Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE).

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Travel-related health events and their risk factors in HIV-infected sub-Saharan migrants living in France and visiting their native country: The ANRS VIHVO cohort study.

BACKGROUND: Literature on health events in HIV-infected travellers is scarce, particularly in sub-Saharan African (SSA) migrants. METHODS: We investigated health events in HIV-infected SSA migrants living in France during and after travel to their native country. All had a pre-travel plasma viral load (pVL) below 200 copies/mL and were on stable combined antiretroviral therapy (cART). Logistic regression models were used to assess the risk factors for at least one adverse health event or febrile event. RESULTS: Among 264 HIV migrants, pre-travel median CD4 count was 439/mm3 and 27 migrants (6%) experienced a low-level viremia between 50 and 200 copies/mL. One hundred (38%) experienced at least one event (13 experienced two events). The most common events were gastrointestinal, including diarrhoea (n = 29, 26%), respiratory events (n = 20, 18%), and malaria (n = 17, 15%; 1 death). In multivariable analysis, a pre-travel low-level viremia and a lack of pre-travel medical advice significantly increased the risk for any event (OR 4.31, 95% CI, 1.41-13.1; and OR 3.62, 95% CI, 1.38-9.47; respectively). A lack of pre-travel advice significantly increased the risk for febrile event. CONCLUSIONS: Early and tailored counselling on pre-travel medical advice regarding diarrhoea and vector-borne diseases prophylactic measures in HIV-infected SSA migrants should be emphasised before travel to Africa.

Early complicated schistosomiasis in a returning traveller: Key contribution of new molecular diagnostic methods.

Early schistosomiasis poses a serious diagnostic challenge, because current standard diagnostic techniques based on serology and egg microscopy lack sensitivity at the initial presentation. We report spinal cord neuroschistosomiasis in a traveller developing 6 weeks after exposure. The diagnosis was confirmed by Schistosoma mansoni-targeted real-time PCR in blood and cerebrospinal fluid, before the results of conventional methods became positive. Molecular assays represent a paradigm shift for the difficult diagnosis of early schistosomiasis and related complications.

Strongyloidiasis in a young French woman raises concern about possible ongoing autochthonous transmission in Spain.

Strongyloidiasis is one of the most common geohelminth infections in tropical and subtropical areas. Accurate diagnosis remains challenging, leading to an overall underestimation of strongyloidiasis prevalence. The possibility of ongoing autochthonous transmission in some temperate areas and especially in southern Europe is still debated, and data supporting this hypothesis are scarce. The case of a young French woman, who had travelled frequently to Spain and had acquired Strongyloides stercoralis infection as revealed by gastrointestinal symptoms and hypereosinophilia, is reported here. Physicians should keep in mind the risk of being infected in some areas of southern Europe, even if low, in order to avoid the life-threatening manifestations of strongyloidiasis favoured by pathological or therapeutic immunosuppression.

Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013.

Artesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of <7 g/dL, and 1 required transfusion. Despite the high incidence of PADH, the resulting anemia remained mild in 85% of cases. This reassuring result confirms the safety and therapeutic benefit of artesunate.

Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report.

BACKGROUND: Parenteral artesunate is recommended as first-line therapy for severe and complicated malaria. Although its efficacy has been proven, long-term safety profile is still under evaluation. Several cases of delayed haemolytic anaemia occurred after initial clinical improvement and resolution of parasitaemia in non-immune travellers and children living in endemic areas. Reports have generated concern that this phenomenon might be related to the treatment itself, either by direct toxicity or immune-related mechanism. This is a report of the first case of autoimmune haemolytic anaemia following treatment of severe malaria initially managed with parenteral artesunate with strong indication for drug-immune related mechanism. CASE: A 17-year old Ivoirian female travelling in France presented with fever, headache and abdominal pain seven days after her arrival. Physical examination was indicative of septic shock while blood analysis showed normal haemoglobin level, but profound thrombocytopaenia and hyperlactataemia. Blood smear analysis showed Plasmodium falciparum infection with a parasitaemia of 0.8%. Severe malaria was diagnosed according to the WHO criteria. The patient was initially managed with artemether/lumefantrine combination and then parenteral artesunate for 48 hours. Empiric antibiotic course was also initiated with ceftriaxone, metronidazole, gentamycin, and then piperacillin and ciprofloxacin. At day 14, haemoglobin dropped to 4.6 g/dL with biologic features indicative of haemolysis (LDH 658 U/L, haptoglobin<0.15 g/L). At that time, parasitaemia was negative and other infections or hereditary disorders were excluded, while Coombs' direct antiglobulin test was positive for IgG and C3d. Antinuclear antibodies were absent. Further investigations evidenced drug-induced antibodies related to artesunate. It was concluded a drug-mediated autoimmune haemolytic anaemia. A corticosteroids regimen was initiated at 1 mg/kg/day. Outcome was favourable and corticosteroids were progressively tapered during two months. At present the patient's condition remains stable without recurrence of haemolytic anaemia. CONCLUSION: This is the first case of delayed haemolytic anaemia related to artesunate with a strong indication for drug-immune related mechanism. Further research is warranted to better characterize this plausible cause of post-treatment haemolysis following parenteral artesunate administration in severe malaria patients.

