rectum), sinuses, lungs andskin1.

Spectrum of pathogens

There is a myriad of pathogens described inneutropenic hosts and the main source is thehost’s endogenous flora. The pathogensresponsible for initial infections are primarilybacteria; whereas antibiotic-resistant bacteria,yeast, other fungi, and viruses are common causesof subsequent infections. The range of infectingpathogens is detailed in Table 11,3.

Bacterial pathogens: Gram-negative bacilliespecially Escherichia coli, Klebsiella speciesand Pseudomonas aeruginosa have been theprominent pathogens in neutropenic hosts in thepast. The incidence of blood stream infectionsdue to gram positive bacteria is increasing, sincethe introduction of extended-spectrum β-lactams,use of central venous catheters (CVCs), use ofquinolone prophylaxis, administration of high-dose, cytarabine-containing regimens, andthe increased use of proton pump inhibitors.

The most common infections in neutropenicpatients are tissue-based infections which arepredominately caused by gram-negative rods.Anaerobic bacteremia occurs in less than 5% ofpatients. It is particularly common in patientswith intra abdominal infections, perirectalabscesses, or periodontal disease1,3.

Fungal pathogens : The most common fungalinfections in febrile neutropenic patients arecandidiasis and aspergillosis. The clinicalspectrum of candidiasis is broad, ranging fromsuperficial to disseminated disease. Candidaspecies also are common causes of catheter-related infections. The most common Candidaspecies that cause candidemia are Candidaalbicans followed by Candida glabrata, Candidatropicalis and Candida parapsilosis. Aspergillosisis the most common invasive mold infection.Aspergillosis initially affects the lungs or sinusesand later disseminates to other organs.Aspergillus fumigatus is the most commonspecies that causes invasive disease1.

Emerging challenge of superbugs: Emergence ofmultidrug-resistant, gram-negative rods, such asP. aeruginosa, E. coli, Citrobacter andAcinetobacter species is of serious concern. Thisis partly as a consequence of antibiotic selectionpressure and induction of extended-spectrumchromosomal β-lactamases (ESBL) after the useof β-lactams. Similarly, the resistance of thegram-positive cocci to β-lactams is increasing.Infections by methicillin-resistant Staphylo-coccus aureus (MRSA), methicillin-resistantStaphylococcus epidermidis, and penicillin-resistant streptococci have become common inthese patients. Furthermore, there is emergenceof resistance to vancomycin in some bacteria,most notably VRE (vancomycin resistantenterococci). In India too, increasing reports ofESBL producing gram-negative infections are ofparticular concern. A total of 81.9% of gram-negative isolates in a countrywide multicentric

17


study were reported to be ESBL producers andESBL production was seen in 86, 89 and 77% ofE. coli, Klebsiella sp. and P. aeruginosa isolatesrespectively4. Similarly, staphylococcalmethicillin resistance has become as high as80 to 87% in some centres5. In fungal pathogens,non-albicans Candida spp., azole-resistantCandida infections and non-fumigatusAspergillus species resistant to amphotericin Bdeoxycholate (AMB), such as Aspergillusterreus, appears to be increasing.

Baseline assessment in febrileneutropenia

Physical examination

The initial evaluation should focus ondetermining the potential sites and causativeorganisms of the suspected infection. It shouldalso include assessment of the patient’s risk ofdeveloping an infection-related complication.A site-specific history and meticulous physicalexamination should be performed promptly.

Table 1. Common pathogens and resistant organisms in febrile neutropenicchildren

Common pathogens Resistant pathogens

Gram positive bacteria Penicillin-resistantStaphylococcus spp. (e.g. S. epidermidis and S. aureus) streptococci, VRE,Streptococcus spp. (alpha-hemolytic; e.g., S. mitis) MRSAEnterococcus spp. (e.g. E. faecium, E. faecalis)Clostridium spp. (C. difficile, C. septicum, C. tertium)

Gram-negative bacteria ESBL,Enterobacteriaceae (E. coli, Klebsiella spp., Enterobacter spp.) Multidrug resistantPseudomonas aeruginosa pseudomonas andStenotrophomonasmaltophilia AcinetobacterAnaerobes (e.g. Bacteroides spp. and Prevotella spp.)

Fungi Amphotericin resistantCandida spp. (e.g. C. albicans, C. glabrata, C. tropicalis, C. krusei) candida, AspergillusAspergillus spp. (e.g. A. fumigatus, A. flavus, and A. terreus)Fusarium spp. (e.g. F. solani and F. oxysporum)Cryptococcus neoformansPneumocystis jiroveci (formerly, P. carinii)

Viruses Ganciclovir resistantHerpes simplex virus cytomegalovirusVaricella-zoster virusCytomegalovirusParvovirusRespiratory viruses

Note: ESBL: extended spectrum beta-lactamase, MRSA: Methicillin resistant S. aureus,VRE: vancomycin resistant enterococci

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Thereafter, cultures should be taken and empiricantibiotics started as soon as possible. Due toabsence of frank inflammatory signs, physiciansshould attempt to elucidate subtle signs andsymptoms of infection and investigate them.Physical examination should be repeated dailyespecially focusing on sites of persistentsymptoms and should always includeexamination of the skin, skin folds, IV sites,genitalia, perianal region, sinuses, oropharynxand fundi.

Laboratory evaluation

Initial laboratory evaluation includes acomplete blood count (including ANC), plateletcount, liver and renal function tests. Chestradiographs should be done for all patients butmay have no (or minimal) findings at presentationeven in patients with pulmonary infection.Conversely, patients with a normal clinicalexamination may have abnormal chestradiographs. Concomitant blood culturesobtained from peripheral veins and the catheterif present also should be performed. Properlycollected blood cultures maximize the chancesof isolating a pathogen. More than one cultureshould preferably be drawn, to increase the yieldas well as to help distinguish from contaminants.Culture samples must be of adequate volume(based on body weight) and should preferablybe plated in continuously monitored enrichedaerobic liquid media (such as BACTEC) whichcan detect 90% to 100% of bacterial pathogenswithin 48 hours6. Culture of stool, urine andlumbar puncture samples should be performedwhen clinically indicated. High-resolution chestcomputed tomography (CT) will demonstrateearly signs of lung infection even in patients witha normal chest radiograph and is stronglyencouraged at presentation. Repeat CT may showincreasing features of lung infection as theneutropenia resolves.

Risk assessment

All patients with fever and neutropenia arenot at the same risk for life-threateningcomplications or death. Risk assessment offebrile neutropenic patients is an integral part ofinitial evaluation. It also allows for theidentification of patients who are suitable foroutpatient treatment. Risk-stratification modelsin adults have been developed by Talcott, et al.7

and the Multinational Association of SupportiveCare in Cancer (MASCC)8. Some pediatricgroups have also proposed risk prediction modelsfor children. Santolaya, et al found serum CRPmore than 90 mg/L, hypotension, relapsedleukemia, platelet count less than 50,000/mm3

and recent chemotherapy to be useful predictorsof serious bacterial infection9. Klaassen et alfound an absolute monocyte count less than100 cell/mm3, co-morbidity and abnormal chestradiograph to correlate with high risk forsignificant bacterial infection10. These modelshave been shown to have a reasonably highsensitivity but are limited by low specificity.Absence of sufficient data on low-risk outpatientmanagement in pediatrics precludes its use inroutine oncologic practice and is an unmet need.

Management of febrile neutropenia

Essentials of management1. Administer empiric high-dose, broad-

spectrum antibiotics promptly in patientswith fever and neutropenia. Empiricaltreatment should begin as soon as possible,even before the results of cultures areavailable. Antibiotics should be given inmaximal therapeutic doses adjusted to renal/hepatic function. This is necessary becauseof the limited sensitivity, specificity andrapidity of current diagnostic tests and highmortality rates associated with inappro-priately treated gram-negative sepsis.

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2. If the cultures yield a specific pathogen, theregimen should be modified accordingly.However, it should still provide broad-spectrum coverage for the possible presenceof copathogens. Select the drugs in such away so as to prevent bacterial superinfection.It is important to note that the infectingorganism is confirmed microbiologicallyonly in one-third of neutropenic patientseven in the best of centers.

3. The selection of initial antimicrobial therapyshould also take into consideration manyfactors, which are depicted in Table 2.Clinicians should be aware of the commonpathogens and their susceptibility patternsin their own institution. This should guidethem in formulating appropriate empiricaltherapy.

4. Discontinuation rules should always be keptin mind to minimize development ofbacterial resistance, optimise cost of therapyand minimize the occurrence of drug-relatedtoxicities. For example, vancomycincontinuation should be based on availableclinical and culture evidence after48-72 hours.

Starting empirical therapy in children withfebrile neutropenia

All children should be admitted andadministered broad-spectrum antibiotics giveneither as monotherapy or combination therapy.Monotherapy with antibiotics with an extendedantimicrobial spectrum such as ceftazidime,cefepime, meropenem, imipenem, or piperacillin/tazobactam are as effective as conventional beta-lactam/aminoglycoside combinations. Efficacyof quinolones and aminoglycosides asmonotherapy is unproven and these should notbe used alone. The limitations of monotherapyinclude the possibility of developing resistanceamong gram-negative pathogens and occurrenceof breakthrough gram-positive infections.Combination therapy has the disadvantages ofincreased possibility of drug related toxicity, needfor drug level monitoring in many instances andhigh cost of care1. In India, high prevalence ofESBL isolates as well as available susceptibilitydata demands use of beta-lactam/ β-lactamaseinhibitor combinations such as cefoperazone-sulbactam and piperacillin-tazobactam orcarbapenems for initial therapy11. Vancomycinshould be included upfront only at institutionsthat have a high rate of infections due to MRSA

Table 2. Important considerations during initial empirical therapy

Risk stratificationAny focal signs and symptoms, site of infection (e.g., lung)Local ecology and antimicrobial susceptibilities of local pathogensRecent hospitalization, recent antibiotic exposure or prophylactic drugsPast history of infection (especially fungal or resistant bacterial such as ESBL or MRSA infection)Most common potentially infecting organism based on type of immune defectCo-morbid conditionsOrgan dysfunction, drug allergyExposure to infections from other household members.

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or S. viridans, documented infections due togram-positive organisms resistant to the initialtherapy, suspected serious catheter relatedinfections, known colonization with MRSA, andhypotension1.

Outpatient therapy in low-risk febrileneutropenic patients

Outpatient treatment with oral antibioticshas many advantages (low cost, avoidance ofcatheter, good quality of life and low risk ofsuperinfection with resistant nosocomialorganisms). However such children still have thepotential risk of life-threatening complications(such as septic shock) away from the hospital.Outpatient therapy may be considered in highlyselected patients after careful consideration ofthe risk status, availability of a broad-spectrumoral antibiotic and ability of the patient topromptly access a suitable medical facility.

Follow-up evaluation

Daily evaluation is essential with focus onsite-specific assessment. After appropriate initialantibiotic therapy, time to defervescence usuallyranges from 2 to 7 days (median, 5 days). Hence,it is advisable not to change the antibiotic regimenfor the first 3-5 days. This should be done evenif the patient remains febrile as long as the childis otherwise stable and there are no newsymptoms or signs. Needless to say, if thepatient’s condition deteriorates or if a pathogenresistant to initial antibiotics is isolated, treatmentshould be modified promptly.

What to do if patient has persistent fever

A challenging scenario is the persistence of feverafter 3-5 days of empirical antibiotic therapywithout clinical or microbiologic documentationof infection. A number of factors may causenonresponsiveness to antibiotics, which areshown in Table 3. Careful re-evaluation of the

patient is crucial and may reveal new signs,symptoms and clues regarding possible cause ofinfection. Laboratory work-up should consist offresh blood cultures, special cultures, serologyfor specific pathogens and imaging studies(including high-resolution chest computedtomography and upper abdomen imaging). If there-evaluation of a persistently febrile neutropenicpatient reveals a specific cause, then treatmentshould be modified accordingly.

If reassessment of the patient yields no newinformation, antimicrobial therapy requiresreconsideration. The need for a change in therapyshould be based on the patient’s clinical statusand likelihood of early bone marrow recovery.In a clinically stable patient with no organismidentified; patient could have a non-bacterialinfection or slow treatment response of aninfection such as viridans streptococcal infection.The antibiotic regimen should not be changed ifpatient is anticipated to recover neutrophil countssoon (except for discontinuation of vancomycinif there is no evidence warranting its continuinguse). In a patient with progressive clinicaldisease; possibilities include a serious non-bacterial infection, bacterial resistance to currentantibiotics and most importantly possibility ofinvasive fungal disease (Table 3). Considerationshould be given to adding vancomycin (especiallyin patients with lung infiltrates, septic shock andclinically documented gram-positive bacterialinfection) and/or a second agent active againstGram-negative organisms (based on clinical cluesand local ecology). Empiric antifungal agentsshould be added in the high risk host withpersistent fever for 5 days (earlier in the settingof appropriate and adequately dosed antibiotics).The choice of agents includes conventionalamphotericin B, voriconazole and lipidformulations of amphotericin B. The latter twodrugs are equally efficacious, less toxic butare costly compared to conventionalamphotericin B. Although rare, the possibility

21


of infections such as malaria and tuberculosisshould always be considered in India1.

Duration of the antibiotic therapyThe duration of antimicrobial therapy is

dictated by the underlying site of infection,causative organism(s), the patient’s conditionalong with response to treatment and recoveryof neutrophils. Antimicrobial therapy fordocumented infections should be continuednot only till patient shows neutrophil recovery(ANC 500/mm³) but also using a defined courseof therapy appropriate for the specific infection.If a patient has a clinically or microbiologicallydocumented specific infection (e.g. pneumonia,cellulitis), then antibiotics should be administereduntil all symptoms and signs are resolved andcultures become sterile. In general, mostuncomplicated skin and alimentary tract mucosalinfections require 4 to 7 days of therapy. For mostbacterial bloodstream infections, 7 to 14 days oftherapy is usually adequate with longer durations(10-14 days) recommended for gram-negativebacteremias. A duration of 14-21 days is usuallyindicated for infections of the lungs, sinuses andbacteremias complicated by major organinfection. The duration of treatment for HSV and

VZV infections has become standardized at7 to 10 days.

For the majority of febrile neutropenicpatients without clinical or microbiologicdocumented infection, decisions about theduration of treatment after defervescence is basedon persistence and depth of neutropenia, patient’srisk group, presence of mucositis, need for furtherchemotherapy and clinical stability of the patient.If the patient is afebrile and stable for more than48 hours, has no focus of infection andneutropenia is resolved antibiotics can be stoppedwith confidence. If the same patient still remainsneutropenic, discontinuation can be consideredafter 5-7 afebrile days provided the patientremains under close monitoring. For patients withprofound neutropenia and mucositis, treatmentshould be continued for at least 2 weeks despitedefervescence of fever.

Discontinuation of antibiotics in persistentlyfebrile neutropenic patients is not without risk.The ideal strategy is to continue antibiotics untilthe neutropenia is resolved or for at least 2 weeks.If the fever persists 5 days after the resolution ofneutropenia, treatment can be discontinued after

Table 3. Important causes of persistent fever

Slow response to initial infection

Resistant bacterial infection (e.g., ESBL, VRE)

Bacterial infection associated with cryptic foci (abcess, endocarditis)

Nonbacterial infection (virus, AFB, malaria, mycoplasma, toxoplasmosis)

Occult fungal infection

Drug or transfusion fever

Suboptimal serum concentration of antibiotics

Phlebitis, catheter related infection

Malignancy related fever

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ruling out cryptic bacterial, fungal, or viralinfections.

The length of therapy with antifungal agentsis not well defined. When an invasive fungalinfection is identified, antifungal therapy istypically continued till the complete clinico-radiological resolution of such infection.Treatment should be stopped in patients withoutany signs or symptoms of fungal infection afterresolution of neutropenia. In the clinically well,persistent neutropenic patient with no evidenceof fungal infection, antifungal therapy can bediscontinued after 2 weeks. In hemodynamicallyunstable patients who have persistent fever andneutropenia, antifungal treatment should becontinued until resolution of both fever andneutropenia1.

Adjunctive therapy

Colony stimulating factors arerecommended only in complicated febrileneutropenia (cases associated with pneumonia,hypotensive episodes, severe cellulitis, sinusitis,systemic fungal infections, multiorgandysfunction and unresponsive infections withexpected delay in recovery of the marrow).Granulocyte transfusions are not routinelyrecommended but may be considered inuncontrolled gram negative bacterial infection orinvasive fungal infection in patients expected torecover from neutropenia soon1,12.

Conclusions

Substantial progress made over the past fewdecades has reduced morbidity as well asmortality of febrile neutropenia. However, majorchallenges still remain in the treatment of febrileneutropenia in children with cancer. Theobjectives for the future include:a) the development of new, effectiveantimicrobials for the emerging resistantpathogens; b) the refinement of the existing

models of risk stratification to reliably identifylow-risk patients; c) the development ofalgorithms for safe ambulatory treatment withoral antibiotics in selected patients and d) theintroduction of novel nonculture-based tools forearly detection of infections (especially fungalinfections). The ultimate aim is replacement ofempirical therapy with pathogen-directed,preemptive therapy to make treatment specificand cost- effective.

Points to Remember

• Fever in a neutropenic patient is the mostcommon oncologic emergency anddemands urgent medical intervention

• Signs and symptoms of infection are oftenabsent or muted in the presence ofneutropenia with fever remaining the onlyconsistent early sign. Approximately48 to 60% of febrile neutropenic patientshave an established or occult infection.

• Promptly administer empiric high-dose,broad-spectrum antibiotics in maximaltherapeutic doses based on local culturesensitivity pattern in patients with fever andneutropenia, even before the results ofcultures are available in view of highmortality rates associated with inappro-priately treated gram-negative sepsis.

• Good initial and continued clinico-laboratory evaluation with properly takenblood cultures, early imaging and timelyuse of antibiotics, antifungals and otheradjunctive measures is key to goodoutcome.

References

1. Hughes WT, Armstrong D, Bodey GP, et al.2002 guidelines for the use of antimicrobialagents in neutropenic patients with cancer. ClinInfect Dis 2002; 34(6): 730-751.

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2. Bodey GP, Buckley M, Sathe YS, Freireich EJ.Quantitative relationships between circulatingleukocytes and infection in patients with acuteleukemia. Ann Intern Med 1966; 64(2): 328-340.

3. Escande MC, Hebrect R. Prospective study ofbacteremia in cancer patients. Support CareCancer 1998; 6:273–280.

4. Uma A, Mehta A, Ayyagari A, et al. Prevalanceof β-lactamase producing strains among clinicalisolates obtained from hospital in-patientsacross India and comparision of antibacterialsusceptibility using disc diffusion method.Hospital Today 2004 IX(1).

5. Mehndiratta PL, Vidhani S, Mathur MD.A study on staphylococcus aureus strainssubmitted to a reference laboratory. Indian JMed Res 2001; 114: 90-94.

6. Gaur AH, Giannini MA, Flynn PM, et al.Optimizing blood culture practices in pediatricimmunocompromised patients: evaluation ofmedia types and blood culture volume. PediatrInfect Dis J 2003; 22(6): 545-552.

7. Talcott JA, Siegel RD, Finberg R, et al. Riskassessment in cancer patients with fever andneutropenia: a prospective, two-centervalidation of a prediction rule. J Clin Oncol1992; 10:316–322.

8. Klastersky J, Paesmans M, Rubenstein EB,et al. The Multinational Association forSupportive Care in Cancer risk index:A multinational scoring system for identifyinglow-risk febrile neutropenic cancer patients.J Clin Oncol 2000; 18(16): 3038-3051.

9. Santolaya ME, Alvarez AM, Aviles CL, et al.Prospective evaluation of a model of predictionof invasive bacterial infection risk amongchildren with cancer, fever, and neutropenia.Clin Infect Dis 2002; 35(6): 678-683.

10. Klaassen RJ, Goodman TR, Pham B, Doyle JJ.Low-risk prediction rule for pediatric oncologypatients presenting with fever and neutropenia.J Clin Oncol 2000; 18(5): 1012-1019.

11. Jones RN, Rhomberg PR, Varnam DJ,Mathai D. A comparison of the antimicrobialactivity of meropenem and selected broad-spectrum antimicrobials tested against multi-drug resistant Gram-negative bacilli includingbacteraemic Salmonella spp.: initial studies forthe MYSTIC programme in India. Int JAntimicrob Agents 2002; 20(6): 426-431.

12. Clark OA, Lyman G, Castro AA, et al. Colonystimulating factors for chemotherapy inducedfebrile neutropenia. Cochrane Database SystRev 2003; (3): CD003039.

NEWS AND NOTES

PG TRAINING COURSE, NEW DELHI

18-20 July, 2008

July 20, 2008 NALS (NRP) Workshop

ContactDr. Anjali Kulkarni, Academic Coordinator,Apollo Center for Advanced Pediatrics,New Delhi, India.E-Mail : [email protected]

24

2008; 10(2) : 115

HEMATOLOGY

DISSEMINATED INTRA-VASCULAR COAGULATION

* Satyendra Katewa* Anupam Sachdeva

* Yadav SP

Abstract : Disseminated intravascularcoagulation is a complex disorder with activationof multiple factors leading to thrombosis andhemorrhage leading to multiple organ systemdamage. Though there are many causes, sepsisis one of the common causes. Clinicalpresentation includes the features of primarydisease, bleeding tendency and multiorganinvolvement. Usual laboratory findings arethrombocytopenia, prolonged clotting times,increased levels of fibrin related markers and lowlevels of coagulation inhibitors. A scoring systemfor the diagnosis of DIC has also been developed.Management of DIC is based on the treatment ofunderlying disease, replacement therapy,supportive measures and control of coagulationmechanism. Recent understanding has resultedin some novel therapeutic agents such asActivated Protein C which as shown somedifference in the mortality.

Keywords : Disseminated intravascularcoagulation, Comsumption coagulopathy,Multiorgan dysfunction.

Disseminated intravascular coagulation(DIC) is a highly complex pathophysiological

disorder secondary to varied triggers oretiological factors, which lead to both thrombosisand hemorrhage. It is also known as consumptioncoagulopathy since the coagulation factors in theplasma are consumed during the clotting processand as a result of plasmin degradation.1,2 Eventhough hemorrhagic manifestations are the mostobvious, yet it is the diffuse thrombosis that leadsto end organ damage and is responsible for mostof its associated morbidity and mortality.Disseminated intravascular coagulation may thusbe defined as a systemic thrombohemorrhagicdisorder seen in association with well-definedclinical conditions and laboratory evidence of:(a) Procoagulant activation(b) Fibrinolytic activation(c) Inhibitor consumption(d) Biochemical evidence of end organ damage

or failure.As we all know that sepsis is one of the

common causes of DIC but not the only cause.One should exclude the other possible causes ofDIC with the help of history, clinical examinationand laboratory investigations. The gram-negativeorganisms cause DIC primarily because of theendotoxemia where as gram-positive organismscause DIC because of mucopolysaccharide of thebacterial cell wall. In a child with DIC in shockand active bleeding, an aggressive and systematicapproach reduces the mortality and morbidity.

Epidemiology

Precise incidence of DIC is not known. Ingeneral it is estimated that out of every1000 admitted patients to a community hospital,only one patient will develop DIC. The frequency

* Pediatric Hematology Oncology Unit and BoneMarrow Transplantation UnitDepartment of Pediatrics Centre For Child HealthSir Ganga Ram Hospital New Delhi

25


of DIC should be seen in relation to theunderlying disease. The most frequent diseases,which lead to DIC are infections and SIRS(Systemic Inflammatory Response Syndrome).The incidence of overt DIC is equal in grampositive and gram-negative infections. Severetrauma with inflammatory response wasassociated with DIC in 50% -70% of cases. Gianthemangioma is associated with clinicallysignificant DIC in up to 25% cases.

