In this retrospective cohort study, we found that eosinophil counts less than 0.02 × 10⁹/L and LDH levels greater than 225 U/L on admission were associated with the severity of COVID patients with underlying chronic bronchitis, COPD and asthma. Moreover, eosinophil counts and LDH levels tend to return to a normal range in severe and non-severe patients after treatment.
Circulating and tissue-resident eosinophils are associated with a variety of diseases, in which eosinophils participate in the pathological process and play a potent proinflammatory role, such as COPD, asthma, and chronic bronchitis. Previously, human eosinophil has been reported to play an important role in virus detection and defending through several Toll-like receptors (TLRs), including TLR1, TLR3, TLR4, TLR7, TLR9, and TLR10 [18–21]. Single-stranded RNA viruses, such as coronavirus, can be recognized by eosinophils in the airway tract through TLR7, whose subsequent stimulation triggers eosinophil cytokine expression and nitric oxide (NO) generation to promote viral clearance [19–22]. In view of elevated eosinophils in patients with chronic airway inflammation, COPD, asthma and chronic bronchitis have not yet been reported as major risk factors for the severity of SARS-CoV-2 infections. According to an ambispective cohort study of 548 COVID-19 patients, only 5 cases of asthma were identified, significantly lower than previously reported asthma prevalence in Wuhan (6.4%) [23–26]. Zhang et al recently reported that none had asthma or other comorbid atopic diseases and only two patients had COPD (1.4%) in a cohort of 140 hospitalized COVID-19 patients, more than half of whom (53%) had eosinopenia on the day of hospital admission . Similarly, Du et al analyzed clinical features of 85 fatal cases of COVID-19 and found that 81% of the patients had very low eosinophil counts on admission . In our cohort including 1 888 patients, 31 patients had chronic bronchitis (1.64%), 18 patients had COPD (0.95%) and only 10 patients had asthma (0.53%). Circulating eosinophil counts were reported to gradually increase over the time in COVID-19 and were synchronous with the improvement of chest CT, revealing the effective role of eosinophil in the prognosis monitoring of COVID-19 patients . Liu et al also suggested that elevated eosinophils might be an indicator for COVID-19 improvement in a small cohort of COVID-19 patients . A recent study has highlighted the significant role of CD101− eosinophils in suppressing acute lung injury and respiratory failure . Therefore, eosinophil could have helped patients with chronic airway inflammation escape from SARS-CoV-2 infections and has been identified as a probable potential indicator for prognosis in COVID-19. Jackson et al found a negative correlation between ACE2 expression in airway epithelium and peripheral blood eosinophil counts, which could explain the reason why severe patients were more vulnerable to SARS-CoV-2 infection . Meanwhile, eosinopenia was more common in critically severe patients, suggesting that the resolution of eosinopenia could be a possible way to improve clinical status .
In our study, lower expression of eosinophil showed worse survival probability and eosinophil counts significantly decreased in severe COVID-19 patients with chronic bronchitis and COPD. No significant difference was observed in asthma patients, partly due to the limited sample size. We further explored dynamic changes of eosinophil counts in patients with chronic airway diseases in the course of COVID-19 and found that eosinophil counts gradually increased over time and returned to normal range in both severe and non-severe patients. It still remains unclear how eosinopenia takes place in COVID-19, but possible mechanisms of decreasing eosinophils could be inhibition of eosinopoiesis and egress of eosinophils from the bone marrow [32, 33], the reduction of chemokine receptors or adhesion factors , and interferon (IFN) mediated eosinophil apoptosis during the virus infection .
LDH has long been reported to be associated with COPD, asthma, and chronic bronchitis and identified as a potential marker of chronic airway inflammation [35–37]. Meanwhile, a large number of studies reported elevated LDH levels in COVID-19, which could be a risk factor of mortality [10–12, 38–41]. Zheng et al conducted a systematic literature review and meta-analysis including 4 studies, a total of 1286 cases, and found that LDH was statistically significantly higher in severe patients compared to non-severe patients . Elevated LDH in severe cases indicated diffuse lung injury and tissue damage [38, 42], therefore, we hypothesized that LDH might be another predictor of chronic airway inflammation exacerbation in COVID-19. Kaplan-Meier survival analysis suggested the hazard of elevated LDH levels. Similar to eosinophil, LDH showed elevated levels in severe COVID-19 patients with chronic bronchitis and COPD, and gradually decreased over time in severe and non-severe COVID-19 patients.
Previous studies have identified older age as a risk factor of mortality in SARS, MERS, and COVID-19 [10–12, 43–45]. However, in our study, age had no statistic difference between severe and non-severe patients, partly due to epidemiological characteristic in respiratory diseases with chronic airway inflammation, since such patients were commonly old regardless of disease severity. Lymphocytopenia was also associated with poor outcomes in our cohort (85%), which is consistent with other reports [40, 46]. Impaired lymphogenesis or increased apoptosis could explain lymphocytopenia in severe cases of COVID-19 . Of note, d-dimer levels greater than 1 µg/L were more common in severe patients compared to non-severe patients, which was reported as a risk factor for mortality of adult inpatients with COVID-19 .
Accumulating evidence reveals that cytokine storm plays a crucial role in the pathogenesis of COVID-19. Extremely increased inflammatory parameters, including CRP and proinflammatory cytokines (IL-6, TNFα, IL-8, et al) were recently reported in critical COVID-19 patients . Th1-dominated responses with significantly elevated cytokines (INF-γ, IL-1β, IL-6, IL-8, IL-12, and TNF-α) were shown previously in plasma cytokine profiles of SARS patients, giving rise to the recruitment of alveolar macrophages and the development of ARDS [49–51]. Similarly, a predominant Th1 and Th17 cytokine profile with elevated IFN-γ, TNF-α, IL-10, IL-15, and IL-17 was reported during the acute phase of MERS-CoV infection . In our cohort, severe patients had markedly higher levels of CRP, procalcitonin, IL-2R, IL-6, IL-8, and TNF-α. Notably, several reports confirmed the elevation of serum IL-6 in critically ill patients with COVID-19, suggesting that mortality might be associated with virally driven hyperinflammation and IL-6 played a predominant role in cytokine release syndrome [10, 11, 41, 48, 53–55]. Tocilizumab (IL-6 receptor blockade) has been approved in some patients with COVID-19 pneumonia, offering an effective treatment option for severe patients [53, 56].
Our study had some limitations. Firstly, due to the retrospective study design, the accuracy of all laboratory results was dependent upon medical records. Observation bias might also exist in this study due to the limited sample size. Secondly, there could be a selection bias in the multivariate regression model when analyzing the risk factors.