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New trends of the microcephaly and Zika virus outbreak in Brazil, July 2016–December 2016
Travel Medicine and Infectious Disease xxx (2017) 1e6
Contents lists available at ScienceDirect
Travel Medicine and Infectious Disease journal homepage: www.elsevierhealth.com/journals/tmid
New trends of the microcephaly and Zika virus outbreak in Brazil, July 2016eDecember 2016
Dear Editor Recently we published an article about the trends of the microcephaly and Zika virus outbreaks in Brazil, from January to July 2016 [1]. There was some evidence that the Zika virus and microcephaly cases were declining over the studied period, mainly in the Northeast region, which was the most heavily affected in the country. However, high incidences of Zika virus infection were still occurring during the first months of 2016 in some states, such as Rio de Janeiro (Southeast region), Bahia (Northeast region) and Mato Grosso (Midwest region). In the present study we analyzed the same publicly available data from July to December 2016 to continue the evidence-based discussion presented in the first article. Data extracted from the epidemiological reports from the Secretary of Health Surveillance of the Brazilian MoH to monitor cases of microcephaly and neurological abnormalities associated with congenital infections from July 3 to December 31, 2016 were analyzed [2]. Probable cases of Zika virus infection reported in Brazil from July 09 to December 31, 2016 were also analyzed to look for any parallels between the Zika virus disease in the general population and microcephaly cases in infants [3]. In the bulletins, the total cumulative number of reported microcephaly cases are classified as being 1) under investigation (investigation not completed), 2) confirmed (by neuroimaging and/or laboratory testing), or 3) excluded (investigation with negative results); and among confirmed cases, whether or not they were associated with Zika virus infection during pregnancy (positive RT-PCR and/ or serology for Zika virus in the mother and/or newborn). To assess trends, we calculated the mean number of cases per week of microcephaly or Zika virus disease. The incidence of Zika virus infection per 100,000 inhabitants in Brazil and regionally was calculated from January to December 2016 and in the first and second half of the year. The incidence of microcephaly per 10,000 live births in Brazil and regionally was calculated from the beginning of the outbreak to December 2016 and then stratified in the periods before and after July 2, 2016. Since the beginning of the outbreak of microcephaly in November 2015, 23.6% of cases (2566/10,867) were reported in the second half of 2016 (EW27-52); from these, 40% (n ¼ 1026) occurred in the Southeast region, and 36.8% (n ¼ 944) in the Northeast region (Table 1). Sixty-three percent of the cases found to be associated with Zika virus infection (442/697) by specific positive
tests (reverse transcriptionepolymerase chain reaction [RT-PCR] and/or serology) in samples from the newborn and/or the mother were confirmed in the second half of 2016 (Table 2). The percentage of cases remaining under investigation presented a very modest decline from the first to the second half of 2016 (37.7% in EW 26 vs. 29.3% in EW 52) (Table 2). The incidence of reported cases of microcephaly in Brazil dropped dramatically between the period before and after July 2016, from 41.3/10,000 to 17.0/10,000 live births, respectively. The Northeast region contributed the most for the decline, while the incidence in the other regions showed fewer variations (Table 1). The incidence of confirmed cases dropped from 8.2/10,000 to 4.7/10,000 live births between the periods before and after July 2016. A marked decline occurred in the Northeast region from 25.4 to 8.9, while the incidence doubled in the Southeast (1.4 vs. 3.1), Midwest (3.4 vs. 7.2), and South (0.4 vs. 0.8) regions (Table 1). Since EW 11 in March, the reported cases of microcephaly had dropped to lesser than 150 cases per week. From EW 27 to 52, the mean number of cases per week was 99, with some fluctuations and a trend to stabilization in the whole country and all the regions (Fig. 1Ae1F). After an initial decline from EW 27 to 36, the reported cases increased in EW 37 and 38 (mainly at the expenses of the Northeast region), followed by a decline from EW 39 to 50 and increased again in EW 51-52, in December (at the expenses of the Northeast and the Southeast regions). Nineteen percent of all cases of Zika virus infection reported in 2016 occurred in the second half of the year (41,316/215,319) (Table 3). The mean number of cases per week dropped from 6445 in the first six months to 2018 in EW 27. From EW 28 to 32 (mid-July to mid-August), it increased again to an average of 4595 cases per week, 64% of which occurred in the Southeast region (n ¼ 2937). Then, it fluctuated around much lower numbers, the Southeast region being the main responsible for this fluctuation in the whole country. Overall, there was a declining trend in the country as a whole (b 126.45; chi-square test for trend p < 0.001) and in all the regions, except in the Midwest (b þ2.02; chi-square test for trend p < 0.001) and in the South (b þ0.35; chi-square test for trend p < 0.001), which presented very few cases. (Fig. 1A and F). A sharp decline in the incidence of probable Zika virus infection occurred in all regions in the second half of 2016. The highest incidence continued to be in the Midwest region (94.1/100,000), followed by the Southeast (54.0/100,000), the Northeast (31.6/100,000), the North (22.5/100,000) and the South
