leukocyte disorders: quantitative and qualitative

DOI: 10.1542/pir.17-1-191996;17;19Pediatrics in Review

Laurence A. Boxer and R. Alexander BlackwoodLeukocyte Disorders: Quantitative and Qualitative Disorders of the Neutrophil, Part 1

http://pedsinreview.aappublications.org/content/17/1/19the World Wide Web at:

The online version of this article, along with updated information and services, is located on

Print ISSN: 0191-9601. Village, Illinois, 60007. Copyright © 1996 by the American Academy of Pediatrics. All rights reserved.trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove

andpublication, it has been published continuously since 1979. Pediatrics in Review is owned, published, Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

at Health Sciences Library State Univ Of New York on January 27, 2012http://pedsinreview.aappublications.org/Downloaded from

http://http://pedsinreview.aappublications.org/content/17/1/19

http://pedsinreview.aappublications.org/

iMPORTANT POINTS

1. The definition of neutropenia varies with age. The normal Caucasianchild more than 6 years of age has at least 1500 neutrophils/mm3.

2. Children who have severe neutropenia may become infected with theirown skin and bowel flora.

3. Mucosal ulceration and gingivitis are common signs of severe chronicneutropenia.

4. Severe chronic neutropenia consists of the subcategories of severe con-

genital neutropenias, cyclic neutropenia, and idiopathic neutropenia.

5. Severe chronic neutropenias respond to therapy with rhG-CSF.6. Viral infections may cause transient neutropenia but do not require spe-

cific treatment.

ABBREVIATIONS

CBC: complete blood countANC: absolute neutrophil countWBC: white blood cell countrhG-CSF: recombinant human granu-

locyte-colony stimulatingfactor

hyper-lgE: hyper immunoglobulin E

syndrome

LAD: leukocyte adhesiondeficiency

CGD: chronic granulomatous

disease

gp9 I : glycoprotein 91 kD

p47: 47 kDa protein

p67: 67 kDa protein

MPO: myeloperoxidase

CD: cluster designation02 : superoxideAD: autosomal dominant

AR: autosomal recessive

phox: phagocyte oxidaseNADPH: nicotinamide adenine

dinucleotide phosphateICAM: intracellular adhesion

molecule

Pediatrics in Review Vol. 1 7 No. 1 January 1996 19

ARTICLE

Leukocyte Disorders: Quantitative and QualitativeDisorders of the Neutrophil, Part 1*Laurence A. Boxer, MD* and R. Alexander Blackwood, MD, PhDt

Introduction

Neutrophils form the first line of de-

fense against most bacterial and fun-gal pathogens after disruption of theskin and mucous membranes. Once

tissue is invaded by microorganisms,

a variety of vasoactive and chemotac-

tic mediators are released by the in-volved tissue. In response to these

chemotactic peptides. neutrophils,normally found in the circulation,

adhere to the inflamed endotheliuniand migrate to the site of infectionwhere the phagocytes ingest and killthe invading microorganisms. Neutro-phils also release a variety of cyto-kines that may modify the neutro-

phils’ own responses as well asinteract with other elements of the

immune system. Neutrophils, there-fore, are both important effectors andregulators of the host defense system.Because of the complexity of thisdefense system and the major roleplayed by neutrophils, both primary

*J�,.�jfessor and Director, Pediatric Hematology!

Oncology, University of Michigan, AnnArbor, MI. Dr Boxer participated in Amgen

Corporation ‘s phase 111 trial evaluating the

efficacy of rhG-CSF in the treatment ofpatients who have severe congenital neutro-penia. He also participated in Genentech ‘strial evaluating the efficacy of gamma-interferon in the treatment of patients whohave chronic granulomatous disease.tAssistant Professor of Pediatrics and

Communicable Diseases, Division of Pediatricinfectious Diseases, University of Michigan,Ann Arbor, Mi.

5Part 2 of this article will appear in theFebruary 1996 issue.

and acquired defects in neutrophilnumber or function result in peisis-tent as well as recurrent infections.

Primary defects in neutrophil nuni-

ber or function are relatively rare. butthey must be considered in a childwho presents with recurrent infec-

tions. Early identification and man-agement of affected children lead to

decreased morbidity and mortality.Although care predominantly has

been supportive in the past throughthe use of prophylactic and therapeu-tic antibiotics, specific therapies now

are becoming available to reduce the

frequency of infections in somediseases.

Quantitative Disorders ofNeutrophils

Absolute neutrophil counts (ANCs)vary widely in healthy individuals.The relative proportion of neutrophilsand lymphocytes in the blood varieswith age. Neutrophils predominate atbirth but decrease rapidly in the first

few days of life. During infancy. they

constitute 20% to 30% of the circu-lating leukocyte population. Approxi-

mately equal numbers of neutrophils

and lymphocytes are found in the

peripheral circulation by the time the

child is about 5 years of age, and the

characteristic 70% predominance of

neutrophils that occurs in adulthoodusually is attained at puberty. Inhealthy children, therefore, 20% to70% of the total circulating white

blood cells may be neutrophils.

Neutropenia is defined as a de-

crease in the absolute number of cir-culating segmented neutrophils and

bands in the blood. This condition

can be identified by obtaining a CBCand differential count. The ANC is

calculated by multiplying the totalWBC by the percentage of seg-mented and band forms. The ANC

for the general population normallyranges between I 500 and 8000 cells/

mm3 for caucasian children more than6 years of age. As much as 30% ofthe African-American population has

functionally normal ANC levels thatmay be as low as 1000 cells/mm3.Individual patients may be character-

ized as having mild neutropenia withan ANC of 1000 to 1500/mm3, mod-erate neutropenia with an ANC of

500 to 1000/mm3, and severe neutro-penia with an ANC of less than 500/mm3. This classification is useful forpredicting the risk associated with

pyogenic infections to counsel fami-

lies better, because generally only

patients who have severe neutropeniaare likely to develop a life-threaten-

ing illness.Patients who have neutropenia are

infected most frequently with endog-enous flora, but colonization with



HEMATOLOGYLeukopenla � . . �

various nosocomial organisms often pathogens isolated from patients who impaired neutrophil production.

