IDDT Journal

Introduction

On the 1st of August, 2020, the United Nations reported that the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported in December 2019 in Wuhan, China, had spread all over the world and had infected over 17 million people and resulted in over 650,000 deaths, with no end in sight to this public health crisis [1]. Of these cases, approximately 80% were considered to be mild to moderate, 13.8% were severe, and approximately 6.1% cases had progressed to a critical stage requiring intensive care [2]. As of March 2020, the World Health Organization (WHO) reported mortality rates ranging from 0.2% in Germany to approximately 7.7% in Italy with a mean of 3.7% around the world [3,4]. In the United Kingdom, the case fatality rate was approximately 26% in patients who received ward care only and was 37% in patients who were on invasive ventilation [5].

ARDS in COVID-19

An increase in acute phase reactants in patients with COVID-19 (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A, and ferritin) point to brisk immune activation. Cytokines are integral to COVID-19 pathogenesis, some of which are beneficial (type-I interferon and interleukin-7), whereas others appear to be harmful (interleukin-1ß, Interleukin-6 (IL-6), tumor necrosis factor (TNF-a)). Moderate levels of cytokines, such as CRP, ferritin, D-dimer, alanine transaminase (ALT), and lactate dehydrogenase (LDH), have been observed in severe ARDS, whereas in the ‘cytokine storm’, very high levels of IL-6, ferritin, and CRP have been observed, leading to ARDS, disseminated intravascular coagulation, or multiple organ failure. This cytokine storm syndrome results in high morbidity and mortality [6-10]. Hyaline membrane formation, pneumocyte atypical hyperplasia, and platelet–fibrin thrombi in small arterial vessels, which are consistent with coagulopathy, and are other unique pathophysiological features of COVID-19 ARDS [11].

The mortality arising from COVID-19 ARDS has been shown to be much higher (26–61.5%) than the mortality due to typical ARDS arising from other conditions (35.3–40%) [12-13]. In other closely related viral infections, such as SARS-CoV-1, Middle East Respiratory Syndrome (MERS) coronavirus, and influenza, viral replication peaks in the second week, whereas in SARS-CoV-2, viremia occurs early (in the first week) and decreases subsequently [14].

Steroids in ARDS

ARDS of any etiology have high rates of morbidity and mortality worldwide. Incidence of ARDS in 459 ICUs worldwide, according to Bellani et al., in 2016 was approximately 10.4%, and approximately a quarter of these required mechanical ventilation. The overall hospital mortality from ARDS ranged from 34.9% for mild ARDS to 46.1% for severe ARDS.12 Similar statistics for mortality (38.5%) was found in a previously conducted study in Washington, which surveyed 21 hospitals, thus confirming the profoundly serious nature of this disease [15].

In trials of corticosteroids used in ARDS conducted prior to 2005, the use of steroids was not based on any set criteria, such as type, dosage, duration, or severity. Therefore, the results were not consistent across studies; hence, the use of corticosteroids in ARDS remained uncertain [16,17].

A negative result was found in a systematic review and meta-analysis of 6548 patients with influenza pneumonia where mortality was higher in the steroid group [18].

In a multicenter randomized controlled trial (RCT) conducted in Spain across five years and published in March 2020 of enrolled patients with moderate to severe ARDS, the steroid group was given dexamethasone (20 mg from day 1 to day 5 and tapered off to 10 mg from days 6 to 10). Both the steroid and non-steroid control groups were ventilated with lung-protective mechanical ventilation. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-groups, difference was 4.8 days, p<0.0001) suggesting a benefit. In addition, the 60-day mortality was favorable towards the steroid group (21% vs. 36%, p=0.0047 in the control group) [19]. This recent study gave hope of steroids, with lung-protective mechanical ventilation, as a treatment option in ARDS.

Steroid Use in COVID-19 ARDS

In January 2020, at the break of the pandemic, the interim guidance from the WHO explicitly stated that unless indicated for another reason, corticosteroids may not be routinely used to treat ARDS due to the possible complications and lack of effectiveness [20]. Soon after, in February 2020, Russel et al. found four studies with conclusive data, all indicating the harmful effects of steroids. It was postulated that steroids not only suppress lung inflammation but also hinder the immune response and pathogen clearance. Furthermore, the use of steroids brought about secondary infections and complications in survivors. From all the above evidence, Russel et al. concluded that steroids should not be used for treatment of COVID-19 outside of a clinical trial [21].

Subsequently, a multicentric trial in June 2020 with intravenous methylprednisolone (40 mg/12 h for 3 days, 20 mg/12 h for 3 days) showed a beneficial effect with a lower risk of ICU admission (8% vs. 28%, p=0.047), lower NIV (6% vs. 10%, ns) and death (20% vs. 18%, ns), and a 50% lower risk of a composite adverse outcome [22].

