Hantavirus infection laboratory findings
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Furqan M M. M.B.B.S[3]
Overview
Diagnosis of hantavirus infection is usually made by a positive serological test result. IgM antibodies directed against the hantavirus nucleocapsid protein are often present at the onset of the febrile prodrome and can be detectable on the very first day of symptoms.[1] When the patient seeks medical attention, both IgM and IgG are found in more than 95% of cases, and on day 6 after onset of symptoms at the latest.[2] Evidence of viral antigen in tissue by immunohistochemistry, or the presence of amplifiable viral RNA sequences in blood or tissue, with a compatible clinical history, is also considered diagnostic.[3] In addition to confirmatory diagnostic testing, routine laboratory findings — particularly the peripheral blood smear — provide critical early clues. In hantavirus cardiopulmonary syndrome (HCPS), the presence of 4 or more of 5 peripheral smear criteria (thrombocytopenia, left shift, absence of toxic granulation, hemoconcentration, and immunoblasts >10% of total leukocytes) has a sensitivity of 96% and specificity of 99% for the diagnosis. [1]
Laboratory Findings
Serologic Assays
- Enzyme-linked immunosorbent assay (ELISA) is the serological standard method for confirmation of hantavirus infection. The CDC ELISA detects IgM and IgG antibodies against Sin Nombre virus (SNV) nucleocapsid protein, with a diagnostic sensitivity of 96.6% and specificity of 90.6%.[1][4] An IgG test can be used in conjunction with the IgM-capture test.[5]
- Immunochromatographic IgM assays (rapid point-of-care tests) provide results within 15 minutes and have assay performance greater than 90% compared with EIA IgM assays. They are available for Puumala virus (PUUV), Hantaan virus (HTNV), and Dobrava virus (DOBV). Positive results should be confirmed with specific EIA to minimize false positives.[1][2]
- A Western blot assay using recombinant antigens and isotype-specific conjugates for IgM–IgG differentiation has also been developed, and its results are generally in agreement with those of the IgM-capture format.[5]
- A rapid recombinant immunoblot strip assay (RIBA) identifies serum antibody to recombinant proteins and peptides specific for SNV and other hantaviruses.[6]
- Neutralizing antibody assays are mainly used for studying natural immunity or evaluating candidate vaccines and monoclonal antibodies.[1]
- Acute and convalescent phase sera should reflect a four-fold rise in IgG antibody titer, or IgM antibody should be present in acute phase sera, to be considered diagnostic.[3]
Polymerase Chain Reaction (PCR)
- Reverse transcriptase-quantitative PCR (RT-qPCR), usually targeting the S segment, is sensitive and specific for hantavirus detection.[1] Reverse transcriptase–PCR tests are useful for both hemorrhagic fever with renal syndrome (HFRS) and HCPS, as they can identify viral genotype by PCR sequencing.[5]
- Viral loads are higher in buffy coat than in plasma.[1]
- RT-qPCR can detect Andes virus (ANDV) RNA for up to 2 weeks before symptom onset and detection of antibodies, and for weeks after resolution of symptoms.[1]
- An RT-qPCR assay for PUUV nucleocapsid protein showed 98.7% sensitivity and 100% specificity within the first 8 days of symptoms; it also established diagnosis in 9.6% of patients who were negative for specific PUUV antibodies early in disease.[1]
- A nested RT-PCR for the L segment can detect virus in both serum and urine; virus was detected earlier in urine than in serum, and in both fluids for up to 1 month after initial symptoms.[1]
- RT-PCR is positive only during the viremic phase of infection (approximately the first 10 days).[3]
- Next-generation sequencing has been used for viral genomic epidemiology, including investigation of suspected person-to-person transmission.[1]
Immunohistochemistry (IHC)
