key: cord-0708984-qe1spo5o
authors: Boglione, Lucio; Olivieri, Carlo; Rostagno, Roberto; Poletti, Federica; Moglia, Roberta; Bianchi, Bianca; Esposito, Maria; Biffi, Stefano; Borrè, Silvio
title: Role of the early short-course corticosteroids treatment in ARDS caused by COVID-19: a single-center, retrospective analysis
date: 2021-04-24
journal: Adv Med Sci
DOI: 10.1016/j.advms.2021.04.002
sha: aa2962d6b47a886a747454a1fc89fc59b6afcd66
doc_id: 708984
cord_uid: qe1spo5o

PURPOSE: Severe coronavirus disease 2019 (COVID-19) is strongly related to interstitial pneumonia with frequent development of acute respiratory distress syndrome (ARDS). The role of corticosteroids (CS) treatment in these patients is still controversial. Some studies evidenced a possible role of an early short-term course of CS treatment in the treatment of severe pneumonia. PATIENTS AND METHODS: This is a single-center, retrospective study considering the patients with confirmed COVID-19 pneumonia admitted to our hospital between 9(th) March and 15(th) June 2020. Two groups were considered: early high-dose of methyl-prednisolone (eHDM; n=31) and the control group (n=52). Patients in the eHDM group received the dose of 5-8mg/kg/day of methyl-prednisolone for 2 consecutive days. Primary outcome was the mortality evaluation; secondary outcomes were clinical improvement, side-effects and laboratory/radiographic changes. RESULTS: Significant differences between the two groups were: length of hospitalization (21.5 vs 28.4 days, p=0.026), length of non-invasive ventilation (NIV) or mechanical ventilation (11.5 vs 14.5 days, p=0.031), death (5 vs 12, p=0.006) and clinical improvement (16 vs 11, p=0.018). The following factors were related to in-hospital mortality in the multivariate analysis: comorbidities (OR=2.919; 95%CI=1.515-16.705; p<0.001), days from the onset of symptoms and the hospital admission (OR=1.404; 95%CI=1.069-12.492; p=0.011), PaO(2)/FiO(2) (P/F) ratio (OR=3.111; 95%CI=2.334-16.991; p=0.009) and eHDM treatment (OR=0.741; 95%CI=0.129-0.917; p=0.007). CONCLUSION: The eHDM is an interesting and promising approach in the ARDS related to COVID-19 pneumonia, which reduces mortality, length of hospitalization and the need for mechanical ventilation.

The outbreak of novel coronavirus disease 2019 (COVID- 19) is currently a global health emergency [1] due to respiratory illness caused by this infection with progression to critical hypoxemia and the development of acute respiratory distress syndrome (ARDS) [2] . The ARDS related to the severe acute respiratory syndrome coronavirus 2 (SARS- infection is associated with a high mortality rate [3] and the main trigger factor is the 'cytokine storm' caused by the hyperinflammation and immune-suppression with a decrease of CD4+ T helper and increase of CD8+ cytotoxic activity; the unregulated release of inflammatory cytokines such as TNF-α, IL-1 and IL-6 leads to lung tissue damage with reduction in the gas alveolar exchange [4] .

In patients with evidence of SARS-CoV-2 pneumonia, the effectiveness of supportive treatment with oxygen, ventilatory support or low molecular weight heparin (LMWH) was reported [5] ; among the adjunctive immunomodulatory agents, corticosteroids (CS) have been widely employed in ARDS and in other viral infections [6] [7] ; despite an initial contraindication of the use of CS in the COVID-19 related pneumonia due to the lack of evidence of a proven advantage or the potential harm, such as the reduction of viral clearance and the bacterial/fungal superinfections [8] [9] , some evidences are currently available about the role of CS in the ARDS related to COVID-19 [10] . The rationale for CS use in this setting is the reduction of hyper-inflammatory syndrome, as observed in previous studies with other causes of ARDS [11] ; in particular the major benefit seems to be observed in more severe patients, in intensive care unit (ICU) with a reduction in mortality and need of intubation or length of intubation time [12] [13] . Some aspects, however, need to be clarified: the type of CS used (dexamethasone, methylprednisolone or others), the dose and treatment duration and the initial timing [14] . Recent studies evidence the improvement in different clinical outcomes with the high-dose, short-term and early administration of methylprednisolone in patients with initial ARDS [12, 15] and this approach seems to be more promising that low-dose, prolonged time in late phase of ARDS, where bacterial or fungal superinfection, diabetes and other sideeffect related to CS administration are more frequent [16] .

In this retrospective study, we analyzed the real-life benefit of early short-course of CS treatment in patients with critical COVID-19 infection and ARDS.

