CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19?
CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics.
WHAT IS NEW?: The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19.
ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.
FUTURE RECOMMENDATIONS: Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.
METHODS: This is a pilot and pragmatic randomized trial conducted at a university hospital in Malaysia. Women with singleton pregnancies planned for elective CS between 37+0 and 38+6 weeks gestation were randomly allocated into the intervention group, where they received two doses of IM dexamethasone 12 mg of 12 h apart, 24 h prior to surgery OR into the standard care, control group, and both groups received the normal routine antenatal care. The primary outcome measures were neonatal respiratory illnesses, NICU admission and length of stay.
RESULTS: A total of 189 patients were recruited, 93 women in the intervention group and 96 as controls. Between the steroid and control groups, the mean gestation at CS was similar, 266.1 ± 3.2 days (38 weeks) vs. 265.8 ± 4.0 days (37+6 weeks), p = 0.53. The mean birthweight of infants was 3.06 ± 0.41 kg vs. 3.04 ± 0.37 kg, p = 0.71. Infants with respiratory morbidities were primarily due to transient tachypnea of newborn (9.7% vs. 6.3%), and congenital pneumonia (1.1% vs. 3.1%) but none had respiratory distress syndrome. Only four infants required NICU admission (2.2% vs. 3.1%, p = 0.63). Their average length of stay was not statistically different; 3.5 ± 2.1 days vs. 5.7 ± 1.5 days, p = 0.27.
CONCLUSIONS: Elective CS at early term before 39 weeks was associated with a modest overall incidence of neonatal respiratory illness (10.1%) in this Asian population. Antenatal dexamethasone did not diminish infants needing respiratory support, NICU admission and length of stay.
METHODS: Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups.
RESULTS: A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47).
CONCLUSIONS: Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.
METHODS: This is a systematic review and a meta-analysis evaluating the evidence from clinical trials on the effect of colchicine and corticosteroids against COVID-19. In this review, we have systematically searched five databases [(PubMed, Embase, clinicaltrials.gov, ICTRP, CINAHL (EBSCO)]. Cochrane's data extraction sheet was used to collect the required information, and RevMan-5.4.1 was used to conduct the meta-analysis and to assess the risk of bias. The review was registered in Prospero (CRD42022299718).
RESULTS: The total number of included studies was 17, with 18,956 participants; the majority were male 12,001. Out of which, 8772 participants were on colchicine, 569 took methylprednisolone, and 64 patients received prednisolone. The meta-analysis has shown that colchicine had no significant effect on reducing the mortality rate among COVID-19 patients [OR 0.98(95% CI 0.90-1.08), p = .70), I2:1%)], corticosteroids have significantly reduced the mortality rates [OR 0.55 (95% CI 0.33-0.91), p = .02, I2:40]. Colchicine did not reduce the incidence of ICU admissions [OR 0.74 (95% CI 0.39-1.40), p = .35, I2:0%], while steroidal drugs significantly reduced the ICU admissions [OR 0.42 (95% CI 0.23-0.78), p = .005, I2:0%]. Unlike steroidal drugs [OR 0.53 (95% CI 0.30-0.95), p = .03, I2:61%], colchicine failed to reduce the need for mechanical ventilation [OR 0.73 (95% CI 0.48-1.10), p = .13, I2:76%]. Steroidal drugs significantly reduced the duration of hospitalization among COVID-19 patients [OR -0.50 (95% CI -0.79-0.21), p = .0007, I2:36%].
CONCLUSIONS: The use of colchicine did not significantly reduce the mortality rate, ICU admissions, and mechanical ventilation among COVID-19 patients. Conversely, corticosteroids significantly reduced the mortality rate, ICU admissions, mechanical ventilation, and hospitalization duration among COVID-19 patients.
METHODS: In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).
RESULTS: The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169.
CONCLUSION: AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.
METHODOLOGY: Pubmed, Medline, SPORTDiscus and Google scholar were searched from inception to 4th January 2021 for randomised controlled trials (RCTs) involving injection therapies (e.g. blood derivatives, corticosteroid, hyaluronic acid, botulinum toxin) for CSTI. The primary and secondary outcomes were pain and function, respectively, at (or nearest to) 6 months. Effect size (ES) was presented as standardised mean difference with 95% confidence interval (CI). Frequentist random effect NMA was used to generate the overall estimates, subgroup estimates (by region and measurement time point) and sensitivity analyses.
RESULTS: A total of 91 articles (87 RCTs; 5859 participants) involving upper limb (74%), lower limb (23%) and truncal/hip (3%) injuries were included. At all time points, prolotherapy had no statistically significant pain benefits over other therapies. This observation remained unchanged when tested under various assumptions and with exclusion of studies with high risk of bias. Although prolotherapy did not offer statistically significant functional improvement compared to most therapies, its ES was consistently better than non-injections and corticosteroid injection for both outcomes. At selected time points and for selected injuries, prolotherapy demonstrated potentially better pain improvement over placebo (<4 months: shoulder [ES 0.65; 95% CI 0.00 to 1.30]; 4-8 months: elbow [ES 0.91; 95% CI 0.12 to 1.70]; >8 months: shoulder [ES 2.08; 95% CI 1.49, to 2.68]). Injections generally produced greater ES when combined with non-injection therapy.
