The

n e w e ng l a n d j o u r na l

introduction of instruments during an invasive

procedure, including an orbitotomy with subperiosteal dissection. In one literature review, fusobacterium infections, although principally monomicrobial, were shown to be mixed infections in
at least 12% of 222 cases.1 In addition, this patient had a known allergy to penicillin, which had
caused urticaria. Although more details are required, it does seem that the patient has an IgEmediated allergy. As such, she may be able to undergo desensitization for a future infection if there
are not suitable alternative antibiotic therapies.
In 80% of patients with an IgE-mediated allergy to penicillin, the allergy will disappear
over a period of 10 years; of note, when desensitization is performed, it is only temporary.2 Although there was not definitive clinical evidence
of central nervous system infection, magnetic
resonance imaging initially indicated subtle leptomeningeal enhancement. Meropenem is a carbapenem antibiotic with good anaerobic activity
that also has acceptable central nervous system
penetration and, as such, was a reasonable initial choice in this patient. The patient returned
after discharge with a fever and a rash that was
believed to be caused by her antibiotic regimen.
Without worrisome evidence of direct central
nervous system involvement at that time, after at
least 20 days of meropenem therapy, coverage
for meningeal infection would have been considered adequate. Clindamycin was chosen as an

of

m e dic i n e

alternative agent having excellent fusobacterium

coverage at this time.
Dammin acknowledges the potential for oral
contraceptives to increase thrombophilia. However,
combined hormone therapy confers a risk of
thrombophilia in only 0.05% of otherwise healthy
adolescents per year.3 In this case, the patient has
an infection with an organism known to be thrombogenic. I am not aware of literature indicating an
increased risk of clotting in Lemierres syndrome in
the context of oral contraceptive agents. Although
these medications were suspended during her
therapy, as discussed during the conference, this
episode alone should not prohibit the consideration
of oral contraceptive use in the future.
Kristian R. Olson, M.D., M.P.H.
Massachusetts General Hospital

Boston, MA
krolson@partners.org
Since publication of his article, the author reports no further
potential conflict of interest.
1. Riordan T. Human infection with Fusobacterium necropho-

rum (necrobacillosis), with a focus on Lemierres syndrome.

Clin Microbiol Rev 2007;20:622-59.
2. American Academy of Allergy, Asthma and Immunology,
American College of Allergy, Asthma and Immunology, Joint
Council of Allergy, Asthma and Immunology. Drug allergy: an
updated practice parameter. Ann Allergy Asthma Immunol
2010;105:259-73.
3. Trenor CC III, Chung RJ, Michelson AD, et al. Hormonal
contraception and thrombotic risk: a multidisciplinary approach.
Pediatrics 2011;127:347-57.
DOI: 10.1056/NEJMc1415357

Elevated Sweat Chloride Levels Due to Arsenic Toxicity

To the Editor: Arsenic toxicity is associated
with gram-negative bacterial lung infections,
bronchiectasis, and diabetes mellitus. The symptoms of arsenic toxicity overlap with those of
cystic fibrosis, an autosomal recessive disease
that is most common in people of Northern European ancestry. Cystic fibrosis is caused by mutations in the gene that encodes the cystic fibrosis
transmembrane conductance regulator (CFTR), a
protein that functions as a chloride channel that
regulates fluid transport in the lungs, pancreas,
and other organs. The diagnostic test for cystic
fibrosis is the sweat test; an elevated sweat chloride level indicates CFTR dysfunction. Recent
studies in cell culture show that arsenic causes
degradation of CFTR.1 We report the findings of
582

a study examining the association between arsenic exposure and sweat chloride level in Bangladeshi adults.
Participants in this cross-sectional study were
recruited from a roster of previous participants
in a casecontrol study of arsenic-related skin
lesions conducted between 2001 and 2003 in
Pabna, Bangladesh,2 a rural area where the
groundwater is contaminated with arsenic. Many
of the patients in this study also participated in
a follow-up study conducted between 2007 and
2009.3 For the current study, we evaluated 30
participants from the group who had been in the
group with lesions and 70 participants who had
been controls in the 20012003 study. Arsenic
levels were measured with the use of ultraviolet

n engl j med 372;6nejm.orgfebruary 5, 2015

The New England Journal of Medicine

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Copyright 2015 Massachusetts Medical Society. All rights reserved.