is observed. Susceptibility to bacterial have neutropenia are Staphylococcus Within this framework, neutropenias

infections, even in the presence of aureus and gram-negative organisms. may be characterized further in termssevere neutropenia, varies. Some pa- The usual signs and symptoms of of onset of clinical symptoms and

tients who have chronic neutropenia local infections and inflammation, signs that occur acutely or chroni-

with an ANC less than 200 cells/mm3 such as exudate, abscess formation, cally. In all cases, the medical signif-

do not experience serious infections. and regional lymphadenopathy, gen- icance of the condition depends onThis is probably because the other erally are less evident in patients who the potential risk for the development

parts of their immune system remain have neutropenia than in those who of life-threatening infections. Neutro-

intact. In contrast, patients receiving do not, because there is a paucity of penias associated with etiologies ex-immunosuppressive drugs, particu- neutrophils to mediate the inflamma- trinsic to the bone marrow myeloid

larly in conjunction with malignan- tory response. Other signs and symp- cells occur more frequently than the

cies, who develop neutropenia are toms (eg, erythema, pain, tenderness, intrinsic disorders.

more likely to develop serious bacte- and warmth in conjunction with fe-

rial infections than are those whose ver) generally are present.

neutropenia is isolated, because their The neutropenias may be classified Neutropenias Associatedentire cellular immune system is pathophysiologically as intrinsic dis- With Etiologies Extrinsiccompromised. The types of pyogenic orders (Table I ) arising from im- to theBone Marrowinfections occurring most frequently paired neutrophil production (ie, iso- Myeloid Cellsin patients who have profound neu- lated disorders of proliferation and

tropenia are cutaneous cellulitis and maturation of myeloid cells or occur- INFECTIONabscesses or furunculosis, pneumonia, ring with phenotypic abnormalities). A large number of acquired condi-

and septicemia. Stomatitis, gingivitis, Neutropenia also may arise from tions may be associated with neutro-

perirectal inflammation, and otitis pathologic processes extrinsic to bone penia (Tables 2 and 3). Infectiousmedia also occur. On the other hand, marrow myeloid cells (Table 2), in- diseases are among the most commonisolated neutropenia does not increase eluding abnormal neutrophil redistri- causes of neutropenia in children.

patients’ susceptibility to parasitic, bution between the marginating and The mechanisms responsible for neu-

viral, or fungal infections or to bacte- circulating pool, shortened neutrophil tropenia are multiple and may in-

rial meningitis. The most common survival in the circulating blood. or elude direct marrow suppression:

TABLE 1. Intrinsic Disorders Associated with Neutropenia

DISORDER GENETICS ASSOCIATED FINDINGS BONE MARROW

Cyclic neutropenia AD Periodic oscillation in ANC Hypoplasia or myeloid maturation

arrest, increased number ofeosinophils

Severe congenital Sporadic Profound neutropenia, Arrest in myeloid maturation atneutropenia occurrence monocytosis, eosinophilia promyelocyte stage(Kostmann syndrome)

Chronic idiopathic ? Acquired Variable pattern, arrest inneutropenia maturation between

promyelocyte and band

Chronic benign ? Mild neutropenia Variable pattern, includingneutropenia normal-appearing marrow

Shwachman syndrome AR Pancreatic insufficiency with fatty Hypocellularity associated withreplacement and atrophy, leukemic transformation

anemia, thrombocytopenia,

metaphyseal dysostosis

Cartilage-hair hypoplasia AR Short-limb dwarfism, fine hair, Myeloid hypoplasiamoderate neutropenia, impairedcellular immunity

Dyskeratosis congenitia X Nail dystrophy, leukoplakia, Marrow hypoplasiareticulated hyperpigmentationof the skin

Abbreviations: X: sex-linked; AD: autosomal dominant; AR: autosomal recessive; ANC: absolute neutrophil count

20 Pediatrics in Review Vol. 17 No. / .Ia,,uary /996



Pediatrics in Review Vol. 17 No. I Ja,,,,ary /996 2/

: #{149}

HEMATOLOGY �:

� Leukopenl#{225}

Extrinsic to Bone Marrow Myeloid Cells

ASSOCIATED FINDINGS

rickettsial, Redistribution from circulating tomarginating pools, impaired

production, accelerated destruction

Hypersensitivity reaction (fever,lymphadenopathy, rash, hepatitis,

nephritis, pneumonitis, aplastic

anemia), antineutrophil antibodies

Variable arrest from metamyclocyte tosegmented neutrophils in bone

marrow

Anemia, thrombocytopenia

lymphoma, Anemia, thrombocytopenia, presenceof immature myeloid and erythroid

precursor in peripheral blood

cell production Bone marrow hypoplasia, anemia,thrombocytopenia

anorexiadeficiency

Megaloblastic anemia, hypersegmentedneutrophils

depletion of marrow reserves of seg-mented neutrophils and bands: redis-tribution of neutrophils from the cir-culating to marginating pools

following activation of endothelialcells by cytokines (eg, tumor necrosisfactor and interleukin- I ), which ren-ders the endothelial cells more adhe-

sive toward neutrophils followingexpression of ICAM-l and ICAM-2on the endothelial surface; and neu-

trophil aggregation and sequestration

following activation of complement.Neutrophils also may be destroyed atan increasing rate as a direct result ofinteractions with pathogens or mdi-rectly as the result of formation of

antineutrophil antibodies.

