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Inhalational, Gastrointestinal, and Cutaneous Anthrax in Children

Article  in  Archives of Pediatrics and Adolescent Medicine · October 2007

DOI: 10.1001/archpedi.161.9.896 · Source: PubMed

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 REVIEW ARTICLE

Inhalational, Gastrointestinal, and

Cutaneous Anthrax in Children
A Systematic Review of Cases: 1900 to 2005
Dena M. Bravata, MD, MS; Jon-Erik C. Holty, MD, MS; Ewen Wang, MD; Robyn Lewis, MA;
Paul H. Wise, MD, MPH; Kathryn M. McDonald, MM; Douglas K. Owens, MD, MS

Objective: To systematically review all published case
reports of children with anthrax to evaluate the predic-
tors of disease progression and mortality.
Data Sources: Fourteen selected journal indexes (1900-
1966), MEDLINE (1966-2005), and the bibliographies
of all retrieved articles.
Study Selection: Case reports (any language) of an-
thrax in persons younger than 18 years published be-
tween January 1, 1900, and December 31, 2005.
Main Exposures: Cases with symptoms and culture or
Gram stain or autopsy evidence of anthrax infection.
Main Outcome Measures: Disease progression, treat-
ment responses, and mortality.
Results: Of 2499 potentially relevant articles, 73 case
reports of pediatric anthrax (5 inhalational cases, 22 gas-
trointestinal cases, 37 cutaneous cases, 6 cases of pri-
mary meningoencephalitis, and 3 atypical cases) met the
inclusion criteria. Only 10% of the patients were younger
than 2 years, and 24% were girls. Of the few children with
inhalational anthrax, none had nonheadache neuro-
logic symptoms, a key finding that distinguishes adult
inhalational anthrax from more common illnesses, such
as influenza. Overall, observed mortality was 60% (3 of
5) for inhalational anthrax, 65% (13 of 20) for gastroin-
testinal anthrax, 14% (5 of 37) for cutaneous anthrax,
and 100% (6 of 6) for primary meningoencephalitis. Nine-
teen of the 30 children (63%) who received penicillin-
based antibiotics survived, and 9 of the 11 children (82%)
who received anthrax antiserum survived.
Conclusions: The clinical presentation of children with
anthrax is varied. The mortality rate is high in children
with inhalational anthrax, gastrointestinal anthrax, and
anthrax meningoencephalitis. Rapid diagnosis and ef-
fective treatment of anthrax in children requires recog-
nition of the broad spectrum of clinical presentations of
pediatric anthrax.
Arch Pediatr Adolesc Med. 2007;161(9):896-905

Author Affiliations: Center for
Primary Care and Outcomes
Research, Stanford University
(Drs Bravata, Holty, Wise, and
Owens and Mss Lewis and
McDonald), and Division of
Pulmonary and Critical Care
Medicine (Dr Holty) and
Departments of Surgery
(Emergency Medicine)
(Dr Wang) and Pediatrics
(Dr Wise), Stanford University
Medical Center, Stanford,
California; and VA Palo Alto
Health Care System, Palo Alto,
California (Dr Owens).
I
N RESPONSE TO THE INTENTIONAL
release of Bacillus anthracis by
mail in 2001 there has been a pro-
liferation of guidelines for the di-
agnosis and treatment of pa-
tients with anthrax.1-9 However, most of
these guidelines have not specified diag-
nostic and management protocols for chil-
dren. Children will likely be among the vic-
tims of future bioterrorism attacks on the
general public, as they were during the
1995 sarin attack in Tokyo, Japan (which
affected 16 children and 5 pregnant wom-
en), and the 1984 intentional Salmonella
contamination of salad bars in Oregon
(which affected numerous high school stu-
dents).10 In addition, children may be the
specific targets of some terrorists, as they
were during the unsuccessful 1995 plot to
release a chlorine gas bomb in Califor-
nia’s Disneyland.11 Efforts to prepare for
and respond to future attacks of anthrax
bioterrorism will be aided by detailed in-
formation about the clinical presentation
and treatment responses of pediatric popu-
lations exposed to anthrax.
Principally because of the paucity of
pediatric cases in large case series of an-
thrax, observers have speculated that
children are less susceptible to anthrax
infection and may have different clinical
courses after infection than adults. For ex-
ample, during the 1979 Sverdlovsk out-
break, 70 patients developed clinical an-
thrax after an airborne release of spores12,13;
however, there were no victims younger
than 24 years reported, despite the fact that
children were in the path of the plume.14
Because there are no published studies syn-
thesizing data from all reported pediatric
cases of anthrax, it is unknown to what ex-
tent patient characteristics, early detec-

