Regional epidemic dynamics and Delta variant diversity resulted in varying rates of spread of Omicron-BA.1 in Mexico (preprint)

The Omicron subvariant BA.1 of SARS-CoV-2 was first detected in November 2021 and quickly spread worldwide, displacing the Delta variant. In Mexico, this subvariant began spreading during the first week of December 2021 and became dominant in the next three weeks, causing the fourth COVID-19 epidemiological surge in the country. Unlike previous SARS-CoV-2 variants, BA.1 did not acquire local substitutions nor exhibited a geographically distinct circulation pattern in Mexico. However, a regional difference in the speed of the replacement of the Delta variant was observed, as some northern states showed persistence of Delta lineages well into February 2022. Mexican states were divided into four regions (North, Central North, Central South, and Southeast) based on the lineage circulation before the dominance of BA.1 to study possible causes for this difference. For each region, the time to fixation of BA.1, the diversity of Delta sublineages in the weeks preceding BA.1 entry, the population density, and the level of virus circulation during the inter-wave interval were determined. An association between a faster Omicron spread and lower Delta diversity, as well as fewer COVID-19 cases during the Delta-BA.1.x inter-wave period, was observed. For example, the North region exhibited the slowest spread but had the highest diversity of Delta sublineages and the greatest number of inter-wave cases relative to the maximum amount of the virus circulating in the region, whereas the Southeast region showed the opposite. Viral diversity and the relative abundance of the virus in a particular area around the time of the introduction of a new lineage seem to have influenced the spread dynamics. Nonetheless, if there is a significant difference in the fitness of the variants or the time allowed for the competition is sufficient, it seems the fitter virus will eventually become dominant, as observed in the eventual dominance of the BA.1.x variant in Mexico. Impact statementThe surveillance of lineage circulation of SARS-CoV-2 has helped identify variants that have a transmission advantage and are of concern to public health and to track the virus dispersion accurately. However, many factors contributing to differences in lineage spread dynamics beyond the acquisition of specific mutations remain poorly understood. In this work, a description of BA.1 entry and dispersion within Mexico is presented, and which factors potentially affected the spread rates of the Omicron variant BA.1 among geographical regions in the country are analyzed, underlining the importance of population density, the proportion of active cases, and viral lineage diversity and identity before the entry of BA.1. Data summaryThis work was carried out using data shared through the GISAID initiative. All sequences and metadate are available through GISAID with the accession EPI_SET_220927gw, accession numbers and metadata are also reported in the supplemental material of this article. Epidemiological data was obtained though the Secretaria de Salud website (https://www.gob.mx/salud/documentos/datos-abiertos-152127),

Knowledge, attitudes, perceptions, and COVID-19 hesitancy in a large public university in Mexico City during the early vaccination rollout (preprint)

Background: Vaccination against COVID-19 is a primary tool for controlling the pandemic. However, the spread of vaccine hesitancy constitutes a significant threat to reverse progress in controlling transmissible diseases such as COVID-19. A previous Mexican survey conducted in 2012 showed that the adult population with more years of formal education and from higher socioeconomic levels was more likely to have incomplete vaccination schedules. Objective: To know the prevalence of COVID-19 vaccine hesitancy and associated factors among academics, students, and administrative personnel of a public university in Mexico City. Methods: We administered an online survey investigating sociodemographic aspects, knowledge, attitudes, practices, and acceptance/hesitancy regarding the COVID-19 vaccine. Using generalized linear Poisson models, we analyzed factors associated with vaccine hesitancy, defined as not intending to be vaccinated within the following six months or refusing vaccination. Results: During May and June 2021, we studied 840 people, prevalence of vaccine hesitancy was 6%. Hesitancy was significantly associated with fear of adverse effects, distrust of physician’s recommendations, lack of knowledge regarding handwashing, age younger than 40 years, refusal to use face masks, and not having received influenza vaccination during the two previous seasons.Conclusions. Vaccine hesitancy in this population is low. Furthermore, our results allowed us the identification of characteristics that can improve vaccine promotion.

