Abstract

The Brazilian context of social inequalities and barriers in accessing health services may deteriorate the situation of the COVID-19 pandemic, which already affects all Brazilian federative states, with the growing curve of increasing confirmed cases and deaths. National governments and scientific field agents have been looking for evidence for the best practices of prevention and control of transmission, and care of infection and disease, including diagnosis, treatment, and health care measures. The large-scale testing strategy, aimed at early diagnosis, quarantine of the mild cases identified, as well as those of the contacts, and adequate care of severe cases, has been revised and indicated as one of the efficient pandemic control measures in several countries in the world. This paper aims to discuss the challenges of COVID-19 testing and diagnosis in Brazil.

Key words
COVID-19; Testing; Diagnosis; Epidemiological surveillance; Brazil

Introduction

Coronaviruses are part of a family of viruses that cause respiratory infections in humans and are the second leading cause of the common cold and, until the last decades, rarely caused more severe diseases. There are seven known human coronaviruses (HCoVs), including SARS-COV (which causes Severe Acute Respiratory Syndrome-SARS), MERS-COV (Middle East Respiratory Syndrome), and SARS-CoV-2.

On December 31, 2019, the World Health Organization (WHO) office in China received notifications of cases of pneumonia of unknown cause among workers at a seafood market in Wuhan, China. In March 2020, WHO characterized this disease as a pandemic, called “Coronavirus Disease 2019” (COVID-19)¹1 World Health Organization (WHO). Rolling updates on coronavirus disease (COVID-19). 2020. [acessado 2020 Maio 31]. Disponível em: https://www.who.int/emergencies/diseases/novel-13 coronavirus-2019/events-as-they-happen
https://www.who.int/emergencies/diseases... ^,22 World Health Organization (WHO). Q&A on coronaviruses (COVID-19). 2020. [acessado 2020 Maio 31]. Disponível em: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-16 and-answers-hub/q-a-detail/q-a-coronaviruses
https://www.who.int/emergencies/diseases... . The etiologic agent of this disease is Coronavirus subtype 2, or SARS-CoV-2²2 World Health Organization (WHO). Q&A on coronaviruses (COVID-19). 2020. [acessado 2020 Maio 31]. Disponível em: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-16 and-answers-hub/q-a-detail/q-a-coronaviruses
https://www.who.int/emergencies/diseases... . Since then, national governments and scientific field agents have sought scientific evidence for the best practices for prevention and control of transmission and care for infection and disease, including diagnostic testing, treatment, and health care. As of May 31, 2020, 5,934,936 cases of COVID-19 and 367,166 associated deaths have been confirmed worldwide, which corresponds to a fatality rate of 6.2%³3 World Health Organization (WHO). COVID-19 Dashboard. 2020. [acessado 2020 Maio 12]. Disponível em: https://covid19.who.int/
https://covid19.who.int/... . The WHO has declared this pandemic as a “public health emergency of international concern”.

SARS-CoV-2 rapidly spread to various parts of the world, indicating a high transmissibility rate⁴4 Ferretti L, Wymant C, Kendall M, Zhao L, Nurtay A, Abeler-Dörner L, Parker M, Bonsall D, Fraser C. Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science 2020; 368(6491):eabb6936.^,55 Huang L, Zhang X, Zhang X, Wei Z, Zhang L, Xu J, Liang P, Xu Y, Zhang C, Xu A. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study. J Infect 2020; 80(6):e1-e13.. There are not yet enough studies relating its high rate of transmission to socioeconomic issues, but notably, locations with a low human development index (HDI) and high socioeconomic inequality are likely to have a high risk of virus spread and reports of higher incidence and fatality rates due to COVID-19, since these communities may struggle to follow and cope with social distancing⁶6 Wang Z, Tang K. Combating COVID-19: health equity matters. Nat Med 2020; 26(4):458.. Another critical factor is that these locations have a high demographic density with people living in houses with few rooms, which hinders social distancing, considered a risk factor for the transmission of respiratory diseases⁷7 Rodrigues NCP, Andrade MKN, O'Dwyer G, Flynn M, Braga JU, Almeida AS, Bastos LS, Lino VTS. Distribuição da tuberculose pulmonar no Rio de Janeiro (Brasil): Uma análise espacial. Cien Saude Colet 2017; 22(12):4125-4134.. Moreover, people living in these environments already suffer from a more significant burden of other acute infectious diseases or chronic non-communicable diseases (NCDs), potential COVID-19 severity factors, such as HIV infection and tuberculosis⁸8 Adepoju P. Tuberculosis and HIV responses threatened by COVID-19. Lancet HIV 2020; 7(5):e319-e320., hypertension, and diabetes⁹9 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229):1054-1062.^,1010 Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223):507-513. and obesity¹¹11 Dietz W, Santos-Burgoa C. Obesity and its Implications for COVID-19 Mortality. Obesity 2020; 00:1-1.. No less critical to the deteriorating situation in these communities is the difficulty of quick access to health services and quality information that enable self-care⁶6 Wang Z, Tang K. Combating COVID-19: health equity matters. Nat Med 2020; 26(4):458..