Of the infectious diseases, viralinfection is the major cause of acute

neutropenia in childhood. Virusescommonly causing neutropenia in-elude respiratory syncytial virus, van-

celIa, influenza A and B, measles,and rubella. Neutropenia often devel-ops during the first 24 to 48 hours of

illness and may persist for 3 to 8days. This usually corresponds to the

period of acute viremia and may berelated to virus-induced redistributionof neutrophils from the circulating tothe marginating pool. Certain viralinfections, such as infectious mono-

nucleosis, infectious hepatitis, andthat caused by the human immunode-ficiency virus (HIV), may cause se-vere or protracted neutropenia and

cytopenia due to infection of hemato-poietic precursor cells or generation

of immune complexes that bind toneutrophils, thereby leading to en-hanced sequestration of neutrophils inthe spleen. It is important to empha-size that the common viruses associ-

ated with childhood diseases may

cause severe neutropenia. but theneutropenia is short-lived and rarelyis associated with severe secondarybacterial infections. Therefore, theneutropenia associated with commonchildhood viruses, including infec-

tious mononucleosis, rarely requiresspecific therapy because of the short

duration of the accompanying neutro-penia.

Significant neutropenias also may

be associated with bacterial, proto-zoal, rickettsial, and severe fungalinfections (Table 3). Some chronic

i nfections causing splenomegaly,such as tuberculosis, brucellosis,

typhoid fever, and malaria, probably

cause neutropenia because of splenic

sequestration and marrow suppres-

sion. The mechanisms responsible for

neutropenia in acute bacterial infec-

tions include those described for the

viral infections. For instance, follow-ing severe gram-negative bacterialinfections, neutropenia likely arisesfrom increased neutrophil margin-ation to the endothelium as well asincreased use at sites of infection.Sepsis is a particularly serious cause

of neutropenia, especially amongyoung infants and children. Neonates

are especially prone to exhaustingtheir marrow reserve pool of seg-

mented neutrophils and bands com-pletely and succumbing rapidly to

bacterial sepsis.

DRUG-INDUCED NEUTROPENIA

Drugs can induce severe neutropenia

by idiosyncratic or hypersensitivityreaction (Table 4). This form of neu-

tropenia should be distinguished fromthat seen with viral infections and

from the severe neutropenia that nor-

mally is seen after the administration

of large doses of cytotoxic drugs or

following radiation therapy. The idio-syncratic reactions, by definition, are

unpredictable. Myeloid precursorsappear to have an abnormal sensitiv-ity to some drugs, such as the phe-nothiazines. In this form of neutrope-

nia, there is a latency period of 20 to



TABLE 3. Infections Associated with Neutropenia

Viral FungalRespiratory syncytial virus Histoplasmosis (disseminated)

Dengue feverColorado tick fever Protozoal I

Psittacosis Malaria

Mumps LeishmaniasisInfectious hepatitis

Infectious mononucleosis RickettsialInfluenza Rocky Mountain spotted feverMeasles Typhus feverRubella Rickettsial poxRoseolaVanicella

CytomegalovirusHuman immunodeficiency virus type I

BacterialTyphoid fever :Paratyphoid feverTuberculosis (disseminated)BrucellosisTularemia I

Gram-negative sepsis

22 Pediatrics in Review Vol. /7 No. 1 January 1996

HEMATOLOGYLukopnla

40 days after the patient has received10 to I 2 g of the drug before neutro-penia is observed. Hypersensitivity-mediated neutropenia is rare and oc-casionally may involve arene oxidemetabolites of aromatic anticonvul-

sants (ie, phenytoin. phenobarbital).

Hypersensitivity reactions have a de-

lay in onset following initiation ofdrug therapy and also may be associ-ated with febrile illness, rash, lymph-

adenopathy, hepatitis, nephritis, andpneumonitis. or aplastic anemia.

Immune neutropenia is thought to

arise from drugs that act as haptensand stimulate antibody formation,

causing an accelerated destruction of

the neutrophils (ie, aminopynine, pen-icillin, and propylthiouracil). Neutro-penia usually begins approximately 7

to 14 days after initial exposure to

the drug or immediately after reexpo-sure. Fever, chills. or severe prostra-

tion are common in these patients.The duration of drug-induced neutro-penia varies greatly. Acute hypersen-sitivity drug reactions may last for

only a few days, whereas chronic

idiosyncratic reactions may last formonths or years. By contrast, im-mune-mediated neutropenia usuallylasts for I week.

Once neutropenia occurs, the mostimportant therapeutic measure is

withdrawal of all drugs that are notessential, particularly drugs suspectedof being myeloid-toxic. Infections

should be treated with antibiotics.

Often the neutropenia will respond towithdrawal of the offending drug. If

the patient’s neutropenia fails to re-

spond to withdrawal of the offendingdrug and the patient subsequently

experiences signs and symptoms re-lated to severe neutropenia, treatmentwith subcutaneous administration of

5 to 10 ;.tg/kg rhG-CSF should be

considered.

IMMUNE NEUTROPENIA

Immune neutropenias are associated

with the presence of circulating anti-

neutrophil antibodies. The antibodiesmay mediate neutrophil destructionby complement-mediated lysis orsplenic phagocytosis of opsonizedneutrophils. A wide variety of neutro-phil antibody assays has been used tostudy patients in whom immune neu-

tropenia is suspected. Whether theassay is immunochemical or func-

tional, all assays measure antibody onthe patient’s own neutrophils or mdi-rectly in the serum. The assays em-

ployed most frequently include mdi-rect or direct immunofluorescence todetect surface antigens on the neutro-

phil. Antibodies of all classes can be

detected by i mmunofluorescence, us-

ing class-specific antiglobulins.

Microcapillary agglutination assays

are employed to detect antineutrophil

antibody by evaluating the ability of

the antibody to clump neutrophils.

Frequently. a combination of bothimmunofluorescence and microcapil-lary agglutination assays is needed to

assure identification of antineutrophil

antibodies. Additionally, it is impor-tant to employ a panel of neutrophils

that have different known antigen

specificities to assure identification ofsuspected antibodies.

ISOIMMUNE NEONATALNEUTROPENIA

Isoimmune neonatal neutropenia is acondition analogous to Rh hemolyticdisease of the newborn. Maternalsensitization to fetal neutrophil anti-

gens occurs during gestation. result-

ing in the production of an immuno-

globulin G antineutrophil antibodythat crosses the placenta. The neutro-

penia is severe and associated with

fever and infections from the usual

microbes that cause neonatal disease.