Clinical and Virological Features of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Vaccinated and Unvaccinated Patients in Mexico City (preprint)

Background: Coronavirus disease 2019 (COVID-19) vaccines are very effective at protecting against severe disease and death. However, the impact of the vaccine used, viral variants, and host factors on disease severity in vaccinated individuals remain poorly understood. Here we compared COVID-19 clinical presentations and outcomes in vaccinated and unvaccinated patients in a tertiary hospital in Mexico City. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants were also determined to study their potential impact on disease severity. Methods: From March to September 2021, clinical and demographic characteristics were obtained from 1,014 individuals with a documented SARS-CoV-2 infection, and viral variants were identified in a subset of 386 patients. We compared three groups of patients: 1) unvaccinated, 2) partially vaccinated, and 3) fully vaccinated, stratifying by age groups (<30 years, 31-60 years, and > 61 years) on the clinical outcomes, and including in-hospital mortality. We fitted different multivariate statistical models to evaluate the impact of vaccination status, SARS-CoV-2 lineages, vaccine types, and clinical parameters. Results: 1,014 patients were included, with 11% being outpatients and 88% hospitalized. Most hospitalized patients were unvaccinated. In patients over 61 years old, mortality was significantly higher in unvaccinated compared to fully vaccinated individuals. In patients aged 31 to 60 years, vaccinated patients were more likely to be outpatients (46%) than unvaccinated individuals (6.1%). The percentage of critical patients over 61 years was higher in unvaccinated than vaccinated individuals (75% vs. 56%, p < 0.001). We found immune disease (OR: 3.12, 95% CI: 1.09-8.34, p = 0.02) and age above 61 years old (OR: 3.51, 95% CI: 2.3-5.2, p = 5.9e-10) as risk factors. While fully vaccination was found as the most protective factor against in-hospital death (OR: 0.25, 95% CI: 0.12-0.46, p = 2.89e-05). Conclusions: This study suggests that vaccination and particularly full vaccination is essential to reduce mortality in a comorbid population such as that of Mexico. When analyzing the presence of comorbidities and advanced ages as risk factors, complete vaccination was the most significant protective factor against death by COVID-19. We found no strong association between SARS-CoV-2 lineages or vaccine type and disease severity.

EVALUATION OF A RAPID ANTIGEN TEST FOR SARS-COV-2 IN SYMPTOMATIC PATIENTS AND THEIR CONTACTS: A MULTICENTER STUDY (preprint)

BACKGROUND Point-of-care rapid tests to identify SARS-CoV-2 can be of great help because, in principle, they allow decisions to be made at the site of care for treatment, or for the separation of cohorts avoiding cross-infection, especially in emergency situations. METHODS A cross sectional study in adults requesting care in Emergency Rooms (ER), or the outpatient clinics of referral hospitals for COVID-19, to define the diagnostic characteristics of a rapid antigen test for SARS-CoV-2 (the Abbott PanbioTM) having as a gold standard the RT-PCR for SARS-CoV-2. Health personnel in a routine situation within an active pandemic in several cities of Mexico performed the tests. RESULTS A total of 1,069 participants with a mean age of 47 years (SD 16 years), 47% with a self-reported comorbidity, and an overall prevalence of a positive RT-PCR test of 45%, were recruited from eight hospitals in Mexico. Overall sensitivity of the Panbio test was 54.4% (95%CI 51-57) with a positive likelihood ratio of 35.7, a negative likelihood ratio of 0.46 and a Receiver-Operating Characteristics curve area of 0.77. Positivity for the rapid test depended strongly on an estimate of the viral load (Cycle threshold of RT-PCR, Ct), and the days of symptoms. With a Ct 25, sensitivity of the rapid test was 0.82 (95%CI, 0.76-0.87). For patients during the first week of symptoms sensitivity was 69.6% (95%CI 66-73). On the other hand, specificity of the rapid test was above 97.8% in all groups. CONCLUSIONS The PanbioTM rapid antigen test for SARS-CoV-2 has a good specificity, but due to low and heterogeneous sensitivity in real life, a negative test in a person with suggestive symptoms at a time of community transmission of SARS-CoV-2 requires confirmation with RT-PCR, and after the first week of symptoms, sensitivity decreases considerably.