http://dx.doi.org/10.1016/j.tmaid.2017.03.009 1477-8939/© 2017 Elsevier Ltd. All rights reserved.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
2
Abbreviations MoH RT-PCR WHO
Ministry of Health reverse transcriptase protein chain reaction World Health Organization
(6.4/100,000) regions (Fig. 2 and Table 3). The rapid spread of the Zika virus across Latin America has been associated to environmental and social changes, such as climate variation, land use change, poverty and human movement that have fueled the epidemic [4]. Questions have been raised about how far it will continue to spread. The present analysis indicates that in Brazil, in the second half of 2016, the Zika virus and microcephaly cases continued to decline and switched from the Northeast to the Southeast and Midwest regions. After July, the weekly reported and confirmed cases of microcephaly presented a trend to stabilization in a much lower level than before July in the whole country and all the regions. However, the incidence rates of confirmed cases more than doubled in the Southeast and Midwest regions. The South region, which has a cooler weather in most months of the year, continued to present the fewer cases and incidence of microcephaly. A marked seasonality similar to other arbovirus infections such as dengue should be expected in the Zika virus infection and actually the weekly reported cases began to fall in June in most regions, except the Midwest, which presented an increase in December and
the highest incidence in 2016, although the absolute number of cases was far behind the Northeast and Southeast regions. In the second half of the year, the total number of probable cases of Zika virus infection was much lower than the numbers before June, mainly in the Northeast region, while the Southeast region contributed the highest number of cases. It is possible that with the beginning of the summer season in December, new peaks of Zika virus infection and microcephaly will still occur in some regions of the country in 2017. However, as to EW 7 in February 18, 2017, 1653 probable cases of Zika virus infection were reported in the whole country, with a dramatic fall in the mean number of cases per week, mainly in the Southeast and Midwest regions, but not in the North (Fig. 3). Meanwhile, as to EW 2, 84 cases of neurodevelopmental abnormalities possibly related to Zika virus or other congenital infections were reported, which represents a fall in the mean numbers per week in all regions of the country. As the rate of confirmation of microcephaly cases depends on the availability of neuroimaging or laboratory tests, the temporal course of the reported cases of microcephaly, but not of the confirmed cases, is expected to be more associated with the temporal course of the Zika virus infection. It is plausible that the increase in the number of reported cases of microcephaly in EWs 37-38 in September was related to the previous peak in the number of Zika virus infection nearly twenty weeks earlier, in May as we showed in the first article [1]. On the other hand, the increase in the number of microcephaly cases in EWs 51-52, in the Southeast and Northeast regions was probably associated to the higher numbers of Zika cases in EWs 28-32 from mid-July to mid-August
Table 1 Reported and confirmed cases of microcephaly and neurological abnormalities associated with congenital infection from November 2015 to December 2016, in Brazil.
Brazil Northeast Southeast North Midwest South
Nº of REPORTED cases of microcephaly
Estimated number of live birthsa
Incidence of reported microcephaly per Incidence ratio (2nd/1st semester) 10,000 live births
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
10,867 7,023 2,324 550 716 254
3,515,433 986,025 1,394,234 372,866 288,045 474,263
30.9 71.2 16.7 14.8 24.9 5.4
8,301 6,079 1,298 329 454 141
2,566 944 1,026 221 262 113
2,008,819 563,443 796,705 213,066 164,597 271,007
1,506,614 422,582 597,529 159,800 123,448 203,256
Nº of CONFIRMED cases of microcephaly Estimated number of live birthsa
Brazil Northeast Southeast North Midwest South a
41.3 107.9 16.3 15.4 27.6 5.2
17.0 22.3 17.2 13.8 21.2 5.6
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
Incidence of confirmed microcephaly per 10,000 live births Nov 15-Dec 16 Before July 2nd semester
2,366 1,804 298 92 145 27
3,515,433 986,025 1,394,234 372,866 288,045 474,263
6.7 18.3 2.1 2.5 5.0 0.6
1,656 1,429 110 50 56 11
710 375 188 42 89 16
2,008,819 563,443 796,705 213,066 164,597 271,007
1,506,614 422,582 597,529 159,800 123,448 203,256
8.2 25.4 1.4 2.3 3.4 0.4
4.7 8.9 3.1 2.6 7.2 0.8
0.41 0.21 1.10 0.90 0.77 1.10 Incidence ratio (2nd/1st semester)
0.57 0.35 2.21 1.13 2.12 2
The estimated numbers of live births are based on preliminary data of 2015 from DATASUS (Brazilian Ministry of Health).
