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      The brazilian tragedy: Where patients living at the ‘Earth's lungs’ die of asphyxia, and the fallacy of herd immunity is killing people.

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      EClinicalMedicine
      Elsevier

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          Abstract

          The Brazilian COVID-19 pandemic has stretched an already overwhelmed, understaffed and underfunded public health system to the breaking point [1]. Brazil's COVID-19 death toll is the second highest in the world behind only the United States, with more than 8.9 million reported cases and 220,000 deaths [at the time of writing]. In the first wave of COVID-19, between May and June 2020, Amazonas state has registered nearly 19 coronavirus deaths per 100,000 residents, compared to 4 deaths? for all of Brazil. As the state experiences a second wave of COVID-19 in January 2021, Amazonas is registering 142 deaths per 100,000 inhabitants, while the national average is 98 [2]. Amazonas's estimated population of 4200,000 includes nearly all of Brazil's reserved land for indigenous people (98.5%). The state has only 100 ICU beds, all located in the state capitol, Manaus, where laboratory surveillance is also centralized. During the first wave of COVID-19, around May 2020, Amazonas also experienced an exponential increase of deaths at home that led to a collapse of both the health care and funerary systems. However, in early June 2020, Manaus was already relaxing social-distancing requirements. By mid August 2020, Manaus had reduced its number of excess deaths from around 120 per day to nearly zero. Pre-prints subsequently suggested that Manaus had achieved herd immunity [3]. Less than a year later, Amazonas is experiencing its second wave of COVID-19, with a faster spread of infection, increased mortality and healthcare and funerary systems collapsing again. In January 2021, oxygen shortages led to the deaths of up to 40 COVID-19 ICU patients in Manaus [4]. The same month, police from Manaus found 33 oxygen cylinders hidden in a truck, which were reportedly being sold to wealthy families eager to save their dying family members. A supply of 150 oxygen cylinders arriving in Manaus required military escort for delivery to hospitals and remote clinics [5]. Amazonas's remote location presents challenging logistics, requiring additional stocks of oxygen and other healthcare supplies to be transported by boat and by plane, making it even more difficult to provide timely surveillance, treatment and care. Key failures at the local and national level contributed to these tragedies [6]. Brazilian President Jair Bolsonaro has been outspoken against lockdowns and described COVID-19 as a “little flu”, frequently appearing at rallies without masks and not observing social distancing. Brazil's federal government claimed that the crisis in Manaus was due to lack of ‘early treatment’ for COVID-19, including the anti-malaria drug hydroxychloroquine in combination with the antibiotic azithromycin, which have not shown efficacy [7]. Since the federal government has relied on clinical diagnoses of COVID-19 (e.g. patients with symptoms) instead of laboratory confirmed COVID-19 cases and contact tracing has been suboptimal, [6] the true scope of the epidemic is unknown. Amazonas’ government did not reinforce the need to adopt preventive measures, and the vast majority of its population did not adhere to social distancing and facemasks. Many turned to herbs and traditional medicines collected in the forest to alleviate symptoms. With a deadly second wave of transmission now occurring in the early days of 2021, the assumption that Manaus achieving heard immunity has proven incorrect [8]. Laboratory surveillance of SARSCoV-2 and its mutations has also been suboptimal - a new variant belonging to the B.1.1.248 lineage that has 12 mutations, including N501Y and E484K in its spike protein – was first detected by the Japanese government among four people who had travelled from Amazonas [9]. Lack of prompt government response, a public health system at the edge of collapse before the pandemic, a federal government in denial and a new, potentially more infectious variant have all likely contributed to a deadly resurgence of SARS-CoV-2 in Amazonas. New variants bring increasing concerns about re-infection and immune escape which may necessitate vaccine boosters [10]. The experience of Manaus is a clear example of how assumptions of reaching herd immunity in the absence of vaccination are counter-productive. This tragic scenario also highlights the urgency to improve the health care infrastructure, surveillance and adequate management of the supply chain to assure that vaccines, medications and health supplies (e.g. oxygen) are not diverted on the black market. Declaration of Competing Interest None.

