Fulminant Leptospirosis

(Weil's disease)

By
Hany Gomaa Saleh Youssef
MB.B.CH.
 Case 1

 A 43-year-old male taxi driver is evaluated in the emergency department for a 3-day
history of fatigue, feverish feeling (unquantified), generalized muscle pain, headache,
liquid bowel movements, dark brown urine, and dyspnea. He is a recovering alcoholic
who stopped drinking 8 months ago. He has no previous history of allergies to
medications, never had a blood transfusion, and has a 1-pack-year smoking history.
He has taken only acetaminophen to manage his symptoms.
 On admission, blood pressure is 120/60 mm Hg, heart rate 104 beats/min, respiratory
rate 39 breaths/min, oxygen saturation 91% on room air, and temperature 36°C
(96.8°F). He is diaphoretic, pale, and jaundiced. He had mild hyperemia of the
pharyngeal mucosa and mild conjunctival injection. Lung fields are clear. His
abdomen is soft and not tender, with no hepatosplenomegaly or adenopathy.
 On admission, laboratory results are: hemoglobin 113 g/L, hematocrit 32.6%,
leukocytes 8.9 × 109/L (3% lymphocytes, 7% monocytes, 50% segmented
neutrophils, 40% banded neutrophils), platelets 20 × 109/L, prothrombin 85%, partial
thromboplastin time 39.7 sec, urea nitrogen 43 mg/dL, creatinine 3.88 mg/dL, lactate
dehydrogenase 304 U/L, creatine kinase 6316 U/L, total bilirubin 7.75 mg/dL, direct
bilirubin 5.08 mg/dL, indirect bilirubin 2.67 mg/dL, aspartate aminotransferase 277
U/L, alanine aminotransferase 116 U/L, alkaline phosphatase 94 U/L, and gamma-
glutamyl transpeptidase 176 U/L.
Arterial blood gas measurements are: pH 7.34, Pao2 52 mm Hg, Paco2 27.8 mm Hg,
bicarbonate 18.3 mEq/L, and oxygen saturation 87%. Urinalysis reveals: density
1005, occult blood +++, leukocytes countless, erythrocytes countless, remaining
findings negative. Serologic findings are: Leptospira immunoglobulin (Ig) M,
negative; hepatitis A, B, and C, negative; cytomegalovirus IgM, negative. After
these findings are obtained, the patient is interviewed again. He reports that he was
working at a construction site 10 days ago. The environment was humid, contained
stagnant water, and was infested with rats, cats, and dogs.
The patient was admitted to the ICU where he soon deteriorates, developing
respiratory failure and severe hypotension with signs of hypoperfusion. He is
intubated, and mechanical ventilation and vasopressor support are initiated.

– Does the patient have signs of either acute or chronic sepsis?

– Which systems are affected most severely?

– What is the epidemiologic link? Does it correlate to the clinical presentation?

