Interventions for palliative symptom control in COVID-19 patients.

BACKGROUND: Individuals dying of coronavirus disease 2019 (COVID-19) may experience distressing symptoms such as breathlessness or delirium. Palliative symptom management can alleviate symptoms and improve the quality of life of patients. Various treatment options such as opioids or breathing techniques have been discussed for use in COVID-19 patients. However, guidance on symptom management of COVID-19 patients in palliative care has often been derived from clinical experiences and guidelines for the treatment of patients with other illnesses. An understanding of the effectiveness of pharmacological and non-pharmacological palliative interventions to manage specific symptoms of COVID-19 patients is required. OBJECTIVES: To assess the efficacy and safety of pharmacological and non-pharmacological interventions for palliative symptom control in individuals with COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), medRxiv); Web of Science Core Collection (Science Citation Index Expanded, Emerging Sources); CINAHL; WHO COVID-19 Global literature on coronavirus disease; and COAP Living Evidence on COVID-19 to identify completed and ongoing studies without language restrictions until 23 March 2021. We screened the reference lists of relevant review articles and current treatment guidelines for further literature. SELECTION CRITERIA: We followed standard Cochrane methodology as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We included studies evaluating palliative symptom management for individuals with a confirmed diagnosis of COVID-19 receiving interventions for palliative symptom control, with no restrictions regarding comorbidities, age, gender, or ethnicity. Interventions comprised pharmacological as well as non-pharmacological treatment (e.g. acupressure, physical therapy, relaxation, or breathing techniques). We searched for the following types of studies: randomized controlled trials (RCT), quasi-RCTs, controlled clinical trials, controlled before-after studies, interrupted time series (with comparison group), prospective cohort studies, retrospective cohort studies, (nested) case-control studies, and cross-sectional studies. We searched for studies comparing pharmacological and non-pharmacological interventions for palliative symptom control with standard care. We excluded studies evaluating palliative interventions for symptoms caused by other terminal illnesses. If studies enrolled populations with or exposed to multiple diseases, we would only include these if the authors provided subgroup data for individuals with COVID-19. We excluded studies investigating interventions for symptom control in a curative setting, for example patients receiving life-prolonging therapies such as invasive ventilation.  DATA COLLECTION AND ANALYSIS: We used a modified version of the Newcastle Ottawa Scale for non-randomized studies of interventions (NRSIs) to assess bias in the included studies. We included the following outcomes: symptom relief (primary outcome); quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We rated the certainty of evidence using the GRADE approach.  As meta-analysis was not possible, we used tabulation to synthesize the studies and histograms to display the outcomes.  MAIN RESULTS: Overall, we identified four uncontrolled retrospective cohort studies investigating pharmacological interventions for palliative symptom control in hospitalized patients and patients in nursing homes. None of the studies included a comparator. We rated the risk of bias high across all studies. We rated the certainty of the evidence as very low for the primary outcome symptom relief, downgrading mainly for high risk of bias due to confounding and unblinded outcome assessors. Pharmacological interventions for palliative symptom control We identified four uncontrolled retrospective cohort studies (five references) investigating pharmacological interventions for palliative symptom control. Two references used the same register to form their cohorts, and study investigators confirmed a partial overlap of participants. We therefore do not know the exact number of participants, but individual reports included 61 to 2105 participants. Participants received multimodal pharmacological interventions: opioids, neuroleptics, anticholinergics, and benzodiazepines for relieving dyspnea (breathlessness), delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms.  Primary outcome: symptom relief All identified studies reported this outcome. For all symptoms (dyspnea, delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms), a majority of interventions were rated as completely or partially effective by outcome assessors (treating clinicians or nursing staff). Interventions used in the studies were opioids, neuroleptics, anticholinergics, and benzodiazepines.  We are very uncertain about the effect of pharmacological interventions on symptom relief (very low-certainty evidence). The initial rating of the certainty of evidence was low since we only identified uncontrolled NRSIs. Our main reason for downgrading the certainty of evidence was high risk of bias due to confounding and unblinded outcome assessors. We therefore did not find evidence to confidently support or refute whether pharmacological interventions may be effective for palliative symptom relief in COVID-19 patients. Secondary outcomes We planned to include the following outcomes: quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We did not find any data for these outcomes, or any other information on the efficacy and safety of used interventions. Non-pharmacological interventions for palliative symptom control None of the identified studies used non-pharmacological interventions for palliative symptom control. AUTHORS' CONCLUSIONS: We found very low certainty evidence for the efficacy of pharmacological interventions for palliative symptom relief in COVID-19 patients. We found no evidence on the safety of pharmacological interventions or efficacy and safety of non-pharmacological interventions for palliative symptom control in COVID-19 patients. The evidence presented here has no specific implications for palliative symptom control in COVID-19 patients because we cannot draw any conclusions about the effectiveness or safety based on the identified evidence. More evidence is needed to guide clinicians, nursing staff, and caregivers when treating symptoms of COVID-19 patients at the end of life. Specifically, future studies ought to investigate palliative symptom control in prospectively registered studies, using an active-controlled setting, assess patient-reported outcomes, and clearly define interventions. The publication of the results of ongoing studies will necessitate an update of this review. The conclusions of an updated review could differ from those of the present review and may allow for a better judgement regarding pharmacological and non-pharmacological interventions for palliative symptom control in COVID-19 patients.