J o u r n a l P r e -p r o o f We considered all the consecutive patients admitted at the ʽSt. Andrea Hospitalʼ, Vercelli, Italy, between 9 th March and 15 th June 2020 with confirmed diagnosis of SARS-CoV-2 infection, with radiological evidence of interstitial pneumonia. We excluded patients with unconfirmed diagnosis (negative PCR assay for SARS-CoV-2) or with positive PCR but without pneumonia or other respiratory illness. The severity of clinical presentation was defined with different score: Pneumonia Severity Index (PSI), sequential organ failure assessment (SOFA) and Brescia-COVID respiratory severity scale (BCRSS).

Based on these parameters, we defined the following clinical categories: mild diseasedefined as the presence of symptoms with pulmonary infiltrate but without hypoxia; moderate disease -defined as pulmonary involvement with the need of supplemental oxygen; severe disease -defined as the presence of moderate or severe ARDS according to the Berlin definition with the need for non-invasive ventilation (NIV) or mechanical ventilation [17] .

The study design was a retrospective analysis in the subgroup patients with severe clinical condition and ARDS according to received CS therapy.

Early ARDS was considered within 72 hours from hospital admission, while late ARDS after 72 hours from admission or after previous treatment failure to standard of care (other CS, antivirals, hydroxychloroquine, tocilizumab).

Early high-dose of methylprednisolone (eHDM) was defined as single bolus IV administration (5-8 mg/kg/day) for 2 days in patients with early ARDS; the ʽrescue therapyʼ (RT) was defined as the late-HDM in patients with previous treatment failure or rapidly worsening condition.

The primary endpoint was the comparison of mortality between patients receiving eHDM treatment vs RT or other CS or without CS (control group); secondary endpoints were the evaluation of clinical improvement between the two groups of patients (defined as escalation to an ICU from a non-ICU hospitalization) and the side-effect or other clinical complications that occurred during the observation period. Changes in WBC, platelets, CRP, ferritin, Ddimer, procalcitonin, PaO 2 /FiO 2 (P/F) ratio and radiological improvement were also assessed and compared among patients receiving eHDM treatment compared to the control group.

In descriptive statistics, continuous variables were summarized as median (inter-quartile range (IQR): 25th to 75th percentiles). Categorical variables were described as frequency and J o u r n a l P r e -p r o o f percentage. All data were assessed for normality using a Shapiro-Wilk test and categorical data were compared using a Mann-Whitney or Kruskal-Wallis statistical test. To investigate continuous data, a Spearman's rank correlation was utilized. The association was calculated using the χ 2 -test. Multivariate logistic regression analysis with stepwise forward selection was performed with p-values of less than 0.05 as the criteria for model inclusion. All p-values were two-tailed. P<0.05 was considered statistically significant. Statistical analyses were conducted using SPSS software package ver. 26.0 (Chicago, IL, USA).

The study protocol was approved by the local Ethics Committee Comitato Etico Interaziendale ASL VC (4/8/2020; Protocol number: 0026301).

This study which involves human participants is in compliance with the 1964 Helsinki declaration and its later amendments.

We evaluated a total of 289 patients with a suspected diagnosis of COVID-19 infection. We after extubation all patients were supported by NIV for a median time of 2.5 days. The median time of hospitalization was 26.5 days.

In our cohort, 17 patients died (20.5%), 27 (32.5%) evidenced a clinical improvement; sepsis was observed in 39 (47%), candidemia in 14 (16.9%), ventilator-associated pneumonia (VAP) in 16 (19.3%). Median P/F increase after 48 hours was 10.5, CRP reduction was 5.5, ferritin reduction 122.5; radiological improvement was observed in 32 patients (38.5%). In the demographic characteristics, we observed that the median time of CS treatment delay after hospital admission showed a statistically significant difference, as expected, between eHDM and controls, being 2 days (IQR:1-2.5) and 4 days (IQR:3.5-9), respectively (p<0.001).

Among the clinical outcomes, significant differences were observed between the two groups As presented in Figure 2 , a statistically significant difference was observed between patients who were directly admitted into ICU compared to those who were not, according to days from the onset of symptoms: 12 days (IQR: 9-14) vs. 6 days (IQR: 5-8), respectively (p<0.001).

In Figure 3 , the median values of CRP after 48h from the CS treatment, according to different therapies, in patients receiving the standard dose of methylprednisolone the median CRP reduction was 3mg/L (IQR: 2-5); in the dexamethasone group the reduction was 6mg/L (IQR: 2.9-8.5); in the eHDM group the reduction was 8.5mg/L (IQR: 0.5-16.5). Differences were statistically significant among all groups (p<0.001).

In Figure 4 , the median P/F changes between patients treated with the standard treatment (control group) and with the eHDM treatment were reported. The median increase was 5 in the control group (IQR: 2-12) and 22 in the eHDM group (IQR: 17.5-38) (p<0.001).