– What is the diagnostic value of the Leptospira seroology in relation to the

evolution of the disease?
 Case 2
A 49 year-old man of Chinese descent with no medical history presented in mid-January to
our hospital for a history of fever (102.5°F), myalgias, and severe bilateral calf pain that
began six days prior.
He had a 30 pack-year history of cigarette smoking, drank four to six beers almost every day
for two years and smoked marijuana occasionally. He denied recent travel, owned two healthy
pets and worked as a construction worker. The patient denied any recent travel outside the
USA. He denied recent antibiotic exposure or sick contacts.
Vital signs in the emergency department were notable for a temperature of 101°F, pulse of
120 beats/min and blood pressure of 156/63 mm Hg. The patient was alert and oriented. The
ocular examination was notable for scleral icterus. The skin appeared jaundiced, the lungs
were clear to auscultation, the abdomen was soft, bilateral lower extremity tenderness was
noted and dorsal pedal pulses were present bilaterally.
Initial laboratory study results were notable for a creatinine of 2.3 mg/dL, platelets of 58,000
cells/mm3, hemoglobin of 12.8 G/dL, white blood cell count of 8.9 × 10 3 cells/mm3 with
lymphopenia of 2.4%, total bilirubin of 4.3 mg/dL, direct bilirubin of 2.6 mg/dL, alkaline
phosphatase (ALP) of 143 U/L, aspartate aminotransferase (AST) of 201 U/L, alanine
aminotransferase (ALT) of 246 U/L, and creatine kinase of 1219 U/L. The urine analysis
showed moderate hematuria but no proteinuria. Results of lower extremity Doppler
ultrasonography and chest radiography were negative, and electrocardiography showed
normal sinus rhythm at 76 beats/min.
The patient was admitted to the intensive care unit for sepsis and multiorgan dysfunction.
Intravenous (IV) ceftriaxone and vancomycin were initiated with aggressive fluid
resuscitation.
The following day, the patient's acute renal failure, hyperbilirubinemia, anemia and
thrombocytopenia worsened. Serologic test results for acute hepatitis A, B and C infections
were negative. A peripheral smear showed no schistocytes. Levels of C3, C4, antinuclear
antibodies, anti-dsDNA, antineutrophil cytoplasmic antibodies, and anti-glomerular basement
membrane antibodies were within normal limits. Renal ultrasonography results were normal.
Computed tomography of the abdomen showed pancolitis, cholelithiasis and nephromegaly.
On the third day, the patient had worsening oxygenation with slight hemoptysis and
developed new inferior bilateral infiltrates. Physical examination revealed the development of
fine crackles at the bases of his lungs. Arterial blood gas on 2 L of oxygen revealed a pH of
7.45, PCO2 (partial pressure of carbon dioxide) of 28, PO2 (partial pressure of oxygen) of 55,
oxygen saturation of 90% and bicarbonate of 19.5. The antibiotic regimen was broadened to
IV cefepime, and vancomycin was continued. The right upper quadrant sonogram showed
thickening of the gallbladder wall. Urine legionella antigen and serum HIV antibody results
were negative. Initial blood cultures and sputum culture results were negative. The patient's
acute renal failure, hyperbilirubinemia, anemia and thrombocytopenia continued to
deteriorate. The patient was started on 125 mg of methylprednisone every six hours for five
days and desmopressin for suspicion of alveolar hemorrhage in the presence of renal failure.
On the fourth hospital day, a nasopharyngeal swab for influenza A was conducted, and results
were positive. All antibiotics were stopped, and the patient received one dose of oseltamivir.
The patient's clinical status and renal failure started to improve, but the cholestatic picture
was worsening, with a total bilirubin of 64.7 mg/dL, direct bilirubin of 44.8 mg/dL, AST of
87 U/L and ALT of 121 U/L.
On the fifth day, the patient developed a maculopapular, nonpruritic rash on the face, torso,
abdomen and upper extremities involving the palms. Biopsy was done and showed lichenoid
dermatitis (drug reaction). Serum leptospira antibodies were sent to the NYC Board of Health
for specialized testing. While the patient was taking corticosteroids, the hyperbilirubinemia,
thrombocytopenia, hemoptysis and renal failure resolved over the next few days. The final
laboratory study results were notable for a creatinine of 0.8 mg/dL, total bilirubin of 1.8
mg/dL and platelets of 165 cells/mm 3. There was a near complete resolution of the chest
radiography findings. Furthermore, the rash and the patient's calf pain gradually improved,
and the patient was subsequently discharged.
Two weeks later, the NYC Board of Health reported the antibodies for leptospira as positive.
A microagglutination test (MAT) confirmed the serovar Leptospira icterohaemorrhagiae,
with the titers 1:6400. The patient was recalled for insertion of an indwelling catheter for a
14-day course of IV ceftriaxone after which he improved. Retrospectively, after having been
asked about any epidemiologic factors that placed him at risk for contracting leptospirosis, the
patient admitted to having been in contact with rat urine with his bare hands at a construction
site in NYC.
 Diagnosis :

High clinical suspicion is the pivotal point for the diagnosis of leptospirosis. It can
cause the following conditions:

1. Mild disease similar to a flu-like illness

2. Weil disease, characterized by jaundice, renal failure, bleeding, and myocarditis

associated with dysrhythmias

3. Pulmonary hemorrhage and respiratory failure

4. Meningoencephalitis and aseptic meningitis

Clinical and laboratory study abnormalities will depend on the affected organs.
A . C l i n i c a l M a n i f e s t a t i o n s:

The incubation period for Leptospira is usually 10 days, but may vary from 5 to 14
days. Two phases are classically described:
1. Leptospiremic phase, during which bacteria disseminate through the bloodstream
to the organs and body tissues; this usually occurs within 5 to 7 days. Death is rare
at this stage, and the symptoms may resolve.
2. Immunologic phase, during which maximal organ injury occurs; it can be fatal.
The clinical presentation may be nonspecific with generalized signs and symptoms,
such as abrupt fever (38°C-40°C [100.4°F-104°F]), chills, generalized myalgia,
headache, anorexia, asthenia, conjunctival injection without exudates, coughing,
pharyngitis, vomiting, abdominal pain, and watery diarrhea. Less frequently seen in
this phase are lymphadenopathies, hepatomegaly, and splenomegaly.The
immunologic phase can start between days 4 and 30 after the initial phase. An
increase is seen in the titer of the specific LeptospiraIgM. The patient may develop
renal failure, jaundice, cardiac dysrhythmias, aseptic meningitis, conjunctival
injection (with or without hemorrhage), ocular pain, myalgia, adenopathy, and
hepatosplenomegaly.
Manifestations will be related to the disease severity and affected organs.
Subclinical presentations are possible.
1. Weil's Disease
This is the most severe presentation of leptospirosis. The most frequently affected systems
are:

■■ Renal: The primary manifestation consists of non oliguric renal failure associated with
hypokalemia and hyponatremia due to increased fluid loss and no reabsorption. Urea nitrogen
is usually below 100 mg/dL, and creatinine between 2 and 8 mg/dL. If not treated
aggressively with fluid replacement, the patient may develop oliguria. Tubulointerstitial
nephritis and glomerulonephritis are caused by immune complexes.

■■ Hepatic: Liver histopathologic findings do not correlate with the increased bilirubin
levels, which can rise to 80 mg/dL, with transaminase levels below 200 U/L. Other
manifestations include degeneration of hepatocytes, Kupffer cell hypertrophy,
erythrophagocytosis, cholestasis, mononuclear infiltrates, and an absence of necrotic foci.

■■ Hematologic: Leptospirosis appears as peripheral leukocytosis with a left shift and

mainly as thrombocytopenia in the absence of disseminated intravascular coagulation.

■■ Cardiovascular: Cardiac failure is uncommon; the main manifestations are dysrhythmia

and nonspecific electrocardiographic changes, often atrial fibrillation, sinus tachycardia, atrial
flutter, and premature ventricular complexes. A sudden cardiovascular collapse can occur,
which requires aggressive support. Histologic findings are interstitial myocarditis with
involvement of the conduction system, as well as coronary arteritis and aortitis.
2. Severe Pulmonary Hemorrhage Syndrome

This complication is usually associated with Weil disease or is the only

manifestation. The symptoms appear early, mainly as dyspnea or coughing and
sometimes hemoptysis, which is seldom detected until the patient is intubated. The
radiologic findings are caused by bilateral lower lobe infiltrates and progress to
global alveolar infiltrates. Clinically this syndrome is consistent with acute
respiratory distress syndrome associated with the hemodynamics of septic shock.
Histopathologic examination shows injury to the capillary endothelium with intra-
alveolar and interstitial hemorrhage, an absence of inflammatory infiltrates, and
severe disruption of the air spaces.
3. Meningoencephalitis and/or Aseptic Meningitis

