Prevalence and impact of SARS-CoV-2 infection on maternal and infant health in African populations: protocol of a multicentre prospective cohort study (MA-CoV project).

INTRODUCTION: Pregnant women are currently considered a vulnerable population to SARS-CoV-2 infection, with increased risk of severe COVID-19, preterm birth and maternal mortality. There is, however, a paucity of data on the burden of maternal SARS-CoV-2 infection in sub-Saharan countries. The objective of this study is to determine the prevalence and health effects of maternal SARS-CoV-2 infection in selected sites from Gabon and Mozambique. METHODS AND ANALYSIS: MA-CoV (MAternal CoVid) is an observational, multicentre prospective cohort study where 1000 pregnant women (500 per country) will be enrolled at the antenatal clinic visits. Participants will undergo monthly follow-up at each antenatal care visit, delivery and postpartum visit. The primary study outcome is the prevalence of SARS-CoV-2 infection during pregnancy. The clinical presentation of COVID-19 in pregnancy will also be characterised, and incidence of infection during pregnancy will be evaluated, as well as the risk factors of maternal and neonatal morbidity and mortality associated with SARS-CoV-2 infection and the risk of mother to child transmission of SARS-CoV-2. SARS-CoV-2 infection screening will be performed through PCR diagnosis. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the Comité National d'Éthique pour la Recherche au Gabon, Comité Nacional de Bioética para Saúde de Moçambique and the Ethics Committee of the Hospital Clinic of Barcelona (Spain). Project results will be presented to all stakeholders and published in open access journals. TRIAL REGISTRATION NUMBER: NCT05303168.

Persistent Immunity against SARS-CoV-2 in Individuals with Oncohematological Diseases Who Underwent Autologous or Allogeneic Stem Cell Transplantation after Vaccination.

The high morbimortality due to SARS-CoV-2 infection in oncohematological diseases (OHD) and hematopoietic stem cell transplant (HSCT) recipients in the pre-vaccine era has made vaccination a priority in this group. After HSCT, the immune responses against common vaccines such as tetanus, varicella, rubella, and polio may be lost. However, the loss of immunity developed by COVID-19 vaccination after HSCT has not been completely defined. In this study, both humoral and cellular immunity against SARS-CoV-2 were analyzed in 29 individuals with OHD who were vaccinated before receiving allogeneic (n = 11) or autologous (n = 18) HSCT. All participants had low but protective levels of neutralizing IgGs against SARS-CoV-2 after HSCT despite B-cell lymphopenia and immaturity. Although antibody-dependent cellular cytotoxicity was impaired, direct cellular cytotoxicity was similar to healthy donors in participants with autologous-HSCT, in contrast to individuals with allogeneic-HSCT, which severely deteriorated. No significant changes were observed in the immune response before and after HSCT. During follow-up, all reported post-HSCT SARS-CoV-2 infections were mild. This data emphasizes that COVID-19 vaccination is effective, necessary, and safe for individuals with OHD and also supports the persistence of some degree of immune protection after HSCT, at least in the short term, when patients cannot yet be revaccinated.

SARS-CoV-2 seropositivity and HIV viral load among Mozambican pregnant women.

INTRODUCTION: Prevalence estimates of SARS-CoV-2 infection in Africa are limited, particularly among pregnant women and in those living with HIV. This study assessed the seroprevalence of SARS-CoV-2 antibodies among Mozambican HIV-infected pregnant women during the first year of the pandemic, before COVID-19 vaccines were deployed in the country. SETTING: The study was conducted in Manhiça district, a semi-rural area in southern Mozambique. METHODS: A prospective cohort study including pregnant women living with HIV was carried out from November 2019 to June 2021. Women were enrolled at the first antenatal care (ANC) clinic visit and followed until post-partum. HIV viral load (HIV-VL) and IgM/IgG antibodies against SARS-CoV-2 were determined in blood samples at first ANC clinic visit and at delivery. Associations between SARS-CoV-2 serostatus and maternal characteristics at enrolment were analysed. RESULTS: A total of 397 women were enrolled. SARS-CoV-2 IgG/IgM antibodies were detected in 7.1% of women at enrolment and in 8.5% of women at delivery. Overall, SARS-CoV-2 antibodies were detected in 45 (11.3%; 95%CI 8.4-14.9%) women during the study period; the first seropositive sample was identified in September 2020. Having undetectable HIV-VL was associated with seropositivity of SARS-CoV-2 IgG/IgM (OR 3.35 [1.10-11.29]; p=0.039). CONCLUSION: Seroprevalence of SARS-CoV-2 antibodies in this cohort of Mozambican unvaccinated pregnant women was similar to reported global estimates of approximately 10% in pregnancy for 2021. Findings also suggest that pregnant women with high HIV- viral load may have an impaired immune response against SARS-CoV-2 and might need to be carefully managed in case of COVID-19.

