key: cord-0855015-9w858bsf
authors: Mitsumura, Takahiro; Okamoto, Tsukasa; Shirai, Tsuyoshi; Iijima, Yuki; Sakakibara, Rie; Honda, Takayuki; Ishizuka, Masahiro; Aiboshi, Junichi; Tateishi, Tomoya; Tamaoka, Meiyo; Shigemitsu, Hidenobu; Arai, Hirokuni; Otomo, Yasuhiro; Tohda, Shuji; Anzai, Tatsuhiko; Takahashi, Kunihiko; Yasuda, Shinsuke; Miyazaki, Yasunari
title: Predictors associated with clinical improvement of SARS-CoV-2 pneumonia
date: 2021-02-16
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.02.012
sha: 980d073a4fd3302ee591d18abfcb3d639fb8dc7f
doc_id: 855015
cord_uid: 9w858bsf

Background There are few agents that have been proven effective for COVID-19. Predicting clinical improvement as well as mortality or severity is very important. Objectives This study aimed to investigate the factors associated with the clinical improvement of COVID-19. Methods Overall, 74 patients receiving treatment for COVID-19 at Tokyo Medical and Dental University Hospital from April 6th to May 15th, 2020 were included in this study. Clinical improvement was evaluated, which defined as the decline of two levels on a six-point ordinal scale of clinical status or discharge alive from the hospital within 28 days after admission. The clinical courses were particularly investigated and the factors related to time to clinical improvement were analyzed with the log-rank test and the Cox proportional hazard model. Results Forty-nine patients required oxygen support during hospitalization, 22 patients required invasive mechanical ventilation, and 5 patients required extracorporeal membrane oxygenation. A total of 83% of cases reached clinical improvement. Longer period of time from onset to admission (≥10 days) (HR, 1.057; 95% CI, 1.002-1.114), no hypertension (HR, 2.077; 95% CI, 1.006-4.287), and low D-dimer levels (<1 μg/ml) (HR, 2.372; 95% CI, 1.229-4.576) were confirmed to be significant predictive factors for time to clinical improvement. Furthermore, a lower SARS-CoV-2 RNA copy number was also a predictive factor for clinical improvement. Conclusions Several predictors for the clinical improvement of COVID-19 pneumonia were identified. These results may be important for the management of COVID-19 pneumonia.

A novel coronavirus disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection has spread rapidly worldwide since it was first reported in December 2019 in Wuhan, China. While clinical trials of antiviral agents approved for other viruses [1] [2] [3] [4] [5] , anti-inflammatory agents [6] [7] [8] , plasma and antibody therapy [9] [10] [11] , and vaccines [12] are ongoing [13, 14] , few agents have been confirmed to be effective so far, and empirical treatments are being performed practically.

A variety of clinical courses are shown in COVID-19. While some patients are discharged from the hospital within 10 days, severe cases prolong the treatment duration [15] . Several predictive factors for mortality and severity have been reported [6, [15] [16] [17] [18] [19] [20] . On the other hand, shortages of medical and human resources have become apparent in many regions of the world [21] . These findings suggest that evaluation of factors affecting clinical improvement is critical in the treatment of COVID-19.

Here, this study aimed to investigate the factors associated with the clinical improvement of COVID-19 with empiric treatments. In this manuscript, the detailed clinical behavior of COVID-19 was reported for the first time in Japan and the factors that affected the time to clinical improvement were analyzed. The findings should be important for predicting disease course.

Seventy-four patients who were treated for COVID-19 in Tokyo Medical and Dental University (TMDU) Hospital from April 6th to May 15th in 2020 were enrolled. These patients were retrospectively reviewed to assess the clinical course.

This study was approved by the Institutional Review Board at TMDU hospital (M2020-027).

Clinical improvement was defined as the decline of two levels on a six-point ordinal scale of clinical status or discharge alive from hospital within 28 days after admission, whichever came first [20, 23] . The six-category scale was defined as follows according to previous reports [23, 24] , death = 6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation = 5; hospital admission for noninvasive ventilation or high-flow oxygen therapy = 4; hospital admission for oxygen therapy (not requiring high-flow or noninvasive ventilation) = 3; hospital admission not requiring oxygen therapy = 2; and discharged = 1.

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The clinical courses of all patients with any degree of respiratory support were shown and the time from admission to clinical improvement were analyzed. The oxygen support for patients during hospitalization is displayed with several color bars in figure 1. The criteria for discharge were as follows: 1) patients with symptom improvement and with two consecutive negative virus tests by SARS-CoV-2 PCR were discharged to their home; 2) patients under the age of 65 who had no coexisting disorder (diabetes, heart disease, respiratory disease, or renal failure requiring dialysis), immunosuppression, pregnancy, or fever of more than 37.5 degrees in the past 24 J o u r n a l P r e -p r o o f hours and whose symptoms improved were discharged to a hotel and continued isolation.