Brazil has one of the highest rates of social inequality, with a Gini index of 53.9¹²12 World Bank (WB). GINI index (World Bank estimate) - Brazil. 2020. [acessado 2020 Maio 12]. Disponível em: https://data.worldbank.org/indicator/SI.POV.GINI
https://data.worldbank.org/indicator/SI.... , ranking as the second poorest income distribution in the world¹³13 Programa das Nações Unidas para o Desenvolvimento (PNUD). Relatório do Desenvolvimento Humano 2019: além do rendimento, além das médias, além do presente - desigualdades no desenvolvimento humano no século XXI. Nova York: PNUD; 2019., and showing profound regional inequalities. About 40% of the Brazilian population is in an informal work situation¹⁴14 Silveira D, Alvarenga D. Trabalho informal avança para 41,3% da população ocupada e atinge nível recorde, diz IBGE. G1. [acessado 2020 Maio 12]. Disponível em: https://g1.globo.com/economia/noticia/2019/08/30/trabalho-informal-avanca-para-413percent-da-populacao-ocupada-e-atinge-nivel-recorde -diz-ibge.ghtml
https://g1.globo.com/economia/noticia/20... , without access to labor rights, which can hamper adherence to social distancing measures i because of the need to circulate on the streets to retain their jobs, and, consequently, to secure income. Furthermore, Brazil experiences an incomplete epidemiological transition, when compared to European countries. For example, Brazil has high rates of incidence and prevalence of infectious diseases and, at the same time, of NCDs¹⁵15 GBD 2016 Brazil Collaborators. Burden of disease in Brazil, 1990-2016: a systematic subnational analysis for the Global Burden of Disease Study 2016. Lancet 2018; 392(10149):760-775.. In this context, COVID-19 outbreak officially reached Brazil on February 26^th, and the first COVID-19-related death was notified on March 17th in São Paulo state. As of May 31, 2020, the country had accumulated 514,849 COVID-19 cases and 29,314 related deaths - fatality rate of of 5.7%. The regions with the highest proportion of cases are the Southeast, with 36.4%, (187,240), and the Northeast, with 34.8% (179,401)¹⁶16 Brasil. Ministério da Saúde (MS). Covid-19: painel coronavírus. Brasília: MS; 2020. [acessado 2020 Maio 31]. Disponível em: https://covid.saude.gov.br/
https://covid.saude.gov.br/... . Compared to the influenza A (H1N1) pdm09 pandemic when a total of 53,797 cases were recorded in the 2009-2010 period, with a fatality rate of 3.9% in 2009¹⁷17 Rossetto EV, Luna EJA. A descriptive study of pandemic influenza A(N1N1)PDM09 in Brazil, 2009 - 2010. Revista do Instituto de Medicina Tropical de São Paulo 2016; 58:78., the COVID-19 pandemic already exceeded the numbers in Brazil.

A significant increase in the incidence rate of SARS was recorded in the first months of 2020 in Brazil, the most severe manifestation of COVID-19, especially among people over 60 years of age, when compared with the incidence data from the previous ten years¹⁸18 Bastos LS, Niquini RP, Lana RM, Villela DAM, Cruz OG, Coelho FC, Codeço CT, Gomes MFC. COVID-19 e hospitalizações por SRAG no Brasil: uma comparação até a 12a semana epidemiológica de 2020. Cad Saude Publica 2020; 36(4):e00070120.^,1919 Fundação Oswaldo Cruz (Fiocruz), Brasil. Ministério da Saúde (MS). Monitoramento de casos reportados de síndrome respiratória aguda grave (SRAG) hospitalizados. 2020. [acessado 2020 Maio 12]. Disponível em: http://info.gripe.fiocruz.br/
http://info.gripe.fiocruz.br/... . However, it has been speculated that this higher incidence is due to the underreported cases in Brazil²⁰20 COVID-19 Brasil. COVID-19: análise subnotificação. 2020. [acessado 2020 Maio 12]. Disponível em: https://ciis.fmrp.usp.br/covid19/analise-subnotificacao/
https://ciis.fmrp.usp.br/covid19/analise... . A study recorded high inequality in the underreporting rates of COVID-19 with states in the north and northeast regions²¹21 Prado M, Bastos L, Batista A, Antunes B, Baião F, Maçaira P, Hamacher S, Bozza F. Análise de subnotificação do número de casos confirmados da COVID-19 no Brasil. Núcleo de Operações e Inteligência em Saúde (NOIS) 2 Metodologia. 2020. [acessado 2020 Maio 12]. Disponível em: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-
https://www.who.int/docs/default-source/... leading the first seven places. Studies report that countries that are not testing their populations do not have a reliable estimate of the infection incidence rate²²22 Hasell J. Testing data provides us with two indicators of the quality of data on COVID-19. 2020. [acessado 2020 Maio 12]. Disponível em: https://ourworldindata.org/what-can-data-on-testing-tell-us-35 about-the-pandemic
https://ourworldindata.org/what-can-data... ^,2323 Okba NMA, Müller MA, Li W, Wang C, Geurtsvankessel CH, Corman VM, Lamers MM, Sikkema RS, Bruin E, Chandler FD, Yazdanpanah Y, Le Hingrat Q, Descamps D, Houhou-Fidouh N, Reusken CBEM, Bosch BJ, Drosten C, Koopmans MPG, Haagmans BL. SARS-CoV-2 specific antibody responses in COVID-19 patients. Emerg Infect Dis 2020; 26(7):1478-1488.. In this sense, this paper aims to discuss the challenges of testing and diagnosing COVID-19 in Brazil.

