ABSTRACT
Background: Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease.Methods: This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15.Results: Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841–2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347–5.950; p = 0.006).Conclusions: Corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).
Subject(s)
COVID-19 , Critical IllnessABSTRACT
Condition:
Coronavirus disease 2019 (COVID-19)COVID-19, pneumonia;C000657245;COVID-19, pneumonia
Intervention:
Combination therapy with favipiravir and methylprednisolone;D004359; C462182; D000998;Drug Therapy, Combination; Favipiravir; MethylprednisolonePrimary outcome:
Proportion of patients who need mechanical ventilation or those who meet the criteria of tracheal intubation* within 14 days of initiation of treatment (*at least one of the following: 5 L/min or more of oxygen flux; unstable circulatory dynamics; or consciousness disturbance)Criteria:
Inclusion criteria: 1. Patients who developed pneumonia* and need inpatient treatment (*pneumonia is defined as the presence of a new infiltrate on a chest radiograph or a computed tomography scan in addition to at least one of the following: new or increased cough or sputum production, new pleuritic chest pain, new or increased dyspnea, fever (temperature >= 37.5 degrees) or hypothermia (temperature <35.0 degrees), leukocytosis [white blood cell count (WBC) >=10,000/mm3] or leukopenia (WBC <4,000/mm3), elevated level of CRP value (exceed the upper threshold of each study institution), or new hypoxemia or deterioration of hypoxemia)2. Positive PCR or antigen testing of SARS-CoV-2
3. Within 12 days of onset of symptoms
4. Patients with hypoxemia who need oxygen therapy (who meet one of the following: SpO2 =< 93% on room air; arterial oxygen partial pressure (PaO2) =< 60 mmHg or PaO2/ fraction of inspired oxygen (FiO2) < 300; or AaDO2 >= 40)
5. Age >= 20 years old
6. Informed consent must be obtained prior to participation in this study
7. Patients who were registered in observational registry studies organized by National Center for Global Health and Medicine or Fujita Health University (This criterion will not be applicable after the approval of favipiravir)
Exclusion criteria: 1. Patients who meet the criteria of tracheal intubation (at least one of the following: 5 L/min or more of oxygen flux; unstable circulatory dynamics; or consciousness disturbance)
2. Intubated or tracheostomy was performed at time of initiation of treatment
3. Patients who need vasopressor(s) at time of initiation of treatment
4. Patients who are receiving systemic corticosteroids or immunosuppressive agents including biological ones at time of initiation of treatment
5. Patients with HIV or immunodeficiency disorders
6. Respiratory failure due to cardiac pulmonary edema
7. Apparent asthma attack
8. Apparent pulmonary embolism
9. Chronic pulmonary diseases (e.g., interstitial pneumonia and severe COPD) which potentially affect assessment of the efficacy of study treatment
10. Long term oxygen therapy
11. Malignant diseases which potentially affect assessment of the efficacy of study treatment
12. Complicating pneumonia due to apparent bacterial infection or aspiration
13. Patients who are receiving anti-SARS-CoV-2 agents (e.g., favipiravir, lopinavir/ritonavir, remdesivir, ciclesonide, etc.)
14. Patients who need to receive medications that affect the effect of corticosteroids (e.g., rifampicin, phenobarbital, phenytoin, and ephedrine)
15. Contraindication for use of favipiravir or corticosteroids (e.g., allergy to them)
16. Pregnant women and women suspected of being pregnant
17. Women who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration
18. Men or their partners who are not able to give informed consent regarding protected sexual intercourse from the initiation of favipiravir to 90 days after the end of its administration
19. Patients who may have difficulty receiving efficacy assessment due to dementia or mental disorders
20. Patients who are participating in other clinical studies which do not allow use of corticosteroids or those who are expected to participate in them
21. Patients in whom physicians in charge judged inappropriate for registration