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tion, and early treatment affect disease progression and
mortality in pediatric populations.
The development of protocols for the evaluation and
management of pediatric patients with suspected an-
thrax should be based on evaluations of the available lit-
erature regarding the clinical presentation and disease pro-
gression of children exposed to anthrax. Thus, we
performed a systematic review of case reports of pediat-
ric anthrax to describe the clinical course, treatment re-
sponses, and predictors of disease progression and mor-
tality in children with anthrax infection. In addition to
cases of inhalational, gastrointestinal, and cutaneous an-
thrax, the analysis included case reports of primary an-
thrax meningoencephalitis (ie, without an identifiable in-
halational, gastrointestinal, or cutaneous source).
METHODS
DATA SOURCES AND SEARCH TERMS
We sought all case reports (all languages) of patients younger
than 18 years with inhalational, gastrointestinal, cutaneous, or
atypical anthrax (eg, primary anthrax meningoencephalitis with-
out an identifiable inhalational, gastrointestinal, or cutaneous
source) presenting between January 1, 1900, and December 31,
2005. We identified case reports of pediatric anthrax referenced
in MEDLINE between January 1, 1966, and June 30, 2005, using
the Medical Subject Headings terms anthrax and case report. We
performed additional comprehensive searches of retrieved bib-
liographies and the indexes of 14 selected general medical and
infectious disease journals published between January 1, 1900,
and January 1, 1966 (ie, New England Journal of Medicine, JAMA,
Archives of Internal Medicine, Lancet, BMJ, Medical Journal of Aus-
tralia, La Presse Médicale, Bulletins et Mémoires de la Société Médi-
cale des Hôpitaux de Paris, Deutsche Medizinische Wochenschrift,
Wiener Medizinische Wochesnschrift, Wiener Klinische Wochen-
schrift, Muenchener Medizinische Wochenschrift, Berliner Klinische
Wochenschrift, and La Semana Medicale).
STUDY SELECTION
We considered articles eligible for inclusion if the authors of the
case report established a definitive diagnosis of anthrax. To con-
firm the diagnosis of anthrax we used the case criteria devel-
oped previously, which require that patients have positive cul-
ture, Gram stain, or immunologic evidence of recent B anthracis
infection or associated clinical or autopsy findings consistent with
anthrax infection.15-18 Because there have been hundreds of case
reports of pediatric cutaneous anthrax we used a random-
number generator to select a random sample of 50 English-
language case reports of pediatric anthrax for abstraction.
DATA EXTRACTION
Three investigators (D.M.B., J.-E.C.H., and E.W.) screened po-
tentially relevant articles to determine whether they met the
inclusion criteria. The same 3 investigators independently ab-
stracted patient data from each included English-language ar-
ticle and reviewed bibliographies for additional potentially rel-
evant studies. We resolved abstraction discrepancies by repeated
review and discussion. If 2 or more studies presented the same
data from a single patient, we included the data only once in
the analyses.
We abstracted 3 primary types of data from each included
article: patient information (eg, age, sex, and nationality),
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symptom and disease progression information (eg, whether the
patient developed meningitis), and treatment information (eg,
treatments received and year of treatment). To evaluate the
quality of the included case reports we determined the extent to
which the diagnosis of anthrax was confirmed (eg, autopsy vs
cultures vs response to therapy during a known outbreak) and
whether the source of infection (eg, inhalational disease) was
established.
DATA SYNTHESIS
Because there are important physiologic differences between in-
fants, toddlers, and adolescents, we analyzed case reports in 3 age
groups: 0 to 2 years, older than 2 to 13 years, and older than 13
to 18 years. We performed univariate analyses to summarize the
key patient and treatment characteristics. We computed corre-
lation coefficients between mortality and patient and treatment
factors. For single comparisons we considered P⬍.05 to be sta-
tistically significant. Comparing survival in patients who re-
ceived a given treatment and those who did not, we applied a Bon-
ferroni correction to account for multiple comparisons (we
considered P⬍.025 to be statistically significant [.05/2=.025]).
RESULTS
We identified 2499 titles of potentially relevant articles from
literature searches. After removing duplicate reports and
reports of patients 18 years and older we included 73 case
reports of pediatric anthrax, including 62 English-
language and 11 foreign-language reports describing 5 cases
of inhalational anthrax, 22 cases of gastrointestinal an-
thrax, 37 cases of cutaneous anthrax, 6 cases of primary
meningoencephalitis, and 3 other atypical cases (Figure).
PATIENT CHARACTERISTICS
Cases were highly heterogeneous with respect to age, year
of disease onset, nationality, diagnostic workup, and treat-
ment regimen. Most of the included cases were adoles-
cents. We found 8 cases of children aged 0 to 2 years, 26
cases of children older than 2 to 13 years, and 37 cases
of adolescents older than 13 to 18 years (Table 1). Among
the 59 case reports that stated the patient’s sex, only 14
(24%) were girls.
The included cases differed with respect to their treat-
ments and treatment responses (Table 2). Overall, ob-
served mortality was 60% (3 of 5) for inhalational an-
thrax, 65% (13 of 20) for gastrointestinal anthrax, 14%
(5 of 37) for cutaneous anthrax, and 100% (6 of 6) for
primary meningoencephalitis (survival data are not avail-
able for all cases). Among patients who received antibi-
otics, 71% survived compared with 82% of patients who
received antiserum alone (P =.29). Only 1 patient (who
survived) was treated with a fluoroquinolone, a key com-
ponent of the current treatment guidelines for an-
thrax.8,19-22 None of the included patients received an-
thrax vaccine. We found no statistically significant
associations between sex or age and survival.
Of the included cases, 14 developed meningoencepha-
litis (7 had gastrointestinal anthrax, 1 had cutaneous an-
thrax, and 6 had primary anthrax meningoencephali-
tis), and all but 1 of these patients died. Because patient
characteristics and treatment responses varied with the
WWW.ARCHPEDIATRICS.COM
 246 Citations from the MEDLINE search 298 Citations from the selected journal search

