3. Tropical Diseases.pdf

TROPICAL DISEASES (Malaria, Dengue, Leptospirosis, Typhoid)

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MALARIA

♥ Is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes

♥ Most important of the parasitic diseases of humans, with transmission in 107 countries containing 3 billion people and causing 1–3 million deaths each year

Cause

♥ Plasmodium species ♥ Types

• P. vivax • P. malariae • P. ovale • P. falciparum

How Malaria Spreads

Characteristics of Plasmodium Species

Clinical Features

♥ P. falciparum ♥ P. malariae ♥ P. vivax ♥ P. ovale ♥ Prostration ♥ Impaired consciousness ♥ Respiratory distress

(acidotic breathing or Kussmaul’s breathing)

♥ Multiple convulsions ♥ Circulatory collapse ♥ Pulmonary edema (radiological) ♥ Abnormal bleeding ♥ Jaundice ♥ Hemoglobinuria ♥ Severe anemia

Severe Falciparum Malaria

Internal Medicine II

Module 6


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Poor Prognosis in Falciparum Malaria Clinical

♥ Marked agitation ♥ Hyperventilation (respiratory distress) ♥ Hypothermia (< 36.5°C) ♥ Bleeding ♥ Deep coma ♥ Repeated convulsions ♥ Anuria ♥ Shock

Laboratory

♥ Biochemistry • Hypoglycemia (< 2.2 mmol/L) • Hyperlactemia (> 5 mmol/L) • Acidosis (arterial pH < 7.3, serum HCO3 < 15 mmol/L) • Elevated serum creatinine (> 265 umol/L) • Elevated total bilirubin (> 50 umol/L) • Elevated liver enzymes (AST/ALT 3 times upper limit of

normal) • Elevated muscle enzymes (CPK ↑, myoglobin ↑) • Elevated urate (> 600 umol/L)

♥ Hematology • Leukocytosis (>12,000/uL) • Severe anemia (PCV < 15%) • Coagulopathy

— Decreased platelet count (< 50,000/uL) — Prolonged prothrombin time (> 3s) — Prolonged partial thromboplastin time — Decreased fibrinogen (< 200 mg/dL)

♥ Parasitology • Hyperparasitemia

— Increased mortality at > 100,000/uL — High mortality at > 500,000/uL — > 20% of parasites identified as pigmented-

containing trophozoites and schizonts — > 5% of neutrophils with visible pigment

Complications

Plasmodium malariae Plasmodium vivax & ovale � Glomerulonephritis � Nephrotic syndrome

� Relapse

Malaria Diagnosis

♥ Microscopy remains as the “Gold Standard” in malaria diagnosis

♥ Alternative diagnostic tools available: • Fluorescent microscopy (QBC, Kawamoto) • Serology: antibody detection (IFAT, ELISA) • Molecular techniques (PCR, DNA hybridization) detects

parasite specific nucleic acid sequence • Antigen detection (Rapid Diagnostic Tests)

♥ Microscopy • Thick blood film

— An unfixed blood spot is stained with Giemsa, Field's, or another Romanowsky stain

— The number of asexual parasites per 200 WBCs (or per 500 at low densities) is counted.

— Gametocytes are counted separately — Sexual parasites/200 WBCs x 40 = parasite

count/L (assumes a WBC count of 8000/L) • Thin blood film

— A fixed smear is stained with Giemsa, Field's, or another Romanowsky stain.

— The number of RBCs containing asexual parasites per 1000 RBCs is counted.

— In severe malaria, assess stage of parasite development and count neutrophils containing malaria pigment.