Dysbiosis and structural disruption of the respiratory microbiota in COVID-19 patients with severe and fatal outcomes (preprint)

COVID-19 outbreak has caused over 3 million deaths worldwide. Understanding disease pathology and the factors that drive severe and fatal clinical outcomes is of special relevance. Studying the role of the respiratory microbiota in COVID-19 is particularly important since it’s known that the respiratory microbiota interacts with the host immune system, contributing to clinical outcomes in chronic and acute respiratory diseases. Here, we characterized the microbiota in the respiratory tract of patients with mild, severe, or fatal COVID-19, and compared with healthy controls and patients with non-COVID-19-pneumonia. We comparatively studied the microbial composition, diversity, and microbiota structure across study groups and correlated the results with clinical data. We found differences in diversity and abundance of bacteria between groups, higher levels of dysbiosis in the respiratory microbiota of COVID-19 patients (regardless of severity level), differences in diversity structure among mild, severe, and fatal COVID-19, and the presence of specific bacteria that correlated with clinical variables associated with increased mortality risk. Our data suggest that host-related and environmental factors could be affecting the respiratory microbiota before SARS-CoV-2 infection, potentially compromising the immunological response of the host against disease and promoting secondary bacterial infections. For instance, the high levels of dysbiosis coupled with low microbial structural complexity in the respiratory microbiota of COVID-19 patients, possibly resulted from antibiotic uptake and comorbidities, could have consequences for the host and microbial community level. Altogether, our findings identify the respiratory microbiota as a potential factor associated with COVID-19 severity.

Emergence and spread of the potential variant of interest (VOI) B.1.1.519 predominantly present in Mexico. (preprint)

SARS-CoV-2 variants have emerged in late 2020 and there are at least three variants of concern (B.1.1.7, B.1.351, P1) reported by WHO. These variants have several substitutions in the Spike protein that affect receptor binding; they present increased transmissibility and may be associated with reduced vaccine effectiveness. In the present work, we are reporting the identification of a potential variant of interest harboring the mutations T478K, P681H, and T732A in the Spike protein, within the newly named lineage B.1.1.519, which rapidly outcompeted the preexisting variants in Mexico and has been the dominant virus in the country during the first trimester of 2021.

Hydroxychloroquine For Prophylaxis Of COVID-19 In Health Workers: A Randomized Clinical Trial. (preprint)

Health care workers are at high risk of being infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Our aim is to evaluate the efficacy and safety of hydroxychloroquine (HCQ) for prophylaxis of COVID19 in health personnel exposed to patients infected by SARS-COV-2. Methods: Double-blind randomized, placebo-controlled single center clinical trial. Included subjects were health care workers caring for severe COVD19 patients. Main outcome was time to symptomatic SARS-CoV2 infection. Results: 127 subjects with a confirmed baseline negative RT-PCR SARS-CoV2 test were included in the trial, 62 assigned to HCQ and 65 to placebo. One subject (1.6%) in the HCQ group and 6 (9,2%) subjects in the placebo group developed COVID-19. (Log Rank test p = 0.09). No severe COVID19 cases were observed. The study was suspended because of a refusal to participate and losses to follow up after several trials reported lack of effectiveness of hydroxychloroquine in hospitalized patients with COVID-19. Conclusion: Although the number of symptomatic infections in health personnel was lower in the HCQ group, the difference was not statistically significant. The trial is underpowered due to the failure to complete the estimated sample size.

