Increased prevalence of clonal hematopoiesis of indeterminate potential in hospitalized patients with COVID-19

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) leads to higher mortality, carries a cardiovascular risk and alters inflammation. All three aspects harbor overlaps with the clinical manifestation of COVID-19. This study aimed to identify the impact of CHIP on COVID-19 pathophysiology. 90 hospitalized patients were analyzed for CHIP. In addition, their disease course and outcome were evaluated. With a prevalence of 37.8%, the frequency of a CHIP-driver mutation was significantly higher than the prevalence expected based on median age (17%). CHIP increases the risk of hospitalization in the course of the disease but has no age-independent impact on the outcome within the group of hospitalized patients. Especially in younger patients (45 - 65 years), CHIP was associated with persistent lymphopenia. In older patients (> 65 years), on the other hand, CHIP-positive patients developed neutrophilia in the long run. To what extent increased values of cardiac biomarkers are caused by CHIP independent of age could not be elaborated solely based on this study. In conclusion, our results indicate an increased susceptibility to a severe course of COVID-19 requiring hospitalization associated with CHIP. Secondly, they link it to a differentially regulated cellular immune response under the pressure of SARS-CoV-2 infection. Hence, a patient's CHIP-status bears the potential to serve as biomarker for risk stratification and to early guide treatment of COVID-19 patients.

Keywords: CHIP; SARS-CoV-2; cardiac function; critically ill; immune system.

Figure 1

CHIP-associated mutations in hospitalized patients with COVID-19. (A) Prevalence of clonal hematopoiesis in hospitalized patients with COVID-19. CHIP-positive = patients carrying at least one CHIP-driver mutation with a VAF≥0.01. Expected prevalence according to Watson et al. (4). Observed and expected prevalence were compared using binomial test. Statistically significant results (P ≤ 0.05) are highlighted by bold print. (B) Number of individual mutations per CHIP-positive patient. (C) Prevalence broken down by affected genes.

Figure 2

Impact of clonal hematopoiesis on patient outcome. (A) Kaplan-Meier survival curve for overall survival of CHIP-positive (n=34) vs. CHIP-negative (n=56) patients within a 60-day period. (B) Kaplan-Meier survival curve for overall survival of patients <45 years (n=8), 45 – 65 years (n=50), and >65 years (n=32) within a 60-day follow-up period. Statistical evaluations were done using log-rank Mantel-Cox test. CHIP prevalence in patients (C) <45 years, (D) 45 – 65 years, and (E) >65 years. Expected prevalences according to Watson et al. (4). Observed and expected prevalence were compared using binomial test. (F) SOFA score at admission, and length of (G) hospitalization and (H) ICU stay. Each data point represents an individual patient (CHIP-positive n=34; CHIP-negative n=56). Horizontal line within the box marks the median, boxes depict the IQR, and whiskers indicate the total range. Group comparisons were performed by two sided Mann–Whitney U-test. Statistically significant results (P ≤ 0.05) are highlighted by bold print.

Figure 3

Infection and organ function related clinical parameters at admission. (A) C-reactive protein (CHIP-positive: n=34; CHIP-negative: n=56), (B) procalcitonin (CHIP-positive: n=33; CHIP-negative: n=56), (C) NT-proBNP (CHIP-positive: n=29; CHIP-negative: n=49), (D) high sensitive Troponin T (CHIP-positive: n=21; CHIP-negative: n=36), (E) serum creatinine (CHIP-positive: n=32; CHIP-negative: n=55), and (F) D-dimer (CHIP-positive: n=29; CHIP-negative: n=52) levels at admission. Each data point represents an individual patient. Horizontal line within the box marks the median, boxes depict the IQR, and whiskers indicate the total range. Group comparisons were performed by two sided Mann–Whitney U-test. Statistically significant results (P ≤ 0.05) are highlighted by bold print.

Figure 4

Age-adjusted cardiac function related clinical parameters at admission. (A) NT-proBNP (< 45: n=5; 45 – 65: n=42; > 65: n=31) and high sensitive Troponin T (<45: n=4; 45 – 65: n=28; >65: n=25) in comparison between the age groups. Group comparisons were done using Kruskal-Wallis test. (B) NT-proBNP (CHIP-positive: n=12; CHIP-negative: n=30) and Troponin T (CHIP-positive: n=7; CHIP-negative: n=21) in the 45 – 65 age group. (C) NT-proBNP (CHIP-positive: n=17; CHIP-negative: n=14) and Troponin T (CHIP-positive: n=14; CHIP-negative: n=11) for the > 65-year-olds. Group comparisons were performed by two sided Mann–Whitney U-test. Each data point represents an individual patient. Horizontal line within the box marks the median, boxes depict the IQR, and whiskers indicate the total range. Statistically significant results (P ≤ 0.05) are highlighted by bold print.

Figure 5

Leucocyte and neutrophil counts. Neutrophil counts at (A) discharge (CHIP-positive: n=34; CHIP-negative: n=53), (B) day 14 after admission, and (C) leucocyte counts at day 14 after admission (CHIP-positive: n=13; CHIP-negative: n=30). (D) Leucocyte and (E) neutrophil counts in comparison between the different age groups at day 14 after admission (<45: n=3; 45-65: n=25; >65: n=15).(F) Leucocyte and (G) neutrophil counts for patients aged >65 years (CHIP-positive: n=9; CHIP-negative: n=6) and (H, I) 45 – 65 years (CHIP-positive: n=4; CHIP-negative: n=21) at day 14 after admission. Group comparisons were performed by two sided (A–C, F–I) Mann–Whitney U-test or (D, E) Kruskal-Wallis test. Each data point represents an individual patient. Horizontal line within the box marks the median, boxes depict the IQR, and whiskers indicate the total range. Statistically significant results (P ≤ 0.05) are highlighted by bold print.

Figure 6

Lymphocyte counts. Lymphocyte counts at (A) admission (CHIP-positive: n=34; CHIP-negative: n=53) and (B) discharge (CHIP-positive: n=34; CHIP-negative: n=53). Lymphocyte counts at discharge for patients aged (C) 45 – 65 years (CHIP-positive: n=16; CHIP-negative: n=31) and (D) > 65 years (CHIP-positive: n=18; CHIP-negative: n=14). (E) Lymphocyte counts at discharge in comparison between the different age groups (<45: n=8; 45-65: n=47; >65: n=32). Group comparisons were performed by two sided (A–D) Mann–Whitney U-test or (E) Kruskal-Wallis test. Each data point represents an individual patient. Horizontal line within the box marks the median, boxes depict the IQR, and whiskers indicate the total range. Statistically significant results (P ≤ 0.05) are highlighted by bold print.