Etiology

Clinical conditions that may be associatedwith disseminated intravascular coagulation aregiven in Table 1.

Pathophysiology

It was thought earlier that the process ofhemostasis starts either with extrinsic or intrinsicpathway and after few steps a common pathwaystarts which ends up making the normalhemostatic plug. However recent literaturesupports that it’s a combination of manybiochemical reactions which occurssimultaneously rather than a cascade. Usually allthe reactions are happening in a single time framebut the rate of the different reactions may varyand hence their outcome.

Once thrombin is generated it leads tothrombin burst. Thrombin burst is the primaryreason for piling up of a huge amount of thrombinwhich by different mechanisms affects thehemostasis. Thrombin has different actions onthe process of hemostasis by means of1) Procoagulant effect a) Converts fibrinogen tofibrin, b) Activates factor XIII, V and VIII andc) Activates platelets and 2) Anticoagulant effectsa) Activates protein C, b) Stimulates fibrinolysis.

Once the hemostatic plug sets in, the regulationpathways start working, via the protein C and S,Antithrombin III, thrombomodulin, tissue factorpathway inhibitor and the fibrinolytic system

(Fig.1). These factors keep the cascade in checkand don’t allow the diffuse microvascularthrombosis to set-in.

Regulation of coagulation pathway

The regulatory mechanisms of the coagulationreactions serve two main functions. a) Limit theamount of fibrin clot formed to avoid ischemiaof tissues and b) Localize clot formation to thesite of tissue or vessel injury, thereby preventingwidespread thrombosis.

Tissue factor pathway inhibitor (TFPI) is aprotein that mediates the feedback inhibition ofthe Tissue Factor-Factor VIIa complex, resultingin decreased activation of both Factor IX and X.Small amounts of Factor Xa are required forTFPI to achieve its inhibition of Factor VIIa-Tissue Factor complex. Of importance, heparinincreases action of TFPI 2-4 fold.

Antithrombin III (AT): This is a proteinsynthesized by liver and endothelial cells whichbinds and directly inactivates thrombin and theother serine proteases (Factors IXa, Xa, and XIa).The uncatalyzed reaction between the serineproteases and AT is relatively slow. However, inthe presence of heparin or similar sulfatedglycosaminoglycans, the reaction between ATand the serine proteases is virtually instantaneousresulting in the immediate blockage of fibrinformation. Normal endothelial cells expressheparan sulfate (a sulfated glycosaminoglycan).AT binds to this and then is able to inactivateany nearby serine proteases, thus preventing theformation of fibrin clot in undamaged areas.Note, in the presence of heparin, the primarytarget of AT is thrombin.

Activated Protein C and Protein S: Proteins Cand S are both vitamin K dependent inhibitorsof the procoagulant system. Protein S markedlyenhances the activity of Protein C.By inactivating Factors Va and VIIa, Proteins C

26

2008; 10(2) : 117

and S significantly decrease the tempo ofthrombin generation, thereby dampening thecascade significantly.

Thrombomodulin: This is an endothelial cellreceptor, which binds thrombin. Whenthrombomodulin and thrombin form a complex,the conformation of the thrombin molecule ischanged. This altered thrombin molecule now

readily activates Protein C and loses its plateletactivating and protease activities thus convertingthrombin from a potent procoagulant into ananticoagulant.

The fibrinolytic system: The fibrinolytic systemhelps to keep clot formation in check by actuallydegrading the fibrin strands. Plasmin has thisability to degrade fibrin strands, preventing the

• Sepsis

- Gram positive or Gram negativeinfections

- Viral hemorrhagic fevers- Severe infection (any microorganism)

• Malignancy

- M y e l o p r o l i f e r a t i v e / l y m p h o -proliferative malignancies (acutepromyelocytic leukemia)

- Solid tumors

• Intravascular hemolysis

- Transfusion reactions- Paroxysmal nocturnal hemoglobinuria- Sickle cell anemia

• Vascular abnormalities

- Kassabach-Merritt syndrome- Large vascular aneurysms- Hereditary hemorrhagic telangiectasia

• Trauma

- Polytrauma- Neurotrauma- Fat embolism- Burns

• Obstetrical calamities

- Amniotic fluid embolism- Abruptio placenta- Retained fetus syndrome

• Organ destruction

- Severe pancreatitis

• Severe toxic or immunologic reactions

- Snake bites- Recreational drugs- Transplant rejection

• Severe hepatic failure

• Cyanotic congenital heart disease

• Collagen vascular disease and allergicvasculitides

- Polyarteritis nodosa- Systemic lupus erythematosis- Henoch Schonlein purpura

• Miscellaneous

- Prosthetic shunts- Acidosis- Heat stroke- Shock- Post cardiac arrest

Table 1. Conditions associated with disseminated intravascular coagulation

27


build-up of excess clot.

The process of DIC is initiated when thereis a triggering stimulus for thrombin generationthat occurs usually via the extrinsic pathway dueto release or increased expression of tissue factoras in sepsis and obstetrical accidents, andoccasionally via the intrinsic pathway due toendothelial damage as in vascular disorders.Activated factor X generates thrombin fromprothrombin by cleaving its N-terminal end andforms prothrombin fragments 1 and 2 (F1+2)(Fig. 1). Thrombin cleaves fibrinogen intofibrinopeptide A and B (FPA and FPB), andgenerates fibrin monomers. Thrombin alsoreleases interleukin-1 (IL-1) and tumor necrosisfactor (TNF) from the monocytes andmacrophages, and this process is enhanced in thepresence of gram-negative lipopolysaccharideendotoxemia.3,4 In addition, thrombin inducesvascular endothelium to release endothelin andselectin.5

In DIC, the fibrinolytic system also getsactivated and plasmin is generated. Plasmincleaves the carboxy terminal end of fibrinogenand forms X, Y, D and E fragments.6 Thesefragments form the fibrinogen degradationproducts (FDPs). The X and Y fragmentscombine with the fibrin monomer and formsoluble fibrin monomer,7 which cannot getpolymerized and hence this would aggravatebleeding.

Plasmin cleaves the complex fibrin polymerand forms D-dimer, which is a more specificfibrin degradation product.8 The complementsystem also gets activated by plasmin, whichresults in aggravation of many of the clinicalmanifestations of DIC as discussed later. Plasminactivation would lead to enhanced bleeding,However, the FDP’s and D-dimer releasesPlasminogen activator inhibitor type I (PAI-1)from the monocytes and macrophages that woulddecrease fibrinolysis and enhance fibrin polymer

precipitation.9 The increased levels of PAI-1 areespecially seen in sepsis that explains why insepsis-induced DIC, thrombosis is predominantand further contributes to the end organ damage.

Cytokines : Recently the role of variouscytokines and vasoactive peptides has beenelucidated which may be contributing to the endorgan damage seen with disseminatedintravascular coagulation and also in potentiationof the entire process. Thrombin induced releaseof TNF from the monocytes activates thecomplement. The FDPs and D-dimer releasesIL-1, IL-6 and tissue factor (TF) from themonocytes and macrophages.10 IL-1 and IL-6damage, disrupt the vascular endothelium, andenhance thrombosis along with tissue factor.11

Thrombin induces release of selectin andendothelin from the vascular endothelium. Thereleased selectin E (ELASM-1) binds togranulocytes, lymphocytes, monocytes andmacrophages, and induces more cytokine releaseas well as platelet activating factor (PAF). ThePAF induces further thrombocytopenia and soaggravates the bleeding.12 The endothelin causesvasoconstriction and vasospasm that inducesthrombosis.13 The granulocytes bind to theendothelium and release proteolytic enzymessuch as elastase and cathepsin that directlydamages tissues and degrades many of theprocoagulant and profibrinolytic factors.14

Complement: In DIC, the complement isactivated by plasmin and TNF.3,6 This results inhemolysis and thrombocytopenia. Complementinduced platelet lysis provides more procoagulantmaterial further accentuating the coagulationprocess. The complement increases vascularpermeability leading to hypotension and shock.

Kinins: The activation of factor XII convertsprekallikrein to kallikrein that in turn convertshigh molecular weight kininogen to kinins.The kinins also increase vascular permeabilityand so induce hypotension and shock.

28

2008; 10(2) : 119

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29


During the process of DIC, the inhibitorssuch as protein C, protein S and antithrombinalso get consumed along with other coagulationfactors.

The following paragraph will summarize theimportant factors in pathogenesis of sepsis.

1. Increased thrombin generation - Mediatedpredominantly by tissue factor/factor VIIapathway.

2. Impaired function of physiologicalanticoagulant pathway

a) Reduction of antithrombin levels :The result of a combination ofincreased consumption, enzymedegradation, impaired liver synthesisand vascular leakage.

b) Depression of protein C system : Theresult of a combination of increasedconsumption, impaired liver synthesis,vascular leakage and down- regulationof thrombomodulin.

c) Insufficient tissue factor pathwayinhibitor (TFPI)

3. Impaired fibrinolysis - Mediated by releaseof plasminogen activators from endothelialcells immediately followed by an increasein the plasma levels of plasminogen activatorinhibitor type 1 (PAI-1).

4. Activation of inflammatory pathway -Mediated by activated coagulation proteinsand by depression of the protein C system.

Clinical features

Disseminated intravascular coagulation is anintermediary mechanism of disease, anepiphenomenon and as such the signs andsymptoms will also depend on the antecedentdisease. Thus it is difficult to make generalizationwith regard to the clinical presentation as the

primary disease frequently clouds these. Theclinical presentation may vary in relationship tothe primary condition.

Along with the obvious signs of DIC on thegeneral physical examination (sick looking child,bleeding, shock, etc.) one should always look forthe signs of thrombosis in large vessels, such asdeep venous thrombosis (DVT), and ofmicrovascular thrombosis, such as renal failure.Bleeding from at least three unrelated sites isparticularly suggestive of DIC. Bleeding can beskin bleeds, epistaxis, gingival bleeding ormucosal bleeding. The important physical signs,which are suggestive of DIC, should be soughtfor systematically.

Circulation: Signs of spontaneous and life-threatening hemorrhage, shock, signs of sub-acute bleeding and signs of diffuse or localizedthrombosis.

Central nervous system: Nonspecific featureslike altered consciousness are present.Focaldeficits are not usually present.

Cardiovascular system: Hypotension,tachycardia or circulatory collapse.

Respiratory system: Pleural friction rub andsigns of acute respiratory distress syndrome(ARDS).

Gastrointestinal system: Hematemesis andhematochezia.

Genitourinary system: Signs of azotemia andrenal failure, acidosis, hematuria, oliguria,metrorrhagia or uterine hemorrhage.

Skin and subcutaneous tissue : Petechiae,purpura, hemorrhagic bullae, acral cyanosis, skinnecrosis of lower limbs (purpura fulminans),localized infarction and gangrene, woundbleeding and deep subcutaneous hematomas andthrombosis.

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2008; 10(2) : 121

Because DIC is a continuously progressingprocess, it can be subdivided into three phasesthat might be helpful in making the diagnosis andtreating them.

Phase 1: Compensated activation of thehemostatic system

Clinical finding : No symptoms

Laboratory parameters: PT, APTT, Thrombintime within normal limits; platelet count normal,prothrombin fragment 1+2 and thrombinantithrombin complex are elevated andantithrombin levels are slightly decreased

Phase 2: Decompensated activation of thehemostatic system

Clinical finding : Bleeding from injuries andvenipuncture sites as well as decreased organfunctions (e.g., kidney, lung, liver)

Laboratory parameters: Platelet counts are low,PT, APTT are constantly prolonged. Thrombintime mostly within normal limits but may beprolonged, fibrinogen levels, coagulation factorsactivities and antithrombin levels are decreased,prothrombin fragment 1+2 and thrombinantithrombin (TAT) complex and FDPs areclearly elevated and soluble fibrin levels areincreased.

Phase 3: Full blown DICClinical finding : Skin bleed of different sizesand multiorgan failure.Laboratory parameters: Platelet counts areseverely low (usually less than 40% of initialvalue), PT, APTT are constantly prolonged orunclottable, Thrombin time prolonged severelyor unclottable, fibrinogen levels, coagulationfactors activities and antithrombin levels aredecreased (less than 50% of initial values),prothrombin fragment 1+2 and Thrombinantithrombin (TAT) complex and FDP’s areclearly elevated and soluble fibrin levels areincreased.

Diagnosis

The most common clinical manifestationsof DIC are bleeding, thrombosis or both, oftenresulting in dysfunction of one or moreorgans.15,16 Since no single laboratory test or setof tests is sensitive or specific enough to allow adefinite diagnosis of DIC, in most cases thediagnosis is based on the combination of resultsof laboratory investigations in a patient with aclinical condition known to be associated withDIC.17,18

The classical characteristic laboratoryfindings include prolonged clotting times(prothrombin time, activated partialthromboplastin time, thrombin time), increasedlevels of fibrin-related markers (fibrindegradation products [FDP], D-dimers), lowplatelet count and fibrinogen levels and lowplasma levels of coagulation factors (such asfactors V and VII) and coagulation inhibitors(such as antithrombin and protein C) .19,20

However, the sensitivity of plasma fibrinogenlevels for the diagnosis of DIC is low, sincefibrinogen acts as an acute-phase reactant andits levels are often within the normal range for along period of time. Thus, hypofibrinogenemiais frequently detected only in very severe casesof DIC.17,21 On the other hand, FDP and D-dimerlevels have a low specificity since many otherconditions, such as trauma, recent surgery,inflammation or venous thromboembolism, areassociated with elevated levels of these fibrin-related markers.

Other more specialized and useful tests, notavailable in all laboratories, include themeasurement of soluble fibrin and assays ofthrombin generation; such as those to detectprothrombin activation fragments F1+2 orthrombin-antithrombin complexes.22,23 However,serial coagulation tests may be more helpful thansingle laboratory results in establishing thediagnosis of DIC. A scoring system for the

31


diagnosis of DIC, developed from a previouslydescribed set of diagnostic criteria24, has beenproposed by the Scientific subcommittee on DICof the International Society on Thrombosis andhemostasis (ISTHSSC).25,26 This system consistsof a five-step diagnostic algorithm (Fig.2), inwhich a specific score, reflecting the severity ofthe abnormality found. A total score of 5 or moreis considered to be compatible with overt DIC.

According to recent observations, thesensitivity and specificity of this scoring systemare high (more than 90%).26 However, anessential condition for the use of this algorithmis the presence of an underlying disorder knownto be associated with DIC.27 Finally, a scoringsystem for diagnosing non-overt DIC (Fig.3) hasrecently been proposed by the ISTH ScientificSubcommittee and validated by Toh and Downey

who demonstrated its feasibility and prognosticrelevance.28

Two most important observations noted by Tohand Downey while validating the score for non-overt DIC were:

• First, the demonstration that non-overt DICitself carries a poor prognosis independentof developing overt DIC. A more probableexplanation would be that overtcoagulopathy, only one mechanistic pathwaythat can lead towards death. In others, themore commonly encountered sub clinicalcoagulopathy could indicate underlyingactivation in critical endothelial processesthat have been indirectly captured via theproposed non-overt DIC diagnosis. Thisobservation therefore appears consistent

Fig. 2. Approach for the diagnosis of overt DIC

Step 1 Does the patient have an underlying disorder known to be associated with DIC, If yes-2 score; If no 0 score

Total score

Platelet count; If > 1 lac - 0 score If < 1 lac - 1 score

+

Minus 1 if counts rising Zero if counts stable Plus one if counts falling

PT prolongation; If <3 seconds - 0 score If >3 seconds - 1 score

+


Step 2 Major criteria

Fibrin related markers If normal - 0 score If raised - 1 score

+


Antithrombin; Normal levels = Minus 1 score, Low levels = Plus 1 score

Step 3 Specific criteria

Protein C; Normal levels = Minus 1 score, Low levels = Plus 1 score

Step 4 Calculate final score

Fig. 3. Scoring for the diagnosis of non-overt DIC

If patient has a condition which underlines the DIC

Yes Coagulation tests: (Platelet count, PT, Fibrinogen, soluble Fibrin monomers and Fibrin degradation product) Platelet counts (x109/L): >100 = 0; <100 = 1; <50 = 2 PT (sec.): <3 = 0; >3 but >6 = 1; >6 = 2 Fibrinogen (g/L): >1 = 0; <1 = 1 Fibrin-related markers: No increase = 0; Moderate increase =2; Strong increase = 3

If no, stop assessment

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2008; 10(2) : 123

with the concept as proposed by the ISTHSSC, of considering the vascular endothelialsystem as a physiological organ in its ownright and that DIC represents failure ordysfunction in this vast organ.

• A second observation of significance is theequivalence in mortality rates between non-overt and overt forms of DIC. Thepathophysiological implications are thatnon-overt DIC could be indicating that hostresponses have changed from being adaptiveand overall protective to becomingmaladaptive, with potentially lethalconsequences. As such, recognition that thisadaptive threshold has been crossed couldhave therapeutic relevance in better timingtargeted intervention, especially as it hasbeen shown the mean interval between non-overt and consequent overt DIC and deathto be 24 h and 5 days, respectively. Inaddition, this tends to happen around days3–5 into admission. A non-overt DICdiagnosis could therefore present atherapeutic window of opportunity fortargeting treatment.

Finally, it is worthwhile re-emphasizing that overtDIC has its own scoring system. The separatenon-overt DIC scoring system, as proposed bythe ISTH SSC, now has a defining score of 5 andgreater. While the non-overt DIC scoring systemdoes capture some patients that evolve onto overtDIC, it also defines those who do not, but whosecoagulopathy nonetheless forewarns of apotentially lethal outcome.

Investigations and their relevance in thediagnosis of DIC

Thrombocytopenia: Low platelet count is aprimary feature of the vast majority of the patientsand around 50% will be having counts less than50,000/mm3. If done accurately this is the mostuseful screening test available except in the

conditions like leukemia where other factors areinvolved.

Peripheral smear: Microangiopathic bloodpicture with associated anemia have beendescribed as hallmarks for DIC but are relativelynon specific as they can also be seen in conditionsassociated with risk of developing DIC, e.g.,Kassabach Meritt Syndrome and vascularprosthesis.

Indicators of activation of coagulation: FPA[Fibrinopeptide A), F1+2, soluble fibrin andthrombin antithrombin complexes]. FPA andF1+2 are not specific parameters for diagnosingDIC as the coagulation can take placeextravascularly also e.g., Pneumonia andperitonitis. In contrast soluble fibrin in plasmacan only be generated intravascularly, thusrepresents a specific test for hypercoagulability.A reliable FPA, F1+2 and soluble fibrinestimation depends upon optimal venouspuncture, so it’s a drawback for these tests.A simple test will be estimation of thrombin-antithrombin complex estimation, whichindirectly indicates thrombin generation.

Indicators of fibrinolysis activation:[Fibrinogen degradation products (FDPs),D-dimers, α 2 antiplasmin and plasmin-antiplasmin complexes]. In the recent years it hasbeen found that D-dimer is more sensitive thanFDPs assay and a normal D-dimer has a highnegative predictive value for the presence ofintravascular fibrin degradation. Since fibrinogenis also degraded extravascularly, an elevated FDPor D-dimer level does not prove intravascularfibrinolysis. Since FDPs are metabolized by liverand excreted by kidney its levels are dependenton liver and kidney functions. Demonstration offibrinogen degradation products (FDP) has beenan essential prerequisite for a diagnosis of DIC.However negative FDPs do not rule out DIC.FDPs are named X, Y, D and E and appear inthis sequence. During FDP assay, when thrombin

33


clot tubes are used with the idea of removingfibrinogen, fragments X and Y are also removed.Newer methods, which assay D and E, haveevolved but if secondary fibrinolytic response isminimal then fibrinolysis may stop at X, whichis not measured. Or else DIC may be formidableand degradation may occur past the stage ofD and E. It is also possible that overwhelmingrelease of granulocyte enzymes degrades FDPs.In the cascade, extreme hyperfibrinolysis isprevented by α2-antiplasmin and does not happenuntil α 2-antiplasmin is depleted. So,α2-antiplasmin is helpful in judging the dynamicsof fibrinolysis. The dynamics of activation,exhaustion or inhibition of fibrinolysis can bebetter judged by measuring plasmin antiplasmincomplexes.

The best initial investigations for screeningof DIC would be APTT, PT, TT, Platelet counts,D-dimer and peripheral smear and reserve themore specific tests for patients showingabnormalities in these tests.

Treatment

The heterogeneity of the underlyingdisorders and of the clinical presentations makesthe therapeutic approach to DIC particularlydifficult. Thus, the management of DIC is basedon the treatment of the underlying disease,supportive and replacement therapies and thecontrol of coagulation mechanisms. The recentunderstanding of important pathogeneticmechanisms that may lead to DIC has resultedin novel preventive and therapeutic approachesto patients with DIC. However, in spite of thisprogress, the therapeutic decisions are stillcontroversial and should be individualized on thebasis of the nature of DIC and the severity of theclinical symptoms.29,30 The treatment for DICincludes replacement therapy, anticoagulants,restoration of anticoagulant pathways and otheragents.31,17,18 Summary of the treatmentmodalities for DIC is given below.

Treatment modalities for disseminatedintravascular coagulation

1. Replacement therapy: Fresh-frozen plasma

2. Anticoagulants: a) Unfractionated and low-molecular-weight heparin, b)Danaparoid sodium,c) Recombinant hirudin, d) Recombinant tissuefactor pathway inhibitor, e) Recombinantnematode anticoagulant protein C2.

3. Restoration of anticoagulant pathways :a) Antithrombin, b) Recombinant humanactivated protein C.

4. Other agents: a) Recombinant activated factorVII, b) Antifibrinolytic agents, c) Antiselectinantibodies, d) Recombinant interleukin-10,e) Monoclonal antibodies against TNF andCD14.

1. Replacement therapy

The aim of replacement therapy in DIC isto replace the deficiency due to the consumptionof platelets, coagulation factors and inhibitors inorder to prevent or arrest the hemorrhagicepisodes.32 Platelet concentrates and fresh frozenplasma (FFP) were, in the past, used verycautiously because of the fear that they might“feed the fire” and worsen thrombosis in patientswith active DIC. However, this fear was notconfirmed by clinical practice and now a daysreplacement therapy is a mainstay of thetreatment of patients with significant bleedingand coagulation parameters compatible with DIC.

Platelets: Transfusion of a) Platelet concentratesat 1–2 U/10 Kg body weight should be consideredwhen the platelet count is less than 20×109/L orif there is major bleeding and the platelet countis less than 50×109/L, b) FFP or Cryoprecipitate:When there is significant DIC-associatedbleeding and fibrinogen levels are below100 mg/dl administrtion of FFP at a dose of15–20 mL/Kg, is justified. Alternatively,

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fibrinogen concentrates (total dose 2–3 g) orCryoprecipitate (1U/10Kg body weight) may beadministered. However, FFP should be preferredto specific coagulation factor concentrates sincethe former contains all coagulation factors andinhibitors deficient during active DIC and lackstraces of activated coagulation factors, whichmay instead contaminate the concentrates andexacerbate the coagulation disorder.