RT-PCR used targets in the open reading flame 1a (ORF1a) and spike (S) of SARS-CoV-2 according to the guideline [25] from the National Institute of Infectious Diseases in Japan. Total RNA was extracted using an EZ1 Virus Mini Kit v2.0 (Qiagen, Tokyo, Japan) according to the manufacturer's instructions. RT-PCR was performed using a QuantiTect Probe RT-PCR Kit (Qiagen) and an N2 primer set.

Continuous and categorical variables are presented as the median (interquartile range [IQR]) and n (%), respectively. The time to clinical improvement were portrayed with a Kaplan-Meier plot and compared it with a log-rank test. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for clinical improvement. A multivariate analysis was performed to predict the clinical improvement. The cutoff values of age [16] , J o u r n a l P r e -p r o o f neutrophil-to-lymphocyte ratio [26] , and D-dimer [15] , C-reactive protein (CRP) [27] , and lactate dehydrogenase [17] levels, were identified according to previous reports.

The cutoff values of white blood cell counts and procalcitonin levels were set at the Table 1 shows demographic clinical characteristics at baseline of the 74 patients. The median age was 56 yr (IQR, 43 -70 yr), and 52 patients (70%) were men.

The median body mass index (BMI) was 24 (IQR, 21 -26) . Forty-five percent had a history of smoking. Among the overall population, 39% had hypertension, 11% had diabetes, 12% had dyslipidemia, 9% had heart disease, 9% had asthma, and 7% had COPD. The median time from onset to admission was 10 days (IQR, 7.3 -13.8 days).

Laboratory data showed mild increases in CRP, lactate dehydrogenase, and D-dimer levels. On admission, the proportions of patients with six-category scale values of 2, 3, and 5 were 53%, 23%, and 24%, respectively. Table 2 shows treatment experiences in TMDU hospital. A majority of the patients (74%) received ciclesonide. Fifty-one percent received favipiravir, and 19% received hydroxychloroquine. Hydroxychloroquine was received in severe COVID-19 patients until the U.S. Food and Drug Administration (FDA) warned us of a potential serious heart risk [28] . Fourteen percent received nafamostat mesylate. Eighteen percent and 19% received tocilizumab and glucocorticoid, respectively, after maximum J o u r n a l P r e -p r o o f possible exclusion of infectious diseases other than COVID-19. One percent received IVIG, which was administered in a critical patient with poor response to glucocorticoid and tocilizumab. Thirty-five percent received heparin. Heparin was administered to all severe patients with mechanical ventilation and 6 mild patients, including 5 with overweight (BMI > 25) and 1 with low activities of daily living (ADL) transferred from another hospital. Oxygen support was required for 66%. Low-flow oxygen, mechanical ventilation and extracorporeal membrane oxygenation (ECMO) were required for 36%, 30%, and 7%, respectively. Six patients received renal replacement therapy, including 2 patients with maintenance dialysis.

The median duration of hospital stay was 10 days (IQR: 6.3 -20.0 days).

The clinical improvement rate of all patients is shown in Figure 1A . Eighty-three percent of patients achieved clinical improvement by day 28. Figure 1B 

The time to clinical improvement has been shown with dichotomy by cutoff values of each factor with univariate analysis using Cox regression and with the log-rank test (Table 3 , Figure 2 , and Supplementary figure 2). In baseline characteristics, younger age (< 60 yr) (hazard ratio [HR], 3.428; 95% CI, 1.787 -6.576) and longer time from onset to admission (≥ 10 days) (HR, 1.933; 95% CI, 1.092 -3.423) were significantly associated with earlier clinical improvement. However, "discharge alive from hospital within 28 days" was included as an indicator of clinical improvement in this study. In addition, the discharge to hotel criteria includes "patients under 65 years old without underlying disease". These affect duration of hospital stay of young cases. Therefore, we performed the analysis excluding the cases discharged to the hotel. As a result, clinical improvement tended to be faster in cases younger than 60 years, but there was no statistically significant difference. Sex, body mass index, smoking, and body temperature were not significant factors. In comorbidities, no hypertension (HR, 2.493; 95% CI, 1.301 -4.777) was significantly associated with J o u r n a l P r e -p r o o f early clinical improvement. None of the patients were treated with ACE inhibitors, and the presence or absence of antihypertensive drugs did not affect clinical improvement (Supplementary figure 3) . Diabetes, dyslipidemia, heart disease, and bronchial asthma were not significant factors. In laboratory data, low D-dimer (< 1 μg/ml) (HR, 3.107; 95% CI, 1.721 -5.610) and low procalcitonin levels (< 0.05 ng/ml) (HR, 2.310; 95% CI, 1.253 -4.261) were significantly associated with early clinical improvement.

