Beyond the Kidneys: Pulmonary-Renal Involvement in Hantavirus Infection - A 10-Year Experience

Introduction

Hantaviruses are a diverse group of enveloped, ssRNA viruses belonging to the Hantaviridae family.¹ These zoonotic pathogens are globally distributed and primarily transmitted to humans through the inhalation of aerosolized particles from the urine, feces, or saliva of infected rodents, their natural reservoirs.^1,2 Human infections can lead to severe disease, often presenting as viral hemorrhagic fevers with significant morbidity and mortality. While rodent-to-human transmission is the primary route, human-to-human transmission has been documented in rare cases, notably with the Andes virus.^1,3,4 Environmental factors such as climate change, deforestation, and urbanization have contributed to increased human exposure and expanding geographic distribution with more frequent serious outbreak situation.⁵

Traditionally, hantavirus infections are divided into two major clinical syndromes based on geographic distribution: Hemorrhagic Fever with Renal Syndrome (HFRS) in Europe and Asia, caused by Old World hantaviruses (e.g., Puumala, Dobrava-Belgrade, and Hantaan viruses), and Hantavirus Cardiopulmonary Syndrome (HCPS) in the Americas, caused by New World hantaviruses (e.g., Sin Nombre and Andes viruses).^1,6 However, this dichotomy is increasingly challenged, as overlapping features, particularly simultaneous renal and pulmonary involvement, are now recognized.^7-9 These atypical or mixed presentations highlight the need for heightened clinical awareness and a more refined perspective on hantavirus pathophysiology across geographic regions.

In the Balkan region, including North Macedonia, hantavirus infections are primarily caused by Dobrava-Belgrade virus (DOBV), carried by the yellow-necked mouse (Apodemus flavicollis), which leads to moderate to severe HFRS and has a fatality rate of up to 15%, and Puumala virus (PUUV), carried by the bank vole (Myodes glareolus), causing nephropathia epidemica, a milder form of HFRS with a fatality rate below 1%.^6,10,11 While AKI remains the hallmark of HFRS, pulmonary involvement, ranging from mild respiratory symptoms to acute respiratory distress syndrome (ARDS), is increasingly recognized, though it is often underreported or misclassified.¹² The coexistence of pulmonary and renal involvement in Hantavirus infection is clinically significant, as it may alter disease severity, diagnostic clarity, and management strategies.¹

This study presents a 10-year experience from a university nephrology hospital in North Macedonia, aiming to highlight the frequency, clinical features, and laboratory profile of patients with dual renal and pulmonary involvement, and to compare them to those with isolated renal disease. Our findings seek to contribute to the growing evidence that pulmonary-renal syndrome may be an under-recognized phenotype of Hantavirus infection in Europe.

Materials and Methods

The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Institutional Review Board of the University Clinic of Nephrology, Skopje, Republic of North Macedonia (Approval No. 07-04/2025). Given the study’s retrospective nature, the requirement for individual informed consent was waived. All patient data were anonymized and handled in compliance with data protection regulations.

An observational, retrospective, single-center case series study was conducted over 10 years (2013 to 2023) on patients >14 years who were hospitalized and treated at the University Hospital of Nephrology in Skopje, Republic of North Macedonia. This institution is a tertiary care hospital and a leading provider of nephrology services in North Macedonia, with more than 2500 hospitalizations per year. The main criterion for inclusion in the study was the definitive diagnosis of Hantavirus infection. Diagnosis was confirmed serologically at the Institute of Public Health of the Republic of North Macedonia using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Progen Biotechnik GmbH, Heidelberg, Germany) detecting hantavirus-specific IgM and IgG antibodies against recombinant nucleocapsid antigens. According to the manufacturer, the assay has reported sensitivities of 100% for IgM and 98-100% for IgG, and specificities of 77-94% for IgM and 93-94% for IgG, depending on the panel tested. Acute infection was defined by the presence of IgM antibodies and/or a ≥4-fold rise in IgG titers (seroconversion) between acute and convalescent sera. Potential cross-reactivity between hantavirus species (e.g., Puumala, Dobrava, Hantaan) was considered, but the ELISA used has minimal cross-reactivity with non-hantavirus pathogens. In our series, alternative viral infections were excluded clinically, and no conflicting serological results were observed. Precise hantavirus subtyping was not performed.

