This is a retrospective study on the clinical characteristics of COVID-19 during rehabilitation, including data from 134 recovered patients. 19 patients were severe cases and 115 were non-severe cases. The patients with severe disease were older and had more underlying comorbidities than those with non-severe disease. Lymphopenia was more common in discharged severe patients. Adult patients were more prone to liver dysfunction than children. In addition, half of the convalescent patients had abnormal radiologic images, most commonly presenting with ground-glass opacity and fibrosis.
We observed that in this cohort, severe patients with COVID-19 were older than non-severe cases. Consistent with our study, Wang et al. found patients who required ICU treatment were older than those who did not. Another study also observed significantly increased average age in severely affected patients. A possible explanation for this might be low immune function in elderly patients that contributes to poor outcomes. Therefore, elderly patients require more attention and protection. In addition, all pediatric patients in this study were non-severe cases. Similar to our findings, previous studies showed that the clinical symptoms and disease severity of children with COVD-19 were milder compared with adults[15,16]. It is known that angiotensin converting enzyme 2 (ACE2) is the receptor that allows SARS-CoV-2 to enter host cells. The number of ACE2 receptors present on host cells determines susceptibility to COVID-19 to a certain extent. Compared with adults, the expression of ACE2 in the nasal epithelium was determined to be lower in younger children . This may be responsible, at least in part, for the less severe condition of children with COVID-19.
Almost all severe patients had an exposure history linked to Hubei, including recent tourism, history of residency, or contact with people from Hubei. 29.6% of non-severe patients had no exposure history to Hubei and had contact with other confirmed patients. These findings echo recent reports that found the proportion of severe cases was higher than that of non-severe cases for patients living in Wuhan. This suggests that patients with an exposure history linked to Hubei may be more likely to develop severe illness. A decrease in virus virulence during intergenerational transmission is a possible explanation for this phenomenon. In this study, children had a significantly higher proportion of cluster cases than adults. This result is consistent with previous findings, which found that all pediatric cases were related to family clusters. A likely reason for this finding is minimal social activity among children due in part to school closures during the outbreak.
Our study found that 25 (18.7%) patients had at least one comorbidity, and the proportion of severe patients with comorbidities was higher than that among the non-severe group. Hypertension and diabetes remained the most common comorbidities observed. A multicenter research study found that hypertension and diabetes were independent risk factors for poor patient outcome after adjusting for age and smoking status, and the greater the number of comorbidities, the worse the COVID-19 prognosis. Consistent with our finding, a study on another beta genus coronavirus, Middle East Respiratory syndrome (MERS), indicated that diabetes was significantly associated with poor prognosis. The underlying mechanisms for diabetes leading to poor prognosis of MERS infection were dysregulated immune response and prolonged lung inflammation, which were identified using diabetic mice models. Therefore, we speculate that similarly to MERS, immune dysfunction and prolonged inflammation may be possible underlying causes of poor outcomes in COVID-19 patients with comorbidities. Further research is needed to confirm the specific mechanisms, and clinicians should pay more attention to the treatment and protection of COVID-19 patients with comorbidities.
In terms of laboratory tests during rehabilitation, 43 (32.1%) patients were found to have a low absolute value of leukocytes. Leukopenia, lymphopenia, and elevated ESR and CRP were more common in recovered patients with severe COVID-19 than those who had non-severe cases. Similar to our finding, previous studies have shown that lymphopenia and elevated CRP are indicators of poor outcome for COVID-19 patients[22,23]. The immune system is triggered by viral infections. Lymphocytes, especially T lymphocytes, play a vital role in regulating the immune response to SARS-CoV-2 infection, and this can cause changes in the levels of peripheral blood leukocytes and lymphocytes. Furthermore, compared with the non-severe group, we observed lower levels of albumin and higher levels of LDH and D-dimer in the severe group. Consistent with our study, Shen et al. observed increased D-dimer and LDH levels were correlated with a worse prognosis in COVD-19 patients. High levels of D-dimer indicate a hypercoagulable state, which may cause pulmonary thrombosis. Albumin is an indicator that reflects nutritional status, and decreased albumin levels indicates the body has lower levels of resistance to viral infection. We suggest that patients need more nutritional support to enhance resistance during rehabilitation.
In our study, 48 (35.8%) discharged patients had elevated ALT levels. The proportion of liver injury was significantly lower in children than adults, but there was no difference observed between severe and non-severe patients. Inconsistent with our results, a recent meta-analysis showed severe patients had higher levels of ALT. The reason for this difference might be that the laboratory tests in the meta-analysis were conducted during hospitalization, while our laboratory results were conducted during the rehabilitation period, and patient liver function might be restored after treatment. The lower risk of liver dysfunction in children during rehabilitation may be related to mild illness and increased repair capability. The pathological features of liver biopsy in patients with COVID-19 were microvesicular steatosis and mild lobular and portal activity, suggesting that liver injury may be related to antiviral drug or SARS-CoV-2 infection. The underlying mechanism of liver injury caused by SARS-CoV-2 infection may be that the virus binds to the ACE2 receptors of bile duct cells. Based on this result, we suggest that adult patients should be dynamically monitored for liver function and treated accordingly during the rehabilitation period.
In the recovery period, a normal chest CT result was observed in 61 (45.5%) patients with COVID-19. This was significantly higher than the 17.9% normal CT in non-severe cases and 2.9% in severe cases on admission reported in a previous study. Consistent with chest CT findings during hospitalization, in this study ground-glass opacity was the most common imaging abnormality observed during rehabilitation. In addition, we found that 26.9% of discharged patients had pulmonary fibrosis, and the proportion of fibrosis in severe patients was higher than that of non-severe cases. ACE2, the receptor of SARS-CoV-2, is mainly expressed by type Ⅱ alveolar epithelial cells. SARS-CoV-2 infection causes damage to alveolar epithelial cells and excessively activates transforming growth factor-β (TGF- β)-related pathways, which contributes to pulmonary fibrosis. Therefore, clinicians should pay attention to the lung function status of severe patients with COVID-19 following discharge. Further studies on how to reduce the incidence of pulmonary fibrosis and improving lung function in recovered patients are needed.
Similar to a recent study, we found that the antibody positivity rate was not significantly different between severe and non-severe patients with COVID-19. Our data showed that positive rates of IgG and IgM were 69.1% and 5.5%, respectively. Inconsistent with our study, Zhao et al. found the seroconversion rate for IgM was 82.7%, which was higher than our results. The seroconversion rate for IgG was similar across the studies. A possible explanation for this might be that the antibody tests were conducted at different stages of the disease. IgM against SARS-CoV-2 is produced around 1 week after symptom onset and peaks in 2-3 weeks, and then gradually decreases. Thus, recovered patients had lower positive rates of IgM in this study. IgG is produced later than IgM and is typically maintained at a high level for 2 months. Therefore, the levels of IgG and IgM can roughly reflect the disease stage.
This study has several limitations. First, only 55 of the 134 convalescent patients were tested for antibodies, and the antibodies were only analyzed in terms of positivity rate and not at a more detailed level, so factors that influence antibody levels or dynamic evolution of antibodies could not be analyzed. Second, the sample size is limited in our study, especially for severe patients. Therefore, differences in clinical characteristics between severe and non-severe patients may be overlooked.