Clinico-Biological Features and Clonal Hematopoiesis in Patients with Severe COVID-19

Abstract

Advanced age or preexisting comorbidities have been characterized as risk factors for severe coronavirus disease 2019 (COVID-19) cases requiring hospitalization and intensive care. In recent years, clonal hematopoiesis (CH) of indeterminate potential (CHIP) has emerged as a risk factor for chronic inflammatory background and subsequent aging-associated diseases. The purpose of this study was to identify biological factors (particularly leukocyte subtypes and inflammatory markers) associated with a risk of clinical deterioration (i.e., orotracheal intubation (OTI)) and to determine whether CH was likely to influence clinical and biological behavior in patients with severe COVID-19 requiring hospitalization. Here, we describe clinical and biological features, including the screening of CHIP mutants in a well-annotated cohort of 122 hospitalized patients with a laboratory-confirmed diagnosis of COVID-19 (55% requiring OTI). We showed that elevated white blood cell counts, especially neutrophils and high C-reactive protein (CRP) levels at admission, were associated with an increased requirement of OTI. We noticed a high prevalence of CH (25%, 38%, 56%, and 82% of patients aged <60 years, 60-70 years, 70-80 years, and >80 years) compared to a retrospective cohort of patients free of hematological malignancy explored with the same pipelines (10%, 21%, 37%, and 44%). However, the existence of CH did not significantly impact clinical outcome, including OTI or death, and did not correlate with other laboratory findings.

Keywords: CHIP; COVID-19; DNMT3A; SARS-CoV-2; TET2; clonal hematopoiesis; sequencing.

Figure 1

Kinetics of laboratory values (mean (95% CI)) during hospitalization in COVID-19 patients according to the requirement (green) or not (blue) of orotracheal intubation (OTI). (A) C-reactive protein; (B) white blood cell count (WBC); (C) neutrophils.

Figure 2

CH in COVID-19 patients requiring hospitalization. (A) Lollipop plots depicting TET2 and DNMT3A mutations in COVID-19 patients. Black, green, pink, and blue dots indicate frameshift/nonsense, missense, in frame, and splicing mutations, respectively. (B) Molecular landscape showing co-mutations in 55 clonal hematopoiesis-positive patients. Red boxes indicate several mutations within the same gene. (C) Violin plot showing the distributions of variant allele frequencies for TET2 and DNMT3A mutations. (D) Frequency of CH among age groups in COVID-19 patients.

Figure 3

Frequency of individuals with (A,D) clonal hematopoiesis, (B,E) TET2 mutations, and (C,F) DNMT3A mutations in COVID-19 positive patients and patients from the retrospective cohort. Subfigures (D–F) show frequency for males only.