Perceptions of COVID-19 Maternal Vaccination among Pregnant Women and Healthcare Workers and Factors That Influence Vaccine Acceptance: A Cross-Sectional Study in Barcelona, Spain.

COVID-19 is associated with poor maternal and pregnancy outcomes. COVID-19 vaccination is recommended in Spain, yet vaccination rates in pregnancy are suboptimal. This study investigates the perceptions of pregnant women and healthcare workers (HCW) regarding COVID-19 vaccination. A web-based cross-sectional quantitative study was conducted in 2021-2022 among 302 pregnant women and 309 HCWs in the Catalan public health system. Most pregnant women (83%) and HCWs (86%) were aware of COVID-19 maternal vaccines. The recommendation of the COVID-19 vaccination by an HCW was identified as the greatest facilitator for maternal vaccine uptake, while the fear of harming the foetus was the most significant barrier reported for rejecting vaccination. HCWs recognised they received limited information and training about COVID-19 vaccination in pregnancy, which hindered them from providing informed recommendations. This study highlights that information and education on COVID-19 vaccines to pregnant women and health professionals are pivotal to ensuring informed decision-making and increasing vaccine uptake.

"Maternal Vaccination Greatly Depends on Your Trust in the Healthcare System": A Qualitative Study on the Acceptability of Maternal Vaccines among Pregnant Women and Healthcare Workers in Barcelona, Spain.

The World Health Organization (WHO) identified vaccine hesitancy as one of the top 10 threats to global health in 2019. Health promotion and education have been seen to improve knowledge and uptake of vaccinations in pregnancy. This qualitative study was conducted based on phenomenology, a methodological approach to understand first-hand experiences, and grounded theory, an inductive approach to analyse data, where theoretical generalisations emerge. Data were collected through semi-structured interviews with pregnant women attending antenatal care services and healthcare workers (HCWs) in Barcelona, Spain. Interviews were audio-recorded, transcribed, and coded, and notes were taken. Inductive thematic analysis was performed, and data were manually coded. Pertussis was reported as the most trusted vaccine among pregnant women due to its long-standing background as a recommended vaccine in pregnancy. The influenza vaccine was regarded as less important since it was perceived to cause mild disease. The COVID-19 vaccine was the least trustworthy for pregnant women due to uncertainties about effectiveness, health effects in the mid- and long-term, the fast development of the vaccine mRNA technology, and the perceptions of limited data on vaccine safety. However, the necessity to be vaccinated was justified by pregnant women due to the exceptional circumstances of the COVID-19 pandemic. The recommendations provided by HCW and the established relationship between the HCW, particularly midwives, and pregnant women were the main factors affecting decision-making. The role of mass media was perceived as key to helping provide reliable messages about the need for vaccines during pregnancy. Overall, vaccines administered during pregnancy were perceived as great tools associated with better health and improved quality of life. Pregnancy was envisioned as a vulnerable period in women's lives that required risk-benefits assessments for decision-making about maternal vaccinations. A holistic approach involving the community and society was considered crucial for health education regarding maternal vaccines in support of the work conducted by HCWs.

Strong Humoral but Not Cellular Immune Responses against SARS-CoV-2 in Individuals with Oncohematological Disease Who Were Treated with Rituximab before Receiving a Vaccine Booster.

The humoral immune response developed after receiving the full vaccination schedule against COVID-19 is impaired in individuals who received anti-CD20 therapy 6-9 months before vaccination. However, there is little information about the cellular immune responses elicited in these individuals. In this study, we analyzed the humoral and cellular immune responses in 18 individuals with hematological disease who received the last dose of rituximab 13.8 months (IQR 9.4-19) before the booster dose. One month after receiving the booster dose, the seroconversion rate in the rituximab-treated cohort increased from 83.3% to 88.9% and titers of specific IgGs against SARS-CoV-2 increased 1.53-fold (p = 0.0098), while the levels of neutralizing antibodies increased 3.03-fold (p = 0.0381). However, the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) from rituximab-treated individuals remained unchanged, and both antibody-dependent cellular cytotoxicity (ADCC) and direct cellular cytotoxicity (CDD) were reduced 1.7-fold (p = 0.0047) and 2.0-fold (p = 0.0086), respectively, in comparison with healthy donors. Breakthrough infections rate was higher in our cohort of rituximab-treated individuals (33.33%), although most of the infected patients (83.4%) developed a mild form of COVID-19. In conclusion, our findings confirm a benefit in the humoral, but not in the cellular, immune response in rituximab-treated individuals after receiving a booster dose of an mRNA-based vaccine against COVID-19.

