HFRS is a zoonotic disease caused by Old World hantaviruses (Hantaan, Dobrava, Puumala, Seoul) transmitted via inhalation of aerosolized rodent excreta. It is endemic to Europe and Asia, classically progresses through five phases (febrile → hypotensive → oliguric → diuretic → convalescent), and carries a case fatality rate of 1–15% depending on the viral species. [1-3]
1. History
- Exposure history is critical: Ask about rural/outdoor activities, farming, military exercises, hiking, cleaning rodent-infested areas (barns, sheds, cabins), or contact with rodent droppings/nests within the past 2–6 weeks (incubation period) [1][4]
- Symptom onset: acute high fever, severe headache, myalgia, back pain, abdominal pain, nausea/vomiting [1-2]
- Timing: fever typically lasts ~7 days; oliguria appears around day 6, polyuria around day 9 [5]
- Ask about decreased urine output, dark or bloody urine, blurred vision
- GI symptoms (abdominal pain, diarrhea, vomiting) can mimic acute abdomen [1]
- Important negatives: no coryza, no sore throat (helps distinguish from typical viral URI)
2. Alarm Features
- Hypotension/shock — indicates transition to hypotensive phase; leading cause of death [1]
- Oliguria/anuria — signals severe AKI; 30% of patients develop oliguric renal failure [6]
- Active hemorrhage: petechiae, epistaxis, GI bleeding, menorrhagia [1]
- Dyspnea/hypoxia — >50% of HFRS patients develop respiratory symptoms; pulmonary edema can occur [1]
- Altered mental status — cerebral edema, toxic encephalopathy [7]
- Severe thrombocytopenia (<50,000) — associated with worse outcomes and higher creatinine [1][7]
- Multiorgan dysfunction — liver failure, ARDS, DIC [7-8]
3. Medications
- No specific antiviral is approved. Treatment is entirely supportive [1-2]
- Ribavirin: showed reduced mortality in one controlled trial for HFRS in China (HTNV), but was ineffective against PUUV-caused HFRS; not standard of care [1]
- Avoid nephrotoxic agents (NSAIDs, aminoglycosides, contrast dye) given AKI risk
- Avoid anticoagulants given hemorrhagic diathesis and thrombocytopenia
- Analgesics: acetaminophen preferred for fever/pain; avoid aspirin (platelet dysfunction)
- Vasoactive drugs (norepinephrine) for refractory hypotension [1]
- Icatibant (bradykinin receptor antagonist) has been used in severe cases on a compassionate basis [1]
4. Diet
- Strict fluid and electrolyte management is the cornerstone — guided by phase of illness [1]
- During oliguric phase: fluid restriction, potassium restriction, low-sodium diet
- During diuretic phase: aggressive fluid and electrolyte repletion to match losses
- Adequate caloric intake; parenteral nutrition if unable to tolerate oral intake
- No specific dietary triggers; hydration status must be closely monitored throughout
5. Review of Systems
- Renal: oliguria, anuria, hematuria, flank/back pain
- Hemorrhagic: petechiae, epistaxis, gingival bleeding, melena, menorrhagia
- Ocular: blurred vision, transient myopia (up to 70% in PUUV) [1]
- Respiratory: cough, dyspnea, chest tightness (>50% have respiratory involvement) [1]
- Cardiovascular: palpitations, chest pain (myocarditis possible) [9]
- GI: nausea, vomiting, diarrhea, severe abdominal pain
- Neurologic: headache, insomnia, confusion
6. Collateral History and Family History
- Occupational exposure: farming, forestry, military, pest control
- Household contacts: others with similar symptoms (though no human-to-human transmission for HFRS-causing viruses) [1]
- Travel history: recent travel to endemic areas (China, Korea, Balkans, Scandinavia, Russia) [1][10]
- Pet rats: Seoul virus can be transmitted from pet/laboratory rats [1]
- HLA haplotype may influence disease severity (genetic predisposition), though not routinely tested [11]
- Family history is generally not contributory unless multiple household members share the same exposure
7. Risk Factors
- Rural residence or outdoor activities in endemic areas (farming, hiking, camping, forestry) [1][4]
- Male sex (M:F ratio ~2.6:1) [1]
- Smoking — risk factor for both contracting PUUV infection and more severe disease [1]
- Seasonal: spring and autumn peaks correlate with rodent population dynamics [12]