2. Anticoagulants

The role of heparin in the treatment of DICremains controversial. However, on the basis ofthe few data available in the literature, heparintreatment is probably useful in patients with acuteDIC and predominant thromboembolism, suchas those with purpura fulminans.17,33 The use ofheparin in chronic DIC is better established andit has been successfully employed in patients withchronic DIC associated with those diseases inwhich recurrent thrombosis predominates, suchas solid tumors, hemangiomas, and dead fetussyndrome.34 The role of heparin in the treatmentof DIC associated with acute promyelocyticleukemia (APL) is another controversy, sincesome authors support its use whereas otherstudies failed to demonstrate its efficacy.35,36

Heparin is given at relatively low doses(5–10U/Kg of body weight per hour) bycontinuous intravenous infusion and may beswitched to subcutaneous injection for long-termoutpatient therapy (i.e., for those patients withchronic DIC associated with solid tumors).Alternatively, low-molecular-weight heparin maybe used, as supported by the positive results inboth experimental and clinical DIC studies.37,38

Experimental and clinical studies have alsoshown the potential role of danaparoid sodium,a low molecular weight heparinoid, in thetreatment of DIC.39-41 A newer anticoagulantagent with direct thrombin inhibitory activity,recombinant hirudin (r-hirudin)42,43 was recentlyshown to attenuate endotoxin-induced

coagulation activation, there by being effectivein treating DIC in preliminary experimentalhuman studies.44

Since activation of the coagulation cascadeduring DIC occurs predominantly through theextrinsic pathway, theoretically the inhibition oftissue factor should block endotoxin-associatedthrombin generation.45

De Jonge and colleagues46 firstdemonstrated in humans that recombinant TFPIdose-dependently inhibits coagulation activationduring endotoxemia. Recombinant TFPI wasevaluated in a phase II randomized trial in patientswith severe sepsis,47 and it did show a trendtoward a reduction in 28-day all-cause mortalitytogether with an improvement in organdysfunction in the group of patients treated withthe recombinant TFPI. No evidence of a survivaladvantage was observed in patients with severesepsis who received recombinant TFPI in a recentphase III large clinical trial.48

Inhibition of the tissue factor and factor VIIapathway is another strategy that has beenexplored. Moons and colleagues demonstratedthe efficacy of recombinant nematodeanticoagulant protein C2 (NAPC2), a potent andspecific inhibitor of the ternary complex betweentissue factor/factor VIIa and factor Xa, ininhibiting coagulation activation in a primatemodel of sepsis and shown promising results.49

3. Restoration of anticoagulant pathways

Since patients with active DIC have anacquired deficiency of coagulation inhibitors,restoration of the physiologic anticoagulationpathways seems to be an appropriate aim of thetreatment of DIC.50 Considering that anti-thrombin (AT) is the primary inhibitor ofcirculating thrombin, its use in DIC is certainlyrational.51 Recent studies in animals and humanswith severe sepsis have demonstrated that

35


antithrombin also has anti-inflammatoryproperties (reduction of C-reactive protein andIL-6 levels), which may further justify itsutilization during DIC.52,53 The administration ofantithrombin concentrates infused atsupraphysiologic concentrations was shown toreduce sepsis-related mortality in animalmodels.54

Based on the fact that the protein C systemis impaired during DIC some authors haveinvestigated the therapeutic efficacy ofexogenous administration of this protein inpatients with DIC.55,56 A dose-ranging clinicaltrial, patients were given recombinant humanactivated protein C (APC) by continuous infusionat doses ranging from 12ìg/Kg/hour to 30 ìg/Kg/hour or placebo.57 A 40 percent reduction inmortality was observed in those patients whoreceived the higher doses of activated protein C.On comparing the safety and efficacy of APCand unfractionated heparin in the treatment ofDIC it was concluded that the former improvedDIC, and finally the survival, more efficientlythan did heparin.58 A very recent trial on 2640patients with severe sepsis and a low risk of death(defined by an Acute Physiology and ChronicHealth Evaluation [APACHE II] score <25 orsingle organ failure) did not find a statisticallysignificant difference in 28-day mortality ratebetween the placebo and APC-treated groups59,suggesting that APC is of benefit only in patientsat high risk of death from sepsis. Ongoing studiesare focusing on the concomitant use of heparinin patients with DIC who receive activatedprotein C.18

4. Other agents

Recombinant factor VII activated (rFVIIa)may be used in patients with severe bleeding whoare not responsive to other treatment options.Bolus doses of 60–120 µg/Kg (after thereconstitution of substrate), possibly repeated

after 2–6 hours, have been found to be effectivein controlling refractory hemorrhagic episodesassociated with DIC.60,61

Antifibrinolytic agents, such as epsilon-aminocaproic acid or tranexamic acid, givenintravenously at a dose of 10–15 mg/Kg/h, areoccasionally used in patients resistant toreplacement therapy who are bleeding profuselyor in patients with disease states associated withintense fibrinolysis (prostate cancer, Kassabach-Meritt syndrome, acute promyelocyticleukemia).62 However, since these agents are veryeffective in blocking fibrinolysis, they should notbe administered unless heparin has beenpreviously infused in order to block theprothrombotic component of DIC. The use ofthese drugs in acute promyetocytic leukemia(APL) has declined in the last few years, giventhe efficacy of all-trans-retinoic-acid inpreventing the majority of the hemorrhagiccomplications of this malignancy.18

The advances in the understanding of thepathophysiology of DIC have resulted in novelpreventive and therapeutic approaches to thisdisease. Based on the fact that tissueinflammation is a fundamental mechanism in DICassociated with sepsis or major trauma, someresearchers have successfully employed thecombined blockade of leukocyte/plateletadhesion and coagulation in a murine model byusing antiselectin antibodies and heparin andhave suggested the potential clinical use of sucha strategy.63 Based on the same rationale, otherresearchers have demonstrated that theadministration of recombinant IL-10, an anti-inflammatory cytokine which may modulate theactivation of coagulation, completely abrogatedendotoxin-induced effects on coagulation inhumans.64 By contrast, the use of monoclonalantibodies against tumor necrosis factor hasshown disappointing or at best modest results inseptic patients.65-67 More recently, Branger and

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colleagues68 found that an inhibitor of p38Mitogen-activated protein kinase (MAPK), animportant component of intracellular signalingcascades that mediates the inflammatory responseto infectious and noninfectious stimuli,attenuated the activation of coagulation,fibrinolysis and endothelial cells during humanendotoxemia. Finally, although studies usingantibodies against the receptor for bacterialendotoxins (CD14) produced positive results69,other studies using endotoxin antibodies failedto improve outcome.70,71

Points to Remember

• DIC is a syndrome characterized bysystemic intravascular activation ofcoagulation, leading to widespread (micro)vascular deposition of fibrin, therebycontributing to multiple organ dysfunction.

• The ongoing activation of coagulation mayresult in exhaustion of platelets andcoagulation factors, which may causebleeding.

• DIC is invariably seen as a complicationof a variety of disorders, most commonly,severe infection or inflammation, cancer,or trauma.

• A diagnosis of DIC can be made by acombination of routinely availablelaboratory tests for which diagnosticalgorithms have become available.

• Recent knowledge on importantpathogenetic mechanisms that may lead toDIC has resulted in novel supportivetherapeutic approaches to patients withDIC. Strategies aimed at the inhibition ofcoagulation activation may theoretically bejustified and are being evaluated in clinicalstudies. These strategies compriseanticoagulant agents or agents that mayrestore physiologic anticoagulantpathways.

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29. Riewald M, Riess H. Treatment options forclinically recognized disseminated intravascularcoagulation. Semin Thromb Haemost 1998;24:53-59.

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32. Bick RL. Disseminated intravascularcoagulation: objective clinical and laboratorydiagnosis, treatment and assessment oftherapeutic response. Semin Thromb Haemost1996; 22:69-88.

33. Feinstein DI. Diagnosis and management ofdisseminated intravascular coagulation: the roleof heparin therapy. Blood 1982; 60:284-287.

34. Majumdar G. Idiopathic chronic DIC controlledwith low molecular-weight heparin. BloodCoagul Fibrinol 1996; 7:97-98.

35. Hoyle CF, Swisky DM, Freedman L, HayhoeGFJ. Beneficial effect of heparin in themanagement of patients with APL. Br J Hematol1988; 68:283-289.

36. Rodeghiero F, Avvisati G, Castaman G,Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocyticleukemia. A GIMEMA retrospective study in268 consecutive patients. Blood 1990; 75:2112-2117.

37. Sakuragawa N, Hasegawa H, Maki M,Nakagawa M, Nakashima M. Clinicalevaluation of low-molecular-weight heparin(FR-860) on disseminated intravascularcoagulation (DIC) – a multicenter co-operativedouble blind trial in comparison with heparin.Thromb Haemost 1993; 72:475-500.

38. Slofstra SH, van’t Veer C, Buurman WA,Reitsma PH, ten Cate H, Spek CA. Lowmolecular weight heparin attenuates multipleorgan failure in a murine model of disseminatedintravascular coagulation. Crit Care Med 2005;33:1365-1370.

39. Fujishima Y, Yokota K, Sukamoto T. The effectof danaparoid sodium (danaparoid) on

endotoxin-induced experimental disseminatedintravascular coagulation (DIC). Thromb Res1998; 91:221-227.

40. Ontachi Y, Asakura H, Arahata M, et al. Effectof combined therapy of danaparoid sodium andtranexamic acid on chronic disseminatedintravascular coagulation associated withabdominal aortic aneurysm. Circ J 2004;69:1150-1153.

41. Ibbotson T, Perry CM. Danaparoid. A reviewof its use in thromboembolic and coagulationdisorders. Drugs 2002; 62:2283-2314.

42. Munoz MC, Montes R, Hermida J, Orbe J,Paramo JA, Rocha E. Effect of theadministration of recombinant hirudin and/ortissue plasminogen activator (T-PA) onendotoxin-induced disseminated intravascularcoagulation model in rabbits. Br J Haematol1999; 105:117-121.

43. Pernerstorfer T, Hollenstein U, Hansen JB,et al. Lepirudin blunts endotoxin-inducedcoagulation activation. Blood 2000; 95:1729-1734.

44. Saito M, Asakura H, Jokaji H, et al.Recombinant hirudin for the treatment ofdisseminated intravascular coagulation inpatients with hematologic malignancy. BloodCoagul Fibrinolysis 1995; 6:60-64.

45. Bajaj MS, Bajaj SP. Tissue factor pathwayinhibitor: potential therapeutic applications.Thromb Haemost 1997;78:471-477.

46. De Jonge E, Dekkers PE, Creasey AA, et al.Tissue factor pathway inhibitor dose-dependently inhibits coagulation activationwithout influencing the fibrinolytic and cytokineresponse during human endotoxemia. Blood2000; 95:1124-1129.

47. Abraham E, Reinhart K, Svoboda P. Assessmentof the safety of recombinant tissue factorpathway inhibitor in patients with severe sepsis:a multicenter, randomized, placebo-controlled,single-blind, dose escalation study. Crit CareMed 2001; 29:2081-2089.

48. Abraham E, Reinhart K, Demeyer I. Efficacyand safety of Tifacogin (recombinant tissue

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49. Moons AH, Peters RJ, Cate H, et al.Recombinant nematode anticoagulant proteinc2, a novel inhibitor of tissue factor factor VIIaactivity, abrogates endotoxin-inducedcoagulation in chimpanzees. Thromb Haemost2002; 88:627-631.

50. De Jonge E, van der Poll T, Kesecioglu J,Levi M. Anticoagulant factor concentrates indisseminated intravascular coagulation:rationale for use and clinical experience. SeminThromb Hemost 2001; 27:667-674.

51. Giudici D, Baudo F, Palareti G, Ravizza A,Ridolfi L, D’Angelo A. Antithrombinreplacement in patients with sepsis and severeshock. Haematologica 1999; 84:452-460.

52. Okajima K, Uchiba M. The anti-inflammatoryproperties of anti-thrombin III: new therapeuticimplications. Semin Thromb Haemost 1998;24:27-32.

53. Inthorn D, Hoffman J, Hartl W, Muhlbayer D,Jochum M. Effect of anti-thrombin IIIsupplementation on inflammatory response inpatients with severe sepsis. Shock 1998; 10:90-96.

54. Kessler CM, Tang Z, Jacobs HM, SzymanskiLM. The suprapharmacological dosing ofantithrombin concentrate for Staphylococcusaureus-induced disseminated intravascularcoagulation in guinea pigs: substantial reductionin mortality and morbidity. Blood 1997;89:4393-4401.

55. Gluck T, Opal SM. Advances in sepsis therapy.Drugs 2004; 64:837-859.

56. Warren HS, Suffredini AF, Eichacker PQ,Munford RS. Risks and benefits of activatedprotein C treatment for severe sepsis.N Engl JMed 2002; 347:1027-1030.

57. Bernard GR, Ely EW, Wright TJ, et al. Safetyand dose relationship of recombinant humanactivated protein C for coagulopathy in severesepsis. Crit Care Med 2001; 29:2051-2059.

58. Aoki N, Matsuda T, Saito H, CTC-111-IMClinical Research Group, et al. A comparativedouble-blind randomized trial of activatedprotein C and unfractionated heparin in thetreatment of disseminated intravascularcoagulation. Int J Hematol 2002; 75:540-547.

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61. Sallah S, Husain A, Nguyen NP. Recombinantactivated factor VII in patients with cancer andhemorrhagic disseminated intravascularcoagulation. Blood Coagul Fibrinolysis 2004;15:577-582.

62. Avvisati G, ten Cate JW, Buller HR, MandelliF. Tranexamic acid for control of hemorrhagein acute promyelocytic leukemia. Lancet 1989;2:122-124.

63. Norman KE, Cotter MJ, Stewart BJ. Combinedanticoagulant and antiselectin treatmentsprevent lethal intravascular coagulation. Blood2003; 101:921-928.

64. Pajkrt D, van der Poll T, Levi M, et al.Interleukin-10 inhibits activation of coagulationand fibrinolysis during human endotoxemia.Blood 1997; 89:2701-2705.

65. Reinhart K, Waheedullah K. Anti-tumornecrosis factor therapy in sepsis: update onclinical trials and lessons learned. Crit Care Med2001; 29:S121-125.

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68. Branger J, van den Blink B, Weijer S, et al.Inhibition of coagulation, fibrinolysis, andendothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during humanendotoxemia. Blood 2003; 101:4446-4448.

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septic shock with HA-1A human monoclonalantibody against endotoxin. A randomized,double blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991;324:429-436.

71. McCloskey RV, Straube RC, Sanders C,Smith SM, Smith CR. Treatment of septic shockwith human monoclonal antibody HA-1A.A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group.Ann Intern Med 1994; 121:1-5.

MADURAI PEDICON 200833rd ANNUAL STATE CONFERENCE OFIAP – TAMILNADU STATE CHAPTER

Date: 8th – 10th August 2008Venue: Lakshmi Sundaram Hall, Madurai

ContactDr.R.MahalingamOrganising SecretaryInstitute of Child Health and Research CentreGovt. Rajaji Hospital, MaduraiMobile No: 93676 76007.E-mail: [email protected]

Dr.S.ShanmugasundaramMobile No: 9344100558

NEWS AND NOTES

41

EIGHTH COURSE OF MEDICAL GENETICS AND GENETIC COUNSELING,LUCKNOW, UP

July 21 to August 2, 2008Contact

Dr.Shubha PhadkeDepartment of Medical Genetics,Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226 014, UP, India.Phone:91-522-2668800,2668005 to 8 Ext 2325(O),256®E-mail:[email protected]


HEMATOLOGY

THROMBOTIC DISORDERSIN CHILDREN

* Nitin K. Shah

Abstract : Thrombo embolic episodes (TEs) areon the rise in pediatric age group due to improvedsurvival of sick children admitted in PICUs,liberal use of central venous and arterialcatheters, increased survival of cancer patientsand increased recognition of TE due toavailability of better diagnostic facilities. Thisarticle gives an overview of thrombotic disordersin chidlren with special reference to managementof venous thrombosis in children.

Key words : Thromboembolism, Central venousCatheter.

Thromboembolism in children is beingincreasingly recognised nowadays. The incidenceof thromboembolism is estimated to be 14.5 per10,000 in babies < 28 days of age and 0.05 per10,000 in children between 1 month to 18 yearsof age.1 This is much less than the estimatedincidence of 2.5 to 5% in adults. Thrombo-embolism can be venous or arterial; associatedwith a specific organ and due to a specific cause.Most of the central venous catheter related TEsare in the upper body venous system whereasidiopathic deep vein thrombosis often involvesthe deep leg veins.

Clinical presentationClinical presentation will depend on the

organ involved and whether it is venous or arterialTE. The incidence of TE depends on the depthto which the investigations are carried out asmany of the TEs are asymptomatic and detectedonly on detailed radiological investigations. Deepvein thrombosis in leg presents with pain,swelling and discoloration of the affected limband occasionally associated with fever andabdominal pain. Homan’s sign will be positive.Upper system venous TE presents with swelling,edema, discoloration of the affected limb. Theremay be collateral circulation in chest, arm, faceor neck. There may be flushing of face withheadache. Arterial TE presents as ischemia ofthe affected organ; e.g. cerebral stroke presentingwith focal neurological deficit in case of carotidartery involvement. Acute pulmonary TEpresents with sudden onset of respiratorydistress, incessant cough, rusty sputum, rightsided cardiac failure, pleuritic pain, cyanosis,increasing oxygen requirements, fever,arrhythmias etc. Chronic pulmonary embolismwill result in pulmonary hypertension andcongestive cardiac failure (CCF).

Underlying disorders

Only 2 to 5% of TEs are idiopathic inchildren as compared to 40% in adults. Most TEshave underlying serious cause as shown inTable 1.1,2 Incidence of various underlyingdisorders varies depending on how aggressivelyone looks for the etiology. Congenital prothrom-botic disorders of TE are uncommon in childrenand hence it is not cost effective to screen eachand every patient with TE for congenital cause.

* Consultant Pediatrician,PD Hinduja National Hospital,andHon. Hematologist Oncologist,BJ Wadia Hospital for Children, Mumbai, India

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Congenital prothrombotic disorders: Variouscongenital disorders are now known to promotethromboembolism in children and adults.3 Theseare listed in Table 2. Heterozygotes are usuallyasymptomatic till later age and develop TEsspontaneously or following anotherprothrombotic insult. Homozygotes present withsevere TEs very early in life as purpurafulminans. Patients with anti-thrombin III(AT III) deficiency will be relatively resistant toeffect of initial heparinization. They are acommon cause of spontaneous TEs in adults,whereas in children they are rare and theycontribute to less than 2-15% of total patients.Hence in pediatric patients one should investigatefor a congenital cause only if there arespontaneous, idiopathic, recurrent TEs,especially in young patients with familial historyfor similar TEs. These tests are not easilyavailable at all the centers. In any case the prioritywhile managing such patients is to startheparinization and not wait till one can collect

samples for all these tests, or still worse awaittill reports become available. Besides, at the timeof initial TE, the level of AT III and some of theother natural anticoagulants may be lower dueto consumption in the thromboembolic processwhile the level of Protein C may be falsely higherthan normal. Hence the best time to test for thesecongenital causes is after 3-6 months when theanticoagulation therapy is stopped.

Central Venous Line (CVL) induced TE: Theincidence of TE is on the rise due to increasinguse of CVL in neonatal intensive care units,pediatric intensive care units and oncology units.Nearly 80% of TEs in newborn and 60% of TEsin children involve upper venous system as theyare all related to placement of CVL in upper bodyveins. CVL related TEs are often linked tocatheter blockage and catheter related sepsis. Theincidence of CVL related TEs varies from 1-80%depending on the depth of investigations carriedout to detect TEs as most of the CVL related TEsare asymptomatic. Blocked catheter is bestdiagnosed by linograms, however it will notdetect TEs in the concerned vein for whichvenogram is the best tool. Radiologicallydiagnosed CVL TEs are clinically significant andshould be treated with anticoagulation.

Table 1. Underlying disordersleading to TE

Catheters: Central venous and arterial cathetersMalignancies: Acute leukemiaSepsisDehydrationHematological conditions like sickle celldiseaseHepatic diseasesRenal diseasesDrugs like L-asparaginase, birth control pillsCongenital prothrombotic diseases like ProteinC deficiencyTrauma, SurgeryCardiac illnessesAutoimmune disorders: SLE, APLAIdiopathic

Table 2. Congenital prothromboticdisorders

Anti-thrombin III deficiencyProtein C deficiencyProtein S deficiencyFactor V leiden mutation and APCresistanceProthrombin G20210A mutationHyper homocysteinemiaDysfibrinogenemiasInherited abnormalities of fibrinolyticpathways like plasminogen deficiency

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Prophylactic use of heparin in a patient with CVLis known to reduce chances of catheter blockageby 67%, bacterial colonization of the catheter by82% and catheter induced bacteremia by 74%.CVL related TEs can lead to postphlebiticsyndrome with loss of venous vasculature due tonon-canalisation which may lead to difficultvenous access later in the life for some of thesepatients.

Diagnosis

The ultimate diagnosis of TEs is based onhigh index of clinical suspicion followed byradiological demonstration of the thrombus. Forjugular or deep vein thrombosis of the legultrasound doppler study is quite sensitive.However for upper venous system doppler maynot detect 80% of the TEs.4,5 Bilateral upper limbvenography remains the investigation of choicein such cases. Echocardiography may help detectcase of pulmonary embolism (PE), howeverventilation perfusion scan is the most sensitivetest to prove PE. One can perform linogram forcentral venous catheter; however it will onlydemonstrate catheter patency or thrombosis and

not the patency of the vein as such for whichvenography is the only answer.

Management

The immediate aim of the management ofTEs is to prevent spread of the thrombus; preventembolism, especially PE; and subsequently toallow natural dissolution of the clot. This isachieved by use of antithrombotic agents.Initially intravenous heparin is used to achieveimmediate antithrombosis which is thenmaintained by using either oral anticoagulationor low molecular heparin. Normallyanticoagulation is maintained for 3-6 monthsfollowing first episode of TE. In case of recurrentTEs, consider life long anticoagulation.Thrombolytic agents can be used to lyse clots ifthere is danger of losing a limb or incur severeorgan damage due to TE.

Initial heparin therapy: Dose of unfractionatedheparin used depends on the age of the child.Newborn and infants require larger doses ascompared to adolescents and adults. Usualloading dose of heparin is 75 mg/kg given as intra

Table 3. Dose adjustments for heparin administration for TE

I. Loading dose: Heparin 75 mg/kg IV bolus over 10 minutesII. Initial maintenance dose: 24 mg/kg/hr for newborn, 20 mg/kg/hr for infant, 18 mg/kg/hr for

adolescentIII. Keep aPTT at 60 to 85 seconds

APTT (Sec) Bolus (units/kg) Hold (min) Rate Change (%) Repeat aPTT< 50 50 0 + 10% 4 hr

50-59 0 0 + 10% 4 hr60-85 0 0 0 Next day86-95 0 0 - 10% 4 hr

96-120 0 30 - 10% 4 hr> 120 0 60 - 15% 4 hr

IV. Obtain blood for aPTT 4 hours after administration of the heparin loading dose and 4 hoursafter every change in the infusion rate

V. When aPTT is in therapeutic range, a daily CBC and aPTT should be done

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venous infusion over 10 minutes. This is thenfollowed by continuous intravenous infusion ofheparin in the dose of 24 mg/kg/hr in newborn,20 mg/kg/hr in infants or 18 mg/kg/hr foradolescents and continued for 5-10 daysdepending on the severity of the disease anddelay in starting the therapy. The anti-thromboticeffect is monitored based on the aPTTwhich is maintained at 60-85 seconds. Thisroughly corresponds to heparin level of 0.2 to0.4 units/mL based on the protamine titrationassay or anti-FXa level of 0.3 to 0.7 units/mL.The dose of heparin is modified based on theaPTT as shown in the Table 3.6

Use of low molecular weight heparin(LMWH): Fractionated heparin has manyadvantages as compared to unfractionatedheparin, which makes it a drug of choice forinitial heparinization and also for long termanticoagulation when compared to oralanticoagulation. Monitoring is needed much lessfrequently with LMWH. It is given bysubcutaneous route which is helpful in smallbabies with difficult intra venous access and isgiven once a day. Complications like heparininduced thrombocytopenia and osteoporosis onchronic use are much less with LMWH.7

Enoxaparine is the most frequently used drug.The dose required is more per kg than adults.8

However it is an expensive drug which makes itout of reach for most patients in developingcountries.