2201 Citations from the bibliography

search

2499 Total articles retrieved for full-text

and bibliographic review

1163 Articles describing adult and pediatric

cases of human anthrax:
138 Inhalational anthrax citations
96 Gastrointestinal anthrax citations
892 Cutaneous anthrax citations
37 Atypical anthrax citations∗

Remove adult cases and duplicate reports

of the same case report

5 Cases of pediatric inhalational anthrax 22 Cases of pediatric gastrointestinal anthrax 451 Cases of pediatric cutaneous anthrax 9 Cases of pediatric atypical anthrax∗
2 English language 20 English language 222 English language† 3 English language
5 Foreign language 2 Foreign language 229 Foreign language 6 Foreign language

Figure. Results of the literature searches. *Atypical anthrax includes anthrax meningoencephalitis. †Of the 222 English-language cutaneous anthrax cases, we
selected a random sample of 50 for abstraction, of which only 37 provided sufficient data for inclusion in the analysis. We did not abstract foreign-language
reports of cutaneous anthrax.

Table 1. Distribution of Cases by Age a

Boys, No. Girls, No.

Age Group,
y Source of Anthrax Infection Total Survived Total Survived
0-2 Inhalational 0 NA 0 NA
Gastrointestinal 2 1 2 0
Cutaneous 1 0 2 2
Atypical: primary meningoencephalitis 0 NA 1 0
⬎2-13 Inhalational 1 0 1b 1
Gastrointestinal 7 3c 1 0
Cutaneous 11 7c 1 1
Atypical: laryngopharyngeal 2 2 0 NA
Atypical: primary meningoencephalitis 1 0 0 NA
⬎13-18 Inhalational 1 1 2 0
Gastrointestinal 6 3 2 0
Cutaneous d 15 8c 4 4
Atypical: nasopharyngeal 0 NA 1 1
Atypical: primary meningoencephalitis 4 0 0 NA

Abbreviation: NA, not applicable.

a Mortality was highest (71%) in children 0 to 2 years old compared with 22% in children older than 2 to 13 years and 46% in adolescents older than 13 to 18
years.
b This girl was 21⁄2 years old.
c One case report of gastrointestinal anthrax and 7 case reports of cutaneous anthrax did not state whether the patients survived.
d Three descriptions of patients with cutaneous anthrax did not state the patients’ sex; 2 of these patients were aged 14 and 17 years and survived; the child
younger than 5 years died.

source of infection, we present these results according thrax (eTable available at: http://www.archpediatrics
to presumed anthrax source. .com). All the children for whom we have signs and
symptoms data were reported to have dyspnea and ab-
INHALATIONAL ANTHRAX normal lung examination findings; however, none had
neurologic symptoms other than headache, nausea, or
We found 2 English-language and the 3 foreign- vomiting. The 2 children with inhalational anthrax who
language case reports of children with inhalational an- had chest radiographs were found to have abnormali-

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ties similar to those classically associated with inhala-
tional anthrax (ie, a widened mediastinum and pleural Table 2. Summary of Treatments Received
effusions).
The 5 published case reports of pediatric anthrax pro- Patients, No. (%)
P
vide insufficient evidence to evaluate the treatment re- Treatment Received Total Survived Value a
sponses of children with inhalational anthrax and to com- Any antibiotic vs no antibiotic or .78
pare them with adults with inhalational disease. However, antiserum
note that the 2 children who survived were treated with Any antibiotics 38 27 (71)
antiserum, a treatment not typically included in current No antibiotics or antiserum 24 14 (58)
treatment guidelines or bioterrorism preparedness in- Penicillin or penicillin-based antibiotic .89
(eg, ampicillin) vs all other antibiotics
ventories. In addition, the child with inhalational an-
or antiserum
thrax who received pleural fluid drainage survived Penicillin or penicillin-based 30 19 (63)
(eTable). antibiotic
All other antibiotics or antiserum 21 18 (86)
Antiserum vs all antibiotics .29
GASTROINTESTINAL ANTHRAX Antiserum alone 11 9 (82)
Any antibiotic 40 28 (70)
Aminoglycosides vs all other antibiotics .85
Of the 20 English-language case reports of pediatric gas- or antiserum
trointestinal anthrax, most were associated with known Aminoglycosides (most often 10 7 (70)
outbreaks, typically resulting from the consumption of streptomycin)
contaminated meat (Table 3). (The 2 foreign-language All other antibiotics or antiserum 41 30 (73)
reports of gastrointestinal anthrax provided insufficient Chloramphenicol vs all other antibiotics .91
or antiserum
clinical data to be included in the analyses.) The aver- Chloramphenicol 8 5 (63)
age age of these patients was 10.5 years, 5 were girls, and Other antibiotics or antiserum 43 32 (74)
none were from the United States. Compared with in-
halational and cutaneous disease, gastrointestinal an- a P value for the comparison of whether patients who received this treatment