Systemic and Neurologic Adverse Events Among 704,003 First-Dose Recipients of the Pfizer-Biontech (BNT162b2) mRNA COVID-19 Vaccine in Mexico (preprint)

​Background: The development of mRNA vaccines to prevent SARS-CoV-2 has been remarkably successful, with highly effective vaccines available less than one year after confirming the first case. Due to the global burden of COVID-19 on health systems, emergency approval was attained after clinical trials with relatively small sample sizes and short follow-up periods. Limited information exists about the incidence of adverse events following immunisation (AEFI), particularly neurologic ones. Here, we describe the neurologic AEFI reported by recipients of the BNT162b2 mRNA COVID-19 vaccine. Methods: We conducted a prospective observational cohort using de-identified information from a database of all systemic and neurologic AEFI reported to the Mexican Ministry of Health throughout a passive Epidemiological Surveillance System by first-dose vaccine recipients, from December 24, 2020 to February 12, 2021. The cut-off date for this data was February 18, 2021. We performed descriptive analyses on demographics, timing from vaccination to AEFI development, event duration, and current outcome.Findings: Nationwide, 704 003 first-doses were administered; 6536 AEFI were reported. Among those, 4258 (65·1%) had at least one neurologic manifestation. Non-serious neurologic AEFI occurred in 99·6%. Headache (62·2%), transient sensory symptoms (3·5%), and weakness (1%) were the most frequent. Thirty-three serious AEFI were reported, of which 17 (2·4/100 000 doses) were neurologic, seven seizures, four functional syndromes, three Guillain-Barré syndrome (GBS) cases, and two of acute transverse myelitis. All GBS cases were related to a gastrointestinal infection before vaccination, 3/7 seizure episodes were related to poor antiepileptic drug compliance, and 2/7 to anaphylactic reactions. At the time of this report, 16/17 cases of serious neurologic AEFI had been discharged with no observed deaths.Interpretation: Our data suggest that the BNT162b2 mRNA vaccine is effective and safe. Their individual and societal benefits outweigh the low-percentage of serious neurologic and non-neurologic AEFI.Funding: Consejo Nacional de Ciencia y Tecnología, México.Declaration of Interest: None to declareEthical Approval: The study was revised and approved by the Ethics and Research Committees of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Ref. NER-3667-2021) and the Mexican Ministry of Health.

Comparison of the clinical characteristics and mortality in ARDS due to COVID-19 versus ARDS due to Influenza A-H1N1pdm09 (preprint)

Importance Infection with the SARS-Cov-2 and Influenza A-H1N1 viruses is responsible for the first pandemics of the 21st century. Both of these viruses can cause severe pneumonia and acute respiratory distress syndrome (ARDS). The clinical differences and mortality associated with these two pandemic pneumonias in patients with ARDS are not well established Objective To compare case-fatality between ARDS-Covid-19 and ARDS-Influenza A (H1N1), adjusting for known prognostic risk factors. Design, Setting and Participants One hundred forty-seven patients with COVID-19 were compared with 94 with Influenza A-H1N1, all of these were admitted to the intensive care unit of the Referral Center for Respiratory Diseases and COVID-19 in Mexico City and fulfilled the criteria of ARDS. Results Patients arrived at the hospital after 9 days of symptoms. Influenza patients had more obesity, more use of Norepinephrine, and higher levels of lactic dehydrogenase and glucose, and fewer platelets and lower PaO 2 /FIO 2 . Crude mortality was higher in COVID than in influenza (39% vs. 22%; p = 0.005). In a Cox proportional hazard model, patients with a diagnosis of COVID-19 had a hazard ratio (HR) = 3.7; 95% Confidence Interval [CI] = 1.9-7.4, adjusted for age, gender, sequential organ failure assessment (SOFA) score, ventilatory ratio, and prone ventilation. In the fully adjusted model, the ventilatory ratio and the absence of prone-position ventilation were also predictors of mortality. CONCLUSION COVID-19 patients treated in an intensive care unit (ICU) had a 3.7 times higher risk of death than similar patients with Influenza A-H1N1, after adjusting for SOFA score and other relevant risk factors for mortality. Question Is the mortality of ARDS associated with Covid-19 greater than that of ARDS associated to influenza H1N1? Findings In a Cox proportional hazard model, patients with a diagnosis of COVID-19 had a hazard ratio (HR) = 3.7; 95% Confidence Interval [CI] = 1.9-7.4, adjusted for age, gender, sequential organ failure assessment (SOFA) score. Meaning COVID-19 patients treated in an intensive care unit (ICU) had a 3.7 times higher risk of death than similar patients with Influenza A-H1N1