An early, short course of methylprednisolone (0.5 to 1 mg/ kg/day divided in 2 intravenous doses for 3 days) in a multicenter health system in Michigan in March 2020 concluded that there was a reduction in length of hospital stay (5 vs. 8 days, p<0.01), which thus reduced escalation of care and improved clinical outcomes [23].

In the CODEX trial in ICUs in Brazil, moderate to severe COVID-19 ARDS patients were administered dexamethasone (20 mg for 5 days, 10 mg for 5 days). Results showed a significant increase in the number of ventilator-free days, suggesting a benefit (6.6 vs. 4, p=0.04). However, for the 28-day mortality, there were no significant differences [24].

The REMAP-CAP study was done with a 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) with a 93% probability of benefit based on improvement in organ support–free days within 21 days [25].

The RECOVERY trial published in July 2020 provided conclusive evidence that treatment with dexamethasone (6 mg once daily for up to 10 days) reduced death by 1/3rd in ventilated patients and by 1/5th in patients on oxygen support, and no benefit among patients who did not receive or require respiratory support. The trial included 2104 patients in the steroid group and 4321 patients in the usual care group. The primary outcome of 28-day mortality for all patients was highly significant (22.9% vs. 25.7%, p<0.001), with maximum benefit noticed in those on invasive ventilation (29.3% vs. 49.4%) and in those on oxygen support (23.3% vs. 26.2%). The secondary outcomes of length of hospital stay and progression to mechanical ventilation were also benefited by dexamethasone [14].

Our Aim

As discussed above, trials prior to the Recovery trial for steroids in COVID-19 ARDS tended towards a benefit but did not result in a clear conclusion due to the heterogeneity in type, dosing, and timing of steroids. The Recovery trial, however, with its large sample size and well-designed trial showed conclusive evidence that dexamethasone is beneficial for treatment of COVID-19 ARDS. With this knowledge, we planned to do a retrospective observational analysis of the COVID-19 patients at our hospital. The patients were classified based on the Berlin criteria of ARDS severity: mild (200-300), moderate (100-200), severe (<100), and critical (if patient was on high flow nasal oxygen (HFNO)/ noninvasive ventilation (NIV)/ mechanical ventilation (MV)) [26]. The patients were divided into two groups: the steroid group (SG) and standard of care (SOC) group.

Methods

Study Design

We conducted a retrospective observational study at NMC Specialty Hospital, Dubai, a 100 bed, tertiary care hospital, over a period of 5 months from March 2020 to July 2020 during the first wave of COVID-19. Hospitalized patients were included in the study if they fulfilled the followingc riteria:

a) a positive RT PCR test (reverse transcriptase polymerase chain reaction),

b) suspected COVID-19 based on clinical and radiological features despite a negative RT PCRt est,

c) bilateral infiltrates and/or interstitial opacities on chest X-ray,

d) PaO2/FiO2 (P/F) ratio of <200 as per Berlin criteria of

moderate ARDS,

e) high inflammatory markers (CRP, ferritin)

f) received any type of corticosteroids during the period of study.

Of the 256 COVID-19 patients admitted to this hospital, 111 patients fulfilled the inclusion criteria and were divided into two groups: 62 patients were treated with steroids and were designated as the steroid group (SG). The other 49 patients were not treated with steroids but received standard of care treatment (SOC). Both groups were treated in accordance with the national guidelines at that time with the addition of steroids in the SG.

Patient data were collected from various departments, namely the medical records department, laboratory, and in-patient pharmacy. This included demographic data and comorbidities, clinical signs and symptoms and severity at presentation, laboratory and radiological data, in-patient treatment, data on steroids and other supportive medications used.

This study has been approved by the Dubai Scientific Research Ethics Committee (DSREC), Dubai Health Authority, dated 17^th September 2020 (Ref: DSREC- 09/2020_22).

Outcome Measures

The primary objectives of the study were to compare the following outcome measures in the SGa nd SOC:

1. 28-day mortality - number of patients who died during hospital day or in the 28-day period (whichever came earlier) following treatment.

2. Number of ventilator days - number of ventilator days following the start of intubation and mechanical ventilation until the last extubation. Ventilator days for reintubated patients are counted as a continuation until final extubation. 3. Number of days on oxygen support - number of days from when oxygen was first started until it was weaned off to 3L of oxygen support or a P/F ratio of >300.