CONCLUSION: While clinical outcomes were generally comparable across types of injection therapy, prolotherapy may be used preferentially for selected conditions at selected times.
METHODS: Electronic databases and country-specific healthcare databases were searched to identify relevant studies/reports. The quality assessment of individual studies was conducted using the Newcastle-Ottawa Scale. Country-specific proportion of individuals with COVID-19 who developed ARDS and reported death were combined in a random-effect meta-analysis to give a pooled mortality estimate of ARDS.
RESULTS: The overall pooled mortality estimate among 10,815 ARDS cases in COVID-19 patients was 39% (95% CI: 23-56%). The pooled mortality estimate for China was 69% (95% CI: 67-72%). In Europe, the highest mortality estimate among COVID-19 patients with ARDS was reported in Poland (73%; 95% CI: 58-86%) while Germany had the lowest mortality estimate (13%; 95% CI: 2-29%) among COVID-19 patients with ARDS. The median crude mortality rate of COVID-19 patients with reported corticosteroid use was 28.0% (lower quartile: 13.9%; upper quartile: 53.6%).
CONCLUSIONS: The high mortality in COVID-19 associated ARDS necessitates a prompt and aggressive treatment strategy which includes corticosteroids. Most of the studies included no information on the dosing regimen of corticosteroid therapy, however, low-dose corticosteroid therapy or pulse corticosteroid therapy appears to have a beneficial role in the management of severely ill COVID-19 patients.
METHODS: This was a planned sub-study of patients with an ED diagnosis of AECOPD identified in the Asia, Australia and New Zealand Dyspnoea in Emergency Departments (AANZDEM) study. The AANZDEM was a prospective, interrupted time series cohort study conducted in 46 ED in Australia, New Zealand, Singapore, Hong Kong and Malaysia over three 72-h periods in May, August and October 2014. Primary outcomes were patient epidemiology, clinical features, treatment and outcomes (hospital length of stay (LOS) and mortality).
RESULTS: Forty-six ED participated. There were 415 patients with an ED primary diagnosis of AECOPD (13.6% of the overall cohort; 95% CI: 12.5-14.9%). Median age was 73 years, 60% males and 65% arrived by ambulance. Ninety-one percent had an existing COPD diagnosis. Eighty percent of patients received inhaled bronchodilators, 66% received systemic corticosteroids and 57% of those with pH < 7.30 were treated with non-invasive ventilation (NIV). Seventy-eight percent of patients were admitted to hospital, 7% to an intensive care unit. In-hospital mortality was 4% and median LOS was 4 days (95% CI: 2-7).
CONCLUSION: Patients treated in ED for AECOPD commonly arrive by ambulance, have a high admission rate and significant in-hospital mortality. Compliance with evidence-based treatments in ED is suboptimal affording an opportunity to improve care and potentially outcomes.
OBJECTIVES: This study aims to evaluate the prevalence and degree of topical corticosteroid phobia and its impact on treatment adherence in various dermatological conditions. Additionally, we explored the sources of information regarding topical corticosteroids.
MATERIALS AND METHODS: A cross-sectional study was conducted among 300 participants with topical corticosteroid usage experience. Topical corticosteroid phobia was assessed with the topical corticosteroid phobia (TOPICOP) scale, and treatment adherence was measured with the Elaboration d'un outil d'evaluation de l'observance des traitements medicamenteux (ECOB) score. Information sources regarding topical corticosteroids were identified, and their level of trust was assessed. The data were collected via questionnaires in three languages, namely English, Malay and Mandarin.
RESULTS: The study found that topical corticosteroid phobia was prevalent, with 98% of participants expressing a certain degree of phobia. The mean global TOPICOP score was 32.7 ± 6.7%. The mean score of each domain was 27.1 ± 17.2% for knowledge and belief, 35.7 ± 23.8% for fears and 40.8 ± 25.8% for behaviour. Patients/caregivers who have eczema, highly educated, severe disease, low tolerability to symptoms, previous adverse effects with topical corticosteroids and tend to traditional/non-steroidal alternative therapy usage had a significant association with topical corticosteroid phobia (p<0.05). Dermatologists were the most common and trusted source of information on topical corticosteroids.
CONCLUSIONS: This study highlights the widespread topical corticosteroid phobia in dermatological practice. Dermatologists should take the lead in combating steroid phobia and provide patients with public awareness regarding topical corticosteroids to improve treatment adherence and therapeutic outcomes.