Early warning system using primary healthcare data in the post-COVID-19-pandemic era: Brazil nationwide case-study (preprint)

BackgroundSyndromic surveillance utilising primary health care (PHC) data is a valuable tool for early outbreak detection, as demonstrated in the potential to identify COVID-19 outbreaks. However, the potential of such an early warning system in the post-COVID-19 era remains largely unexplored. MethodsWe analysed PHC encounter counts due to respiratory complaints registered in the Brazilian database of the Universal Health System between January and July 2023. We applied EARS (variation C1-C2-C3) and EVI to estimate the weekly thresholds. An alarm was determined when the number of encounters exceeded the week-specific threshold. We used data on hospitalisation due to respiratory disease to classify weeks in which the number of cases surpassed predetermined thresholds as anomalies. We compared EARS and EVIs efficacy in anticipating anomalies. FindingsA total of 119 anomalies were identified across 116 immediate regions during the study period. The EARS-C2 presented the highest early alarm rate, with 81/119 (68%) early alarms, and C1 the lowest, with 71 (60%) early alarms. The lowest true positivity was the EARS-C1 118/1354 (8.7%) and the highest EARS-C3 99/856 (11.6%). ConclusionRoutinely collected PHC data can be successfully used to detect respiratory disease outbreaks in Brazil. Syndromic surveillance enhances timeliness in surveillance strategies, albeit with lower specificity. A combined approach with other strategies is essential to strengthen accuracy, offering a proactive and effective public health response against future outbreaks.

Vaccine coverage and effectiveness against laboratory-confirmed symptomatic and severe Covid-19 in indigenous people in Brazil: a cohort study (preprint)

Background Indigenous people have historically suffered devastating impacts from epidemics and continue to have lower access to healthcare and be especially vulnerable to respiratory infectious. We estimated the coverage and effectiveness of Covid-19 vaccines against laboratory-confirmed Covid-19 cases among indigenous people in Brazil.Methods We linked nationwide Covid-19 vaccination data with flu-like surveillance records and studied a cohort of vaccinated indigenous people aged ≥ 5 years between 18th Jan 2021 and 1st Mar 2022. We considered individuals unexposed from the date they received the first dose of vaccine until the 13th day of vaccination, partially vaccinated from the 14th day after the first dose until the 13th day after receiving the second dose, and fully vaccinated onwards. We estimated the Covid-19 vaccination coverage and used Poisson regression to calculate the relative risks (RR) and vaccine effectiveness (VE) of CoronaVac, ChAdOx1, and BNT162b2 against Covid-19 laboratory-confirmed cases incidence, mortality, hospitalisation, and hospital-progression to Intensive Care Unit (ICU) or death. VE was estimated as (1-RR)*100, comparing unexposed to partially or fully vaccinated.Results By 1st Mar 2022, 48·7% (35·0–62·3) of eligible indigenous people vs 74·8% (57·9–91·8) overall Brazilians had been fully vaccinated for Covid-19. VE for the three Covid-19 vaccines combined was 53% (95%CI:44–60%) for symptomatic cases, 53% (95%CI:-56-86%) for mortality and 41% (95%CI:-35-75%) for hospitalisation. Among hospitalised patients, VE was 87% (95%CI:27–98%) for progression to ICU and 96% (95%CI: 90–99%) for death.Conclusions Lower coverage but similar Covid-19 VE among indigenous people than overall Brazilians suggest the need to expand access, timely vaccination, and urgently offer booster doses to achieve a great level of protection among this group.

Prevalence and risk factors for long COVID after mild disease: a longitudinal study with a symptomatic control group. (preprint)

Background There is limited data on the prevalence and risk factors for long COVID, with a shortage of prospective studies with appropriate control groups and adequate sample size. We therefore performed a prospective study to determine the prevalence and risk factors for long COVID. Methods We recruited patients age [≥] 15 years who were clinically suspected of having acute SARS-CoV-2 infection from September 2020 to April 2021. Nasopharyngeal swabs were collected for RT-PCR 3-5 days post symptom onset. Clinical and sociodemographic characteristics were collected using structured questionnaires from persons positive and negative for SARS-COV-2. Follow-up was performed by telephone interview to assess early outcomes and persistent symptoms. For COVID-19 cases, 5D-3L EuroQol questionnaire was used to assess the impact of symptoms on quality of life. Results We followed 814 participants (412 COVD-19 positive and 402 COVID-19 negative persons) of whom the majority (741 / 814) had mild symptoms. Both the COVID-19 positive and the COVID-19 negative groups had similar sociodemographic and clinical characteristics, except for the rate of hospitalization (15.8% vs 1.5%, respectively). One month after disease onset, 122 (29.6%) individuals reported residual symptoms in the COVID-19 positive group or the long COVID group versus 24 (6%) individuals in the COVID-19 negative group. In the long COVID group, fatigue, olfactory disorder, and myalgia were the most frequent symptoms which occurred in the acute phase. Compared to recovered patients, female sex, older age and having > 5 symptoms during the acute phase were risk factors for long COVID. Quality of life was evaluated in 102 out of 122 cases of long COVID with 57 (55.9%) reporting an impact in at least one dimension of the EuroQol 5D-3L questionnaire. Conclusion In this prospective study consisting predominantly of patients with mild disease, the persistence of symptoms after acute disease was highly associated with long COVID-19 (29.6% vs 6% of COVID negative group). The risk factors for long COVID were older age, female sex, and polysymptomatic acute disease.