- Flooding events increase rodent displacement and human contact [13]
- Comorbidities increasing mortality risk: older age, hypertension, diabetes [7]
- Cleaning rodent-infested spaces without respiratory protection [4]
8. Differential Diagnosis
- Leptospirosis — the closest mimic; both cause fever + AKI + thrombocytopenia. Leptospirosis tends to have higher bilirubin, more shock, and more hematuria [1][14]
- Dengue / other arboviral infections — fever + thrombocytopenia, but typically no AKI [1]
- Sepsis / bacterial endocarditis — fever, hypotension, multiorgan dysfunction
- Crimean-Congo hemorrhagic fever — fever + hemorrhage + thrombocytopenia in overlapping endemic regions [1]
- Rickettsiosis (scrub typhus, RMSF) — fever, rash, thrombocytopenia
- Acute abdomen — HFRS abdominal pain can mimic appendicitis, pancreatitis [1]
- HELLP syndrome — in pregnant women with thrombocytopenia, hypertension, renal dysfunction [1]
- Thrombotic microangiopathy (TTP/HUS) — thrombocytopenia + AKI
- Acute glomerulonephritis — hematuria, proteinuria, AKI
9. Past Medical History
- Prior hantavirus infection (confers some immunity to the same strain)
- Pre-existing CKD — increases risk of severe renal outcomes
- Hypertension, diabetes — independently associated with mortality [7]
- Immunosuppression — may alter disease course
- Prior episodes of unexplained AKI in endemic areas should raise suspicion for undiagnosed prior infection
10. Physical Exam
- Vitals: high fever (often >39°C), relative bradycardia (80% of PUUV patients), hypotension [1][15]
- Skin: petechiae (axillae, trunk, extremities), facial flushing, periorbital edema
- Eyes: conjunctival injection/hemorrhage, scleral icterus (rare) [2][6]
- Abdomen: diffuse tenderness (especially flank/costovertebral angle), hepatomegaly possible
- Lungs: crackles if pulmonary edema; decreased breath sounds if pleural effusion [1]
- Cardiovascular: signs of shock (tachycardia, weak pulses, delayed cap refill) — though bradycardia may paradoxically coexist with fever
- Neurologic: altered sensorium in severe cases
11. Lab Studies
- CBC: thrombocytopenia (95% of patients), leukocytosis (55%), elevated hematocrit/hemoglobin (hemoconcentration from plasma leak) [1][5]
- BMP/CMP: elevated creatinine and BUN (peaks days 5–9), hyponatremia (≤133 mM predicts oliguric ARF), hypoalbuminemia [1][6]
- LFTs: elevated AST, ALT, LDH [1]
- Coagulation: prolonged PT/aPTT in severe cases; DIC panel if hemorrhagic [7]
- Inflammatory markers: CRP markedly elevated (99%), procalcitonin elevated (91%) [5]
- Urinalysis: proteinuria and hematuria on dipstick — highly supportive of diagnosis [1][6]
- Peripheral smear: immunoblasts may be present [1]
- Serology (confirmatory): IgM EIA against hantavirus nucleocapsid protein — often positive at symptom onset; IgG EIA for confirmation [1]
- RT-qPCR (S segment): sensitive and specific; buffy coat preferred over plasma [1]
12. Imaging
- Chest X-ray: interstitial infiltrates and pleural effusions in ~50% of Balkan HFRS cases; pulmonary edema in oliguric phase [1]
- Renal ultrasound: enlarged, edematous kidneys with increased cortical echogenicity; useful to rule out obstruction
- CT abdomen: may show renal enlargement, perirenal fluid, retroperitoneal hemorrhage in severe cases
- Imaging is not required for diagnosis but helps assess complications and rule out surgical pathology when abdominal pain is prominent
- Cardiac MRI: consider if myocarditis suspected (troponin elevation, chest pain); can detect myocardial edema and late gadolinium enhancement [9]
13. Special Tests
- Hantavirus IgM/IgG EIA — gold standard serologic confirmation; IgM typically positive at presentation [1]
- Immunochromatographic rapid IgM test — >90% sensitivity compared to EIA; useful for point-of-care in endemic settings; should be confirmed with EIA [1]
- RT-qPCR — can detect viral RNA before antibody seroconversion and for weeks after symptom resolution [1]
- Urine dipstick — proteinuria + hematuria is a rapid bedside clue supporting HFRS [1]
- Neutralizing antibody assays — mainly for research/seroprevalence, not routine clinical use [1]
14. ECG
- Relative (sinus) bradycardia in 80% of PUUV-infected patients — a hallmark finding despite fever [15]
