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 [23]. 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
[27]. 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
[14]. Liu et al also suggested that elevated eosinophils might be an
indicator for COVID-19 improvement in a small cohort of COVID-19
patients [28]. A recent study has
highlighted the significant role of CD101− eosinophils
in suppressing acute lung injury and respiratory failure [29].
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 [30]. Meanwhile, eosinopenia was more common in critically
severe patients, suggesting that the resolution of eosinopenia could be
a possible way to improve clinical status [31].
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 [34], and interferon
(IFN) mediated eosinophil apoptosis during the virus infection [33].
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 [38]. 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 [47]. 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 [10].
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
[48]. 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 [52]. 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.