Table 2 Cases of microcephaly that completed investigation, cases that remained under investigation and cases confirmed to be.associated with Zika virus infection from November 2015 to December 2016, in Brazil.
Completed investigated cases (confirmed þ excluded) Under investigation cases Zika-associated cases
Cases of micrcephaly EW 46/2015 to EW 26/2016 Nov 2015 to Jun 2016
Cases of micrcephaly EW 27/2016 to EW 52/2016 Jul 2016 to Dec 2016
Cases of micrcephaly EW 46/2015 to EW 52/2016 Nov 2015 to Dec 2016
5,171 (1,656 þ 3,515) 3,130 255
1,754 e 442
7,635 (2,366 þ 5,269) 3,183 697
EW e epidemiological week; confirmed cases of microcephaly e cases confirmed by neuroimaging (independent of specific tests for Zika virus) or by laboratory tests; Zikaassociated cases e cases of microcephaly confirmed to be associated with Zika virus by specific RT-PCR tests or serology in the mother and or newborn.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
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Fig. 1. eReported and confirmed cases of microcephaly and Zika virus infection cases from epidemiological week 27e52/2016, in Brazil and regionally: 1A - Brazil; 1B e Northeast; 1C e Southeast; 1D e North; 1E e Midwest; and 1F e South.
Table 3 Reported cases of Zika virus infection from Epidemiological Week 1e52 (January 3 to December 31), 2016, in Brazil. Nº of REPORTED cases of Zika virus infection
Brazil Northeast Southeast North Midwest South a
Estimated number of inhabitantsa Incidence of reported cases of Zika virus infection per 100,000 inhabitants
JaneDec 16 1st semester 2nd semester JaneDec 16
JaneDec 16 1st semester 2nd semester
214,193 75,922 90,573 12,896 33,848 954
105.3 134.4 106.2 74.2 222.0 3.4
174,003 66,991 67,544 10,944 26,674 1,850
40,190 8,931 23,029 1,952 7,174 896
203,412,156 56,489,583 85,285,311 17,380,053 15,246,847 28,058,824
171.1 237.2 158.4 125.9 349.9 13.2
39.5 31.6 54.0 22.5 94.1 6.4
Incidence ratio (2nd/1st semester)
0.23 0.13 0.34 0.18 0.27 0.48
The estimated numbers of inhabitants are based data of 2016 from the Brazilian Institute of Geography and Statistics (IBGE).
in these regions, nearly twenty weeks earlier. These intervals between peak of Zika virus infection in the general population and peak of microcephaly favors the evidence that the risk for neurologic abnormalities in the fetus is greater in the first and second trimester of pregnancy [5]. The relative stabilization in the weekly number of reported and confirmed cases of microcephaly in the second semester were expected because of various factors. In the first months of 2016,
during the most favorable hot season for Zika dissemination by its most common vector in Brazil (Aedes aegypti), cases of Zika infection were already declining in the Northeast, probably due to development of immunity, which limits the virus dissemination in the population. Therefore, subsequent cases of microcephaly were expected to decline. On the other hand, the switch of Zika infection cases toward the Southeast and Midwest regions in the beginning of 2016, was associated with an increased awareness
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
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~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
Fig. 2. Incidence (/100 mil hab.) Zika vírus disease according to place of residence by Epidemiological Week 52, Brazil, 2016. Source: Weekly epidemiological report on Dengue, Chikungunya and Zika from the Brazilian MoH.
Fig. 3. Probable cases of Zika vírus infection, by epidemiological week of the begining of symptoms, Brazil, 2016 and 2017.