Colchicine for the treatment of COVID-19.

BACKGROUND: The development of severe coronavirus disease 2019 (COVID-19) and poor clinical outcomes are associated with hyperinflammation and a complex dysregulation of the immune response. Colchicine is an anti-inflammatory medicine and is thought to improve disease outcomes in COVID-19 through a wide range of anti-inflammatory mechanisms. Patients and healthcare systems need more and better treatment options for COVID-19 and a thorough understanding of the current body of evidence. OBJECTIVES: To assess the effectiveness and safety of Colchicine as a treatment option for COVID-19 in comparison to an active comparator, placebo, or standard care alone in any setting, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (comprising CENTRAL, MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv), Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index), and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 21 May 2021. SELECTION CRITERIA: We included randomised controlled trials evaluating colchicine for the treatment of people with COVID-19, irrespective of disease severity, age, sex, or ethnicity. We excluded studies investigating the prophylactic effects of colchicine for people without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but at high risk of SARS-CoV-2 exposure. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. We used the Cochrane risk of bias tool (ROB 2) to assess bias in included studies and GRADE to rate the certainty of evidence for the following prioritised outcome categories considering people with moderate or severe COVID-19: all-cause mortality, worsening and improvement of clinical status, quality of life, adverse events, and serious adverse events and for people with asymptomatic infection or mild disease: all-cause mortality, admission to hospital or death, symptom resolution, duration to symptom resolution, quality of life, adverse events, serious adverse events. MAIN RESULTS: We included three RCTs with 11,525 hospitalised participants (8002 male) and one RCT with 4488 (2067 male) non-hospitalised participants. Mean age of people treated in hospital was about 64 years, and was 55 years in the study with non-hospitalised participants. Further, we identified 17 ongoing studies and 11 studies completed or terminated, but without published results. Colchicine plus standard care versus standard care (plus/minus placebo) Treatment of hospitalised people with moderate to severe COVID-19 All-cause mortality: colchicine plus standard care probably results in little to no difference in all-cause mortality up to 28 days compared to standard care alone (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.93 to 1.08; 2 RCTs, 11,445 participants; moderate-certainty evidence). Worsening of clinical status: colchicine plus standard care probably results in little to no difference in worsening of clinical status assessed as new need for invasive mechanical ventilation or death compared to standard care alone (RR 1.02, 95% CI 0.96 to 1.09; 2 RCTs, 10,916 participants; moderate-certainty evidence). Improvement of clinical status: colchicine plus standard care probably results in little to no difference in improvement of clinical status, assessed as number of participants discharged alive up to day 28 without clinical deterioration or death compared to standard care alone (RR 0.99, 95% CI 0.96 to 1.01; 1 RCT, 11,340 participants; moderate-certainty evidence). Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is very uncertain about the effect of colchicine on adverse events compared to placebo (RR 1.00, 95% CI 0.56 to 1.78; 1 RCT, 72 participants; very low-certainty evidence). Serious adverse events: the evidence is very uncertain about the effect of colchicine plus standard care on serious adverse events compared to standard care alone (0 events observed in 1 RCT of 105 participants; very low-certainty evidence). Treatment of non-hospitalised people with asymptomatic SARS-CoV-2 infection or mild COVID-19 All-cause mortality: the evidence is uncertain about the effect of colchicine on all-cause mortality at 28 days (Peto odds ratio (OR) 0.57, 95% CI 0.20 to 1.62; 1 RCT, 4488 participants; low-certainty evidence). Admission to hospital or death within 28 days: colchicine probably slightly reduces the need for hospitalisation or death within 28 days compared to placebo (RR 0.80, 95% CI 0.62 to 1.03; 1 RCT, 4488 participants; moderate-certainty evidence). Symptom resolution: we identified no studies reporting this outcome. Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is uncertain about the effect of colchicine on adverse events compared to placebo . Results are from one RCT reporting treatment-related events only in 4412 participants (low-certainty evidence). Serious adverse events: colchicine probably slightly reduces serious adverse events (RR 0.78, 95% CI 0.61 to 1.00; 1 RCT, 4412 participants; moderate-certainty evidence). Colchicine versus another active treatment (e.g. corticosteroids, anti-viral drugs, monoclonal antibodies) No studies evaluated this comparison. Different formulations, doses, or schedules of colchicine No studies assessed this. AUTHORS' CONCLUSIONS: Based on the current evidence, in people hospitalised with moderate to severe COVID-19 the use of colchicine probably has little to no influence on mortality or clinical progression in comparison to placebo or standard care alone. We do not know whether colchicine increases the risk of (serious) adverse events. We are uncertain about the evidence of the effect of colchicine on all-cause mortality for people with asymptomatic infection or mild disease. However, colchicine probably results in a slight reduction of hospital admissions or deaths within 28 days, and the rate of serious adverse events compared with placebo. None of the studies reported data on quality of life or compared the benefits and harms of colchicine versus other drugs, or different dosages of colchicine. We identified 17 ongoing and 11 completed but not published RCTs, which we expect to incorporate in future versions of this review as their results become available. Editorial note: due to the living approach of this work, we monitor newly published results of RCTs on colchicine on a weekly basis and will update the review when the evidence or our certainty in the evidence changes.

Vitamin D supplementation for the treatment of COVID-19: a living systematic review.

BACKGROUND: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required. OBJECTIVES: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events. MAIN RESULTS: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7,  whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically.