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Steroid resistance and rebound phenomena in patients with COVID-19

Background In patients with coronavirus disease (COVID-19) pneumonia, corticosteroids reduce progression to respiratory failure and death. Some patients, however, remain unresponsive to this treatment, or experience a rebound after termination. Methods This retrospective cohort study included COVID-19 patients treated with systemic corticosteroids in a Japanese hospital between June 1, 2020, and January 17, 2021. Patients were categorized into three groups: success, rebound, and refractory, and clinical characteristics and outcomes were compared. Results A total of 319 COVID-19 patients were admitted to our hospital and 113 patients met inclusion criteria. The success group had 83 patients (73.5%), the rebound group had nine patients (8.0%), and the refractory group had 21 patients (18.6%). Compared with the success group, the rebound group received corticosteroids earlier, for a shorter duration, and stopped them sooner. The median time from symptom onset to rebound was 12 days. There was no rebound after 20 days. Compared with the success group, the hazard ratio for the number of days from corticosteroid onset to an improvement of two points on a seven-point ordinal scale was 0.29 (95% confidence interval [CI], 0.14–0.60, P < .001) for the rebound group versus 0.13 (95% CI, 0.07–0.25, P < .001) for the refractory group. Conclusions COVID-19 patients treated with corticosteroids were classified into three response groups: success, rebound, and refractory, between which recovery time and prognosis differed. It was found that corticosteroid administration may prevent rebound phenomena if administered at least two weeks from symptom onset.


Introduction
Coronavirus disease (COVID-19), causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in the city of Wuhan, China, at the end of 2019 and has since spread worldwide. In a report of 72,314 cases from China, 14% of cases were severe, requiring ventilation in an intensive care unit, and 5% of cases were critical [1]. The availability of data regarding specific treatments for these COVID-19 patients has, however, been limited.
The host immune response is considered to play a key role in causing a cytokine storm syndrome in patients with severe COVID-19 [2]. Therefore, immunomodulatory agents that inhibit an excessive inflammatory response, such as corticosteroids, may be a potential adjunctive therapy for severe COVID-19. The efficacy of corticosteroids has been established in several clinical studies [3,4], and they are widely used in clinical practice to treat COVID-19 patients. In clinical practice, however, cases refractory to corticosteroids, or a rebound phenomenon during steroid reduction or after cessation, have been experienced [3,5].
The purpose of this study was to review COVID-19 patients who had been treated with corticosteroids, to clarify the characteristics of the rebound and refractory cases and examine the optimal timing and duration of corticosteroid administration.

2.
Patients and methods

Patients
This retrospective cohort study was conducted at a tertiary care hospital in Tokyo, Japan, between June 1, 2020, and January 17, 2021. Adult inpatients (18 years of age) diagnosed with COVID-19, according to the World Health Organization definition [6], and treated with systemic corticosteroids were included. Patients who were still in-patients after February 5, 2021, were excluded, as well as patients with unclear outcomes. Patients with interstitial lung disease, human immunodeficiency virus (HIV) infection, those taking immunosuppressive agents, and those who were transferred to another hospital during the course of their illness, were excluded. The success group was defined as consisting of patients who were responsive to initial corticosteroid therapy and discharged without rebound after corticosteroid cessation. The rebound group was defined as follows: 1. patients who were responsive to initial corticosteroid therapy; 2. patients who subsequently showed a clinical deterioration of at least one point on the seven-point ordinal scale, experienced worsened oxygenation, or required additional treatment for COVID-19 within one week after corticosteroid reduction or cessation; and 3. those in whom infection was ruled out by retrospective analysis. The refractory group was defined as consisting of patients who were unresponsive to initial corticosteroid therapy and showed a clinical deterioration of at least one point on the seven-point ordinal scale, experienced worsened oxygenation, or required an additional treatment for COVID-19, 24 h after corticosteroid therapy was initiated.

Data collection and definitions
The study objectives were as follows: 1. to determine the frequency of the rebound phenomenon and the unresponsiveness to corticosteroids in COVID-19 patients; 2. to identify risk factors associated with the development of the rebound phenomenon; 3. to investigate the clinical outcomes of patients with varying responses to corticosteroids; and 4. to determine the optimal timing and duration of corticosteroid treatment.

Statistical analyses
For descriptive statistics, continuous data are represented in terms of the median (interquartile range [IQR]); and categorical variables are represented in terms of frequencies (percentages). With regard to the analytical statistical process, because the number of events was limited, the least absolute shrinkage and selection operator (LASSO) regression was performed as a multivariable analysis. First, the LASSO regression was adopted on presumed variables that affected the results of corticosteroid treatment for the success and rebound groups. Based on our knowledge of COVID-19 and available data, variables such as sex, age, BMI, hypertension, white blood cells, C-reactive protein, time of symptom onset to the start of steroid administration, time of symptom onset to the end of steroid administration, and clinical status on a seven-point ordinal scale at the start of corticosteroids, were included. For each of these variables, the estimated odds ratio was determined for the success of corticosteroid therapy.
Second, the number of days from disease onset until a twopoint improvement in clinical status was compared between the three response groups. KaplaneMeier curves were plotted with the right censor defined as patients who died without clinical improvement at two points. Thereafter, Cox proportional-hazards regression was used to determine the hazard ratio for two points of clinical improvement, using the success group as a reference.
All statistical tests were two-tailed, and significance was accepted at P .05. All analyses were performed using R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria).