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          Most cited references6

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          Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

          Abstract Background Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. Methods We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. Results A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P=1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P=1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Conclusions Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.)
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            Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence

            After initially containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many European and Asian countries had a resurgence of COVID-19 consistent with a large proportion of the population remaining susceptible to the virus after the first epidemic wave. 1 By contrast, in Manaus, Brazil, a study of blood donors indicated that 76% (95% CI 67–98) of the population had been infected with SARS-CoV-2 by October, 2020. 2 High attack rates of SARS-CoV-2 were also estimated in population-based samples from other locations in the Amazon Basin—eg, Iquitos, Peru 70% (67–73). 3 The estimated SARS-CoV-2 attack rate in Manaus would be above the theoretical herd immunity threshold (67%), given a basic case reproduction number (R0) of 3. 4 In this context, the abrupt increase in the number of COVID-19 hospital admissions in Manaus during January, 2021 (3431 in Jan 1–19, 2021, vs 552 in Dec 1–19, 2020) is unexpected and of concern (figure ).5, 6, 7, 8, 9, 10 After a large epidemic that peaked in late April, 2020, COVID-19 hospitalisations in Manaus remained stable and fairly low for 7 months from May to November, despite the relaxation of COVID-19 control measures during that period (figure). Figure COVID-19 hospitalisations, excess deaths, and Rt in Manaus, Brazil, 2020–21 (A) Dark lines are the 7-day rolling averages and lighter lines are the daily time series of COVID-19 hospitalisations and excess deaths. Hospitalisation data are from the Fundação de Vigilância em Saúde do Amazonas. 5 Total all-cause deaths for 2020–21 were reported initially by the Prefeitura de Manaus 6 and subsequently in the daily COVID-19 bulletin of the Fundação de Vigilância em Saúde do Amazonas. 7 All-cause deaths from 2019 were from Arpen/AM (Associação dos Registradores Civis das Pessoas Naturais do Amazonas). 8 The compiled excess death data are from Bruce Nelson from the Instituto Nacional de Pesquisas da Amazônia. 9 (B) R t was calculated using the time series of COVID-19 hospitalisations after removal of the past 14 days to account for delays in notification. R t was calculated using the EpiFilter method. 10 Lines are median R t estimates; shaded areas are the 95% CIs. R t=Effective reproduction number. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. There are at least four non-mutually exclusive possible explanations for the resurgence of COVID-19 in Manaus. First, the SARS-CoV-2 attack rate could have been overestimated during the first wave, and the population remained below the herd immunity threshold until the beginning of December, 2020. In this scenario, the resurgence could be explained by greater mixing of infected and susceptible individuals during December. The 76% estimate of past infection 2 might have been biased upwards due to adjustments to the observed 52·5% (95% CI 47·6–57·5) seroprevalence in June, 2020, to account for antibody waning. However, even this lower bound should confer important population immunity to avoid a larger outbreak. Furthermore, comparisons of blood donors with census data showed no major difference in a range of demographic variables, 2 and the mandatory exclusion of donors with symptoms of COVID-19 is expected to underestimate the true population exposure to the virus. Reanalysis and model comparison 11 by independent groups will help inform the best-fitting models for antibody waning and the representativeness of blood donors. Second, immunity against infection might have already begun to wane by December, 2020, because of a general decrease in immune protection against SARS-CoV-2 after a first exposure. Waning of anti-nucleocapsid IgG antibody titres observed in blood donors 2 might reflect a loss of immune protection, although immunity to SARS-CoV-2 depends on a combination of B-cell and T-cell responses. 12 A study of UK health-care workers 13 showed that reinfection with SARS-CoV-2 is uncommon up to 6 months after the primary infection. However, most of the SARS-CoV-2 infections in Manaus occurred 7–8 months before the resurgence in January, 2021; this is longer than the period covered by the UK study, 13 but nonetheless suggests that waning immunity alone is unlikely to fully explain the recent resurgence. Moreover, population mobility in Manaus decreased from mid-November, 2020, with a sharp reduction in late December, 2020, 14 suggesting that behavioural change does not account for the resurgence of hospitalisations. Third, SARS-CoV-2 lineages might evade immunity generated in response to previous infection. 15 Three recently detected SARS-CoV-2 lineages (B.1.1.7, B.1.351, and P.1), are unusually divergent and each possesses a unique constellation of mutations of potential biological importance.16, 17, 18 Of these, two are circulating in Brazil (B.1.1.7 and P.1) and one (P.1) was detected in Manaus on Jan 12, 2021. 16 One case of SARS-CoV-2 reinfection has been associated with the P.1 lineage in Manaus 19 that accrued ten unique spike protein mutations, including E484K and N501K. 16 Moreover, the newly classified P.2 lineage (sublineage of B.1.128 that independently accrued the spike E484K mutation) has now been detected in several locations in Brazil, including Manaus. 20 P.2 variants with the E484K mutation have been detected in two people who have been reinfected with SARS-CoV-2 in Brazil,21, 22 and there is in-vitro evidence that the presence of the E484K mutation reduces neutralisation by polyclonal antibodies in convalescent sera. 15 Fourth, SARS-CoV-2 lineages circulating in the second wave might have higher inherent transmissibility than pre-existing lineages circulating in Manaus. The P.1 lineage was first discovered in Manaus. 16 In a preliminary study, this lineage reached a high frequency (42%, 13 of 31) among genome samples obtained from COVID-19 cases in December, 2020, but was absent in 26 samples collected in Manaus between March and November, 2020. 16 Thus far, little is known about the transmissibility of the P.1 lineage, but it shares several independently acquired mutations with the B.1.1.7 (N501Y) and the B.1.325 (K417N/T, E484K, N501Y) lineages circulating in the UK and South Africa, which seem to have increased transmissibility. 18 Contact tracing and outbreak investigation data are needed to better understand relative transmissibility of this lineage. The new SARS-CoV-2 lineages may drive a resurgence of cases in the places where they circulate if they have increased transmissibility compared with pre-existing circulating lineages and if they are associated with antigenic escape. For this reason, the genetic, immunological, clinical, and epidemiological characteristics of these SARS-CoV-2 variants need to be quickly investigated. Conversely, if resurgence in Manaus is due to waning of protective immunity, then similar resurgence scenarios should be expected in other locations. Sustained serological and genomic surveillance in Manaus and elsewhere is a priority, with simultaneous monitoring for SARS-CoV-2 reinfections and implementation of non-pharmaceutical interventions. Determining the efficacy of existing COVID-19 vaccines against variants in the P.1 lineage and other lineages with potential immune escape variants is also crucial. Genotyping viruses from COVID-19 patients who were not protected by vaccination in clinical trials would help us to understand if there are lineage-specific frequencies underlying reinfection. The protocols and findings of such studies should be coordinated and rapidly shared wherever such variants emerge and spread. Since rapid data sharing is the basis for the development and implementation of actionable disease control measures during public health emergencies, we are openly sharing in real-time monthly curated serosurvey data from blood donors through the Brazil–UK Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE) Centre GitHub website and will continue to share genetic sequence data and results from Manaus through openly accessible data platforms such as GISAID and Virological.
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              Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated epidemic

