Predictive factors of clinical assays on hydroxychloroquine for COVID-19 mortality during the first year of the pandemic: A meta-synthesis

AJOL : Background: The COVID-19 pandemic led to a violent debate about the efficacy of a repurposed drug hydroxychloroquine (HCQ) and a new broad-spectrum antiviral (remdesivir) and about randomized controlled trials (RCTs) and observational studies. To understand conflicting results in the literature, we performed a metasynthesis to determine whether intrinsic qualitative criteria within studies may predict apparent efficacy or ineffectiveness of HCQ and remdesivir. Methodology: Predictive criteria were identified through critical review of studies assessing HCQ and remdesivir for COVID-19 mortality from March to November 2020. Multiple correspondence analysis, comparative metaanalysis, and predictive value were used to explore and identify criteria associated with study outcomes. Results: Among the 61 included studies, potential conflict of interest, detailed therapeutic protocol, toxic treatment (overdose or use in contraindicated patients), known centers and doctors, and private data computing company were the most predictive criteria of the direction of effect of the studies. All 18 observational studies evaluating HCQ and reporting detailed therapeutic protocol without conflict of interest were Pro. Potential conflict of interest was a perfect predictor for remdesivir efficacy. RCTs were associated with HCQ inefficacy and potential conflict of interest. The most predictive criteria were validated and allowed perfect classification of 10 additional studies.Conclusion: In therapeutic trials on COVID-19, the major biases predicting the conclusions are not methodology nor data analysis, but conflict of interest and absence of medical expertise. The thorough search for declared or undeclared and direct or indirect conflict of interest, and medical expertise should be included in the quality criteria for the evaluation of future therapeutic studies in COVID-19 and beyond. A new checklist evaluating not only methodology but also conflict of interest and medical expertise is proposed

Épidémiologie des Coronavirus 229E dans les infections respiratoires

Déclaration de liens d’intérêts: Les auteurs déclarent ne pas avoir de liens d’intérêts.

18F-FDG brain PET hypometabolism in patients with long COVID.

PURPOSE: In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as "long COVID." We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection. METHODS: PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients' characteristics and functional complaints. RESULTS: In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001). CONCLUSION: This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients' symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders?

PURPOSE: Several brain complications of SARS-CoV-2 infection have been reported. It has been moreover speculated that this neurotropism could potentially cause a delayed outbreak of neuropsychiatric and neurodegenerative diseases of neuroinflammatory origin. A propagation mechanism has been proposed across the cribriform plate of the ethmoid bone, from the nose to the olfactory epithelium, and possibly afterward to other limbic structures, and deeper parts of the brain including the brainstem. METHODS: Review of clinical examination, and whole-brain voxel-based analysis of 18F-FDG PET metabolism in comparison with healthy subjects (p voxel < 0.001, p-cluster < 0.05, uncorrected), of two patients with confirmed diagnosis of SARS-CoV-2 explored at the post-viral stage of the disease. RESULTS: Hypometabolism of the olfactory/rectus gyrus was found on the two patients, especially one with 4-week prolonged anosmia. Additional hypometabolisms were found within amygdala, hippocampus, parahippocampus, cingulate cortex, pre-/post-central gyrus, thalamus/hypothalamus, cerebellum, pons, and medulla in the other patient who complained of delayed onset of a painful syndrome. CONCLUSION: These preliminary findings reinforce the hypotheses of SARS-CoV-2 neurotropism through the olfactory bulb and the possible extension of this impairment to other brain structures. 18F-FDG PET hypometabolism could constitute a cerebral quantitative biomarker of this involvement. Post-viral cohort studies are required to specify the exact relationship between such hypometabolisms and the possible persistent disorders, especially involving cognitive or emotion disturbances, residual respiratory symptoms, or painful complaints.

Evaluating the serological status of COVID-19 patients using an indirect immunofluorescent assay, France.