Our research was based on the analysis of medical histories and hospital discharge tickets for the patients. We compiled the epidemiological, clinical, and laboratory parameters (complete blood count, liver enzymes, electrolyte and protein profiles, D-dimers, C-reactive protein (CRP), blood glucose, and proteinuria) on the 1^st, 3^rd_, and 7^th day of hospitalization. Pulmonary involvement was defined as the presence of respiratory symptoms with radiological computed tomography abnormalities, including pleural effusion, interstitial or alveolar infiltrates, ground-glass opacities, consolidations, or pulmonary edema [Figure 1]. Differentiation between cardiogenic and non-cardiogenic pulmonary edema was based on clinical presentation, electrocardiography, and echocardiography. All imaging studies were independently reviewed by two radiologists.

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Figure 1:

CT of the lungs in a patient with Hantavirus infection and renal–pulmonary involvement. (a) Bilateral pleural effusions (black arrows) and diffuse alveolar consolidation with ground-glass attenuation (white arrow). (b) Diffuse ground-glass attenuation (white arrows), consistent with acute respiratory distress syndrome (ARDS).

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Renal replacement therapy was initiated in both groups according to identical criteria: hyperkalemia, metabolic acidosis, volume overload with pulmonary edema, or uremic symptoms. Hemodynamically stable patients underwent standard intermittent hemodialysis with unfractionated heparin or low-molecular-weight heparin (LMWH). In contrast, patients who developed ARDS were managed with continuous venovenous hemodiafiltration (CVVHDF) with continuous heparinization. Antibiotics were administered only in cases of highly suspected or microbiologically confirmed bacterial superinfection. No patient received ribavirin. Corticosteroid therapy (methylprednisolone 1 mg/kg body weight for several days) was given exclusively to patients with ARDS, in accordance with the 2023 Society of Critical Care Medicine/European Society of Intensive Care Medicine SCCM/ESICM guidelines. Fluid management strategies in both groups focused on maintaining euvolemia and preventing pulmonary congestion, with close monitoring of urine output and hemodynamic status.

Statistical analysis was performed using SPSS version 17 (IBM Corp., Armonk, NY). Categorical variables were compared using the Chi-square test or Fisher’s exact test when expected cell counts were <5. Continuous variables were first tested for normality using the Shapiro-Wilk test. Normally distributed variables were summarized as mean ± standard deviation (SD) and compared with the independent-samples Student’s t-test. Non-normally distributed variables were reported as median with interquartile range (IQR) and compared using the Mann-Whitney U test. A p-value ≤0.05 was considered statistically significant.

Results

A total of 20 patients with serologically confirmed Hantavirus infection were included in the analysis; 19 were male, aged 14-66 years (mean age 36 years). Additionally, 16 lived in a rural environment, and 16 were infected during the spring/summer period. In the analyzed period, an average of 2.2 cases were identified and treated per year, with the largest number (8) diagnosed in 2017 and none in 2020. Most referred patients had a clear epidemiological context; four worked as shepherds or farmers, and the rest had a recent stay in nature and contact with rodents. Clinical-laboratory data were fully available for 17 patients.

Symptoms developed 2 to 10 days before admission to the hospital (average of 6.4 days). Three patients were initially hospitalized at the University Clinic for Digestive Surgery with an acute abdomen. Most patients (15/17) had gastrointestinal symptoms, abdominal pain, and fever, and 14 had pretibial edema, cough, and conjunctival suffusion. Additionally, 13/17 were without comorbidities, three had hypertension, and one had hypertension and bronchiectasis. At admission, all patients had thrombocytopenia and AKI KDIGO stage III. Thirteen patients (77%) underwent hemodialysis (HD). Seven exhibited pulmonary involvement. All patients with pulmonary involvement required supplemental oxygen, and five were stabilized with low-flow oxygen via nasal cannula (3-5 L/min). Two patients developed ARDS according to the Berlin criteria and were transferred to the intensive care unit. Both required invasive mechanical ventilation and vasopressor support with noradrenaline and dopamine. One patient improved and was successfully extubated after 5 days, while the other died on day 4 of hospitalization.

Urine analysis on the first day of hospitalization was available for 17 patients: 13 (76%) had some degree of proteinuria (from + to +++), and 15 (88%) had hematuria. 24-hour proteinuria was measured in five patients, with a mean value of 1.886 g/L (normal <0.2 g/L); nephrotic-range proteinuria was documented in two patients. Both patients showed normalization of proteinuria by day 10 (0.08 g/L and 0.16 g/L, respectively).

Based on pulmonary affection, patients were divided into two groups: Group 1 - patients with Hantavirus infection with renal and pulmonary involvement, and Group 2 - patients with Hantavirus infection with renal but without pulmonary involvement.