              Attack rate in Manaus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence peaked in Manaus, Brazil, in May 2020 with a devastating toll on the city's inhabitants, leaving its health services shattered and cemeteries overwhelmed. Buss et al. collected data from blood donors from Manaus and São Paulo, noted when transmission began to fall, and estimated the final attack rates in October 2020 (see the Perspective by Sridhar and Gurdasani). Heterogeneities in immune protection, population structure, poverty, modes of public transport, and uneven adoption of nonpharmaceutical interventions mean that despite a high attack rate, herd immunity may not have been achieved. This unfortunate city has become a sentinel for how natural population immunity could influence future transmission. Events in Manaus reveal what tragedy and harm to society can unfold if this virus is left to run its course. Science, this issue p. 288; see also p. 230

                Author and article information

                Contributors
                Journal
                EClinicalMedicine
                EClinicalMedicine
                EClinicalMedicine
                Elsevier
                2589-5370
                12 February 2021
                February 2021
                12 February 2021
                : 32
                : 100757
                Affiliations
                [a ]Institute for Mental Health Policy Research (IMHPR/CAMH); Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON; Department of Social Science, National School of Public Health, Oswaldo Cruz Foundation (ENSP/FIOCRUZ), Rio de Janeiro, Brazil
                [b ]Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
                [c ]School of Public Health, Universidad Peruana Cayetano Heredia, Lima Peru
                Author notes
                [* ]Corresponding author. monica.malta@ 123456camh.ca
                Article
                S2589-5370(21)00037-7 100757
                10.1016/j.eclinm.2021.100757
                7890368
                33659889
                722ab61e-c65b-4d9a-aa2b-092764fca9b9
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 27 January 2021
                : 28 January 2021
                : 1 February 2021
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