Side effects of heparin: Heparin can lead toclinical bleeding which can be managed by usingprotamine sulphate or FFP. The risk of bleedingis much less with LMWH than unfractionatedheparin. Long term use of heparin is associatedwith osteoporosis though it is less common inchildren as compared to adults. Heparin can alsolead to heparin induced thrombocytopenia (HIT),the incidence of which is lesser with LMWH thanwith unfractionated heparin.

Maintenance with oral anticoagulation: Afterinitial heparinization, oral anticoagulant is addedon day 2-3 while continuing intravenous heparininfusion. After 5-7 days heparin is stopped andoral anticoagulation is continued. After firstepisode of TE oral anticoagulation is continuedfor at least 3-6 months after which it is stopped.In case the patient has recurrent TEs or haspresence of congenital prothrombotic tendencyor has family history of similar congenitaldisorders, one has to use oral anticoagulation lifelong. One may use LMWH for maintenance; butis expensive.

The most common drug used for maintenanceanticoagulation is oral coumadin group of drugs

Table 4. Schedule for oral anti-coagulation therapy using coumarin

I. Day 1: If the baseline INR is 1 to 1.3 –Give 0.2 mg/kg of orally

II. Days 2-4: If the INR is:INR Action1.1 – 1.3 Repeat initial loding dose1.4 – 1.9 50% of initial loading dose2.0 – 3.0 50% of initial loading dose3.1 – 3.5 25% of initial loading dose> 3.5 Hold until INR < 3.5 and then

restart at 50% less thanprevious dose

III. Maintenance oral anticoagulation doseINR Action1.1 – 1.4 Increase by 20% of dose1.5 – 1.9 Increase by 10% of dose2.0 – 3.0 No change3.1 – 3.5 Decrease by 10% of dose> 3.5 Hold until INR < 3.5 and then

restart at 20% less thanprevious dose

45


like coumarin. The oral route makes it the mostpreferred drug for this purpose. Besides, it is alsocost effective as compared to LMWH, the otherchoice for maintenance therapy. The initialloading dose used is 0.2 mg/kg orally on day 1.6,9

This is then adjusted on subsequent days toachieve INR of 2 to 3 as shown in Table 4.Normally it takes 3-5 days to achieve INR of2-3. For next 3 months dose is adjusted to keepINR at 2-3 and the dose required per day isusually 0.1 mg to 0.3 mg per kg. Older childrenneed lesser dose. In children, where risk ofrecurrent TEs is lower or where monitoring usingINR is difficult, one can use lower dose ofcoumarin to keep INR at 1.5-2.5.

Side effects: Oral coumarin can lead to 20% riskof minor bleeding and 2-3% chances of seriousbleeding.10 It can be easily reversed by usingvitamin K. In case of severe bleeding one mayhave to use FFP infusions as vitamin K will take12-24 hours to revert INR to normal. Other sideeffects seen with coumarin include trachealcalcification or hair loss. It can also lead to fetalwarfarin syndrome if given to pregnant women.

Thrombolytic therapy: Thrombolytic therapyis indicated in patients with significant effectson end organ due to TEs or as a resort to salvagea blocked catheter due to thrombosis. Tissueplasminagen activator (tPA), urokinase (UK) orstreptokinase (SK) are the drugs used.11,12 tPA ismore safer and more effective than UK or SK, atleast in vitro tests. Local tPA is the best therapyfor blocked catheter in the dose of 0.5 mg dilutedin normal saline to volume enough to fill the linefor less than 10 kg weight child and 1.0 mg formore than 10 kg weight child. For systemicthrombolytic therapy one can use tPA in the doseof 0.1-0.6 mg/kg/hr for 6 hours or UK in the doseof 4400 U/kg/hr for 6-12 hours or SK in the doseof 2000 U/kg/hr for 6-12 hours. Monitoring forthe effect is done by monitoring FDP leveland fibrinogen levels and kept at more than

100 mg/dL. 20% of children treated withthrombolytic therapy develop bleeding and 1-2%of patients develop intracranial bleeding.

Complications of venous TEs: Complicationsof TE can be immediate or late. Immediatecomplications include death due to extension ofthrombus into heart or fatal pulmonary embolism;non-fatal PE, superior vena cava syndrome orchylothorax. Late complications can be due toTE itself like post-phlebitic syndrome (PPS),recurrence or blocked catheter leading to repeatedinsertion of CVL, or due to anticoagulation usedlike bleeding, osteoporosis, HIT etc. as discussedbefore. Mortality in pediatric TE is reported as2-3%. 7-8% of children with TE haverecurrence.1,2,13

Pulmonary embolism (PE): Incidence of PE inpediatric patients varies depending on the depthof investigations carried out to detect one.Estimated incidence reported is 8.6/100,000hospitalization in children of 1 month to 18 yearsof age.14 50% of the PEs are asymptomatic andonly 15% are considered for diagnosis.15 PEcarries nearly 50% mortality.2 Patient usuallypresents with sudden onset of unexplainedbreathlessness, cough, rusty sputum, chest pain,cyanosis and increasing requirements of oxygen.Often PE is confused as pneumonia or sepsis andit should be kept in mind as a differentialdiagnosis in a critically ill child. The best tool todiagnose PE is ventilation perfusion scan. Evenpulmonary angiography can be used fordiagnosis.

Postphlebitic syndrome (PPS): It occurs dueto imperfectly performing venous valvespermitting backflow of blood from central toperipheral venous system leading to damage tosubcutaneous tissues. It presents as edema, pain,pigmentation, induration of the involved skin andchronic non-healing ulcerations. It can occur upto 5-10 years after the occurrence of TE.

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The incidence is estimated to be 30 % in pediatricpatients.2 This means loss of peripheral venoussystem forever leading to difficulties in venousaccess.

Points to Remember

• Pediatric TEs are increasingly recogniseddue to better awareness and improveddiagnostic facilities.

• Congenital prothrombotic disorderscontribute only to a small percentage.

• Unfractionated heparin or LMWH remainthe drug of choice for initial rapidanticoagulation.

• Recurrent TE may require life longanticoagulation.

• Monitoring of small children on long termanticoagulants is difficult and needscareful management.

References

1. Van Ommen CH, Heijboer H, Buller HR, et al.Venous thromboembolism in childhood.A prospective two-year registry in TheNetherlands. J Pediatr 2001;139:676-681.

2. Monagle P, Adams M, Mahoney M, et al.Outcome of pediatric thromboembolic diseases:a report from the Canadian childhoodthrombophilia registry. Pediatr Res2000;47:763-766.

3. Heijboer H, Brandjes D, Buller Hr, et al.Deficiencies of coagulation-inhibiting andfibrinolytic proteins in outpatients with deepvein thrombosis. N Eng J Med 1999;323:1512-1516.

4. Andrew M, Marzinotto V, Pencharz P, et al.A cross-sectional study of catheter-relatedthrombosis in children receiving total parenteralnutrition at home. J Pediatr 1995;126:358-363.

5. Mitchell L, Abshire T, Hanna K, et al.A prospective cohort determining the incidence

of Thrombotic event in children with acutelymphoblastic leukemia treated withL-asparaginase: Results of the PARKKA study.Blood 1999;94(S):649.

6. Mongale P, Michelson AD, Bovill E, et al.Antithrombotic therapy in children. Chest2001;119:344-370.

7. Murphy MS, John PR, Mayer AD, et al. Heparintherapy and bone fractures. Lancet1992;340:1098.

8. Massicotte MP, Adams M, Marzinotto V, et al.Low molecular weight heparin in pediatricpatient with Thrombotic disease; a dose findingstudy. J Pediatr 1996;128:313-318.

9. Andrew M, Marzinotto V, Brooker LA, et al.Oral anticoagulation therapy in pediatricpatients; a prospective study. Thromb Hemostat1994;71:265-269.

10. Streif W, Andrew M, Marzinotto V, et al.Analysis of warfarin therapy in pediatricpatients; a prospective cohort study of 319patients. Blood 1999;94:3007-3014.

11. Leaker M, Massicotte MP, Brooker LA, et al.Thrombolytic therapy in pediatric patients; acomprehensive review of the literature. ThrombHemostat 1996;76:132-134.

12. Zenz W, Arlt F, Sodia S, et al. Intracerebralhemorrhage during fibrinolytic therapy inchildren; a review of the literature of the last 30years. Semin Thromb Hemostat 1997;23:321-332.

13. Massicotte MP, Dix D, Mongale P, et al. Centralvenous catheter related thrombosis in children:analysis of the Canadian registry of venousThromboembolic complications. J Pediatr1998;133:770-776.

14. Andrew M, David M, Adams M, et al. Venousthromboembolic complications (VTE) inchildren: first analysis of the Canadian registryof VTE. Blood 1994;83:1251-1257.

15. Buck JR, Connor RH, Cook WW, et al.Pulmonary embolism in children. J PediatrSurgery 1981;16:385-391.

47


CHRONIC IMMUNETHROMBOCYTOPENIC PURPURAIN CHILDREN

* Lalitha Kailas,** Abhilash TG

Abstract : About 20% of children with acuteimmune thrombocytopenic purpura (ITP)progress to chronic ITP, which could be due tounderlying conditions like autoimmune disorders,lymphoproliferative disorders or persistentinfections like HIV. Children with chronic ITPcan tolerate low platelet counts; hence the goalis to treat the symptoms and not to achieve anormal platelet count. Therapies like steroids,IVIG and IV anti-D are to be tried beforeconsidering splenectomy in children with chronicITP.

Key words : Chronic ITP, Steroids, IVIG,IV anti-D, Immunosuppressants

Immune thrombocytopenic purpura (ITP) inchildren is a bleeding disorder which occurseither as an acute self- limiting condition or as arecurrent or chronic auto immune disorder.Chronic ITP is defined arbitrarily as thepersistence of thrombocytopenia (i.e. plateletcount <1,50,000/µl) for longer than 6 monthsafter the acute presentation. 20% of children withacute ITP progress to chronic ITP. In adults andadolescents, chronic ITP is more common inwomen in the ratio of 3:1. Table 1 shows the

conditions associated with chronic ITP ofchildhood.

In up to one third of patients with chronicITP, spontaneous remissions will occur monthsor years later and an estimated five percent haverecurrent ITP characterized by intermittentepisodes of thrombocytopenia (at intervals of3 months) followed by lengthy periods ofremissions. This is presumed to reflect a chroniccompensated state of ITP. During periods ofremission, increased platelet production balancesthe increased rate of platelet destruction. Duringexacerbations, platelet production by the marrowis suppressed by viral infections or other factorsand is unable to offset the rate of destruction.Table 1. Conditions associated withchronic ITP of childhood

• Collagen vascular disorderso SLEo Auto immune hepatitiso Autoimmune thyroiditiso Anti phospholipid syndrome

• Lymphoproliferative disorderso Autoimmune lymphoproliferative

syndrome (ALPS)o Hodgkins lymphoma

• Immune deficiency stateso Hypogammaglobulinemiao Ig A deficiencyo Common variable immunodeficiency

• Infectionso HIVo Hepatitis Co Helicobacter pylori

HEMATOLOGY

* Professor and Head of the Department** Junior Resident

Department of Pediatrics, SAT Hospital,Medical College, Thiruvananthapuram, Kerala.

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Clinical features of chronic ITP

The onset is usually insidious:antecedent infections or fever and splenicenlargement are uncommon. Patients withchronic ITP usually have a fluctuating clinicalcourse. Episodes of bleeding of mild to moderateseverity may last few days or few weeks and maybe intermittent. Spontaneous remissions areuncommon and are likely to be incomplete.Relapses in some cases appear to be associatedwith vaccination, for e.g., MMR. The differencesbetween acute and chronic ITP are given inTable 2.

Lab findings

Complete blood count

Platelet counts: In chronic ITP platelet countat the time of presentation is usually higher[30,000-75,000/µl] compared to acute ITP. In theperipheral smear, platelets are often large andreveal more than normal variation in size andshape. Mean platelet volume [MPV] and plateletdistribution width are increased in chronic ITP.

If anemia present, it is proportional to the extentof blood loss and usually normocytic. Irondeficiency anemia may occur if bleeding has beensevere and long standing. Patients may also have

a positive Coomb’s test and autoimmunehemolytic anemia, the combination is known asEvan’s syndrome.

Total leukocyte count: is usually normal exceptfor those changes resulting from acute bleedingsuch as mild to moderate neutrophilia with someincrease in immature forms. Mild peripheraleosinophilia may be seen but is by no meansconsistent.

Bone marrow examination: This should bedone in cases of persistent thrombocytopenia ifnot already done. Megakaryocytes are usuallyincreased in size and are numerous. Examinationof the bone marrow is helpful, particularly inruling out other conditions with which ITP maybe confused. Panel of American Society ofHematology Practical Guidelines recommendbone marrow biopsy in children with ITP whohave persistent thrombocytopenia (more than6 months) or are unresponsive to IVIG.

ESR: helps to suspect autoimmune disorder.

Coombs test: helps to differentiate Evan’ssyndrome.

Autoimmune profile: to exclude autoimmunediseases (ANA, anti ds-DNA etc.).

Table 2. Differentiating features between acute and chronic ITP

Features Acute ITP Chronic ITPPeak age Younger, 2-4 years Older, above 10 yearsSex predilection None More in femalesAntecedent infection Common, 1-3 weeks before Unusual

bleedingOnset of bleeding Abrupt InsidiousPlatelet count < 20,000/µl 30,000-80,000/µlEosinophilia and lymphocytosis Common RareDuration 2-6 weeks Months or yearsSpontaneous remissions Occurs in 80% of cases Uncommon

49


Serology for HIV and Hepatitis C.

Blood grouping: Before giving anti-D

Antiplatelet antibodies: Although these tests arehighly sensitive they have very low specificityas the patients with both immune and nonimmunethrombocytopenia have elevated PAIgG (plateletassociated IgG). As per the recommendations ofAmerican society of hematology (ASH)guidelines testing for platelet antibody is notnecessary for the diagnosis of ITP.

Treatment of chronic ITP

The primary goal of treatment in chronic ITPis to prevent the bleeding episodes and not tocure the disease. As with acute ITP decisionshould be based on symptoms than on plateletcount.

Because the goal of treatment is a safeplatelet count and not necessarily a normalplatelet count observation alone is an appropriateapproach for many patients especially withminimal symptoms. This conservative approachis based on the fact that spontaneous remissionsmay occur in one third of children, even as lateas fifteen years.

Steroids: patients who had initial response tosteroids can be treated with one to two coursesof steroids (prednisolone 1-2mg/kg for 2-3 weeks,with tapering in one week). In some patients asafe platelet count (above 20000 - 30000/µl) maybe maintained with low doses of prednisolone.

Mega dose steroid therapy

Methyl prednisolone 30mg/kg/day IV ororally for 3 days is effective in increasing plateletcount to a safe level.

Pulse oral dexamethasone (20mg/m2/day for foursequential days/month for 6 months) has beentried with a response rate of 17 % in children.

IVIG: A dose of 0.8g/kg elevates the plateletcount in most children with chronic ITP. Periodicdoses of IVIG may be used as a maintenancetherapy to defer splenectomy in young childrenwith chronic ITP. About 25% of children withITP will become refractory to maintenancetherapy with IVIG. Low dose alternate dayprednisolone therapy can be used as adjunct tomaintenance IVIG therapy

Intravenous Anti-D can also be used as aneffective maintenance therapy in Rh positive,Coomb’s test negative nonsplenectomisedpatients. Anti D is preferred over IVIG becauseof ease of administration (shorter 5-30 minutesinfusion time), comparable efficacy and lowercost. Anti D binds Rh positive erythrocytes andleads to their destruction in the spleen blockingthe splenic Fc receptors thus more antibodycoated platelets survive in the circulation.A single dose of 50-100µg/kg is recommendedby IV infusion over 3-5 minutes.

Splenectomy

Splenectomy is deferred longer in childrenwith ITP than in adults, because of delayedremissions and significant post-splenectomysepsis.

American Society of Hematology(ASH) guidelines for splenectomy(Table 3)

Splenectomy can often be deferred throughthe use of maintenance therapy withcorticosteroid, IVIG or anti-D, although there isno evidence that any of these medical treatmentsalters the natural history of chronic ITP inchildren.

Splenectomy is effective because in mostpatients the spleen is the major site of plateletdestruction and auto antibody production.At least 2-4 weeks before surgery, patients should

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be immunized with pneumococcal vaccine,H.influenzae b vaccine and meningococcalvaccine as they are susceptible to overwhelmingsepsis especially from bacterial infections.

Laparoscopic splenectomy is preferred inchildren with chronic ITP in view of the shorterhospitalization and more rapid normalization ofactivities.

A complete remission rate of 72% has beenreported with splenectomy. Relapse aftersplenectomy may be due to transient viralsuppression of thrombopoiesis. If thrombo-cytopenia persists, an accessory spleen shouldbe considered.

Table 3. Splenectomy-ASH guidelines

• Children with ITP persisting for more thanone year

and• Those who have symptoms of bleeding and

a platelet count< 10,000/µl (3-12 years) or10-30,000/µl (8-12 years)

Second line therapies

In approximately 10-15% patients ITPcannot be controlled with splenectomy orfrontline medical therapy. ASH practiceguidelines recommend alternate treatment forchildren with symptomatic thrombocytopenia(less than 30,000/µl) that has failed to respondto splenectomy and primary drugs such ascorticosteroids, IVIG, and Anti-D. No regimenis universally effective though several drugs havebeen tried.

Danazol

Danazol, an attenuated androgen with mildvirilising effect has been shown to increase the

platelet counts in patients with refractory ITP.The dose is 300-400mg/m2/day orally. In general,2 months of therapy is required before a responseis seen.

Vinca alkaloids

The vinca alkaloids, vincristine andvinblastine may induce a response in somepatients with chronic refractory ITP. The usualdose of vincristine is 1.5mg/m2 and vinblastineis 6mg/m2 weekly IV for 4-8 weeks.

Azathioprine

Azathioprine, a potent immunosuppressiveagent is also effective in the treatment ofrefractory ITP. The dose is 1-4mg/kg/day for3-6 months.

Cyclophosphamide

Cyclophosphamide has also been used inITP with variable success rates given orally1-2mg/kg/day or intermittent IV in dose of750-1000mg/m2 every 3 weeks.

Cyclosporine

Cyclosporine has been recently tried inrefractory ITP in the dose of 5mg/kg/day for4 weeks.

Other therapies

Many other therapies including interferon,dapsone, ascorbic acid, colchicine andplasmapheresis have been studied forrefractory ITP cases but none has been clearlyfound to be effective. Several investigators havereported that Rituximab, a monoclonal antibodyagainst CD20, presumably by depleting the autoreactive B cell clone is effective in the treatmentof refractory ITP. Agents designed to reducebleeding without necessarily affecting the plateletcount like aminocaproic acid can be used forexcessive menstrual bleeding in young womenand may reduce blood loss.

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Points to Remember

• About 10-20% of children with acute ITPprogress to chronic ITP.

• In chronic ITP, treat the child and not theplatelet count. The goal of treatment is toprevent bleeding episodes, not to cure thedisease.

• Achieve a safe platelet count as patientswith chronic ITP can tolerate very lowplatelet counts.

• Children with significant mucosal bleedsmay be treated with steroids, IVIG or intravenous anti-D. Immune suppressive drugsmay have a role in refractory cases.

• Though splenectomy is the definitetreatment, it is to be deferred longer inchildren in view of the overwhelming postsplenectomy sepsis.

Bibliography

1. British Committee for Standards inHaematology, General Haematology TaskForce (2003). Guidelines for theinvestigation and management of idiopathic

thrombocytopenic purpura in adults, childrenand in pregnancy. Br J Haematol 120:4, 574–596.

2. George JN, El-Harake MA, Aster RH.Thrombocytopenia due to enhanced plateletdestruction by immunologic mechanisms, In:Beutler E, Lichtman MA, Coller BS, Kipps TJ(Eds): Williams Hematology. New York,McGraw-Hill, 1995, p 1315.

3. Bussel JB. Immune ThrombocytopenicPurpura, in Alan D, Michelson MD (Eds),Platelets. 2

nd edn, Elsevier, 2007, p831.

4. George JN, Woolf SH, Raskob GE, et al.Idiopathic thrombocytopenic purpura: apractice guideline developed by explicitmethods for the American Society ofHematology. Blood, 1996; 88: 3 - 40.

5. Pearson HA. The spleen and disturbances ofsplenic function. In: Nathan DG, Oski FA (Eds),Hematology of Infancy and Childhood.Philadelphia, PA, Saunders, 1993; p 1058.

6. Parker S, Levine. Thrombocytopenia caused byImmunologic Platelet Destruction, In: John P.Greer, John Forester, John N. Lukens (Eds)Wintrobe’s Clinical Hematology, 11

th Ed,

Lippincott Williams & Wilkins, Philadelphia,2003;pp1537-1544.

APLS: THE PEDIATRIC EMERGENCY MEDICINE COURSE

6th-7th December 2008

Organizer: IAP, Delhi and Center for Child Health, Sir Ganga Ram Hospital, Delhi

Venue: Auditorium, Working Women Hostel, Sir Ganga Ram Hospital, Delhi

Registration: Limited to 40 delegates, Registration Fee: Rs 2000/- in favor of “AmbulatoryPediatrics”.

Course Director and Mailing AddressDr Suresh Gupta, Consultant, Pediatric Emergency Medicine,Centre for Child Health, Sir Ganga Ram Hospital, Rajender Nagar, Delhi 110060Email: [email protected], Phone: 9811426628, 28312591, 42251156

NEWS AND NOTES

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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

* Revathi Raj

Abstract : Hemophagocytic lymphohistiocytosisis not uncommon in children. It is due todysregulation of the normal immunologicaldownregulation, occuring ususlly after viralinfections like EBV, CMV. The hyper cytokinemiasecondary to this is responsible for the symptomslike fever,pallor and splenomgaly.

Key words : Hemophagocytosis,Children

Histiocytosis is a group of disorderscharacterised by abnormal proliferation of cellsof the mononuclear phagocytic system with thehistiocyte being the central cell. These cells couldbe Langerhan cells or macrophages. Histiocytosisis now classified based on their cell of origin(Table 1).

Classification of histiocytic disorders

Class I - Dendritic cell histiocytosis(arise from dendritic cells)

Langerhans cell histiocytosis

Class II - Non dendritic cell histiocytosis(arise from macrophages)

Familial hemophagocyticlymphohistiocytosisSecondary hemophagocyticlymphohistiocytosisRosai-Dorfman disease

Class III – Mailgnant histiocytosis(arise from monocytes)

Hemophagocyticlymphohistiocytosis (HLH)

HLH can be familial or acquired.

Familial HLH: An autosomal recessivecondition that results in reduced apoptosistriggering. This leads to reduced natural killer(NK) cell activity and T cell cytotoxicity.Mutations have been identified in pertorin gene,munic gene and syntaxin gene that are essentialin cytolysis. The incidence is 1 in 1 million andgenerally presents in infancy after a minor viraltrigger. The condition is fatal if left untreated.Children can also present with central nervoussystem manifestations such as seizures, ataxia,meningeal signs or regression of developmentalmilestones. A family history of consanguinity andage less than 2 years at presentation are highlysuggestive of familial HLH.

Secondary or acquired HLH: Increasedmacrophage activity is seen in the followingconditions. 1) Viral associated HLH (VAHS) seenafter viral infections, 2) Macrophage activationsyndrome (MAS) seen in connective tissuedisorders and 3) Malignancy associated HLHwhich is seen in T cell lymphomas.