Patients with pulmonary involvement had statistically significant more frequent cough at presentation compared to patients without pulmonary involvement (p<0.05). The number of patients without comorbidities and without pulmonary affection was significantly higher compared to the number of patients without comorbidities with pulmonary affection (p<0.05). Serum levels of CRP, alkaline phosphatase (ALP), and D-dimers on the first day and lymphocytes count, CRP, and lactate dehydrogenase (LDH) on the third day were significantly higher in patients with pulmonary involvement compared to patients without pulmonary involvement (p<0.05). On the first and third days of hospitalization, platelet counts were significantly lower in patients with pulmonary involvement than in those without, as determined by the Mann–Whitney U test (p < 0.05). Serum creatinine on the first day, along with serum alanine transaminase and potassium levels on the third day, and serum hemoglobin and calcium on the seventh day, were significantly higher in patients without pulmonary involvement compared to patients with pulmonary involvement (p < 0.05). Mean hospitalization was significantly longer in Group 1 compared to Group 2 (12.8 ± 5.3 vs. 7.4 ± 3.2 days, p = 0.020). For all other analyzed parameters on the first, third, and seventh day of hospitalization, there were no statistically significant differences between Group 1 and Group 2 [Table 1].

Due to the small sample size of the cohort, it is difficult to draw firm conclusions or identify reliable predictors of pulmonary involvement. Although logistic regression analysis showed a borderline association between the number of hospitalization days and pulmonary affection (p=0.052), this finding should be interpreted with caution. It is more likely that prolonged hospitalization reflects the increased severity of illness in patients with pulmonary involvement, rather than serving as an independent predictor of pulmonary complications. Given the observational nature of the data and the limited number of cases, no definitive predictors can be established, and further research in larger cohorts is warranted to clarify this association.

Discussion

According to the European Centre for Disease Prevention and Control (ECDC), 1,885 hantavirus infections were reported in 2023 across 28 EU/EEA countries, corresponding to a notification rate of 0.4 cases per 100,000 population. Germany and Finland accounted for 60.5% of all cases. PUUV was the predominant pathogen, responsible for 95.6% of infections, followed by HTNV and DOBV. The highest incidence occurred in individuals aged 45-64 years, with a male-to-female ratio of 1.7:1 and a seasonal peak in July-August.⁶ In the Balkans, PUUV dominates in northern areas such as Slovenia and Croatia, whereas in southern regions, including North Macedonia, most cases are attributed to DOBV.^6,13,14 Our cohort demonstrated similar trends: strong male predominance, younger mean age (36 years), and spring-summer predominance, with rural residence and rodent exposure as major risk factors.^11,14,15 The marked male predominance (19/20) in our cohort may reflect referral bias, as our tertiary nephrology center predominantly admits patients with more severe clinical presentations, as well as male-dominated occupational exposures (farming and shepherding) of the patients, testing patterns, or simply chance due to the small sample size.

The clinical course of HFRS typically progresses through febrile, hypotensive, oliguric, polyuric, and convalescent phases.¹ Onset is abrupt, with fever, myalgia, abdominal pain, and blurred vision, followed by thrombocytopenia and, in severe cases, hemorrhagic complications or shock. Hemorrhagic events occur in 20-35% of patients, especially in DOBV and HTNV infections.^16,17 Renal function usually recovers within 3-7 days once hemodynamic stability is achieved. Proteinuria and hematuria are common; proteinuria may reach nephrotic range levels due to podocyte involvement.¹⁸ In our series, nephrotic-range proteinuria was documented in 2/6 patients with available data. Mortality in HFRS ranges between 5-15%, whereas in HCPS, pulmonary capillary leakage, non-cardiogenic pulmonary edema, and cardiogenic shock drive higher mortality (30-50%).¹ Despite these distinctions, overlapping renal and pulmonary involvement remains underrecognized in Europe, where focus is often nephrological.

Our 10-year analysis underscores the clinical heterogeneity of hantavirus infection, particularly when renal and pulmonary manifestations coexist. Although, historically divided into HFRS and HCPS, evidence suggests a clinical continuum. In our series, 35% of patients exhibited concurrent AKI and pulmonary involvement, including cough with radiographic abnormalities and, in two cases, ARDS requiring mechanical ventilation. Similar cases have been reported across Europe. Rasmuson et al. described three PUUV-associated HFRS cases complicated by ARDS and cardiovascular dysfunction, while Santini et al. (2023) reported a 23-year-old with PUUV infection and severe ARDS but only mild AKI.^19,20 Sarıgüzel et al. documented a severe DOBV infection in Turkey with renal failure, shock, pulmonary failure, and panhypopituitarism.¹² Comparative studies indicate that DOBV more often results in severe AKI, higher creatinine, and need for dialysis, while PUUV is more frequently linked to respiratory involvement and pleural effusions.^14,21