- ECG abnormalities in 18–50% depending on viral strain and geographic cohort [1][15]
- Most common: T-wave inversions (most frequent), ST-segment changes (elevation or depression) [15]
- These abnormalities are typically transient and revert to normal during convalescence without major adverse cardiac events [15]
- Consider ECG in all admitted patients; if troponin elevated, evaluate for hantavirus-induced myocarditis [9]
- Monitor for arrhythmias, especially with electrolyte derangements during oliguric/diuretic phases
15. Assessment
HFRS is a systemic endothelial disease driven by increased vascular permeability, coagulopathy, and immune-mediated injury, primarily targeting renal medullary capillaries. [11] Severity varies by viral species:
Atypical presentations include isolated abdominal pain mimicking acute abdomen, or predominantly respiratory symptoms overlapping with HCPS. [1] Complications include shock, multiorgan failure, ARDS, cerebral edema, and myocarditis. [1][7][9]
16. Treatment Plan
Initial stabilization
- ABCs; IV access, continuous monitoring
- Aggressive but carefully titrated IV crystalloid resuscitation — avoid fluid overload during oliguric phase [1][16]
- Vasopressors (norepinephrine) for refractory hypotension [1]
Supportive care (cornerstone of management)
- Analgesics (acetaminophen) for pain and fever
- Correct electrolyte imbalances (especially hyperkalemia during oliguria, hypokalemia during diuresis)
- Renal replacement therapy (hemodialysis or CRRT) for severe AKI — required in ~15% of DOBV, <5% of PUUV cases [1]
- Supplemental oxygen; mechanical ventilation if ARDS develops [1]
- Blood products as needed for significant hemorrhage
Antivirals
- Ribavirin is not routinely recommended; limited and conflicting evidence [1]
- No FDA/EMA-approved antiviral for HFRS [11][17]
Monitoring
- Strict I&O, daily weights, serial BMP (creatinine, potassium, sodium), CBC (platelets), coagulation studies
- Urine output monitoring is essential for phase identification [1]
17. Disposition
Admit (30–50% of confirmed HFRS cases in Europe require hospitalization): [1]
- Hypotension or hemodynamic instability
- Oliguria/anuria or rising creatinine
- Significant thrombocytopenia (<100,000)
- Active hemorrhage
- Respiratory distress or hypoxia
- Inability to maintain oral hydration
- Severe abdominal pain requiring monitoring
ICU admission
- Shock requiring vasopressors
- Need for renal replacement therapy
- Respiratory failure / ARDS
- Multiorgan dysfunction [7-8]
Discharge criteria
- Hemodynamically stable, entering diuretic or convalescent phase
- Improving renal function (downtrending creatinine)
- Platelet count recovering
- Tolerating oral intake
- Adequate follow-up arranged
Specialist consultation
- Nephrology — for AKI requiring dialysis or persistent renal dysfunction
- Infectious disease — for diagnostic confirmation and management guidance
- Pulmonology/Critical care — if respiratory failure
- Cardiology — if myocarditis suspected [9]
18. Follow Up / Return Precautions
- Follow-up within 1–2 weeks post-discharge for renal function monitoring (creatinine, GFR) [2]
- Renal recovery may take weeks to months; some patients develop chronic kidney disease [11]
- Ophthalmology follow-up if visual symptoms persist (transient myopia usually resolves) [1]
- Return precautions — instruct patients to return immediately for:
- Decreased urine output or dark/bloody urine
- Worsening shortness of breath
- Persistent vomiting or inability to drink
- New bleeding (nosebleeds, blood in stool, bruising)
- Lightheadedness, fainting, or confusion
- Expected recovery: most patients recover fully over weeks; the diuretic phase (polyuria) can last ~7 days and requires adequate fluid intake [5]
- Reportable disease in most countries — notify public health authorities [1]
- Prevention counseling: avoid contact with rodent excreta, seal entry points in homes, use respiratory protection when cleaning rodent-infested areas, wet-mop rather than sweep/vacuum [4]
References
1. Hantavirus in Humans: A Review of Clinical Aspects and Management. — Vial PA, Ferrés M, Vial C, et al. The Lancet. Infectious Diseases. 2023.
