This study has two main findings. First, corticosteroid administration during the acute phase did not affect the positivity rate of specific IgG antibodies during the recovery phase. Second, patients who were positive for specific IgM antibodies in the acute phase were more likely to require oxygen but not ventilatory management.
Corticosteroid administration did not affect positivity rates for specific antibodies during the recovery phase. Based on the results of the RECOVERY trial, systemic corticosteroid administration, mainly dexamethasone, is recommended for patients with COVID-19 who require an oxygen supply [8]. This study was conducted before the RECOVERY trial was reported, and approximately half of the patients with moderate COVID-19 did not receive corticosteroids. None of the patients had mild ARDS, and all the patients with severe ARDS were treated with corticosteroids according to protocols, such as those of the ARDS [12] Clinical Network (ARDSNet). The IgG and IgM positivity rates in the severe cases were similar to those in the mild cases. Among patients with moderate COVID-19 infection, there was no statistically significant difference in the percentage of positive antibodies during the recovery phase between the steroid and non-steroid groups. IgG levels have been reported to decrease after corticosteroid administration [13, 14]. However, in patients with COVID-19, the antibody positivity rate is not been proven to be affected by corticosteroid administration [15]. In this study, the patients had different COVID-19 severities, and the antibody positivity rate was similar in those with severe disease who received corticosteroids and in those with mild disease who did not require corticosteroids.
Second, if specific IgM antibodies were positive on days 6–10, the patient was more likely to require an oxygen supply but not ventilatory management. A high percentage of patients with mild or severe COVID-19 test negative for IgM antibodies on days 6–10. In mild and asymptomatic patients, the focus of infection is thought to be on the upper respiratory tract [16, 17] and the symptoms are localized; hence, the humoral immune response is reported to be slow [18]. It has also been reported that antibody titers are higher in severe cases than in non-severe [19, 20] cases. However, in this study, patients with severe disease underwent non-invasive positive-pressure ventilation (NPPV) therapy, which was also considered for those with moderate disease. Moreover, both IgG and IgM have been reported to have low antibody titers during the acute phase, and delayed antibody positivity has been previously reported [21]. The kit used in this study is specific for the spike (S) protein in IgM and Nucleocapsid (N) protein in IgG. Since SARS-CoV-2 requires the S protein to infect human cells [22], IgM may be more useful.
COVID-19 symptoms in patients usually worsen approximately a week after onset [23]. Measurement of IgM levels, together with other physical and vital signs, may predict illness severity. If an IgM-positive patient is likely to require oxygen, the patient should be hospitalized; if an IgM-negative patient is likely to require oxygen, the patient may require ventilatory management. In addition, if corticosteroid administration does not play a significant role in antibody production during the recovery phase, a diagnosis can be made by measuring IgG levels during the recovery period, even if the patient has been treated clinically and administered corticosteroids during the pandemic. In addition, since the IgG of this reagent is specific to the N protein, it is possible to confirm this by measuring IgG levels in patients receiving corticosteroids for other diseases, such as collagen, inflammatory bowel, and allergic diseases.
This study has several limitations. First, the sample size was small. However, there was a good balance between mild, moderate, and severe COVID-19 cases among the 75 patients. Moreover, the samples were obtained from patients with mild disease during the recovery phase, which was considered sufficient for evaluation. Second, vaccines were not included in our study. COVID-19 vaccines were not yet clinically available during this research period, and antibody responses may differ among vaccines. However, vaccination of SARS-CoV-2 infected patients has been reported to enhance immune acquisition owing to hybrid immunity, and it is assumed that patients receiving corticosteroids for underlying conditions will not have a reduced rate of antibody acquisition. However, the IgG antibodies in this reagent are against the S protein and may be difficult to distinguish from those detected after vaccination. Finally, in the comparison between moderate cases in which steroids were or were not administered, the backgrounds were not identical. In particular, the rate of nasal high-flow (NHF) use was greater in the steroid-treated group, and it is possible that there were more severe cases in this group. However, all severe cases were treated with steroids, and their course was similar to that of the mild and moderate non-steroid groups, suggesting that the effect of steroids on the antibody positivity rate was not significant. In addition, because steroids were recommended for all moderate cases in this study, it is difficult to conduct a comparative study.
In conclusion, this study showed that even if corticosteroids were administered during the acute phase, patients with COVID-19specific IgG antibodies during the recovery phase became positive and were maintained for a long time. Moreover, the effect of corticosteroids on the definitive diagnosis was minor, even during the recovery phase when the viral genome disappeared. Positive specific IgM antibodies one week after symptom onset were noted in patients requiring oxygen without ventilatory management. In contrast, IgM antibodies were not detected in the patients who did not require oxygen or ventilation. Thus, by measuring specific IgM antibodies in accordance with clinical symptoms approximately one week after the onset of symptoms, the severity of the disease can be predicted and appropriate medical interventions can be planned.