Hantavirus Disease and COVID-19

Evaluation of the Hantavirus 5-Point Screen in 139 COVID-19 Patients

Allison K. Joyce, MSc; Tarrah T. Oliver; Aaron D. Kofman, MD; Donna L. Talker; Shahrokh Safaeian; Deniz Peker Barclift, MD; Adam J. Perricone, MD, PhD; Shawn M. D'Andrea, MD; Amy N. Whitesell, MPH; Del Yazzie, MPH; Jeannette Guarner, MD; Mozafar Saleki, MS; Glynnis B. Ingall, MD, PhD; Mary J. Choi, MD; Ramona Antone-Nez, MPH


Am J Clin Pathol. 2022;157(3):470-475. 

In This Article

Abstract and Introduction


Objectives: Navajo Nation is disproportionately affected by hantavirus cardiopulmonary syndrome (HCPS), a severe respiratory disease that can quickly progress to respiratory failure and cardiogenic shock. The initial signs and symptoms of HCPS are indistinguishable from coronavirus disease 2019 (COVID-19). However, this distinction is critical, as the disease course differs greatly, with most patients with COVID-19 experiencing mild to moderate illness. We set out to determine if the evaluation of peripheral blood smears for five hematopathologic criteria previously identified as hallmarks of hantavirus infection, or "the hantavirus 5-point screen," could distinguish between COVID-19 and HCPS.

Methods: The hantavirus 5-point screen was performed on peripheral blood smears from 139 patients positive for COVID-19 seeking treatment from Tséhootsooí Medical Center and two Emory University hospitals.

Results: Of these 139 individuals, 136 (98%) received a score of 3/5 or below, indicating low suspicion for HCPS. While thrombocytopenia, one of the key signs of HCPS, was seen in the patients with COVID-19, it was generally mild and remained stable on repeat specimens collected 12 to 24 hours later.

Conclusions: Given these findings, the 5-point screen remains a useful rapid screening tool for potential HCPS cases and may be useful to distinguish early HCPS from COVID-19 in HCPS endemic regions.


Hantavirus cardiopulmonary syndrome (HCPS) due to Sin Nombre virus is a severe respiratory disease with average case fatality rates as high as 35%.[1] HCPS was first identified in 1993 in the Four Corners region of the United States—an area largely belonging to Navajo Nation where Utah, Colorado, Arizona, and New Mexico intersect.[2] HCPS is a rare disease, with a 20-year surveillance period reporting 624 cases throughout the United States.[3] However, Navajo Nation continues to be disproportionately affected by HCPS, with Navajos making up 1.7% of the US population but accounting for 18% of all HCPS cases.[4]

HCPS begins with a nonspecific febrile prodrome.[5] This initial phase lasts 2 to 6 days and is characterized by fever, malaise, and myalgias.[5,6] Gastrointestinal signs and symptoms have also been reported, including nausea, vomiting, and diarrhea.[5,6] The disease quickly progresses to the cardiopulmonary phase, characterized by the abrupt onset of cough, shortness of breath, and hypoxia.[5–8] These symptoms are caused by the sudden development of severe noncardiogenic pulmonary edema and cardiogenic shock.[5–8] Without immediate medical intervention, most deaths occur within 24 to 48 hours from onset of the cardiopulmonary phase.[5–8] However, early initiation of extracorporeal membrane oxygenation (ECMO) has been shown to improve survival in severe HCPS.[9] Due to the aggressive nature of the disease, early clinical suspicion, timely diagnosis, and proactive clinical management are critical to saving the lives of patients with HCPS.

Current diagnostic options for hantavirus are limited to real-time reverse transcription polymerase chain reaction (rRT-PCR) or serology for immunoglobulin M and immunoglobulin G. However, these tests are not widely available and can take considerable time to return results. To address this problem, the University of New Mexico Health Sciences Center developed a rapid screening tool in 2001 with the aim of quickly classifying patients with suspected hantavirus into low, intermediate, or high risk for HCPS.[10] The screen is based on the five criteria the hematopathologists identified as hallmarks of HCPS: thrombocytopenia, elevated hemoglobin/hematocrit, a left shift on neutrophils, absence of significant toxic granulation of the neutrophils, and immunoblasts and plasma cells more than 10% of lymphoid cells.[10] The "5-point" screen is most accurate when the specimen was collected during the cardiopulmonary phase.[10] In addition, the thrombocytopenia seen in patients with hantavirus tends to be profound, with platelet counts decreasing more than 20 × 103 μL per 12 hours.[10] A decade-long retrospective review confirmed that individuals with hantavirus score high on the 5-point screen, receiving an average score of 4.22 out of 5.[11] The review also found that by using a score cutoff of 4 out of 5, the screen demonstrated a sensitivity of 89% and a specificity of 93% for HCPS, thus validating its use as a rapid screen for HCPS.[11] Therefore, in areas endemic for hantavirus, the 5-point screen is a useful tool to quickly screen for potential HCPS cases where rapid commercial diagnostic tests are not available and would take time to return when critical decisions regarding patient care need to be made.

Navajo Nation has also been heavily affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly transmissible novel zoonotic virus that emerged in 2019 and causes coronavirus disease (COVID-19).[12] In May 2020, Navajo Nation surpassed New York and New Jersey as the highest per-capita coronavirus infection rate in the United States.[13] The signs and symptoms of acute COVID-19 overlap with those of HCPS. As a result, in Navajo Nation and other regions endemic for HCPS, it may be difficult to clinically distinguish early symptoms of COVID-19 and HCPS from each other.[14] However, this distinction is critical, as the expected clinical courses differ greatly. Most healthy adults with COVID-19 experience mild to moderate disease, and severe disease tends to develop over days to weeks.[15] In contrast, the clinical course for those with HCPS is more severe and often develops within hours, with most requiring urgent intensive care treatment and some requiring ECMO. Given the ongoing COVID-19 pandemic, a screening tool that could rapidly differentiate between the two disease entities is critical for preventing excess deaths due to hantavirus disease in hantavirus endemic regions. Therefore, we sought to determine whether the hantavirus 5-point screen could be used to differentiate between HCPS and COVID-19.