Familial and secondary forms need therapyand carry a high mortality.

Diagnostic criteria

1. Molecular diagnosis consistent withHLH or 2. Clinical features: 5 out of 8 of thesefollowing criteria:

* Consultant Pediatric HematologistApollo Hospitals, Chennai

HEMATOLOGY

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Treatment includes steroids in the form ofdexamethasone (since it has better penetrationinto the central nervous system), cyclosporin andetoposide. All three drugs have specific actionagainst T lymphocytes and result in profoundimmunosuppression. The treatment of HLH withimmunosuppression is one of the most heroictherapies that a hemato-oncologist can embarkon (Figs.2 and 3). The children are often very illwith fever and pancytopenia and commencingetoposide under such circumstances increasestheir susceptibility to infections. Prophylacticantifungals, antivirals and intravenousimmunoglobulins in infants are used insupportive care.

Children with neurological involvementneed repeated intrathecal chemotherapy and thisis often seen in the familial form of the disease.Hematopoietic stem cell transplantation hasincreased the survival in this group to 60%, aschemotherapy alone is not enough to achievedurable remission.

Viral associated HLH is most often seenwith Ebstein Barr virus infection. In India, HLHassociated with Dengue fever and malaria with ahigh parasite index has been documented.Children with primary immune deficiencies canalso present with HLH following viral infectionsand the distinction can often be difficult.Systemic lupus erythematosus or juvenileidiopathic arthritis can present with a stormypicture and HLH. Therapy is the same as thefamilial form and early etoposide has been shownto make a difference between life and death.

HLH is underrecognized and undertreatedin pediatric practice. Awareness should be createdto make early diagnosis and start specific therapyto reduce mortality.

Points to Remember

• A high index of suspicion is required tosuspect and diagnose this condition .

a) Fever > 38.5 0 C, b) Splenomegaly,c) Bicytopenia – Hb < 9g/dL, Platelets<100,000cells/cumm, Neutrophils < 1000/cumm,d) Fasting triglycerides > 275 mg/dL or Serumfibrinogen < 1.5 gm/dL, e) Serum ferritin> 500 mcg/dL, f) Soluble CD 25 > 2400 IU/L orlow/absent NK cells and g) Erythrophagocytosisin the bone marrow, liver or spleen (Fig.1).

Management

Current therapy for HLH is prescribed bythe HLH 2004 protocol of the Histiocyte Society.Once the diagnosis of HLH is made, early therapyshould be instituted to reduce macrophageactivity. The immediate aim in the treatment ofany patient with HLH is to suppress the severehyperinflammation that is responsible for the life-threatening symptoms. Another aim is to killpathogen-infected antigen-presenting cells andthus remove the stimulus for the ongoing butineffective activation of T cells. Pathogen-directed therapy is usually not sufficient to controlhyperinflammation with the possible exceptionof leishmaniasis, in which most patients promptlyrespond to liposomal amphotericin. In geneticHLH the ultimate aim must be stem celltransplantation to exchange the congenitallydefective immune system with normalfunctioning immune effector cells.

Fig. 1. Erythrophagocytosis in thebone marrow

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2008; 10(2) : 145

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• Suspect HLH in any child with prolongedfever,progressive splenomegaly with morethan 2 cell lineage depression of theperipheral blood count.

• Early initiation of treatment improvesoutcome.

Bibliography

1. Janka GE, Schneider EM. Modern managementof children with haemophagocytic lympho-histiocytosis. BrJHaematol 2004;124:4–14.

2. Janka G, Imashuku S, Elinder G, Schneider M,Henter JI. Infection- and malignancy-associatedhemophagocytic syndromes. Secondaryhemophagocytic lymphohistiocytosis. HematolOncol Clin North Am 1998;12:435–444.

3. Katano H, Cohen JI. Perforin and lympho-histiocytic proliferative disorders. Br JHaematol2005;128:739–750.

4. Emmenegger U, Frey U, Reimers A, et al.Hyperferritinemia as indicator for intravenous

immunoglobulin treatment in reactivemacrophage activation syndromes. Am JHematol 2001;68:4–10.

5. Henter JI, Elinder G. Cerebromeningealhaemophagocytic lymphohistiocytosis. Lancet1992;339:104–107.

6. Ravelli A, Magni-Manzoni S, Pistorio A, et al.Preliminary diagnostic guidelines formacrophage activation syndrome complicatingsystemic juvenile idiopathic arthritis. J Pediatr2005;146:598–604.

7. Imashuku S, Kuriyama K, Teramura T, et al.Requirement for etoposide in the treatment ofEpstein-Barr virus-associated hemophagocyticlymphohistiocytosis. J Clin Oncol 2001;19:2665–2673.

8. Henter JI, Samuelsson-Horne A, Arico M,et al. Treatment of hemophagocytic lympho-histiocytosis with HLH-94 immunochemo-therapy and bone marrow transplantation. Blood2002;100:2367–2373.

57

NEWS AND NOTES

IAP-AAP CME 2008JAIPUR (INDIA)

1-3 August 2008

Venue: Birla Science & Technology Centre, Statue Circle, Jaipur

Proposed Scientific Program of IAP-AAP CME 2008

Pediatrics in review: Short presentations on issues in clinical practice

Conference Secretariat25, Chetak Marg, M.D.Road, Jaipur-302004.Tel: +91-141-2606060Mobile: +91-9829017060E-mail: [email protected]: www.iap-aapcme2008.com


HEMATOLOGY

PRENATAL DIAGNOSIS OFHEMATOLOGICAL CONDITIONS

* Sujatha Jagadeesh* Lathaa Bhat

Abstract : With the rapid advances in prenataldiagnosis it is important to know about themethods available for early detection of varioushematological disorders. This article deals withvarious methods that are available for prenataldiagnosis of hematological disorders.

Key words : Prenatal diagnosis, Hematologicaldisorders.

What is prenatal diagnosis (PND)?

Prenatal diagnosis is a process of performingtests on the unborn fetus, for specific problems.The process involves detailed examination of thefetus using non invasive methods such asultrasound and doppler studies and invasivemethods such as chorionic villous and fetal bloodsampling.

Indications for PND

Fetus may be affected with conditions that maymanifest during pregnancy or after birth. Prenataldiagnosis for hematological conditions may beattempted in the following scenarios:

1. To rule out inherited disorders in babies withpositive family history. In certain conditionsthe fetus generally does not show evidenceof a hematological problem, but prenatal

diagnosis is offered because the fetus isconsidered to be at a risk of being affectedwith an inherited blood disorder. The carrierstatus of the parents has to be ascertained inthe following situations:-

• Previous child with a diagnosed inheritedhematological problem such as thalassemia,hemophilia – the parents are obligate carriersin this situation

• Family history of hematological problems,as in males on the maternal side beingaffected with hemophilia

• In high risk communities where knowngenetic disorders are considered to be moreprevalent – for eg. Sindhis and Bengalis havea high prevalence of thalassemia trait in theircommunities.

In these conditions and in asymptomatic parentswith incidentally diagnosed recessive problems(for example thalassemia trait) diagnosed inroutine tests, the fetus is tested to assess if thebaby is likely to manifest the hematologicalcondition after birth.

2. Abnormality in antenatal ultrasonogram inthe fetus such as evidence of anemia onultrasound and evidence of bleed, usuallyintracranial.

Steps in PND (Fig. 1)

Establishing the diagnosis

Detailed history and examination : Establishingdiagnosis in the affected individual (index case)is the single most important step in PND. Theelicitation of general history in the affectedperson is useful in arriving at a reasonable

* Consultant Dysmorphologist,Department of Genetic Counseling,Fetal Care Research Foundation,Mediscan, Chennai.

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conclusion. The age of onset of symptoms, thenature of problems such as anemia or unexplainedbleeding and progression of disease have to beelicited. Detailed clinical examination includinganthropometry of the affected child is the nextstep in diagnosis. Clinical examination mayreveal clues like limb anomalies seen in TARsyndrome (Thrombocytopenia absent radius),organomegaly as in hemolytic anemias andstorage disorders and history of repeated packedcells and specific concentrate transfusions inthalassemia and hemophilia respectively.

Investigations: Perusal of reports helps inarriving at a conclusion at times. When thereports are inconclusive, careful ordering of testsis an essential step to identify the exact diagnosis.For eg. Xrays are diagnostic of osteopetrosis.

Expert opinion : If a condition does not fit intoany particular category, help may be obtainedfrom experts in the field to arrive at a conclusion.

When the affected child is not alive,information has to be obtained from availablerecords, reports, notes of the primary physicianwho had looked after the child and by reviewingthe photographs.

Identifying the mutation

Molecular diagnosis is an essentialprerequisite for PND. Molecular diagnosis variesfrom condition to condition. For example bloodsent for molecular diagnosis of hemophilia canestablish only that condition and not all or otherrelated coagulation abnormalities such as VonWillebrand disease. Identifying the mutations inthe affected individual is essential, because themutation responsible for the same condition mayvary in different families.

Family pedigree as an aid indiagnosis and counselling

A detailed pedigree charting will not onlyhelp in identifying the mode of inheritance ofthe condition but will also help in identifying

Specific clinical diagnosis

Identify patternof inheritance

Supportive lab tests in affectedchild / parents

Discretion – keyword

Plan molecular diagnosis in affectedchild / carrier status in parents

Mutationidentified

Plan PND – in early pregnancy

Fig. 1. Algorithm for PND

Fig. 2. Autosomal recessiveinheritance

59


the members of the family who are at risk oftransmitting the condition. In Fig 2, the pedigreeis that of an autosomal recessive (AR) conditionsuch as thalassemia and Fig. 3 shows the pedigreeof an X-linked recessive (XLR) condition suchas hemophilia.

in each of their pregnancies. Fetal tissue iscollected and sent for molecular analysis.Chorionic villous sampling (CVS) is ideal as itcan be collected early between 12 – 13 weeks ofgestation. Under local anesthesia and ultrasoundguidance, a needle is passed transabdominallyand a small amount of placental tissue isaspirated. (Fig. 4). This tissue is then sent to thelab for further studies. Simultaneously a maternalEDTA sample is also sent to rule out maternalcontamination.

Some important facts

1. The specific diagnosis for which the prenataltest is being attempted should be known. Forexample PND can not be offered for anonspecific condition such as ‘hemolyticanemia’.

2. Tests that may be used after birth may notalways be useful in prenatal diagnosis. Forexample hemoglobin electrophoresis willhelp in diagnosis of β thalessemiapostnatally, however in fetal life presence

Fig. 3. X-Linked inheritanceSquares represent males and circles females.Fully shaded figures represent affectedindividuals; Carriers are represented by halfshaded figures in AR conditions. Circles withcentral spot represent female carriers in XLRconditions.

Carrier testing

Once the mutation is identified in theaffected child, the blood samples of parents ofthe affected child are sent to screen for carrierstatus. The samples of the child and the parentsmay all be sent at the same time for work up.The lab has to be contacted prior to sending thesamples to identify the type of sample requiredfor testing. Where the affected child is not alive,carrier testing may be attempted for the parents,after contacting the concerned lab. However asmall percentage of lab - based errors may beanticipated, as confirmation with the affectedchild is not possible.

Prenatal diagnosis

Once the mutation has been identified,prenatal diagnosis may be offered to the couple

Fig. 4. Diagrammatic representationof chorionic villus sampling - underultrasound guidance placental tissueis aspirated transabdominally

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of foetal hemoglobin (HbF) is normal andhence diagnosis of β thalessemia will bemissed when only hemoglobinelectrophoresis is used prenatally.

3. The mutation in the affected family shouldbe known; the affected child and / or theparents should have been tested and themolecular abnormality should be identifiedbefore planning PND.

4. PND may be attempted in early pregnancy.As the gestational age advances, the reportsmay not be available even until delivery!Late information is of no use.

5. PND carries a small risk of fetal loss andlab based errors.

6. Prenatal treatment for most fetal conditions(except immune anemia, thrombocytopenia)is not available.

7. Prenatal diagnosis is offered in conditionswhere the mortality or morbidity in affectedchildren is high. In conditions where themorbidity is low, such as hereditaryspherocytosis, PND is generally not offered.

8. Parents may opt for termination ofpregnancy if fetus is found to be affected.

9. Carrier status of a fetus is generally notrevealed due to ethical reasons. They arereported as “unaffected”.

Prenatal diagnosis and managementof a fetus with anemia

Rh isoimmunisation

It is a condition that occurs in an Rh negativemother, usually after her first pregnancy. The redcells of an Rh negative mother do not bear theD antigen on them. When such a system issuddenly exposed to the D antigen present in anRh positive blood, there is a response in thematernal system by production of anti-D

antibodies. This exposure generally occurs afterdelivery or termination of pregnancy with an Rhpositive fetus. These antibodies are then presentin the maternal circulation eternally. When themother bears an Rh positive fetus again, theseantibodies enter the fetal circulation through theplacenta causing hemolysis in the fetus resultingin fetal anemia.

Detection of fetal anemia

Rh isoimmunisation should be anticipatedin an Rh negative mother whose indirect Coomb’stest (ICT) is positive. In such cases, serialmonitoring with scan and doppler isrecommended from early pregnancy. Early pickup and appropriate intervention help inpreventing fetal and neonatal morbidity andmortality.

Evidence of fetal hemolysis may be seen inthe form of hepatosplenomegaly, placentomegalyand cardiomegaly with or without hydrops dueto anemia. Doppler changes of fetal middlecerebral artery (MCA) is a sensitive, reliable andnon invasive method of detecting fetal anemia.

Fig. 5. Showing fetal middle cerebralartery - peak systolic velocity (MCAPSV) values for corresponding gesta-tional age and the follow up plan.

61


(Fig.5). It is used to plan timing of fetal samplingand therapy

Intervention

When fetal anemia is suspected, fetal bloodsampling is done to assess blood counts and adirect Coomb’s test is also done to confirm if itis immune hemolytic anemia. Discretion is usedin fetal blood transfusion1. When there isevidence of anemia with a low hematocrit of30 % or less, intrauterine transfusion may be donewith O negative packed cells cross matched withmaternal serum, under strict aseptic precautions.Umbilical vein or portal vein is catheterized andfetal transfusion is done. The volume oftransfusion will depend upon the initial fetalhematocrit, hematocrit of the donor packed cellsunit, gestational age of the fetus and thetransfusion volume is calculated using standardnomograms.(Figs. 6a & 6b). The mother is given

low dose antibiotics and tocolytics24 hours before and 48 hours after the procedure.

Monitoring

The fetus is monitored every 2 – 4 weeksfor evidence of anemia. Most fetuses requiretransfusions 4 weekly, however there areindividual variations. The decision fortransfusion is based on fetal age and the neonatalfacilities available. Timing of delivery and placeof delivery have to be planned so that the newborn is neither too sick nor too premature oranemic and is in a centre where neonatalinterventions may be performed if necessary.These neonates have to be monitored for anemiaand hyperbilirubinemia. They may requirepostnatal exchange transfusions. Howeverantenatal therapy helps in reducing mortality andmorbidity of these neonates as they are lessanemic and hence are able to withstand

Fig. 6a. Fetoplacental blood volumefor fetuses of varying ages. For ex-ample 28 weeks old fetus has a vol-ume of about 100 ml. (Nicolaides et al)

Fig. 6b. Conversion factor. [This ismultiplied with fetoplacental volumeand the volume to be transfused isdecided (Nicolaides, et al)

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2008; 10(2) : 153

procedures better. Long term outcome of wellmanaged cases of Rh isoimmunisation haveshown encouraging results.

Other causes of fetal anemia

When there is fetal anemia and the maternalICT is positive but mother is Rh positive, minorgroup incompatibility is to be ruled out. Findingsuitable donors for fetal transfusions is difficultand outcome in these situations will depend onthe availablity of compatible blood fortransfusion.

When there is fetal anemia and the maternalICT is negative, the condition is generallysecondary to a nonimmune process. The causescould be varied. Some of them are:

1. Transplacental infections : Parvovirus andCMV, are common. Parvovirus has aclassical feature of pure red cell hypoplasiaor aplasia which can be seen on theperipheral smear.

2. Other rare hemoglobinopathies–such asalpha thalassemia that can be detected inhemoglobin electrophoresis.

3. Storage disorders–such as Gaucher’s diseasecan also have features of anemia.

Diagnosis

These conditions when suspected can beconfirmed by fetal sampling. The amniotic fluidor fetal blood sample may be collected,depending on the period of gestation. Fetal bloodsample is beneficial as more information may beobtained. However the procedure itself may beperformed after 22 weeks when the umbilicalcord size is good enough to be accessed.Amniocentesis may be done after 16 weeks. Theprocedure guidelines are the same as for CVS.Under local anesthesia, through a transabdominalapproach, amniotic fluid is aspirated or fetalblood sample is collected from the umbilical cord.Fetal blood may be sent for peripheral smear,

hemoglobin electrophoresis and antibodyestimation for specific investigations. Baselineliver function tests may be done. Amniotic fluidor fetal blood may be used for PCR studies forfetal infections.

Simultaneously maternal samples may becollected wherever necessary for correspondingestimation of hemogram, smear studies andinfection screen.

Prenatal diagnosis and managementof bleeding diathesis in a fetus /neonate

At times it may be possible to identifyneonates with intracranial bleed on the scan.There are many causes that can result inintracranial bleed. It could arise secondary to acombination of local and systemic factors.Systemic factors associated with intracranialbleed include thrombophilic2 conditions thatproduce infarcts which may then get lodged inthe systemic circulation resulting in vascularcatastrophes2. It may also result from neonatalallo immune thrombocytopenia3. This is animmune mediated condition the mechanism ofwhich is similar to Rh isoimmunisation. Howeverit may manifest even in the first pregnancy.Platelets also express specific antigens. Problemsoccur when the fetus inherits platelet antigensfrom the father, which is absent in the maternalplatelets. When the maternal system producesantibodies against the paternally derived plateletantigen, they enter the fetal circulation andproduce fetal thrombocytopenia. When this valueis critically low, it manifests as bleeding in thefetus. Diagnosis and management may bedifficult in primi, however when there is a historyof bleeding in a fetus / neonate, this conditionhas to be suspected and the parental blood maybe sent to a special lab for further work up. Insubsequent pregnancies, management optionssuch as fetal platelet transfusions andimmunoglobulin therapy may be attempted.

63


Other conditions requiring prenataldiagnosis

Immunity and infection related conditionsare more complex. These conditions (such asInterleukin deficiencies) are now beingdiagnosed, though the task is not very easy.As already explained, once the genetic tests aremade, prenatal diagnosis may be offered on thesame lines.Points to Remember

• In fetus with anemia on the scanea) confirm maternal blood group Rh type,b)Repeat ICT for monther. Rh isoimmuni-sation is the single most importantcondition to be identified by PND becauseit is treatable.

• Diagnosis of other conditions requiresmore extensive investigations on the fetusand can be done by invasive tests only.

• Specific diagnosis in the affected child isessential to predict recurrence risk and tooffer prenatal diagnosis.

• Prepregnancy period is the best time tooffer genetic counseling for the couple.They need the time and frame of mind toaccept the information given.

References

1. Suresh S, Vijayalakshmi R, Indrani S, et al.Prevention and management of Rhisoimmunization. Clin Perinatol 2004; 31:721.

2. Petaja J, Hiltunen L, Fellman V. Increased riskof intraventricular hemorrhage in preterminfants with Thrombophilia. Pediatr Res2001;49: 643-646.

3. Kaplan C, et al: Fetal and neonatal alloimmunethrombocytopenia: Current trends in diagnosisand therapy. Transfus Med 2001;2: 245.

PEDIATRIC EMERGENCY MEDICINE COURSE, CHENNAI7th & 8th June 2008

ContactDr.Janani SankarSenior Consultant, Pediatric Medicine,Kanchi Kamakoti CHILDS Trust Hospital,12-A, Nageswara Road, Nungambakkam, Chennai 600 034, India.E-mail: [email protected] Mobile: 9841078101

64

NEWS AND NOTES

5TH NATIONAL CONFERENCE OF CHILDHOOD DISABILITY GROUP,MEERUT, UP

October 11-12, 2008

ContactDr.Priyanka Jain(Developmental Pediatrician),Organising Chairperson,Jain Medical Center, 166, Civil Lines, Meerut (UP), India.Mobile: 09927008961, Web: http://www.iapcdg2008.com E-mail: [email protected]

2008; 10(2) : 155

ACUTE MYOCARDITIS

* Shakuntala Prabhu** Sumitra Venkatesh

Abstract : Most common aetiology of acutemyocarditis is viral. The true incidence ofmyocarditis is unknown. Myocarditis should beruled out in any child presenting with cardiacfailure, unexplained shock, disproportionatetachycardia or with respiratory distress withcardiomegaly. Differential diagnosis,investigating approach and management in detailare outlined.

Keywords : Acute Myocarditis, Aetiology,Management, Children.

Acute myocarditis is an inflammatorydisease of the myocardium and is diagnosed byan established histological, immunologic, andimmunochemical criteria. It is an elusive illnessto study, diagnose and treat, as the clinicalpresentation may range from nearly no symptomsto overt heart failure or sudden death. A myriadof etiological causes have been reported, withviral being the most common and almostsynonymous with the disease.1,2

Pathophysiology

Myocarditis is caused by a wide variety ofinfectious organisms, autoimmune disorders andexogenous agents in hosts with genetic and

environmental predisposition (Table 1). Virusesare the most common cause of myocarditis withadenovirus (55-60%) and coxsackievirus(30-35%) being the most common. Others likeinfluenza A and B, herpes simplex, Ebstein Barrvirus, and cytomegalovirus contribute to less than15 % of cases. The cardiac tropism of the twomost common viruses (Coxsackie virus andAdeno virus) is explained from the isolation ofthe coxsackie virus-adenovirus receptor (CAR),a protein mapped to chromosome 2q11. TheCAR, a member of the immunoglobulin helps ininternalization of the coxsackie virus andadenovirus genome. This genomic theory helpsone to speculate that the expression of thesereceptors could play a major role in determiningthe individual susceptibility and to developingviral myocarditis. Myocardial damage occurs inthree phases, one evolving into another withtransient period of distinctness. (Fig.1).

Phase I, Acute (0-4 days) - A period of viralmultiplication and replication leads to furtherdisruption of metabolism and perturbation ofinflammation and its response. Diagnosis is byvirus isolation and treatment seems promisingwith antiviral agents and CAR receptor blockersduring this phase.

Phase II, Sub acute phase (4- 14 days) : Thisphase is marked by cell-mediated cytotoxicity,cytokine release and autoimmune mediatedmyocardial damage and dysfunction. Detectionof the causal agent is uncommon during thisstage. Myocardial biopsy could reveal necrosisof myocyte and inflammatory infiltrate as definedby Dallas criteria, which helps in diagnosis.Immunomodulation or immunosuppresion has

CARDIOLOGY

* Professor & Head,** Lecturer,

Division of Pediatric CardiologyB.J.Wadia Hospital for ChildrenMumbai.