— Gametocytes are counted separately — Parasitized RBCs (%) x hematocrit x 1256 =

parasite count/L — The presence of >100,000 parasites/L (2%

parasitemia) is associated with an increased risk of severe malaria

♥ Rapid Diagnostic Tests (RDT) are also used in remote rural areas for malaria diagnosis

• HRP 2 test (histidine-rich protein 2)

— P. falciparum specific [ParacheckTM] • pLDH enzyme test (parasite lactate dehydrogenase)

— Pan specific for 4 Plasmodium species [OptimalTM]

*RDTs provide a simple, rapid, sensitive method for determining the presence of antigens produced by malaria parasites *RDTs rely on specific antigen-antibody reactions and immune-chromatographic (dipstick) technology *Variable reports on performance (sensitivity and specificity), hence quality control/assurance (QC/QA) is necessary Application of RDTs

♥ RDTs may be useful in: • Remote malaria endemic areas with no microscopy

centers, or requires 2 hrs travel (MCP-DOH, 2002) • Special situations: epidemics/outbreaks, stand-by

emergency diagnosis (travelers) • Military situations, organized work forces

♥ Microscopy remains as the gold standard for malaria diagnosis in hospital and RHU settings [RDT + malarial smear]

Objective of Treatment

♥ Objective of treatment in malaria is the attainment of, as quickly as possible, parasiticidal plasma concetrations of the anti-malarial drug that is sustained long enough to ensure rapid clearance of parasitemia


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Anti-malarial Drugs by Species

Uncomplicated P. falciparum Malaria First line drug: Arthemether + Lumefantrine (CoartemTM)

Adult Dose Pediatric Dose Day 1 4 tabs 5 - < 15kg: 1 tab

8 hours 4 tabs 15 - < 25kg: 2 tabs Day 2 4 tabs bid 25 - < 35kg: 3 tabs

Day 3 4 tabs bid and PQ (SD) (follow 3-day bid regimen as in adult schedule)

♥ Given with a fatty meal on confirmed diagnosis ♥ Not recommended in pregnancy, lactation and infants < 6 months

old

Day 4

PQ 1) Use body weight in kgs as basis: use 0.75 mg-base/kg b.w. single dose 2) If weight cannot be taken, use age as basis < 1 y.o. 1-3 y.o. 4-6 y.o. 7-11 y.o. ≥ 12 y.o.

Contraindicated

Primaquine single dose

Primaquine tablet single dose

Primaquine tablets single dose

Primaquine tablets single dose

Second line drug: QS + T/D/C

Severe P. falciparum Malaria

parenteral Quinine Dihydrochloride Infusion PLUS

Tetracycline/Doxycycline/Clindamycin (shift to AL if patient can already tolerate oral meds)

P. vivax or P. ovale

Chloroquine (1 tab contains 150mg of Chloroquine base) for Day 1-3

AND Primaquine

(1 tab contains 15mg of Primaquine base) for Day 4-17

P. malaria

Chloroquine (1 tab contains 150mg of Chloroquine base) for Day 1-3

AND Primaquine

(1 tab contains 15mg of Primaquine base) for Day 4 (single dose)

Chemoprophylaxis

♥ Atovaquone/proguanil (Malarone) ♥ Chloroquine phosphate (Aralen and generic) ♥ Doxycycline ♥ Hydroxychloroquine sulfate (Plaquenil) ♥ Mefloquine (Lariam and generic) ♥ Primaquine


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Individual Preventive Measures

♥ Use long-sleeved clothing and trousers when going out at night ♥ Apply insect repellant to exposed skin ♥ Stay in rooms with screened windows and doors ♥ Use insecticide-treated mosquito nets ♥ Use pyrethroid mosquito coils

Control of Mosquitoes

DENGUE VIRUS ♥ Belongs to the family Flaviviridae ♥ 4 serotypes

• DEN-1, DEN-2, DEN-3, DEN-4 ♥ Infection to one serotype confers lifelong immunity only to that

serotype ♥ Humans are the main reservoir ♥ Transmitted by mosquitoes

• Aedes aegypti – principal vector • Aedes albopiticus

♥ Aedes aegypti • Feeds preferentially on human blood • A daytime feeder • Has an imperceptible bite • Well-adapted to life in the urban settings • Breeds in clean, stagnant water in containers that collect

rainwater Epidemiology

♥ Endemic in more than 100 countries ♥ Estimated 50 million dengue infections occur annually ♥ 2.5 billion people living in endemic areas between 2001 and

2008, 1,020,333 cases were reported in Cambodia, Malaysia, Philippines, and Viet Nam -- the four countries in the Western Pacific Region with the highest numbers of cases and deaths.

