Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. METHODS: We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. FINDINGS: The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI -0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference -0·5% [95% BCI -2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group. INTERPRETATION: In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19. FUNDING: UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.

Murine typhus mistaken for COVID-19 in a young man.

Fever is a widely recognised presenting symptom of COVID-19. Consequently, other febrile illnesses may be difficult to distinguish from COVID-19-leading to delays in diagnosis and treatment. One such illness is murine typhus, a fleaborne illness with worldwide distribution caused by Rickettsia typhi It often presents with fever, headache and myalgia, all of which have been commonly reported with COVID-19. Although the disease is usually mild with a good prognosis, there have been reports of severe illness and death. I present a case of murine typhus in a young male who had 2 weeks of headaches and daily fevers during the COVID-19 pandemic. He was ultimately tested for murine typhus when his occupation as a dog trainer was queried, and he experienced resolution of symptoms after treatment with doxycycline. During this pandemic, clinicians must be vigilant of other febrile illnesses whose symptoms overlap with COVID-19.

Pemphigus and COVID-19: Critical overview of management with a focus on treatment choice.

COVID-19 is a serious multisystem disease caused by severe acute respiratory syndrome coronavirus 2. Due to the COVID-19 crisis, that still keeps its impacts worldwide, numerous scheduled medical activities have been postponed and this interruption has a potential to modify the management of many cutaneous conditions including pemphigus. This narrative review aims to discuss the management of pemphigus in the era of COVID-19, considering the necessity to balance suitable pemphigus treatment with minimal risk of COVID-19-related mortality and morbidity. The data on the effect of treatments used for pemphigus on COVID-19 are limited. However, the evidence to manage patients properly is evolving and our knowledge is updated. Current expert recommendations include that patients with pemphigus should be informed clearly to avoid mismanagement and they should be monitored regularly for symptoms of COVID-19. Patients with mild disease can be managed with topical or intralesional corticosteroids, dapsone, or doxycycline. Systemic corticosteroids should be tapered to the lowest effective dose during the pandemic. Prednis(ol)one ≤10 mg/d can be continued in patients with COVID-19 while prednis(ol)one >10 mg/d may be reduced considering the activity of the disease. Conventional immunosuppressive therapies should only be discontinued in confirmed cases of COVID-19. Postponing rituximab treatment should be considered on a case by case basis. Intravenous immunoglobulin is not likely to increase the risk of infection and may be considered a safe option in patients with COVID-19. Given the psychological burden brought by COVID 19, online or face-to-face psychological support programs should be considered.

Doxycycline treatment of high-risk COVID-19-positive patients with comorbid pulmonary disease.

Infection with novel SARS-CoV-2 carries significant morbidity and mortality in patients with pulmonary compromise, such as lung cancer, autoimmune disease, and pneumonia. For early stages of mild to moderate disease, care is entirely supportive.Antiviral drugs such as remdesivir may be of some benefit but are reserved for severe cases given limited availability and potential toxicity. Repurposing of safer, established medications that may have antiviral activity is a possible approach for treatment of earlier-stage disease. Tetracycline and its derivatives (e.g. doxycycline and minocycline) are nontraditional antibiotics with a well-established safety profile, potential efficacy against viral pathogens such as dengue fever and chikungunya, and may regulate pathways important in initial infection, replication, and systemic response to SARS-CoV-2. We present a series of four high-risk, symptomatic, COVID-19+ patients, with known pulmonary disease, treated with doxycycline with subsequent rapid clinical improvement. No safety issues were noted with use of doxycycline.Doxycycline is an attractive candidate as a repurposed drug in the treatment of COVID-19 infection, with an established safety profile, strong preclinical rationale, and compelling initial clinical experience described here.The reviews of this paper are available via the supplemental material section.

A novel approach to managing COVID-19 patients; results of lopinavir plus doxycycline cohort.

This manuscript aims to present a treatment algorithm we applied to manage COVID-19 patients admitted to our hospital. During the study period, 2043 patients with suspected COVID-19 were admitted to the emergency department. Molecular tests indicated that 475 of these patients tested positive for COVID-19. We administered hydroxychloroquine plus doxycycline to mild cases (isolated at home) for 3 days and lopinavir plus doxycycline to moderate and severe cases (hospitalized) for 5 days. The overall case fatality rate was 4.2% (20/475).