J o u r n a l P r e -p r o o f

In Table 2 we report the antimicrobial and antiviral treatment administered in the study population; empiric therapy was used in 36 patients (43.4%) and the most commonly given drugs were: ceftriaxone alone (n=11; 13.2%), ceftriaxone plus azithromycin (n=6; 7.2%), levofloxacin (n=4; 4.8%) and piperacillin/tazobactam (n=15; 18%). The choice of these different antimicrobials was related to different factors, including clinical approach, presence of comorbidities, such as COPD, known drug allergies, previous home therapies. Specific oriented therapy based on the microbiological isolation from blood or other samples was administered in 47 patients (56.6%) with different antimicrobial or antifungal drugs. Antiviral treatment was administered in 71 (85.5%) patients according to different clinical conditions and changes in guidelines; 12 patients (14.4%) did not receive any antiviral treatment due to different reasons i.e. presence of major contraindications, such as cardiac arrhythmias, inability to take medications orally or more severe clinical condition.

In the univariate analysis, we considered the following factors : age, male sex, body mass Table 3) .

The major findings of our study included the statistically significantly lower mortality rate in patients treated with the eHDM -similar to that reported in the study by Fadel et al. [12] -in comparison to other treatments (16% vs 23%, p=0.006), considering that the control group had similar baseline characteristics without significant heterogeneity; higher clinical improvement (51.6% vs 21.1%, p<0.018); and the reduction of hospitalization period. [7] , due to a reduction of viral clearance and major incidence of side-effects such as diabetes or bacteria/fungal infections, some studies report a decrease in the risk of death or need of mechanical ventilation using both methylprednisolone and dexamethasone in patients with critical illness due to COVID-19 pneumonia [2, 19] , and lower 28-day mortality rate was confirmed in a recent trial evaluating the effect of dexamethasone in patients with COVID-19 pneumonia [13] . Therefore, the treatment with dexamethasone reduces mortality rate in patients with the need of respiratory support or mechanical ventilation, while no effect was demonstrated in patients without the need for oxygen. The studies about the role of CS in SARS-CoV-2 infection showed higher heterogeneity and many aspects should be clarified. [20] . The evidence of timing in CS therapy has been previously demonstrated in studies on potential role of glucocorticoids in ARDS conditions; the available data were favorable to the use of CS in the early phase of ARDS, with a better effectiveness when using high-dose, short-time course of methylprednisolone [16] . Based on these evidences and other small case-series [15] we report in our study similar and encouraging results of the early, high-dose and short term treatment with methylprednisolone in patients with SARS-CoV-2 infection and initial phase of ARDS.

The beneficial effect of this approach was also confirmed by the improvement in inflammatory, biochemical and radiographic parameters in the eHDM group. Among the factors significantly associated with higher mortality rate in our study population, we highlight the time from the onset of symptoms to the hospital admission (OR=1.404); for this J o u r n a l P r e -p r o o f reason, clinicians should play an active role in promoting the correct information about the COVID-19 risk in the outpatients, regarding the need of home-treatment and monitoring, and early hospital admission before the worsening of clinical condition and ARDS onset. In fact, a median difference of 6 days late was strongly related to the direct ICU admission of patients with consequent higher mortality rate.

The relationship between the early use of CS in COVID-19 pneumonia and lower mortality was recently reported in the study by Monedero et al. [21] ; patients who have never received CS during the hospital admission had higher mortality rate than patients with early CS treatment; in this setting, patients with higher inflammatory markers requiring ventilatory support may benefit from the CS treatment. Beneficial effect of the standard dose of dexamethasone may conversely be an alternative for patients with mild COVID-19 pneumonia with the need for oxygen support but without ARDS, as reported in the RECOVERY study [22] .

In our present study, the most important factor associated with higher mortality, was the presence of one or more comorbidities (OR=2.919). The presence of chronic heart failure, diabetes mellitus, COPD and other illnesses leads to the unfavorable outcome in patients with COVID-19 pneumonia [2] . The clinicians should focus their attention on the modifiable factors, such as timing of admission, timing of therapy and early CS administration.

Moreover, the lower rate of VAP in the eHDM group can be related to the shorter hospitalization time and lower rate of mechanical ventilation in this group.

The conclusions of this study are not definitive, and several limitations are related to the retrospective design: limited sample size of the two groups, the heterogeneity of the control group, without randomization. In addition, the standard definition of "early" and "late" ARDS were derived from the Berlin criteria [17] , although the COVID-19 related ARDS presents some different characteristics which could make inapplicable the same parameters used in the "standard" definition of ARDS [23] .

In conclusion, we focus the attention on the role of early CS administration in COVID-19 ARDS, with encouraging results in mortality reduction and shortening of hospitalization time using the eHDM approach. Further randomized studies are urgently needed to confirm these promising results in patients with COVID-19 related ARDS. 

The authors declare no conflict of interests 

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