Clinical Significance of CBC and WBC Morphology in the Diagnosis and Clinical Course of COVID-19 Infection

Olga Pozdnyakova, MD, PhD; Nathan T. Connell, MD, MPH; Elisabeth M. Battinelli, MD, PhD; Jean M. Connors, MD; Geoffrey Fell, MS; Annette S. Kim, MD, PhD


Am J Clin Pathol. 2021;155(3):364-375. 

In This Article

Abstract and Introduction


Objectives: To investigate the clinical significance of numeric and morphologic peripheral blood (PB) changes in coronavirus disease 2019 (COVID-19)–positive patients in predicting the outcome, as well as to compare these changes between critically ill COVID-19–positive and COVID-19–negative patients.

Methods: The study included 90 COVID-19–positive (51 intensive care unit [ICU] and 39 non-ICU) patients and 30 COVID-19–negative ICU patients. We collected CBC parameters (both standard and research) and PB morphologic findings, which were independently scored by two hematopathologists.

Results: All patients with COVID-19 demonstrated striking numeric and morphologic WBC changes, which were different between mild and severe disease states. More severe disease was associated with significant neutrophilia and lymphopenia, which was intensified in critically ill patients. Abnormal WBC morphology, most pronounced in monocytes and lymphocytes, was associated with more mild disease; the changes were lost with disease progression. Between COVID-19–positive and COVID-19–negative ICU patients, significant differences in morphology-associated research parameters were indicative of changes due to the severe acute respiratory syndrome coronavirus 2 virus, including higher RNA content in monocytes, lower RNA content in lymphocytes, and smaller hypogranular neutrophils.

Conclusions: Hospitalized patients with COVID-19 should undergo a comprehensive daily CBC with manual WBC differential to monitor for numerical and morphologic changes predictive of poor outcome and signs of disease progression.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic of coronavirus disease 2019 (COVID-19), an acute viral illness with a spectrum of disease presentation and severity.[1] During review of peripheral blood of patients with COVID-19 admitted to our hospital, we have noticed significant alterations of WBC morphology. While there are an increasing number of publications and preprints in peer-reviewed and non-peer-reviewed journals regarding COVID-19 pathogenesis, clinical presentation, and treatment, the studies that have addressed the morphologic changes in peripheral blood associated with SARS-CoV-2 are all limited to case and image reports.[2–5] The most recent study by Nazarullah et al[6] that includes a detailed quantitative and qualitative analysis of peripheral blood changes was conducted on 12 COVID-19–positive patients. In addition, very few studies provide correlation between peripheral blood WBC morphologic changes and disease outcomes and address the dynamics of CBC parameters and morphology.[2]

Viral-induced numeric and morphologic changes in the peripheral blood WBC are well characterized in other infections and can direct diagnostic workup to ensure timely therapeutic intervention. For example, in infectious mononucleosis, caused by the Epstein-Barr virus, there is a significant lymphocytosis with the presence of large atypical lymphocytes, termed Downey cells,[7] while in human immunodeficiency virus infection, the lymphocytes are morphologically unremarkable in the setting of lymphopenia.[8]

This study presents a systematic analysis of peripheral blood CBC, including standard and research parameters, as well as morphologic findings in 90 consecutive patients with COVID-19. Importantly, the study compares the peripheral blood findings between patients with COVID-19 in the intensive care unit (ICU) and non-ICU settings, as well as between COVID-19–positive ICU and COVID-19–negative ICU patients, and demonstrates significant differences between these two groups, suggesting an important role of CBC with manual smear review in patient risk stratification. To our knowledge, this is the first study to monitor dynamic changes in CBC numeric and morphology parameters in COVID-19–positive patients who died of the disease and to investigate morphology-associated research parameters measured by hematology analyzers and compare them between COVID-19–positive and COVID-19–negative patients.