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Cite   this   article:   Ronchetti   MP,   Ronchetti   F,   Bianco   PM,   Ronchetti   R   (2017)   Is   the   Zika   V irus   the   Cause   of   Mic r ocephaly   Epidemic   in   Brazil?   Epidemiological   Data Suggest a Negative   Answe r .   A r ch Paediatr Dev Pathol 1(4): 1016.             Central Archi v es of P aediatrics and D e v elopmental P athology R esearch A r ti c le Is the Zika  V irus the Cause  of Mic r oc e phaly Epidemic in  B r azil? Epidemiol o gical Data  Sug g est a N eg at i v e An s w er Maria Paola Ronchetti 1 , Francesco Ronchetti 2 , Pietro Massimiliano Bianco 3 , and Roberto Ronchetti 4,5 * 1 Department of Neonatal Intensive Ca r e,  Pediatric Hospital “Bambino Gesù”, Italy 2 Department of Ea r - Nose - Th r oat , Sant’And r ea Hospital, University ‘la Sapienza”, Italy 3 Institute for Envi r onmental P r otection and Resea r ch (ISPRA), Italy 4 Department of Pediatrics, University “Sapienza”, Italy 5 P r esident Section Latium of International Society of Doctors for the Envi r onment  – (ISDE), Italy *Corresponding author Robert o Ronchetti , Departmen t o f Pediatrics , Universit y  “Sapienza ” Rome , Vi a Vessell a 6 , - 00199 , Roma , Italy ,  Tel : 393381108897 ; Email : Submitted:  27 September 2017 Accepted:  16 October 2017 Published:  18 October 2017 Copyright © 2017 Ronchetti et al. OPEN ACCESS Keywords • Zika virus • Microcephaly • Brazilian  epidemics Abstract In Brazil thousands of cases of congenital microcephaly appeared “simultaneously” with the spread of an epidemic of Zika virus infections. As consequence  the World Health Organization, launched an international alarm under the hypothesis that the Zika virus was the cause of the epidemic of microcephaly. If an  infection caused by this virus is the cause of the many observed congenital malformations, we should expect to find a time interval of 7 - 9  months between the  mother infection and the birth of a malformed child. On the contrary, the peak incidence of the malformation took place three – four months before the maximum  spread of the virus. Moreover the large majority of the children with  microcephaly were born exclusively in the North - Eastern states of Brazil while the Zika  virus rapidly spread throughout the rest of the country. Therefore from an epidemiological point of view, the “causal link” between the two events appears to  be largely unproven. BACKGROUND In the year “July 2015 - June 2016” in Brazil thousands of cases  of congenital microcephaly appeared “simultaneously” with the  spread of an epidemic of Zika virus infections. Following several alarms initially launched by the Brazilian  Health Authorities [1 - 3], and rapidly magnified by the media,  on February 1, 2016 the president of “ Public Health Emergency  of International Concern”  [4], in Brazil: in practice the temporal  coincidence was assumed as the proof of a causal link between the  two events. This WHO declaration was completely (and in large  measure passively) accepted by the scientific community [5 - 7],  and this fact produced a general belief that a world - wide health  disaster (the Zika virus is present in a geographic area where two  billion people live) was not only possible but already existent.  The WHO declaration has also had enormous environmental and  economic consequences for the human community. After more than two years it is nowadays possible to ask if  epidemiological data confirm or disprove the hypothesis of a  causal link between Zika virus and microcephaly epidemics. METHODS We tried to critically summarize the available scientific  literature and the innumerable contributions of Health Authorities  and of “Experts” trying to reconstruct the epidemiology of the two Brazilian epidemics, spread of Zika virus infections and  congenital microcephaly, in order to understand if the hypothesis  of the causal link between them was justified. To reconstruct the temporal trend of the epidemiological  curve of the spread of virus Zika infections we have official data  only relative to the whole country [8]. The report begins in n  January in spite of the fact that it is well known that the virus was  largely present in Brazil in the year 2015 [9,10]. This probably  happens because suitable laboratory investigations were not yet  sufficiently available in 2015. To  reconstruct the  epidemiological curve of  microcephaly  in Brazil, we have available the epidemiological bulletins [11].  