Correspondence
Zika Virus Infection and Associated Neurologic Disorders in Brazil
To the Editor: The first cases of a new illness
involving fever and rash that was deemed to have
been caused by Zika virus (ZIKV) infection in
Brazil were reported in 2014, and the presence
of the virus was confirmed in April 2015. In
October 2015, an unusual increase in the num-
ber of cases of microcephaly among newborn
infants was reported in Brazil; this disorder was
apparently linked to ZIKV infection. From the
first investigations of microcephaly, and from
subsequent studies in Brazil and elsewhere, it is
now clear that ZIKV is a cause of a range of
neurologic disorders, including the Guillain
Barr syndrome (GBS) in adults and abnormali-
ties in fetuses and newborn infants, including
microcephaly.1 Here, we use routinely collected
surveillance data and medical records to show
how the spread of ZIKV in Brazil was associated
with an increase in the incidence of GBS and
microcephaly during 2015 and 2016. We also
highlight the limitations of routinely collected
data, which cannot yet explain, for example, why
there were many fewer cases of microcephaly
than expected in 2016.
To explore the temporal and geographic dis-
tribution of ZIKV infection, we used data provid-
ed by municipalities and states in each of the
five regions of Brazil, as compiled by the Minis-
try of Health. These data describe the number of
suspected and confirmed cases of ZIKV infection
and of cases reported as GBS and microcephaly
(Sections 1 and 2 in the Supplementary Appen-
dix, available with the full text of this letter at
NEJM.org).
The number of suspected cases of ZIKV infec-
tion began to increase in the northeast region of
Brazil starting in March 2015 (week 9) (Fig. 1A).
Cases were subsequently reported in the other
four regions, beginning in late 2015 and greatly
expanding in 2016. Together with phylogenetic
analysis of viral RNA sequences,2 these findings
suggest that ZIKV was dispersed widely after a
single introduction of infection in the northeast
region.
The spread of ZIKV in Brazil has been associ-
ated with an increase in the incidence of neuro-
logic disorders, most visibly in cases reported as
GBS and microcephaly. Weekly reports of cases
from hospitals reveal that the incidence of GBS
was markedly higher in the northeast region in
2015 and 2016 and in other areas of Brazil in
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2016 than in the years before the ZIKV epidemic
(2010 to 2014) (Fig. 1B, and Section 3 in the
Supplementary Appendix). The rise and fall of
suspected cases of ZIKV infection and GBS were
approximately synchronous in 2015, although a
comparison of the two case series suggests that
the incidence of ZIKV infection was underreport-
ed in the northeast region early in 2015 (Fig. 1B).
In Pernambuco state, some of the cases of ZIKV
infection were probably misclassified (mainly as
dengue) in clinics in 2015, and such misclassifi-
cation could have been widespread.3
The incidence of microcephaly peaked in late
November 2015 (week 47), an average of 23 weeks
after the start of the epidemics of ZIKV infec-
tion and GBS (Fig. 1B). If there was a delay of
3 weeks between the exposure of patients to ZIKV
and the development of GBS (i.e., an incubation
period plus a typical reporting delay), infections
leading to microcephaly would have occurred
on average 12 weeks after conception (i.e., with
about half the cases occurring during the first
trimester and half later in pregnancy) (Section 4
in the Supplementary Appendix).
In view of the apparent resurgence of ZIKV
infection and GBS early in 2016, we anticipated
a further increase in cases of microcephaly later
in the year. But such a resurgence did not happen
(Fig. 1B), for at least three possible reasons. The
first possibility is that in 2016, infections that
were attributed to ZIKV and that were linked to
an increase in the incidence of GBS were caused
by another arbovirus that is also transmitted by
Aedes aegypti mosquitoes, since by then there was
herd immunity against ZIKV infection after wide-
spread infection in 2015.4 Dengue virus has been
identified throughout the Americas (Section 5 in
the Supplementary Appendix) but does not ap-
pear to be a major cause of GBS. Chikungunya
virus was introduced into Brazil in 2014 and
caused successively larger epidemics in the north-
east region in 2015 and 2016. Chikungunya is a
cause of GBS as well, and some chikungunya
infections were evidently misclassified as ZIKV
infection in Pernambuco in 2016 (Brito C: per-
sonal communication). Chikungunya has not been
identified as a cause of microcephaly.5
A second possibility is that ZIKV infection dur-
ing pregnancy is a necessary but not a sufficient
condition for the development of microcephaly in
newborn infants in other words, the presence
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Suspected Cases of ZIKV Infection in the Five Major Regions of Brazil

8000
Northeast
Southeast
7000
Midwest
No. of Cases of ZIKV Infection per Wk

North
6000 South

5000

4000

3000

2000

1000

0
1 6 11 16 21 26 31 36 41 46 51 4 9 14 19 24 29 34 39 44 49
2015 2016
Week

B Suspected Cases of ZIKV Infection, GuillainBarr, and Microcephaly in Northeast Region