about the risk for the fetus and probably led people to take preventive measures against mosquito bites. This might contribute to minimize the outbreak of microcephaly in these regions. Still, other environmental, social, genetic or unknown factors may not be
excluded to explain why the Northeast region had such a higher number of cases of microcephaly. Messina et al. mapped the areas that provide conditions that are highly suitable for the spread of the virus. These areas include many
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
tropical and subtropical regions around the globe In addition to Brazil, Colombia and Venezuela are the largest areas of risk in the Americas. A large portion of the subcontinent of India, the Southeast region from Texas to Florida, much of the sub-Saharan Africa, the Indochina region, southeast China, and Indonesia all have large areas of environmental suitability, extending into Oceania [6]. Monitoring and surveillance systems need to be implemented in all susceptible countries. In Brazil, improvements in the confirmation system are necessary. The capacity of the Surveillance System to investigate the cases of microcephaly did not improve over the period of the outbreak. Availability of serology (IgM and IgG) for Zika virus on a large scale is paramount, since the RT-PCR test may be only useful in the early acute phase (first five to seven days) of the disease. The findings in this report are subject to the same limitations mentioned in our previous report on trends of microcephaly and Zika virus infection in Brazil [1]. First, the report of probable Zika virus infection are based on the presence of symptoms and refers to the general population. However, most cases are asymptomatic, which may lead to a gross underestimation of Zika virus cases. Moreover, the assessment of Zika cases in the pregnant women, would be ideal to show the association with microcephaly. Second, the number of live births in 2016, an indirect estimate of the pregnancy rate, was unavailable and impaired the assessment of deferral of pregnancy as a factor contributing to microcephaly declining. Third, inaccuracy in the measurement of head circumference may have occurred and could have resulted in under or over ascertainment of cases of microcephaly. Fourth, the large number of cases of microcephaly, which has not completed the investigation, reduces the ability to estimate the true number of microcephaly cases. Fifth, confirmed cases include all cases of microcephaly and neurological abnormalities associated to congenital infections that had been confirmed by neuroimaging or by laboratory tests and not just those linked to Zika virus. The limited availability of specific tests for Zika virus makes difficult to assess the real impact of the virus as a cause of neurological abnormalities in some cases, although compelling data supports a causal relationship [7]. Sixth, the report does not capture newborns with brain growth impairment and normal head circumference. In conclusion, in the second half of 2016, the Zika virus epidemic continued to decline in the country as a whole, but the virus was still spreading toward the Midwest. The incidence of reported cases of microcephaly and neurological abnormalities associated with congenital infection fell dramatically in the Northeast region, but not in the other regions. In the first summer weeks of 2017 the numbers of Zika virus infection continue to decline in all regions, but the North, while the numbers of neurodevelopmental abnormalities is decreasing in all regions. Ongoing monitoring and surveillance are essential. Sufficient resources for investigation of all reported cases are urgently needed.
Contributors All of the authors participated in the conception, design and conducting of the study, as well as the management, analyses and interpretation of data. MCMB drafted the manuscript, and all of the authors contributed substantially to its revision. All of the authors approved the final version to be submitted.
Competing interests None.
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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References [1] Magalh~ aes-Barbosa MC, Prata-Barbosa A, Robaina JR, Raymundo CE, LimaSetta F, Cunha AJ. Trends of the microcephaly and Zika virus outbreak in Brazil, January-July 2016. Sep - Oct Travel Med Infect Dis 2016;14(5):458e63. http:// dx.doi.org/10.1016/j.tmaid.2016.09.006. PubMed PMID: 27702683. rio da Saúde. Centro de Operaço ~ es de Emerge ^ncias em Saúde Púb[2] Brasil Ministe lica sobre Microcefalias. Monitoramento de Casos de Microcefalia no Brasil. gico nº 57/2016. Semana epidemiolo gica (se) 52/2016 (25 Informe epidemiolo rio da Saúde, 2016 (in Portuguese). [Monitoring a 31/12/16). Brasília: ministe Cases of Microcephaly in Brazil]Available at:: http://combateaedes.saude.gov. br/images/pdf/Informe-Epidemiologico-n57-SE-52_2016 09jan2017.pdf. Accessed on February 17, 2017. rio da Saúde. Secretaria de Vigil^ [3] Brasil Ministe ancia em Saúde. Boletim Epidegico nº 3/2017 - monitoramento dos casos de dengue e febre de chikungumiolo a semana epidemiolo gica (SE) 52 (03/01/2016 a 31/12/2016) (in nya ate Portuguese). [Monitoring cases of dengue, chikungunya fever and Zika virus fever until Epidemiological Week 52/2016 (Jan 3 to Dec 31 2016)]Available at:: http://combateaedes.saude.gov.br/images/boletins-epidemiologicos/2016 Dengue_Zika_Chikungunya-SE52.pdf. Accessed on February 17, 2017. [4] Ali S, Gugliemini O, Harber S, Harrison A, Houle L, Ivory J, et al. Environmental and social change drive the explosive emergence of Zika virus in the Americas. Feb 9 PLoS Negl Trop Dis 2017;11(2):e0005135. http://dx.doi.org/10.1371/journal.pntd.0005135. Review. PubMed PMID:28182667. [5] Brasil P, Pereira Jr JP, Moreira ME, Ribeiro Nogueira RM, Damasceno L, Wakimoto M, et al. Dec 15 Zika Virus Infect Pregnant Women Rio de Janeiro.N Engl J Med 2016;375(24):2321e34. PubMed PMID: 26943629. [6] Messina JP, Kraemer MU, Brady OJ, Pigott DM, Shearer FM, Weiss DJ, et al. Mapping global environmental suitability for Zika virus. Apr 19;5. pii: e15272 Elife 2016. http://dx.doi.org/10.7554/eLife.15272.PubMed. PMID: 27090089; PubMed Central PMCID: PMC4889326. [7] Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birthdefectsereviewing the evidence for causality. N Engl J Med 2016;374(20): 1981e7. http://dx.doi.org/10.1056/NEJMsr1604338. May 19.
