Monsoon Illnesses affecting Lungs (Part 1 of 2)Dr. Manjit S. Tendolkar

Department of Chest Medicine,

Seth G. S. Medical College and K. E. M. Hospital.

Leptospirosis

Introduction

In 1885, Adolf Weil described the clinical

hallmarks of this disease as an acute process

characterized by splenomegaly, jaundice, and

nephritis. With time, the designation Weil's

disease came to signify severe leptospirosis

characterized by diverse clinical findings,

particularly fever, jaundice, acute renal injury,

refractory shock, and hemorrhage (especially

pulmonary hemorrhage).

Etiologic Agent

The genus Leptospira (order Spirochetales,

family Leptospiraceae) constitutes the most

ancient lineage of spirochetes pathogenic for

humans and the only spirochetes that can live

both in animals and free in the environment

Epidemiology

Sources of transmission to humans are rats, dogs, cattle, and pigs

No Human to Human transmission

Patterns of transmission-

-Epidemic (Seasonal rains and seasonal flooding)

-Endemic (Tropical Humid Environment & Poor Sanitation leading to rodent infestation)

-Sporadic (Veterinary, Sewage, Slaughter House Workers)

o Infection by Leptospira does not occur via inhalation, and leptospirosis is a rare cause of laboratory-acquired infection. Laboratory strains usually used for serologic diagnosis have been serially passaged for long periods and usually have lost their virulence.

Pathogenesis

Leptospires infect humans through the mucosa (usually conjunctival and possibly oral or tonsillar) or through macerated, punctured, or abraded skin. The organisms resist innate immune defenses (e.g., complement), proliferate in the bloodstream or extracellularly within organs, and then disseminate hematogenously to all organs.

Incubation Period: 2 - 30 days

The life cycle is completed as leptospires traverse the interstitial spaces of the kidney, penetrate the basement membrane of the proximal renal tubules, cross through proximal renal tubuleepithelial cells, and become adherent to the proximal renal tubular brush border, whence they are excreted in the urine

Chronic and persistent renal colonization can last for weeks or years, with unknown pathophysiologic

Pathology of Multiple

System InvolvementKidneys

Acute Tubular Necrosis and Interstitial Nephritis.

Primary injury of the proximal convoluted tubules is the primary renal pathophysiologic lesion in acute leptospirosis, with secondary increased distal tubular potassium excretion, hypokalemia, and polyuria.

Lungs

o Pulmonary Hemorrhage in absence of

Inflammation and paucity of organisms

o Septal capillary lesions seem to be

causally related to death, leading to

pulmonary hemorrhage

Liver

o Plugging of Bile Canaliculi

o Focal Periportal Cellular Necrosis and Steatosis

o widespread hepatocellular necrosis is not found

Coagulation Profile

o The prothrombin and activated partial thromboplastin times are not necessarily elevated in severe leptospirosis, and fibrinogen levels are typically elevated.

o Thrombocytopenia is characteristic, probably reflecting platelet consumption in the activated endothelial surface

Hearto Pericardial and Endocardial hemorrhage, disruption of myocardial fiber organization, and

scattered myocyte necrosis (accompanied, grossly, by dilation of both right and left ventricles)

are pathological lesions associated with severe leptospirosis

Despite the traditional view that leptospirosis is

characterized by vasculitis, formal demonstration of

inflammatory infiltrates within any blood vessel has not

been shown to be involved in the pathogenesis of this

disease.

A more likely possibility is that leptospires induce

endothelial cell dysfunction with organ dysfunction and

systemic disease

Clinical Manifestations

Clinical Expression : Subclinical Infection, Undifferentiated Febrile Illness, Weil’s Disease.

o Biphasic:

-Leptospiremic Phase:

--3-10 days

-- Organism may be cultured in blood

-Immune Phase

-- Non Responsive to antibiotic therapy

-- Leptospires can be isolated from urine

Physical Examination

o Conjunctival Suffusion

without discharge

o Pharyngeal Erythema without exudates

oMuscle Tenderness

oRales on Auscultation or Dullness on chest

percussion over areas of pulmonary

hemorrhage

Rash – Macular, Maculopapular, Erythematous,

Echymotic or Petechial

o Jaundice

o Meningismus

o Hypo/Hyper Reflexia (legs)

Weil’s DiseaseWeil's disease is characterized by variable combinations of jaundice, acute kidney injury, hypotension, and hemorrhage, most commonly involving the lungs but also potentially affecting the gastrointestinal tract, retro peritoneum, pericardium, and brain.

