key: cord-0784012-h4fjcmui authors: Nomoto, Hidetoshi; Suzuki, Setsuko; Asai, Yusuke; Hayakawa, Kayoko; Gatanaga, Hiroyuki; Terada, Mari; Suzuki, Kumiko; Ohtsu, Hiroshi; Toyoda, Ako; Ohmagari, Norio title: Clinical Characteristics and Prognosis of Immunosuppressed Inpatients with COVID-19 in Japan 1 1 Abbreviations: ARDS, acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease; DMARDs, disease-modifying anti-rheumatic drugs; ECMO, extracorporeal membranous oxygenation; IMV, invasive mechanical ventilation; IQR, interquartile range; OR, odds ratio; SpO2, oxygen saturation; HIV, human immunodeficiency virus date: 2021-10-28 journal: J Infect Chemother DOI: 10.1016/j.jiac.2021.10.021 sha: 5fb27b830371bf4eedc04c412ce4f47b6f3c9b6b doc_id: 784012 cord_uid: h4fjcmui Introduction We aimed to analyze the clinical characteristics and outcomes of immunosuppressed inpatients with coronavirus disease (COVID-19). Methods In this observational study, we utilized a large nationwide registry of hospitalized patients with COVID-19 in Japan. Patients’ baseline characteristics and outcomes were compared according to the immunosuppressed state of the patient. The impact of different therapeutic agents on the clinical courses of the patients was evaluated. Results Data of 14,977 patients were included, and 887 (5.9%) were immunosuppressed. The immunosuppressed state of the patient resulted from solid tumor (43.3%, n=384), chemotherapy within 3 months (15.6%, n=138), collagen disease (16.9%, n=150), use of immunosuppressive agents (16.0%, n=142), and metastatic solid tumor (13.5%, n=120). Immunosuppressed patients were older and had a higher severity of illness at admission and during hospitalization than non-immunosuppressed patients. The mortality rates for major diseases causing immunosuppression were as follows: solid tumor, 12.5% (48/384; P < 0.001; relative risk [RR], 3.41); metastatic solid tumor, 31.7% (38/120; P < 0.001; RR, 8.43); leukemia, 23.1% (9/39; P < 0.001; RR, 5.87); lymphoma, 33.3% (20/60; P < 0.001; RR, 8.63); and collagen disease, 15.4% (23/150; P <0.001; RR 3.97). Underlying diseases with high mortality rates were not necessarily associated with high rates of invasive supportive care. Conclusions The prognosis of immunosuppressed inpatients with COVID-19 varied according to the different immunosuppressed states. Multiple factors, including the severity of the underlying diseases, might have affected the indications for invasive supportive care. During this global pandemic, concerns have been raised regarding the impact of coronavirus disease (COVID-19) on immunosuppressed patients [1] . COVID-19 causes the release of potent cytokines in the host, and an excessive immune response is implicated in the progression of the disease [2] . However, it is not fully understood how the suppression of biological responses due to an originally immunosuppressed state affects the patients' clinical course. Several studies that focused on individual diseases found that certain immunosuppressed states, such as those due to solid organ tumor, hematological malignancies, and solid organ transplantation, were associated with a risk of severe illness, comorbidities, and poor prognosis [3] . In collagen diseases, the use of biologics may not worsen the prognosis, although chronic use of moderate-to-high doses of steroids is associated with severe COVID-19 [4] . Nevertheless, there is a lack of comprehensive studies investigating the effects of multiple immunosuppressed states on the clinical course and outcomes of COVID-19. Such a study is important for prioritizing medical management and determining the optimal allocation of medical resources to overcome severe outbreaks [5] . In this study, we aimed to descriptively analyze the epidemiological characteristics of immunosuppressed COVID-19 patients and to compare their clinical courses between 7 "Severe disease" at admission was defined as a condition requiring supplemental oxygen or invasive or noninvasive mechanical ventilation or characterized by oxygen saturation (SpO 2 ) of 94% or less on room air or tachypnea (respiratory rate ≥ 24 breaths per minute). Respiratory support during hospitalization was categorized into three groups: no oxygen, oxygen required, and invasive mechanical ventilation (IMV)/extracorporeal membranous oxygenation (ECMO). The groups and the corresponding intervention of supplementary oxygen provided were: no oxygen (i.e., no respiratory support was provided during hospitalization), oxygen (oxygen was supplied, except for IMV/ECMO), and IMV/ECMO (IMV or ECMO was required). In addition, supportive care through IMV or ECMO was defined as invasive supportive care. Patients' deaths were captured at each facility at the time of data collection and were not followed-up after transfer or discharge. Continuous variables are described as the median (interquartile range [IQR]), and categorical variables are described as the number of cases and percentages. Wilcoxon's rank sum test was performed for continuous variables, and the Chi-square test was performed for categorical variables. The 95% confidence intervals for the rate of symptomatic cases were obtained using the Clopper-Pearson method. All statistical analyses were conducted using R version 4.0.2 (R Core Team) [10] . This study was approved by the National