Challenges for the diagnosis of COVID-19

The diagnosis of COVID-19 is a challenge worldwide. Some of the reasons for this are: 1) the biological material to be used, for example, nasal or oropharynx swab, plasma, serum or whole blood; 2) the definition of the biological marker to be detected; 3) the type of methodology employed (virological methods, molecular biology, and immunoassays); 4) the ideal time of the infection for sample collection and the ideal type of sample; and 5) the accuracy of the available diagnostic tests.

Moreover, the pandemic declared by the WHO has hampered the acquisition of supplies for greater availability of molecular tests for the detection of viral RNA, since this has become a global need. Brazil depends on imports of many equipment/supplies, due to the limited number of local companies²⁴24 Barifouse R. Coronavírus: por que o Brasil ainda não conseguiu fazer testes em massa? BBC News Brasil 2020. [acessado 2020 Maio 12]. Disponível em: https://www.bbc.com/portuguese/brasil-41 52145795
https://www.bbc.com/portuguese/brasil-41... ^,2525 Onofre R. Sem insumos, laboratórios privados limitam exames para detectar coronavírus. Folha de São Paulo 2020. [acessado 2020 Maio 12]. Disponível em: https://www1.folha.uol.com.br/equilibrioesaude/2020/03/sem-insumos-45laboratorios-privados-limitam-exames- para-detectar-coronavirus.shtml 46
https://www1.folha.uol.com.br/equilibrio... .

However, the laboratory methods may be precise and fast, we should consider that the diagnosis of COVID-19 requires an adequate collection of the patient samples at the right moment of the infection to increase the likelihood of detecting the investigated biomarker²⁶26 Loeffelholz MJ, Tang YW. Laboratory diagnosis of emerging human coronavirus infections-the state of the art. Emerg Microbes Infect 2020; 9(1):747-756.. The confirmatory test is the detection of the genetic material of the virus, such as viral RNA, by real-time PCR (RT-qPCR), which can be detected in stool, urine, and blood samples, albeit with less sensitivity and specificity than in respiratory samples²⁶26 Loeffelholz MJ, Tang YW. Laboratory diagnosis of emerging human coronavirus infections-the state of the art. Emerg Microbes Infect 2020; 9(1):747-756.. An exception is the SARS-CoV-2 RNA, which is continuously detected in the stool up to two weeks after the onset of symptoms²⁷27 Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol 2020; 5(4):335-337.. Thus, the combined oral/nasal swab RT-qPCR is considered as a gold standard test for SARS-CoV- 2 so far. However, there are some limiting aspects of this test, such as: 1) test positivity usually occurs within the first 4 to 8 days after the onset of symptoms, usually becoming negative after about 14 days²⁸28 Lou B, Li T-D, Zheng S-F, Su Y-Y, Li Z-Y, Liu W, Yu F, Ge SX, Zou QD, Yuan Q, Lin S, Hong CM, Yao XY, Zhang XJ, Wu DH, Zhou GL, Hou WH, Li TT, Zhang YL, Zhang SY, Fan J, Zhang J, Xia NS, Chen Y. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. Eur Respir J 2020; 2000763.^,2929 Pan Y, Zhang D, Yang P, Poon LLM, Wang Q. Viral load of SARS-CoV-2 in clinical samples. Lancet Infectious Diseases 2020; 20:411-412.; 2) It is a test of high technical complexity, which requires an infrastructure with an adequate level of biosafety to perform it. It is relatively expensive, costing between R$ 150.00 to R$ 350.00 (currently around US$ 30 and US$ 70, respectively) per sample, with significant variations among supplying establishments²⁶26 Loeffelholz MJ, Tang YW. Laboratory diagnosis of emerging human coronavirus infections-the state of the art. Emerg Microbes Infect 2020; 9(1):747-756.^,3030 Negri F, Zucoloto G, Miranda P, Koeller P. Ciência e Tecnologia frente à pandemia: Como a pesquisa científica e a inovação estão ajudando a combater o novo coronavírus no Brasil e no mundo. Centro de Pesquisa em Ciência, Tecnologia e Sociedade 2020. [acessado 2020 Maio 12]. Disponível em: https://www.ipea.gov.br/cts/pt/central-15 de-conteudo/artigos/artigos/182-corona
https://www.ipea.gov.br/cts/pt/central-1... .

Some studies have shown the importance of assays based on blood antibody detection for the diagnosis of COVID-19 in asymptomatic and symptomatic individuals, besides the production of data on the humoral immune response for the development of vaccines or treatment²⁸28 Lou B, Li T-D, Zheng S-F, Su Y-Y, Li Z-Y, Liu W, Yu F, Ge SX, Zou QD, Yuan Q, Lin S, Hong CM, Yao XY, Zhang XJ, Wu DH, Zhou GL, Hou WH, Li TT, Zhang YL, Zhang SY, Fan J, Zhang J, Xia NS, Chen Y. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. Eur Respir J 2020; 2000763.. They are called Enzyme-Linked Immunosorbent Assay (ELISA) and allow detecting specific antibodies. Moreover, their edge lies in the speed of results and detection of relatively low cost, but they may show low sensitivity²⁶26 Loeffelholz MJ, Tang YW. Laboratory diagnosis of emerging human coronavirus infections-the state of the art. Emerg Microbes Infect 2020; 9(1):747-756.. The average detection time of IgM and IgA antibodies for SARS-CoV-2 infection is five days (IQR=3-6 days), while IgG can be detected in less than 14 days (IQR=10-18 days) after the onset of symptoms, with a positivity rate of 85.4%, 92.7% and 77.9%, respectively³¹31 Guo L, Ren L, Yang S, Xiao M, Chang D, Yang F, Cruz CSD, Wang Y, Wu C, Xiao Y, Zhang L, Han L, Dang S, Xu Y, Yang Q, Xu S, Zhu H, Xu Y, Jin Q, Sharma L, Wang L, Wang J. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis 2020; ciaa310.. On the other hand, an essential disadvantage of methods based on antibody detection is the possibility of cross-reactions with other viruses, especially those of the same family, which cause colds and other respiratory diseases³²32 Petherick A. Developing antibody tests for SARS-CoV-2. Lancet 2020; 395(10230):1101-1102..