HYDROXYCHLOROQUINE FOR THE TREATMENT OF SEVERE RESPIRATORY INFECTION BY COVID-19: A RANDOMIZED CONTROLLED TRIAL (preprint)

The novel coronavirus pandemic (COVID 19) represents a major public health problem due to its rapid spread and its ability to generate severe pneumonia. Thus, it is essential to find a treatment that reduces mortality. Our objective was to estimate whether treatment with 400 mg/day of Hydroxychloroquine for 10 days reduces in-hospital mortality in subjects with severe respiratory disease due to COVID 19 compared with placebo. Material and methods: A double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of Hydroxychloroquine for the treatment of severe disease by COVID 19 through an intention-to-treat analysis. Eligible for the study were adults aged more than 18 years with COVID-19 confirmed by RT-PCR and lung injury requiring hospitalization with or without mechanical ventilation. Primary outcome was 30-day mortality. Secondary outcomes: days of mechanical ventilation, days of hospitalization and cumulative incidence of serious adverse events. Results: A total of 214 patients with COVID 19 were recruited, randomized and analyzed. They were hypoxemic with a mean SpO2 of 65%{+/-}20, tachycardic (pulse rate 108{+/-}17 min 1) and tachypneic (32{+/-}10 min 1); 162 were under mechanical ventilation at randomization. Thirty-day mortality was similar in both groups (38% in Hydroxychloroquine vs. 41% in placebo, hazard ratio [HR] 0.88, 95% Confidence Interval [95%CI] 0.51 1.53). In the surviving participants, no significant difference was found in secondary outcomes. Conclusion: No beneficial effect or significant harm could be demonstrated in our randomized controlled trial including 214 patients, using relatively low doses of Hydroxychloroquine compared with placebo in hospitalized patients with severe COVID 19.

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials (preprint)

Background: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Results: Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I-square=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-square=0%; 4 trials; 307 patients). We identified no subgroup effects. Conclusions: We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Genomic analysis of early SARS-CoV-2 strains introduced in Mexico (preprint)

The COVID-19 pandemic has affected most countries in the world. Studying the evolution and transmission patterns in different countries is crucial to implement effective strategies for disease control and prevention. In this work, we present the full genome sequence for 17 SARS-CoV-2 isolates corresponding to the earliest sampled cases in Mexico. Global and local phylogenomics, coupled with mutational analysis, consistently revealed that these viral sequences are distributed within 2 known lineages, the SARS-CoV-2 lineage A/G, containing mostly sequences from North America, and the lineage B/S containing mainly sequences from Europe. Based on the exposure history of the cases and on the phylogenomic analysis, we characterized fourteen independent introduction events. Additionally, three cases with no travel history were identified. We found evidence that two of these cases represent local transmission cases occurring in Mexico during mid-March 2020, denoting the earliest events described in the country. Within this Mexican cluster, we also identified an H49Y amino acid change in the spike protein. This mutation is a homoplasy occurring independently through time and space, and may function as a molecular marker to follow on any further spread of these viral variants throughout the country. Our results depict the general picture of the SARS-CoV-2 variants introduced at the beginning of the outbreak in Mexico, setting the foundation for future surveillance efforts. This work is the result of the collaboration of five institutions into one research consortium: three public health institutes and two universities. From the beginning of this work, it was agreed that the experimental leader of each institution would share the first authorship. Those were the criteria followed to assign first co-first authorship in this manuscript. The order of the other authors was randomly assigned. IMPORTANCEUnderstanding the introduction, spread and establishment of SARS-CoV-2 within distinct human populations is crucial to implement effective control strategies as well as the evolution of the pandemics. In this work, we describe that the initial virus strains introduced in Mexico came from Europe and the United States and the virus was circulating locally in the country as early as mid-March. We also found evidence for early local transmission of strains having the mutation H49Y in the Spike protein, that could be further used as a molecular marker to follow viral spread within the country and the region.