Vaccine effectiveness of CoronaVac against symptomatic and severe COVID-19 among children in Brazil during the Omicron period (preprint)

Compared to previous variants, the SARS-CoV-2 B.1.1.529 (Omicron) variant has relatively high infection rates, including among children. Even though severe COVID-19 in children is rare, this group is susceptible to the multisystem inflammatory syndrome in Children (MIS-C), long-COVID and downstream effects of COVID-19, including social isolation and education disruption. There is evidence that vaccination with an mRNA vaccine offers protection against infection and severe forms of COVID-19 for children. However, data on the effectiveness of inactivated virus vaccine, the most used platform worldwide, is scarce during the Omicron period. In Brazil, children between 6 to 11 years are eligible to receive the CoronaVac vaccine. Using a national linked database from January 21, 2022, up to April 19, 2022, during the Omicron dominant period in Brazil, we conducted a test-negative design with 194,258 tests to assess CoronaVac effectiveness against infection and severe (hospitalisation or death) outcomes among children aged 6 to 11 years. The estimated VE for symptomatic infection was 35.0% (95% CI 27.7–41.5) at 0–13 days and 41.5% (95% CI: 34.4–47.7) at ≥ 14 days post-second dose. For severe outcomes (hospitalisation or death) VE was 69.2% (95% CI: 11.7–93.6) at 0–13 days and 63.5% (95% CI: 5.8–90.0). Two doses of CoronaVac in children during the Omicron period showed low levels of protection against symptomatic infection, and modest levels against severe illness.

Protection conferred by vaccine plus previous infection (hybrid immunity) with vaccines of three different platforms during the Omicron variant period in Brazil (preprint)

Hybrid immunity (infection plus vaccination) provided high protection against infection and severe disease in the periods of delta and gamma variants of concern. However, the protection of hybrid immunity in the Omicron era remains unknown. We performed a test-negative study using Brazilian national databases between January 01 and March 22, 2022, a period of predominant circulation of the Omicron variant in Brazil. Hybrid immunity offered low protection against infection, with rapid waning, compared to unvaccinated with or without previous infection. For severe illness (hospitalisation or death), the protection, although already high for unvaccinated pre-infected increased regardless of the type of vaccine (Ad26.COV2.S, BNT162b2, ChAdOx-1 or CoronaVac). In conclusion, during the Omicron-dominant period in Brazil, hybrid immunity offered high protection against severe illness and low protection against infection.

Effectiveness of CoronaVac, ChAdOx1, BNT162b2 and Ad26.COV2.S among individuals with prior SARS-CoV-2 infection in Brazil (preprint)

Background. COVID-19 vaccines have proven highly effective among SARS-CoV-2 naive individuals, but their effectiveness in preventing symptomatic infection and severe outcomes among individuals with prior infection is less clear. Methods. Utilizing national COVID-19 notification, hospitalization, and vaccination datasets from Brazil, we performed a case-control study using a test-negative design to assess the effectiveness of four vaccines (CoronaVac, ChAdOx1, Ad26.COV2.S and BNT162b2) among individuals with laboratory-confirmed prior SARS-CoV-2 infection. We matched RT-PCR positive, symptomatic COVID-19 cases with RT-PCR-negative controls presenting with symptomatic illnesses, restricting both groups to tests performed at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity, and the odds of hospitalization or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines. Findings. Among individuals with prior SARS-CoV-2 infection, vaccine effectiveness against symptomatic infection [≥] 14 days from vaccine series completion was 39.4% (95% CI 36.1-42.6) for CoronaVac, 56.0% (95% CI 51.4-60.2) for ChAdOx1, 44.0% (95% CI 31.5-54.2) for Ad26.COV2.S, and 64.8% (95% CI 54.9-72.4) for BNT162b2. For the two-dose vaccine series (CoronaVac, ChAdOx1, and BNT162b2), effectiveness against symptomatic infection was significantly greater after the second dose compared with the first dose. Effectiveness against hospitalization or death [≥] 14 days from vaccine series completion was 81.3% (95% CI 75.3-85.8) for CoronaVac, 89.9% (95% CI 83.5-93.8) for ChAdOx1, 57.7% (95% CI -2.6-82.5) for Ad26.COV2.S, and 89.7% (95% CI 54.3-97.7) for BNT162b2.