An indirect in-house immunofluorescent assay was developed in order to assess the serological status of COVID-19 patients in Marseille, France. Performance of IFA was compared to a commercial ELISA IgG kit. We tested 888 RT-qPCR-confirmed COVID-19 patients (1302 serum samples) and 350 controls including 200 sera collected before the pandemic, 64 sera known to be associated with nonspecific serological interference, 36 sera from non-coronavirus pneumonia and 50 sera from patient with other common coronavirus to elicit false-positive serology. Incorporating an inactivated clinical SARS-CoV-2 isolate as the antigen, the specificity of the assay was measured as 100% for IgA titre ≥ 1:200, 98.6% for IgM titre ≥ 1:200 and 96.3% for IgG titre ≥ 1:100 after testing a series of negative controls. IFA presented substantial agreement (86%) with ELISA EUROIMMUN SARS-CoV-2 IgG kit (Cohen's Kappa = 0.61). The presence of antibodies was then measured at 3% before a 5-day evolution up to 47% after more than 15 days of evolution. We observed that the rates of seropositivity as well as the titre of specific antibodies were both significantly higher in patients with a poor clinical outcome than in patients with a favourable evolution. These data, which have to be integrated into the ongoing understanding of the immunological phase of the infection, suggest that detection anti-SARS-CoV-2 antibodies is useful as a marker associated with COVID-19 severity. The IFA assay reported here is useful for monitoring SARS-CoV-2 exposure at the individual and population levels.

Critical reappraisal of remdesivir investigational trials in COVID-19.

During disease outbreaks, the pharmaceutical industry generally puts a lot of effort into promoting clinical trials studying their new drugs. We review evidence of the ten most recent reports on remdesivir. We conclude that it is far too premature to identify remdesivir as a curative or life-saving intervention during the COVID-19 pandemic.

What could explain the late emergence of COVID-19 in Africa?

At the end of November 2019, a novel coronavirus responsible for respiratory tract infections emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in southern Europe and America in spring 2020. Many studies predicted an epidemic in Africa similar to that currently seen in Europe and the USA. However, reported data do not confirm these predictions. Several hypotheses that could explain the later emergence and spread of the coronavirus disease 2019 (COVID-19) pandemic in African countries are being discussed, including the lack of health-care infrastructure capable of clinically detecting and confirming COVID-19 cases, the implementation of social distancing and hygiene, international air traffic flows, the climate, the relatively young and rural population, the genetic polymorphism of the angiotensin-converting enzyme 2 receptor, cross-immunity and the use of antimalarial drugs.

Nullane salus extra ecclesiam.

Randomized clinical trials are not relevant for infectious disease outbreaks due to a new pathogen, for which public health decisions have to be made urgently. An approach based on group comparisons, in silico, may provide valuable results in a reasonably short period of time for a negligible amount of money.

Caractéristiques épidémiologiques et cliniques de 136 infections à coronavirus OC43 diagnostiquées dans des hôpitaux universitaires de 2017 à 2019

Introduction Les coronavirus humains OC43 (HCoV-OC43) sont des agents communs, notamment chez les jeunes enfants, d’infections des voies respiratoires hautes et parfois basses. Ils appartiennent au genre Betacoronavirus et sont génétiquement très différents d’autres HCoV incluant les HCoV-229E et -NL63. De plus, il a été décrit que l’épidémiologie et la symptomatologie associées à leurs infections différent de celle des autres HCoV. Depuis 2017, nous réalisons au laboratoire de microbiologie et virologie clinique de notre centre hospitalo-universitaire (CHU) l’identification des HCoVs. Nous décrivons ici les caractéristiques épidémiologiques et cliniques des infections à HCoV-OC43 diagnostiquées au cours des trois dernières années. Matériels et méthodes Les prélèvements respiratoires testés pour la présence du HCoV-OC43 ont été ceux adressés de janvier 2017 à décembre 2019 pour recherche de virus respiratoire au laboratoire de diagnostic microbiologique et virologique de notre CHU. Le diagnostic de HCoV-OC43 a été réalisé par PCR en temps réel avec les trousses FTD Respiratory pathogens 21 (Fast Track Diagnosis, Luxembourg) ou Biofire Filmarray Respiratory panel 2 plus (Biomérieux, France). Résultats Un total de 16 357 prélèvements respiratoires de 11 976 patients ont été testés au cours de la période de l’étude (3 ans). Un HCoV a été détecté dans 554 prélèvements (3,4 %) obtenus de 483 patients (4 %). HCoV-OC43 a été détecté dans 157 prélèvements (1,0 % ;29 % de ceux HCoV-positifs) de 136 patients (1,1 % ;28 % des patients HCoV-positifs) : 66 femmes et 70 hommes (sex-ratio H :F=1,1). L’âge moyen des patients HCoV-OC43-positifs était de 36±34 ans (min.–max. : 0–97 ans) avec respectivement 26 (19 %), 26 (19 %), 7 (5 %), 4 (3 %), 9 (7 %), 23 (17 %), 17 (12 %) et 24 (18 %) patients de<1, 1–5, 5–15, 15–25, 25–45, 45–65, 65–75 et>75 ans. Deux pics d’incidence ont été observés en octobre 2017 lorsqu’ils ont représenté 83 % des infections à HCoV et en septembre-octobre 2018 (81 %). Douze patients HCoV-OC43-positifs (9 %) ont été admis en réanimation. Trois (2,2 %) sont décédés : une femme de 95 ans institutionnalisée ayant présenté une pneumopathie sans co-infection, un nourrisson de 10 mois ayant présenté hypoxie d’étiologie inconnue, et un homme de 77 ans ayant présenté une pneumopathie sur cancer pulmonaire et co-infecté par Streptococcus pneumoniae. Conclusion Cette large série de cas montre que les HCoV-OC43 sont dans notre CHU une cause non négligeable d’infections respiratoires touchant particulièrement les âges extrêmes et pour lesquelles il n’existe pas actuellement de médicament actif approuvé. Ces résultats justifient d’inclure systématiquement dans le diagnostic des infections respiratoires le dépistage et l’identification des HCoV-OC43 qui restent des virus négligés. Ceci permettra de mieux caractériser l’épidémiologie, la symptomatologie, les co-infections et la mortalité associés à leurs infections.