This condition occurs in 80% of patients with leptospirosis and is manifested by an

intense pulsating headache located in the frontal and bitemporal regions and by neck
stiffness; it may be associated with delirium. Cerebrospinal fluid reveals mild
pleocytosis and a lymphocyte count below 500/mm3, mild increase in proteins (50-
100 mg/mL), and a normal glucose level. Neurologic manifestations are not
frequently described, such as transverse myelitis, hemiplegia, Guillain-Barré
syndrome, and severe meningoencephalitis.
B . L a b o r a t o r y D i a g n o s i s:
Several detection techniques for the isolation of spirochetes, as well diagnostic tests for the
disease, have been developed. Their value depends on the stage of the disease and whether the
patient has received antibiotics.
1. Direct detection methods: Leptospira can be seen in the leptospiremic phase in urine and
blood using a dark field microscope, though the method is not very sensitive (40.2%) or
specific (61.2%). The use of other direct techniques is not widespread. The most sensitive
detection method is polymerase chain reaction (PCR), which can be helpful early in disease
development or as a confirmation tool.
2. Cultures and identification: The culture sample must be obtained during the febrile phase
in the 10 first days of the disease and before the patient has received antibiotics. Isolation is
possible in cerebrospinal fluid, blood, and peritoneal fluid. The sample should be placed in
the culture medium immediately after being collected (ie, at the patient’s bedside). The urine
test is performed on a sample obtained after a week of symptom development. The sample
should be processed in less than an hour because the viability of the bacteria in an acid
medium is poor. After isolation, the microorganism should be serotyped according to the
antigens.
3. Indirect detection methods: The methods used most often are the microscopic
agglutination test and the detection of Leptospira IgM. This is a live antigen test;
agglutination occurs when the bacteria come in contact with the serum of an infected patient.
Results are considered positive when the serotype titers increase fourfold during the course of
the disease. Its greatest limitation is poor sensitivity in the initial phases; Leptospira can be
determined after day 5 of symptom onset.
 Management
The severe presentations of leptospirosis require monitoring and an approach to the
affected systems that includes an early start and aggressive support measures.
Infected patients recover completely.

Admission to the ICU: The biggest challenge is in identifying patients with the most
severe forms of leptospirosis, such as Weil disease and severe pulmonary
hemorrhage syndrome. The following clinical findings confer a higher risk of death:

1.Age 30 to 40 years and older

2. Acute renal failure (oliguria, hyperkalemia, creatinine ≥3.0–4.0 mg/dL)

3. Respiratory failure (dyspnea, pulmonary rales, radiologic evidence of infiltrates)

4. Hypotension

5. Arrhythmia

6. Altered mental status

Isolation: These patients must be admitted to the ICU. They do not require special
isolation measures; however, level 2 biosafety measures must be maintained,
especially with body fluids such as blood and urine.

Fluid and electrolyte replacement: From the standpoint of renal compromise,

nonoliguric hypokalemic renal failure can be managed with aggressive intravenous
fluid replacement and supplemental potassium to avoid oliguric renal failure and
severe hypokalemia.

Cardiovascular support: Guidelines for vasopressor use should follow the

Surviving Sepsis Campaign guidelines. The target mean arterial pressure should be
65 to 70 mm Hg in adults. Caveats for higher mean arterial pressure in patients with
a history of hypertension or inadequate end-organ perfusion should be considered.
Norepinephrine is the first-line treatment because of these patients’ higher risk of
arrhythmia. Epinephrine is a second-line drug.
Dobutamine can be considered for inotropic support. Arrhythmias must be treated
according to advanced cardiac life support guidelines.

Liver dysfunction disturbances: A severe elevation of bilirubin levels (above 30–

40 mg/dL) is typical, associated with cholestasis and sepsis. Liver function returns
to normal with recovery from illness without sequelae.
Acute renal failure: If renal support is required, it must be started early because it
has been shown to impact survival; in countries with limited resources, peritoneal
dialysis has been used. However, the use of continuous hemofiltration has been
shown to be more effective than peritoneal dialysis in treating infection-associated
acute renal failure.

Respiratory failure: Ventilatory support, when necessary, is based on pulmonary

protection measures, as in acute respiratory distress syndrome, with strategies based
on low tidal volumes (<6 mL/kg) and high positive end-expiratory pressure.
Nevertheless, the mortality rate for severe pulmonary hemorrhage syndrome is more
than 50%.