Effectiveness of the CoronaVac Vaccine in Prevention of Symptomatic and Progression to Severe COVID-19 in Pregnant Women in Brazil (preprint)

Background: The effectiveness of Covid-19 inactivated vaccines in pregnant women is unknown. We estimated vaccine effectiveness (VE) of CoronaVac against symptomatic and severe Covid-19 and in preventing progression from symptomatic to severe Covid-19 in pregnant women in Brazil. Methods: We conducted a test-negative design study in all pregnant women aged 18 to 49 years in Brazil, linking records of negative and positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) tests to national vaccination records. We also linked records of test positive cases with notification of severe, hospitalized or fatal Covid-19. Using logistic regression, we estimated adjusted odds and VE against symptomatic Covid-19 by comparing vaccine status in test positive (confirmed cases) to that in subjects with a negative test result. We also calculated the odds/VE against progression by comparing vaccine status in symptomatic cases to that in severe Covid-19 cases. Results: Of 19838 tested pregnant women, 7424 (37.4%) tested positive for Covid-19 and 588 (7.9%) had severe disease. Only 83% of pregnant women who received a first dose of CoronaVac completed the vaccination scheme. A single dose of the CoronaVac vaccine was not effective at preventing symptomatic Covid-19. Effectiveness of two doses of CoronaVac was 41% (95% CI 27.1- 52.2) against symptomatic Covid-19, 85% (95% CI 59.5-94.8) against severe Covid-19 and (75%; 95% CI 27.9- 91.2) in preventing progression to severe Covid-19 among those infected. Conclusion: A complete regimen of CoronaVac in pregnant women was effective in preventing symptomatic Covid-19, and highly effective against severe illness in a setting that combines high disease burden and elevated Covid-19 related maternal deaths.Funding Information: This study is part of the VigiVac Fiocruz program, partially supported by a donation from the "Fazer o bem faz bem" program. EPS is funded by the Wellcome Trust [Grant number 213589/Z/18/Z]. Declaration of Interests: We declare no competing interests. VO, VB, MB, and MB-N are employees from Fiocruz, a federal public institution, which manufactures Vaxzevria in Brazil, through a full technology transfer agreement with AstraZenecaEthics Approval Statement: This study analysed de-identified data and was approved by the National Ethics committee (CONEP) (CAAE registration no. 50199321.9.0000.0040).

The effectiveness of Vaxzevria and CoronaVac vaccines: A nationwide longitudinal retrospective study of 61 million Brazilians (VigiVac-COVID19). (preprint)

BackgroundHigh rates of virus transmission and the presence of variants of concern can affect vaccine effectiveness (VE). Both conditions occur in low-income countries, which primarily use viral vector or inactivated virus vaccine technologies. Such countries conducted few VE analyses, and most lack the power to evaluate effectiveness in subgroups. MethodsThe present retrospective cohort study evaluated the effectiveness of Vaxzevria and CoronaVac vaccines for COVID-19-related infection in 75,919,840 Brazilian vaccinees from January 18 to July 24, 2021. Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19-related hospitalization, ICU admission, and death. We estimated VE using Cox regression adjusted for individual demographic characteristics. ResultsVaccination with Vaxzevria or CoronaVac was effective against SARS-CoV-2 infection and highly effective against hospitalization, ICU admission, and death in individuals up to 79 years. From 80-89 years of age, Vaxzevria led to 89.9%(95CI:87.7-91.7) VE against death versus 67.2%(95CI:63.6-70.5) for CoronaVac. Above 90 years, 65.4%(95CI:46.1-77.8) protection was conferred to Vaxzevria-vaccinated individuals versus 33.6%(95CI:21.9-43.5) in CoronaVac-vaccinated individuals. Furthermore, the post-vaccination daily incidence rate shows a stepwise increase from younger to elder decades of life. ConclusionsVaxzevria demonstrated overall effectiveness against severe COVID-19 up to 89 years and CoronaVac up to 79 years of age. There is a stepwise effectiveness reduction for both vaccines for each decade of life. Our results suggest that individuals aged 80 years or older may benefit from an expedited booster dose. Ongoing evaluations, including any additional vaccines authorized, are crucial to monitoring long-term vaccine effectiveness.