Considering the potential and limitations of the main diagnostic methods used, it is essential to note that the advantages of tests based on immunoassays are: 1) the shorter time to perform and obtain the results (rapid tests range from 15 to 30 minutes; ELISA, from 1 to 2 hours); 2) rapid tests (immunochromatography) can be performed in field research, from a drop of blood collected from the digital pulp; 3) ELISA, while of medium complexity, can be performed by automation with results obtained in a maximum of 2 to 3 hours; 3) since it is an acute infection, the test based on the detection of viral RNA is likely not to be positive after 10 to 14 days, whereas the IgG class antibodies may be detected, in principle, throughout life. Furthermore, IgG titers may be measured to investigate recent serological conversion³¹31 Guo L, Ren L, Yang S, Xiao M, Chang D, Yang F, Cruz CSD, Wang Y, Wu C, Xiao Y, Zhang L, Han L, Dang S, Xu Y, Yang Q, Xu S, Zhu H, Xu Y, Jin Q, Sharma L, Wang L, Wang J. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis 2020; ciaa310.. While information regarding cut-off points for days of sensitivity and specificity of RT-qPCR and immunological tests are still under investigation, some studies point to that the more at the onset of symptoms, the higher the likelihood of positive RT-qPCR, and the more distant from the onset of symptoms, the higher the likelihood of positive IgM and IgG. Tests with methodological principles of molecular biology and immunology are essential at different times of the infection, and the simultaneous application has been shown with more exceptional diagnostic and prognostic proficiency³³33 Tang YW, Schmitz JE, Persing DH, Stratton CW. The Laboratory Diagnosis of COVID-19 Infection: Current Issues and Challenges. J Clin Microbiol 2020; 58(6):e00512-20.. Thus, detecting the production of antibodies, especially IgM, which are produced quickly after infection, can be a tool combined with RT-qPCR to improve sensitivity and diagnostic accuracy³¹31 Guo L, Ren L, Yang S, Xiao M, Chang D, Yang F, Cruz CSD, Wang Y, Wu C, Xiao Y, Zhang L, Han L, Dang S, Xu Y, Yang Q, Xu S, Zhu H, Xu Y, Jin Q, Sharma L, Wang L, Wang J. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis 2020; ciaa310..

Testing for COVID-19: evidence, strategies, challenges

The transmission of the coronavirus can occur through droplets of saliva, sneeze, cough or phlegm, which can be passed on by touching or shaking hands, objects or surfaces contaminated by the infected person⁵5 Huang L, Zhang X, Zhang X, Wei Z, Zhang L, Xu J, Liang P, Xu Y, Zhang C, Xu A. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study. J Infect 2020; 80(6):e1-e13.^,3434 Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020; 382(13):1199-1207., and the early diagnosis of new cases of COVID-19 through testing is crucial to stop the virus spread³⁵35 Reusken CBEM, Broberg EK, Haagmans B, Meijer A, Corman VM, Papa A, Charrel R, Drosten C, Koopmans M, Leitmeyer K, On Behalf Of Evd-LabNet And Erli-Net. Laboratory readiness and response for novel coronavirus (2019-nCoV) in expert laboratories in 30 EU/EEA countries, January 2020. Euro Surveill 2020; 25(6):2000082. through social distancing and quarantine strategies.

Confirming COVID-19 cases is a challenge, as there is usually a mismatch between the onset of symptoms and the precise laboratory diagnosis³⁶36 National Health Commission & State Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia. 2020. [acessado 2020 Maio 12]. Disponível em: http://www.kankyokansen.org/uploads/uploads/files/jsipc/protocol_V7.pdf 36
http://www.kankyokansen.org/uploads/uplo... . Furthermore, about 80% of COVID-19 cases are asymptomatic or oligosymptomatic³⁷37 Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, Duan G. Virology, epidemiology, pathogenesis, and control of covid-19. Viruses 2020; 12(4):372. and often go undiagnosed. In China, at the onset of the outbreak in Wuhan, it is estimated that non registered infections were the source of infection for 79% of recorded cases³⁴34 Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY, Xing X, Xiang N, Wu Y, Li C, Chen Q, Li D, Liu T, Zhao J, Liu M, Tu W, Chen C, Jin L, Yang R, Wang Q, Zhou S, Wang R, Liu H, Luo Y, Liu Y, Shao G, Li H, Tao Z, Yang Y, Deng Z, Liu B, Ma Z, Zhang Y, Shi G, Lam TTY, Wu JT, Gao GF, Cowling BJ, Yang B, Leung GM, Feng Z. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020; 382(13):1199-1207..

