The peripheral lymphocyte count as a predictor of severe COVID-19 and the effect of treatment with ciclesonide

Yamasaki, Yukitaka; Ooka, Seido; Tsuchida, Tomoya; Nakamura, Yuta; Hagiwara, Yuta; Naitou, Yoshiyuki; Ishibashi, Yutaka; Ikeda, Hiroki; Sakurada, Tsutomu; Handa, Hiroshi; Nishine, Hiroki; Takita, Mumon; Morikawa, Daiki; Yoshida, Hideki; Fujii, Shuichi; Morisawa, Kenichiro; Takemura, Hiromu; Fujitani, Shigeki; Kunishima, Hiroyuki

doi:10.1016/j.virusres.2020.198089

Cited by 30 publications

(23 citation statements)

References 18 publications

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“…The treatment regime involves inhalation of 400 μg ciclesonide (two or three times per day; total, 1200 μg/day) for 2 weeks. Three cases of COVID-19 pneumonia treated successfully with ciclesonide have been reported on November 2, 2020 by guest http://jvi.asm.org/ Downloaded from (28), as have several case reports (29)(30)(31). None of these studies reported significant side effects.…”

Section: Discussionmentioning

confidence: 99%

The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells

Matsuyama

Kawase

Nao

et al. 2020

J Virol

203

158

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Here, we screened steroid compounds to obtain a drug expected to block host inflammatory responses and MERS-CoV replication. Ciclesonide, an inhaled corticosteroid, suppressed replication of MERS-CoV and other coronaviruses, including SARS-CoV-2, the cause of COVID-19, in cultured cells. The effective concentration (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 μM. Eight consecutive passages of 43 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single amino acid substitutions in non-structural protein 3 (nsp3) or nsp4. Of note, ciclesonide suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade. Under the microscope, the viral RNA replication-transcription complex in cells, which is thought to be detectable using antibodies specific for nsp3 and double stranded RNA, was observed to fall in the presence of ciclesonide in a concentration-dependent manner. These observations indicate that the suppressive effect of ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the treatment of COVID-19 patients. IMPORTANCE The outbreak of SARS-CoV-2, the cause of COVID-19, is ongoing. New and effective antiviral agents that combat the disease are needed urgently. Here, we found that an inhaled corticosteroid, ciclesonide, suppresses replication of coronaviruses, including beta-coronaviruses (MHV-2, MERS-CoV, SARS-CoV, and SARS-CoV-2) and an alpha-coronavirus (HCoV-229E), in cultured cells. Ciclesonide is safe; indeed, it can be administered to infants at high concentrations. Thus, ciclesonide is expected to be a broad-spectrum antiviral drug that is effective against many members of the coronavirus family. It could be prescribed for treatment of MERS and COVID-19.

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Section: Discussionmentioning

confidence: 99%

The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells

Matsuyama

Kawase

Nao

et al. 2020

J Virol

203

158

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“…Various studies have also demonstrated that lymphocyte counts were closely correlated with the disease progression in patients with COVID-19. 18 , 19 Several mechanisms have been proposed for the occurrence of lower lymphocyte counts in patients infected with COVID-19 disease. It has been reported that the cytokine storm might have led to a rise in the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), thereby leading in a lymphocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Is prognostic nutritional index a predictive marker for estimating all-cause in-hospital mortality in COVID-19 patients with cardiovascular risk factors?

et al. 2021

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Background: This study examined the possible association between the prognostic nutritional index (PNI) and in-hospital mortality rates in cases with a high cardiovascular risk burden and hospitalized with the diagnosis of coronavirus disease 2019 . Material and Methods: This retrospective and cross-sectional study included 294 COVID-19 patients hospitalized in a tertiary referral pandemic center. The study cohort was grouped into tertiles based on the initial PNI values as T1, T2, and T3. The PNI was calculated for each case and the prognostic value of this index was compared to CURB-65 and 4C mortality risk scores in predicting in-hospital mortality. Results: Patients stratified into the T1 tertile had a lower lymphocyte count, serum albumin level, and PNI values. In a multivariate analysis, the PNI (OR: 0.688,%95CI: 0.586À0.808, p < 0.001) was an independent predictor for all-cause in-hospital death. After adjusting for confounding independent parameters, patients included in the T1 tertile were found to have 11.2 times higher rates of in-hospital mortality compared to the T3 group, which was presumed as the reference group. In addition, we found that the area under curve (AUC) value of PNI was significantly elevated than that of serum albumin level and total lymphocyte counts alone. [(AUC):0.79 vs AUC:0.75 vs AUC:0.69; respectively). Conclusion: This study demonstrated that the PNI is independently related with in-hospital mortality in patient with COVID-19 and cardiovascular risk factors. The power of the PNI was also validated using wellaccepted risk scores of COVID-19 such as CURB-65 and 4C mortality risk scores.

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“…The treatment regime involves inhalation of 400 μ g ciclesonide (two or three times per day) for 2 weeks. Three cases of COVID-19 pneumonia treated successfully with ciclesonide have been reported (15), as have several case reports (16)(17)(18). None of these studies reported significant side effects.…”

Section: Introductionmentioning

confidence: 94%

The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting viral replication-transcription complex in culture cells

Matsuyama

Kawase

Nao

et al. 2020

Preprint

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We screened steroid compounds to obtain a drug expected to block host inflammatory responses and MERS-CoV replication. Ciclesonide, an inhaled corticosteroid, suppressed replication of MERS-CoV and other coronaviruses, including SARS-CoV-2, the cause of COVID-19, in cultured cells. The effective concentration (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 μM. Ciclesonide inhibited formation of double membrane vesicles, which anchor the viral replication-transcription complex in cells. Eight consecutive passages of 43 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single amino acid substitutions in non-structural protein 3 (nsp3) or nsp4. Of note, ciclesonide still suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot completely overcome ciclesonide blockade. These observations indicate that the suppressive effect of ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the treatment of COVID-19 patients.

show abstract

The peripheral lymphocyte count as a predictor of severe COVID-19 and the effect of treatment with ciclesonide

Cited by 30 publications

References 18 publications

The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells

The Inhaled Steroid Ciclesonide Blocks SARS-CoV-2 RNA Replication by Targeting the Viral Replication-Transcription Complex in Cultured Cells

Is prognostic nutritional index a predictive marker for estimating all-cause in-hospital mortality in COVID-19 patients with cardiovascular risk factors?

The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting viral replication-transcription complex in culture cells

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