To the Editor:
The spread of the coronavirus disease-2019 (COVID-19) remains a
worsening global health crisis. Although many studies have reported risk
factors for severe COVID-19, asthma characterization in COVID-19 is
still controversial, with different early reports from China and recent
reports from the Europe and United States.1 Prolonged
viral shedding is not only a risk factor for poor outcome of COVID-19,
but also clues to host immune response against the virus. However, there
is limited data on this except for results from relative small group
studies.2 In this study, 2 200 adult patients
hospitalized for COVID-19 in Daegu were evaluated for prevalence of
asthma and clinical outcomes with COVID-19 according to asthma. In
addition, the risk factors for delayed viral clearance were evaluated.
The prevalence of asthma in patients with COVID-19 was 3.2% which was
not different from its prevalence in the Korea National Health and
Nutrition Examination Survey (KNHANES) (Figure 1A and Table S1). By age
group, the prevalence of asthma showed a similar U-shaped pattern as the
general prevalence pattern in Korea. However, the prevalence of asthma
in the 19–29-year age group (2.1%) was lower than that of KNHANES
(Figure 1B).
Table S2 compares the characteristics between the asthma group and the
non-asthma group. Older age, overweight, and comorbidity of chronic
obstructive pulmonary disease, and initial symptoms of dyspnea and
nausea/vomiting were more common in the asthma group. Compared with the
non-asthma group, the asthma group had a greater risk of death (13.6%vs. 6.4%, P = 0.02) and a greater need for high-flow
oxygen therapy (18.2% vs . 10.5%, P = 0.048) (Figure 1C
and Table S3). The higher mortality rate in asthma patients compared
with non-asthmatic patients was particularly noticeable in female and
overweight patients. Older patients (> 65 years) with
asthma tended to have a higher mortality rate than those without asthma
(Figure 1D). After adjusting for potential confounders, asthma had no
significant association with clinical outcomes of COVID-19 (Figure 1E
and Table S4). Meanwhile, older age, male gender, and comorbid diseases
including overweight, diabetes, chronic kidney disease, cancer,
autoimmune disease, dementia, and other psychological disorder were
significant risk factors for mortality (Tables S5 and S6).
Asthma is considered to have a lower risk of death than other well-known
risk factors.3, 4 However, asthma is a heterogeneous
disease and is often associated with atopic and eosinophilic asthma in
younger patients. Meanwhile, obese asthma and elderly asthma are known
to have common neutrophilic phenotypes.5, 6 The recent
results of higher expression of COVID-19 receptors in respiratory
specimens with neutrophilic asthma phenotype compared with the
eosinophilic asthma phenotype.7 Considering prevalence
and clinical outcome results, it is possible that neutrophilic asthma is
a risk factor for infection and poor prognosis of COVID-19 rather than
eosinophilic asthma.
When delayed viral clearance was divided into two groups based on 30
days, 906 patients were included in the non-delayed viral clearance
group and 415 patients in the delayed viral clearance group. After
adjusting for potential confounders,
delayed viral clearance was not
significantly associated with asthma (Figure 1E and Table S4). However,
older age >65 years (Odds ratio (OR) 2.002, 95% Confidence
interval (CI) 1.292–3.101; P = 0.002), comorbid diseases
including dementia (OR 3.123, 95% CI 1.833–5.321; P<0.001), and other psychological disorder (OR 2.084, 95% CI
1.178–3.687; P = 0.012), initial symptom of skin rash (OR
15.943, 95% CI 1.613–157.535; P = 0.018), and initial
laboratory abnormalities including hemoglobin <10 g/dL (OR
2.156, 95% CI 1.161–4.003; P = 0.015) and C-reactive protein
(CRP) ≥1.0 mg/dL (OR 1.588, 95% CI 1.061–2.377; P = 0.025) were
significant risk factors for delayed viral clearance. On the other hand,
male sex (OR 0.752, 95% CI 0.567–0.997; P = 0.047),
hypertension (OR 0.704, 95% CI 0.519–0.953; P = 0.023), and
initial symptom of headache (OR 0.673, 95% CI 0.485–0.932; P =
0.017) were significant protective factors for delayed viral clearance
(Figure 2A and Table S7). In
particular, when limited to the mild COVID-19 group classified as no
activity limitations in the outcome parameters, older age, dementia,
initial symptoms of skin rash and headache, and initial hemoglobin
<10 g/dL showed significant differences (Figure 2B, Table S8).
Several factors related to the nervous system were identified as
important risk factors for delayed viral clearance. Previous studies
have shown that the coronavirus can initially invade the peripheral
nerves and enter the central nervous system through a synapse
path.8 It is hypothesized that the ability of the
immune system to find and remove viruses that have penetrated the
nervous system is important for virus clearance. Male sex, hypertension
and elevated CRP did not show a significant difference when analyzed
only mild patients, and these may be indicators associated with severity
rather than a direct effect on viral clearance.
Anti-inflammatory drugs such as hydroxychloroquine and systemic steroid
were shown to be risk factors for mortality and delayed viral clearance
(Table S6 and S8). These medications were used more often when the
hospitalization period was extended or when showing poor prognosis
factors. Notwithstanding these, our results suggest that
anti-inflammatory drugs need to be used with proper consideration of
appropriate indications.
On May 9, 2020, there were 6,859 patients with PCR-confirmed COVID-19 in
Daegu. This data excluded asymptomatic or minimal symptomatic patients
who did not require hospitalization. However, our study covered almost
all hospitalized patients diagnosed with COVID-19 in Daegu from February
to May ,therefore, selection bias is minimized.9 In
Korea, most hospitals decided to terminate the quarantine by repeating
PCR every week. In addition, the Korea Centers for Disease Control &
Prevention (KCDC) thoroughly managed the criteria for quarantine
termination and PCR results. Through this, in our study, we were able to
perform a large-scale study to confirm the risk factors for delayed
viral clearance.
In summary, despite the positivity of differences depending on
phenotypes, the prevalence of asthma was not significantly different in
patients with COVID-19, and asthma did not affect the outcomes of
COVID-19. Age, dementia, and initial presentations of headache, skin
rash, and anemia were independently associated with viral clearance.