85
51
89
77
114
80
78
54
104
1.69
3.07
12.99
11.61
26.48
12.83
4.71
5.86
11.54
1.30
1.90
11.81

10.84
29.43
4.15
45.19
15.95
4.00
9.85
11.86
9.64
18.28
19.42
3.47
24.06
15.72
12.0
8.9
19.4
60.6
0.4
1.1
1.8
0.9
15.2
150.0
69.0
43.0

30.0
900.0
11.0
920.0

24.2
38.6
535.0
1.1
661.0
553.0
33.0
697.0
839.0
63
66
68
69
70
72
75
76
78
86
98
76
76
74
58
83
88
84
No
Yes
Yes
No
Yes
Yes
No
Yes
Yes
Previous
Never
Never
Current
Current
Previous
Never
Current
Previous

12.52

9.42
151.9

88.3
63
69
No
Current

mmol/liter
75
62
No
Never

87

p.I807 M
(c.2421AG)
p.V456A
(c.1367TC)
c.346920TC
c.424316AG
No mutations
12/5T; 10/9T
No mutations
No mutations
No mutations
No mutations
No mutations

Reportable
Variant

Arsenic in Drinking Water

Arsenic in Fingernails
FEV1
At
At
At
At
Enrollment
Follow-up
Currently
Enrollment
Follow-up
Currently
(20012003) (20072009) (20132014) (20012003) (20072009) (20132014)
g/liter
g/g
%
431.0
420.0
155.7
14.08
17.83
20.86
97
History
of Skin
Sweat
Sweat
Lesions Conductivity Chloride

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes

n engl j med 372;6nejm.orgfebruary 5, 2015

The New England Journal of Medicine

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Copyright 2015 Massachusetts Medical Society. All rights reserved.

* FEV1 denotes forced expiratory volume in 1 second, and dashes indicate that the participant was not evaluated in a 20072009 follow-up study.3
All reported variants were heterozygous. No deletions or duplications were identified.
Analysis of intron 8 CFTR TGrepeat/poly(T) variants revealed that one participant had the indicated genotype; all other participants had the nonreportable sequence 7T/7T poly(T).

Dhaka, Bangladesh

33
40
30
38
55
58
37
42
65

Dhaka Community Hospital

3
4
5
6
7
8
9
10
11

O. Sharif Ibne-Hasan, M.B., B.S.

28

Dhaka, Bangladesh

Bangabandhu Sheikh Mujib Medical University

No

Subrata K. Biswas, M.D., Ph.D.

yr
55

Boston, MA

Harvard School of Public Health

Smoking
Status

David C. Christiani, M.D., M.P.H.

Male
Sex

Boston, MA
maitreyi.mazumdar@childrens.harvard.edu

Participant
No.
Age

Boston Childrens Hospital

Table 1. Clinical Characteristics and Laboratory Results for Persons with Elevated Sweat Chloride Levels.*

visible spectrophotometry.4 Fingernails were analyzed by means of inductively coupled plasma

mass spectrometry.5 Sweat conductivity was
measured with the use of a Sweat-Chek analyzer
(Wescor); values for sweat conductivity were converted by the instrument to equivalent levels of
sodium chloride and reported in millimoles per
liter. For the 54 participants whose sweat conductivity was 50 mmol per liter or higher, a
second sample was obtained and sweat chloride
level was measured with the use of a Dimension
RxL Max analyzer (Siemens). Sweat was obtained
from skin that had not been affected by arsenicrelated or other lesions. Pulmonary-function
tests were conducted with a SpirHOMEter
(Cosmed). DNA from participants whose sweat
chloride reached a level that was diagnostic for
cystic fibrosis (60 mmol per liter) underwent
CFTR full-gene sequencing analysis (sequencing
was performed by Ambry Genetics).
None of the 11 participants with sweat chloride levels of 60 mmol per liter or higher had a
genetic diagnosis of cystic fibrosis (Table 1).
Current arsenic levels in water were higher for
the 40 participants with abnormal sweat conductivity (>60 mmol per liter) than for participants with normal or intermediate sweat conductivity (median, 11.9 g per liter vs. 2.7 g per
liter; P=0.01). The same pattern was seen with
current arsenic levels in fingernails (median,
5.64 g per gram vs. 1.39 g per gram; P=0.008).
Adjusted models revealed no significant confounding according to age, sex, smoking status,
or body-mass index. There was no relationship
between sweat chloride level and scores on lungfunction tests or pulmonary symptoms. Our
study shows that elevated sweat chloride levels are
found among persons exposed to arsenic in the
absence of a genetic diagnosis of cystic fibrosis.
Maitreyi Mazumdar, M.D., M.P.H.