By 7 weeks of age, the infant’s neu-trophil count usually returns to nor-

mal, which reflects the survival ofmaternal antibody in the infant’scirculation. Treatment consists of

supportive care and appropriateantibiotics.

AUTOIMMUNE NEUTROPENIA

Autoimmune neutropenia is analo-gous to autoimmune hemolytic ane-mia or thrombocytopenia. Antibodies

causing neutropenia have been de-

tected in patients who have had noother signs of autoimmune disease; inpatients who have had additional an-

tibodies against red cells and/or

platelets; and in patients who have

had connective tissue disorders. Au-toimmune neutropenia is distinguish-able from other forms of neutropeniaonly by the demonstration of antineu-trophil antibodies rather than by bonemarrow histology.

Autoimmune neutropenia ofinfancy (AN!) is a benign conditionthat has been diagnosed more fre-

quently as reliable techniques for de-tecting antineutrophil antibodies havebecome more widely available. The



---- � � - � - � �

� TABLE 4. Drugs Associated with Neutropenia

$�

Used with permission from Young NS. Agranulocytosis. JAMA. 1994;271:935.

Pediatrics in Review Vol. 1 7 No. I January 1996 23

HEMATOLOGY

Heavy metals

Gold, arsenic compounds, mercurial diuretics

Analgesics and nonsteroidal anti-inflammatory drugsAminopynineDipyronePhenylbutazone

IbuprofenIndomethacinDiflunisal

BenoxaprofenSulindacFenoprofenTolmetinCinchophen

Antipsychotics, sedatives, antidepressantsPhenothiazinesClozapineImipraminesChlordiazepoxideAmoxapineMeprobamate

Anticonvulsants

PhenytoinsEthosuximideCarbamazepine

Antithyroid drugsThiouracilsMethimazolePotassium perchlorateThiocyanate

Cardiovascular drugsProcainamides

CaptoprilAprindinePropafenoneNifedipine

QuinidineSulfa drugs

Sulfonamides, including thiazide diuretics,

spironolactone, methazolamide, and acetazolamideOral hypoglycemicsSulfasalazineDapsoneSulfa antibiotics

Antibiotics (other than sulfa.s)PenicillinsVancomycinCephalosponins

GentamicinClindamycin

Nitrofurantoin

NovobiocinAntituberculosis agents, including isoniazid. rifampin,

streptomycin, and thiacetazone

Flucytosine

PyrimethamineMebendazoleLevamisoleAntimalanials, including quinine, chloroquine,

hydroxychloroquine, quinacrine, and dapsoneAntivirals, especially zidovudine

AntihistaminesCimetidine and ranitidineTripelennamine, thenalidine, chlorpheniramine,

brompheniramine, and methaphenileneMianserin

Miscellaneous drugs

Retinoic acidPhenindione (anticoagulant)

ColchicineAllopurinolAminoglutethimideMetoclopramide

TiclopidineTamoxifen

Penicillamine1 ,2-dimethyl-3-hydroxypyrid-40-one

Miscellaneous chemicalsDinitrophenolInsecticides, dichlorodiphenyltrichloroethane (DDT)

Mustard gasChinese herbal medicineHair dye

exact incidence of ANI is unknown,

but because of its benign nature the

disorder may be more common than

is suggested by the literature. In onestudy, ANI occurred with an annualincidence of approximately I per100 000 among children between the

ages of infancy and 10 years. All

patients recognized as having ANI

have severe neutropenia on presenta-

tion; the ANC usually is less than

500/mm3, but the total white cell

count always is within normal limits.

Monocytosis or eosinophilia may oc-

cur but does not seem to affect the

rate of infection. Anemia has been

reported either as being secondary to

coincidental iron deficiency or as aresult of recurrent infection. Themedian age of diagnosis usually is

8 months (range 3 to 30 months); thefemale-to-male ratio is 6:4. None of

the affected children has evidence ofother autoimmune diseases.

Most of the children present withminor infections such as otitis media,gingivitis, respiratory tract infections,gastroenteritis. or cellulitis. The diag-

nosis often is considered only afterthe blood count reveals neutropenia.

Occasionally, affected children maypresent with more severe infections,

including pneumonia, sepsis, or ab-



HEMATOLOGYLeukopenia

An absolute neutrophil count between 500 and 1000/mm3

represents moderate neutropenia.

24 Pediatrics in Review Vol. 17 No. / January / 996

scesses. Longitudinal studies of in-

fants who have ANI demonstrate aclinical course of the disorder. Themedian duration of disease usually isapproximately 30 months (range, 6 to

60 months), but 95% of children usu-

ally recover by 4 years of age.Generally, no treatment other than

effective personal hygiene and occa-sional antibiotics (usually oral) forminor infections is required. Childrenwho are subject to more serious re-

current infections often respond totransient administration of rhG-CSF(3 jtg/kg subcutaneously), whichshould be administered to allow re-covery of the ANC to normal values.

RETICULOENDOTHELIALSEQUESTRATION

Splenic enlargement due to portalhypertension, intrinsic splenic dis-ease, or splenic hyperplasia can leadto neutropenia. Often the neutropeniais moderate and accompanied by asimilar degree of thrombocytopeniaand anemia. The reduced neutrophil

survival corresponds to the size ofspleen, and the extent of the neutro-penia is proportional to bone marrow

compensatory mechanisms. Often theneutropenia is mild to moderate andmay be improved by successful treat-

ment of the underlying disease. In

selected cases, splenectomy may be

necessary to restore the neutrophil

count to normal, but this approach

predisposes the patient to infections

by encapsulated organisms.

REPLACEMENT OF THEBONE MARROW

A variety of acquired diseases may

lead to neutropenic disorders. The

most important among these are ma-

lignancies. including leukemia, lym-phomas, and metastatic solid tumorssuch as neuroblastoma. rhabdomyo-sarcoma, and Ewing sarcoma, whichinfiltrate the bone marrow and lead tosuppression of myelopoiesis. Neutro-penia also may accompany preleuke-mia syndromes, which typically are

characterized by peripheral cyto-penias and macrocytic red blood cell

association with impaired productionof myeloid precursors.