The secondary objectives involved comparing the following outcome measures in the SG and SOC groups:

1. Length of stay in the ICU,

2. Length of stay in the hospital,

3. Morbidities in terms of cardiac, renal, and neurological complications.

Other secondary objectives included:

1. To enumerate the type of steroid used, dosage, and duration in the SG

2. To examine other supportive medications used in both groups.

Statistical Analysis

The data collected from electronic records were compiled in an Excel worksheet. Descriptive analysis was performed for demographics and clinical and laboratory records. The mean/ median, standard deviation, and percentages are reported in the tables below. To investigate the association between SG and SOC to mortality (dead/alive) and morbidity, the Chi square test was used. Analysis of outcome measures with continuous variables, such as ventilator days, oxygen days, ICU days, and hospital days, was performed using the Independent T test for mean duration, and Mann Whitney U test for median duration. All analyses were performed using IBM SPSS (version 27.0; IBM Corp., Armonk, NY, USA). A two-sided p-value of <0.05 was considered as statistically significant.

Results

Demographics and Comorbidities - Table 1:

In both groups, most patients were in the 40–60 age range with the SG having a mean (±SD) age of 50.4±10.4 and the SOC having a mean (±SD) age of 47.2±11. Both groups were made up of a much larger percentage of males with 90.3% in SG and 83.7% in SOC. A variety of nationalities were treated, the majority being of South Asian descent (Indian, Pakistani and Bangladeshi), which made up 66.1% and 67.3% of patients in SG and SOC, respectively (Table 1).

Table 1: Demographics and Comorbidities.

Comparison and Severity of Disease -Table 2 and Figure 3:

The SG consisted of more critical or severe ARDS patients (82.3%), whereas only 24.5% of patients in SOC presented the same. This observation confirmed that SG consisted of patients with a more serious disease compared to SOC, which consisted of mild and moderate cases (Table 2).

Table 2: Clinical Severity.

Figure 3(a) shows the lab parameters of inflammation and coagulation markers (e.g., CRP, ferritin, D-dimer, and IL-6), which are direct indicators of COVID disease severity. The mean (±SD) CRP value in SG was 147.2±93.7 versus 103.1±66.0 in SOC with statistical significance (p<0.05). Similarly, statistical significance was also achieved for the mean D-dimer values (SG= 1079±1512.3 and SOC= 597.5±843.3). Although the mean values for ferritin and IL-6 did not achieve statistical significance, the values were higher in SG than in SOC for both markers.

The different levels of severity based on chest X-ray were graded as unilateral lobar pneumonia, bilateral pneumonia, and worsening of bilateral pneumonia. In SG, 41 (66.1%) patients had worsening of bilateral pneumonia compared with 17 (34.7%) in SOC (p<0.05). These laboratory and radiological values measured during the worsening of symptoms clearly points to the more severe nature of the disease of SG when compared to that of SOC (Figure 3(b)).

Primary and Secondary Outcomes - Table 4:

As patients are sub-categorized by ARDS severity, outcome measures were examined individually for each ARDS category. Furthermore, in all outcome measures, a combined value of ARDS critical + severe cases were taken, which provided a more meaningful analysis (Table 4).

Primary Objectives:

28-day mortality- Of the 62 patients, there were 11 deaths (17.7%) in SG, whereas there were 4 deaths (8.2%) of the 49 patients in SOC. However, when analyzed by severity, the mortality of patients for ARDS critical + severe, was lower in SG- 11 out of 51 patients (21.6%) than in SOC- 4 out of 12 patients (33.3%). Although this did not achieve statistical significance, it does show a trend towards reduced mortality in the SG.

Number of ventilator days- A total of 25 patients in SG were placed on ventilators compared with 5 patients in SOC for the ARDS critical category. In SG patients, the median ventilator days was 7, whereas for SOC, the median was 9. The trend showed a reduction of ventilator days in SG, although statistical significance was not achieved due to the small sample size.

Three antivirals were used, hydroxychloroquine sulfate, lopinavir + ritonavir, and favipiravir, whereas remdesivir was not used due to a lack of availability. Clexane was used as per the guidelines and Actemra was given infrequently. The aim of presenting this information was to shed light on the clinical practices used during the first wave of the pandemic.

Conclusion

There were some limitations to our study, namely the retrospective study design, small sample size, unevenly matched groups, heterogenous steroids used and the ongoing nature of the pandemic. All of these resulted in non-standardized, modified treatment protocols based on individual physicians’ preferences. Many of the outcome measures could not achieve statistical significance, though there was a clear trend towards favorable outcomes from using steroids. There is adequate data to support the use of steroids in COVID-19 in large international trials, and our study presented us with results that favored the use of steroids. Our future studies will be aimed towards comparing treatment of COVID-19 patients during the first and subsequent waves of the pandemic. Due to much heterogeneity in the selection of steroids during the first wave, we hope to show the evolution of our treatment protocol in the subsequent waves of the pandemic.

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