(Missed lecture)

Tropical Infectious
Diseases:
Dra. Rosario

I.
II.

III.

Outline
Introduction: Case 4
Leptospirosis
A. Pathogenesis
B. Transmission
C. Leptospirosis in the Philippines
D. Clinical manifestations
Weils Disease
E. Treatment
F.
Laboratory Diagnosis
G. Prognosis
H. Prevention
Key Concepts

CASE 4
A 28 year-old male, a government employee
consulted the ER because of fever, jaundice, and
oliguria
o Reported abdominal and leg pains
o Wading in floodwater 2 weeks ago
PE: BP=120/90; HR=100/min; RR=26/min; T=39C
With conjunctival suffusion, icteric sclerae
Breath sounds clear
No abnormal heart sounds
Voluntary abdominal guarding; LS: 12 cms; Traube
space obliterated
Calf muscle tenderness

Primary Impression?
1. Dengue fever
2. Enteric fever
3. Malaria
4. Leptospirosis

ISSUES
Early clinical recognition and diagnosis
Management of complications
Prevention and control
LEPTOSPIROSIS
Zoonotic disease caused by spirochetes of the
genus Leptospira
o Thin, flexible, finely coiled, Gram-negative
bacteria
o Obligately aerobic, slow-growing, fastidious
Reservoir: Wild and domestic animals
Human infection acquired through direct contact
with infected animals or by contact with water/soil
contaminated by infected urine
Leptospires are tightly and regularly coiled, with
characteristic hooked ends and are highly motile,
spinning around their longitudinal axis and darting back
and forth [Harrisons]

Leptospira interrogans var. icterohaemorrhagiae

on EM
Question: What is the primary underlying problem in
Leptospirosis?
1. Toxin secretion
2. Invasion of reticulo-endothelial system
3. Hypersensitivity reaction to leptospiral
antigens
4. Systemic vasculitis

Ang, Angulo, Aover; Edited by Aover

PATHOGENESIS
Proliferation in bloodstream and spread to distant
organs
No tissue tropism
Capillary leakage and hemorrhage due to
disruption of endothelial cell membrane (systemic
vasculitis)
o Accounts for broad spectrum of clinical
illness
Leptospires infect humans through the mucosa/abraded
skin. The organism will resist innate immune defenses
and proliferate in the bloodstream or extracellularly
within organs, and then disseminate hematogenously to
all organs. Incubation period averages 5-14 days.
Life cycle will be completed as leptospires traverse the
interstitial space of the kidney, penetrate the basement
membrane of the proximal renal tubules, cross through
proximal renal tubuloepithelial cells, and become
adherent to the proximal renal tubular brush border,
whence they are excreted in the urine. In humans,
colonization can last up to years, with unknown
pathophysiologic consequences[Harrisons]

TRANSMISSION OF LEPTOSPIROSIS
Epidemics common after natural disasters in
endemic areas (flooding, tropical storms,
hurricanes)
Risk factors:
o Walking through streams, creeks, puddles
o Swimming, kayaking, white-water rafting
o Exposure to rodents
Factors that facilitate human infection are those that
bring susceptible persons into indirect contact with
contaminated animal urine through surface waters, moist
soil or other wet environments or into direct contact with
urine and other excreta of infected animals. [Harrisons]

LEPTOSPIROSIS IN THE PHILIPPINES

Average of 680 cases and 40 deaths reported every
year
Prevalence of 10/100,000
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Seasonal; peak incidence during the rainy

months of July to October
Urban domestic rats, rural field rats,
water buffalo, cattle, pigs, dogs and
monkeys: tested positive for leptospiral
antibodies

October 2009 Outbreak

Declared by DOH two weeks after widespread

flooding caused by Tropical Storm Ondoy
(Sept. 26, 2009)

Average: 680 cases and 40 deaths per year

As of 13 November 2009: 2,292 suspected

cases (257 confirmed) and 178 deaths (CFR
7.4%) in 15 hospitals in Metro Manila

Figure 2

Classic leptospirosis is usually biphasic. Initial

Leptospiremic phase with acute fever lasting for 310 days, wherein the organism may still be cultured
from blood. Later Immune phase, fever will be
unresponsive to antibiotics, but leptospires can be
isolated from urine. [Harrisons]
Weils Syndrome can be monophasic and
fulminant. [Harrisons]