INEFFECTIVE MYELOPOIESIS

Ineffective myelopoiesis may be ac-quired as a result of deficiencies ofvitamin B,2 or folic acid. Megalo-

blastic pancytopenia also can resultfrom extended use of folate-inhibiting

antibiotics, such as trimethoprim-

sulfamethoxazole. Neutropenia also

occurs with starvation in such condi-

tions as anorexia nervosa, marasmusin infants, and occasionally in pa-

tients recei ving prolonged parenteralfeedings.

CYTOXIC CHEMOTHERAPY ANDRADIATION THERAPY

Much more common are the neutro-

penias accompanying the use of anti-cancer drugs and radiation therapy.Neutropenia that accompanies use ofanticancer drugs is secondary to the

effects of the accompanied cytotox-

icity of the drugs upon replicatingcells. Typically, a drop in the whiteblood cell count occurs 7 to 10

days following administration of theanticancer drugs and may persistfor 2 to 3 weeks. It is important toemphasize that the neutropenia ac-companying both malignancy andthe use of cancer chemotherapy fre-

quently is associated with attenu-ated cellular immunity, thereby pre-

disposing the patient to a muchgreater risk of infection than dothose disorders associated with iso-lated neutropenia.

Intrinsic Disorders ofProliferation and Maturationof Myeloid Stem CellsThe isolated disorders of proliferation

and maturation from myeloid stemcells include clinical diseases rarelyencountered by the general pediatri-cian. It is important to be aware of

these clinical conditions, however,because the patients who have the

rare disorders of neutropenia fre-quently can benefit from rhG-CSFtherapy.

CYCLIC NEUTROPENIA

Cyclic neutropenia is a rare congeni-

tal granulopoietic disorder. Cyclic

neutropenia is inherited in some pa-tients in an autosomal dominant fash-ion and is characterized by regular,

periodic oscillations in the number ofperipheral neutrophils from normal to

neutropenic values (Figure 1 ). The

mean oscillatory period is 2 1 ± 3days. During the neutropenic phasethe majority of patients suffer fromoral ulcers, stomatitis, or pharyngitisassociated with lymph node enlarge-ment. Serious infections occur occa-

sionally and may lead to pneumoniaor recurrent ulcerations of the oral,

vaginal, and rectal mucosa. Bone

marrow aspirations obtained during

periods of neutropenia show eitherhypoplasia or an apparent arrest of

maturation at the myelocyte stage,

with increased numbers of eosi-

nophils and monocytes. Many pa-tients live for a considerable numberof years, some actually experiencingimprovement in symptoms as theyage. The cycles tend to become lessnoticeable in older patients, and thehematologic picture begins to resem-ble that of chronic neutropenia. Ten

percent of patients die of infectious

complications, usually during theneutropenic phase. Pneumonias and

chronic periodontitis often occur, andsepsis may arise from Clostridiu,n

perfringens. A variety of studies havesuggested that cyclic neutropeniamay result from a regulatory abnor-

mality involving early hematopoieticprecursor cells. However, the exactnature of the regulatory defect is notknown.

SEVERE CONGENITALNEUTROPENIA

Severe congenital neutropenia, alsoknown as Kostmann disease, is char-acterized by an arrest in myeloidmaturation at the promyelocyte stage

of the bone marrow, resulting in anANC of less than 200 cells/mm3.This disorder occurs sporadically.Patients typically show monocytosis



#{163}a.0

3

z

SS

U0C02

S

S

S

S

a.

SS

U0

3U

S

S. II ISI lie SC ICC III ZS SiC 24C

Day

Pediatrics in Review Vol. / 7 No. / January / 996 25

HEMATOLOGYLeukopenla

FIGURE 1. Serial neutrophil, monocvte. platelet, andreticuloevie COUF1tS franz a patient �i’ho has cyclic

neutropenia before and during 10 weeks of rhG-C’SF

treatment (blood cell counts/mmi). Used wit/I permissionfrom Wright DG, Kennev RF, Oette DH, et al.

Contrasting efects of recombinant human granulocvte-

tnacrophage colony stimulating factor (GM-C’SF) and

granulocvte colony stimulating factor (G-C’SF) treattnenton the cycling of blood elements iii childhood-onset cyclic

neutropenia. Blood. 1994;84: /257-1267

and eosinophilia andsuffer from recurrent,severe pyogenic infec-tions, especially of the

skin, mouth (Figure 2),and rectum. The plate-

let count is normal,and often these pa-tients have anemia as-sociated with chronic

inflammatory disease.In the past, two thirdsof patients died from

fatal infections beforereaching adolescence.In most patients. invitro maturation ofprogenitor cells in neu-

trophils fails to occur.The addition of rhG-

CSF to marrow cul-tures from these pa-

tients, however, resultsin normal neutrophil

differentiation of my-eloid colonies. Bonemarrow matrix fromthese patients gener-

ates normal levels ofG-CSF, and their my-eloid cells express

normal G-CSF recep-tors. Taken together,these findings suggestthat the underlyingdefect in this disorderis at the level of sig-nal-transduction path-ways. Transformationto acute myelogenousleukemia or myelo-

dysplasia associatedwith monosomy 7 oncytogenetic analysisof the bone marrow

occasionally has beennoted in some pa-

tients who have se-

vere congenital neu-tropenia.