Studies with infectious diseases such as tuberculosis³⁸38 Uys PW, Warren R, van Helden PD, Murray M, Victor TC. Potential of rapid diagnosis for controlling drug-susceptible and drug-resistant tuberculosis in communities where Mycobacterium tuberculosis infections are highly prevalent. J Clin Microbiol 2009; 47(5):1484-1490. and African viral hemorrhagic fever³⁹39 Okeke IN, Manning RS, Pfeiffer T. Diagnostic schemes for reducing epidemic size of african viral hemorrhagic fever outbreaks. J Infect Dev Ctries 2014; 8(9):1148-1159., besides COVID-19⁴⁰40 Rong X, Yang L, Chu H, Fan M. Effect of delay in diagnosis on transmission of COVID-19. Mathematical Biosciences and Engineering 2020; 17:2725-2740., highlight how the delayed diagnosis and treatment of infected individuals are decisive for the speed of the spread of infections in epidemic contexts. In several countries, one of the most effective measures for detecting and preventing new COVID-19 cases was the large-scale testing of the population⁴¹41 Ng Y, Li Z, Chua YX, Liang W, Zhao Z, Er B, Pung R, Chiew CJ, Lye DC, Heng D, Lee VJ. Morbidity and Mortality Weekly Report Evaluation of the Effectiveness of Surveillance and Containment Measures for the First 100 Patients with COVID-19 in Singapore. MMWR Morb Mortal Wkly Rep 2020; 69(11):307-311

42 Peto J. Covid-19 mass testing facilities could end the epidemic rapidly. BMJ 2020; 368:m1163.^-4343 Beeching NJ, Fletcher TE, Beadsworth MBJ. Covid-19: Testing times. BMJ 2020; 369:m1403., already recommended by the WHO¹1 World Health Organization (WHO). Rolling updates on coronavirus disease (COVID-19). 2020. [acessado 2020 Maio 31]. Disponível em: https://www.who.int/emergencies/diseases/novel-13 coronavirus-2019/events-as-they-happen
https://www.who.int/emergencies/diseases... , and the indication of quarantine for 14 days for the identified cases, and their direct contacts after the onset of symptoms⁴⁴44 Brasil. Ministério da Saúde (MS). Emergência de Saúde Pública de Importância Nacional pela Doença pelo Coronavírus 2019: Vigilância Integrada de Síndromes Respiratórias Agudas Doença pelo Coronavírus 2019, Influenza e outros vírus respiratórios. Brasília: MS; 2020. [acessado 2020 Maio 12]. Disponível em: https://portalarquivos.saude.gov.br/images/pdf/2020/April/07/GuiaDeVigiEpidemC19-v2.pdf
https://portalarquivos.saude.gov.br/imag... .

Some countries in Asia and Oceania have shown control of the pandemic by combining strategies with extensive testing. For example, in China, important measures for the control of COVID-19, were: early detection of cases through testing, isolation of cases and screening of all contacts, and quality clinical care for those infected⁴⁰40 Rong X, Yang L, Chu H, Fan M. Effect of delay in diagnosis on transmission of COVID-19. Mathematical Biosciences and Engineering 2020; 17:2725-2740.. In Singapore, epidemiological surveillance included testing all suspected cases and contact persons. Thus, this strategy contributed to the early detection of approximately half (53%) of the COVID-19 cases and was also an effective strategy for the progressive reduction of the appearance of indigenous cases of the disease right at the onset of the epidemic⁴¹41 Ng Y, Li Z, Chua YX, Liang W, Zhao Z, Er B, Pung R, Chiew CJ, Lye DC, Heng D, Lee VJ. Morbidity and Mortality Weekly Report Evaluation of the Effectiveness of Surveillance and Containment Measures for the First 100 Patients with COVID-19 in Singapore. MMWR Morb Mortal Wkly Rep 2020; 69(11):307-311. The example of Singapore and Hong Kong indicates the importance of expanding testing, the surveillance system with selective control of travelers, and financing measures for state funding for treatment, planning, articulation, and management of health services⁴⁵45 Legido-Quigley H, Asgari N, Teo YY, Leung GM, Oshitani H, Fukuda K, Cook AR, Hsu LY, Shibuya K, Heymann D. Are high-performing health systems resilient against the COVID-19 epidemic? Lancet 2020; 395:848-850.. New Zealand has managed to control the pandemic in its territory and eliminate community transmission⁴⁶46 Cousins S. New Zealand eliminates COVID-19. Lancet 2020; 395:1474., by adopting, among other strategies (such as lockdown, border control, health education promotion, among others), large-scale testing of the population for screening and rapid detection of cases and contacts, and implementation of quarantine⁴⁷47 New Zealand's elimination COVID-10. [acessado 2020 Maio 12]. Disponível em: https://www.nzma.org.nz/journal-articles/new-zealands-elimination-strategy-for-the-covid-19-pandemic-and-what-is-required-to-make-it-work
https://www.nzma.org.nz/journal-articles... . In Australia, the testing actions associated with the organization of the health system combined with telehealth actions resulted in a low fatality rate, with 7,185 confirmed cases and 103 deaths, equivalent to fatality rate of 1.4% on May 31, 2020³3 World Health Organization (WHO). COVID-19 Dashboard. 2020. [acessado 2020 Maio 12]. Disponível em: https://covid19.who.int/
https://covid19.who.int/... ^,4848 Australian Government. Department of Health. Coronavirus (COVID-19) current situation and case numbers. 2020. [acessado 2020 Maio 12]. Disponível em: https://www.health.gov.au/news/health-alerts/novel-coronavirus-2019-ncov-health-alert/coronavirus-covid-19-current-situation-and-case-numbers
https://www.health.gov.au/news/health-al... .

