Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus

A 73-year-old woman was admitted to the intensive care unit (ICU) with acute respiratory distress. She was a lifelong non-smoker living with her husband in a rural area, and had a medical history of hypertension and type II diabetes. The day prior to admission she fell ill with malaise and fever. Nausea, vomiting and pronounced shortness of breath ensued. The initial findings at admission included fever, tachycardia, tachypnoea, hypoxia and somnolence. Laboratory findings during hospitalisation indicated coagulopathy, elevated levels of lactate dehydrogenase (LDH), and development of renal failure (Table 1). There was release of cardiac enzyme troponin T (peak value 1.6; normal value <0.01 μg/L), indicating myocardial tissue damage.

Lung computer tomography (CT) on admission revealed pronounced diffuse bilateral interstitial infiltrates with pulmonary oedema, dependant atelectasis, and moderate pleural effusions (Fig. 1) which were later drained (>800 ml). Echocardiography showed inferior hypokinesia, moderate mitral valve insufficiency, normal sized left ventricle and atrium, and systolic pulmonary arterial pressure estimated at 55 mm Hg. Despite non-invasive positive pressure respiratory support and furosemide, her respiratory distress progressed and she was intubated and mechanically ventilated on the first hospital day. The preliminary diagnosis was acute respiratory distress syndrome of uncertain cause, and she was treated with broad-spectrum antibiotics and corticosteroids without improvement. Vasopressor and inotropic support was required to maintain adequate circulation. Repeated echocardiogram showed no overt signs of cardiac failure, though several days into her illness the systolic pulmonary arterial pressure increased to >65 mm Hg. Maximal inspiratory pressures (40 cm H₂O) were required to maintain minimally adequate oxygenation. She suffered a pneumothorax, and received a large bore thoracostomy with negative pressure drainage. The patient developed multiple organ dysfunction engaging the central nervous, respiratory, cardiovascular, renal and coagulatory systems, and she died after 13 days of ICU care.

Autopsy revealed oedematous and atelectatic lungs with no normal aerated tissue. Pulmonary histopathological features consisted of diffusely oedematous parenchyma with interstitial and intraalveolar fibrosis. The alveoli contained exudates of fibrinous fluid, high number of alveolar macrophages (CD68⁺), proliferative epithelial cells and thick septa but without characteristic hyaline membranes. Interstitial mononuclear cell infiltrates were common, consisting mainly of CD3⁺ T lymphocytes whereof a vast majority was CD8⁺. Many mononuclear cells were expressing cytotoxic markers granzyme B and T cell restricted intracellular antigen-1, TIA-1 (Fig. 2). In pulmonary vessels, focal thrombosis was evident. Microscopy of the heart showed thrombosis in small vessels and focal massive infiltrates of granulocytes and macrophages. In the brain there was focal vasculitis, perivascular infiltration of CD8⁺ T lymphocytes and non-occlusive thrombosis. Infarctions were seen in the brain, lungs and spleen. Notably, the kidneys had no prominent inflammatory infiltrates.

A 65-year-old woman was admitted to the ICU with acute respiratory distress and circulation insufficiency. Besides a history of Waldenstrom’s macroglobulinemia that had not required active treatment, she had no history of health problems, infections or recent hospitalisations. She was a lifelong non-smoker, lived in a rural home with her husband, and handled firewood for home heating. Four days prior to admission the patient noted fever, chills, dyspnoea with dry cough and diarrhoea. On the day of admission, these symptoms were more severe, and an ambulance had been called because of syncope. Her ability to oxygenate deteriorated progressively during the first hospital day, and she was intubated and mechanically ventilated.

Chest X-ray on admission showed bilateral diffuse lung infiltrates and signs of interstitial oedema. Large bilateral pleural effusions were noted, and >1000 ml were drained. Echocardiographic examination identified normal left ventricular wall motion, and no signs of structural abnormalities or of pulmonary hypertension. Thin-cut CT images of the lungs on the third ICU day showed diffuse bilateral alveolar and interstitial infiltrates with dependent consolidation (Fig. 1). The clinical course during the first seven days was dominated by respiratory insufficiency requiring maximal ventilatory support with high levels of inspired oxygen, as well as circulatory shock requiring treatment with vasopressor and inotropic infusions. Other important clinical aspects included coagulopathy with diffusely spread petechiae, progression of renal failure with anuria requiring dialysis, and elevated levels of LDH (Table 1). She was treated presumptively for bacterial pneumonia and sepsis with a series of broad spectrum antibiotics and corticosteroids, without apparent response.

Hantavirus infection was verified with the detection of PUUV RNA in plasma (630,000 copies/ml) on the day of admission, while IgM and IgG were negative. Seroconversion with positive IgM and IgG occurred two and seven days later, respectively. Consecutive plasma samples were analysed for PUUV RNA with declining viral copy numbers until negative 16 days post onset of disease (data not shown). PUUV RNA was found in bronchoalveolar lavage fluid (11,000 copies/ml) nine days after onset of disease. Bacterial cultures were all negative. The patient remained ventilator-dependent for 13 days, but was finally extubated. She developed critical illness myopathy and needed six weeks in-hospital rehabilitation. At follow-up six months later, she complained of muscle ache during exercise and lowered general fitness, but was steadily improving.

A 63-year-old male construction worker was admitted to the ICU with acute respiratory distress, confusion and hypotension. He was a current and long-time smoker with a medical history of mild chronic obstructive pulmonary disease and hypertension. Three days prior to admission he had fallen ill with fever, chills, diarrhoea, dry cough, and dyspnoea. In the emergency room, physical examination was notable for fever, somnolence, tachycardia and hypotension. Arterial blood gas analysis on room air revealed hypoxia and respiratory alkalosis. The patient was taken to the ICU and therapy was started with broad spectrum antibiotics due to suspicion of pneumonia and sepsis. As with the other patients, coagulopathy, increased LDH levels, and renal failure were detected (Table 1).

Initial bedside chest X-ray showed no findings to explain the respiratory distress. During the two days ICU course, the patient complained mostly of dyspnoea. He received supplemental oxygen and non-invasive ventilator support initially, but was eventually intubated and mechanically ventilated. CT findings which included only the lower lung lobes revealed bilateral pleural effusions and bibasilar atelectasis (data not shown). During the first day blood pressure was maintained with i.v. fluid, but on the second day his circulatory condition rapidly deteriorated. Despite massive efforts with i.v. fluid, corticosteroids and vasoactive drugs, the patient died in refractory circulatory shock.

PUUV serology on the first hospital day was IgM positive, while IgG was negative. The patient had 130,000 copies of PUUV RNA/ml in plasma. Bacterial cultures were all negative. At autopsy, PUUV RNA was detected in samples from lungs, heart, liver, kidney, brain and spleen. The organs were examined for viral antigen, which was found in the vascular endothelium and in mononuclear cells (Fig. 2).

Post mortem examination showed that pulmonary architecture was preserved but with oedema and focal non-occlusive thrombosis. Similar to patient 1, there were pulmonary infiltrates of lymphocytes with the same immunophenotype as described (data not shown). Kidneys showed no prominent inflammation.