SEVERE CHRONICIDIOPATHICNEUTROPENIA

Some patients can be

classified as having

acquired idiopathicchronic symptomaticneutropenia. The onsetof neutropenia typi-cally affects children

beyond the age of 2 years and ischaracterized by neutrophil countsbelow 500 cells/mm3. Patients whoconsistently maintain an ANC below500 cells/mm3 typically are afflictedwith recurrent pyogenic infectionsinvolving the skin, mucous mem-

branes, lungs, and lymph nodes.Bone marrow examination revealsvariable patterns, with arrest gener-

ally occurring between the promye-locyte and band forms. Rarely,

some forms of chronic neutropeniaarise from an impaired release ofneutrophils from the bone marrow

into the peripheral blood. On occa-sion, some disorders of chronicsymptomatic neutropenia can be

associated with disorders of immu-noglobulin production. Thus, it isimportant to determine levels of

1gM, IgG, IgA when evaluating pa-

tients who have chronic idiopathicneutropenia. One of the featuresdistinguishing chronic idiopathicneutropenia from severe congenitalneutropenia and cyclic neutropeniarelates to the onset of mucousmembrane involvement and gingivi-tis. In the latter two disorders, theonset of clinical symptomatology

affecting the oral cavity typicallybegins in infancy.

CHRONIC BENIGN NEUTROPENIAOF CHILDHOOD

In contrast to patients who havesevere congenital neutropenia,

chronic benign neutropenia ofchildhood represents a commongroup of disorders characterized by

neutropenia in an otherwise normalindividual. The neutropenia tends tobe mild-to-moderate and is not as-sociated with an increased risk ofrepeated pyogenic infections. Spon-

taneous remissions have been re-

ported, although these may repre-

sent misdiagnosed cases ofautoimmune neutropenia of infancyin which remissions occur corn-inonly during childhood. Because oftheir relatively low risk of seriousinfections, most patients should not

be subjected to the potential toxiceffects of prolonged administrationof corticosteroids, splenectomy, orcytotoxic therapy.



FIGURE 2. The oral pathology observed

in patients who have severe chronic

neutropenia. Apthou.s ulcers (A) and

gingivitis (B) are noted frequently on

physical examination. bor patients who

have chronic gingivitis, marked

periodontal hone reabsorption (C) is a

common finding on dental radiographs.

26 Pediatrics in Review Vol. 17 No. / January /996

HEMATOLOGYL.ukopenla

Neutropenias Associatedwith PhenotypicAbnormalities

SHWACHMAN SYNDROME

Shwachman syndrome is a familialdisorder characterized by chronicmoderate neutropenia and pancreaticinsufficiency. The pancreatic insuffi-

ciency is a result of atrophy and fattyreplacement of the pancreas. The dis-order is inherited as an autosomalrecessive trait and is differentiatedfrom cystic fibrosis by normal so-

dium and chloride levels in the sweat

and by the absence of pulmonarydisease. The blood count and smearreveal decreased numbers of neutro-

phils and occasionally thrombocyto-penia and anemia. The hone marrowoften is markedly hypocellular.

Roentgenograms may reveal meta-physeal dysostosis in toddlers. The

most prominent symptoms are related

to pancreatic insufficiency, whichcauses malahsorption and growthfailure. Patients can suffer from re-current bacterial infections resultingprimarily from neutrophil counts be-low 500 cells/mm3. Aplastic anemiadevelops in approximately 25% ofpatients. Leukemic transformationoccasionally has been noted in

Shwachman syndrome.

CARTILAGE-HAIR HYPOPLASIA

Cartilage-hair hypoplasia, an autoso-

mal recessive disorder, is found par-

ticularly in the Amish population andis characterized by short-limb dwarf-ism, fine hair, moderate neutropenia

( 100 to 2000/mm3), and increasedsusceptibility to life-threatening in-fections, especially via the varicellazoster virus. Variable immunologic

alterations are found, the most impor-tant being impaired cellular immune

functions. In patients who have se-vere recurrent infections, the treat-ment of choice is allogeneic bonemarrow transplantation from HLA-identical siblings.

DYSKERATOSIS CONGENITIA

Dyskeratosis congenitia is anX-li nked recessive disorder character-ized by nail dystrophy, leukoplakia,

and reticulated hyperpigmentation ofthe skin. Many of these patients have

associated marrow hypoplasia, andabout one third have neutropenia.Most patients do not have seriousinfections and survive into adulthood.

Evaluation of Children WhoHave NeutropeniaEvaluation begins with confirmation

of neutropenia, according to stan-

dards of neutrophil counts for age.

Many clinical laboratories employcomputer image recognition tech-niques to examine peripheral smearsautomatically, which signals an oper-ator when the computer is unable to

recognize a certain cell. Evaluation ofthe peripheral smear by optical analy-sis provides statistically valid neutro-

phil and band counts. On the otherhand, if patients are found to have an

ANC below 1000/mm3, a manualdifferential count should be requestedto determine whether blasts or imma-

ture neutrophils are present in theperipheral smear. Then a thoroughhistory to establish the onset of neu-

tropenia: the type, frequency, andseverity of infections: drug or toxicexposures: and family history of re-current infections or unexplained in-fant deaths is required. The physical

examination should note growth anddevelopment: phenotypic ahnormali-

ties; and sites of bacterial infections.including mucous membranes, gingi-vae, skin, tympanic membranes, and

rectum. Lymphadenopathy, hepato-splenomegaly, and signs of an under-lying disease should he noted. Also,the presence of pallor, suggesting

anemia, and petechiae or ecchymo-ses, suggesting thrombocytopenia,should be considered so that a more

generalized disease process can he

excluded. Frequent temperature mea-surements may be necessary to docu-ment fever, hut rectal temperaturesshould be avoided in the neutropenic

patient to prevent possible injury tothe mucosa and subsequent spread of

bacteria into the circulation.The extent of laboratory evaluation

is determined by the severity andduration of the neutropenia. If the

child is determined to be neutropenicat the time or shortly following aviral infection, a CBC should he per-formed 3 to 4 weeks later so that

recovery of the ANC can be evalu-

ated. If the patient is an infant and

remains largely asymptomatic clini-

cally, but the neutropenia persists,studies should he initiated to deter-mine if the patient’s serum contains

antineutrophil antibodies. A honemarrow examination usually is notneeded in the child who has the acute

onset of neutropenia, is not experi-encing more than the normal num-hers of childhood bacterial infections,

and does not have a history of

chronic gingivitis or recurrent mouthulcers.