~es-Barbosa, MD, PhD* Maria Clara de Magalha Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil Arnaldo Prata-Barbosa, MD, PhD Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil Faculdade de Medicina da Universidade Federal do Rio de Janeiro, ria, Rua Bruno Lobo, nº Departamento de Pediatria, Cidade Universita 50, Rio de Janeiro, 21941-612, Brazil E-mail address: [email protected]. Jaqueline Rodrigues Robaina, PhD Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Carlos Eduardo Raymundo, MSc Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Fernanda Lima-Setta, MD, MSc Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Ledo Alves da Cunha, MD, PhD Antonio Jose
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
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~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Departamento de Pediatria, Rua Bruno Lobo, nº 50, Cidade ria, Rio de Janeiro, 21941-612, Brazil Universita E-mail address: [email protected]. *
~esE-mail address: [email protected] (M.C. Magalha Barbosa). 8 March 2017 Available online xxx
Corresponding author. Instituto D’Or de Pesquisa e Ensino (IDOR), Rua Diniz Cordeiro 30, Rio de Janeiro, RJ, 22281-100, Brazil.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
Contents lists available at ScienceDirect
Travel Medicine and Infectious Disease journal homepage: www.elsevierhealth.com/journals/tmid
New trends of the microcephaly and Zika virus outbreak in Brazil, July 2016eDecember 2016
Dear Editor Recently we published an article about the trends of the microcephaly and Zika virus outbreaks in Brazil, from January to July 2016 [1]. There was some evidence that the Zika virus and microcephaly cases were declining over the studied period, mainly in the Northeast region, which was the most heavily affected in the country. However, high incidences of Zika virus infection were still occurring during the first months of 2016 in some states, such as Rio de Janeiro (Southeast region), Bahia (Northeast region) and Mato Grosso (Midwest region). In the present study we analyzed the same publicly available data from July to December 2016 to continue the evidence-based discussion presented in the first article. Data extracted from the epidemiological reports from the Secretary of Health Surveillance of the Brazilian MoH to monitor cases of microcephaly and neurological abnormalities associated with congenital infections from July 3 to December 31, 2016 were analyzed [2]. Probable cases of Zika virus infection reported in Brazil from July 09 to December 31, 2016 were also analyzed to look for any parallels between the Zika virus disease in the general population and microcephaly cases in infants [3]. In the bulletins, the total cumulative number of reported microcephaly cases are classified as being 1) under investigation (investigation not completed), 2) confirmed (by neuroimaging and/or laboratory testing), or 3) excluded (investigation with negative results); and among confirmed cases, whether or not they were associated with Zika virus infection during pregnancy (positive RT-PCR and/ or serology for Zika virus in the mother and/or newborn). To assess trends, we calculated the mean number of cases per week of microcephaly or Zika virus disease. The incidence of Zika virus infection per 100,000 inhabitants in Brazil and regionally was calculated from January to December 2016 and in the first and second half of the year. The incidence of microcephaly per 10,000 live births in Brazil and regionally was calculated from the beginning of the outbreak to December 2016 and then stratified in the periods before and after July 2, 2016. Since the beginning of the outbreak of microcephaly in November 2015, 23.6% of cases (2566/10,867) were reported in the second half of 2016 (EW27-52); from these, 40% (n ¼ 1026) occurred in the Southeast region, and 36.8% (n ¼ 944) in the Northeast region (Table 1). Sixty-three percent of the cases found to be associated with Zika virus infection (442/697) by specific positive
tests (reverse transcriptionepolymerase chain reaction [RT-PCR] and/or serology) in samples from the newborn and/or the mother were confirmed in the second half of 2016 (Table 2). The percentage of cases remaining under investigation presented a very modest decline from the first to the second half of 2016 (37.7% in EW 26 vs. 29.3% in EW 52) (Table 2). The incidence of reported cases of microcephaly in Brazil dropped dramatically between the period before and after July 2016, from 41.3/10,000 to 17.0/10,000 live births, respectively. The Northeast region contributed the most for the decline, while the incidence in the other regions showed fewer variations (Table 1). The incidence of confirmed cases dropped from 8.2/10,000 to 4.7/10,000 live births between the periods before and after July 2016. A marked decline occurred in the Northeast region from 25.4 to 8.9, while the incidence doubled in the Southeast (1.4 vs. 3.1), Midwest (3.4 vs. 7.2), and South (0.4 vs. 0.8) regions (Table 1). Since EW 11 in March, the reported cases of microcephaly had