In Europe, we observed some countries that experienced a collapse of the hospital care network, such as Italy, which implemented extensive testing, including for asymptomatic people, only after the dramatic situation of lack of intensive care beds⁴⁹49 Paterlini M. On the front lines of coronavirus: The Italian response to covid-19. BMJ 2020; 368:m1065.. Spain adopted a testing protocol only for people with symptoms of the acute respiratory syndrome and symptomatic health professionals, and also exceeded the installed capacity of the number of intensive care beds⁵⁰50 Tanne JH, Hayasaki E, Zastrow M, Pulla P, Smith P, Rada AG. Covid-19: How doctors and healthcare systems are tackling coronavirus worldwide. BMJ 2020; 368:m1090.. The United Kingdom also adopted late measures to tackle the pandemic and testing⁵¹51 Lacobucci G. Covid-19: What is the UK's testing strategy? BMJ (Clinical research ed) 2020; 368:m1222., but recently adopted a surveillance protocol that involves people with influenza-like symptoms, and the collection of serological samples from all age groups, with regular data monitoring⁵²52 de Lusignan S, Lopez Bernal J, Zambon M, Akinyemi O, Amirthalingam G, Andrews N, Borrow R, Byford R, Charlett A, Dabrera G, Ellis J, Elliot AJ, Feher M, Ferreira F, Krajenbrink E, Leach J, Linley E, Liyanage H, Okusi C, Ramsay M, Smith G, Sherlock J, Thomas N, Tripathy M, Williams J, Howsam G, Joy M, Hobbs R. Emergence of a Novel Coronavirus (COVID-19): Protocol for Extending Surveillance Used by the Royal College of General Practitioners Research and Surveillance Centre and Public Health England. JMIR Public Health and Surveillance 2020; 6(2):e18606.. On the other hand, Germany is one of the continent’s exceptions, showing a rapid and coordinated response to the pandemic, associated with decentralized testing, including young people and cases with mild symptoms from the start of the pandemic⁵³53 Stafford N. Covid-19: Why Germany's case fatality rate seems so low. BMJ 2020; 369:1-2..

Two countries are highlighted in the Americas. First, the United States of America, the largest country in North America, which showed a late and uncoordinated national response to testing and social isolation⁵⁰50 Tanne JH, Hayasaki E, Zastrow M, Pulla P, Smith P, Rada AG. Covid-19: How doctors and healthcare systems are tackling coronavirus worldwide. BMJ 2020; 368:m1090., which may have led it to rank first in the number of confirmed COVID-19 cases (1,716,078) and deaths (101,567) as of May 31, 2020⁵⁴54 Centers for Disease Control and Prevention (CDC). Cases in the U.S. 2020. [acessado 2020 Maio 12]. Disponível em: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html
https://www.cdc.gov/coronavirus/2019-nco... . Then Brazil, the largest country in Latin America, which registers an increasing trend of confirmed cases and deaths, with an uncoordinated response from national government⁵⁵55 Lancet. COVID-19 in Brazil: "So what?" Lancet 2020; 395:1461. and with limited testing of the population²¹21 Prado M, Bastos L, Batista A, Antunes B, Baião F, Maçaira P, Hamacher S, Bozza F. Análise de subnotificação do número de casos confirmados da COVID-19 no Brasil. Núcleo de Operações e Inteligência em Saúde (NOIS) 2 Metodologia. 2020. [acessado 2020 Maio 12]. Disponível em: https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-
https://www.who.int/docs/default-source/... . On the other hand, the importance of the National Health System (SUS) with universal access⁵⁶56 Paim J, Travassos C, Almeida C, Bahia L, MacInko J. The Brazilian health system: History, advances, and challenges. Lancet 2011; 377(9779):1778-1797., with a broad National Health Surveillance System (SNVS), which favors the adoption of quick responses by many regional and local governments.

Thus, while not exhausting the literature on the countries’ testing response, the importance of testing strategies⁴²42 Peto J. Covid-19 mass testing facilities could end the epidemic rapidly. BMJ 2020; 368:m1163. associated with the organization of the health system in addressing the pandemic is emphasized, as the number of confirmed cases allows monitoring of progression disease⁵⁷57 Hasell J, Ortiz-Ospina E, Mathieu E, Ritchie H, Beltekian DMB, Roser M. To understand the global pandemic, we need globas testing - the Our World in Data COVID-19 Testing dataset. Oxford: University of Oxford; 2020., which can prevent the collapse of the hospital care network, based on the articulation between different health care levels. Moreover, although we are still unable to isolate the effect of the testing strategy on disease incidence rates, international experiences show the importance of these efforts coordinated with health systems in controlling the COVID-19 pandemic.