In contrast, children who have aclinical history consistent with infec-tions secondary to chronic neutrope-

nia (eg, gingivitis since infancy and

recurrent mouth ulcers) need to be

evaluated more extensively. CBCsshould be obtained twice weekly for

6 weeks to establish whether there isa cycle of 21 ± 3 days. which differ-entiates cyclic neutropenia from se-vere congenital neutropenia. A bone

marrow aspirate and hone marrow



Acute viral infections are the most common cause of mild

neutropenia in children. If the child is asymptomatic, a

repeat WBC without therapy is sufficient.

Pediatrics in Review Vol. / 7 No. / January 1996 27

HEMATOLOGYLukopenla

cytogenetics to evaluate the risk forleukemia or myelodysplasia also arenecessary to assess cellular morphol-ogy and the extent of myeloid cellmaturation. As indicated previously,

children who have severe congenitalneutropenia and Shwachman syn-drome have a predisposition to devel-

oping monosomy 7 associated withacute myelogenous leukemia or my-elodysplasia. Children who present

with a history consistent with malab-sorption and neutropenia should be

evaluated for Shwachman syndrome.These patients require studies to eval-

uate pancreatic enzymes and skeletal

evaluation to assess the possibility ofmetaphyseal chondrodysplasia. All

children who have chronic neutrope-nia with recurrent infections shouldhave growth curves plotted to evalu-

ate the effect of recurrent infections

on growth and development. Children

who are suspected of having Shwach-man syndrome should have a growth

curve plotted to evaluate the detri-mental effects of pancreatic insuffi-

ciency on physical development. An-tinuclear antibody determination,serum folate, and B1, levels are mdi-cated in patients in whom collagen

vascular disease or nutritional defi-ciencies, respectively, are suspected.More extensive immunologic evalua-

tion would be indicated in selectedpatients suspected of having a con-current immunodeficiency.

Children presenting with pancyto-penia should undergo a bone marrowaspiration and biopsy to aid in thediagnosis and assess cellularity. Ad-ditional marrow studies, such as cyto-genetic analysis and special stains fordetecting leukemia and other malig-nant disorders, should be obtained incertain cases. Selection of other labo-ratory tests will be determined by theduration and severity of the neutrope-nia and by the findings obtained inthe physical examination. Steroidmobilization tests can prove useful inproviding a rough index of whetherneutrophils can be released from thebone marrow into the circulation,thereby predicting the probable clini-

cal course of selected patients whohave idiopathic forms of neutropenia.The use of epinephrine to assess therelease of neutrophils into the circu-lation from the marginating pool thatlines the endothelium has not proven

useful in defining the basis of mostneutropenic states. Employment of invitro bone marrow culture systemshas had only variable results in eval-uating the pathophysiology of most

forms of neutropenia.

Principles of Therapy forNeutropenia

The management of neutropenia

present at the time of diagnosis in

patients who have acute leukemias orother malignancies or following bonemarrow suppression by chemothera-peutic agents differs from the ap-proach taken for patients who have

selected neutropenias without under-lying diseases or those who have

chronic neutropenia not associatedwith malignancy. The diminishedinflammatory capability found in pa-

tients who have acquired neutropenia

arising from malignancy can alter theusual signs and symptoms so that theoccurrence of fever may be the her-

aiding sign of infection. Apparentsepticemia is the major hazard forany patient who has neutropeniaand, in spite of antibiotics, is re-sponsible for the considerable mor-

tality rate among those who haveacquired neutropenia. There is atleast a 20% chance that a febrile

episode in a severely neutropenicpatient is due to bacterial infection.Acute septicemia is more commonin acute-onset neutropenia and usu-

ally does not occur with the in-

trinsic neutropenias.

ACUTE ONSET NEUTROPENIA

Early recognition and treatment ofinfections may save patients whohave acute onset neutropenia associ-ated with malignancies or followingmyelosuppressive chemotherapy. Pa-tients who have a temperature greater

than 38.5#{176}C(orally) on one episodeor a temperature greater than 38#{176}Con two consecutive readings and aneutrophil count less than 500/mm3should be considered to have a pre-sumptive diagnosis of bacterial sep-sis. Blood samples for culturesshould be drawn from a peripheralvein and from each lumen of thecentral venous catheter. Cultures or

biopsies should be made of local cu-

taneous lesions, and a chest roentgen-ogram should be examined for infil-

trates or cavitation. Nasal secretionsand sputum should be cultured forthe presence of fungi. Sinus roent-genograms may reveal evidence ofasymptomatic sinusitis. Meningitis is

unusual among neutropenic febrilecancer patients, and lumbar punctureshould be avoided as a routine proce-

dure. Ongoing chemotherapy shouldbe withdrawn.

Prompt use of intravenously ad-

ministered broad-spectrum antibioticssuch as ticarcillin 200 to 300 mg/kgof body weight per day and tobramy-

cm 7 mg/kg per day divided in three

doses should be instituted. Doublebeta-lactam therapy, with an extendedgram-negative spectrum carboyx- orureidopenicillin (carbenicillin, ticar-

cillin, piperacillin) and a cephalospo-rim (ceftazidine, cefotaxime, ceftriax-one), is another broad-spectrumbactericidal regimen that avoids po-tentially nephrotoxic drugs. If thepatient has evidence of septic shock,

a combination of a third-generationcephalosporin or an extended gram-negative penicillin plus an aminogly-coside is the treatment of choice. Theduration and modification of antimi-crobial therapy depends on the per-

sistence of fever and neutropenia and

on the physician’s ability to identifya specific pathogen. The source of

possible bacterial infections in theneutropenic patient includes the skin;

the mucous membranes; and theintestinal, renal, and respiratory sys-

tems. Blood cultures should be re-

peated when there are any tempera-ture spikes, even during antibiotic

therapy. If there is defervescence andblood cultures do not reveal anygrowth while the patient is receiving

antibiotic therapy, the antibioticshould be continued for at least 3days after the patient is afebrile. Onthe other hand, if the cultures repeat-edly are negative and the patient con-



tinues to have fevers exceeding 38#{176}C,antimicrobial therapy should be con-

tinued until the neutropenia resolvesand the patient becomes afebrile. Alarge percentage of febrile patientswho have neutropenia and receiveantibiotics for 7 days develop fungalinfections. Thus, some advocate plac-

ing these patients on amphotericin B

until they become afebrile and are nolonger neutropenic. Other studieshave demonstrated benefit from rhG-