IHC testing of formalin-fixed tissues with specific monoclonal and polyclonal antibodies can be used to detect hantavirus antigens and has proven to be a sensitive method for laboratory confirmation of hantaviral infections. IHC has an important role in the diagnosis of HCPS in patients from whom serum samples and frozen tissues are unavailable for diagnostic testing, particularly in fatal cases, and in the retrospective assessment of disease prevalence in a defined geographic region.[3][5]
Other Laboratory Findings
Other laboratory findings are helpful in the diagnosis and management of the complications of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS).[7]
Complete Blood Count and Peripheral Blood Smear
HCPS
- Thrombocytopenia is observed early, even before onset of the cardiopulmonary phase. Platelet count 150,000/μL was present in 71% (12/17) at admission in the original 1993 series.[8] Thrombocytopenia was found in 95% of a 19-patient Canadian series.[9] A platelet count >115,000/μL at admission is associated with lower risk of progression to severe HCPS; 40,000/μL is associated with increased mortality.[1]
- Leukocytosis was present in 79% of patients.[9] Leukocytosis without toxic granulation is characteristic. In the original series, 92% had ≥10% band forms, 46% had metamyelocytes, and 23% had atypical lymphocytes at admission. Subsequently, metamyelocytes were noted in 69% and atypical lymphocytes in 38%.[8]
- Immunoblasts (>10% of total leukocyte population) are a key diagnostic criterion in the cardiopulmonary phase.[1]
- Hemoconcentration: Elevated hematocrit (≥50% in men, ≥48% in women) was present in 76% at admission.[8][3]
HFRS
- Thrombocytopenia is present in 95% of patients; median duration 4 days.[10] Severity of thrombocytopenia is associated with longer hospital stays and higher creatinine concentrations.[1]
- Leukocytosis is present in 55% of patients.[10]
- Elevated hemoglobin due to plasma leakage and hemoconcentration.[1]
Presumptive Diagnostic Criteria (HCPS — Peripheral Blood Smear)
The presence of ≥4 of the following 5 criteria has a sensitivity of 96% and specificity of 99% for the diagnosis of HCPS:[1]
| # | Criterion |
|---|---|
| 1 | Thrombocytopenia (platelet count 150,000/μL) |
| 2 | Left shift in the granulocytic lineage |
| 3 | Absence of toxic granulation in the myeloid series |
| 4 | Hemoconcentration (hematocrit >50% in men, >48% in women) |
| 5 | Immunoblast population >10% of total leukocyte population |
A decade-long retrospective validation at the University of New Mexico (188 smears) confirmed the 4-of-5 cutoff as the most clinically useful, with sensitivity 89% and specificity 93%. All patients meeting 5 of 5 criteria had confirmed infections.[11]
Coagulation Studies
HCPS
- Partial thromboplastin time (PTT) ≥40 seconds in 67% (8/12) at admission and 83% (10/12) subsequently.[8]
- D-dimer elevated in 3/7 patients tested; fibrinogen normal in all 7 tested.[8]
HFRS
- Coagulation abnormalities and thrombocytopenia accompany the febrile phase.[1]
- Disseminated intravascular coagulation (DIC) was present in 27.3% (107/392) of HFRS patients on admission and was more common in fatal cases.[12]
- The death group had longer PT and APTT, higher D-dimer and fibrin degradation products (FDP), and lower platelets and fibrinogen compared with survivors. Prolonged PT, low fibrinogen, and elevated total bilirubin on admission were independent risk factors for death.[12]
- PUUV-infected patients have an increased risk for both DIC and venous thromboembolism (VTE).[13]
- Circulating extracellular vesicle tissue factor (EVTF) activity is transiently increased during HFRS and is associated with intravascular coagulation.[14]
Metabolic Panel and Biochemistry
HCPS
- Mild elevation of plasma creatinine (did not rise above 2.5 mg/dL [220 μmol/L] in any patient in the original series).[8]
- Metabolic acidosis with increased anion gap in 5/17 patients at hospitalization.[8]
HFRS
| Laboratory Parameter | Frequency | Median Duration |
|---|---|---|
| Elevated creatinine | 94% | 9 days |
| Diminished GFR | 87% | 8 days |
| Elevated ALT | 87% | 3 days |