2. What Is Hantavirus?. — Abdoler EA, Malani PN. The Journal of the American Medical Association. 2025.
3. Hantavirus Infections. — Avšič-Županc T, Saksida A, Korva M. Clinical Microbiology and Infection : The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2019.
4. Epidemiology of Hantavirus Infections in Humans: A Comprehensive, Global Overview. — Watson DC, Sargianou M, Papa A, et al. Critical Reviews in Microbiology. 2014.
5. Sequential Assessment of Clinical and Laboratory Parameters in Patients With Hemorrhagic Fever With Renal Syndrome. — Pal E, Korva M, Resman Rus K, et al. PloS One. 2018.
6. Clinical and Laboratory Findings in Patients With Oliguric and Non-Oliguric Hantavirus Haemorrhagic Fever With Renal Syndrome: An Analysis of 128 Patients. — Turčinov D, Puljiz I, Markotić A, Kuzman I, Begovac J. Clinical Microbiology and Infection : The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases. 2013.
7. Epidemiological and Clinical Characteristics of Death From Hemorrhagic Fever With Renal Syndrome: A Meta-Analysis. — Lu W, Kuang L, Hu Y, et al. Frontiers in Microbiology. 2023.
8. Case Report: Multiple Organ Failure Caused by Hemorrhagic Fever With Renal Syndrome. — Wang R, Zhao XY, Liu XJ, et al. The American Journal of Tropical Medicine and Hygiene. 2023.
9. Young Patient With Hantavirus-Induced Myocarditis Detected by Comprehensive Cardiac Magnetic Resonance Assessment. — Krumm P, Zitzelsberger T, Gawaz M, Greulich S. BMC Infectious Diseases. 2019.
10. Hemorrhagic Fever With Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention. — Sehgal A, Mehta S, Sahay K, et al. Viruses. 2023.
11. The Kidney in Hantavirus Infection-Epidemiology, Virology, Pathophysiology, Clinical Presentation, Diagnosis and Management. — Koehler FC, Di Cristanziano V, Späth MR, et al. Clinical Kidney Journal. 2022.
12. Epidemic Trend and Molecular Evolution of HV Family in the Main Hantavirus Epidemic Areas From 2004 to 2016, in P.R. China. — Wang Q, Yue M, Yao P, et al. Frontiers in Cellular and Infection Microbiology. 2021.
13. The 2016 Severe Floods and Incidence of Hemorrhagic Fever With Renal Syndrome in the Yangtze River Basin. — Ji H, Li K, Shang M, Wang Z, Liu Q. JAMA Network Open. 2024.
14. Comparison of Clinical and Laboratory Data Between Hantavirus Infection and Leptospirosis: A Retrospective Case Series Study in Southern Taiwan. — Lo SH, Chen TC, Lin CY, et al. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2025.
15. Electrocardiographic Abnormalities and Relative Bradycardia in Patients With Hantavirus-Induced Nephropathia Epidemica. — Kitterer D, Greulich S, Grün S, et al. European Journal of Internal Medicine. 2016.
16. Standard of Care for Viral Haemorrhagic Fevers (VHFs): A Systematic Review of Clinical Management Guidelines for High-Priority VHFs. — Rigby I, Michelen M, Dagens A, et al. The Lancet. Infectious Diseases. 2023.
17. Hantavirus: An Overview and Advancements in Therapeutic Approaches for Infection. — Afzal S, Ali L, Batool A, et al. Frontiers in Microbiology. 2023.