dropped to lesser than 150 cases per week. From EW 27 to 52, the mean number of cases per week was 99, with some fluctuations and a trend to stabilization in the whole country and all the regions (Fig. 1Ae1F). After an initial decline from EW 27 to 36, the reported cases increased in EW 37 and 38 (mainly at the expenses of the Northeast region), followed by a decline from EW 39 to 50 and increased again in EW 51-52, in December (at the expenses of the Northeast and the Southeast regions). Nineteen percent of all cases of Zika virus infection reported in 2016 occurred in the second half of the year (41,316/215,319) (Table 3). The mean number of cases per week dropped from 6445 in the first six months to 2018 in EW 27. From EW 28 to 32 (mid-July to mid-August), it increased again to an average of 4595 cases per week, 64% of which occurred in the Southeast region (n ¼ 2937). Then, it fluctuated around much lower numbers, the Southeast region being the main responsible for this fluctuation in the whole country. Overall, there was a declining trend in the country as a whole (b 126.45; chi-square test for trend p < 0.001) and in all the regions, except in the Midwest (b þ2.02; chi-square test for trend p < 0.001) and in the South (b þ0.35; chi-square test for trend p < 0.001), which presented very few cases. (Fig. 1A and F). A sharp decline in the incidence of probable Zika virus infection occurred in all regions in the second half of 2016. The highest incidence continued to be in the Midwest region (94.1/100,000), followed by the Southeast (54.0/100,000), the Northeast (31.6/100,000), the North (22.5/100,000) and the South
http://dx.doi.org/10.1016/j.tmaid.2017.03.009 1477-8939/© 2017 Elsevier Ltd. All rights reserved.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
2
Abbreviations MoH RT-PCR WHO
Ministry of Health reverse transcriptase protein chain reaction World Health Organization
(6.4/100,000) regions (Fig. 2 and Table 3). The rapid spread of the Zika virus across Latin America has been associated to environmental and social changes, such as climate variation, land use change, poverty and human movement that have fueled the epidemic [4]. Questions have been raised about how far it will continue to spread. The present analysis indicates that in Brazil, in the second half of 2016, the Zika virus and microcephaly cases continued to decline and switched from the Northeast to the Southeast and Midwest regions. After July, the weekly reported and confirmed cases of microcephaly presented a trend to stabilization in a much lower level than before July in the whole country and all the regions. However, the incidence rates of confirmed cases more than doubled in the Southeast and Midwest regions. The South region, which has a cooler weather in most months of the year, continued to present the fewer cases and incidence of microcephaly. A marked seasonality similar to other arbovirus infections such as dengue should be expected in the Zika virus infection and actually the weekly reported cases began to fall in June in most regions, except the Midwest, which presented an increase in December and
the highest incidence in 2016, although the absolute number of cases was far behind the Northeast and Southeast regions. In the second half of the year, the total number of probable cases of Zika virus infection was much lower than the numbers before June, mainly in the Northeast region, while the Southeast region contributed the highest number of cases. It is possible that with the beginning of the summer season in December, new peaks of Zika virus infection and microcephaly will still occur in some regions of the country in 2017. However, as to EW 7 in February 18, 2017, 1653 probable cases of Zika virus infection were reported in the whole country, with a dramatic fall in the mean number of cases per week, mainly in the Southeast and Midwest regions, but not in the North (Fig. 3). Meanwhile, as to EW 2, 84 cases of neurodevelopmental abnormalities possibly related to Zika virus or other congenital infections were reported, which represents a fall in the mean numbers per week in all regions of the country. As the rate of confirmation of microcephaly cases depends on the availability of neuroimaging or laboratory tests, the temporal course of the reported cases of microcephaly, but not of the confirmed cases, is expected to be more associated with the temporal course of the Zika virus infection. It is plausible that the increase in the number of reported cases of microcephaly in EWs 37-38 in September was related to the previous peak in the number of Zika virus infection nearly twenty weeks earlier, in May as we showed in the first article [1]. On the other hand, the increase in the number of microcephaly cases in EWs 51-52, in the Southeast and Northeast regions was probably associated to the higher numbers of Zika cases in EWs 28-32 from mid-July to mid-August
Table 1 Reported and confirmed cases of microcephaly and neurological abnormalities associated with congenital infection from November 2015 to December 2016, in Brazil.