Epidemiological surveillance

The process of investigation, notification, and monitoring of COVID-19 cases by the SNVS of the Brazilian SUS is fundamental in response to COVID-19, as it operates throughout the Brazilian territory in an articulated and hierarchical way, through the Strategic Health Surveillance Information and Response Centers (CIEVS), from the municipal and state health secretaries⁵⁸58 Teixeira MG, Costa MCN, Carmo EH, Oliveira WK, Penna GO. Health surveillance at the SUS: Development, effects and perspectives. Cien Saude Colet 2018; 23(6):1811-1818.. Besides routine activities, the SNVS is triggered in the event of situations of Public Health Emergencies of National Importance, such as the COVID-19 pandemic⁴⁴44 Brasil. Ministério da Saúde (MS). Emergência de Saúde Pública de Importância Nacional pela Doença pelo Coronavírus 2019: Vigilância Integrada de Síndromes Respiratórias Agudas Doença pelo Coronavírus 2019, Influenza e outros vírus respiratórios. Brasília: MS; 2020. [acessado 2020 Maio 12]. Disponível em: https://portalarquivos.saude.gov.br/images/pdf/2020/April/07/GuiaDeVigiEpidemC19-v2.pdf
https://portalarquivos.saude.gov.br/imag... . In these cases, the service network must be organized to respond quickly with the urgent use of measures to prevent, control, and contain risks, damage, and harm to public health⁵⁹59 Brasil. Ministério da Saúde (MS). Centro de informações estratégicas em vigilância em saúde-CIEVS. Brasília: MS; 2020. [acessado 2020 Maio 12]. Disponível em: https://www.saude.gov.br/vigilancia-em-saude/emergencia-em-saude-publica/cievs
https://www.saude.gov.br/vigilancia-em-s... .

Decentralized testing is a fundamental strategy for increasing the detection of new cases, linking to adequate care and epidemiological surveillance, but it faces some challenges such as socioeconomic inequalities and the distribution of equipment/supplies and infrastructure available for diagnosis. In this sense, some initiatives aimed at expanding testing have been adopted by the National Health Surveillance Agency (ANVISA), such as the approval of rapid tests (RT) in pharmacies⁶⁰60 Nascimento L. Anvisa aprova testes rápidos para covid-19 em farmácias. 2020. [acessado 2020 Maio 12]. Disponível em: https://agenciabrasil.ebc.com.br/saude/noticia/2020-04/anvisa-aprova-testes-rapidos-para-covid-19-em-farmacias
https://agenciabrasil.ebc.com.br/saude/n... , and new diagnostic tests for the detection of antibodies for SARS-CoV-2⁶¹61 Agência Nacional de Vigilância Sanitária (Anvisa). Covid-19: aprovados seis novos testes. 2020. [acessado 2020 Maio 12]. Disponível em: http://portal.anvisa.gov.br/noticias/-/asset_publisher/FXrpx9qY7FbU/content/covid-19-aprovados-seis-novos-testes/219201
http://portal.anvisa.gov.br/noticias/-/a... ^,6262 Agência Nacional de Vigilância Sanitária (Anvisa). Aprovados primeiros testes rápidos para Covid-19. 2020. [acessado 2020 Maio 12]. Disponível em: http://portal.anvisa.gov.br/noticias/-/asset_publisher/FXrpx9qY7FbU/content/aprovados-primeiros-testes-rapidos-para-covid-19/219201
http://portal.anvisa.gov.br/noticias/-/a... . Furthermore, a national epidemiological and laboratory surveillance strategy for COVID-19 was launched on May 6, 2020 to test about 22% of the Brazilian population⁶³63 Brasil. Ministério da Saúde (MS). Programa Diagnosticar para Cuidar prevê ações de testagem em 2020. 2020. [acessado 2020 Maio 12]. Disponível em: https://www.saude.gov.br/noticias/agencia-saude/46848-programa-diagnosticar-para-cuidar-preve-acoes-de-testagem-em-2020
https://www.saude.gov.br/noticias/agenci... .

However, the testing strategy should consider the accuracy of the tests for antibody detection, since the sensitivity and specificity of the tests approved in Brazil vary between kits from different manufacturers⁶⁴64 Brasil. Ministério da Saúde (MS). Acurácia dos diagnósticos registrados para COVID-19. Brasília: MS; 2020. [acessado 2020 Maio 12]. Disponível em: https://portalarquivos.saude.gov.br/images/pdf/2020/April/29/Acuracia-Diagnosticos-COVID19.pdf
https://portalarquivos.saude.gov.br/imag... . Few validation studies have been published⁶⁵65 Castro R, Luz PM, Wakimoto MD, Veloso VG, Grinsztejn B, Perazzo H. COVID-19: a meta-analysis of diagnostic test accuracy of commercial assays registered in Brazil. Braz J Infect Dis 2020; 24(2):180-187.. For example, among the tests approved in Brazil, sensitivity is found in low to moderate levels, which may result in the difficulty in detecting infected individuals, especially in tests for the detection of anti-SARS-CoV-2 antibodies of the IgM class in the initial phase of infection⁶⁵65 Castro R, Luz PM, Wakimoto MD, Veloso VG, Grinsztejn B, Perazzo H. COVID-19: a meta-analysis of diagnostic test accuracy of commercial assays registered in Brazil. Braz J Infect Dis 2020; 24(2):180-187.. Moreover, the positive predictive value may vary with the prevalence of infection in the population, with higher values in populations with a prevalence equal to or greater than 10%⁶⁶66 Nadanovsky P. A utilidade do teste para detecção de anticorpos do SARS-CoV-2. Notícias UERJ 2020. [acessado 2020 Maio 12]. Disponível em: https://www.ims.uerj.br/2020/04/27/a-utilidade-do-teste-para-deteccao-de-anticorpos-do-sars-cov-2/
https://www.ims.uerj.br/2020/04/27/a-uti... . It is also important to note that many of the tests available are still in the process of technical improvement. Besides, there are few studies related to the dynamics of biomarkers in the humoral immune response.

