Clonal hematopoiesis in patients with Covid‐19 is stable and not linked to an aggravated clinical course

Abstract

To the Editor: The strength of host immune reaction to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) determines the severity of corona virus disease 2019 (Covid-19). While a basic antiviral immune response involving innate immune mechanisms and an induction of adaptive immunity is needed to resolve the disease, particularly innate myeloid cells can also induce a dysregulated, excessive, aberrant and non-effective host immune response in severe Covid-19. The latter is termed “hyperinflammation,” “cytokine storm,” “macrophage activation syndrome” or “cytokine release syndrome.” Hyperinflammation contributes to the pathogenesis of Covid-19 related acute respiratory distress syndrome (ARDS), which is associated with a fatal outcome in the majority of patients, but may also induce multi-organ damage, which is the second most common cause of death in Covid-19. Thus, a better understanding of underlying host-intrinsic factors driving immune dysfunction is warranted for the immediate identification of patients at risk and eventually also for selecting novel targeted therapies. Thus, SARS-CoV-2 has been found to infect multiple cells expression ACE-2 receptors including human monocytes, macrophages and dendritic cells, emphasizing their contribution to disease pathology. Of relevance, clonal hematopoiesis (CH; defined as somatic variants in the peripheral blood at a variant allele frequency ≥2%) is considered to imprint inflammation in myeloid cells, which may perpetuate acute (e.g., infectious-triggered) and chronic inflammatory processes. Moreover, CH is associated with some of the comorbidities relevant for higher risk of severe Covid-19, especially age and cardiovascular disease. Augmented injury in cardiovascular tissues was attributed to increased inflammatory tension in clonal myeloid and T cells, which drive pro-inflammatory circuits via NLRP3-inflammasome activation and subsequent IL-1β production. Moreover, while published data regarding the risk of patients with hematological malignancies to acquire Covid-19 are discordant, these papers consistently show that these patients have a higher case fatality rate. In addition, case reports of acute leukemia and concomitant Covid-19 are increasingly reported. Especially newly diagnosed, refractory or relapsed cases pose a challenge, as these patients often need immediate therapy. However, diagnostic work-up prior to therapy initiation is essential for the selection of the optimal patienttailored therapy. For example, for acute myeloid leukemia, besides a complete blood count, flow cytometric analysis and a bone marrow smear, genetic work-up including molecular genetics is indispensable for proper classification and risk assessment. Indeed, the American Society of Hematology recommends starting with induction chemotherapy in eligible patients regardless of Covid-19 status. Thus, knowledge about the influence of viral infections in general and Covid-19 specifically, on molecular analyses and their dynamics during fulminant infection would help to better manage and interpret findings of such newly diagnosed/relapsed/refractory leukemia patients. However, to the best of our knowledge there are currently no reports on the dynamics of aberrations detected during acute (viral) infections. Against this background, we herein investigated the prevalence and clinical impact of CH in Covid-19. Moreover, we analyzed clonal size during the disease and upon its resolution. In total, 169 patients were screened for participation in this study. Nine patients turned out to be SARS-CoV-2 PCR negative, and thus were excluded from further analysis. Of the remaining 160 patients, 43 patients were included during hospitalization due to Covid-19 (median time to blood test for CH analysis: 24 days; range: 0– 57 days), 117 patients, who were either treated as outpatients or also being hospitalized during the acute phase, were included when they came for follow-up evaluation performed between 31–119 days (median: 56 days) after initial diagnosis of Covid-19 (Figure S1). Eight patients were analyzed at two or more time points. Both trial protocols were approved by the institutional review board at Innsbruck Medical University (EK-Nb: 1091/2020 and 1103/2020). Informed consent was obtained from each patient. Laboratory analyses and complete blood count were assessed by standard methods as part of patient care at the Medical University of Innsbruck. Detection of CH variants was performed by next generation sequencing on MiSeq devices using the TrueSight Myeloid sequencing panel from Illumina. For data analysis, the SeqNext software of JSI Medical Systems was utilized. Only coding variants not frequent in the general population with a variant allele frequency (VAF) between 2% and 45% were included in the dataset. Further details on genetic analysis are given in the supplemental file. Statistical analysis was performed using GraphPad Prism software. In order to assess correlation between disease groups and CH, chi-square test was used. For comparison between disease groups, two-sided Mann–Whitney U test was used, because of non-normal Received: 16 April 2021 Revised: 18 May 2021 Accepted: 20 May 2021