It must be noted that, for several reasons, these bulletins do not  allow the correct description of the real epidemiological curve. First of all the bulletins describe the progression of the  epidemiological situation beginning from November 2015 [8],  while other official data certify that in April of the same year  a huge number of congenital microcephaly had been already  registered in the North - East part of Brazil [12]. Moreover in each bulletin a huge number of cases still “Under Investigation (UI) “is always cumulatively reported: in the North - Eastern part of Brazil: UI cases were 2960 in January and still 1580 in December of 2016. Ronchetti et al. (2017)   Email:   Arch Paediatr Dev Pathol 1(4): 1016 (2017)         Finally the bulletins do not take in account the fact that the  number of confirmed cases has certainly been influenced by the  three changes of the definition of microcephaly performed by the  Health Authorities in Brazil [13]. Making  simple  reasonable  hypotheses  but with  rather  complex numerical procedures we could “correct” most of the  cited defects of the data in the official bulletins, but the results  would not  significantly influence the conclusions of the present  paper. Therefore, in reconstructing the epidemiological curves of  microcephaly, we used the figures of “confirmed” cases as they  appear in the official bulletins, without “corrections”. RESULTS Zika  virus epidemic Literature suggests that, well before it was first isolated  (April 2015) and since the last months of 2015, the Zika virus  was already present in Brazil [9], especially in the North - Eastern  states  of  the  country:  from  there,  in  the  course  of  the  year 2015, the virus invaded the whole Brazil and starting from the  beginning of 2016 the infective epidemic of the virus was mainly  active in the opposite part of the country [8]. Available official data concerning documented Zika virus infections are only relative to the whole country (Figure 1).  These data describe a “bell shaped” curve beginning somewhere  in 2015, reaching its maximum around March 2016 and slowly  ending before the end of the year. The epidemic of congenital microcephaly The   dimension   of   the   epidemic   is   huge:   according  to  the Brazilian Ministry of Health, 2,775 cases of congenital  microcephaly have been confirmed by clinical, radiological,  and/or laboratory methods (928 were confirmed by  laboratory  criteria, RT - PCR or serological test) [8]. The epidemic of microcephaly began before September 2015  (58 cases of microcephaly were already present in the hospitals  of the state of Pernambuco between September and October)  [13,14], reached its p eak between November 2015 and January 2016, and came to an end in March 2016 (Figure 2). The fact  that in the 18 months since then only sporadic cases have been  reported in Brazil seems to exclude the hypothesis of an epidemic  characterized by a seasonal  trend, which is recurring in certain  periods of the year due to climatic factors or linked to the biology  of Aedes Aegypti , the insect responsible for the virus spread. The geographic localization of the microcephaly epidemic is  highly important (Figure  3). It can be seen that in Brazil almost  all the malformations (more than 90% of the cases) have been  registered in the North - Eastern states (a quarter of the country),  vice - versa only a limited number of cases were reported in the  Western or Southern stat es of the country where in 2016 Zika  virus infection had its highest incidence. Moreover, it must be said that in none of the over 80  countries of the tropical belt  of the planet in which the Zika  virus continuously causes infective epidemics an increase in the  incidence of congenital microcephaly, comparable to the one  observed in Brazil, has ever been reported. D I S C U S S IO N A N D C ON C L U S IO NS Before discussing the over reported epidemiological data it is  worthwhile to consider the meaning of the numerous scientific  reports dealing with newborns bearing congenital microcephaly  in whose brain the Zika virus was isolated: In most of these cases  the mother reported an episode of severely symptomatic viral  infection in the early phase of their pregnancy. It is  well known  [15], which Zika virus infection is completely asymptomatic in  about 80% of cases and with very mild clinical symptoms in about 20% of infected people: therefore pregnant women with clearly  symptomatic infection belong to the less than 1% of infected  persons. The cited publications seem therefore to demonstrate Figure 1  Suspec t ed and confirmed Zi k a cases in B r azil (data f r om:  P AN WH O , 29 June 2017). Figure 3 Epidemic cur v es (in t er v al bet w een points= t w o w ee k s) of mic r ocepha l y in the North - East sta t es (black lines) and in the r est of B r asil ( g r e y lines) acco r ding  t o “confirmed“cases  r epor t ed in the  official bulletins [3]. that the Zika virus, like many other viral or non viral infective  agents can cause malformations in early infected pregnant  women. The paper of Cordeiro [13], which deals with about half  of the cases admitted to Perna mbuco hospitals in September  - October 2015 is difficult to evaluate because it is not population  based and does not provide clinical information about the  pregnancy of the mothers. In summary the small number and the  quality (poor from epidemiological point of view) of the reports  dealing with cases with documented association Zika virus  – congenital microcephaly cannot