Center for Global Health and Medicine Ethics Review. J o u r n a l P r e -p r o o f Data of 14,977 patients from 444 hospitals were included in this study, and 887 (5.9%) were immunosuppressed (Table 1) . Patients with underlying diseases with less than 20 registrations were shown separately (Supplementary Table 1 Table 2 . For solid tumor, metastatic solid tumor, and collagen disease, the patients in the treatment group for underlying diseases were younger than those in the no treatment group (solid tumor, P = 0.001; metastatic solid tumor, P < 0.001; collagen disease, P = 0.001). Conversely, there was no difference in age between the groups with and without treatment for lymphoma and leukemia. For all five diseases, the severity at admission was not affected by the presence or absence of the specific treatments. Patients with lymphoma had shorter time to hospitalization in the treatment group for underlying diseases than those in the no treatment group (P = 0.001). Symptoms at admission in immunosuppressed patients compared with non-immunosuppressed patients are shown in Fig. 1 . Fever and shortness of breath tended to occur more frequently in immunosuppressed than in non-immunosuppressed patients, whereas headache, dysgeusia, and olfactory abnormalities were less frequent. A higher number of immunosuppressed patients needed oxygen and IMV/ECMO than non-immunosuppressed patients ( immunosuppressed patients and 993 (7.2%) non-immunosuppressed patients were admitted to an intensive care unit. The most common complication in J o u r n a l P r e -p r o o f immunosuppressed patients was bacterial pneumonia (11.3%, n = 100), followed by acute respiratory distress syndrome (ARDS) (11.2%, n = 99). The outcomes and impact of supportive therapy for the five major immunosuppressed states are shown in Table 3 Table 3 . These specific treatments for underlying diseases did not affect the rate of IMV/ECMO or mortality during hospitalization. For many complications during hospitalization, the presence of immunosuppressed states increased the prevalence of complications, but treatments for underlying diseases did not have a significant effect on that prevalence. Information on the medication used during hospitalization is summarized in Supplementary Table 4 . The drugs used to treat COVID-19 and anticoagulants were more frequently administered to immunosuppressed patients, such as those with solid J o u r n a l P r e -p r o o f tumors, metastatic solid tumors, and collagen diseases (Supplementary Table 5 ). Antibiotics were more commonly used in immunosuppressed than in non-immunosuppressed patients. In this study, we used a multicenter registry from Japan to comprehensively evaluate the clinical epidemiological characteristics of immunosuppressed patients. Immunosuppressed COVID-19 inpatients had a poor prognosis and required aggressive supportive care. Patients with metastatic tumors, leukemia, and lymphoma had relatively high mortality rates compared with those having solid tumors and collagen diseases. However, IMV/ECMO was not always applied to patients with underlying conditions with higher mortality rates. Use of invasive therapies for patients with COVID-19 may depend on several factors, including the severity of underlying conditions. Therapeutic options may also depend on the condition of medical infrastructure, although it was not explicitly documented in the present study. In addition, government policies changed over time during the pandemic, influencing the indications for hospitalization. Although further research is necessary to determine the indications for supportive therapies for immunosuppressed COVID-19 patients, our study highlighted that underlying health conditions might influence the need for invasive therapies. Immunosuppressed patients were more likely to present with fever and shortness of breath at admission than non-immunosuppressed patients. Hospitalization is usually indicated for patients with COVID-19 showing these symptoms. Moreover, immunosuppressed patients presented with more severe disease at admission. Therefore, J o u r n a l P r e -p r o o f these two symptoms suggest the severity of COVID-19 in immunosuppressed patients. Conversely, dysgeusia, olfactory abnormality, and headache were less prevalent in patients with solid tumors and metastatic solid tumors in our study. These sensory abnormalities are common among cancer patients receiving chemotherapy [11] , and tumors could cause a variety of headaches [12] . However, our results showed that only 9.5% and 38.3% of patients with solid and metastatic solid tumors, respectively, were receiving chemotherapy. Therefore, we could not fully evaluate the impact of treatments for underlying diseases on the symptoms in these patients. Detailed studies will be needed to investigate the effects of underlying diseases on COVID-19 patients' symptoms. In our study, patients with solid tumor and metastatic solid tumors were associated with higher mortality rates than those without tumors, as in a previous study [13] . However, the presence of specific tumor treatment did not affect the severity and the outcomes of COVID-19, or other indicators, such as symptoms and supportive therapies. Whether chemotherapies should be withheld during the COVID-19 epidemic is a crucial question. Studies