CSF administration in selected pa-tients who have a fever and neutro-

tion of infection and inflammation.The long-term effects of rhG-CSF

therapy remain unknown but includea propensity for the development ofmoderate splenomegaly. Autoimmuneneutropenia may be responsive to

intermittent corticosteroids, especiallyif it is part of a underlying diseaseprocess such as systemic lupus ery-

thematosus. Although unproven bycontrolled studies, use of rhG-CSFhas benefited some patients who haveimmune neutropenia.

CHRONIC NEUTROPENIA

Therapy of chronic neutropenia isdictated by the patient’s history. Pa-tients who have benign neutropenia

and no evidence of repeated bacterialinfections or chronic gingivitis re-quire no specific therapy. Superficial

infections in children who have mild-to-moderate neutropenia may betreated with appropriate oral antibiot-

ics. However, in patients who havelife-threatening infections, broad-spectrum intravenous antibiotics

should be started promptly. Effective

treatment of severe chronic neutro-penia encompassing severe congenitalneutropenia, chronic symptomaticidiopathic neutropenia, and cyclic

neutropenias is now possible. In arandomized trial among patients whohad severe chronic neutropenia, using

subcutaneously administered rhG-CSF at doses ranging from 3.4 to

11.50 j.tg/kg per day. led to dramaticincreases in the neutrophil counts ofpatients, resulting in marked attenua-

2/� Pediatrics in Review Vol. 17 No. / Janua� /996

HEMATOLOGYLeukopema

penia to accelerate the return of theANC. SUGGESTED READINGS

Arnaout MA. Dynamics and regulation of

leukocyte-endothelial cell interactions. C’urr

Opin Hematol. 1993: 1 : I I 3

Boxer LA. Neutrophil disorders: qualitative

abnormalities of the neutrophil. In: Williams

Wi, Beutler E, Erslev AJ, Lichtman MA,

eds. Hematology. 5th ed. New York, NY:

McGraw-Hill; 1995:828-843

Curnutte JT. Molecular basis of the autosomal

recessive forms of chronic granulomatous

disease. Immunodeficiency Rev. 1992:3:149

Dale DC, Bonilla MA, Davis MW, et al. A

randomized controlled phase Ill trial of

recombinant human G-CSF for treatment of

severe chronic neutropenia. Blood. 1993:81:

2496-2502

Hutchinson Ri, Boxer LA. Disorders of granu-

locyte and monocyte production. In:

Hoffman R, Benz El Jr. Shattil SJ, et al,

eds. Hematology: Basic Principles andPractice. New York, NY: Churchill

Livingstone: 1991:198

Wilson JM, Ping AJ, Krauss JD, et al. Cor-

rection of CD 18-deficient lymphocytes by

retrovirus-mediated gene transfer. Science.

1990:248:1413

Wright DG. Kenney RF, Oette DH, et al.

Contrasting effects of recombinant human

granulocyte-macrophage colony stimulating

factor (GM-CSF) and granulocyte colony

stimulating factor (G-CSF) treatment on the

cycling of blood elements in childhood-onset

cyclic neutropenia. Blood. 1994:84:1257-

1267

PlR QUIZI 1. In a 2-year old Caucasian child,

neutropenia is defined as an abso-

lute neutrophil count less than:

A. 500/pt

B. 1500/pt

C. 2500/ptD. 3500/pt

E. 4500/pt

I 2. Which one of the following is the

most common cause of neutropenia

in a 4-year old child?

A. Acute lymphoblastic leukemia.

B. Cyclic neutropenia.

C. Intercurrent viral infection.

D. Kostmann syndrome.

E. Nutritional deficiency.

I 3. Cyclic neutropenia is characterized

by regularly recurring episodes of

neutropenia that last for 3 to 6 days.

The interval between the neutropenic

phases is most likely to be:

A. I week.

B. 3 weeks.

C. 6 weeks.

D. 12 weeks.

E. 16 weeks.

14. Antimicrobial therapy in a patient

who has long-standing neutropenia

and presents with fever. tachycar-

dia, and poor peripheral perfusion

should be directed against:

A. Crvptosporidiurn sp.

B. Cytomegalovirus.

C. Pneu,nocystis carinii.

D. Respiratory tract flora.

E. Skin and bowel flora.

IS. Which one of the following is the

most common presenting feature of

neutropenia?

A. Bacterial meningitis.

B. Bacterial pneumonia.

C. Mucocutaneous candidiasis.

D. Oral mucosal ulcerations and

gingivitis.

E. Septic arthritis.

16. Which one of the following causes

of neutropenia carries the least risk

of developing severe systemic bac-

terial infections?

A. Cyclic neutropenia.

B. Intercurrent viral infections.

C. Kostmann syndrome.

D. Schwachman syndrome.

E. Treatment with antineoplastic

drugs.



DOI: 10.1542/pir.17-1-191996;17;19Pediatrics in Review

Laurence A. Boxer and R. Alexander BlackwoodLeukocyte Disorders: Quantitative and Qualitative Disorders of the Neutrophil, Part 1

ServicesUpdated Information &

http://pedsinreview.aappublications.org/content/17/1/19including high resolution figures, can be found at:

Permissions & Licensing

/site/misc/Permissions.xhtmlits entirety can be found online at: Information about reproducing this article in parts (figures, tables) or in

Reprints/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:



leukocyte disorders: quantitative and qualitative

Documents