Primary dengue fever associated with hemophagocytic syndrome: a report of three imported cases, Bordeaux, France.

The dengue virus is responsible for a wide range of symptoms that can be classified into two distinct syndromes: classical dengue fever and severe dengue fever. Among the complicating forms, hemophagocytic syndrome (HPS) has been previously reported in case series of patients with secondary dengue fever outside of endemic settings. Of note, the occurrence of HPS has not yet been included among the criteria for defining severe dengue fever. We herein present three patients with HPS related to confirmed primary dengue virus infection. Clinicians should therefore consider hemophagocytosis as a complication during severe dengue infection in naïve patients.

Immunogenicity and tolerability of yellow fever vaccination in 23 French HIV-infected patients.

BACKGROUND: Vaccination of asymptomatic human immunodeficiency virus (HIV)-infected patients with a CD4 cell count ≥ 200/mm³ is strongly suggested prior to travel to a region where yellow fever (YF) is endemic. However, few data describing YF vaccination in such patients are available. METHODS: In this retrospective observational study of 23 HIV-infected patients, YF antibody titers, CD4 cell counts, and viral loads were measured before and after vaccination. Serologies were performed retrospectively on samples that had been stored as part of routine hospital procedures. RESULTS: Ninety-three percent of patients (13/14) with no baseline immunity, seroconverted after vaccination. Immunogenicity appeared slowly; only 2 of the 5 patients tested within 5 weeks of vaccination had seroconverted. A booster effect was noted in 3 of the 9 patients with baseline immunogenicity. Finally, due to unawareness of his HIV status, one patient was vaccinated and was found later to have a CD4 cell count < 200/mm³.The YF vaccine was well tolerated and no serious adverse events were reported. The impact of vaccination on immunologic and viral parameters was variable. Both decreases (n = 7) and increases (n = 5) in CD4 cell counts were recorded. Viral loads became undetectable in 2 patients and doubled or became positive in 3 patients. CONCLUSIONS: Yellow fever vaccination was safe and effective in a large majority of this cohort of stable, HIV-infected patients.

Quinine-resistant malaria in traveler returning from Senegal, 2007.

We describe clinical and parasitologic features of in vivo and in vitro Plasmodium falciparum resistance to quinine in a nonimmune traveler who returned to France from Senegal in 2007 with severe imported malaria. Clinical quinine failure was associated with a 50% inhibitory concentration of 829 nmol/L. Increased vigilance is required during treatment follow-up.

Malaria prevention behaviour and risk awareness in French adult travellers.

Travellers from Europe to tropical areas risk acquiring malaria against which they have no immunity. The objective of this study was to assess malaria protection measures in European travellers as a function of the risk of infection with malaria. This questionnaire-based, retrospective study evaluated 13,017 French adults. 3066 travellers to malaria-endemic countries were identified and data collected on duration and purpose of stay, knowledge of malaria, use of mechanical protection measures and chemoprophylaxis. Complete data on protection measures were available for 2225 travellers to malaria risk countries. Mechanical protection was used by 1735/2225 of travellers (94.9% of travellers to high-risk areas and 80.4% of travellers to low-risk areas). Appropriate chemoprophylaxis use rates were 47.6% for high-risk areas versus 9.5% for low-risk areas. Chemoprophylaxis compliance was low, even in the case of travellers to high risk areas (18.2%). Many travellers (38%) were unaware that malaria was potentially fatal. The only variables significantly associated with compliant use of appropriate chemoprophylaxis were awareness that malaria was serious (odds-ratio: 2.03; p=0.033) and receiving malaria information from a physician (odds-ratio: 3.01; p=0.042). Use of malaria chemoprophylaxis is very inadequate. Education campaigns are needed to improve the use of chemoprophylaxis and thus minimise the risk of acquiring malaria.

Factors associated with persistence of arthralgia among Chikungunya virus-infected travellers: report of 42 French cases.

BACKGROUND: In 2005-2006, a major epidemic of CHIKV infection occurred in the Islands of the south-western Indian Ocean, and longstanding manifestations seemed to be more frequent than described before. OBJECTIVES: To describe the frequency and related factors of late clinical manifestations of CHIKV infection among imported cases living in Aquitaine area, France. STUDY DESIGN: All patients recruited through the travel clinic and tropical medicine unit of the University Hospital Centre of Bordeaux with possible CHIKV infection were prospectively recorded, and confirmed cases of CHIKV infection were interviewed 2 years after infection. Factors associated with the persistence of symptoms were determined by multivariate logistic regression. RESULTS: Among the 29 cases followed, 17 still suffered from arthralgia 2 years after infection, and most of them had never recovered from the initial phase of the condition. The risk of persistent arthralgia tended to be higher among subjects with low educational level, subjects infected in the Reunion Island, and when initial phase lasted 30 days or more and was characterised by a severe pain. CONCLUSIONS: Consistent with previous studies, our findings showed worsened late manifestations among patients returning from Indian Ocean area. Persistence of symptoms tended to be linked with clinical burden during the acute phase, which can be informative for early recognition and management of patients at risk for developing persistent rheumatic symptoms. Cryoglobulins failed to be identified in seronegative patients with invalidating dengue-like syndrome.

Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies.

BACKGROUND: Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood. CASE PRESENTATION: We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection. CONCLUSIONS: Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.