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A Nonfatal Case of Dobrava Hantavirus Hemorrhagic Fever with Renal Syndrome Combined with Hantavirus Cardiopulmonary Syndrome

IntroductIon Based on the epidemiological findings and clinical characteristics, hantaviruses (HTNV) (Bunyaviridae family) can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS) (respectively hantavirus pulmonary syndrome [HPS]).[1,2] HCPS was first recognized in 1993 in the Four Corners region of the southwestern United States.[3] Based on the available data, HCPS-causing viruses show a rapid disease course with serious pulmonary symptoms[1,4-8] with a 40% case-fatality rate (CFR).[1,2] There is growing evidence that HFRS and HCPS partly overlap.[6,9] In patients with HFRS, respiratory symptoms are frequent and are linked to Puumala virus (PUUV) infection.[2,6,10] In areas where both PUUV and Dobrava virus (DOBV) circulate, more than half of HFRS patients present with abnormal pulmonary X-ray findings and transient EKG changes, mostly in the oliguric phase.[11] In Kosovo, each year, we treat several sporadic cases of HFRS, and every fourth or 5th year, epidemic features present with different clinical forms of the HTNV disease.[12] Over 30 years, we have evidenced only one confirmed case that developed severe HCPS. Here, we report a case of a 20 year old male with HFRS and HCPS caused by Dobrava-Belgrade hantavirus, successfully treated in the Department of Infectious Diseases.

day 2 (day 9 PSO), BUN and creatinine increased rapidly, and the patient became anuric, with hypertension and bradycardia. Renal replacement therapy was initiated and continued until day 52 PSO. On hospital day 4 (day 11 PSO), the disease was complicated with agitation and high fever, and the patient became tachy dyspneic and developed acute severe respiratory distress. Chest X-ray showed extensive bilateral infiltrates and enlarged heart shadow with rapid improvement by day 15 PSO [ Figure 1d-f]. EKG (day 11 PSO) showed sinus rhythm 114 b/min, with 2 mm ST depression on lead II, III, and aVF suggesting acute coronaritis [ Figure 1b and c]. Abdominal ultrasound presented enlarged liver (182 mm), acute renal inflammation, and abdominal-free liquid [ Figure 1g-i]. In addition, laboratory tests presented acute kidney injury and acute lung injury [ Table 1]. The patient was intubated and mechanically ventilated; intravenous ampicillin, ribavirin, and crystalloid infusions were commenced immediately on arrival to the Intensive Care Unit. The critical respiratory phase lasted 7 days, contrary to the renal phase that lasted 15 days, after which urine output increased entering polyuric phase. Ventilation support was weaned off after 11 days. On day 25 PSO, the patient was transferred to the Infectious Disease department, and after 44 hospital days (day 52 PSO), the patient was discharged in good clinical condition; still with mild anemia, elevated BUN, and creatinine, but without the need for dialysis. After a 2-year follow-up, the patient still had mild anemia and findings of CK disease. Nombre, Hantaan, Dobrava, and Seoul was used. Following manufacturer's instructions (Mikrogen Diagnostik, Germany), serotyping is possible using the recommended Line HantaPlus IgG test. Based on instructions for result interpretation from the producer, IgM antibodies were reactive on Dobrava, Hantaan, and Seoul HTNV, and IgG antibodies were more reactive on Dobrava compared to Hantaan and were negative to other hantavirus serotypes. RT-PCR from a blood sample was negative for HTNV, tested by commercial test (Primerdesign UK). Following information gained through serological tests, infection with Hantavirus Dobrava could be taken into consideration [ Table 2].
Written informed consent from the patient who participated in this study was obtained.

dIscussIon
The HTNV cause vascular leak by injuring the endothelial vascular cells resulting in capillary leak. [1,2] The form of clinical presentation depends directly on the localization of the process, causing tubulointerstitial damage in the renal system or pulmonary edema with perialveolar infiltration and pleural effusion. [1,2,7,13] The severe form of HFRS has a CFR of 5%-15%, whereas HCPS has a much higher CFR, 40%. [1,2,7] Viral strain seems to be determinant key for the organ tropism and the diseases. [7,14] In patients with HFRS, respiratory symptoms appear more frequently and are especially linked to PUUV infection. [9,10] In areas where both PUUV and DOBV are circulating, half of HFRS patients present with abnormal pulmonary X-ray findings and transient EKG changes, mostly in the oliguric phase. [11] Contrary to adult acute respiratory distress syndrome (ARDS) seen in systemic infections and systemic noninfectious diseases, respiratory failure in HCPS usually resolves within a few days and is followed by a polyuric phase, as our case demonstrates. [1] With increasing contact between humans and the natural host for HTNV, the spreading of these viruses can be easier and can be responsible for the pulmonary syndrome in all endemic areas. [14] conclusIon In endemic areas, hantavirus infection should be considered in the differential diagnosis of acute respiratory distress in previously healthy adults with acute renal failure, hemorrhagic syndrome, fever, leukopenia, thrombocytopenia, and a history of possible exposure. We wish to point out that the lung involvement during HFRS is frequent, and ARDS may also be encountered in Europe, which is usually caused by the PUUV of the Hantavirus genus but does not rule out Dobrava strain, as in our case.

Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/ their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest. Negative Negative Not tested Not tested PCR: Polymerase chain reaction; + : very low intensity (lower than cut-off band); +: low intensity (equivalent to the cut-off band); ++: high intensity (higher than the cut-off band); +++: very strong intensity.