♥ The combined death toll for these four countries was 4798 (official country reports)

♥ Compared with other countries in the same region, the number of cases and deaths remained highest in Cambodia and the Philippines in 2008

♥ Case fatality rate is 2.5-5% n Higher up to 12-44% when shock sets in

♥ With appropriate supportive treatment, fatality is 1%. Dengue in the Philippines

♥ January 1 – September 7, 2013: A total of 117,658 dengue cases was reported nationwide

• This is 5.25% lower compared to the same time period in the previous year (124,173)


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Pathogenesis

♥ Persons who have experienced a dengue infection develop serum antibodies that can neutralize the dengue virus of that same serotype (homologous)

♥ In a subsequent infection, preexisting heterologous antibodies

form complexes with the new infecting virus serotype, but do not neutralize the new virus

♥ Antibody-dependent enhancement is the process in which certain

strains of dengue virus, complexed with non-neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production

♥ 90% of DHF cases occur in secondary heterologous dengue

infection • 10% only in primary infection

♥ Cells targeted by the dengue virus are predominantly the cells of the reticulo-endothelial system.

• Spleen, liver, bone marrow • Monocytes, lymphocytes, Kupffer cells, alveolar

macrophages ♥ Incubation period: 4-10 days ♥ The dengue virus enters via the skin while an infected mosquito

is taking a blood meal ♥ During the acute phase of illness the virus is present in the blood

and its clearance from this compartment generally coincides with defervescence.

♥ Humoral and cellular immune responses are considered to contribute to virus clearance via the generation of neutralizing antibodies and the activation of CD4+ and CD8+ T lymphocytes.

♥ In addition, innate host defense may limit infection by the virus. ♥ After infection, serotype-specific and cross-reactive antibodies

and CD4+ and CD8+ T cells remain measurable for years. ♥ Local viral replication is believed to take place in target dendritic

cells following the bite of ♥ An infected Aedes mosquito. Infection of dendritic cells leads to

production of ♥ TNF-alpha, IFN-alpha, IL-10. ♥ In primary infection, neutralizing antibodies are protective ♥ Plasma leakage, haemoconcentration and abnormalities in

homeostasis characterize severe dengue. ♥ The mechanisms leading to severe illness are not well defined

but the immune response, the genetic background of the individual and the virus characteristics may all contribute to severe dengue

In secondary heterologous dengue infection Antibody-dependent enhancement causes ↑ viral entry leading to

↑ viral burden to the host ↓

Results in amplified cascade of cytokines and complement activation, causing endothelial dysfunction, platelet destruction,

and consumption of coagulation factors ↓

Plasma leakage in DHF Viral Risk Factors for DHF Pathogenesis

♥ Virus strain (genotype) • Epidemic potential: viremia level, infectivity

♥ Virus serotype • DHF risk is greatest for DEN-2, followed by DEN-3, DEN-

4 and DEN-1 Host Risk Factor for DHF

♥ Immune status ♥ Age ♥ Genetic predisposition ♥ Previous infection with dengue virus

Classic Dengue Fever

♥ Sudden onset of fever ♥ Severe headache ♥ Retro-orbital pain ♥ Fatigue ♥ Associated with myalgia and arthralgia

• “Breakbone fever” ♥ Fever lasts 2-7 days


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♥ Maculopapular rash • Appears near the time of

defervescence • Often lasts for 2-4 days and may

be accompanied by scaling and

pruritus Other Signs and Symptoms

♥ Flushed facies during the 1st 24-48 hours ♥ Lymphadenopathy ♥ Injected conjunctivae ♥ Inflamed pharynx ♥ Mild respiratory and gastrointestinal symptoms