Severe Leptospirosis: Weils Disease

Rapidity of progression to fulminant illness is

variable

Fatality rate: ranges from 5-40%

Highly dependent on severity of illness caused

by different serovars and quality of supportive
medical care

Weils Disease is characterized by variable

combinations of jaundice, acute kidney injury,
hypotension and hemorrhage, most commonly in the
lungs.[Harrisons]

Question: What is the pathophysiologic

mechanism of hepatic failure in Weils disease?
1. Hepatocyte degeneration
2. Centrilobular necrosis
3. Periportal necrosis
4. 2 and 3 only

Figure 1. Showing increased incidence of

leptospirosis cases in 2009

CLINICAL MANIFESTATIONS
Subclinical manifestation with subsequent
seroconversion
Two clinical syndromes:
o 90%: self-limited, systemic illness
o 10%: severe, potentially fatal illness
characterized by renal and hepatic
failure and pneumonitis with a
hemorrhagic diathesis (Weils
disease)

Hepatic Failure in Weils Disease

Results from hepatocyte degeneration with

cholestasis and concomitant vascular injury

Hepatosplenomegaly (>25% of icteric

patients)

Bilirubin: normal or slightly increased

(<20mg/dL), peak by day 7 in 85% of patients
o Fulminant disease (>80mg/dL)

AST, ALT rarely >200 U/L, Inc. PT rare

Hepatocellular necrosis is absent

Hepatic histopathology in fatal cases is associated

with disruption of cellular cohesion, plugging of bile
canaliculi, occasional acute inflammatory infiltrates,
and focal periportal cellular necrosis and steatosis.
Widespread hepatocellular necrosis is NOT FOUND.
[Harrisons]

Question: What is the primary pathophysiologic

mechanism of renal failure in Weils disease?
1. Renovascular obstruction
2. Rapidly progressive glomerulonephritis
3. Interstitial nephritis
4. Diffuse acute tubular necrosis
Renal Failure in Weils Disease

Hallmarks: impaired sodium reabsorption,

increased distal sodium delivery, and K+
wasting

Rapid onset of uremia, oliguria (2nd week)

If with thrombocytopenia (even without DIC) or

anuria poor prognosis

BUN: Usually <100, may be >300mg/dL

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Creatinine: Usually 2-8, may be >18mg/dL

Biopsy: interstitial nephritis with focal ATN
Leptospirosis and Renal Failure
o Leptospirosis can account for up to
40% of cases of acute renal failure in
Asia (Sitprija et al. 1975)
o Correlates well with prognosis (Marcial
M, Phil J Microbiol Infect Dis 1995)
Oliguria and need for dialysis
Hemorrhage
Duration of jaundice
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. Hypotension is associated with acute tubular
necrosis and oliguria. Renal function typically returns
to normal in survivors of severe disease [Harrisons]

Cardiopulmonary Dysfunction in Weils Disease

Hemorrhagic pneumonitis, ARDS: seen in

severe infection
o CXR: multiple patchy infiltrates =
suggestive of alveolar haemorrhage

Mainly due to widespread vasculitis

Worsened by impaired hepatic production of
coagulation factors
Aggravates existing jaundice and further
compromises renal function

Question: Which patient will need hospital

admission?
1. Outpatient (Mild LEPTOSPIROSIS)

Any suspected case of leptospirosis presenting

with acute febrile illness and various
manifestations BUT
o Stable vital signs
o Anicteric sclerae
o With good urine output
o No evidence of
meningismus/meningeal irritation,
sepsis/septic shock, difficulty of
breathing nor jaundice
o Can take oral medications (Grade A)
2. Healthcare/Hospital Setting (Moderate to
Severe)

Any suspected case of leptospirosis presenting

with acute febrile illness associated with
o Unstable vital signs
o Jaundice/icteric sclerae
o Abdominal pain, nausea, vomiting and
diarrhea
o Oliguria and anuria
o Meningismus, meningeal irritation
o Sepsis/septic shock
o Altered mental states
o Difficulty of breathing and hemoptysis
TREATMENT OF LEPTOSPIROSIS

Figure 3. Pulmonary hemorrhage in Leptospirosis

Cardiac arrhythmias in up to 20% of patients;

may progress to cardiovascular collapse with
shock

Histopath: Pulmonary congestion and intraalveolar hemorrhage with severe airspace

disorganization; myocarditis; acute coronary
arteritis and aortitis

Severe pulmonary hemorrhage in leptospirosis is a

clinical problem, manifesting with cough, chest pain,

and hemoptysis but without purulent sputum. Cases
of severe pulmonary hemorrhage syndrome that
come to autopsy are characterized by the absence
of inflammation, the paucity of organisms visible by
silver or immunohistochemical staining, and grossly
obvious frank hemorrhage. Immunoglobulin and
complement deposition have been demonstrated in
lung tissue involved in leptospiral pulmonary
hemorrhage.
Cardiac involvement is commonly reflected on the
electrocardiogram as nonspecific ST and T wave
changes but also as right-bundle-branch block and
right- and/or left-sided ventricular dilation indicating
myocarditis. [Harrisons]

MILD LEPTOSPIROSIS:

Hemorrhagic Diathesis
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powerpoint)

Mild leptospirosis often is not specifically identified and

typically resolves without antibiotic treatment. If clinical
suspicion is high or the diagnosis is suggested or
confirmed by laboratory findings in an appropriate
context (e.g., clinical presentation, exposure history);
mild disease should be treated with oral antibiotics
particularly, doxycycline. [Harrisons]

When Would You Suspect Pulmonary

Complications of Leptospirosis?

Tachypnea (RR>30/min) is the first sign of

pulmonary involvement

One should consider lung involvement:

o Onset of cough
o Hemoptysis
o Dyspnea

Pulmonary symptoms usually appear on the

4th-6th day of disease
Pulmonary complications in Leptospirosis:

MODERATE TO SEVERE LEPTOSPIROSIS:

Dosage of Antibiotics in ADULTS WITH RENAL

IMPAIRMENT:

What Are the Indications for Acute Renal

Replacement Therapy or Dialysis?

Any one of the following is an indication for

dialysis:
o Uremic symptoms nausea, vomiting,
altered mental status, seizure, coma
o Serum creatinine >3mg/dL
o Serum K >5meq/L in an oliguric
patient
o ARDS, pulmonary hemorrhage
o pH <7.2
o Fluid overload
o Oliguria despite measures following
the algorithm (see figure at the end
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Which Patients Will Need Admission to the

Intensive Care Unit?

A management-oriented approach should be

utilized in the decision to determine the site of
care for patients

ICU admission is needed:

o Tachypnea
o Chest x-ray findings of localized or
multilobar infiltrates or pleural effusion
o Moderate to severe hypoxemia
What is the Role of Steroids in Pulmonary
Complications of Leptospirosis?

Bolus methyl prednisone given within the first

12 hours of onset of respiratory involvement

Methylprednisone should be given at a dose of

1gm IV/day for 3 days followed by oral
prednisolone 1mg/kg/day for 7 days
LABORATORY DIAGNOSIS OF LEPTOSPIROSIS
Direct Detection Method
1. Dark-field
microscopy/immunofluorescence/light
microscopy

Sensitive during the first 7-10 days of the

acute illness

Histopathological stains and

immunohistochemical leptospires in tissues

Direct examination of urine or blood by dark-field

microscopy has the potential to provide a rapid
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diagnosis but is not recommended because of

complicating artifacts [Harrisons]

Culture and isolation

Remains the GOLD standard
Requires 6 to 8 weeks for the result
Can identify the serovar but is insensitive
Requires biosafety level II facility

Leptospires can be cultured from blood and CSF

during the first 710 days of illness and from urine
beginning in the second week. Cultures usually
become positive after 24 weeks (range, 1 week to 6
months). Urine cultures can remain positive for
months or years despite antibiotic therapy
[Harrisons]

3. Polymerase Chain Reaction (PCR)

Has the advantage of early confirmation of the

acute leptospiremic phase

Currently not generally available because of

the cost-limiting nature of the test and the
need for trained personnel
Indirect Detection Method
1. Microagglutination Test (MAT)