Patient characteristics
In total, 319 patients diagnosed with COVID-19 were admitted to our hospital during the study period; among them, 121 patients were treated with systemic corticosteroids. After excluding three patients with interstitial lung disease, one patient with HIV infection, one who had prior corticosteroid use, one who was transferred to another hospital, one without available information in the medical records, and one with a recent treatment history for COVID-19, 113 patients met the inclusion criteria. Eighty-three patients (73.5%) were classified into the success group, 9 (8.0%) into the rebound group, and 21 (18.6%) into the refractory group (Fig. 1). Table 1 shows the demographic characteristics of patients, laboratory data, and clinical status on a seven-point ordinal scale when corticosteroid therapy was started for the three groups. In approximately 60% of the total patients, corticosteroids were started when supplemental oxygen was required.

Corticosteroids between success and rebound groups
In the success group, corticosteroids were started at a median of seven days after symptom onset, administered for a median of seven days, and stopped at 13 days after symptom onset. In contrast, in the rebound group, steroids were started at a median of five days after symptom onset and administered for a median of five days (Table 2 and Fig. 2). The median (IQR) days from symptom onset to rebound was 12 days (11e13 days), and no cases rebounded 20 days after symptom onset. Compared to the success group, the rebound group tended to be started on corticosteroids earlier in the disease process, received them for a shorter duration, and terminated them earlier in the disease process (Fig. 2). In the LASSO regression analysis, five potential predictors of the rebound phenomenon were identified. These variables were increasing age (odds ratio, 1.02), decreasing BMI (odds ratio, 0.96), hypertension (odds ratio, 1.70), fewer days from symptom onset to starting corticosteroids (odds ratio, 0.94), and fewer days from symptom onset to ending corticosteroids (odds ratio, 0.98).

3.4.
Clinical outcomes The number of days from corticosteroid initiation to an improvement of two points on the seven-point ordinal scale was shortest in the success group and longest in the refractory group (Fig. 3). The hazard ratio was 0.29 (95% confidence interval [CI], 0.14e0.60) in the rebound group compared with that in the success group (P < .001) and 0.13 (95% CI, 0.07e0.25) in the refractory group compared with that in the success group (P < .001). In the rebound group (n ¼ 9), five patients improved on resuming corticosteroids, four patients improved without resuming corticosteroids, and all were discharged. In the refractory group (n ¼ 21), thirteen patients eventually improved, and eight patients died. (Table 3).

Discussion
In this study, we demonstrated that COVID-19 patients treated with corticosteroids were classified into three response groups: success, rebound, and refractory, between which recovery time and prognosis differed. The rebound groups started and finished corticosteroids earlier, which suggests that rebound could be caused by a shorter treatment duration. In addition, corticosteroids, antivirals, and anticoagulation therapies are considered standard care for patients with moderate to severe COVID-19 in our hospital; immunosuppressive agents, other than corticosteroids, are rarely used. Therefore, we believe that the present results reflect the effects of corticosteroids alone. Furthermore, in Japan, it is recommended that patients with mild COVID-19 be hospitalized; therefore, this study included patients with mild to severe disease. Long et al. reported that in patients with confirmed COVID-19, the median number of days for both IgG and IgM seroconversion was 13 days after symptom onset [8], around the time when severe or critical disease usually develops [9]. This finding suggests that host immune responses trigger the cytokine storm syndrome, causing severe disease [2,10]. In COVID-19 patients, the release of proinflammatory cytokines, neutrophil recruitment, and T cell activation are considered to be delayed, relative to that of other typical viral infections [11]; thus, it is beneficial to administer corticosteroids for a sufficient period of time to mitigate the cytokine storm.  In our study, the success group was treated with steroids until a median of 13 days after symptom onset, while the rebound group was treated until a median of 10 days after symptom onset. This implies that corticosteroids should be used until 14 days after symptom onset when the cytokine storm has subsided sufficiently. Thus, the rebound group may be managed by extending the duration of corticosteroid administration.  r e s p i r a t o r y i n v e s t i g a t i o n 5 9 ( 2 0 2 1 ) 6 0 8 e6 1 3 As for the timing of the initiation of corticosteroids, patients in the rebound group started corticosteroids earlier than the success group in our study, suggesting that early initiation of corticosteroids does not contribute to improved prognosis, which is consistent with the results of a previous study [3]. Furthermore, in the RECOVERY trial [3], the benefits of corticosteroids were not exhibited in patients without respiratory failure. Hence, corticosteroids should be started in patients with the onset of respiratory difficulties, not earlier.
Moreover, the refractory group showed a worsened prognosis than the success or rebound groups. For patients who do not respond to initial corticosteroid therapy, immunomodulators and cytokine-storm-targeted therapies besides corticosteroids should be considered to restrain the excessive inflammatory and dysregulated immune responses [10].
Although numerous immunomodulators, including an antiinterleukin-6 receptor antibody and Janus kinase inhibitor have been investigated, further data are needed in the search for a definitive therapy for refractory cases.
In addition, apart from the short-term rebound phenomenon discussed, organizing pneumonia in the later stages is often experienced [12]. The two can be distinguished, and further study is required to clarify the clinical characteristics of the latter.
The present study has some limitations. First, because of the small number of rebound patients, a LASSO regression analysis was conducted instead of a logistic regression analysis, which is the multivariable analysis usually used. Further studies with more cases are required. Second, it was difficult to clarify the cause or pathogenesis of the rebound phenomenon in this study. Further investigation is needed to determine why SARS-CoV-2 causes more prolonged systemic inflammation than other viral infections.

Conclusions
In conclusion, the clinical characteristics of the rebound and refractory groups' response to corticosteroids in patients with COVID-19 was clarified. Patients with the rebound phenomenon tended to receive corticosteroids for a shorter time; thus, steroids should be administered for a sufficient period of time, at least two weeks from symptom onset, to reduce prolonged systemic inflammation.    r e s p i r a t o r y i n v e s t i g a t i o n 5 9 ( 2 0 2 1 ) 6 0 8 e6 1 3