65


Table 1. Major causes of mycocarditis

Infectious causesViral Bactrial Spirochetal ProtozoalCoxsackie B virues Diphtheria Syphilis Chagas’ disease (SouthEchovirus Tuberculosis Leptospirosis American trypanosomiasis)Epstein-Barr virus Salmonella Relapsing fever Sleeping sickness (AfricanCytomegalovirus Staphylococcal Lyme disease trypanosomiasis)Influenza A and B Gonococcal ToxoplasmosisAdenovirus Clostridial Mycotic MalariaRubeola Brucellosis Candidiasis LeishmaniasisRubella Psittacosis Histoplasmosis AmebiasisVaricella Tetanus SporotrichosisHerpes virus Tularemia Coccidiomycosis HelminthicMumps Streptococcal Aspergillosis TrichinosisHepatitis virus Legionnaire’s Disease Blastomycosis EchinococcosisPoliomyelitis Meningococcal Cryptococcosis SchistosomiasisHIV Mycolasma AscariasisVariola pneumoniae Rickettsial FilariasisRabies Typhus StrongyloidiasisArbo virus Q fever

Rocky mountain spotted fever

Noninfectious causesCardiotoxins Hypersensistivity reactions Systemic disordersCatecholamines Antibiotics Collagen-vascular diseasesAnthracyclines Diuretics SarcoidosisCocaine Lithium Kawasaki disease

Tetanus toxoid Hypereosinophilia

helped to down tone the antibody damage to themyocardium during this stage.3,4

Phase III, Chronic phase- (14 days –3 months): Remodeling, fibrosis, cytokineinduced transformation and apoptosis leading todilated cardiomyopathy is the hallmark of thisphase. Diagnosis is usually by endomyocardialbiopsy. Treatment is mainly supportive. Immunemodulation has been tried with mixed response.

The resultant injury to the myocardium,whatever be the inciting agent, leads to a decreasein myocardial function with concomitantenlargement of the heart and an increase in the

end-diastolic volume due to increased preload.Due to the damaged myocardial muscle, cardiacdecompensation occurs, resulting in increase inleft atrial, pulmonary venous and arterialpressures, resulting in increasing hydrostaticforces. These increased forces lead to bothpulmonary edema and congestive heart failure.Without treatment, this process may progress toend-stage cardiac failure and death.

Epidemiology

The true incidence of myocarditis isunknown because the majority of cases areasymptomatic or at times is the cause of

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unexplained death and studies give a widespectrum of mortality and morbidity statistics.No racial or sex predilection exists. Youngerpatients, especially newborns and infants mayhave increased susceptibility and mortality rate(75%) than older infants and children (10-25%).Complete recovery of ventricular function hasbeen reported in as many as 50% of patients.Some patients develop chronic myocarditis(ongoing or resolving) and/or dilatedcardiomyopathy and may eventually requirecardiac transplantation.5

Clinical manifestations

Acute myocarditis should be suspected inany child presenting in cardiac failure with astructurally normal heart without a history ofheart disease.

In fact, one should rule out an underlyingmyocarditis in any infant with unexplainedshock, disproportionate tachycardia or withrespiratory distress with cardiomegaly withoutmurmur.

Generally, children present with vaguecomplaints, often coincident with a history of aviral prodrome. In the myocarditis treatment trial,89% of patients reported a viral-like prodromewith infectious symptoms which at timespredominate. The cardiovascular symptoms maybe entirely missed initially. The cardio respiratorycomplaints of dyspnea, orthopnea, pedal edema,palpitations, syncope, CHF and dysrhythmias arenoted usually 7-10 days later.Physical examination often reveals

• Signs of diminished cardiac output such astachycardia, weak pulse, cool extremities,decreased capillary refill and pale or mottledskin. Mild hypotension, unexplainedmetabolic acidosis and occasionally syncope(due to heart block or other arrhythmias) maybe seen.

• Heart sounds may be muffled, especially inthe presence of pericarditis. An S3 may bepresent and a heart murmur caused byatrioventricular valve regurgitation may beheard.

Fig.1. Events after viral infection of myocardium

67


• Hepatomegaly may be present in youngerchildren.

• Rales due to pulmonary edema may be heardin older children.

• Jugular venous distention and edema of thelower extremities may be present.

Neonates may seem irritable withrespiratory distress and exhibit signs of sepsis.Somnolence, hypotonia and seizures can beassociated if the CNS is involved. Hypothermiaor hyperthermia, oliguria, elevated liver enzymesand elevated blood urea nitrogen and creatininecaused by direct viral damage and/or low cardiacoutput may be present.6,7

If the presentation is more fulminant andsevere, the course may be either death orcomplete recovery (Fig 2) .

Diagnosis

A diagnosis of acute myocarditis must bemade based on clinical history, physicalexamination, imaging studies and laboratorytests. The following are the diagnostic modalitiesavailable or reported in literature with theirrelative strength and weaknesses.8

Chest radiograph : The cardiac silhouette isgenerally enlarged with acute myocarditis butoccasionally may be normal in size andconfiguration. Pulmonary congestion may bepresent along with pleural effusion andinterstitial infiltrates.

Electrocardiography : The diagnostic triad ofsinus tachycardia, ST – T wave changes and lowvoltage QRS complexes (< 5 mm) in standardand precordial leads has been popularly

Fig.2. Natural history based on clinical presentation

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described. However, it is important to rememberthat the diagnostic triad may not be present inall. Other findings include, arrhythmias likesupraventricular tachycardia, atrial ectopictachycardia, ventricular premature beats,ventricular tachycardia and ventricularfibrillation. Variable degrees of atrioventricularblocks including complete heart block have alsobeen reported.Other laboratory values : Elevated C-reactiveprotein and white blood cell count withlymphocyte predominance may be seen in acutemyocarditis. Serum LDH (lactic dehydrogenase),SGOT, SGPT may be elevated but are nonspecific. Positive viral titers, especially a fourfoldrise in acute and convalescent IgM antibody titersestablishes a diagnosis of viral myocarditis.However it is not routinely available andreporting takes time thus, when available thediagnosis is postdated.

There is limited data on myocardial musclecreatine kinase isoenzyme (CPK-MB) indiagnosis of myocarditis and is found elevatedin only 25 % of the cases. Soongswang et al.demonstrated that CPK –MB and cardiactroponin-T were significantly higher inmyocarditis as compared to dilatedcardiomyopathy and left to right shunts withcongestive heart failure.9-11

Echocardiography : This is the most usefulinvestigation in an appropriate clinical setting.Echocardiography often shows globally reducedventricular systolic functions, although thisfinding is certainly not specific for myocarditis.Other common echocardiographic findingsinclude, increased ventricular cavity dimensions(a dilated left ventricle) with or withoutventricular wall thinning, atrio-ventricular (AV)valve regurgitation, segmental wall motionabnormalities and pericardial effusion.Occasionally, diastolic functions are alsoaffected.

Endomyocardial biopsy

Endomyocardial biopsy remainstheoretically, the standard for diagnosing acutemyocarditis despite its known limitations suchas sampling error, procedural complications,variability of pathological interpretation and lownegative predictive value. The standardhistological criteria for establishing the diagnosisin adult population (the Dallas criteria) have beenwidely used in children (Table 2). Recentadvances in molecular biology, especially thepolymerase chain reaction and ribonucleic acidhybridization to detect viral genetic material haveimproved the yield and sensitivity ofendomyocardial biopsy. Myocardial biopsy is

Table 2. Dallas criteria for diagnosis of myocarditis

General definition Myocardial cell injury with degeneration or necrosis withinflammatory infiltrate not caused by ischemia.

Active myocarditis Both myocyte degeneration or necrosis and definite cellularinfiltrates (usually lymphocytes) with or without fibrosis.

Borderline myocarditis Definite cellular infiltrate without myocardial injury

Persistent myocarditis Continued active myocarditis on repeat myocardial biopsy.

Resolving /Resolved Diminished or absent infiltrate with evidence of connective myocarditis tissue healing

169


always not feasible in children and is availableonly at selected centers. Since its introduction inthe early 1980s, it has highly variable results witha reported incidence of myocarditis ranging from0 to 80%. A second clinicopathologicalclassification system was proposed in 1991, buthas received only limited acceptance.12-14

Magnetic resonance imaging : Several imagingtechniques are emerging as adjunct diagnostictests. Antimyosin scintigraphy to judge thedegree of myocardial necrosis, contrast enhancedcardiovascular magnetic resonance imaging andechocardiographic digital image processing helpin localization and assessment of the extent ofinflammation in patients with presumed viralmyocarditis. These non-invasive modalities indiagnosis of acute myocarditis seem promisingin future.15

Differential diagnosis

Viral infections are responsible for themajority of cases of acute myocarditis. These aredifficult to prove as viral particles are rarely seenin myocardium either on biopsy or autopsy. Mostviral cultures or serology are also not consistentlysupportive. Hence the diagnosis of acute viralmyocarditis starts with ruling out other causesof myocardial dysfunction.16

Structural cardiac lesions with left sidedoutflow tract obstruction like coarctation of aorta,aortic stenosis and anomalous coronary artery cancause congestive cardiac failure and myocardialdysfunction.

Arrhythmias which are incessant likesupraventricular tachycardia and junctionalreciprocating tachycardia should be ruled outusing an electrocardiogram.

Systemic hypertension can present withcongestive heart failure and dysfunction.

Inherited metabolic causes (like glycogenstorage disorders, carnitine deficiency) could

present with myocardial dysfunction and has tobe ruled out especially in neonates and infants.A positive family history of cardiomyopathy,failure to thrive, significant metabolic acidosisand/or hypotonia may give clue to the diagnosis.

Occasionally, hypocalcemia and vitamin Ddeficiency in infants have been reported to causeleft ventricular failure and dysfunction.

Treatment

Supportive care is the first line of treatmentin acute myocarditis. A minority of patients whopresent with fulminant or acute myocarditis willrequire an intensive level of hemodynamicsupport, fluid and electrolyte monitoring andaggressive pharmacological intervention,including vasopressors and positive inotropicagents. The goal of treatment is to support theblood pressure and cardiac output, keeping inmind that an increase in oxygen consumptionmay be harmful to the injured myocardium. Inchildren with acute heart failure and clinical signsof low cardiac output or oxygen delivery,inotropic support with beta agonists such asdobutamine and phosphodiesterase inhibitorssuch as milirinone is indicated . More severecardiogenic shock states would need low doseepinephrine and presence of hypotension maymerit use of inotropic agents with alphaadrenergic activity such as dopamine or higherdose of epinephrine (Table 3). Non-invasiveventilation may be effective in treatingpulmonary edema which also helps to reduce leftventricular after load8.

Several drugs used for chronic heart failureare also useful in cardiac failure due to acutemyocarditis with less severe presentation.Diuretics (particularly loop diuretics), should beused to decrease pulmonary edema and total bodywater, and addition of spironolactone may becomplementary. Angiotensin converting enzymeinhibitors (ACEI) should be started early after

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establishing adequate renal perfusion. The useof digoxin is controversial and traditionally hasbeen avoided, although clinical data neithersupport nor refute this and the presentrecommendation is that digoxin should probablybe used with caution and in low doses in thesepatients.

Use of anticoagulation is common and antiarrhythmic drugs are frequently used to treatarrhythmias in acute myocarditis.

Levosimendan, a novel inotropic agent thatincreases the sensitivity of myofilaments tocalcium have been tried in 15 children with eitherend stage or acute myocarditis. However resultswere interpreted with caution due to the smallnumber of study group and a lack of controlgroup.

Studies using beta agonists and antagonistsin severe heart failure have concluded that overallsurvival is better with latter as opposed to former.Carvedilol, metoprolol, and bisoprolol have allbeen subject to at least one large scale trial andshown to be effective in reducing mortality inadults.17,18

Immunotherapy for acute myocarditis –Despite a common practice of immune globulinadministration in acute myocaridits , there areno randomized , controlled studies in children todefinitely support its use. There is no class Ievidence in pediatric literature and no meaningfulmeta-analysis of available studies. Likewise,there is also a lack of evidence based data toconclude whether the use of immuno-suppressive agents benefit children with acutemyocarditis. Similarly, early trials of antiviraltherapies, such as interferon suggest a potentialtherapeutic role but require furtherinvestigation.19-22

A ventricular assist device or extracorporealmembrane oxygenation may rarely be requiredto sustain patients with refractory cardiogenicshock. These devices favorably alter ventriculargeometry, reduce wall stress, decrease cytokineactivation and improve myocyte contractilefunction. Although the data on survival afterventricular assist device or extracorporealmembrane oxygenation implantation are largelyobservational, the high likelihood of spontaneous

Table 3. Commonly used medications for the treatment of acute myocarditis

Inotropic support Afterload reduction Diuresis

Dobutamine Milrinone Frusemide 1 mg/kg IV5–20 µg/kg/min 0.5–0.75 µg/kg/min

Milrinone Nitroprusside Chlorothiazide 20 mg/kg/day0.5–0.75 µg/kg/min 0.5–3.0 µg/kg/min orally divided BID 4 mg/kg/day IV

divided every 6–12 hours

Dopamine Enalaprilat 5–10 µg/kg/dose Spironolactone 1–3 mg/kg/day5–10 µg/kg/min IV every 8–24 hours orally divided every 6–12 hours

Epinephrine Enalapril 0.1–0.5 mg/kg/day0.05–0.1 µg/kg/min orally divided BID

Captopril 0.15–0.5 mg/kg/doseorally every 8 hours

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recovery of ventricular function argues foraggressive short-term hemodynamic support.

Natural history and prognosis

The myocarditis treatment trial reportedmortality rates for biopsy-verified myocarditis as20% and 56% at 1 year and 4.3 years,respectively. These outcomes are similar to theMayo clinic’s observational data of 5-yearsurvival rates that approximate 50%. Survivalwith giant cell myocarditis is lower with less than20% of patients surviving for 5 years.

Poor prognostic markers have been reportedin viral myocarditis. In fulminant myocarditis,cardiac arrest and ventricular tachycardia duringacute phase have poor prognosis while those withchest pain at presentation, younger age group(except neonates) and those with atrioventricularblock have good prognosis on a long term followup with complete recovery of left ventricularfunctions. Most cases of asymptomaticmyocarditis and those presenting in congestiveheart failure with insidious onset, either havesudden cardiac death during acute stage or mayhave complete recovery or develop into dilatedcardiomyopathy on long term follow up. (Fig 2)23

Points to Remember

• Acute myocarditis is a major cause ofacquired cardiac problem in infancy andchildhood. Most of them are caused byviruses.

• It is an important contributor to leftventricular dysfunction and dilatedcardiomyopathy in children.

• Age and mode of presentation are twoimportant factors in determining the longterm natural history and prognosis.

• Treatment of myocarditis, still remainslargely supportive.

References1. Feldman AM, McNamara D. Myocarditis. N

Engl J Med 2000; 343: 1388-1398.2. Levi D, Alejos J. Diagnosis and treatment of

pediatric viral myocarditis. Curr Opin Cardiol2001; 16:77-83.

3. Jared W, Magnani MD, William D.Myocarditis: Current Trends in Diagnosis andTreatment. Circulation. 2006; 113:876-890.

4. Abzug MJ. Presentation, diagnosis, andmanagement of enterovirus infections inneonates. Paediatr Drugs 2004; 6(1): 1-10.

5. Wheeler DS, Kooy NW. A formidablechallenge: the diagnosis and treatment of viralmyocarditis in children. Crit Care Clin2003;19:365-91.

6. McCarthy RE, Boehmer JP, Hruban RH et al.Long-term outcome of fulminant myocarditisas compared with acute (non-fulminant)myocarditis. N Engl J Med. 2000;342:690–695.

7. Inwald D, Franlkin O , Cubitt D et al.Enterovirus myocarditis as a cause of neonatalcollapse. Arch Dis Child Fetal Neonatal Ed.2004; 89: 461-462.

8. Bohn D, Chang AC. Guidelines for thetreatment of myocarditis in infants and children.Pediatr Crit Care Med 2006 Vol 7, No6 (suppl.)S1-S24.

9. Lauer B, Niederau C, Kuhl U, et al. Cardiactroponin T in patients with clinically suspectedmyocarditis.J Am Coll Cardiol 1997; 30:1354-1359.

10. Lemesle FG, Lumumba E, Spadaro Sapari J,et al. Troponin 1c in acute myocarditis inchildren. Presse Med 2000;29:81-82(Medline).

11. Songswang J, Durongpisitkul K, RatanarapeeS, et al. Cardiac troponin T: its role in thediagnosis of clinically suspected acutemyocarditis and chronic dilated cardiomyo-pathy in children. Pediatr Cardiol 2002; 23:531-535.

12. Schmaltz AA, Apitz J, Hort W, et al.Endomyocardial biopsy in infants and children.Experience in 60 patients. Pediatr Cardiol1990;11: 15-21.

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13. Bowles NE, Ni J, Kearney DL, Pauschinger Met al. Detection of viruses in myocardial tissuesby polymerase chain reaction: evidence ofadenovirus as a common cause of myocarditisin children and adults. J Am Coll Cardiol 2003;42: 466–472.

14. Caforio LP, Calabrese F, Angelini A.et al.A prospective study of biopsy-provenmyocarditis: prognostic relevance of clinicaland aetiopathogenetic features at diagnosis. EurHeart J 2007; 28(11): 1326 - 1333.

15. Skouri HN, Dec GW, Friedrich MG, et al.Noninvasive Imaging in Myocarditis. J Am CollCardiol 2006; 48(10): 2085 - 2093.

16. Prabhu SS, Dalvi BV. Treatable cardiomyo-pathies. Indian J Pediatr 2000;67(4):279-82.

17. English RF, Janosky JE, Ettedgui JA, et al.Outcomes for children with acute myocarditis.Cardiol Young 2004; 14: 488-493.

18. McNamara DM, Holubkov R, Starling RC, etal. Controlled trial of intravenous immune

13th INTERNATIONAL CONGRESS OF INFECTIOUS DISEASESat Kuala Lumpur, Malaysia

19th to 22nd, June, 2008ContactInternational Society for infectious Diseases1330, Beacon Street, Suite 228,Brookline. Massachusetts,02446-3202 [email protected]://www.isid.org

globulin in recent-onset dilated cardio-myopathy. Circulation. 2001; 103: 2254–2259.

19. Gullestad L, Aass H, Fjeld JG, et al.Immunomodulating therapy with intravenousimmunoglobulin in patients with chronic heartfailure. Circulation 2001; 103: 220–225.

20. Menghini VV, Savcenko V, Olson LJ, et al.Combined immunosuppression for thetreatment of idiopathic giant cell myocarditis.Mayo Clin Proc 1999; 74: 1221–1226.

21. Robinson J, Hartling L, Vandermeer B, et al.Intravenous immunoglobulin for presumed viralmyocarditis in children and adults. TheCochrane Database of Systematic Reviews2006; Issue 4.

22. Chen H, Liu J, Yang M .Corticosteroids forviral myocarditis.The Cochrane Database ofSystematic Reviews 2006 Issue.

23. Lee KJ, Mc Crindle BW, Bohn DJ, et al. Clinicaloutcomes of acute myocarditis in children.Heart 1999; 82:226-233.

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NEWS AND NOTES

VI National Conference of Pediatric RheumatologyDate: 11th, 12th October 2008

Venue: Dr.TMA Pai International Convention Centre,M.G.Road, Mangalore

For further details contactDr.Nutan KamathOrganising SecretaryDepartment of Pediatrics, KMC Hospital, Attavar,Mangalore – 575 001, Karnataka.E-mail: [email protected]


A CLINICAL APPROACH TOSKELETAL DYSPLASIA

* Elizabeth KE** Binoy Thomas

Abstract: Skeletal dysplasia (SD) is one of themajor causes of pathological short stature. Itrepresents a heterogeneous group of geneticdisorders with variable presentation, severity andassociated morbidities. In the diagnosis of shortstature, a systematic approach is necessary forproper early diagnosis. Radiological findings arecharacteristic in most of these conditions. A briefaccount of the common skeletal dysplasias ispresented. In the management, multidisciplinaryteam approach and genetic counselling arerecommended.

Key words: Skeletal dysplasia, Constitutionalbone disorders, Short stature.

Skeletal dysplasia (SD) is a group of geneticconditions with inherent or constitutionaldisorders of bone formation and modeling dueto genetic mutations. These are also calledconstitutional bone disorders. There are severalhundred conditions in this group. These maypresent at birth or later in life. One fourth of thesedisorders are lethal or lead to still birth and onethird may result in postnatal death. Those whosurvive will present with pathological short

stature and associated orthopedic problems,neurological problems, deafness, blindnessetc 1.

Definitions

When bone alone is affected, the conditionis called ‘skeletal dysplasia’ and when cartilageis also affected, it is called ‘osteo-chondrodysplasia’. The term ‘dysostosis’ is usedexclusively for bone malformations. Disordersof bone density include inherited osteopenias like‘osteogenesis imperfecta (OI)’ and inheritedosteosclerosis like ‘osteopetrosis’1. Non geneticconditions that mimic genetic SD are fetalwarfarin syndrome and vitamin D deficiencysyndrome.

Hemimelia refers to the absence of part of alimb, e.g., forearm, hand, foot etc. Phocomeliais used to denote marked reduction in the size oflimb, e.g., hand close to trunk. Syndactyly isfusion of fingers/ toes. Polydactyly is extrafingers/ toes. Pre-axial polydactyly is on theradial side and post axial on the ulnar side.

The classification of skeletal dysplasiadepends on the prognosis, associated anomalies,site of involvement, etc2.

Classifications

1. Based on outcome - lethal or non lethal

Some of the mutations are severe orhomozygous and are florid at birth andoften lethal leading to miscarriage orstill birth, e.g. rhizomelic-thanatophoricdysplasia, homozygous achondroplasia andacromelic- achondrogenesis.

SKELETAL DISORDERS

* Professor and Consultant in Nutrition and Genetics** Senior Resident,

Department of Pediatrics,SAT Hospital. Govt. Medical College,Thiruvananthapuram - 695 011.

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2. Based on associated anomalies

SD may be purely bone disorders likeachondroplasia or may be associatedwith multiple congenital anomalies (MCA),SD-MCA syndrome, e.g. Ellis van Creveldsyndrome. Sometimes, i t may also beassociated with mental retardation (MR) likeSD- MCA-MR syndrome, e.g. camptomelicdysplasia. The usual associated anomalies arecleft palate, polydactyly, syndactyly, myopia/cataract, congenital heart disease, club foot,cystic ears, short rib, long narrow thorax,kypho-scoliosis, large head, prominentforehead, flat face, platybasia, cranio-vertebralanomalies, peg shaped teeth, hitchhiker thumb,etc3.

3. Based on physis involvement

SDs usually affect long bones and may beconfined to epiphysis, metaphysis or diaphysis,e.g. epiphyseal dysplasia, diaphyseal dysplasia(Multiple diaphyseal dysplasia) or metaphysealdysplasia or may be overlap syndromes like meta– epiphyseal dysplasia. Sometimes it may alsobe ‘expanded syndromes’ involving spine andcranium, e.g., spondylo epiphyseal dysplasia,cranio metaphyseal dysplasia, fronto epiphysealdysplasia and so on. Spondylo-meta-epiphysealdysplasia is referred to as pseudoachondroplasia.

4. Based on limb shortening

When the proximal segment of the limb,e.g., humerus/femur is short, it is called‘rhizomelic short stature’. When the midsegment, e.g., radius-ulna/tibia-fibula is short,it is ‘mesomelic short stature’ and when the distalsegment, e.g., hands /feet are short, it is‘acromelic short stature’. Examples of rhizomelicdwarfing are achondroplasia, spondylo-epiphyseal dysplasia and metaphyseal dysplasias.Example of mesomelic dwarfing is mesomelicdysplasia and examples of acromelic dwarfingare Ellis van Creveld syndrome (chondro-

ectodermal dysplasia), asphyxiating thoracicdysplasia (Jeune syndrome) and diastrophicdysplasia.

Most of the skeletal dysplasias present asshort stature. Short stature may or may not beevident at birth. In the severe forms, it isrecognizable at birth, but in some, it becomesevident only during follow up. Short stature mayalso be classifed as normal variant(physiological) or pathological (Fig. 1).

Normal variant versus pathologicalshort stature

Short stature may also be a normal variant.Genetic short stature (GST) and constitutional/maturational growth delay (CGD/ MGD) areincluded in this group. The term MGD ispreferred than CGD as the condition is due todelayed maturation and correctable, unlike otherconstitutional disorders.