including a small number of patients with solid tumors showed that chemotherapies had an undesirable effect on COVID-19 prognosis and infectious risk [14, 15, 16] . However, according to more recent large studies, chemotherapies were not shown to have any effect on the prognosis of COVID-19 [17, 18, 19] , which was consistent with the results of our study. Consequently, large-scale studies to date have suggested that there has not been remarkable evidence to withhold treatments for solid tumors. Regarding metastatic solid tumor, the mortality rate was quite high at 31.7%, but again, there was no difference between the treatment and no treatment groups for underlying diseases. Notably, in the present study, the rate of IMV/ECMO was not high, J o u r n a l P r e -p r o o f 13 although this population was likely to be more severely ill. One possible explanation is that patients with untreated metastatic solid tumors were suggested palliative care, meaning that this population was unlikely to receive invasive treatments at the end of their lives. In our study, the mortality rate of patients with COVID-19 with hematologic malignancies was relatively higher than that of patients with other immunosuppressed states. The mortality rates of COVID-19 patients with hematologic malignancies were likely to be high, but they vary widely among studies [20, 21, 22, 23] . The mortality rates for leukemia and lymphoma in our study were similar to those in existing studies on COVID-19 inpatients with hematologic malignancies [20] , although a small number of patients was included in our study and selection bias may have affected the prognosis. Despite these high mortality rates, the rate of IMV/ECMO was not significantly higher in hematologic malignancies in our study. More than half of the patients with hematologic malignancies received chemotherapy, meaning these patients received active treatments for the underlying diseases, but only few of them received IMV/ECMO when they became severely ill. This discrepancy between the severity of [60/68]) used other immunosuppressive agents, suggesting that the treatment group for underlying diseases almost exclusively received immunosuppressive therapies other than steroids. Patients with collagen diseases presented higher mortality rates, and more of these patients received IMV/ECMO than those without collagen diseases. Nevertheless, there was no differences in invasive respiratory support and mortality rates between the patients under treatment for collagen diseases and those without such treatment. Our cohort lacked an informative breakdown of collagen disease, severity, and the details of immunosuppressive agents. Therefore, we were unable to assess whether specific treatments were associated with poorer prognosis in this population. Previous cohort studies have also reported that patients with collagen diseases tend to be more severely ill [24] , but considerable variation has been observed in correlation between medications for collagen disease and poor prognosis by COVID-19 [25, 4] . According to a large cohort study [26, 27] , prednisolone ≥ 10 mg/day was associated with a high rate of hospitalization. Conversely, use of biological or targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), conventional synthetic DMARDs, and a combination of both were not associated with hospitalization. These studies should be interpreted with caution because case-reporting bias and hidden confounders need to be addressed. The accumulation of pathophysiological findings on medications that may pose a risk of exacerbating COVID-19 is still insufficient, and the causal relationship between medications used for collagen diseases and the prognosis of COVID-19 remains to be further investigated. There are some limitations in our study. First, due to the definition of diseases or states in the original registry data, some potential immunosuppressed states might have been excluded. Several patients with solid tumor did not undergo chemotherapy, and other underlying diseases might have resulted in their poor clinical outcomes. Second, we believe that our study provided useful clinico-epidemiological information of immunosuppressed COVID-19 patients in Japan, but we did not adjust for the already-known risk factors, such as age, while investigating the effect of immunosuppressed status on the outcomes. Therefore, it is difficult to make simple and meaningful comparisons between our study and previous studies. Third, due to the nature of the registry study, some detailed information about the cases was lacking; thus, it was difficult to determine the extent to which each specific disease and immunosuppressive agent contributed to the outcomes. 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Patients' baseline demographics for diseases with small number of cases Supplementary Table 2. Patient's baseline demographics by comorbidities and treatment Supplementary Table 3. Supportive care during hospitalization by comorbidities and treatment Supplementary Table 4. Administered medication during hospitalization Supplementary Table 5. Comparison of administered medication during hospitalization by comorbidities The authors thank all the participating facilities for their care of patients with COVID-19 and their cooperation with data entry into the registry.