The epidemiology of severe malaria at Manhiça District Hospital, Mozambique: a retrospective analysis of 20 years of malaria admissions surveillance data.

BACKGROUND: Most malaria burden estimates rely on modelling infection prevalence to case incidence data, with insufficient attention having been paid to the changing clinical presentation of severe disease and its relationship with changing transmission intensity. We present 20 years of longitudinal surveillance data to contribute to the understanding of the relationship between malaria transmission and the burden and clinical presentation of severe malaria and to inform policy. METHODS: This retrospective analysis of clinical surveillance hospital data included all children younger than 15 years admitted with malaria to Manhiça District Hospital (MDH), Mozambique, from July 1, 1997, to June 30, 2017. Case fatality ratios (CFRs) were calculated as the number of patients who died having a specific diagnosis or syndrome divided by the total number of patients with known outcome admitted with that diagnosis or syndrome. FINDINGS: Over the study period, 32 138 children were admitted to MDH with a malaria diagnosis. Malaria accounted for a large proportion of admissions, ranging from 4083 (76·9%) of 5307 admissions in 2000-01 to 706 (27·5%) of 2568 admissions in 2010-11. Since 2000-02, the absolute and relative number of malaria admissions and deaths presented a decreasing trend. The age pattern of patients with malaria shifted to older ages with a median age of 1·7 years (IQR 0·9-3·0) in 1997-2006 and 2·6 years (IQR 1·3-4·4) in 2006-17, although most malaria deaths (60-88% in 2009-17) still occurred in children younger than 5 years. The clinical presentation of severe malaria changed, with an increase in cerebral malaria and a decrease in severe anaemia and respiratory distress, leading to similar yearly cases for the three syndromes. CFRs for severe malaria fluctuated between 1·1% (2 of 186 in 2014-15) and 7·2% (11 of 152 in 2010-11), varying by severe malaria syndrome (3·3% [70 of 2105] for severe anaemia, 5·1% [191 of 3777] for respiratory distress, and 14·8% [72 of 487] for cerebral malaria). Overall malaria CFRs (1·8% [543 of 30 163]) did not vary by age group. INTERPRETATION: Despite the unprecedented scale up of malaria control tools, malaria still represented around 30-40% of paediatric hospital admissions in 2006-17. The age shift towards older children was not accompanied by an increase in severe malaria or deaths; however, control programmes should consider adapting their high-risk target groups to include older children. Malaria remains a leading cause of disease and health-care system use and the massive unfinished malaria control agenda warrants intensified efforts. FUNDING: Spanish Agency for International Cooperation and Development.

Minimally Invasive Tissue Sampling Findings in 12 Patients With Coronavirus Disease 2019.

BACKGROUND: Minimally invasive tissue sampling (MITS), a postmortem procedure that uses core needle biopsy samples and does not require opening the body, may be a valid alternative to complete autopsy (CA) in highly infectious diseases such as coronavirus disease-19 (COVID-19). This study aimed to (1) compare the performance of MITS and CA in a series of COVID-19 deaths and (2) evaluate the safety of the procedure. METHODS: From October 2020 to February 2021, MITS was conducted in 12 adults who tested positive before death for COVID-19, in a standard, well-ventilated autopsy room, where personnel used reinforced personal protective equipment. In 9 cases, a CA was performed after MITS. A thorough histological evaluation was conducted, and the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: The diagnoses provided by MITS and CA matched almost perfectly. In 9 patients, COVID-19 was in the chain of events leading to death, being responsible for diffuse alveolar damage and mononuclear T-cell inflammatory response in the lungs. No specific COVID-19 features were identified. Three deaths were not related to COVID-19. All personnel involved in MITS repeatedly tested negative for COVID-19. SARS-CoV-2 was identified by RT-PCR and immunohistochemistry in the MITS samples, particularly in the lungs. CONCLUSIONS: MITS is useful for evaluating COVID-19-related deaths in settings where a CA is not feasible. The results of this simplified and safer technique are comparable to those of CA.

