Weil’s disease with haemoptysis and acute respiratory distress syndrome

Abstract

A 35-year-old male patient reached the emergency department after an episode of massive haemoptysis a few hours ago. Fever and dyspnea were mentioned to be present the last 5 days. His medical history included only malaria, successfully treated 2 years ago. Clinical examination revealed high fever, jaundice, cyanosis, tachypnea and bilateral rales on pulmonary auscultation. Laboratory investigation showed high erythrocyte sedimentation rate and C reactive protein, leucocytosis, anaemia, mild thrombocytopaenia, renal impairment, hyperbilirubinaemia and abnormal liver function tests; arterial blood gas analysis showed respiratory alkalosis with severe hypoxia. Thoracic X-ray revealed bilateral pulmonary infiltrates, whereas abdominal and heart ultrasound detected hepatomegaly and small pericardial infusion, respectively. The diagnosis of leptospirosis along with acute respiratory distress syndrome was confirmed by positive IgM Leptospira antibodies. Empirical treatment with triple antibiotic therapy and corticosteroids was applied. The patient was discharged after 1 week, without any symptoms and with almost normal laboratory tests.

Background

Leptospirosis is one of the most common zoonoses in the world, endemic in tropical areas, where 73% of all cases are accounted.^{1 2} It is an infectious, bacterial disease of humans and animals, caused by spirochetes of the genus Leptospira. The pathogenic Leptospira uses as reservoir a wide range of mammals, birds and reptiles along with the contaminated environment, completing its life circle by spreading haematogenously and being excreted to urine.^{3 4} Thus, transmission is succeeded either via direct contact with an infected animal or more commonly via contaminated soil, water and urine, as survival of pathogenic leptospires in the environment usually ranges from 3 to 14 days, even for months in soil and water with a neutral pH. Usual entrance spot are mucous membranes and injured skin.⁵ As a result, leptospirosis mostly affects populations whose work is related to animals, such as farmers, veterinarians, pet shop owners, workers in food production and packaging. Although the brown rat is thought to be the main cause for human infection, domestic animals may also be a spirochetes reservoir. Due to the wide range of transmission pathways and conditions, the control of leptospirosis is a very challenging matter. It is estimated that about a million cases are reported annually worldwide with a significant number of deaths (approximately 60.000) among them.¹

Human leptospirosis has a biphasic presentation, with an initial febrile phase lasting 5–7 days (septicaemic phase) followed by an asymptomatic period lasting 1–3 days and a secondary phase of illness (immune phase). In the majority of cases, it appears as an acute, self-constricted, febrile disease with non-specific symptoms (rigours, headache, nausea, anorexia, myalgias, cough, conjunctival suffusion, skin rash) and therefore can be under- or misdiagnosed (anicteric disease). In some cases though (approximately 10%), it can be presented with life-threatening manifestations, such as haemolysis, liver failure, jaundice, acute renal injury and pulmonary haemorrhage (icteric disease).^6–8 Weil’s disease, the icterohaemorrhagic infection, is the most severe and fatal form of leptospirosis and is characterised by jaundice, haemorrhagic predisposition and multi-organ damage, including renal, hepatic, pulmonary, cardiac and central nervous system dysfunction.^9–11 Signs of pulmonary attack may be cough, dyspnea, thoracic pain, blood stain in sputum or even haemoptysis and respiratory failure. A rare but serious and life-threatening complication of lung involvement is the pulmonary haemorrhagic syndrome, which is related to high mortality rates (>50%).^{6 10 12} The case of a patient with Weil’s disease and acute respiratory distress syndrome (ARDS) is described below.

Case presentation

A 35-year-old farmer presented with fever, flu-like symptoms and dyspnea the last 5 days. He mentioned massive haemoptysis (>200 mL) a few hours before admission. His medical history, other than malaria successfully treated 2 years ago, was free without any smoking habits. His vital signs were: severe hypoxia (sO₂=78%), increased respiratory rate (>30 breaths/min) and high temperature (38.5°C). Clinical examination revealed jaundice, cyanosis, tachypnea, bilateral rales on lungs’ auscultation, normal heart sounds and normal abdominal examination. A palpable liver was found with smooth, slightly painful borders, whereas no other significant findings were detected in the abdomen.