Post-Acute COVID Syndrome, the Aftermath of Mild to Severe COVID-19 in Brazilian Patients (preprint)

ABSTRACT Objective To describe persistent symptoms after acute COVID-19 in different spectrum of disease severity in a population from an upper/middle income country, and identify the main clinical features impacting the quality of life. Design Cross-sectional study. Setting Outpatient clinic from a public post-COVID-19 health center (CPC) at Bahia-Brazil, a state where 80% are black or mixed race. Participants Patients admitted between August 2020 and February 2021 with symptoms at least one month after the onset of COVID-19. Main outcome measures PACS and related disorders such as hospitalization one month or later after disease onset, biochemical dysregulation and reduced quality of life (EQ-5D-5L questionnaire). Results Among 683 individuals assisted at CPC in this period, 602 were recruited. Patients had average of 52 (±14.6) years, 355 (59%) were female, 528 (88%) black/brown. Individuals were classified as mild (39.9%), moderate (27.9%) or severe (32.2%) during acute illness if outpatient, hospitalized non-UCI or UCI, respectively. Most patients reported a polysymptomatic profile, in median eight (IQR=6-9) acute symptoms. The most frequent residual symptoms were dyspnea (66%), fatigue (62%) and chest pain (43%). Women were more affected regardless disease severity at acute stage: presented more residual symptoms [4 (2-6) vs 3 (2-4)] and a higher impact in quality of life. Altered HbA1c [(184/275 (66.9%)], high CRP levels [195/484 (40.3%)] and anemia [143/545 (26.2%)] were the most common abnormalities in laboratory exams. 76 patients presented HbA1c above 6.4% although only 42 referred previous diagnosis of diabetes mellitus. After one month of disease onset, 30 patients required hospitalization, including seven cases with mild acute illness. Hospital admission after acute disease was required on 30 patients, seven (23%) were mild. Quality of life had been affected for 357/404 (88.4%) patients according to EuroQoL (EQ-5D-5L), mainly the domains of anxiety/depression [severe or extreme anxiety for 79/401 (19.7%)] and pain/discomfort [severe or extreme pain for 71/403 (17.6%)]. The median EuroQoL Global Score was 70 [IQR 50-80]. PACS symptoms such as dyspnea, chest pain, and fatigue, was associated with decreased quality of life. Conclusions PACS, such as dyspnea, chest pain and fatigue, occurred after variable degree of disease severity. Among this majority black/mixed-race patients, woman seemed to be more affected. Other consequences included post-acute hospitalization, and abnormal glucose metabolism and reduced quality of life. Summary Box Section 1: What is already known on this topic: ✓ Post-Acute COVID Syndrome (PACS) comprises a set of persistent or new-onset symptoms after illness onset. ✓ As far as we know, there are no studies describing PACS in a population principally black and mixed-race. Additionally, few studies have addressed PACS among outpatients. Section 2: What this study adds: ✓ Similar PACS were reported after mild, moderate and severe illness. Dyspnea, fatigue and chest pain were the most prevalent symptoms in this population presenting majority of black/mixed-race patients. ✓ Women presented more residual symptoms, a higher frequency of myalgia and worse score for mobility, usual activities, anxiety/depression, and pain. ✓ Hospitalization may occur one month or later after mild or moderate/severe acute infection due to respiratory and vascular disorders. Abnormal glucose metabolism was detected in the absence of previous diagnosis of diabetes mellitus.

Efficacy of propolis as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial (preprint)

Among candidate treatment options for COVID-19, propolis, produced by honey bees from bioactive plant exudates, has shown potential against viral targets and has demonstrated immunoregulatory properties. We conducted a randomized, controlled, open-label, single center trial, with a standardized propolis product (EPP-AF) on hospitalized adult COVID-19 patients. Patients received standard care plus propolis at an oral dose of 400mg/day (n=40) or 800mg/day (n=42) for seven days, or standard care alone (n=42). Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement defined as the length of hospital stay or oxygen therapy dependency. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Time in the hospital after intervention was significantly shortened in both propolis groups compared to the controls; median 7 days with 400mg/day and 6 days with 800mg/day, versus 12 days for standard care alone. Propolis did not significantly affect the need for oxygen supplementation. With the higher dose, significantly fewer patients developed acute kidney injury than in the controls (2 versus 10 of 42 patients). Propolis as an adjunct treatment was safe and reduced hospitalization time. The registration number for this clinical trial is: NCT04480593 (20/07/2020).