thrax is considered rare in adults, especially in the United
States. However, in children there have been more
case reports of gastrointestinal disease than inhalational
disease.
Of the 20 presentations of gastrointestinal anthrax, 3
presented with symptoms of upper tract disease charac-
terized by dysphagia and oropharyngeal findings, and the
remaining presented with lower tract disease character-
ized by abdominal pain and vomiting. The most com-
mon presenting symptoms were fever (60%), abdomi-
nal pain (45%), and vomiting (45%); however, none had
hematemesis. Four patients (20%) had diarrhea, and only
1 reported a bloody stool. All 3 patients who went on to
have abdominal surgery had mesenteric lymphadenop-
athy. Of the 4 patients with gastrointestinal anthrax who
had radiographs, 2 were found to have pulmonary ab-
normalities, 1 had “ascites but no other abnormalities,”
and 1 had normal examination findings.
Seven patients (35%) developed meningoencephali-
tis, presumably as a result of hematologic dissemina-
tion. The development of secondary meningoencepha-
litis was a poor prognostic indicator, present in 6 of the
12 children with gastrointestinal disease who died.
Thirteen of the 14 patients who received antibiotic
agents were given a regimen that included a penicillin-
based antibiotic, 10 patients received more than 1 anti-
biotic, and no patients received antiserum. The use of peni-
cillin-based antibiotics likely reflects the year of the case
report and the country of origin of the patient, among
other factors. We found no patient or treatment factors
that were significantly associated with survival from gas-
trointestinal anthrax; however, this analysis had limited
power to detect predictors of survival given the small
sample size. It is notable that whereas all 5 girls with gas-
trointestinal anthrax died, only 7 of the 14 boys with gas-
trointestinal anthrax died.
were more likely to survive than those who did not receive this treatment. For
this analysis, only the 62 cases for which adequate treatment information was
reported were used. Eleven patients received neither antibiotics nor serum, of
whom 6 (55%) survived.
CUTANEOUS ANTHRAX
Of the 50 randomly selected English-language case re-
ports of children with cutaneous anthrax, only 37 pro-
vided sufficient information about individual patients to
be included in this analysis.45-75 In general, the included
reports of pediatric cutaneous anthrax were of very poor
quality, often providing only a few sentences about the
patients and their clinical course (and rarely describing
the skin lesions in detail). The clinical course of cutane-
ous anthrax typically progressed as has historically been
described from a small, painless, pruritic papule on an
exposed area to an enlarging lesion that becomes an oval
eschar surrounded by vesicles with marked, painless
brawny edema and tissue necrosis.76 Findings from chest
radiographs available from 4 patients with cutaneous an-
thrax were normal.
Sixteen children received penicillin, and 8 had surgi-
cal debridement of their lesions. Only 5 children with
cutaneous anthrax died (14% case fatality rate), which
is within the range of adult case fatality rates.76 All cases
of fatal cutaneous disease were boys, 3 of whom had not
received antibiotic agents. One child with cutaneous an-
thrax developed meningoencephalitis before he died.
ATYPICAL ANTHRAX
Historically, anthrax has been classified according to the
3 principal exposures—inhalational, gastrointestinal, and
cutaneous—that result in the described presentations. Al-
though rare, atypical anthrax presentations, including la-

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 Table 3. English-Language Pediatric GI Anthrax Case Reports