Brazil Northeast Southeast North Midwest South
Nº of REPORTED cases of microcephaly
Estimated number of live birthsa
Incidence of reported microcephaly per Incidence ratio (2nd/1st semester) 10,000 live births
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
10,867 7,023 2,324 550 716 254
3,515,433 986,025 1,394,234 372,866 288,045 474,263
30.9 71.2 16.7 14.8 24.9 5.4
8,301 6,079 1,298 329 454 141
2,566 944 1,026 221 262 113
2,008,819 563,443 796,705 213,066 164,597 271,007
1,506,614 422,582 597,529 159,800 123,448 203,256
Nº of CONFIRMED cases of microcephaly Estimated number of live birthsa
Brazil Northeast Southeast North Midwest South a
41.3 107.9 16.3 15.4 27.6 5.2
17.0 22.3 17.2 13.8 21.2 5.6
Nov 15-Dec 16 Before July 2nd semester
Nov 15-Dec 16 Before July 2nd semester
Incidence of confirmed microcephaly per 10,000 live births Nov 15-Dec 16 Before July 2nd semester
2,366 1,804 298 92 145 27
3,515,433 986,025 1,394,234 372,866 288,045 474,263
6.7 18.3 2.1 2.5 5.0 0.6
1,656 1,429 110 50 56 11
710 375 188 42 89 16
2,008,819 563,443 796,705 213,066 164,597 271,007
1,506,614 422,582 597,529 159,800 123,448 203,256
8.2 25.4 1.4 2.3 3.4 0.4
4.7 8.9 3.1 2.6 7.2 0.8
0.41 0.21 1.10 0.90 0.77 1.10 Incidence ratio (2nd/1st semester)
0.57 0.35 2.21 1.13 2.12 2
The estimated numbers of live births are based on preliminary data of 2015 from DATASUS (Brazilian Ministry of Health).
Table 2 Cases of microcephaly that completed investigation, cases that remained under investigation and cases confirmed to be.associated with Zika virus infection from November 2015 to December 2016, in Brazil.
Completed investigated cases (confirmed þ excluded) Under investigation cases Zika-associated cases
Cases of micrcephaly EW 46/2015 to EW 26/2016 Nov 2015 to Jun 2016
Cases of micrcephaly EW 27/2016 to EW 52/2016 Jul 2016 to Dec 2016
Cases of micrcephaly EW 46/2015 to EW 52/2016 Nov 2015 to Dec 2016
5,171 (1,656 þ 3,515) 3,130 255
1,754 e 442
7,635 (2,366 þ 5,269) 3,183 697
EW e epidemiological week; confirmed cases of microcephaly e cases confirmed by neuroimaging (independent of specific tests for Zika virus) or by laboratory tests; Zikaassociated cases e cases of microcephaly confirmed to be associated with Zika virus by specific RT-PCR tests or serology in the mother and or newborn.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
~es-Barbosa et al. / Travel Medicine and Infectious Disease xxx (2017) 1e6 M.C. Magalha
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Fig. 1. eReported and confirmed cases of microcephaly and Zika virus infection cases from epidemiological week 27e52/2016, in Brazil and regionally: 1A - Brazil; 1B e Northeast; 1C e Southeast; 1D e North; 1E e Midwest; and 1F e South.
Table 3 Reported cases of Zika virus infection from Epidemiological Week 1e52 (January 3 to December 31), 2016, in Brazil. Nº of REPORTED cases of Zika virus infection
Brazil Northeast Southeast North Midwest South a
Estimated number of inhabitantsa Incidence of reported cases of Zika virus infection per 100,000 inhabitants
JaneDec 16 1st semester 2nd semester JaneDec 16
JaneDec 16 1st semester 2nd semester
214,193 75,922 90,573 12,896 33,848 954
105.3 134.4 106.2 74.2 222.0 3.4
174,003 66,991 67,544 10,944 26,674 1,850
40,190 8,931 23,029 1,952 7,174 896
203,412,156 56,489,583 85,285,311 17,380,053 15,246,847 28,058,824
171.1 237.2 158.4 125.9 349.9 13.2
39.5 31.6 54.0 22.5 94.1 6.4
Incidence ratio (2nd/1st semester)
0.23 0.13 0.34 0.18 0.27 0.48
The estimated numbers of inhabitants are based data of 2016 from the Brazilian Institute of Geography and Statistics (IBGE).
in these regions, nearly twenty weeks earlier. These intervals between peak of Zika virus infection in the general population and peak of microcephaly favors the evidence that the risk for neurologic abnormalities in the fetus is greater in the first and second trimester of pregnancy [5]. The relative stabilization in the weekly number of reported and confirmed cases of microcephaly in the second semester were expected because of various factors. In the first months of 2016,
during the most favorable hot season for Zika dissemination by its most common vector in Brazil (Aedes aegypti), cases of Zika infection were already declining in the Northeast, probably due to development of immunity, which limits the virus dissemination in the population. Therefore, subsequent cases of microcephaly were expected to decline. On the other hand, the switch of Zika infection cases toward the Southeast and Midwest regions in the beginning of 2016, was associated with an increased awareness
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
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Fig. 2. Incidence (/100 mil hab.) Zika vírus disease according to place of residence by Epidemiological Week 52, Brazil, 2016. Source: Weekly epidemiological report on Dengue, Chikungunya and Zika from the Brazilian MoH.