Remdesivir investigational trials in COVID-19: a critical reappraisal.

During outbreak of emerging disease, the most important aim is to discover an effective drug to save life. Consequently, a lot of effort are generally made by the industry to promote clinical trials with new drugs. Here we review evidence of the 8 most recent reports including 3 randomized controlled trials on the clinical efficacy of remdesivir in treating COVID-19 patient. We conclude that it is far too premature to identify remdesivir as a curative or life-saving intervention.

Clinical efficacy of chloroquine derivatives in COVID-19 infection: comparative meta-analysis between the big data and the real world.

In the context of the current coronavirus disease 2019 (COVID-19) pandemic, we conducted a meta-analysis on the effects of chloroquine derivatives in patients, based on unpublished and published reports available publicly on the internet as of 27 May 2020. The keywords 'hydroxychloroquine', 'chloroquine', 'coronavirus', 'COVID-19' and 'SARS-Cov-2' were used in the PubMed, Google Scholar and Google search engines without any restrictions as to date or language. Twenty studies were identified involving 105 040 patients (19 270 treated patients) from nine countries (Brazil, China, France, Iran, Saudi Arabia, South Korea, Spain and the USA). Big data observational studies were associated with conflict of interest, lack of treatment dosage and duration, and absence of favourable outcome. Clinical studies were associated with favourable outcomes and details on therapy. Among clinical studies, three of four randomized controlled trials reported a significant favourable effect. Among clinical studies, a significant favourable summary effect was observed for duration of cough (OR 0.19, p 0.00003), duration of fever (OR 0.11, p 0.039), clinical cure (OR 0.21, p 0.0495), death (OR 0.32, p 4.1 × 10-6) and viral shedding (OR 0.43, p 0.031). A trend for a favourable effect was noted for the outcome 'death and/or intensive care unit transfer' (OR 0.29, p 0.069) with a point estimate remarkably similar to that observed for death (∼0.3). In conclusion, a meta-analysis of publicly available clinical reports demonstrates that chloroquine derivatives are effective to improve clinical and virological outcomes, but, more importantly, they reduce mortality by a factor of 3 in patients with COVID-19. Big data are lacking basic treatment definitions and are linked to conflict of interest. The retraction of the only big data study associated with a significantly deleterious effect the day after (June 5, 2020) the acceptance of the present work (June 4, 2020) confirms the relevance of this work.

Influence of conflicts of interest on public positions in the COVID-19 era, the case of Gilead Sciences.

Funding and gifts from the pharmaceutical industry have an influence on the decisions made by physicians and medical experts. In the context of the coronavirus disease 2019 epidemic, several treatments are available to treat patients infected with the virus. Some are protected by patents, such as remdesivir, others0020stare not, such as hydroxychloroquine. We wanted to observe the possible correlation between the fact, for an academic doctor in infectious diseases, of having benefited from funding by Gilead Sciences, producer of remdesivir, and the public positions taken by this doctor towards hydroxychloroquine. Our results show a correlation (Spearman test, p = 0.017) between the amount received from the Gilead Sciences company and public opposition to the use of hydroxychloroquine in France. This should open up the debate on the role of the interest links of doctors with pharmaceutical companies in the medical and scientific public debate.