A four-fold rise of the titer from acute to

convalescent sera is confirmatory of the
diagnosis

Highly sensitive and specific BUT timeconsuming

Cross-reactions may occur with syphilis, viral

hepatitis, HIV, relapsing fever, Lyme disease,
legionellosis and autoimmune diseases

A single titer of at least 1:1600 in

symptomatic patients is indicative of
leptospirosis

A positive MAT result reflects the presence only of

Leptospira-specific antibodies and cannot be used to
precisely identify the infecting serovar because one
serovar may induce antibodies that cross-react with
other serovars. When patients have a high pretest
probability of leptospirosis, a single antibody titer
>1:200 is considered strong evidence of infection;
however, in regions where leptospirosis transmission
and subclinical disease are common, higher titers
are generally required for a confident diagnosis
because of long-lasting antibodies after a previous
infection. Because the MAT is generally negative in
the first 710 days after the onset of infection,
paired acute- and convalescent-phase serum
samples are preferred to document seroconversion
or a fourfold rise in titer. [Harrisons]

2. Specific IgM Rapid Diagnostic Tests

(LeptoDipstick, Leptospira IgM ELISA
(PanBio), MCAT and Dridot)

Serologic tests in a single test format

Quick detection of Leptospira genus-specific

IgM antibodies

Sensitivity improves if taken beyond 7 days

(>90%)
3. Nonspecific Rapid Diagnostic Tests like
LAATS (Leptospira Antigen-Antibody
Agglutination Test (Leptospira Serology BioRad)
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Detects Leptospira antibody in human serum

through agglutination reaction
Used as a screening test and should be
confirmed with MAT
PROGNOSIS
Case fatality rate of about 10% in severe cases
Dependent on several factors
o Timely administration of effective
chemotherapeutic agents
o Quality of supportive care provided
o Virulence of infecting serovar
o Severity of the disease on admission
o Presence of co-morbidities

Adverse Prognostic Factors

Strongest predictor of death: Altered mental

status

Other poor prognostic signs:

o Acute renal failure (oliguria,
hyperkalemia, serum creatinine
>3.0mg/dL)
o Respiratory insufficiency (dyspnea,
pulmonary rales, CXR infiltrates)
o Hypotension
o Arrhythmias
**Hepatic failure alone (without renal failure)
rarely leads to a fatal outcome

The severity of illness in terms of pulmonary and

renal dysfunction is the most important determinant
of prognosis. Advanced age, clinically evident
pulmonary involvement, elevated serum creatinine
level, oliguria, and thrombocytopenia are associated
with a poor prognosis. [Harrisons]

PREVENTION
Avoid exposure
Chemoprophylaxis?

Antibiotic Prophylaxis for Leptospirosis

The most effective preventive measure is

avoidance of high-risk exposure

Pre-exposure antibiotic prophylaxis is NOT

ROUTINELY RECOMMENDED

Recommended regimen for pre-exposure

prophylaxis for non-pregnant, non-lactating
adults:
o Doxycycline 200mg once weekly (to
begin 1 to 2 days before exposure and
continued throughout the period of
exposure [Grade B])
Recommended Post-Exposure Prophylaxis for
Leptospirosis

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KEY CONCEPTS
Tropical infectious diseases usually occur,
but not exclusively, in developing countries
with warmer climates
Formulate a diagnosis of microbial infection
based on clinical and epidemiologic evidence,
supported by laboratory examinations
Inexpensive and effective medications are
available to treat most tropical infectious
diseases
Cost, as well as antimicrobial resistance, can
become a barrier to effective treatment
Adequate supportive measures are necessary,
to prevent complications and mortality
o Host factors, including the severity of
the illness and co-morbid conditions,
as well as the intervention-related
factors, are important to consider in
the overall management
Many tropical infections are preventable by
means of simple, inexpensive, and currently
available methods

Algorithm for the MANAGEMENT OF

OLIGURIA IN LEPTOSPIROSIS

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(Missed lecture)

Getting Sick in the

Tropics
Dra. Rosario

Ang, Angulo, Aover; Edited by Aover

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