Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus
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- Rasmuson, J., Andersson, C., Norrman, E. et al. Eur J Clin Microbiol Infect Dis (2011) 30: 685. doi:10.1007/s10096-010-1141-6
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Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.
The present paradigm is that hantaviruses in the Americas cause hantavirus pulmonary syndrome (HPS), while hemorrhagic fever with renal syndrome (HFRS) is caused by hantaviruses present in Eurasia [1–3]. Hantaviruses associated with HFRS and HPS are primarily transmitted by inhalation of viral particles shed by infected rodents [4, 5]. In both syndromes there is a local immune reaction in the lungs, mainly in terms of a CD8+ T lymphocyte response [2, 6, 7]. Another important feature is endothelial dysfunction and capillary leakage [1–3, 8]. After the prodromal phase, including fever, nausea, myalgia and headache, patients with HFRS commonly develop renal failure whereas in HPS the kidneys are often spared and instead the patient frequently presents with severe cardiopulmonary dysfunction [1, 3, 9].
Although usually less severe and sometimes overlooked, pulmonary symptoms are common in European HFRS caused by Puumala virus (PUUV). Frequent clinical findings include cough, dyspnoea, interstitial lung infiltrates, pleural effusion and impaired pulmonary function [10–12]. Pronounced lung involvement in HFRS has previously been reported [13–16]. However, none of those reported patients had a fatal outcome that could be attributed to the acute infection, and there is no description of histopathological findings.
Our hypothesis is that also European hantaviruses can cause HPS. The aim of this study was to investigate whether HFRS patients with severe cardiopulmonary distress fulfil HPS criteria and have similar clinical and pathological features.
Materials and methods
In a prospective study, during the latest hantavirus outbreak in 2007 in the county of Västerbotten, Sweden , HFRS patients with cardiopulmonary failure and need of invasive assisted ventilation, i.e. intubation and mechanical ventilation, were selected. We identified three patients, two of which had fatal outcome and one survived. The two patients who died both underwent autopsy three days post-mortem. Organ samples were investigated using immunohistochemistry to describe the immunological response and detect presence of viral antigen. Quantitative real-time RT-PCR was used to detect viral RNA in organ samples, plasma and bronchoalveolar lavage .
For defining HPS we used the case definition criteria published by the U.S. Centers for Disease Control and Prevention (CDC) . The project was approved by the Research Ethics Committee of Umeå University. Informed consent was obtained either from the patient, or a close relative when not possible.
Laboratory findings in three European hantavirus patients suffering from hantavirus pulmonary syndrome
Patient No., Sex/Age
1: F/73 y
2: F/65 y
3: M/63 y
PUUV serology was initially negative, but seroconversion occurred during the first week with development of positive immunoglobulin M (IgM) and IgG. No PUUV RNA could be detected in serum or bronchoalveolar lavage fluid, sampled two days after onset of disease. At autopsy PUUV RNA was detected in lung tissue, but not in samples from heart, brain, spleen and liver. Sequencing of the PUUV RNA from lung tissue showed that it was homologous to PUUV strains circulating in northern Sweden. No PUUV antigen could be detected in the tissue by immunohistochemistry using PUUV specific monoclonal antibody. Relevant bacterial cultures were all negative. Notably, three weeks prior to ICU admission the patient had sought medical treatment at our clinic for a urinary tract infection caused by E. coli. In the serum collected at that time PUUV RNA (1,700 copies/ml) was later detected.
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.
Growing evidence show that there are similarities between HFRS and HPS, as both syndromes can give rise to hemorrhagia, renal impairment and cardiopulmonary dysfunction, which have been attributed to thrombocytopenia and capillary leakage [1, 3, 8, 9, 11, 20, 21].
Severe pulmonary involvement has not been generally perceived to be a significant feature of HFRS. Previously, respiratory symptoms were commonly attributed to fluid overload as a result of renal failure. However, increasing evidence show that lung and heart involvement is common during the acute phase of HFRS [10, 11, 22, 23]. Concerning the cases of European hantavirus infection in our present report, there was only mild or no renal impairment at the time of admission, whereas the respiratory involvement was early and severe, consistent with acute respiratory distress syndrome (ARDS), fulfilling criteria of HPS according to CDC case definition . As described in HPS, the three reported patients suffered from cardiovascular dysfunction, requiring treatment with inotropic and vasopressor drugs . Autopsy results support the cause of death to be cardiopulmonary distress due to hantavirus infection. The lungs of both the deceased patients were oedematous and contained mononuclear cell infiltrates with predominantly CD8+ T lymphocytes, as described in HPS patients [2, 7]. Many cells expressed granzyme B and TIA-1, indicating a cytotoxic activity, which could further be supported by high levels of LDH. We chose to demonstrate the immune response in a non-smoker’s lungs (patient 1), but a similar picture was seen in patient 3.
In the first two patients, the IgM response was delayed, while the quantitative real-time RT-PCR for PUUV RNA was positive, suggesting it as a valuable tool to hasten the aetiological diagnosis . Notably, in patient 1 PUUV RNA was found in serum from three weeks prior to the acute onset of disease, that is, in incubation phase and consistent with hantavirus incubation time ranging from one to four weeks [3, 24].
Pulmonary involvement is well documented in European Puumala hantavirus infection. From a single outbreak in our county, we report on three cases of life-threatening hantavirus pulmonary syndrome. Arguably, additional cases are likely to either go undiagnosed or unreported. A clinical implication of this observation is that hantavirus infection should be included as a differential diagnosis for patients with febrile illness and acute respiratory distress of uncertain cause in endemic areas in Eurasia.
Irene Eriksson and Ingrid Gustafsson are greatly acknowledged for their skilled technical assistance. This work was supported with grants from the Swedish Heart Lung Foundation, the Heart Foundation of Northern Sweden, the County Councils of Northern Sweden, the County Council of Västerbotten, and the Medical Faculty of Umeå University.
Conflict of interest
The authors declare that they have no conflict of interest.
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