Internal Medicine II

Module 6

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 13 million deaths each year

Cause

Plasmodium species

Types

P. vivax

P. malariae

P. ovale

P. falciparum

Characteristics of Plasmodium Species

How Malaria Spreads

Clinical Features

P. falciparum

P. malariae

P. vivax

P. ovale

Prostration

Impaired consciousness

Respiratory
distress
(acidotic
breathing
or
Kussmauls breathing)

Multiple convulsions

Circulatory collapse

Pulmonary edema (radiological)

Abnormal bleeding

Jaundice

Hemoglobinuria

Severe anemia

Severe Falciparum Malaria

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Poor Prognosis in Falciparum Malaria

The number of asexual parasites per 200 WBCs

(or per 500 at low densities) is counted.

Clinical

Marked agitation

Gametocytes are counted separately

Hyperventilation (respiratory distress)

Hypothermia (< 36.5C)

Sexual parasites/200 WBCs x 40 = parasite

count/L (assumes a WBC count of 8000/L)

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)

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

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)

TM

P. falciparum specific [Paracheck ]

pLDH enzyme test (parasite lactate dehydrogenase)

Parasitology

HRP 2 test (histidine-rich protein 2)

Hyperparasitemia

Pan specific
TM
[Optimal ]

for

Plasmodium

species

Increased mortality at > 100,000/uL

High mortality at > 500,000/uL

*RDTs provide a simple, rapid, sensitive method for determining the

presence of antigens produced by malaria parasites

> 20% of parasites identified as pigmentedcontaining trophozoites and schizonts

*RDTs rely on specific antigen-antibody reactions and immunechromatographic (dipstick) technology

> 5% of neutrophils with visible pigment

*Variable reports on performance (sensitivity and specificity), hence

quality control/assurance (QC/QA) is necessary

Complications
Plasmodium malariae
Glomerulonephritis
Nephrotic syndrome

Plasmodium vivax & ovale

Relapse

Application of RDTs

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

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,

emergency diagnosis (travelers)

Military situations, organized work forces

stand-by

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 antimalarial drug that is sustained long enough to ensure rapid
clearance of parasitemia

Thick blood film

An unfixed blood spot is stained with Giemsa,

Field's, or another Romanowsky stain

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Anti-malarial Drugs by Species

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
Uncomplicated P. falciparum Malaria
TM

First line drug: Arthemether + Lumefantrine (Coartem )

Pediatric Dose
5 - < 15kg: 1 tab
15 - < 25kg: 2 tabs
25 - < 35kg: 3 tabs
(follow 3-day bid regimen as
Day 3
in adult schedule)

Given with a fatty meal on confirmed diagnosis

Day 1
8 hours
Day 2

Adult Dose
4 tabs
4 tabs
4 tabs bid
4 tabs bid and PQ (SD)

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.
Contraindicate
d

Primaquine
single dose

Primaquine
tablet
single
dose

Primaquine
tablets single
dose

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)

Primaquine
tablets single
dose

Second line drug: QS + T/D/C

Chemoprophylaxis

Severe P. falciparum Malaria

parenteral Quinine Dihydrochloride Infusion

Atovaquone/proguanil (Malarone)

Chloroquine phosphate (Aralen and generic)

Doxycycline

Hydroxychloroquine sulfate (Plaquenil)

Mefloquine (Lariam and generic)

Primaquine

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

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DENGUE VIRUS

Belongs to the family Flaviviridae

4 serotypes

Infection to one serotype confers lifelong immunity only to that

serotype

Humans are the main reservoir

Transmitted by mosquitoes

DEN-1, DEN-2, DEN-3, DEN-4

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

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

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)

Spleen, liver, bone marrow

Monocytes, lymphocytes,
macrophages

Kupffer

cells,

alveolar

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

In a subsequent infection, preexisting heterologous antibodies

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

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)

Virus serotype

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

Epidemic potential: viremia level, infectivity

DHF risk is greatest for DEN-2, followed by DEN-3, DEN4 and DEN-1

Host Risk Factor for DHF

Immune status

Age

Genetic predisposition

Previous infection with dengue virus

Classic Dengue Fever

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.

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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Clinical Course of Dengue Fever: Things to watch out for

Maculopapular rash

Appears near
defervescence

the

time

of

Often lasts for 2-4 days and may

be accompanied by scaling and

Febrile phase

Critical phase

Recovery phase

pruritus

Dehydration; high fever may cause neurological

disturbances and febrile seizures in young
children
Shock
from
plasma
leakage;
severe
hemorrhage, organ important
Hypervolemia (only if IV fluid therapy has been
excessive and/or has extended into this period)

Other Signs and Symptoms

st

Differential Diagnosis

Flushed facies during the 1 24-48 hours

Lymphadenopathy

Typhoid fever

Injected conjunctivae

Leptospirosis

Inflamed pharynx

Malaria

Mild respiratory and gastrointestinal symptoms

Measles, rubella

Acute HIV syndrome

Chikungunya

Hemorrhagic Manifestations

Skin hemorrhages: petechiae, purpura, ecchymoses

West Nile virus infection

Gingival bleeding

Viral hemorrhagic fevers

Nasal bleeding

Early severe acute respiratory syndrome

Gastrointestinal bleeding, hematemesis, melena, hematochezia

Rickettsial diseases

Hematuria

Increased menstrual flow

Any other disease that can manifest in the acute phase as an

undifferentiated febrile syndrome

WHO (2009): Suggested Dengue Classification and Levels of

Severity

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

Clinical Course of Dengue Fever

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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

Treatment

Mainly supportive

Use of antipyretics

Fluid resuscitation

Correction of breathing disorders

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

Renal failure may develop, often during the second week

of illness dialysis is sometimes required

Hemorrhagic manifestations:
purpura, and ecchymoses

epistaxis,

petechiae,

Laboratory Findings
Clinical Manifestations

What clinical manifestation should alert a health practitioner to

suspect leptospirosis among patients presenting with acute
fever?
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]

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

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 13 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 (Weils Syndrome)

Characterized by jaundice, renal dysfunction, and

hemorrhagic diathesis

Mortality rate: 515%

The onset of illness is no different from that of less

severe leptospirosis

After 49 days, jaundice as well as renal and vascular

dysfunction generally develop

Pulmonary involvement in many cases cough,

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

Direct Detection Method

Culture and Isolation
Remain the GOLD standard BUT
is
time-comsuming,
laborinsensitive
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

Indirect Detection Method

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

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Antigen-Antibody Agglutination
Test (Leptospira Serology BioRad)
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

Prevention

Isolation of the organism from the

patient o

Seroconversion or a rise in
antibody titer in the microscopic
agglutination test (MAT)

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

Definitive diagnosis

Most effective preventive measure is avoidance of high-risk

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

Post-exposure Prophylaxis for Leptospirosis

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

TYPHOID FEVER
ENTERIC FEVER

Differential Diagnosis

Dengue fever

Malaria

Enteric fever

Viral hepatitis

Hantavirus infections

Rickettsial diseases

Classic syndrome

Acute illness

Fever, headache, abdominal pain,

bradycardia, splenomegaly, leukopenia

Prototype: typhoid fever, Salmonella enterica

serotype typhi

relative

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

Treatment

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

Antibiotic therapy should be completed for 7 days, except for

azithromycin dehydrate which could be given for 3 days

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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 Peyers 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

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%

Diagnosis

Rose Spots

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

Clinical Features

Gastrointestinal bleeding (10-20%) and intestinal perforation (13% most commonly occur in the third and fourth weeks of illness
and results from hyperplasia, ulceration, and necrosis of the
ileocecal Peyers 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 10 -10 colony-forming units

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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 (Katayamas 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 all things, God may be glorified

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