be taken as a valid explanation of  the Brazilian huge epidemic of malformations we are describing. As shown before, the Brazilian epid emic of Zika virus  infection probably begun in 2014, slowly spread in the course of 2015, reaching a peak of diffusion around March 2016. If we are to believe that an infection caused by this virus is the  cause of the many observed congenital malformations, we should  expect to find a time interval of 7 - 9 months between the mother  infection and the birth of a malformed child. From the moment  that, obviously, the higher the number of infected persons the  greater the probability for a mother to be contaminated, in  practical terms we should expect to find the peak of microcephaly  incidence  several  months  after  the  maximal  diffusion  of  the virus.  On  the  contrary,  as  shown  before,  the  peak  incidence  of the malformation takes place three – four months before the  maximum spread of the virus: if the hypothesis of the causal link  between Zika and microcephaly is true, why the virus resulted  maximally dangerous for pregnant women at the beginning of the  epidemic when its circulation was  low and almost innocuous at  the moment of its maximal diffusion? A question which has not a  simple explanation. More difficult is to answer the next question: if the cause of  microcephaly is the Zika virus, an infective agent which rapidly  spread from Bah ia - Pernambuco to the rest of the country, why  the large majority of the almost three thousands children with  microcephaly were born exclusively in the North - Eastern states  of Brazil? In  summary  the  analysis  of  available  data  demonstrates  that the  two epidemics, Zika virus infections and congenital  microcephaly, are not “simultaneous” and not coincident in their  geographical location: therefore, from an epidemiological point  of view, the “causal link” between the two events appears to be  largely unp roven. We think that the Brazilian and International Health  Authorities  and  the  scientific  medical  community  should  try  to answer the over reported questions or suggest alternative  explanations for the etiology of the epidemic of microcephaly in  Br azil. R E F E R E N CE S 1.  Fauci  AS,  Morens  DM.  Zika  Virus  in  the  Americas  - Yet  Another Arbovirus Threat. N Engl J Med. 2016; 374:  601 - 604. 2.  Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine  infection causes fetal brain abnormality and microcephaly: tip of the iceberg? Ultrasound Obstet Gynecol. 2016; 47: 6 - 7. 3.  COES - Microcefalias (Centro de Operações de Emergências em saú de pública Sobre microcefalias, Brazil).Informes Epidemiológicos  4.  WHO.  WHO  statement  on  the  first  meeting  of  the  International Health   Regulations   (IHR   2005)   Emergency   Committee   on   Zika virus and observed increase in neurological disorders and neonatal malformations. WHO statements. 2016. 5. Portal de a Saude. Ministério da Saúde investiga 4.293 casos de microcefalia no país. Boletim de Portal de a Saude. 2016. 6.  Schuler - Faccini L, Ribeiro EM, Feitosa IM, Horovitz DD, Cavalcanti DP, Pessoa A, et al. Possible association between Zika virus infection and microcephaly - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016; 65: 59 - 62. 7.   Mlakar J, Korva M, Tul N, Popović M, Poljšak - Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Eng J Med. 2016; 374: 951 - 958. 8.   PAN - WHO Zika - Epidemiological Report Brazil. 2017. 9.   Brito CA, Brito CC, Olive ira AC, Rocha M, Atanásio C, Asfora C, et al. Zika in Pernambuco: rewriting the first outbreak. Rev Soc Bras Med Trop. 2016; 49: 553 - 558. 10. Zanluca C, Melo VC, Mosimann AL, Santos GI, Santos CN, Luz K. First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz. 2015; 110: 569 - 572. 11. Informe Epidemiológico edited by COES - Microcefalias, Centro De Operações De Emergência sem Saúde Pública Sobre Microcefalias. 12. Microcephaly in Infants, Pernambuco State, Brazil, 2015. Microcephaly Epidemic Research group. 2016. 13. Cordeiro MT, Pena LJ, Brito CA, Gil LH, Marques ET. Positive IgM for Zika virus in the cerebrospinal fluid of 30 neonates with microcephaly in Brazil. Lancet. 2016; 387: 1811 - 1812. 14. Brito CA, Cordeiro MT. One year after the Zika virus outbreak in Brazil: from hypotheses to evidence. Rev Soc Bras Med Trop. 2016; 49: 537 - 543. 15. Moghadas  SM,  Shoukat  A,  Espindola  AL,  Pereira  RS,  Abdirizak  F, Laskowski M, et al. Asymptomatic Transmission and the Dynamics of Zika Infection. Sci Rep. 2017; 7: 5829. Cite this article  Ronchetti  M  P Ronchetti F , Bianco PM, Ronchetti R (2017) Is the Zika V irus the Cause of Microcephaly Epidemic in Brazil? Epidemiological Data Suggest a Nega - tive Answe r .
Ronchetti MP, Ronchetti F, Bianco PM, Ronchetti R (2017) Is the Zika Virus the Cause of Microcephaly Epidemic in Brazil? Epidemiological Data Suggest a Nega tive Answer. Arch Paediatr Dev Pathol 1(4): 1016.
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Professor Roberto Ronchetti