| Elevated CRP | 99% | 7 days |
| Elevated procalcitonin | 91% | 3 days |
- Elevated serum creatinine and urea concentrations are observed 5–9 days after disease onset during the oliguric phase.[1]
- Patients infected with DOBV have a higher proportion of acute renal failure, severe thrombocytopenia, and other abnormal laboratory findings than patients infected with PUUV.[1]
Serum Electrolytes
- Hyponatremia may be present in both HCPS and HFRS.[7][8]
Arterial Blood Gases
- In HCPS, arterial blood gas analysis may show metabolic acidosis (with increased anion gap) and respiratory alkalosis.[8][7]
Urinalysis
HFRS: Proteinuria and hematuria are typical early findings. Detection of proteinuria and hematuria with urine dipstick analysis supports clinical suspicion of HFRS.[1] Proteinuria was present in 93.7% of pediatric HFRS patients.[15] Nephrotic-range proteinuria may occur but is rapidly reversible, associated with podocyte foot-process effacement.[16] At follow-up (7–35 months), 7% had proteinuria and 25% had hematuria.[17]
HCPS: Proteinuria may be present. Positive quantitative proteinuria at hospital admission has been linked to mortality.[1] The marked proteinuria followed by oliguria that is characteristic of severe HFRS is not seen in HCPS.[8]
Liver Function Tests
- Seoul virus infection is notable for distinct elevation of liver enzymes, often more prominent than renal dysfunction.[1]
Inflammatory and Prognostic Biomarkers
- IL-6: Independent marker of disease severity in HCPS (OR 2.25; 95% CI 1.01–5.01). IL-6 levels were 40-fold higher in severe versus mild ANDV-HCPS (crude OR 14.4; 95% CI 3.3–63.1).[18][19] IL-6 trans-signaling (sIL-6R/sgp130 ratio) is increased in HFRS patients and correlates with need for oxygen treatment.[20]
- I-FABP (intestinal fatty acid-binding protein): Independent marker of fatal outcome in HCPS (OR 1.64; 95% CI 1.01–2.64).[18]
- Neutrophil-to-lymphocyte ratio (NLR): Elevated in acute hantavirus infection. In PUUV-HFRS, median NLR on admission was 3.82 (range 1.75–7.59); higher NLR correlated with maximum serum creatinine (r=0.5069, p=0.0097) and length of hospital stay (r=0.5653, p=0.0032). NLR cutoff for mortality: >5.5 for HTNV-HFRS, >8.1 for ANDV-HCPS.[21]
- Neutrophil activation products: Myeloperoxidase and neutrophil elastase are strongly elevated in acute PUUV-HFRS and positively correlate with kidney dysfunction.[22]
- Complement factor C5/5a: Higher in HCPS survivors compared with fatal cases.[18]
Summary Table: Key Laboratory Differences Between HCPS and HFRS
| Laboratory Finding | HCPS | HFRS |
|---|---|---|
| Thrombocytopenia | 71–95%; 40,000/μL associated with mortality[8][9][1] | 95%; median duration 4 days[10] |
| Leukocytosis | 79%; without toxic granulation[9][8] | 55%[10] |
| Hemoconcentration | 76% (Hct ≥50% men, ≥48% women)[8] | Present (elevated hemoglobin)[1] |
| Immunoblasts | >10% of leukocytes (diagnostic criterion)[1] | Not a diagnostic criterion |
| Creatinine | Mild elevation (≤2.5 mg/dL)[8] | Elevated in 94%; median duration 9 days[10] |
| ALT | May be mildly elevated | Elevated in 87%; median duration 3 days[10] |
| CRP | May be elevated | Elevated in 99%; median duration 7 days[10] |
| Procalcitonin | Not well characterized | Elevated in 91%; median duration 3 days[10] |
| Proteinuria | May be present; linked to mortality[1] | 93.7% (pediatric); nephrotic-range possible[15][16] |
| Hematuria | Not typical | Common; 25% persistent at follow-up[17] |
| PTT | ≥40 sec in 67–83%[8] | Prolonged; independent risk factor for death when PT also prolonged[12] |
| DIC | Rare[8] | 27.3% on admission; more common in fatal cases[12] |
| IL-6 | 40-fold higher in severe vs. mild ANDV-HCPS[19] | Elevated; trans-signaling correlates with oxygen need[20] |
| NLR mortality cutoff | >8.1[21] | >5.5 (HTNV)[21] |
Diagnostic Algorithm
The following table summarizes the recommended diagnostic approach by clinical phase and specimen availability:
| Clinical Scenario | Recommended Test(s) | Notes |
|---|---|---|
