Atypical lymphocytes in the peripheral blood of COVID-19 patients: A prognostic factor for the clinical course of COVID-19

Abstract

Background: Clinical observations have shown that there is a relationship between coronavirus disease 2019 (COVID-19) and atypical lymphocytes in the peripheral blood; however, knowledge about the time course of the changes in atypical lymphocytes and the association with the clinical course of COVID-19 is limited.

Objective: Our purposes were to investigate the dynamics of atypical lymphocytes in COVID-19 patients and to estimate their clinical significance for diagnosis and monitoring disease course.

Materials and methods: We retrospectively identified 98 inpatients in a general ward at Kashiwa Municipal Hospital from May 1st, 2020, to October 31st, 2020. We extracted data on patient demographics, symptoms, comorbidities, blood test results, radiographic findings, treatment after admission and clinical course. We compared clinical findings between patients with and without atypical lymphocytes, investigated the behavior of atypical lymphocytes throughout the clinical course of COVID-19, and determined the relationships among the development of pneumonia, the use of supplemental oxygen and the presence of atypical lymphocytes.

Results: Patients with atypical lymphocytes had a significantly higher prevalence of pneumonia (80.4% vs. 42.6%, p < 0.0001) and the use of supplemental oxygen (25.5% vs. 4.3%, p = 0.0042). The median time to the appearance of atypical lymphocytes after disease onset was eight days, and atypical lymphocytes were observed in 16/98 (16.3%) patients at the first visit. Atypical lymphocytes appeared after the confirmation of lung infiltrates in 31/41 (75.6%) patients. Of the 13 oxygen-treated patients with atypical lymphocytes, approximately two-thirds had a stable or improved clinical course after the appearance of atypical lymphocytes.

Conclusion: Atypical lymphocytes frequently appeared in the peripheral blood of COVID-19 patients one week after disease onset. Patients with atypical lymphocytes were more likely to have pneumonia and to need supplemental oxygen; however, two-thirds of them showed clinical improvement after the appearance of atypical lymphocytes.

Fig 1. Representative atypical lymphocytes in the peripheral blood of COVID-19 patients.

All images are of May-Giemsa-stained peripheral blood smears. (A, B) Atypical lymphocytes with condensed chromatin, deep basophilic cytoplasm and eccentric nuclei. (C, D) Atypical lymphocytes with abundant pale cytoplasm and indented nuclei, resembling Downey II cells.

Fig 2. Distribution of the fractions of atypical lymphocytes.

The number of patients in each fraction of atypical lymphocytes is shown. Each patient was classified according to their peak value. Numbers above bars indicate the actual counts of each fraction.

Fig 3. First appearance of atypical lymphocytes after disease onset.

Patients were counted according to the day of the first identification of atypical lymphocytes after disease onset. The total number of patients who had atypical lymphocytes in their peripheral blood was 51. The median value was eight days.

Fig 4. Comparison of dates on which pneumonia and atypical lymphocytes appeared.

(A) Difference between the days on which radiographic evidence of pneumonia and atypical lymphocytes were detected in each patient. Total number of patients was 41. Bars represent the difference for each patient in days and are arranged in ascending order. A negative value (blue bar) indicates that the radiographic evidence of pneumonia appeared first, and a positive value (orange bar) indicates that atypical lymphocytes appeared first. (B) Beeswarm plot of the first day of detection. The bold dotted line indicates the median, and the thin dotted lines indicate the upper and lower quantiles. * p < 0.0001 by Wilcoxon rank-sum test.

Fig 5. Clinical courses of representative patients who received supplemental oxygen.

Abbreviations: LyC, lymphocyte count; ALyC, atypical lymphocyte count. (A-D) Time course of lymphocyte count (yellow diamond), atypical lymphocyte count (blue circle) and amount of supplemental oxygen (gray bar) in representative patients. The number above the gray bar demonstrates the amount of oxygen in liters per minute, and double-headed arrows indicate the period of data collection for each patient. (A) A patient who improved after atypical lymphocytes were detected. (B) A patient who had already stopped oxygen therapy when atypical lymphocytes appeared. (C) A patient whose condition worsened after atypical lymphocytes appeared. (D) A patient who worsened when the presence of atypical lymphocytes was detected. This patient was admitted to the ICU on day 8. (E) Proportion of patients in each clinical category. A–D correspond to the categories mentioned above.

Fig 6. Comparison of clinical indices among clinical courses.

(A) Comparison of the date on which atypical lymphocytes appeared. (B) Comparison of the peak fraction of atypical lymphocytes. (C) Comparison of the peak number of atypical lymphocytes. Each plot indicates a patient in a group. No significant differences were detected among groups by one-way ANOVA.