When the stature is abnormally short,e.g. less than 3rd centile or less than 3 standarddeviation of the normal, it is referred to aspathological short stature or dwarfing3. In thiscondition, the adult height is often less than145 cm. Hypochondroplasia is an exception tothis rule, in which the adult height may be morethan 145 cm. Usually, in pathological shortstature, the limbs are shorter and the upper limbsstop above mid pelvis in infants and above upperthigh after infancy.

More insight regarding “Stature” is nowavailable. “Short stature homeobox containinggene (SHOX gene)” located on thepseudoautosomal region of p arm of X andY chromosomes is in highlight now3. It isinteresting to note that it is active on both XXand XY. This explains short stature in Turnersyndrome. Deletion of SHOX gene is said to bethe cause for idiopathic short stature (ISS).

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The infancy, childhood and puberty (ICP)concept of growth is yet another break throughmodel. In infants, nutrition is the prime influenceon growth. In children, growth hormone,thyroxine, IGF 1 and IGF binding protein(IGFBP 3) have major influences. In puberty, sexsteroids exert major influence on growth3.

The mid point of the body is umbilicus inthe newborn and it is pubic symphysis in theadult. The upper segment is up to the hip socketand lower segment is below that. The uppersegment to lower segment ratio should becalculated and compared with that for thechronological age (CA) of the child. It is roughly1.7:1 at birth, 1.6:1 at 6 months, 1.5:1 at 1 year,1.4:1 at 2 years, 1.2:1 at 4 years and 1:1 by10 years of age.

In proportionate dwarfing, body proportionsare comparable to that for the chronological age,but in disproportionate dwarfing, it does notcorrespond to that for the chronological age. It is

Normal or variant

Pathologic shot stature

Genetic/ familial short stature

Constitutional/ Maturational Growth Delay (i.e. “late bloomer”) keep growing when others stop

Disproportionate short stature: ex: skeletal dysplasia Metabolic bone disease /“Dwarf”

Proportionate short stature: ex : endocrine problems, Down Syndrome, (Exception: Hypothyroid- infantile proportion)

Short stature

usually infantile in conditions with limbshortening, i.e. lower segment will be shorter thanupper segment. In those with trunk shortening,the upper segment will be shorter. If upper andlower segments are equally affected,proportionate dwarfing can occur. Thus the shortstature may be short limbed, short trunked orproportionate.

Dysostosis multiplex

This term refers to the various bonemanifestations in diseases with involvement ofother systems as well. The exact diagnosis of theunderlying condition will need other laboratoryevidences, for eg, the bone changes inmucopolysaccharidosis and mucolipidosis are thesame. The differentiation is possible only by urinestudies and enzyme studies. The bone changesin this category includes osteoporosis with coarselaced trabeculations, thick calveria, J shapedsella, wide clavicle, ‘oar’ shaped ribs, ‘oval andhook’ shaped vertebrae, wide ileum, coxa valga,

Fig.1. Approach to short stature: Physiological vs. Pathological

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Table 1. Causes of short stature

1. Racial or genetic : e.g. Pygmies

2. Maturational/Constitutional growth delay:e.g. delayed puberty

3. Low birth weight / intra uterine growthretardation/primordial dwarfing :e.g. Syndromic and non-syndromicmalformations, Hypoplastic babies

4. Chromosomal : e.g. Down, Turner

5. Metabolic : e.g. Morquio

6. Skeletal : e.g. Achondroplasia

7. Nutritional : e.g. Chronic PEM

8. Emotional deprivation

9. Endocrine : e.g. Hypopituitarism

10. Chronic diseases : e.g. Congenital heartdisease and Chronic asthma

irregular diaphysis, metaphyseal widening,epiphyseal dysplasia and proximally taperedbullet nosed 2nd to 5th metacarpals4.

Diagnosis

SD are a heterogeneous group of geneticconditions that result in abnormal short statureand handicaps. A proper history, thoroughclinical examination, anthropometric,biochemical and radiological evaluation arehelpful in diagnosis and management. Specialdisease specific growth curves are now availablefor evaluation of common conditions likeachondroplasia5.

Based on the chronologic age (CA), heightage (HA) and bone age (BA) by ossification inX-ray, a working classification can be arrived :

• BA=CA - genetic short stature• BA=HA - but < CA, constitutional

maturational delay• BA<HA - pathologic short stature

Apart from proper history, clinical,anthropometric, radiological and other tests likekaryotyping, metabolic screen, etc are importantin the diagnosis. Rickets, mucopolysaccharidosis,chromosomal anomalies, sporadic syndromes,etc. come in the differential diagnosis. Many ofthese disorders may be fresh mutations withoutany family histroy. The causes of short statureare given in Table 1. The diagnostic clues fromhistory and physical examination are given inTable 2. The diagnostic approach for skeletaldysplasias and the categorization are given inTables 3 and 4. Table 5 summarizes the associatedmedical conditions, that need special attentionin the evaluation and management.

Common skeletal dysplasias

1. Achondroplasia

It is the commonest SD with an autosomaldominant inheritance. It may be a fresh mutationin many cases. The fibroblast growth factor

receptor (FGFR3) gene on chromosome 4 p16.3is defective. It is a spondylo-metaphysealdysplasia with disproportionate rhizomelic shortlimbs and characteristic cranio-facial features likelarge head, prominent forehead, depressed nasalbridge, mid facial hypoplasia and trident likehands, kyphosis and cranio-vertebral anomalies.Intelligence is normal. The radiological featuresare metaphyseal flare with ball and socketarrangement of metaphysis with epiphysis,cuboid vertebra with L1 and L2 anterior beakingand flat pelvis with rounded tomb stone like ileum(Fig.2). Hydrocephalus may occur due to narrowforamen magnum. The adult height is around131 cm in male and 124 cm in female.Homozygous achondroplasia is lethal.

2. Pseudoachondroplasia

It is spondylo-meta epiphyseal dysplasiawith normal cranium and face. Epiphysealossification is severely affected and there areabnormally short limbs.

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Table 2. Clues in history and clinical signs leading to diagnosis

HISTORY DIAGNOSISAntenatal substance abuse, medications, Intrauterine growth retardationlow birth weight, breech delivery,neonatal hypoglycemiaHypoglycemia, jaundice, hepatomegaly Glycogen storage diseaseMicropenis Growth hormone deficiencyEdema hands and feet Turner syndromePolyuria Chronic renal failureShortness of breath, cyanosis, cough, fever Congenital heart disease,asthma,tuberculosisDiarrhea, steatorrhea, abdominal pain MalabsorptionConstipation, weight gain, HypothyroidismInadequate growth Pituitary-hypothalamic region massSocial history Psychosocial dwarfismInadequate dietary intake, sunlight exposure Protien energy malnutrition, ricketsFamily history for height, timing of puberty Familial short stature and maturationalin parents delay of growth and puberty

CLINICAL SIGN DIAGNOSISDisproportion Skeletal dysplasia, rickets, hypothyroidismDysmorphism, midline defect Chromosomal anomalies, sporadic syndromes,

hypopituitarism, septo-optic dysplasiaPallor Chronic anemia, chronic renal failure,

hypothyroidismVitamin deficiency signs Undernutrition, malabsorbtionHypertension Chronic renal failureJaundice, clubbing Chronic liver diseaseFrontal bossing, depressed nasal bridge, Growth hormone deficiencycrowded teeth, small penisGoitre, impalpable thyroid, coarse skin, Hypothyroidismdelayed return of tendon jerksCentral obesity, striae, proximal weakness Cushing syndromeRound face, short 4th metacarpal, mental PseudohypoparathyroidismretardationVisual field defect, optic atrophy, optic nerve Pituitary/hypothalamic tumorhypoplasia, papilledema

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Table 3. Diagnostic approach for skeletal dysplasia

Step I Family history, pedigree, antenatal, natal/ neonatal events

Step II Recognition of short stature, type, site, evolution / follow upand course

Step III Clinical categorization- proportionate/ disproportionate,rhizomelic/mesomelic/acromelic,

Step IV Associated anomalies, multiple congenital anomalies/ MR

Step V Radiolgical assessment, bone age, Epi/meta/diaphyseal

Step VI Diagnosis, course, follow up,

Step VII Genetic diagnosis, genetic counseling

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Fig. 2. Tomb stone ileum, metaphy-seal widening, and ball and socketmetaphysis and epiphysis in achon-droplasia

3. HypochondroplasiaIt is a milder type compared to

achondroplasia with the defect in the same gene,but a different mutation. Bow legs appearing inschool age and vertebral involvement suggestthe diagnosis. The adult height may be more than145 cm. There may be mental subnormality,cataract, ptosis, post axial polydactyly in thelower limbs and brachycephaly. It may bemistaken as a case of maturational delay.

4. Spondylo epiphyseal dysplasia (SED)

The features are short neck, short spine,kyphoscoliosis, pectus carinatum, coxa vara andgenu valgus. The other features are flat facies,wide set eyes, high myopia, club foot and cleftpalate. The acetabular roofs are horizontal. Itmimics Morquio disease, but without cornealopacity and keratin sulfaturia. There are 2 types,early onset congenital type and a late onset tardatype.

5. Spondylo metaphyseal dysplasia (SMD) –Koslowski type

The features are short trunk, waddling gait,kypho scoliosis, genu valgum, hyperopia, coxavara and irregular metaphysis.


Table 4. Categorization of skeletal dysplasias

Primary Category Other areas Expanded syndromesinvolvement involved

Epiphysis Multiple Spine Spondylo-epiphyseal epiphyseal dysplasiadysplasia (Fairbank/Ribbing Types)

Metaphysis Metaphyseal Spine Spondylo- metaphyseal dysplasiadysplasia (Achondroplasia,Kozlowski Type )

Cranium Cranio-metaphyseal dysplasiaForehead Fronto- metaphyseal dysplasia

Others Multiple exostosisEnchondromatosis (Ollier)

Diaphysis Diaphyseal Spine Spondylo- epiphyseal dysplasiadysplasia

Cranium Cranio-epiphyseal dysplasia

Others Progressive diaphyseal dysplasia (Englemann)Polyostotic fibrous dysplasia ( McCune Albright)Infantile cortical hyperostosis (Caffey)

Mixed Types Spondylo-epi-metaphyseal dysplasiaSpondylo-meta-epiphyseal dysplasia(Pseudo achondroplasia)

Special Types

Facial Acro-facial dysostosis (Gene Wiedmann with postaxial defects and Nager typewith preaxial defects)

Bowed limbs Camptomelic dysplasia (SD+MCA+MR syndrome)Diastrophic dysplasia (SD+MCA syndrome)

Cartilage+bone Metaphyseal-chondro dysplasia/ chondro dystrophy(Schimid, Jansen Types)

Ectoderm Chondro-ectodermal dysplasia (Ellis van Creveld)Cartilage hair hypoplasia (metaphyseal+ectodermal)

Bone density disorders Osteopenia - Osteogenesis ImperfectaOsteosclerosis - Osteopetrosis, Pyknodysostosis

SD- Skeletal dysplasia,MCA- Multiple congenital anomaliesMR- Mental retardation

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6. Metaphyseal chondrodysplasia- Schmidtype

Short limbs, bow legs, waddling gait, coxavara and genu varus become evident by 2 yearsof age. It is an autosomal dominant condition thatmimic rickets, but without any biochemicalabnormalities. The Jansen type is associated withhypercalcemia.

7. Diastrophic dysplasia

The word, diastrophic means ‘twisted’. It isan autosomal recessive condition with metaepiphyseal dysplasia, platyspondyly, scoliosis,etc. The features are short bow legs, club foot,knee contractures, clino camptodactyly and lowset hitchhiker thumb (Fig.3). They have ear cyststhat become inflamed leading to ‘cauliflowerear’, that later become calcified and ossified.There may be cleft palate or high arched palate.

8. Camptomelic dysplasia

It is associated with camptomelic or bowedlimbs. The inheritance may be dominant or

recessive. Micrognathia and cleft palate are theother anomalies. Aspirations are common in thiscondition.

9. Asphyxiating thoracic dystrophy (Jeunesyndrome)

It is associated with severe respiratorydistress and early death.

Fig.3. Low set hitchhiker thumb indiastrophic dysplasia

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Table 5. Medical complications of skeletal dysplasias

Respiratory – dyspnea, hypoxia, pneumonia

CNS - hydrocephalus, cord compression, Cranio vertebral junctionanomalies

Muscular – hypotonia, contractures

Dental – malocclusion, dentigenesis imperfecta

Eye – myopia, cataract, retinal detachment

Nutrition – obesity, short stature

Joint – arthropathy, deformity

Obstetrics – difficult delivery and cesarian, cephalo pelvicdisproportion

Psychological – emotional problems, lack of confidence

Others - various handicaps


10. Osteogenesis Imperfecta (OI)

It is a heterogeneous group of conditionswith inherited osteopenia and pathologicalfractures due to defective Type 1 collagen (Fig.4).Types I and IV of Sillence are milder types withautosomal dominant inheritance. Variable typesof inheritance have been described in other types.Type I has persistent blue sclera and type IV haswhite sclera. Types II and III are severe types,type II has intrauterine presentation and earlydeath and type III survive with severe deformities.

11. Osteopetrosis

It is a recessively inherited condition withosteosclerosis. The infantile variety presentsearly and is lethal in the first decade and the tardatype may survive longer. There is large head,blindness, deafness, hepatosplenomegaly andpancytopenia or leukoerythroblastic bloodpicture. Due to defective bone resorption andsecondary hyperparathyroidism, there may behypocalcemia and hypophosphatemia resultingin rickets and this condition is called‘osteopetrorickets’ (Fig.5).

Management

A multidisciplinary team approach iswarranted in the management. The team shouldconsist of pediatrician, orthopedician, pediatricsurgeon, neurosurgeon, geneticist, psychologist,special teachers and counselors. Evaluation forother medical conditions, cranio vertebralanomalies, multiple other anomalies and mentaland learning disabilities should be undertaken.

Bone lengthening operations are expensiveand very time consuming requiring dedication,commitment and multiple procedures. Externalfixator technique of Ilizarov is tried inachondroplasia. Growth hormone therapy is triedin hypochondroplasia6. Bone marrow stem celltransplant may be helpful in osteopetrosis and

Fig-4: Thin fragile bone with patho-logical fracture in osteogenesisimperfecta

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Fig-5: Osteopetrosis with pathologi-cal fracture and rachitic changes(Osteopetrorickets)

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certain metabolic bone disorders likemucopolysaccharidosis. Genetic counseling isthe mainstay in the approach to most of theseconditions.

Points to Remember

• Skeletal dysplasia is an important cause ofpathological short stature.

• It is a heterogeneous group of geneticconditions with variable severity.

• A systematic approach is needed for thediagnosis of short statute.

• Radiological findings are characteristic formost of the skeletal dysplasias.

• Multidisciplinary team work and geneticcounseling are recommended for themanagement.

Acknowledgement

We acknowledge the consent given by theindividuals to publish their photos and X-rays.

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References

1. Horton WA, Hecht J. The skeletal dysplasias.In: Behrman RE, Kliegman RM, Arvin AM eds,Nelson Textbook of Pediatrics, 17

th Edn,

WB Saunders Company, Philadelphia, 2004;pp 2113-2138.

2. Hall BD. Approach to skeletal dysplasia. PediatrClin N Am 1992; 39: 279-305.

3, Barucha BA, Kher AS. Skeletal dysplasias andother dysmorphic syndromes with abnormalstature. In: Desai MP, Bhatia V, Menon PSNeds, Pediatric endocrine disorders, 1

st Edn,

Orient Longman, Hyderabad, 2001;pp 70-84.

4. Spranger J. Radiological nosology of bonedysplasia. Am J Med Genet 1989; 34: 96-99.

5. Erik PA Jr., Hague M. Congenital generalizedbone dysplasias: A clinical, radiological andepidemiological survey. J Med Genet 1989; 27:37-39.

6. Appan S, Laurent S. Chapman M. Growth andgrowth hormone therapy in hypochondroplasia.Acta Pediatr Scand 1990;79:796-798.

NEWS AND NOTES

PALS Course, Andhra Pradesh

June 28-29, 2008ContactDr.K.SeshagiriSecretary, IAP,R.K.Children’s Hospital,Krishna Nagar,Visakhapatnam-530 002,Andhra Pradesh, India.Te: 0891-2706888-92Mobile: 9885277895, 9247565894E-mail: [email protected]


URTICARIA IN CHILDREN ANDTHE ROLE OF ANTIHISTAMINESIN PRURITUS

* Jayakar Thomas

Abstract : About 20% of the pediatric populationexperience episodes of urticaria at least once intheir lifetime. Type I hypersensitivity reactionsmay be involved in acute conventional andcontact urticaria, but uncommonly in chronicurticaria. The diagnosis of urticaria can oftenbe made only from the history. Patients may notpresent with skin lesions. Drug intake andprsence of an infective focus have to be assesed.Nearly 50% of chronic idiopathic urticaria isassociated with histamine-releasingautoantibodies. Episodes of urticaria lasting formore than 24 hours need to be evaluated forvasculitis and systemic disease. Antihistaminesae the mainstay of treatment. Caution is to betaken while combining antihistamines with drugslike erythromycin and ketoconazole, for risk ofcardiac arrhythmia (torsade de pointes).

Key words : Urticaria, Children, Antihistamines,Prutitus.

The coining of the term urticaria is attributedto Johann Peter Frank of Vienna, and in theEnglish literature, to William Cullen of Scotland.Angio-oedema was recognized by Donato in thesixteenth century but named so by Strubing onlyin the 1880s. Robert Willan first described theassociation of urticaria with factors such as

certain foods. Urticaria, commonly known as‘nettle rash’ or ‘hives’, presents with short-lived,itchy weals that may be pale or pink in the centre,surrounded by a red flare. Deeper swellings ofthe skin or submucosa are termed ‘ angio-oedema’. They are usually seen in the mouth,over the eyelids or genitalia, but may occuranywhere on the skin.

Etiopathogenesis

Urticaria is caused by transient leakage ofplasma through small blood vessels, usually as aresult of release of histamine from skin mast cells.Histamine also causes itching by stimulatingnerve receptors, and contributes to the axon reflexflare. Other mediators causing vasopermeabilityinclude kinins in hereditary angio-oedema, andleukotrienes in pseudoallergic reactions causedby aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs).

Immunologic and non-immunologiccauses are recognized, but some casesremain idiopathic even after full evaluation.

Allergic urticaria is caused by type Ihypersensitivity reactions. Mast celldegranulation is triggered by the binding ofmultivalent allergen to specific IgE on high-affinity IgE (FceRI) membrane receptors.Localized reactions at the site of contact withthe allergen cause contact urticaria. Generalizedurticarial reaction can also occur. Anaphylaxisis a severe systemic reaction caused by type Ihypersensitivity reaction. It involvesbronchospasm, a fall in blood pressure or bothand is usually associated with widespreadurticaria and itching.

* Senior Consultant Dermatologist,Kanchi Kamakoti CHILDS Trust Hospital,Chennai, INDIA

DERMATOLOGY

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Idiopathic urticaria comprises up to 70% of caseswith chronic duration. Histamine-releasingautoantibodies are present in the blood duringdisease activity. IgG antibodies are directedagainst FceRI on mast cells or IgE bound to it.There is increasing evidence that a good numberof this subgroup of idiopathic urticaria patientshave an autoimmune disease.Non-immunological urticaria can be as severe asimmunologic disease. Anaphylactoid reactionsto radiocontrast may be caused by direct releaseof mast cell contents without involvement of IgE.Pseudoallergic reactions to aspirin and NSAIDsmay occur up to 20 hours after taking the drug,and are thought to involve the release of newlysynthesized sulphidopeptide leukotrienes inaddition to histamine. Inhibition of kininbreakdown by angiotensin-converting enzymeinhibitors probably explains the rare occurrenceof angio-oedema with this class of drugs.Types of urticaria

Urticaria can be classified into five maingroups on the basis of the history, appropriatechallenge tests and simple laboratoryinvestigations. However, it must be rememberedthat these groups are not mutually exclusive andfair amount of overlap exists. The duration ofindividual weals can be helpful in the history.Weals lasting less than 1 hour usually have aphysical cause (the exception is delayed pressureurticaria, which characteristically developsseveral hours after exposure and lasts up to24 hours). Contact urticaria usually resolveswithin 2 hours, conventional urticaria within24 hours and urticarial vasculitis within 3 days.Angio-oedema may be present for days, butsevere contact dermatitis should be suspected ifthe swelling lasts for several days and resolveswith scaling.Conventional urticaria

Recurrent urticaria is termed ‘conventional’or ‘ordinary’ if there is no predominantly physical

cause or underlying small vessel vasculitis. It isthe most common pattern. Attacks may occurdaily or less frequently. It is considered acute ifsymptoms last for less than 6 weeks and chronicif for a longer period. Attacks of shorter durationmay go on for long periods of time, the so-called‘acute on chronic urticaria’ (personalobservation). Weals are often numerous, and mayoccur on any part of the skin, including the scalp,palms and soles, where they may be painful ratherthan itchy. They generally last 2 to 24 hours, varyin size from less than 1 cm to many centimetresacross, and may coalesce. Nonspecific symptoms(e.g. lassitude, indigestion) may accompanysevere attacks, but wheezing is not a feature.Onset is often abrupt and unexpected, butoccasionally there is a history of streptococcalinfection, immunization, consuming an unusualfood (e.g. fish, eggs, and nuts) or drug therapy(e.g. aspirin, penicillin). Acute conventionalurticaria caused by food or drug is often apparentfrom the history because it occurs within 2 hoursof ingestion, but most cases remain unexplained(idiopathic).

Blood tests are almost always normal. Testsfor specific IgE (fluoroimmunoassay, oftenmisnamed ‘RAST’ because radioallergosorbenttests were used in the past) may be useful forconfirming the cause of allergy. In specialistcentres, skin testing with autologous serum is auseful in vivo test for histamine-releasingautoantibodies, for which there is nocommercially available test. Intradermal skintesting with different antigens proves to be a futileexercise in most cases.

Physical urticaria

Physical urticarias are defined by thetriggering stimulus. Immediate dermographismcan be elicited by stroking the skin firmly with ablunt instrument, cholinergic urticaria by physicalexercise to the point of sweating (sweat glands

85


have cholinergic sympathetic innervations), andcold urticaria by contact with ice or generalizedchilling. Cutaneous mast cells degranulate inresponse to these stimuli; the mechanism is notclear. More than one stimulus may be necessaryto elicit urticaria (e.g. cholinergicdermographism). Simple physical challenge testsare useful to confirm the diagnosis.

Contact urticariaContact urticaria is not uncommon, but is

seldom a reason for referral to the specialist.Immunologic contact urticaria involves bindingof percutaneous allergen to specific IgE inpreviously sensitized individuals. Localizedwealing occurs within 10 minutes. Atopicpatients are particularly susceptible.Nonimmunologic contact urticaria from directmast cell degranulation or eicasanoid release isprobably more common; the mechanism isunclear and difficult to define. Preservatives andfragrances in cosmetics may cause stinging,itching and burning. Food preservatives(e.g. benzoic acid, sorbic acid) and flavourings(e.g. cinnamic aldehyde) may cause contacturticaria around the mouth.Urticarial vasculitis

Urticarial vasculitis is an uncommonsystemic disorder occurring in patients withunderlying small-vessel vasculitis caused byimmune complex deposition. The skin lesionsmay be indistinguishable from other forms ofurticaria, or may resemble erythema multiforme.They last 2 to 3 days and resolve with a typicalviolaceous hue. They may burn rather than itch.Patients feel unwell with fever and joint pains,and associated renal, pulmonary or neurologicaldisease must be excluded. The defining featureis venulitis as seen in skin biopsy; erythrocytesedimentation rate is raised, and some individualsshow hypocomplementaemia; this could be a signof poor prognosis and is associated with renaldisease.