| Acute presentation (first 1–8 days of symptoms) | ELISA for IgM and IgG; RT-qPCR on buffy coat or whole blood | IgM and IgG are present in >95% of patients by day 6[2]; RT-qPCR may establish diagnosis in 9.6% of patients who are seronegative early in disease[1] |
| Rapid triage in endemic area (suspected HCPS) | Peripheral blood smear review (5-criteria scoring); immunochromatographic rapid IgM test | ≥4 of 5 smear criteria: sensitivity 96%, specificity 99%[1]; rapid IgM test results in 15 minutes with >90% performance[1][2] |
| Convalescent or late presentation (>10 days) | ELISA for IgM and IgG; paired acute/convalescent sera for four-fold IgG rise | RT-PCR may be negative after the viremic phase (~10 days)[3] |
| Fatal case or no serum available | Immunohistochemistry (IHC) on formalin-fixed tissue | Sensitive method for postmortem confirmation[3][5] |
| Epidemiological investigation or suspected person-to-person transmission | Next-generation sequencing | Used for viral genomic epidemiology and transmission chain analysis[1] |
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 Vial PA, Ferrés M, Vial C, Valdivieso F, Mertz GJ, Godoy P (2023). "Hantavirus in humans: a review of clinical aspects and management". Lancet Infect Dis. 23 (9): e371–e382. doi:10.1016/S1473-3099(23)00128-7. PMID 37105214 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 Vaheri A, Henttonen H, Voutilainen L, Mustonen J, Sironen T, Vapalahti O (2013). "Hantavirus infections in Europe and their impact on public health". Rev Med Virol. 23 (1): 35–49. doi:10.1002/rmv.1722. PMID 23027245.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Llah ST, Mir S, Sharif S, Khan S, Mir MA (2018). "Hantavirus induced cardiopulmonary syndrome: a public health concern". J Med Virol. 90 (6): 1003–1009. doi:10.1002/jmv.25054. PMID 29322515.
- ↑ Alonso DO, Iglesias AA, Coelho R, Periolo N, Bruno A, Córdoba MT, Filomarino N, Quipildor M, Biber P, Castellar A, Díaz M, Enría D, Levis S (2019). "Epidemiological description, case-fatality rate, and trends of hantavirus pulmonary syndrome: 9 years of surveillance in Argentina". J Med Virol. 91 (7): 1173–1181. doi:10.1002/jmv.25446. PMID 31163681.
- ↑ 5.0 5.1 5.2 5.3 5.4 Lednicky JA (2003). "Hantaviruses. a short review". Arch Pathol Lab Med. 127 (1): 30–5. doi:10.1043/0003-9985(2003)12730:>2.0.CO;2. PMID 12521363.
- ↑ Levy H, Simpson SQ (1994). "Hantavirus pulmonary syndrome". Am J Respir Crit Care Med. 149 (6): 1710–3. doi:10.1164/ajrccm.149.6.8004332. PMID 8004332.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Sargianou M, Watson DC, Chra P, Papa A, Starakis I, Gogos C, Panos G (2012). "Hantavirus infections for the clinician: from case presentation to diagnosis and treatment". Crit Rev Microbiol. 38 (4): 317–29. doi:10.3109/1040841X.2012.673553. PMID 22553984.
- ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 Duchin JS, Koster FT, Peters CJ, Simpson GL, Tempest B, Zaki SR, Ksiazek TG, Rollin PE, Nichol S, Umland ET (1994). "Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease". N Engl J Med. 330 (14): 949–55. doi:10.1056/NEJM199404073301401. PMID 8189152.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Verity R, Prasad E, Grimsrud K, Artsob H, Drebot M, Miedzinski L, Preiksaitis J (2000). "Hantavirus pulmonary syndrome in northern Alberta, Canada: clinical and laboratory findings for 19 cases". Clin Infect Dis. 31 (4): 942–6. doi:10.1086/318142. PMID 10738918.
- ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 Pal E, Korva M, Resman Rus K, Fajs L, Strle F, Avšič-Županc T (2018). "Sequential assessment of clinical and laboratory parameters in patients with hemorrhagic fever with renal syndrome". PLoS One. 13 (5): e0197661. doi:10.1371/journal.pone.0197661. PMID 29791494.
- ↑ Dvorscak L, Czuchlewski DR (2014). "Successful triage of suspected hantavirus cardiopulmonary syndrome by peripheral blood smear review: a decade of experience in an endemic region". Am J Clin Pathol. 142 (2): 196–201. doi:10.1309/AJCPNFVL4QFGYWET. PMID 24502438.
