Clinical efficacy of hydroxychloroquine in patients with Covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Tang W, Cao Z, Han M et al 

BMJ 2020, May 14; 369:m1844   doi: https://doi.org/10.1136/bmj.m1844

The objective of this study was to assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with Covid-19. This was a multicentre, open-label, randomised controlled trial set in 16 government designated Covid-19 treatment centres in China, from February 11-29, 2020.

A total of 150 patients admitted to hospital with laboratory confirmed Covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Hydroxychloroquine was administrated at a loading dose of 1,200mg daily for three days followed by a maintenance dose of 800mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).

Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, was analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3 to 41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% CI -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.

This study found that the administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate Covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

Compassionate remdesivir treatment of severe Covid-19 pneumonia in ICU and non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status

Antinori S, Cossu MV, Ridolfo AL et al

Pharmacol Res 2020 May 11:104899. doi: 10.1016/j.phrs.2020.104899. [Epub ahead of print]

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥ 18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤ 94% in air or a National Early Warning Score 2 of ≥ 4. The primary outcome was the change in clinical status based on a seven-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). 

The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in an infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25 to 44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalised and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalised. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). 

The data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

Use of renin-angiotensin-aldosterone system inhibitors and risk of Covid-19 requiring admission to hospital: a case-population study

de Abajo FJ, Rodríguez-Martín S, Lerma V et al

Lancet Online First: May 14, 2020   doi: https://doi.org/10.1016/S0140-6736(20)31030-8

Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe Covid-19; however, epidemiological evidence is lacking. 

In this case-population study, the authors consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of Covid-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted on March 1-24, 2020. As a reference group, they randomly sampled 10 patients per case, individually matched for age, sex, region, and date of admission to hospital (month and day; index date), from a Spanish primary healthcare database, in its last available year (2018). They extracted information on comorbidities and prescriptions up to the month before index date (ie. current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with Covid-19. To minimise confounding by indication, the main analysis focused on assessing the association between Covid-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. Odds ratios (ORs) and 95% CIs, were calculated and adjusted for age, sex and cardiovascular comorbidities and risk factors. 

Data for 1,139 cases and 11,390 population controls was collected. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62 to 2·41) and risk factors (1·46, 1·23 to 1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for Covid-19 requiring admission to hospital of 0·94 (95% CI 0·77 to 1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64 to 1·00) or angiotensin-receptor blockers (1·10, 0·88 to 1·37). Sex, age and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and Covid-19 requiring admission to hospital, whereas a decreased risk of Covid-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34 to 0·80). The adjusted ORs were similar across severity degrees of Covid-19.

RAAS inhibitors do not increase the risk of Covid-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of Covid-19.

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Verdoni L, Mazza A, Gervasoni A et al 

Lancet Online First: May 13, 2020   doi: https://doi.org/10.1016/S0140-6736(20)31103-X

The Bergamo province, which was extensively affected by the Covid-19 epidemic, is a natural observatory of virus manifestations in the general population. In April 2020, the authors recorded an outbreak of Kawasaki disease; they aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the Covid-19 epidemic.

All patients diagnosed with a Kawasaki-like disease at the centre in the past five years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the Covid-19 epidemic. Kawasaki-like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.

Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between January 1, 2015, and February 17, 2020. Group 2 included 10 patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between February 18 and April 20, 2020; eight of 10 were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1 versus group 2, 0·3 versus 10 per month), mean age (3·0 versus 7·5 years), cardiac involvement (two of 19 versus six of 10), KDSS (zero of 19 versus five of 10), MAS (zero of 19 versus five of 10), and need for adjunctive steroid treatment (three of 19 versus eight of 10; all p < 0·01).

In the month prior to start of study a 30-fold increased incidence of Kawasaki-like disease was found. Children diagnosed after the Covid-19 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The Covid-19 epidemic was associated with high incidence of a severe form of Kawasaki disease. The authors expect a similar outbreak of Kawasaki-like disease in countries involved in the Covid-19 epidemic.