Hemorrhagic Manifestations

♥ Skin hemorrhages: petechiae, purpura, ecchymoses ♥ Gingival bleeding ♥ Nasal bleeding ♥ Gastrointestinal bleeding, hematemesis, melena, hematochezia ♥ Hematuria ♥ Increased menstrual flow

WHO (2009): Suggested Dengue Classification and Levels of Severity

Clinical Course of Dengue Fever

Clinical Course of Dengue Fever: Things to watch out for

1 Febrile phase Dehydration; high fever may cause neurological disturbances and febrile seizures in young children

2 Critical phase Shock from plasma leakage; severe hemorrhage, organ important

3 Recovery phase Hypervolemia (only if IV fluid therapy has been excessive and/or has extended into this period)

Differential Diagnosis

♥ Typhoid fever ♥ Leptospirosis ♥ Malaria ♥ Measles, rubella ♥ Acute HIV syndrome ♥ Chikungunya ♥ West Nile virus infection ♥ Viral hemorrhagic fevers ♥ Early severe acute respiratory syndrome ♥ Rickettsial diseases ♥ Any other disease that can manifest in the acute phase as an

undifferentiated febrile syndrome Laboratory Diagnosis

♥ Approximate time-line of primary and secondary dengue virus infections and the diagnostic methods that can be used to detect infection

♥ Comparison of diagnostic tests according to their accessibility

and confidence


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Treatment ♥ Mainly supportive

• Use of antipyretics • Fluid resuscitation • Correction of breathing disorders

Home Care

LEPTOSPIROSIS Etiologic Agent

♥ Spirochetes belonging to the order Spirochaetales and the family Leptospiraceae

♥ Leptospires are thin, long, slender, spiral or helically curved, tightly coiled, motile, gram negative aerobic bacteria

Epidemiology

♥ Leptospires can be: • Free living in water, soil or sewage contaminated with the

animal urine • Associated with renal infection with animals

♥ Incidence is high in warm climate countries because they survive longer in humid condition.

♥ The disease is seasonal with peak incidence occurring during rainy season.

♥ Rodents,especiallyrats, are the most important reservoir, although other wild mammals as well as domestic and farm animals may also harbor leptospires.

♥ This infection occurs most commonly in the tropics because the climate as well as the poor hygienic conditions favor the pathogen's survival and distribution

♥ Peak incidence during the rainy season in the tropics Transmission

♥ Human become incidental/ accidental host: • Direct contact with infected animals or • Indirectly through contact with water contaminated with

excreta. ♥ Human infections can be acquired through occupational and

recreational exposures. ♥ Portal of entry:

• Abrasions or cuts in the skin • Conjunctiva

♥ Epidemics of leptospirosis may result from exposure to flood waters contaminated by urine from infected animals


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Pathogenesis

Clinical Manifestations

♥ What clinical manifestation should alert a health practitioner to suspect leptospirosis among patients presenting with acute fever?

♥ Anicteric Leptospirosis • May present as an acute influenza-like illness with fever,

chills, severe headache, nausea, vomiting and myalgias • Muscle pain, which especially affects the calves, back

and abdomen • Intense headache (frontal or retroorbital) • Most common PE finding: fever with conjunctival

suffusion • Most patients become asymptomatic within 1 week • After an interval of 1–3 days, the illness recurs in a

number of cases — The start of this second (immune) phase

coincides with the development of antibodies. — Fever is less pronounced and the myalgias are

less severe — Development of aseptic meningitis

♥ Severe Leptospirosis (Weil’s Syndrome) • Characterized by jaundice, renal dysfunction, and

hemorrhagic diathesis • Mortality rate: 5–15% • The onset of illness is no different from that of less

severe leptospirosis • After 4–9 days, jaundice as well as renal and vascular

dysfunction generally develop • Pulmonary involvement in many cases à cough,

dyspnea, chest pain, and blood-stained sputum, hemoptysis, respiratory failure

• Renal failure may develop, often during the second week of illness → dialysis is sometimes required

• Hemorrhagic manifestations: epistaxis, petechiae, purpura, and ecchymoses

Laboratory Findings

Diagnosis What are the locally available laboratory tests that can be used to confirm the diagnosis of leptospirosis?

Direct Detection Method Indirect Detection Method Culture and Isolation � Remain the GOLD standard BUT is time-comsuming, labor-insensitive � Requires 6 to 8 weeks for the result, needs darkfield microscopy and has low diagnostic yield

Polymerase Chain Reaction (PCR) � Has the advantage of early confirmation of diagnosis especially during the acute leptospiremic phase (first week of illness) before the appearance of antibodies

Microagglutination Tets (MAT) � A four-fold rise of the titer from acute to convalescent sera is confirmatory to the diagnosis � It is highly sensitive and specific BUT time-consuming and hazardous to perform because of the risk of exposure to the live antigen � In endemic areas like the Philippine, a single titer of atleast 1:1600 in symptomatic patients is indicative of leptospirosis

Specific IgM Rapid Diagnostic Tests like LeptoDipstick , Leptospira IgM ELISA (PanBio)< MCAT and Dridot � Are serologic test in a single test format for the quick detection of Leptospira genus-specific IgM antibodies in human sera � The sensitivity rates are between 63%-72% and specificity rates between 93%-96% when tested in illnesses of less than 7 days. If serum sample are taken beyond 7 days, sensitivity improves to > 90%

Nonspecific Rapid Diagnostic Tests like LAATS (Leptospira

Any individual presenting with acute febrile illness of at least 2 days AND either residing in a flooded area or has high-risk exposure (defined as wading in floods and contaminated water, contact with animal fluids, swimming in flood water or ingestion of contaminated water with or without cuts or wounds) AND presenting with at least two of the following symptoms: myalgia, calf tenderness, conjunctival suffusion, chills, abdominal pain, headache, jaundice, or oliguria should be considered a suspected leptospirosis case. [Grade A]


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Antigen-Antibody Agglutination Test (Leptospira Serology Bio-Rad) � Detects Leptospira antibody in human serum through agglutination reaction, which may persist fro years. This is used as a screening test but is NOT sensitive � A positive result should be confirmed with MAT

Diagnosis

♥ Definitive diagnosis • Isolation of the organism from the

patient o • Seroconversion or a rise in

antibody titer in the microscopic agglutination test (MAT)

♥ Leptospires can be isolated from blood and/or CSF during the first 10 days of illness and from urine for several weeks beginning at ~ 1 week

Differential Diagnosis

♥ Dengue fever ♥ Malaria ♥ Enteric fever ♥ Viral hepatitis ♥ Hantavirus infections ♥ Rickettsial diseases

Treatment

Antibiotic therapy should be completed for 7 days, except for azithromycin dehydrate which could be given for 3 days

Prevention ♥ Most effective preventive measure is avoidance of high-risk

exposure (i.e. wading in floods and contaminated water, contact with animal’s body fluid).

• If high risk exposure is unavoidable, appropriate personal protective measures include wearing boots, goggles, overalls, and rubber gloves

♥ Avoidance of exposure to urine and tissues from infected animals ♥ Rodent control ♥ Vaccination of animals ♥ Chemoprophylaxis with doxycycline

Post-exposure Prophylaxis for Leptospirosis

TYPHOID FEVER ENTERIC FEVER

♥ Classic syndrome ♥ Acute illness ♥ Fever, headache, abdominal pain, relative

bradycardia, splenomegaly, leukopenia ♥ Prototype: typhoid fever, Salmonella enterica

serotype typhi TYPHOID FEVER

♥ An acute, generalized infection of the reticuloendothelial system, the intestinal lymphoid tissue and gallbladder

♥ Caused by Salmonella enterica serotype Typhi (a.k.a. S typhi), a gram-negative bacterium

Transmission

♥ S. typhi has no known hosts other than humans ♥ Food-borne or waterborne transmission results from fecal

contamination by ill or asymptomatic chronic carriers ♥ Sexual transmission between male partners has been described ♥ Health care workers occasionally acquire enteric fever after

exposure to infected patients or during processing of clinical specimens and cultures


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Clinical Features

Symptoms (%) Fever

Headache Nausea Vomiting

Abdominal cramps Diarrhea

Constipation Cough

39-100% 43-90% 23-36% 24-35% 8-52%

30-57% 10-79% 11-86%

Physical Findings (%) Fever

Abdominal tenderness Splenomegaly Hepatomegaly

Relative bradycardia Rose spots

Rales or rhonchi Epistaxis

Meningisumus

98-100% 33-84% 23-65% 15-52% 17-50% 2-46% 4-84% 1-21% 1-12%

Rose Spots

Clinical Features

♥ Gastrointestinal bleeding (10-20%) and intestinal perforation (1-3% most commonly occur in the third and fourth weeks of illness and results from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration

♥ Both complications are life-threatening and require immediate fluid resuscitation and surgical intervention, with broadene antibiotic coverage for polymicrobial peritonitis

Pathogenesis

♥ Infection begins with ingestion of organisms in contaminated foor or water

♥ The infectious dose is 103-106 colony-forming units

♥ Once salmonellae reach the small intestine, they penetrate the mucous layer of the gut and traverse the intestinal layer through phagocytic microfold (M) cells that reside within Peyer’s patches

♥ After crossing the epithelial layer of the small intestines, S. typhi is phagocytosed by macrophages. These salmonellae survive the antimicrobial environment of the macrophage

♥ Once phagocytosed, salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow).

♥ Patients have relatively few or no signs and symptoms during this initial incubation stage.

♥ Signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages and epithelial cells in response to bacterial products that are recognized by innate immune receptors when a critical number of organisms have replicated.

♥ The development of hepatosplenomegaly is likely to be related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. typhi colonization.

♥ The recruitment of additional mononuclear cells and lymphocytes to Peyer's patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis of the Peyer's patches, which may be mediated by bacterial products that promote cell death as well as the inflammatory response

Diagnosis

♥ Definitive diagnosis: isolating S. typhi or Salmonella spp. From blood, bone marrow, stool, urine or a specific anatomic location

♥ The presence of clinical symptoms characteristic of typhoid fever or the detection of a specific antibody response is suggestive of typhoid fever but not definitive.

♥ Blood culture is the mainstay of the diagnosis of this disease. ♥ Bone marrow culture is 55-90% sensitive, and, unlike that of

blood culture, its yield is not reduced by up to 5 days of prior antibiotic therapy.

♥ Stool cultures, while negative in 60-70% of cases during the first week, can become positive during the third week of infection in untreated patients

♥ If blood, bone marrow, and intestinal secretions are all cultured, the yield is >90%

Laboratory Diagnosis


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Systemic Infections that may Mimic Enteric Fever ♥ Malaria ♥ Septicemic plague ♥ Intestinal anthrax ♥ Acute septicemic melioidosis ♥ Acute bartonellosis (Oroya fever) ♥ Leptospirosis ♥ Psittacosis ♥ Ricketsial infection ♥ Ehrlichiosis ♥ Legionella ♥ Dengue ♥ Amebiasis ♥ Replapsing fever (Borrelia hermsii) ♥ Intestinal tuberculosis ♥ Abdominal actinomycosis ♥ Intraabdominal pyogenic abscess ♥ Mycoplasma pneumoniae ♥ Rat-bite fever (Streptobacillus moniliformis) ♥ Visceral leishmaniasis ♥ Schistosomiasis (Katayama’s fever) ♥ Non infectious causes

Treatment

Prevention and Control

♥ Monitor food and water intake, especially for travelers ♥ Hand hygiene ♥ Typhoid vaccines

• Parenteral vaccine — Vi capsular polysaccharide vaccine (ViCPS)

Given IM or SC Revaccination is recommended every 2 years

• Oral vaccine — Live attenuated S. typhi strain (Ty 21) – NOT

locally available — Enteric-coated capsules taken every other day

for 1 week — Booster every 5 years

~END~

“That in al l th ings , God may b e g lor i f i ed”

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3. Tropical Diseases.pdf