- ↑ 12.0 12.1 12.2 12.3 12.4 Chen Y, Li R, Jiang Y, Xiang Y, Gao Y, Yin Y, Sun J, Shen X (2024). "Coagulation dysfunction and risk factors for mortality in hemorrhagic fever with renal syndrome: a retrospective study". J Med Virol. 96 (3): e29530. doi:10.1002/jmv.29530. PMID 38413218 Check
|pmid=value (help). - ↑ Koskela S, Laine O, Mäkelä S, Pessi T, Tuomisto S, Huhtala H, Karhunen P, Mustonen J, Vaheri A (2021). "Coagulation and fibrinolysis in Puumala hantavirus infection". Thromb Res. 198: 79–84. doi:10.1016/j.thromres.2020.11.024. PMID 33803655 Check
|pmid=value (help). - ↑ Schmedes CM, Grover SP, Engel NW, Hölscher M, Renné T, Mackow ER (2020). "Circulating extracellular vesicle tissue factor activity during orthohantavirus infection is associated with intravascular coagulation". J Infect Dis. 222 (8): 1392–1399. doi:10.1093/infdis/jiaa096. PMID 32093085 Check
|pmid=value (help). - ↑ 15.0 15.1 Li R, Sun J, Chen Y, Xiang Y, Gao Y, Yin Y, Jiang Y, Shen X (2023). "Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus". J Med Virol. 95 (1): e28339. doi:10.1002/jmv.28339. PMID 36571133 Check
|pmid=value (help). - ↑ 16.0 16.1 Boehlke C, Hartleben B, Huber TB, Hopfer H, Walz G, Neumann-Haefelin E (2014). "Hantavirus infection with severe proteinuria and podocyte foot-process effacement". Am J Kidney Dis. 64 (3): 452–6. doi:10.1053/j.ajkd.2014.04.030. PMID 24885916.
- ↑ 17.0 17.1 Latus J, Schwab M, Tacber E, Segerer S, Kitterer D, Braun N, Alscher MD, Muller GA, Dominik A (2015). "Clinical and laboratory findings in patients with acute kidney injury due to Puumala hantavirus infection". BMC Infect Dis. 15: 73. doi:10.1186/s12879-015-0824-6. PMID 25884821.
- ↑ 18.0 18.1 18.2 Maleki KT, García M, Iglesias A, Alonso D, Ciez M, Cuauro A, Vial PA, Ferrer F, Saavedra F, Mertz GJ, Klingström J (2019). "Serum markers associated with severity and outcome of hantavirus pulmonary syndrome". J Infect Dis. 219 (11): 1832–1840. doi:10.1093/infdis/jiz005. PMID 30707108.
- ↑ 19.0 19.1 Angulo J, Martínez-Valdebenito C, Marco C, Galeno H, Villagra E, Vera L, Lagos N, Becerra N, Mora J, Bermúdez A, Díaz J, Ferrés M, López-Lastra M, Vial PA (2017). "Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes virus". PLoS Negl Trop Dis. 11 (3): e0005757. doi:10.1371/journal.pntd.0005757. PMID 28329389.
- ↑ 20.0 20.1 Maleki KT, Tauriainen J, García M, Kerkman PF, Nilsson S, Maucourant C, Ljunggren HG, Smed-Sörensen A, Ahlm C, Björkström NK, Klingström J (2025). "IL-6 trans-signaling in acute hantavirus infection". mSphere. 10 (1): e0082024. doi:10.1128/msphere.00820-24. PMID 39757222 Check
|pmid=value (help). - ↑ 21.0 21.1 21.2 Nusshag C, Stütz A, Hägele S, Speer C, Kälble F, Eckert C, Brenner T, Zeier M, Krautkrämer E (2024). "Neutrophil-to-lymphocyte ratio as a prognostic marker in hantavirus infection". Viruses. 16 (3): 378. doi:10.3390/v16030378. PMID 38483893 Check
|pmid=value (help). - ↑ Strandin T, Mäkelä S, Gn S, Hägglund S, Vaheri A, Mustonen J (2018). "Neutrophil activation in acute hemorrhagic fever with renal syndrome is mediated by hantavirus-infected microvascular endothelial cells". Front Immunol. 9: 2098. doi:10.3389/fimmu.2018.02098. PMID 29925880.