Angio-oedema

Angio-oedema can occur in conventional,physical and vasculitic urticaria, but may alsooccur without weals. These cases need to bespecially considered to rule out hereditary andacquired C1 esterase inhibitor deficiency.Measurement of C4 is a useful screening test. Itis reduced in both type I hereditary disease(reduced absolute levels of C1 inhibitor) and theless common type II hereditary disease (normalquantitative C1 inhibitor on immunochemicalassay but reduced function).

Management

The first step in the management involvesthe identification and removal of any specificcausative factor. The next step is use ofantihistamines. Over-the-counter products suchas chlorpheniramine and diphenhydramine areusually adequate. Prescription products such ashydroxyzine and loratadine may be consideredwhen over-the-counter drugs fail. One shouldinitiate therapy with a dose that is within theupper recommended level. This dose can begradually increased until either improvementoccurs or side effects become troublesome. Anamount twice the recommended dose shouldnever be exceeded.

General measures

Detailed history-taking, careful explanation,written information and cooling lotions(e.g. Calamine lotion) can help patients cope withtheir disease, particularly when drug treatmentis disappointing. Identifying the causes ofphysical or contact urticarias may help patientsavoid them. Drugs that may aggravate theurticaria nonspecifically (e.g. aspirin) should beavoided. Stress, alcohol and overheating shouldbe minimized. Exclusion diets (e.g. foodcolourings, preservatives, natural salicylates)

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may be useful when indicated by the history, butare difficult to follow and are usually reserveduntil after first-line drug therapies have beentried.

First-line treatment

Antihistamines are the treatment of choicein all urticarias except C1 esterase inhibitordeficiency. Most patients prefer a low dose andnon-sedating antihistamine by day (e.g. levo-cetrizine, 5 mg/day). Addition of a sedatingantihistamine (e.g. hydroxyzine, 10 mg/day) inthe night can help the patient sleep and relievethe pruritus. Caution is required while combiningcertain antihistamines with drugs likeerythromycin and ketoconazole, for risk ofcardiac arrhythmias (torsade de pointes). Thetricyclic antidepressant doxepin, 10 mg thricedaily or as a single dose of 30 mg at night, haspotent H1 and H2 antagonistic properties and ispreferred for some patients. Alternatively, anH2 antagonist (e.g. ranitidine, 150 mg twice daily)or a mast cell stabilizer (e.g. nifedipine, 5 mg)can be added, but the results may bedisappointing. H2 antagonists should never beused alone in urticaria, as there may beoverreaction of H1 receptors resulting inworsening of lesions.

Second-line treatment

Prednisolone, usually 0.5 mg/Kg bodyweight initially followed by a tapering dosageschedule over a period of 1 to 2 weeks may benecessary in severe acute urticaria or angio-oedema. Prolonged treatment of chronic urticariawith oral corticosteroids should be avoidedexcept in disabling delayed-pressure urticaria andurticarial vasculitis, which are usuallyunresponsive to antihistamines. Subcutaneousadministration of 0.5 to 1.0 ml of 1:1000adrenaline is useful in severe angio-oedema ofthe mouth, and can be life-saving in anaphylaxis.

Third-line treatment

Studies on immunosuppressive therapies indisabling chronic autoimmune urticaria, usingplasmapheresis or intravenous immunoglobulins,have been encouraging. The efficacy ofcyclosporin A in such cases has recently beenconfirmed.

Hereditary angio-oedema

Hereditary angio-oedema can often beprevented by low-dose anabolic steroids(e.g. stanozolol, 2.5 to 5 mg/day), which increasefunctional inhibitor levels. Virilizing effects area disadvantage in women. Tranexamic acid, anantifibrinolytic agent is used for acute episodes,but is contraindicated in thromboembolic disease.Antihistamines are of no use.

Antihistamines and pruritus

No aspect of pruritus has evoked moredebate than the use of antihistamines to relieveitching. To many non-dermatologists thepresence of a patient with a dermatologicaldisorder evokes a reflex desire to prescribeantihistamines.

The anaesthetic effect of topicalantihistamines may be used to benefit the patientwith pruritus. Topical antihistamines carry asignificant risk of sensitization and hence mustbe used with caution. For the short term (up to7 days) management of pruritus, 5% doxepinehydrochloride cream is effective. However, itssystemic absorption causes sedation. Visiblediscontinuity on the skin is a definitecontraindication.

Systemic therapy with antihistamines is usedas a panacea for all itchy dermatoses. Wherehistamine plays the major role in causing itching,as in urticaria, antihistamines are absolutelyindicated. But in the vast majority of itchydisorders where histamine is not the mediator,

87


antihistamines at best work by virtue of theirsedative action. In such cases, the newernonsedating antihistamines are never effective.

Points to Remember• About 20% of the pediatric population

experience episodes of urticaria at leastonce in their lifetime.

• The diagnosis of urticaria can often bemade only from the history. Patients maynot present with skin lesions.

• Drug intake or an infective focus may beassociated.

• Episodes of urticaria lasting for more than24 hours need to be evaluated for vasculitisand systemic disease.

• Antihistamines are the mainstay oftreatment in urticaria.

Bibliography

1. Rook AJ. The historical background. In. WarinRP, Champion RH, eds. Urticaria. London:Saunders, 1974: 1-2.

2. Czarnetzki BM. The history of urticaria. Int JDermatol 1989; 28: 52-57.

3. Peters MS, Winkelmann RK. Neutrophilicurticaria. Br J Dermatol 1985; 113: 25-30.

4. Winkelmann RK, Wilson-Jones E, Smith NP etal. Neutrophilic urticaria. Acta Derm Venereol1988; 68: 129-133.

5. Beaven MA. Histamine. New Engl J Med 1976;294: 320-325.

6. Asad SI, Kemenn DM, Youlten LJF et al .Effectof aspirin in “aspirin sensitive” patients. Br MedJ 1984; 288: 145-146.

7. Quaranta J, Rohr AS, Rachelefsky GS et al. Theetiology and natural history of chronic urticariaand angioedema. J Allergy Clin Immunol 1987;79: 182-187.

8. Ferrer M, Kinet J-P, Kaplan AP. Comparativestudies of functional and binding assays for IgGAnti-FceR1a in Chronic Urticaria. J AllergyClin Immunol 1998; 101: 672-676.

9. Parish WE. Clinical Immunology and Allergy.In. Champion Rh, Burton JL, Ebling FJG, eds.Textbook of Dermatology.London, BlackwellScientific Publications, 1992, 253-304.

10. Sabroe RA, Grattan CEH, Francis DM et al.The Autologous Serum Skin Test: A ScreeningSkin Test for Autoantibodies in ChronicIdiopathic Urticaria. Br J Dermatol 1999; 140:446-452.

11. Brunet C, Bedard PM, Hebert J. Analysis ofcompound 48/80- induced skin histaminerelease and leukotriene production in chronicurticaria. J Allergy Clin Immunol 1988; 82: 398-402.

12. Wood SM, Mann RD, Rawlins MM. Angio-oedema and urticaria associated withangiotensin-converting enzyme inhibitors. BrMed J 1987; 294; 91-93.

13. Beall GN. Urticaria: a review of laboratory andclinical observations. Medicine 1964; 43: 131-151.

14. Illig L. Physical urticaria, its diagnosis andtreatment. Curr Probl Dermatol 1973; 5: 79-116.

15. Krogh G von, Maibach HI. The contact urticariasyndrome – an updated review. J Am AcadDermatol 1981; 5: 328-342.

16. Lahti A. Non-immunologic contact urticaria.Acta Derm Venereol 1980; 60 Suppl. 91): 1-49.

17. Sanchez NP, Winkelmann RK, Schroeter ARet al. The clinical and histopathologic spectrumsof urticarial vasculitis: study of forty cases. JAm Acad Dermatol 1982; 7: 599-605.

18. Kobza Black A, Lawlor F, Greaves MW.Consensus Meeting on Definition of PhysicalUrticarias and Urticarial vasculitis. Clin ExpDermatol 1996; 21: 424-426.

19. Donaldson VH, Evans RR. A biochemicalabnormality in hereditary angioedema.Am JMed 1963; 35: 37-44.

20. Kobza Black A. The Urticarias. In. GreavesMW, Shuster S, eds. The Pharmacology of theSkin. Berlin: Springer-Verlag, 1989: chapter 31.

21. Pollock I, Young E, Stoneham M et al. Surveyof colourings and preservatives in drugs. BrMed J 1989; 299: 649-651.

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22. Greaves MW. Antihistamine treatment: a patientself-assessment method in chronic urticaria. BrMed J 1981; 283: 1435-1436.

23. Faber TS, Zehender M, Just H. Drug-inducedtorsades de pointes. Incidence, management andprevention. Drugs 1994; 11: 463-476.

24. Lader M, Petursson H. Rational use ofanxiolytic/sedative drugs. Drugs Saf 1983; 25:514-528.

25. Monroe EW, Cohen SH, Kalbfleisch J SchulzCI. Combined H1 and H2 antihistamine therapyin chronic urticaria. Arch Dermatol 1981; 117:404-405.

26. Fairley JA, Pentland AP, Voorhees JJ. UrticariaPigmentosa responsive to nifedipine. J AmAcad Dermatol 1984; 11: 740-741.

27. Weston WL, Hogan PA. Vascular Reactions. In.Schachner LA, Hansen RC, eds. PediatricDermatology. New York: Churchill Livingstone,1996: 915-952. chapter20.

28. Grattan CEH, O’Donnell BF, Francis DM et al.Randomized double-blind study of CyclosporinA in chronic idiopathic urticaria. Br J Dermatol2000; 148: 365-372.

29. Gelfand JA, Sherins RJ, Alling VW et al.Treatment of hereditary angioedema withdanazol. New Engl J Med 1976; 295: 1444-1447.

30. Donaldson VH. The challenge of hereditaryangioneurotic edema. New Engl J Med 1983;308: 1094-1095.

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BOOK REVIEW

Title : Essentials of Pediatric Pulmonology (3rd edition)

Authors : Dr. L.Subramanyam, Dr. So. Shivbalan, Dr. N.C.Gowrishankar,Dr. D.Vijayasekaran, Dr. A.Balachandran

Foreword : Dr. (Capt) N. Somu

Publisher : Pediatric Pulmonology Foundation of India (PPFI), Chennai - 600 031.

Review : The third edition of this book “Essentials of Pediatric Pulmonology” which hascome after a span of twelve long years after the second edtion is worth the wait. Allthe sections in this book have been rewritten. New sections have been added in tunewith the emerging fields in pediatrics like intensive care. The book covers almostthe entire aspects in the field of pediatric pulmonology starting from the basics,applied anatomy and physiology to the most advanced ventilator therapy includingloops and curves. The flow of language is simple and easy to understand. Oneinteresting aspect is the addition of lot of figures for easy understanding. Anothersalient aspect is the seperate chapters on newborn respiratory problems, radiologyin newborn and sleep disorders. The radiology and bronschoscopy pictures havebeen printed clearly. After going through the book, it promises to provide completesatisfaction for not only those pediatrictans in medical colleges and in practice, butalso for all the pediatric postgraduates.

Price : Rs. 500/-


SEIZURES AND EPILEPSY -ROLE OF RADIOLOGICALINVESTIGATIONS

* Vijayalakshmi G** Elavarasu E

** Vijayalakshmi M*** Venkatesan MD

The use of radiological investigations forthe evaluation of seizures continues to becontroversial. No decision based on studies canreplace clinical judgement that depends on eachpatient and each clinical setting. No algorithmcan be total and exclusive. However it is usefulto remember that radiation due to a CT scan ofthe head is equivalent to 200 chest x-rays andchildren are more sensitive to the harmful effectsof radiation. The estimated lifetime risk of deathfrom radiation – induced malignancy caused bya single CT scan of the head at one year of age is0.07 percent.1 Caution is therefore necessarywhen you request for a CT scan. In view of this,CT with low dose raidation can be asked for anddone. One point that everyone agrees on is thatCT or MRI is not essential for the simple febrileseizure or even complex febrile seizures.Neuroimaging should however be consideredwhen there is a postictal focal neurological defector in children who take long time to return tonormal neurological function. The CT brain

(Fig.1) of a child who presented with seizuresfollowed by hemiplegia, showed hypodensity inthe right basal ganglia with white spots ofhemorrhage. This is a hemorrhagic infarct.

Adults with an unprovoked seizuredefinitely need neuroimaging, but in childrenuncomplicated seizures and epilepsy are commonwhere neuroimaging will be normal. Certainspecific childhood epilepsy syndromes likebenign rolandic epilepsy, absence seizures andjuvenile myoclonic epilepsy do not require CTor MRI but have specific diagnostic EEGpatterns.

In a study conducted in Institute of ChildHealth and Hospital for Childrne, Chennai, of111 children with all types of seizures 53(ie. 47% ) had an abnormality on CT. These 111children (70 children had simple partial seizures)were not randomly chosen but referred bypediatricians on a suspicion of underlyingabnormality. 37% had ring enhancing lesions,13% had a chronic infarct and 11% had cerebralatrophy. Another 11% had hydrocephalus. Otherconditions found were phakomatosis, neoplasmand intrauterine infection.

Mesial temporal sclerosis (MTS) orhippocampal sclerosis is a rare condition whichmanifests in late childhood or adolescence. It isinteresting because it is a cause of temporal lobeepilepsy for which surgery offers a cure in almostninety percent of patients. It is imperative toidentify MTS as surgery has a high rate ofeliminating seizures and is associated with a lowincidence of new neurological impairments.Imaging techniques for diagnosing MTS include

RADIOLOGIST TALKS TO YOU

* Associate Professor** Asst. Professor

*** ProfessorDepartment of Radiology,Chenglepet Medical College Hospital,Chenglepet, Tamilnadu.

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Fig.3. Focal atrophy - right parietalarea as evidenced by the adjacentwider subdural space. This patienthad a history of head injury.

Fig.4.Chronic infarct in left MCAterritory in a 1 year old. The infarctarea has liquefied and is of samedensity as CSF in the passivelydilated left lateral ventricle.

Fig.2. Mesial temporal sclerosis.Note the hyperintensity in left medialtemporal area.

Fig.1. Right basal ganglia infarct

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MRI , ictal and interictal SPECT (single photonemission computerized tomography) and PET(Positron emission tomography). MRI is widelyused and is more easily available.

The MRI features of hippocampal sclerosisinclude hippocampal atrophy, increased signalon T2-weighted images or fluid-attenuatedinversion recovery (FLAIR) sequences, anddecreased signal on inversion recoverysequences. The detection of these abnormalitiesshould be carried out with optimized imagingtechniques. Technique is important to make outsubtle changes. If these primary features are notpresent the patient has a less than 50% likelihoodof becoming seizure – free after surgery. Othersecondary features are temporal lobe volume loss,temporal horn dilatation, narrow collateral whitematter, smaller fornix and an atrophic mamillary

body. These are considered secondary as mildasymmetries occur in normal people and alsobecause volume loss alone might reveal onlyhippocampal gliosis on surgery. This group ofpatients have poor postoperative seizure control.

PET also shows hypometabolism in thetemporal lobe in MTS. Another growing use ofPET is in the identification of dysfunctionalcortical regions of hypometabolism thatcorrespond to epileptic foci. Children withintractable infantile spasms classified ascryptogenic can show hypometabolic foci ofcortical dysplasia in PET. If the area is single,surgical removal of the epileptic focus can offergood seizure control. PET as an imaging modalityis limited due to its use of tracers with a veryshort half-life that requires a cyclotron in closeproximity. PET and SPECT are indicated whensurgery is contemplated.

Seizures can also be due to developmentalabnormalities like schizencephaly andhemihypertrophy. Hemorrhage should beconsidered when there is a history of trauma,increased blood pressure or bleeding disorders.CT is a useful modality to rule out neoplasms.In children with seizures CT is the primarymodality while in young infants ultrasound is agood screening investigation. MRI is forintractable seizures with normal CT examination.

Reference

1. Brenner DJ, Eliston, Hall, Burden. Estimatedrisks of radiation induced fatal cancer frompediatric CT. Am J Roentgenol 2001;176:289-296.

Fig.5. Large porencephalic cyst – rightparietal region. Patient had a historyof injury.

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2008; 10(2) : 183

McCUNE ALBRIGHT SYNDROME

* Chitra Ayyappan** Arun Prasath TS

* Meikandan D*** Vasanthakumari ML

Abstract : Precocious puberty, presenting aspremature thelarche or menarche in girls, asearly as 2-3 years in association with polyostoticfibrous dysplasia, cafe-au-lait spots and otherendocrinopathies should suggest the possibilityof McCune Albright Syndrome (MAS). Theprecocious puberty associated with MAStypically is gonadotrophin independent.Fractures, malignancies and endocrine disordersare the modalities associated with this syndrome.

Key words : Precocious puberty, Polyostoticfibrous dysplasia, McCune Albright syndrome,Endocrinopathies.

Donavan McCune first described the classictriad and hyperthyroidism. MAS has been shownto be due to post zygotic mutation of the GS alphagene in the affected tissues. Females have agreater risk of breast cancer probably due to theirprolonged exposure to elevated estrogen levels.

Case Report

A 5 year old girl presented with bleedingper vaginum since six months of age, breast

enlargement and facial asymmetry since 1 year(Fig.1). On examination, she was tall for her age.Height 125cms (> 97th percentile) and sheweighed 23kg. Intelligence and dental agewere normal for chronological age. She hadfacial asymmetry with right pseudo proptosis,multiple (7) cafe-au-lait spots over chest andabdomen. She had an SMR of 4 on Tannerstaging. She also had a small goiter.

GnRH stimulation test showed low FSH of2.09 mIU/ml (normal 11.8-18.6mIU/ml) and LHwas 0.29l mIU/ml (normal 10.7-15.6mIU/ml).Estradiol 16.09 mIU/ml (normal 11.8-18.6mIU/ml) corresponding to Tanner staging II.Serum cortisol level 18µ/dL (7-24µg/dL) andTSH 5.6mlU/ml (0.7-6.4mlU/ml) were withinnormal limits. Serum and urinary phosphoruswere normal. Imaging studies revealed

CASE STUDY

* Addl. Professor** Postgraduate

*** Professor and Head of the Department,Institute of Child Health and Research Centre,Madurai Medical College,Madurai.

93

Fig.1. Premature thelarche


polyostotic fibrous dysplasia of skull, involvingright orbital plate and lesser wing of sphenoid(Fig.2). Bone age was between 11 and 14 yearsof age. Ultrasound abdomen showed endometrialthickness and a cyst in ovary. Ultra sound thyroidshowed cysts in the left lobe of thyroid.

A provisional diagnosis of McCune AlbrightSyndrome with GnRH independent precociouspuberty was made. Child was started onTamoxifen (40mg/1.73sq.m2). At the time of thisreport she had completed 8 weeks of tamoxifenand had no further episodes of vaginal bleeding.

Discussion

MAS is a very rare disorder, having noethnic predisposition. The disease has beenreported more frequently in girls than in boys,presumably due to the dramatic presentationcharacterized by the early onset of puberty,menarche and thelarche. In cases wherepolyostotic fibrous dysplasia is marked, multiplefractures are prominent early in the history.Symptoms begin in childhood. In some, thephenotypic features are mild and the onset ofsymptoms is considerably delayed, subtlefindings such as mild asymmetry, dysmorphismand mild unequal limb length. Existing bonelesions may slowly worsen, remain stable or newlesions may develop. Spontaneous improvementor resolution of the bony lesions does not occur.

The worsening of the bone lesions is due to thetrophic effect of estrogen on the fibrousdysplastic bone, which contain estrogen sensitivereceptors.

Goiters with hyperthyroidism, diabetesmellitus, acromegaly, Cushing syndrome,herprolactinemia, painless myxomas,hypophosphatemic rickets, alopecia have alsobeen found in association with MAS. Cafe-au-lait spots are often ipsilateral and predominanton the side with more bony lesions.

Management is often challenging andrequires a multi disciplinary approach.Orthopedic surgical care for multiple bonyfractures and deformities can be particularlyfrustrating. Endocrinopathies need to beidentified and treated. Therapy for precociouspuberty is available and should be tried, it is stilllargely experimental.

Because precocious puberty in patients withMAS is gonadotrophin-independent, continuousGnRH therapy has little utility. For femalepatients, the central theme is to block estrogeneffects. Testolactone, a competitive aromataseinhibitor, is used for this purpose. Preliminarydata from the testolactone therapeutic trialssuggest that this medication causes reduction inestradiol and estrone levels, with reducedfrequency of menses and reduction in growth andbone maturation. Other preliminary trials of otheraromatase inhibitors, such as fadrozole andanastrazole, are underway with the goal ofachieving better management of precociouspuberty. Estrogen receptor antagonists, such astamoxifen, have a therapeutic role. GnRHanalogues may be added to testolactone as anadjunct for treatment of precocious puberty tosuppress pituitary gonadotrophin production.Depot leuprolide acetate at a dose of 7.5mg (300-500mcg/kg) every 28 days is a typical regimen,the dose of which can be adjusted upwards ordownwards based on clinical and laboratory

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Fig.2. CT skull showing thickeningof orbital plate and lessor wing ofsphenoid.

2008; 10(2) : 185

findings. Other alternative treatment optionsinclude medroxyprogesterone acetate, which isparticularly useful for controlling menstrualbleeding. The preferred agent is Depo-Proverain intramuscular doses of 4-15mg/kg monthly.Adequate medical therapy for precocious pubertyin males consists of both antiandrogen andantiestrogen preparations. This typically consistsof a combination of spironolactone andtestolactone. Alternative antiandrogens, such asketoconazole, also may be used in.

Some preliminary data suggest thatbiphosphonates, pamidronate and alendronatemay have beneficial effects on the bone disease.

Other identified co morbidities require tobe treated. Oral phosphorus, Vit D, calciumreplacement for hypophosphotemic rickets,bilateral adrenalectomy for Cushing,thyroidectomy (partial/total) for thyrotoxicosisare indicated. Ovariectomy or ovarian cystectomymay be used as the last resort for control ofprecocious puberty when medicl therapy fails.Bibliography

1. Weinstein LS. The stimulatory G protein alphasub unit gene mutations and imprinting leads tocomplex phenotypes, J Clin Endocrinol andMetab 2001;86:4622-2626.

2. Farel Z, Bourne HR, Taroh J. The expandingpsectrum of G protein diseases, New England JMed 199;340:1012-1020.

3. Walker JM, Hughes IA. Gonadotropin releasinghormone test. In: Clinical pediatricendocrinology, 3

rd Edn, Black well science,

Victoria, Australia 1995; p787.

4. Luigi, Garibaldi. Precocious pubertywithpolyostotic fibrous dysplasia and abnormalpigmentation. In: Nelson text book of Pediatrics,17

th Edn, Behrman, Klegman, Arvin (Eds), WB

Saunders, philadelphia, 2004;pp1867-1868.

5. Melvin M. Grumbuch, Styne DM. McCuneAlbright Syndrome clinical manifestations. In:Williams text book of endocrinology, 10

th Edn,

Saunders Elsievier sciences, philadelphia,2003;pp1225-1227.

6. Gareden AS, Colin smith. McCune Albrightsyndrome investigations and treatment.Pediatric and adolescent gynecology OxfordUniversity Press, New York, 1998;pp287-288.

7. Boston BA, Mandel S, LaFranchi S. Activatingmutation in the stimulatory guanine nucleotidebinding protein in an infant with Cushing’ssyndrome and nodular adrenal hyperplasia.J Clin Endocrinol Metab 1994;79:890-893.

8. Bruce A. Boston McCune Albright syndromehttp://www.emedicine.com/ped/topic1386.htm

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