20
ZIKV infection Microcephaly GuillainBarr
Predicted microcephaly 18

No. of Excess Cases of GuillainBarr per Wk

10,000 100
23 Wk
16
No. of Cases of ZIKV Infection per Wk

No. of Cases of Microcephaly per Wk

8,000 80 14

12

6,000 60
10

8
4,000 40
6

4
2,000 20
2

0 0 0
1 6 11 16 21 26 31 36 41 46 51 4 9 14 19 24 29 34 39 44 49
2015 2016
Week

Figure 1. Suspected Cases of Zika Virus (ZIKV) Infection, GuillainBarr Syndrome, and Microcephaly in Brazil (20152016).
Panel A shows the suspected cases of ZIKV infection that were reported weekly in clinics and hospitals in the five regions of Brazil dur-
ing 2015 and 2016. Panel B shows the suspected cases of ZIKV infection, GuillainBarr syndrome (GBS), and microcephaly in 2015 and
2016, along with the predicted cases of microcephaly in 2015 and 2016. The suspected cases of GBS are reported as excess cases that
is, the numbers of cases that surpass the average number reported each week in the years before the ZIKV epidemic (in 2010 to 2014).
In 2015, the incidence of microcephaly followed the identification of ZIKV infection and GBS by an interval of 23 weeks on average.
However, there was no predicted resurgence of microcephaly after the apparent seasonal increases in the incidence of ZIKV infection
and GBS in 2016. Case series in Panels A and B are plotted as 3-week moving averages. Data were collected by the Ministry of Health in
Brazil.

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 Correspondence
of some other unknown cofactor that is not es-
sential for GBS is required. A third possibility is
that fear of the adverse consequences of ZIKV
infection led to fewer conceptions or a greater
number of pregnancy terminations in 2016. Rou-
tinely collected data are not yet complete enough
to determine whether birth rates fell or abortion
rates increased in 2016 (Section 6 in the Supple-
mentary Appendix). However, since any changes
in the number of live births would be small, this
hypothesis cannot be the principal reason why
few cases of microcephaly were reported in the
northeast region in 2016.
Among these hypotheses, the first seems to
be the most plausible that is, both ZIKV and
chikungunya viruses are important causes of GBS,
but among the arboviruses circulating in Brazil,
only ZIKV causes microcephaly and other neuro-
logic disorders after infection during pregnancy.
However, the three possibilities are not mutually
exclusive, and none can be ruled out with the
present data. Further investigations are needed
aided by more sensitive and specific diagnos-
tic tools and the careful interpretation of surveil-
lance data to clarify the causal links between
arbovirus infections, GBS, and microcephaly in
Brazil.
Wanderson K.de Oliveira,M.D.
Eduardo H.Carmo,Ph.D.
Ministry of Health
Brasilia, Brazil
Claudio M.Henriques,M.D.
Oswaldo Cruz Foundation
Brasilia, Brazil
Bezlotoxumab and Recurrent Clostridium difficile Infection
To the Editor: Wilcox et al. (Jan. 26 issue)1
found that the risk of recurrent Clostridium difficile
infection was nearly 40% lower among patients
treated with bezlotoxumab than among those
who received standard care. In the accompany-
ing editorial, Bartlett speculates about whether
bezlotoxumab, although clearly efficacious, will be
cost-effective.2 We think this discussion would
be incomplete without citing the efficacy and rela-
tively low cost of probiotics in the prevention of
C. difficile infection. In multiple systematic reviews
that included meta-analyses of randomized, con-
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GiovaniniCoelho,M.D.
Ministry of Health
Brasilia, Brazil
EnriqueVazquez,M.D., Dr.PH.
JuanCortez-Escalante,Ph.D.
JoaquinMolina,M.D.
Pan American Health Organization
Brasilia, Brazil
SylvainAldighieri,M.D.
Marcos A.Espinal,M.D., Dr.PH.
Pan American Health Organization
Washington, DC
ChristopherDye,D.Phil.
World Health Organization
Geneva, Switzerland
dyec@who.int
Supported by the Ministry of Health in Brazil, the Pan Ameri-
can Health Organization, and the World Health Organization.
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on March 29, 2017, and updated on
April 6, 2017, at NEJM.org.
1. Broutet N, Krauer F, Riesen M, et al. Zika virus as a cause of
neurologic disorders. N Engl J Med 2016;374:1506-9.
2. Faria NR, Azevedo Rdo S, Kraemer MU, et al. Zika virus in
the Americas: early epidemiological and genetic findings. Science
2016;352:345-9.
3. Brito CA, Brito CC, Oliveira AC, et al. Zika in Pernambuco:
rewriting the first outbreak. Rev Soc Bras Med Trop 2016;49:553-8.
4. Ferguson NM, Cucunub ZM, Dorigatti I, et al. Countering
the Zika epidemic in Latin America. Science 2016;353:353-4.
5. Fritel X, Rollot O, Gerardin P, et al. Chikungunya virus infec-
tion during pregnancy, Reunion, France, 2006. Emerg Infect Dis
2010;16:418-25.
DOI: 10.1056/NEJMc1608612
trolled trials in which the rates of both initial
and recurrent infections were measured, probi-
otics were shown to have safety and impressive
efficacy, with a relative risk reduction of more
than 50% in the prevention of C. difficile infection
in high-risk immunocompetent populations.3,4 Pro-
biotics have also been shown to be cost-effective.5
Given their substantial efficacy and greatly reduced
cost, we urge providers to review the literature
and consider the use of probiotics for immuno-
competent patients who are receiving antibiotics
and are at high risk for C. difficile infection.