Fig. 3. Probable cases of Zika vírus infection, by epidemiological week of the begining of symptoms, Brazil, 2016 and 2017.
about the risk for the fetus and probably led people to take preventive measures against mosquito bites. This might contribute to minimize the outbreak of microcephaly in these regions. Still, other environmental, social, genetic or unknown factors may not be
excluded to explain why the Northeast region had such a higher number of cases of microcephaly. Messina et al. mapped the areas that provide conditions that are highly suitable for the spread of the virus. These areas include many
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
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tropical and subtropical regions around the globe In addition to Brazil, Colombia and Venezuela are the largest areas of risk in the Americas. A large portion of the subcontinent of India, the Southeast region from Texas to Florida, much of the sub-Saharan Africa, the Indochina region, southeast China, and Indonesia all have large areas of environmental suitability, extending into Oceania [6]. Monitoring and surveillance systems need to be implemented in all susceptible countries. In Brazil, improvements in the confirmation system are necessary. The capacity of the Surveillance System to investigate the cases of microcephaly did not improve over the period of the outbreak. Availability of serology (IgM and IgG) for Zika virus on a large scale is paramount, since the RT-PCR test may be only useful in the early acute phase (first five to seven days) of the disease. The findings in this report are subject to the same limitations mentioned in our previous report on trends of microcephaly and Zika virus infection in Brazil [1]. First, the report of probable Zika virus infection are based on the presence of symptoms and refers to the general population. However, most cases are asymptomatic, which may lead to a gross underestimation of Zika virus cases. Moreover, the assessment of Zika cases in the pregnant women, would be ideal to show the association with microcephaly. Second, the number of live births in 2016, an indirect estimate of the pregnancy rate, was unavailable and impaired the assessment of deferral of pregnancy as a factor contributing to microcephaly declining. Third, inaccuracy in the measurement of head circumference may have occurred and could have resulted in under or over ascertainment of cases of microcephaly. Fourth, the large number of cases of microcephaly, which has not completed the investigation, reduces the ability to estimate the true number of microcephaly cases. Fifth, confirmed cases include all cases of microcephaly and neurological abnormalities associated to congenital infections that had been confirmed by neuroimaging or by laboratory tests and not just those linked to Zika virus. The limited availability of specific tests for Zika virus makes difficult to assess the real impact of the virus as a cause of neurological abnormalities in some cases, although compelling data supports a causal relationship [7]. Sixth, the report does not capture newborns with brain growth impairment and normal head circumference. In conclusion, in the second half of 2016, the Zika virus epidemic continued to decline in the country as a whole, but the virus was still spreading toward the Midwest. The incidence of reported cases of microcephaly and neurological abnormalities associated with congenital infection fell dramatically in the Northeast region, but not in the other regions. In the first summer weeks of 2017 the numbers of Zika virus infection continue to decline in all regions, but the North, while the numbers of neurodevelopmental abnormalities is decreasing in all regions. Ongoing monitoring and surveillance are essential. Sufficient resources for investigation of all reported cases are urgently needed.
Contributors All of the authors participated in the conception, design and conducting of the study, as well as the management, analyses and interpretation of data. MCMB drafted the manuscript, and all of the authors contributed substantially to its revision. All of the authors approved the final version to be submitted.
Competing interests None.
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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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~es-Barbosa, MD, PhD* Maria Clara de Magalha Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil Arnaldo Prata-Barbosa, MD, PhD Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil Faculdade de Medicina da Universidade Federal do Rio de Janeiro, ria, Rua Bruno Lobo, nº Departamento de Pediatria, Cidade Universita 50, Rio de Janeiro, 21941-612, Brazil E-mail address: [email protected]. Jaqueline Rodrigues Robaina, PhD Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Carlos Eduardo Raymundo, MSc Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Fernanda Lima-Setta, MD, MSc Instituto D’Or de Pesquisa e Ensino (IDOR), Departamento de Pediatria, Rua Diniz Cordeiro 30, Botafogo, Rio de Janeiro, Rio de Janeiro, 22281-100, Brazil E-mail address: [email protected]. Ledo Alves da Cunha, MD, PhD Antonio Jose
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009
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Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Departamento de Pediatria, Rua Bruno Lobo, nº 50, Cidade ria, Rio de Janeiro, 21941-612, Brazil Universita E-mail address: [email protected]. *
~esE-mail address: [email protected] (M.C. Magalha Barbosa). 8 March 2017 Available online xxx
Corresponding author. Instituto D’Or de Pesquisa e Ensino (IDOR), Rua Diniz Cordeiro 30, Rio de Janeiro, RJ, 22281-100, Brazil.
~es-Barbosa Maria Clara de, et al.New trends of the microcephaly and Zika virus outbreak in Brazil, July Please cite this article in press as: Magalha 2016eDecember 2016, Travel Medicine and Infectious Disease (2017), http://dx.doi.org/10.1016/j.tmaid.2017.03.009