White blood cell count, neutrophil-to-lymphocyte ratio, platelet count, CRP level, and lactate dehydrogenase level were not significant factors. The six -category scale for groups with longer period of time from onset to admission (≥ 10 days), low D-dimer levels (< 1 μg/ml), and low procalcitonin (< 0.05 ng/mL) were low (Supplementary J o u r n a l P r e -p r o o f 95% CI, 1.229 -4.576) remained statistically significant. Of these, age (< 60 yr) was a factor affected by the criteria for discharge to hotels. Therefore, age (< 60 yr) was included in the variables of multivariate analysis as an adjustment factor rather than a predictive factor. In severe patients who required mechanical ventilation, category 5 on 

Therefore, we performed the analysis excluding the cases discharged by two consecutive negative virus tests. As a result, RNA copy number was significantly associated with early clinical improvement (HR, 2.693; 95% CI, 1.087 -6.673). RNA copy number was an independent factor for clinical improvement with low correlation with other factors (Supplementary table 3 ).

In this study, the clinical course of COVID-19 in Tokyo, Japan, which is the center of the outbreak in Japan were detailed. A total of 83% of patients improved, and only three patients died during hospitalization, while the proportion of severe cases requiring invasive mechanical ventilation was fairly high, at 30% in the cohort. From this population, several predictive factors for the clinical improvement of COVID-19 pneumonia were identified.

Several models have been proposed to predict mortality and severity [6, [15] [16] [17] [18] [19] [20] 29 ]. However, time to clinical improvement is extremely useful information in the clinical setting of COVID-19 in the absence of standard treatment and shortages of medical care and human resources [30] . This study confirmed that longer time from onset to admission, no hypertension, and low D-dimer levels were significant factors related to earlier clinical improvement. And younger cases, excluding discharge to the J o u r n a l P r e -p r o o f hotel, tended to shorted time to clinical improvement. Older age, hypertension, and high D-dimer levels are also known predictive factors of mortality and severity [6, 15, 16, 18, 19, 31] . Lower D-dimer levels were associated with time to clinical improvement in this study, which was consistent with previous reports that COVID -19 caused abnormal coagulation and thrombosis [15, [32] [33] [34] [35] [36] [37] . The updated NIH guidelines also recommended caution and treatment for complications of thrombosis. In this study, heparin was administered to patients with embolism or at high risk of thrombosis (with mechanical ventilation, overweight, or low ADL). A longer time from onset to admission was a significant predictor for clinical improvement in all cases and even in severe cases (Supplementary figure 4) . Some severe cases take a long time from onset to admission. Previous reports showed no difference in the time from onset to admission between survivors and non-survivors between [15] . On the other hand, another report showed that the time from onset to admission in the critical group was shorter than in the mild and severe groups [38] . In our study, the group with shorter period of time from onset to admission (< 10 days) had already had poor respiratory status at admission. In addition, all deaths were included in the group with shorter period of time from onset to admission (< 10 days). These suggested that the group with a shorter time from onset to admission (<10 days) progressed quickly and was refractory to treatment.

In this study, a higher RNA copy number was a predictive factor for a longer time to clinical improvement. This result is consistent with a previous report showing that the ΔCt values of severe cases remained significantly lower for the first 12 days after onset than those of corresponding mild cases [37] . SARS-CoV-2 RNA copy number was reported to peak 4 days after onset [39] . PCR was purportedly performed after peak virus shedding in mild cases. This finding is also consistent with the result that a longer time from onset to admission predicts a longer time to clinical improvement. These findings suggest that patients with higher viral copy numbers and shorter time from onset to admission need to be managed more carefully. Measurement of SARS-CoV-2 RNA copy number can predict the clinical improvement of COVID-19 and provide better care in each region of the world where viral epidemics with different genomic variants are prevalent [40, 41] .

The limitations of this study are as follows. First, this study was a single-institution retrospective study with a small sample size. In a previous report, many bias interventions had been pointed out in the COVID-19 diagnosis and prognosis prediction models [19] , and more accurate data will be required in the future.

Second, most treatments for COVID-19 were based on empirical experience.

Remdesivir [2] [3] [4] , which was approved with emergency authorization by the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) in Japan as a treatment for COVID-19, was not used in this study.

Furthermore, this study is not large enough to prove the efficacy and safety of each agent. J o u r n a l P r e -p r o o f 

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Great appreciation goes to all the staff involved in COVID-19 treatment.J o u r n a l P r e -p r o o f