Type
Sex/Age, y/ of GI Initial Initial Physical
Source a Country Disease Symptoms Examination Findings Treatment b Complications Died Autopsy Findings
Mansour-Ghanaei M/15/Iran LG Fever, abdominal Febrile but vital signs P Sh, DIC Yes Subendocardial petechiae,
et al,30 2002 pain, diarrhea otherwise normal; nonhemorrhagic effusion;
abdominal tenderness, stomach, small-bowel,
no splenomegaly mesentery, and spleen
had edema, hemorrhage,
and adenopathy but no
ulcerations; esophagus
hemorrhagic spots
Alizad et al,31 1991 F/2/Iran LG Fever, abdominal Febrile, tachycardic, A, G, Ch None reported Yes None reported
pain, emesis tachypnea, hypotensive,
cyanotic, abdominal
tenderness with
distention and absent
bowel sounds, no skin
lesions
Mansour-Ghanaei M/8/Iran LG None reported None reported None reported None reported Yes None reported
et al,30 and Alizad
et al,31 2002
Sekhar et al,32 1989 M/11/India LG No info Antibiotics, None reported Not None reported
type not stated
specified
Nalin et al,33 1976 M/17/Bangladesh LG Fever, anorexia, Febrile, no lung findings, P, A, Ch, Sm, T, Sh No Not applicable
abdominal pain abdominal tenderness Tr, E
without distention, slight
right flank tenderness,
bowel sounds slightly
decreased
Kanafani et al,34 M/7/Lebanon LG Periumbilical pain, Distended abdomen, P S No Not applicable
1965 fever, vomiting palpable mass in right
iliac fossa ascites,
hypotension
Kanafani et al,34 M/17/Lebanon LG Fever, abdominal Tender distended P, Sm S No Not applicable
1962 pain abdomen, ascites
Kanafani et al,34 M/15/Lebanon LG None reported Ascites, oculofacial P S, Sh No Not applicable
1974 congestion
Tantachumroon and M/14/Thailand LG Fever, abdominal Vital signs were stable on “Antimicrobials Sh, RF Yes No cerebral findings, lung
Panas-Ampol,35 pain, emesis, admission but not given” hemorrhage;
1965 diarrhea progressed rapidly to small-bowel, mesentery,
respiratory distress, and spleen edema and
delirium, abdominal hemorrhage; small-bowel
tenderness with ulcerations; mesenteric
distention and ascites adenopathy
Case report,36 1932 M/7/Philippines LG Fever, abdominal None reported None reported None reported No Not applicable
pain
Tabatabaie and M/6/Iran LG Fever, emesis Febrile, tachypnea, nuchal P, Sm PE, PFD, Sh, M No Not applicable
Syadati,37 1989 rigidity, positive Kernig
sign
Tabatabaie and F/2/Iran LG Febrile, tachypnea, coma, P, Sm M Yes None reported
Syadati,37 1989 seizure, nuchal rigidity,
positive Kernig sign,
ptosis, dilation of right
pupil
Kwong,38 1997 M/13/Asia LG Emesis Febrile, dehydrated, right Cf, A, Cm MV, Sh, RF, Yes Grossly swollen brain with
lower quadrant DIC, M focal subarachnoid
tenderness, no rebound hemorrhage, lots of
or guarding, decreased gram-positive bacteria;
bowel sounds, no cecum hemorrhagic and
meningeal or skin signs necrotic with polys,
macrophages, bacteria

(continued)

ryngopharyngeal and nasopharyngeal disease and pri-
mary anthrax meningoencephalitis, do occur in adults.77
Some researchers have speculated that the port of entry for
primary anthrax meningoencephalitis is either an unrec-
ognized lower respiratory tract port of entry78 or transeth-
moidal migration of occult nasopharyngeal infection.79-81
We found 2 nonfatal cases of laryngopharyngeal an-
thrax. Both were boys, aged 6 and 11 years, from the same
East African case report from 1944.82 Other than noting
signs of respiratory distress and laryngeal obstruction on
hospital admission, no other signs, symptoms, or other
clinical data are available. The 6-year-old required a tra-
cheostomy, but no additional procedure or treatment data
were reported.
We found 1 report of a 17-year-old Argentinian girl
suspected of inhaling horsehair in a bristle mill who de-

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 Table 3. English-Language Pediatric GI Anthrax Case Reports (cont)

Type
Sex/Age, y/ of GI Initial Initial Physical
Source a Country Disease Symptoms Examination Findings Treatment b Complications Died Autopsy Findings
Berthier et al,39 F/11/Europe LG Fever, abdominal Febrile, altered level of None reported MV, RF, M Yes None reported
1996 pain, emesis consciousness, no
nuchal rigidity, no skin
signs
Raper,40 1953 M/15/Africa LG Emesis Febrile, coma, nonfocal P M Yes Petechial, subarachnoid
neurologic findings, no hemorrhage, no
nuchal rigidity hemorrhagic lesions of
mouth, no lung findings,
small-bowel hemorrhage
and small ulcer, no
splenic findings, mild
jaundice of all tissues
Yeung,41 1994 M/13/Asia LG Fever, abdominal None reported A, Cx, Cm, Me, M Yes Meningeal involvement of
pain, emesis Fl, Ac anthrax bacilli
Department of M/2/Asia LG Fever, abdominal Altered level of None reported M Yes None reported
Health Hong pain, emesis consciousness, coma
Kong,42 2003
Pandey,43 1977 India UG Emesis No fever on admission P None reported No Not applicable
(antibiotics earlier),
blebs, ulceration and
sloughing of gums and
hard palate, ulcerations
covered with
“dirty-looking slough”
Doğanay et al,44 F/18/Turkey UG Fever, dyspnea, None reported P, G RF Yes Brain, lung hemorrhage,
1981 dysphagia tonsillar findings, ENT
adenopathy, no
abdominal findings noted
Doğanay et al,44 F/16/Turkey UG Fever, dysphagia Febrile, lethargic, None reported Sh Yes Brain, lung hemorrhage,
1983 orolaryngeal edema, tonsillar findings, ENT
large tonsil with adenopathy, small-bowel
pseudomembrane and hemorrhage, hyperemic
right-sided neck mass kidneys and liver