Minimally Invasive Tissue Sampling as an Alternative to Complete Diagnostic Autopsies in the Context of Epidemic Outbreaks and Pandemics: The Example of Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Infectious diseases' outbreak investigation requires, by definition, conducting a thorough epidemiological assessment while simultaneously obtaining biological samples for an adequate screening of potential responsible pathogens. Complete autopsies remain the gold-standard approach for cause-of-death evaluation and characterization of emerging diseases. However, for highly transmissible infections with a significant associated lethality, such as COVID-19, complete autopsies are seldom performed due to biosafety challenges, especially in low-resource settings. Minimally invasive tissue sampling (MITS) is a validated new approach based on obtaining postmortem samples from key organs and body fluids, a procedure that does not require advanced biosafety measures or a special autopsy room. METHODS: We aimed to review the use of MITS or similar procedures for outbreak investigation up to 27 March 2021 and their performance for evaluating COVID-19 deaths. RESULTS: After a literature review, we analyzed in detail the results of 20 studies conducted at international sites, whereby 216 COVID-19-related deaths were investigated. MITS provided a general and more granular understanding of the pathophysiological changes secondary to the infection and high-quality samples where the extent and degree of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related damage could be evaluated. CONCLUSIONS: MITS is a useful addition in the investigation and surveillance of infections occurring in outbreaks or epidemics. Its less invasive nature makes the tool more acceptable and feasible and reduces the risk of procedure-associated contagion, using basic biosafety measures. Standardized approaches protocolizing which samples should be collected-and under which exact biosafety measures-are necessary to facilitate and expand its use globally.

Acceptability of Clinical Trials on COVID-19 during Pregnancy among Pregnant Women and Healthcare Providers: A Qualitative Study.

Participation of pregnant women in clinical trials entails challenges mainly related to concerns about the risks for fetuses. We undertook a qualitative study from June to October 2020 to assess the acceptability of participating in COVID-19 clinical trials among pregnant women in Spain. Phenomenology and grounded theory were used as methodological approaches. Semi-structured interviews were conducted with 24 pregnant women and six healthcare providers. Women were unsure if pregnancy was a risk factor to acquire the infection or to develop severe disease and expressed the limited information they had received, which led to uncertainties and emotional suffering. They had concerns regarding participation in clinical trials on COVID-19, regardless of the drug under study. Healthcare providers alluded to the importance of involving pregnant women's relatives at the recruitment visit of the clinical trial. These findings may be useful to facilitate pregnant women's participation in clinical trials.

Minimally Invasive Autopsy Practice in COVID-19 Cases: Biosafety and Findings.

Postmortem studies are crucial for providing insight into emergent diseases. However, a complete autopsy is frequently not feasible in highly transmissible diseases due to biohazard challenges. Minimally invasive autopsy (MIA) is a needle-based approach aimed at collecting samples of key organs without opening the body, which may be a valid alternative in these cases. We aimed to: (a) provide biosafety guidelines for conducting MIAs in COVID-19 cases, (b) compare the performance of MIA versus complete autopsy, and (c) evaluate the safety of the procedure. Between October and December 2020, MIAs were conducted in six deceased patients with PCR-confirmed COVID-19, in a basic autopsy room, with reinforced personal protective equipment. Samples from the lungs and key organs were successfully obtained in all cases. A complete autopsy was performed on the same body immediately after the MIA. The diagnoses of the MIA matched those of the complete autopsy. In four patients, COVID-19 was the main cause of death, being responsible for the different stages of diffuse alveolar damage. No COVID-19 infection was detected in the personnel performing the MIAs or complete autopsies. In conclusion, MIA might be a feasible, adequate and safe alternative for cause of death investigation in COVID-19 cases.

Hydroxychloroquine efficacy and safety in preventing SARS-CoV-2 infection and COVID-19 disease severity during pregnancy (COVID-Preg): a structured summary of a study protocol for a randomised placebo controlled trial.

OBJECTIVES: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. TRIAL DESIGN: Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. PARTICIPANTS: Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. • Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact* of a SARS-CoV-2 confirmed or suspected case in the past 14 days • More than 12 weeks of gestation (dated by ultrasonography) • Agreement to deliver in the study hospitals Exclusion criteria • Known hypersensitivity to HCQ or other 4-amonoquinoline compounds • History of retinopathy of any aetiology • Concomitant use of digoxin, cyclosporine, cimetidine • Known liver disease • Clinical history of cardiac pathology including known long QT syndrome • Unable to cooperate with the requirements of the study • Participating in other intervention studies • Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: • SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) • SARS-CoV-2 PCR negative pregnant women in contact* with a SARS-CoV-2-infected confirmed or suspected case (n=514). *The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. INTERVENTION AND COMPARATOR: Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). MAIN OUTCOMES: The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). RANDOMISATION: Allocation of participants to study arms will be done centrally by the trial's Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. BLINDING (MASKING): Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. TRIAL STATUS: Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). TRIAL REGISTRATION: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562 , retrospectively registered 1 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in 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.