Acute kidney injury manifests after several days of illness and can be nonoliguric or oliguric, with serum electrolyte abnormalities reflecting proximal renal tubular dysfunction

Hypokalemia and hypomagnesemia are common in nonoliguric renal failure; hypomagnesemia can cause severe muscle weakness

Skeletal Muscle – Myalgia [Calves & Abdominal Muscles (mimicking Acute Abdomen)]

Heart – Nonspecific ST – T changes, RBBB, Rt/Lt Ventricular Dilatation indicating Myocarditis.

Aseptic Meningitis

Diagnosis

o In the context of an appropriate exposure history and in the absence of a more likely explanation, classic Weil's disease is suggested by elevated levels of blood urea nitrogen and serum creatinine in conjunction with mixed conjugated and unconjugated hyperbilirubinemia with aminotransferase elevation to less than five times the upper limit of normal

o Elevation of the noncardiac isoform of creatine kinase may indicate skeletal muscle damage.

o Troponin levels indicative of myocarditis have not been adequately studied in leptospirosis

o Hematologic abnormalities are variable but common: leukocytosis (typical in severe disease), leukopenia, hemolytic anemia, mild to moderate anemia, and thrombocytopenia.

o CXR: Alveolar infiltrates predominate and are associated with hemoptysis but not with purulent sputum.

o Leptospires can be cultured from blood and CSF during the first 7–10 days of illness and from urine beginning in the second week. Cultures usually become positive after 2–4 weeks (range, 1 week to 6 months)

o Definitive diagnosis rests on demonstrating the presence of the organism by culture isolation, detection of nucleic acids or antigen in body fluids, or immunohistochemical

Differential Diagnosis

o When fever and severe myalgia predominate, influenza is often considered, although the absence of coryza, sore throat, and cough is not consistent with this diagnosis

o malaria,

o rickettsial diseases,

o arboviral infections (e.g., dengue and chikungunya),

o typhoid fever,

o hantavirus infection (hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome),

o viral hepatitis.

Treatment

Malaria

Characteristic of Malarial

Parasites

Erythrocyte Changes

At the same stage, these P. falciparum infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythrocytes (agglutination). The processes of cytoadherence, rosetting, and agglutination are central to the pathogenesis of falciparum malaria. They result in the sequestration of RBCs containing mature forms of the parasite in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the principal host defense mechanism: splenic processing and filtration. As a consequence, only the younger ring forms of the asexual parasites are seen circulating in the peripheral blood in falciparum malaria, and the level of peripheral parasitemiaunderestimates the true number of parasites within the body.

In the other three ("benign") human malarias, sequestration does not occur, and all stages of the parasite's development are evident on peripheral-blood smears. Whereas P. vivax, P. ovale, and P. malariaeshow a marked predilection for either young RBCs (P. vivax, P. ovale) or old cells (P. malariae) and produce a level of parasitemia that is seldom >2%, P. falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.

Host Response

Splenic immunologic and filtrative clearance functions are augmented in malaria

parasitized cells escaping splenic removal are destroyed when the schizont ruptures

The material released induces the activation of macrophages and the release of proinflammatorymononuclear cells derived cytokines, which cause fever and exert other pathologic effects

Temperatures of 40°C damage mature parasites [Regular fever patterns (tertian, every 2 days; quartan, every 3 days) are seldom seen today in patients who receive prompt and effective antimalarial treatment]

Clinical FeaturesThe first symptoms of malaria are nonspecific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness

Although headache may be severe in malaria, there is not neck stiffness or photophobia as occurs in meningitis

While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus

The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale

generalized seizures are specifically associated with falciparum malaria and may herald the development of encephalopathy (cerebral malaria)

splenic enlargement is found in a high proportion of otherwise healthy individuals in malaria-endemic areas and reflects repeated infections.

Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated malaria and usually resolves over 1 - 3 weeks

Manifestations of Severe F.

Malaria

Cerebral Malaria

Coma is a characteristic and ominous feature of falciparum malaria

Any obtundation, delirium, or abnormal behavior should be taken very seriously.

Whereas adults rarely (i.e., in <3% of cases) suffer neurologic sequelae, 5% of children surviving cerebral malaria especially those with hypoglycemia, severe anemia, repeated seizures, and deep coma have residual neurologic deficit when they regain consciousness; hemiplegia, cerebral palsy, cortical blindness, deafness, and impaired cognition and learning (all of varying duration) have been reported. The majority of these deficits improve markedly or resolve completely within 6 months. Approximately 10% of children surviving cerebral malaria have a persistent language deficit. The incidence of epilepsy is increased and the life expectancy decreased among these children.