Abbreviations: A, ampicillin; Ac, acyclovir; Cf, cefuroxime; Ch, chloramphenicol; Cm, cefotaxime; DIC, disseminated intravascular coagulation; E, erythromycin;
ENT, ears, nose, throat; Fl, fluconazole; G, gentamicin; GI, gastrointestinal; LG, lower gastrointestinal tract; M, meningitis; Me, metronidazole; MV, mechanical ventilation;
P, penicillin; PE, pleural effusion(s); PFD, pleural fluid drainage; RF, respiratory failure; S, surgery; Sh, shock; Sm, streptomycin; Tr, transfusion(s); UG, upper
gastrointestinal tract.
a The year given is the year that the case occurred, not the year of publication.
b Antibiotics or anthrax antiserum.

veloped nasopharyngeal disease.83,84 She presented ini-
tially with epistaxis, nasal obstruction, and neck swell-
ing, similar to what was observed among the 5 adults
presenting between 1902 and 1942 with nasal/naso-
pharyngeal anthrax.77 She survived.
We found 1 English-language and 5 foreign-language
case reports of children with primary meningoencepha-
litis; all 6 patients died (Table 4). The patient de-
scribed in greatest detail was a 14-year-old Mexican boy
who was thought to have been exposed in a slaughter-
house. He presented with high fever but otherwise nor-
mal vital signs, headache, delirium, seizures, and eme-
sis. Initial physical examination was notable for the absence
of pulmonary symptoms. Neurologic findings included
meningeal signs, eye deviation with horizontal nystag-
mus and nonreactive pupils, and coma. He had normal
findings on chest radiography.
Among the 5 children described in the foreign-lan-
guage reports of patients with primary meningoencepha-
litis, we have little patient or treatment information;
however, fever, headache, and abdominal complaints, in-
cluding emesis and diarrhea, were common at presenta-
tion. The single patient with primary anthrax meningo-
encephalitis for whom we have treatment information
received penicillin and chloramphenicol but died despite
treatment.
COMMENT
This study is the first published synthesis of the litera-
ture describing the spectrum of clinical anthrax in chil-
dren. The 73 pediatric cases included in this review pro-
vide 4 key findings.
First, children with anthrax present with a wide range
of clinical signs and symptoms. Although there have been
very few case reports of children with inhalational an-
thrax, most children at presentation were febrile and com-
plained of cough and dyspnea, and all had abnormal lung
findings on examination. None presented with nonhead-
ache neurologic symptoms (eg, altered mental status or
coma), which are key symtoms that have been shown
among adults to distinguish inhalational anthrax from
more common illnesses, such as influenza.91 Given the
paucity of inhalational pediatric cases, the significance
of this finding is unknown. Similar to adults, children
with gastrointestinal anthrax have 2 distinct clinical pre-
sentations: one resulting from upper respiratory tract dis-

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 Table 4. Pediatric Primary Meningoencephalitis Anthrax Case Reports a

Sex/Age, y/ Anthrax Symptoms at Initial Physical

Source Country Exposure Risk Presentation Examination Findings Died Autopsy Findings
English-Language Case
Rangel and M/14/Mexico Slaughterhouse Headache, emesis, Febrile, comatose, neurologic Yes Congested lungs, b patchy
Gonzalez,85 delirium, malaise, deficits, meningeal signs; no bronchopneumonia,
1975 fever, seizures skin or abdominal splenic congestion,
abnormalities; normal chest cerebral, hemorrhagic
radiographic findings meningoencephalitis,
few bowel ulcerations;
no skin lesions
Foreign-Language Cases
Marandian and M/16/Iran Unknown, food Headache, emesis, Febrile, comatose, neurologic Yes Not reported
Kamali,86 1981 product fever, convulsions deficits, meningeal signs; no
salesman c skin, lung, or abdominal
abnormalities
Bezzi,87 1951 F/1/Italy Not reported Fever, diarrhea, Febrile; tonsillar and oral cavity Yes Not reported
restlessness erythema/edema without
ulceration/plaques; no skin,
lung, or abdominal
abnormalities
Gross and M/17/Germany Not reported Fever, headache, Febrile; no skin, lung, or Yes Not reported
Plate,88 1940 back pain, stomach abdominal abnormalities; no
complaints neurologic deficits
Slatineanu,89 M/18/Romania Not reported Fever, headache, Comatose, cyanosis, abnormal Yes Hemorrhagic
1936 abdominal pain, lung examination findings, meningoencephalitis;
delirium abdominal distention, ascites and mesenteric
neurologic deficits; no skin adenopathy without
lesions bowel ulcerations; no
lung or skin lesions
Aguiah,90 1927 M/11/France Horses, cattle Anorexia, headache, Febrile, tachycardia, neurologic Yes Not reported
chills, malaise, deficits, meningeal signs; no
fatigue, emesis, skin, throat, lung, or
delirium abdominal abnormalities