Thus, information and communication on the limiting aspects of these tests and the interpretation of the tests by the professionals who will apply the RT and other tests are essential, so that there is no low perception of the risk of transmission by the population, due, for example, to false-negative results, as it could enhance social interaction and increase transmission. Moreover, we should consider that testing must be linked to the recording and monitoring of the SNVS, and the assistance of trained health professionals for clinical-individual care in case management, and guidance on the limitations of sensitivity and specificity of the tests. It is also necessary to ensure the testing of Brazilian citizens from local income communities who cannot pay for tests, as well as the secrecy and confidentiality of individual results.

The Brazilian and international response to the HIV/AIDS epidemic showed that testing decentralization is fundamental to increase the early diagnosis of the infection, and the rapid link to care, also through the application of RT for screening by trained lay people⁶⁷67 Estem Kristecia S, Catania J, Klausner JD. HIV Self-Testing: a Review of Current Implementation and Fidelity. Current HIV/AIDS Reports 2016; 13(2):107-115.

68 Brasil. Ministério da Saúde (MS). The HIV self-test in SUS. 2020. [acessado 2020 Maio 12]. Disponível em: http://www.aids.gov.br/pt-br/autoteste/o-autoteste-de-hiv-no-sus
http://www.aids.gov.br/pt-br/autoteste/o... ^-6969 World Health Organization (WHO), UNITAID. Landscape for HIV rapid diagnostic tests for HIV self-testing. 2015. [acessado 2020 Maio 12]. Disponível em: https://www.who.int/hiv/pub/vct/hiv-self-testing _landscape_2015-unitaid-who.pdf?ua=1
https://www.who.int/hiv/pub/vct/hiv-self... . In this way, primary health care (PHC), which is the preferred gateway to the SUS, can play an essential role in expanding testing, as it is present in the remote Brazilian locations⁷⁰70 Garnelo L, Lima JG, Rocha ESC, Herkrath FJ. Acesso e cobertura da Atenção Primária à Saúde para populações rurais e urbanas na região norte do Brasil. Saúde em Debate 2018; 42(n. esp. 1):81-99., with teams of community workers accessing communities⁷¹71 Nunes CA, Aquino R, Medina MG, Vilasbôas ALQ, Pinto Júnior EP, Luz LA. Visitas domiciliares no Brasil: características da atividade basilar dos Agentes Comunitários de Saúde. Saúde em Debate 2018; 42(n. esp. 2):127-144., and health professionals trained in the application of other RTs (HIV, syphilis and viral hepatitis)⁷²72 Brasil. Ministério da Saúde (MS). Testes Rápidos. 2020. [acessado 2020 Maio 12]. Disponível em: http://www.aids.gov.br/pt-br/profissionais-de-saude/testes-rapidos
http://www.aids.gov.br/pt-br/profissiona... . Thus, PHC can become the central locus for decentralized and democratized RT to identify COVID-19 cases in the Brazilian territory, with an active search of cases and contacts, with the link of users to quarantine strategies, and the provision of primary care to those infected with mild symptoms and the articulation with other points in the health care network.

In this sense, the testing response for COVID-19 can be coordinated by SNVS on two fronts: 1) individual: with access to the test through the supplementary health network (private services: hospitals, clinics or pharmacies), with notification of cases and monitoring by local epidemiological surveillance, and clinical care with appropriate guidance; and 2) community: with priority access through PHC (without the elimination of access via other levels of care), with due notification of cases, organized and monitored through local epidemiological surveillance. Furthermore, the active search should be adopted as a starting point for the investigation of all contacts of confirmed COVID-19 cases, using the RT-qPCR test with an oral/nasal swab sample collected within seven days after the onset of symptoms or immunological test (rapid test by immunochromatography or serology by ELISA) seven days after the onset of symptoms. For asymptomatic patients, the collection can be based on the number of days reported after contact with the infected person: <7 days (RT-qPCR) and ≥ 7 days (immunological). Cases confirmed with a positive result should be tested and recommended to be quarantined for 14 days, according to the Ministry of Health protocol (Figure 1)⁴⁴44 Brasil. Ministério da Saúde (MS). Emergência de Saúde Pública de Importância Nacional pela Doença pelo Coronavírus 2019: Vigilância Integrada de Síndromes Respiratórias Agudas Doença pelo Coronavírus 2019, Influenza e outros vírus respiratórios. Brasília: MS; 2020. [acessado 2020 Maio 12]. Disponível em: https://portalarquivos.saude.gov.br/images/pdf/2020/April/07/GuiaDeVigiEpidemC19-v2.pdf
https://portalarquivos.saude.gov.br/imag... .

Conclusions

The expansion of the COVID-19 testing and diagnosis is a challenge to Brazilian society and the SUS. While we have faced a process of chronic de-financing and constant threats to the public health system for years, we have decentralized management and epidemiological surveillance mechanisms capable of responding appropriately to the challenge. Moreover, we have a network of laboratories, universities, and public research institutes in all states of the country, which can organize a diagnostic service network, under the coordination of the SNVS, to expand COVID-19 testing. Therefore, it is necessary to eliminate bureaucratic barriers for the accreditation of laboratories in universities and research institutes for diagnosis, expand financing for training and hiring staff, invest in research studies on serological diagnosis, epidemiology, vaccine development and treatment, and have a political-scientific articulation for decision-making based on local and global scientific evidence.

Acknowledgments

We are grateful to the Brazilian Health Reform Movement for helping to found and build the National Health System (SUS), which is a source of inspiration for all of us Brazilian health workers. We also thank the Brazilian public universities for having trained us and for being our workspace.

References

Publication Dates

History