Our findings show that pulmonary involvement correlated with elevated CRP, D-dimer, and alkaline phosphatase on admission, reflecting systemic inflammation, endothelial activation, and coagulation pathway engagement. In addition, platelet counts on the first and third hospital days were significantly lower in patients with pulmonary involvement, consistent with consumptive coagulopathy and thrombocytopenia observed in severe hantavirus disease.^22,23 However, CRP’s utility as a severity biomarker in hantavirus infections, especially PUUV, is inconsistent: some cohorts show only weak associations with severe disease.²² By contrast, elevated D-dimer is more reliably linked to vascular complications, hyperfibrinolysis, and disease severity in HFRS cohorts.²³ Higher day-3 lymphocyte counts, CRP, and LDH in our pulmonary group may reflect sustained immune activation, consistent with the immunopathogenesis of HCPS, where lung injury is largely immune-mediated rather than directly cytopathic.^23,24

Interestingly, some abnormalities were more prominent in patients without pulmonary involvement. ALT was higher on day 3, consistent with reports of hepatic involvement in 41-85% of European HFRS cases, with one Finnish study documenting transaminase elevations in 60% of patients.²⁵ Renal-only cases also showed higher hemoglobin and potassium, likely due to hemoconcentration and impaired excretion in severe AKI. In contrast, pulmonary cases may have experienced more pronounced vascular leakage and fluid shifts, modifying these parameters. All patients presented with KDIGO stage 3 AKI, reflecting the central role of renal dysfunction in HFRS.²⁶ Serum creatinine was significantly higher at admission in the renal-only group (619.7 ± 259.2 vs. 377.8 ± 207.4 µmol/L, p = 0.050). Over three-quarters of all patients required HD, reflecting the severity of disease in DOBV-predominant areas. Renal recovery was slower in those with pulmonary involvement. At day 7, creatinine remained elevated in both groups, consistent with acute kidney disease (AKD). No renal biopsies were performed in our present series. However, earlier reports from our center described variable histopathological findings in hantavirus infection, including tubulointerstitial nephritis with interstitial edema, T-cell infiltration, and acute tubular necrosis, as well as a case of diffuse proliferative glomerulonephritis, with generally favorable outcomes but occasional progression to chronic renal disease.^6,27

Hospitalization was longer in patients with combined pulmonary-renal involvement, emphasizing the added clinical burden of pulmonary manifestations. Although mortality in our cohort was low (5%), the fatality occurred in a patient with pulmonary involvement, aligning with reports that respiratory compromise predicts poor outcomes.²⁸ In a Chinese cohort of 86 critically ill HTNV-HFRS patients, 55.8% developed ARDS with 43.8% mortality, and prognostic factors included lower creatinine and fibrinogen, prolonged clotting times, and elevated AST.²⁹

Diagnostic challenges are also significant. In our study, three patients were initially misdiagnosed with acute abdomen, illustrating the nonspecific early presentation of hantavirus infection.¹⁴ Pulmonary symptoms may be overlooked in nephrology wards unless respiratory failure develops, while differential diagnosis often includes immune-mediated pulmonary-renal syndromes. Our findings suggest that baseline chest imaging and closer respiratory monitoring should be considered in suspected cases, particularly in endemic regions.

This study has limitations: its retrospective, single-center design, small sample size, and lack of viral subtyping limit generalizability. Although patient sera are stored, technology for hantavirus subtyping (RT-PCR or neutralization) is currently unavailable, preventing differentiation between DOBV and PUUV, which may partly explain the observed variability in renal and pulmonary involvement reported in the literature.¹ Nonetheless, strengths include detailed clinical and laboratory data collected over a decade and systematic comparison between patients with and without pulmonary involvement. These results contribute to the growing recognition of hantavirus infection as a clinical continuum with overlapping renal and pulmonary syndromes in Europe.

To conclude, Hantavirus infection in our cohort manifested with a spectrum of disease that frequently includes both renal and pulmonary involvement, indicating that it is better viewed as a clinical continuum rather than dichotomous syndromes. Hantavirus infection should be considered as a cause of ARDS in all endemic areas worldwide. Patients with dual organ involvement experienced more severe disease and protracted recovery, underscoring the need for heightened clinical vigilance, thorough respiratory evaluation, and prolonged follow-up in affected individuals, even in regions where the renal presentation predominates.