a We classified cases according to 1 of 3 anatomical sites: nasal/nasopharyngeal, laryngeal/laryngopharyngeal, or primary meningoencephalitis (without a
known cutaneous, gastrointestinal, or respiratory port of entry). Cases were classified primarily according to the authors’ suspicion of the port of entry and the
anatomical sites of mucosal and lymph node abnormalities on examination or at autopsy.
b The authors suspected a primary nasopharyngeal infection with a secondary stomach/intestinal infection from swallowing nasal secretions.
c What the authors of the case report suspected as the route of entry for Bacillus anthracis spores.

ease characterized by dysphagia and oropharyngeal find-
ings and another resulting from lower respiratory tract
disease characterized by fever, abdominal pain, and vom-
iting. In addition, children with inhalational disease may
have atypical presentations, including primary menin-
goencephalitis. Physicians and public health officials need
to recognize the broad spectrum of potential presenta-
tions of anthrax in children for timely diagnosis and for
the design of syndromic surveillance systems.92
Second, mortality is high in children with inhala-
tional anthrax, gastrointestinal anthrax, and anthrax me-
ningoencephalitis. In particular, children aged 0 to 2 years
had the highest observed mortality (71%), and all chil-
dren with primary meningoencephalitis died. In addi-
tion, children with gastrointestinal anthrax (treated and
untreated) had a somewhat higher observed mortality rate
(65%) than what has typically been reported for adults
(40%).93 Most children included in this analysis who re-
ceived an antibiotic drug were given penicillin-based an-
tibiotics, which produced a 63% survival rate. Current
treatment guidelines do not include penicillin as a single
agent due to concerns of penicillin-resistant organ-
isms.8,19-21 Other successful treatments included antise-
rum, which was associated with 82% survival.
Antiserum is not currently included in treatment guide-
lines or bioterrorism preparedness inventories; how-
ever, before the introduction of antibiotic agents an-
thrax infection was primarily treated with antiserum.94
Anthrax antiserum used in adults reportedly decreased
mortality by 75% compared with untreated patients.95-100
However, anaphylactic reactions and serum sickness were
major adverse effects.101 Because anthrax virulence is caused
by the production of bacterial toxins,9 it has been theo-
rized that therapeutics, such as antiserum, that are di-
rected against these toxins could be superior to antimi-
crobial agents.101-106 Further evidence supporting this
rationale for the efficacy of anthrax immunotherapy in-
cludes recent animal data using neutralizing monoclo-
nial antibodies.107-110 Anthrax antiserum is no longer com-
mercially available in most Western countries, including
the United States, but it is still available in the Russian Fed-
eration and in China.1,101,111 Recently, the US Department
of Health and Human Services awarded a contract to Can-
gene Corp (Winnipeg, Manitoba, Canada) to produce an-
thrax immunoglobulin for the Strategic National Stock-
pile.112-117 Anthrax immunoglobulin is a highly purified
human antibody that is specific to anthrax and is col-
lected from the plasma of soldiers who were inoculated