Investigations

Thoracic X-ray revealed bilateral pulmonary infiltrates (figure 1A, B) while arterial blood gas analysis (fractional inspired oxygen (FiO₂)=21%) showed partial pressure of oxygen (pO₂)=41 mm Hg, partial pressure of carbon dioxide (pCO₂)=30 mm Hg, sO₂=78%, pH=7.54, HCO₃=25.7 mmol/L, pO₂/FiO₂=195. Laboratory investigation showed white blood cells (WBC)=20.2x10⁹/L, erythrocyte sedimentation rate (ESR)=120/1 hour, hematocrit (Ht)=31.1%, haemoglobin=98 g/L, mean corpuscular volume=85 fL, mean corpuscular haemoglobin=30 pg, platelets (PLTs)=130.000, INR=1.2, prothrombin time (PT)=15 s, activated partial thromboplastin time (aPTT)=38 s, urea=55 mg/dL, creatinine=1.6 mg/dL, AST=47 IU/L, ALT=58 IU/L, bilirubin total/direct=7.8/3.9 mg/dL, γ-GT=219 IU/L and C reactive protein (CRP)=30 mg/dL (normal value <0.7). Fibrinogen degradation products (FDP) was between normal limits (<10 µg/mL) and D-dimer was slightly increased (270 µg/L, normal value <250 µg/L). Microscopic examination of red blood cell morphology revealed basophilic stippling with no schistocytes or fragmented cells. Abdominal ultrasound depicted increased liver’s size whereas heart ultrasound a small pericardial effusion. IgM antibodies against Leptospira were positive 2 days after the admission. Urine and blood cultures were proved to be negative.

Figure 1.

Bilateral pulmonary infiltrates compatible with acute respiratory distress syndrome before (A, B) and 4 days after treatment (C).

Differential diagnosis

Potential differential diagnosis must include febrile diseases with multi-organ involvement. Pulmonary-renal syndromes such as Goodpasture syndrome, Wegener granulomatosis, systemic lupus erythematosus and microscopic polyangiitis may present fever, general symptoms, haemolytic anaemia, renal failure and pulmonary haemorrhage. Specific antibodies (anti–glomerular basement membrane, c-antineutrophil cytoplasmic antibody (c-ANCA) and anti-dsDNA antibodies) should be positive to confirm the diagnosis. Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura meet the standards for thrombocytopaenia, renal failure and haemolytic anaemia, but respiratory involvement and failure can be present as a sepsis manifestation. In addition, other infectious causes must be excluded. Sepsis during community acquired pneumonia should be considered, and so has to be a relapse of malaria with life-threatening complications (renal-liver failure, pulmonary oedema, anaemia). Brucellosis is also a zoonotic disease that could be met in a farmer, although pulmonary and renal involvement is very rare. Another possible diagnosis, transmitted by small animals serving as a reservoir, includes viral haemorrhagic fevers (hantaan virus, lassa fever, krimea-kongo virus, ebola, yellow and dengue fever), which may present haemorrhages and multi-organ involvement.

Treatment

A possible diagnosis of Weil’s disease with ARDS was considered, based on its typical presentation and the strong clinical suspicion due to patient’s occupation. Empirical antibiotic treatment was applied (ampicillin/sulbactam 3 g tid, azithromycin 500 mg qd, metronidazole 500 mg tid) with addition of methylprednisolone 40 mg tid and ventilation with high oxygen flow rate (50%) to maintain adequate oxygenation. Definite diagnosis of Weil’s disease was confirmed by the specific antibodies.

Outcome and follow-up

There was complete resolution of fever, X-ray’s findings and haemoptysis after 4 days of treatment (figure 1C). The patient was discharged 1 week later. On dismissal, laboratory investigation showed improved blood counts: WBC=10.1x10⁹/L, ESR=50/1 hour, Hct=33.9%, Hb=106 g/L (normochromic normocytic anaemia, for which he was referred to a haematologist for further evaluation), PLTs=430.000, INR=1.1, bilirubin total/direct=2.4/1.05 mg/dL and CRP=4.1 mg/dL (<0.7). Renal function came back to normal.

Discussion

Leptospirosis is one of the leading causes of morbidity and mortality in the world among the zoonotic diseases, as it has a wide range of transmission routes. It is endemic in many tropical countries, where large sections of the population are engaged in agricultural activities (muddy land, paddy fields) and the climate conditions (high moisture content, frequent rainfalls) favour the survival of the microbe. It may also occur in temperate regions, with a 10-fold lower incidence than the tropical ones.¹³ Nevertheless, high humidity and heavy rainfalls may cause extensive outbreaks worldwide, because of widespread exposure to flood water.^{14 15} Another possible route of transmission is via recreational activities such as river rafting, adventure races or lake swimming as well as in military personnel.^{16 17} Poverty (poor housing, absence of sanitation, low education) is also an important factor contributing to the emergence of the disease, especially in rapidly developing urban areas with slum settlements.^18–21 Therefore, it should always be considered as a diagnosis regarding infectious diseases, especially if there is suspicion of previous exposure to the pathogenic spirochetes.

Lung involvement is frequent in leptospirosis (20%–70%), with cough, chest pain and mild dyspnea being the most common symptoms.²² Pulmonary haemorrhage, presenting with bloodstained sputum or haemoptysis, is a rare clinical manifestation, usually but not always associated with hepatic and renal dysfunction (Weil’s disease).^{23 24} This clinical entity, described as severe pulmonary haemorrhagic leptospirosis, is a condition of high mortality (30%–60%) that may lead to ARDS and mechanical ventilation.²⁵ In the majority of severe cases, pulmonary leptospirosis has characteristic chest radiographic signs of bilateral, non-lobar, diffuse nodular densities, mostly involving lower lung fields. Many attempts have been made to identify potential risk factors for this severe complication. Cigarette smoking seems to be an important causative factor, probably through toxin-mediated small vessel vasculitis, increased permeability of lung capillaries or local inflammatory response.^{26 27} Delayed antibiotic therapy, thrombocytopaenia and Leptospira interrogans serogroup icterohaemorrhagiae have been associated with pulmonary complications, as well as other severe manifestations.^{28 29} An association was found between the level of leptospiremia (at least 10⁴ leptospires/mL of blood) and the development of severe pulmonary haemorrhage syndrome.³⁰ Biochemical markers such as tumour necrosis factor α (TNF-α) were correlated with the severity of lung involvement.³¹ Mortality in acute lung injury and ARDS seems to be directly related with haemodynamic disturbance, previous history of chronic obstructive pulmonary disease (COPD), thrombocytopaenia, high serum creatinine, bilirubin and potassium levels.³² Various scores estimating mortality, such as Simplified Acute Physiology Score II, have shown conflicting results.^{33 34}

Thrombocytopaenia is a frequent and well-known complication of leptospirosis as it is present in more than half of the patients.³⁵ Disseminated intravascular coagulation (DIC) is common among patients with sepsis, like in leptospirosis, where fragmented red cells and schistocytes are the hallmark in microscopic examination of red blood cell morphology. Activation of the coagulation system results in increased FDP and D-Dimer levels, thrombin-antithrombin III complexes, prolonged PT and aPTT, increased fibrinolytic activity, reduced levels of anticoagulant markers (protein C, antithrombin) and lower PLT counts.^{36 37} Nevertheless, both conditions cannot justify all the cases of severe pulmonary haemorrhage, suggesting other pathogenetic mechanisms such as toxin- or immune-mediated.^{22 38} Pulmonary haemorrhage and ARDS seem to be produced by disruption of endothelial cell junctions and therefore, by an increase in paracellular permeability that explains both haemorrhage and oedema.⁵ Studies with lung tissue specimens from dead patients with severe haemorrhagic manifestations have shown that thrombocytopaenia is not related to DIC but is due to activation, adhesion and aggregation of PLTs to the stimulated vascular endothelium.³⁹ Swelling of endothelial cells was noticed with giant dense bodies in their cytoplasm, whereas increased production of nitric oxide was found in alveolar macrophages as well as immunoglobulin deposition in alveolar septum and space.⁴⁰ Leptospiral antigens were detected by immunohistochemistry in lung tissue suggesting a local direct destructive action. Peptidoglycans, membrane glycoproteins and other possible toxins may directly activate vascular endothelial cells resulting in local and systemic inflammation.^{41 42} Lipopolysaccharides may activate cells through toll-like receptor two and CD14 dependant mechanism initiating antibodies production.⁴³ Deposition of IgG, IgA and C₃ along the alveolar basement membrane suggests an autoimmune mechanism of severe alveolar haemorrhage.^{44 45} PLTs dysfunction caused by increased binding with von Willebrand factor and fibrinogen, is another possible mechanism of haemorrhagic diathesis in patients with leptospirosis.⁴⁶ In experimental models, Leptospira infection disturbs normal coagulation through X-like and thrombin-like factor increased activity, which is accelerated in the prothrombinase complex.⁴⁷ Increased production of the pro-inflammatory mediator bradykinin and pro-coagulant microvesicles activate both extrinsic and intrinsic coagulation cascades.⁴⁸