CFTR
Sequencing

correspondence

583

The

n e w e ng l a n d j o u r na l

Kush Kapur, Ph.D.

Christopher Hug, M.D., Ph.D.
Boston Childrens Hospital

Boston, MA
Supported by the Harvard University Center for the Environment and the HarvardNational Institute of Environmental
Health Sciences (NIEHS) Center (ES000002) and by a Mentored
Career Development Award from the NIEHS, National Institutes
of Health (K23 ES017437, to Dr. Mazumdar).
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Bomberger JM, Coutermarsh BA, Barnaby RL, Stanton BA.

Arsenic promotes ubiquitinylation and lysosomal degradation of

cystic fibrosis transmembrane conductance regulator (CFTR)

of

m e dic i n e

chloride channels in human airway epithelial cells. J Biol Chem

2012;287:17130-9.
2. Breton CV, Houseman EA, Kile ML, et al. Gender-specific
protective effect of hemoglobin on arsenic-induced skin lesions.
Cancer Epidemiol Biomarkers Prev 2006;15:902-7.
3. Seow WJ, Pan WC, Kile ML, et al. Arsenic reduction in drinking water and improvement in skin lesions: a follow-up study in
Bangladesh. Environ Health Perspect 2012;120:1733-8.
4. Frisbie SH, Mitchell EJ, Yusuf AZ, et al. The development and
use of an innovative laboratory method for measuring arsenic in
drinking water from western Bangladesh. Environ Health Perspect 2005;113:1196-204.
5. Chen KL, Amarasiriwardena CJ, Christiani DC. Determination of total arsenic concentrations in nails by inductively coupled
plasma mass spectrometry. Biol Trace Elem Res 1999;67:109-25.
DOI: 10.1056/NEJMc1413312

West African Ebola Epidemic after One Year

Slowing but Not Yet under Control
To the Editor: During the period from early
June to mid-September 2014, the epidemic of
Ebola virus disease (EVD) in Guinea, Liberia, and
Sierra Leone grew exponentially, with national
doubling times of between 16 and 30 days.1 On
the basis of case reports through mid-September,
and assuming no change in the trajectory of the
epidemic, we predicted a cumulative total of 21,000
cases in these three countries by November 2.1 In
fact, the epidemic did change course in September: the increase in case incidence appears to
have halted in Guinea and Sierra Leone and has
reversed in Liberia (Fig. 1). Now, 1 year after the
first case was reported in December 2013,2 we
report updated epidemiologic findings for the
three countries that have been most affected, using data recorded through December 14.
In the 4 weeks preceding December 14, the
number of confirmed or probable cases of EVD
ranged from 77 to 154 per week in Guinea, 73 to
138 in Liberia, and 327 to 537 in Sierra Leone. By
December 14, a total of 18,625 confirmed, probable, or suspected EVD cases had been reported
in eight affected countries (the three mentioned
above, plus Mali, Nigeria, Senegal, Spain, and
the United States), with 6971 recorded deaths.2
The true burden of illness and death is certainly
higher, but the changes in epidemic trends between August and December are clear (Fig. 1).
National summary statistics do not tell the
whole story, however; within the affected coun-

584

tries, the geographic distribution of cases has

shifted markedly (Fig. S3 and S7 in the Supplementary Appendix, available with the full text of
this letter at NEJM.org). In Gueckedou, Guinea,
where the epidemic began, the incidence of EVD
has decreased from an average of 11 confirmed
or probable cases per week between March and
September to 2 cases per week since the beginning of October, whereas the incidence has increased sharply in the neighboring districts of
Kerouane, Macenta, and Nzerekore. Districts at
the epicenter in eastern Sierra Leone (Kailahun and
Kenema) and northern Liberia (Lofa) reported
an average of 120 cases per week during July and
August but only 2 per week since the beginning
of November. EVD has been persistently active in
Conakry, the capital of Guinea, since March and
highly active in all three national capitals since
June. During the period of peak incidence between August 11 and October 5, Monrovia, Liberia, averaged close to 200 confirmed or probable
cases per week. In Sierra Leone, the center of activity had moved from the east to the west of the
country by October; by the second week of December, the rise in case incidence had slowed in
Freetown, but the case incidence may still not have
peaked (Freetown is shown as part of Western
Area in Fig. S6 and S10 in the Supplementary
Appendix).
Guided by targets for patient isolation and safe
burial practices set by United Nations Mission for

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