Pregnancy: Leptospira infection can result in miscarriage in more than 50% of

patients in some series. Late infections can result in the fetus having active
leptospirosis at birth but does not appear to be associated with congenital
abnormalities or long-term sequelae in surviving children; as such, leptospirosis
acquired in pregnancy is not an indication for termination.
 Treatment

Antibiotic treatment must be started as soon as possible (Table 1). Leptospira

bacteria are very sensitive to antibiotic therapy, which achieves early response and
control of the infection. However, most patients present in advanced stages of the
disease and often have multiorgan compromise, making the impact of antibiotic
therapy difficult to determine.
Other proposed therapies:

1.Steroids: The use of high doses of steroids has been proposed as an option for
severe cases of leptospirosis. Treatment plans using methylprednisolone, from
250 mg/day to 1 g/day for 3 days, followed by prednisone, 1 mg/kg/day, show
apparent benefit to the patient with severe pulmonary hemorrhage syndrome.
However, the evidence is not robust and there is a lack of well-designed studies
to show efficacy. Studies of dexamethasone treatment have not shown any
benefit.

2. Plasma exchange: Some cases have been reported of patients with elevated
creatinine levels and renal failure who were treated with plasmapheresis, resulting in
recovery of liver and renal functions. The beneficial effects of plasma exchange
could be attributed to amelioration of the toxic effects of hyperbilirubinemia in the
hepatocytes and renal tubular cell function.

3. Desmopressin: This medication has been used as adjunct therapy in patients with
massive hemoptysis. The level of evidence for it is limited to cases using an infusion
of 0.3 μg/kg in 30 mL of saline administered over 30 minutes; this treatment could
be repeated two or three times at 12- or 24-hour intervals if minor bleeding
occasionally persists.
 Prevention

Disease prevention should be based on avoiding contact with the

bacteria while in high-risk environments. A vaccine is useful, but may
not be readily available in some countries. Doxycycline, 200 mg
weekly, can provide prophylaxis.
Case 1: Study Rationale:
– Does the patient have signs of either acute or chronic sepsis?
Yes, our patient has signs and laboratory findings of sepsis. His Sequential Organ Failure
Assessment (SOFA) score is 11 and quick SOFA (qSOFA) score is 1. He also has evidence of
compromise of the renal, hepatic, hematologic, and respiratory systems; therefore, he has
severe sepsis with an acute presentation.
– Which systems are affected most severely?
He has multi systemic compromise, initially with severe renal, hematologic, and hepatic
failures; this is the most severe presentation of leptospirosis, Weil disease, and is seen before
cardiovascular and respiratory failure.
– What is the epidemiologic link? Does it correlate to the clinical presentation?
The patient reported working at a construction site 10 days ago. The environment was humid,
contained stagnant water, and was infested with rats, cats, and dogs. Other high risk sites are
rivers and areas of humid soil. Farmers, cattle ranchers, veterinarians, fishermen, adventure
sportsmen, swimmers, and nature tourists are also at high risk of Leptospira infection.
– What is the diagnostic value of the Leptospira serology in relation to the evolution of the
disease?
The incubation time of Leptospira is usually 10 days, but may vary from 5 to 14 days. The
immunologic phase is between 4 and 30 days before symptoms appear. This patient’s
nonspecific symptoms began 6 to 7 days after his exposure, and he presented within 10 days
of his exposure. The disease is in the immunologic phase. Organ compromise is present. In
the case study, the IgM result was negative at admission (3 days after onset), inconclusive on
hospital day 5 (8 days after onset), and positive on hospital day 8 (10 days after onset). The
PCR result was positive, and the disease was confirmed.
REFRENCES:

•Jiménez, J. I. S., Marroquin, J. L. H., Richards, G. A., & Amin, P. (2018).

Leptospirosis: Report from the task force on tropical diseases by the World
Federation of Societies of Intensive and Critical Care Medicine. Journal of Critical
Care, 43, 361–365. doi:10.1016/j.jcrc.2017.11.005

•Delmas, B., Jabot, J., Chanareille, P., Ferdynus, C., Allyn, J., Allou, N., …
Vandroux, D. (2018). Leptospirosis in ICU. Critical Care Medicine, 46(1), 93–99.
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