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902
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©2007 American Medical Association. All rights reserved.
with the anthrax vaccine.108,118 In addition, Human Ge-
nome Sciences Inc (Rockville, Maryland) was awarded a
similar contract to develop a monoclonal antibody inhibi-
tor specific for anthrax protective antigen to also be in-
cluded in the Strategic National Stockpile.22,114-117,119,120 In
the event of shortfalls in stockpiles of the currently rec-
ommended antibiotics, penicillin and therapeutics di-
rected against anthrax toxins may provide some therapeu-
tic benefit.
Third, anthrax is reported relatively rarely in the young-
est children and in girls (only 24% of the included cases).
The sex discrepancy is similar to that observed in adults
and has historically been attributed to the fact that an-
thrax has largely been an occupational disease among pro-
fessions dominated by men and boys (eg, woolsorters and
butchers); however, other biases may be contributing to
the underdiagnosis and underreporting of anthrax in girls
relative to boys.
Finally, we did not find evidence to support or refute
the claim that children may be less susceptible to an-
thrax infection. In general, the relatively small number
of pediatric cases of anthrax may reflect that children may
not have the same degree of exposure to anthrax spores
as adults through occupational and environmental ex-
posures (eg, young children may be more likely to be in-
doors than adults, whereas older children may be more
likely to be outdoors than adults) or that anthrax may
be underdiagnosed or underreported in children.
The potential for underdiagnosis of anthrax in chil-
dren has implications for syndromic surveillance sys-
tems. The presenting symptoms for inhalational and gas-
trointestinal anthrax are common for many childhood
diseases, and it is likely that naturally occurring pediatric
anthrax has been attributed to one of the common child-
hood infections.121,122 Thus, effective surveillance sys-
tems require data sources that can readily distinguish an-
thrax from other common childhood infectious diseases.
This review has several limitations. First, because we
did not have access to the original hospital and medical
records the analyses depend on the data presented in the
case reports. Second, because most of the included cases
are presumed to have contracted anthrax from occupa-
tional exposures or direct contact with contaminated ani-
mal products, the results may have limited generalizabil-
ity to anthrax infection that occurs from bioterrorism.
Third, most included cases were older children; thus, these
results may not be generalizable to infants and toddlers
with anthrax. Finally, the general paucity of inhala-
tional pediatric cases suggests that there may be substan-
tial publication bias in this literature.
Because anthrax in children has a high mortality rate,
clinical and public health measures should emphasize
the rapid diagnosis and initiation of effective therapies
for this population. However, more research is needed to
clarify the optimum management. The broad spectrum of
clinical presentations in children with anthrax and the
similarity of many of these presenting symptoms to other
common pediatric infectious diseases pose serious chal-
lenges to current diagnostic criteria and surveillance
systems.
Accepted for Publication: March 6, 2007.
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903
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©2007 American Medical Association. All rights reserved.
Correspondence: Dena M. Bravata, MD, MS, Center for
Primary Care and Outcomes Research, 117 Encina Com-
mons, Stanford University, Stanford, CA 94305-6019
(dbravata@stanford.edu).
Author Contributions: Dr Bravata had full access to all
of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analy-
sis. Study concept and design: Bravata, Holty, McDonald,
and Owens. Acquisition of data: Bravata, Holty, Wang,
Lewis, and Owens. Analysis and interpretation of data: Bra-
vata, Wang, Wise, and Owens. Drafting of the manu-
script: Bravata, Holty, and Owens. Critical revision of the
manuscript for important intellectual content: Bravata, Holty,
Wang, Lewis, Wise, McDonald, and Owens. Statistical
analysis: Bravata and Holty. Obtained funding: Bravata,
McDonald, and Owens. Administrative, technical, and ma-
terial support: Bravata and Lewis. Study supervision: Bra-
vata and Owens.
Financial Disclosure: None reported.
Funding/Support: This work was performed by the Stan-
ford–University of California San Francisco Evidence-
based Practice Center under contract 290-02-0017 from
the Agency for Healthcare Research and Quality. This
project was also supported in part by the Department of
Veterans Affairs.
Role of the Sponsor: The funders had no role in the de-
sign or conduct of the study; the collection, manage-
ment, analysis, or interpretation of the data; or the prepa-
ration, review, or approval of the manuscript.
Additional Information: The eTable is available at http:
//www.archpediatrics.com.
Additional Contributions: Rebecca Kim, BS, assisted with
searching the indices of selected journals, Emilee Wilhelm,
BA, helped with article retrieval, and Corinna Haber-
land, MD, provided translations.
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eTable. Pediatric Inhalational Anthrax Case Reports

Anthrax Initial
Sex/Age, y/ Exposure Symptoms at Initial Physical Laboratory Autopsy
Source Country Risk Presentation Examination Values Treatment Complications Died Findings
English-Language Pediatric Cases
McKitterick and F/21⁄2/US Unknown Cough, Febrile, abnormal lung WBC count, H PE, PFD, C No Not applicable
Pearson,23 1928 restlessness examination, cyanosis, 18 000/µL;
pharyngeal erythema purulent
and edema, abdominal urine
distention, mottled skin,
erythematous bulging
tympanic membranes
Vessal et al,24 1975 F/16/Iran Unknown Dyspnea, axilla Abnormal lung examination − P, Ch − Yes Pulmonary
swelling findings, afebrile, edema,
abnormal chest mediastinal
radiographic findings widening,
hemorrhagic
mediastinal
and axillary
nodes
Foreign-Language Pediatric Cases
Krzyszkowski,25,26 1901 F/16/Poland Unknown “In agony” − − None M, PE Yes None reported
Schereffetin,27 1929 M/17/Germany Wool Fever, chills, Febrile, tachycardia, − As − No Not applicable
pleurisy, abnormal lung
cough, examination findings
dyspnea,
hemoptysis
Skolubovich and M/13/Russia Dust from − − − None M Yes None reported
Ruban,28,29 1954 infected
sheep and
calf

Abbreviations: As, anthrax antiserum; C, cyanosis; Ch, chloramphenicol; H, horse antiserum; M, meningitis; P, penicillin; PE, pleural effusion(s); PFD, pleural
fluid drainage; WBC, white blood cell; −, either not seen before death or no additional signs or symptoms noted in case report at presentation.

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