A good clinical history is possibly the key to accurate diagnosis. Physical progression of the disease can be characteristic, but it is not always typical. Potential direct or indirect exposure to infected animals, urine, soil or water (related occupation, travel to an endemic area, river activities, pets) during the last 2 weeks must be investigated. Findings on clinical examination and laboratory testing may range from a flu-like disease with mild symptoms and no laboratory abnormalities to a severe icterohaemorrhagic condition with multi-organ symptoms and failure. As for the laboratory confirmative tests, serology testing is most commonly used. It includes microscopic agglutination, ELISA and immunofluorescence detection of Leptospira IgM antibodies, which appear 5–7 days after infection. Seroconversion or fourfold rise in antibody titre is indicative of Leptospira infection. Molecular methods (classic PCR and real-time PCR) are useful in the early stages of the illness, as leptospiral DNA in serum disappears once antibodies are detectable. Other less used diagnostic tools are direct observation of the pathogen in serum and urine via microscope and culture.⁴⁹

In any suspicion of leptospirosis, starting empirical therapy can be life-saving. There is no gold standard antibiotic therapy for severe leptospirosis. Therefore, third-generation cephalosporins (ceftriaxone, cefotaxime), piperacillin-tazobactam, meropenem and doxycycline have been used with good outcome as alternatives to penicillin G.^{50 51} In our case, the patient responded well to triple antibiotic therapy. In addition, several reports indicate that steroid therapy, specifically methylprednisolone first administered bolus intravenously and then orally, is linked to a better outcome of the patient with severe leptospirosis.^{6 50} Supportive therapy is important to treat any possible complications in Weil’s disease, such as fluids and electrolytes restoration, haemodialysis in severe renal impairment, supportive ventilation or even mechanical ventilation if necessary. Finally, PLTs transfusion and desmopressin can be effective in haemorrhage control, especially in massive pulmonary bleeding.²⁴

Unfortunately, because of the large amount of pathogenic serovars, infection reservoirs and transmission routes, leptospirosis is very difficult to be controlled. Natural phenomena, temperature, humidity and other environmental unpredictable factors play a key role in the transmission of the disease. Therefore, proper sanitation, vaccination of pets and humans, avoidance of risky activities as well as endemic areas offer the only prevention plan. Leptospirosis usually presents as an acute fever with potential severe complications. Thus, clinicians should maintain high level of suspicion, in order to start antibiotic treatment in time.

Learning points.

• Leptospirosis is a worldwide zoonotic disease with a high mortality rate, especially when it is accompanied by one or more organ complications.

• Weil’s disease is the most fearing presentation of leptospirosis with high mortality rate.

• Leptospirosis pulmonary complications occur in a low percentage of patients, with haemorrhage and acute respiratory distress syndrome constituting the worst presentations.

• Accurate diagnosis is based mostly on history, clinical examination and serologic tests.

• Proper sanitation, vaccination of vulnerable populations and animals and high clinical suspicion constitute the main prevention means.