Diagnosis of Malaria

Thick Blood Film : Sensitive, Species Specific, Requires Expertise

Thin Blood Film : Insensitive, Rapid, Species Specific

Repeat blood smears should be performed at least every 12 - 24 h for 2 days if the first smears are negative and malaria is strongly suspected

PfHRP2 : Sensitive, Rapid, Detects only P. falciparum

Plasmodium LDH : Rapid, Sensitive, Not Species Specific

Microtube concentration methods with acridineorange staining : For processing large number of samples rapidly

Treatment

If there is any doubt as to the identity of the

infecting malarial species, treatment for

falciparum malaria should be given

If there is any doubt about the resistance status

of the infecting organism, it should be considered

resistant.

In all endemic areas, the World Health

Organization (WHO) now recommends

artemisinin-based combinations as first-line

treatment for uncomplicated falciparum malaria.

Properties of Antimalarials

To eradicate persistent liver stages and prevent relapse (radical treatment), primaquine (0.5 mg of base/kg, adult dose) should be given daily for 14 days to patients with P. vivax or P. ovale infections after laboratory tests for G6PD deficiency have proved negative. If the patient has a mild variant of G6PD deficiency, primaquine can be given in a dose of 0.75 mg of base/kg (45 mg maximum) once weekly for 6 weeks. Pregnant women with vivax or ovalemalaria should not be given primaquine but should receive suppressive prophylaxis with chloroquine (5 mg of base/kg per week) until delivery, after which radical treatment can be given.

Dengue

Flavivirus

All four distinct dengue viruses (dengue 1-4)

have Aedes aegypti as their principal vector, and

all cause a similar clinical syndrome. (Fever,

Malaise)

In rare cases, second infection with a serotype of

dengue virus different from that involved in the

primary infection leads to dengue HF with severe

shock

Clinical Presentation

Incubation Period : 2–7 days

Sudden onset of fever, headache, retroorbital pain, and back pain

along with the severe myalgia that gave rise to the colloquial

designation "break-bone fever.”

Often a macular rash on the first day as well as adenopathy, palatal

vesicles, and scleral injection.

The illness may last a week, with additional symptoms usually

including anorexia, nausea or vomiting, marked cutaneous

hypersensitivity, and near the time of defervescence a

maculopapular rash beginning on the trunk and spreading to the

extremities and the face

Epistaxis and scattered petechiae are often noted in uncomplicated

dengue, and preexisting gastrointestinal lesions may bleed during

the acute illness.

Laboratory Findings

Leukopenia

Thrombocytopenia

Elevated Serum Aminotransferase

The diagnosis is made by IgM ELISA or paired

serology during recovery or by antigen-detection

ELISA or RT-PCR during the acute phase

Virus is readily isolated from blood in the acute phase

if mosquito inoculation or mosquito cell culture is

used.

Dengue Hemorrhagic

Fever / Dengue Shock

SyndromeThe transient heterotypic protection after dengue virus infection is replaced within several weeks by the potential for heterotypic infection resulting in typical dengue fever (see above) or uncommonly in enhanced disease (secondary DHF/DSS).

Macrophage/monocyte infection is central to the pathogenesis of dengue fever and to the origin of DHF/DSS. Previous infection with a heterologous dengue-virus serotype may result in the production of nonprotective antiviral antibodies that nevertheless bind to the virion's surface and through interaction with the Fc receptor focus secondary dengue viruses on the target cell, the result being enhanced infection.

The induction of vascular permeability and shock depends on multiple factors, including the following:

-Presence of enhancing and nonneutralizing antibodies:Transplacental maternal antibody may be present in infants <9 months old, or antibody elicited by previous heterologous dengue infection may be present in older individuals. T cell reactivity is also intimately involved.

-Age: Susceptibility to DHF/DSS drops considerably after 12 years of age.

-Sex: Females are more often affected than males.

-Race: Whites are more often affected than blacks.

-Nutritional status: Malnutrition is protective.

-Sequence of infection: For example, serotype 1 followed by serotype 2 seems to be more dangerous than serotype 4 followed by serotype 2.

Diagnosis of Dengue HF/

Dengue SSDengue HF is identified by the detection of bleeding tendencies (tourniquet test, petechiae) or overt bleeding in the absence of underlying causes such as preexisting gastrointestinal lesions.

Dengue shock syndrome, usually accompanied by hemorrhagic signs, is much more serious and results from increased vascular permeability leading to shock.

In mild DHF/DSS, restlessness, lethargy, thrombocytopenia (<100,000/L), and hemoconcentration are detected 2-5 days after the onset of typical dengue fever, usually at the time of defervescence.

In more severe cases, frank shock is apparent,

with low pulse pressure, cyanosis,

hepatomegaly, pleural effusions, ascites, and in

some cases severe ecchymoses and

gastrointestinal bleeding. The period of shock

lasts only 1 or 2 days, and most patients respond

promptly to close monitoring, oxygen

administration, and infusion of crystalloid or in

severe cases colloid.

Thank You.

Contd in Part 2..