Chapter 197 ◆ Pertussis (Bordetella pertussis and Bordetella parapertussis) 1377

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Chapter 197
Pertussis (Bordetella
pertussis and Bordetella
parapertussis)
Sarah S. Long

Pertussis is an acute respiratory tract infection that was well described

initially in the 1500s. Sydenham first used the term pertussis, meaning
intense cough, in 1670; it is preferable to whooping cough because most
infected individuals do not “whoop.”

ETIOLOGY
Bordetella pertussis is the cause of epidemic pertussis and the usual
cause of sporadic pertussis. Bordetella parapertussis is an occasional
cause of sporadic pertussis that contributes significantly to total cases
of pertussis in Eastern and Western Europe but accounts for <5% of
Bordetella isolates in the United States. B. pertussis and B. parapertussis
1378 Part XVII ◆ Infectious Diseases
are exclusive pathogens of humans and some primates. Bordetella
holmesii, first identified as a cause of bacteremia in immunocompro-
mised hosts, is also reported to cause pertussis-like cough illness in
healthy persons in Japan, France, and the United States. Bordetella
bronchiseptica is a common animal pathogen. Occasional reports in
humans describe a variety of body sites involved, and cases typically
occur in immunocompromised persons or young children with intense
exposure to animals. Protracted coughing (which in some cases is
paroxysmal) can be caused by Mycoplasma, parainfluenza viruses,
influenza viruses, enteroviruses, respiratory syncytial viruses, or
adenoviruses.
EPIDEMIOLOGY
Estimates from the World Health Organization suggest that in 2008,
approximately 16 million cases of pertussis and 195,000 childhood
deaths occurred worldwide, 95% of which were in developing coun-
tries. The World Health Organization also estimated that in 2008, 82%
of infants worldwide received 3 doses of pertussis vaccine, and that
global vaccination against pertussis averted 687,000 deaths. Before
vaccination was available, pertussis was the leading cause of death from
communicable disease among children younger than 14 yr of age in
the United States, with 10,000 deaths annually. Widespread use of
whole-cell pertussis vaccine (DTP) led to a >99% decline in cases. After
the low number of 1,010 cases in the United States reported in 1976,
there was an increase in annual pertussis incidence to 1.2 cases per
100,000 population from 1980 through 1989, with epidemic pertussis
in many states in 1989-1990, 1993, and 1996. Since then, pertussis has
become increasingly endemic, with shifting burden of disease to young
infants, adolescents, and adults. By 2004, the incidence of reported
pertussis in the United States was 8.9 cases per 100,000 in the general
population and approximately 150 per 100,000 in infants younger than
2 mo of age, resulting in a total of 25,827 cases, the highest number
since 1959. Prospective and serologic studies suggested that pertussis
is underrecognized, especially among adolescents and adults, in whom
the actual number of cases is estimated to be 600,000 annually. A
number of studies documented pertussis in 13-32% of adolescents and
adults with cough illness for longer than 7 days. A total of 40 pertussis-
related deaths were reported in 2005, and 16 were reported in 2006;
more than 90% of these cases occurred among young infants.
Universal recommendation of tetanus toxoid, reduced content diph-
theria toxoid, and acellular pertussis antigens (Tdap) in 2006 for 11-12
year olds was aimed to enhance control. With >70% uptake of Tdap in
adolescents, the burden of disease in young adolescents has fallen com-
mensurately, but without evidence of herd protection of young infants
or older adolescents or adults. In fact, a new epidemiology of pertussis
has emerged in this decade, with substantial evidence of rapidly waning
protection following acellular pertussis vaccines (both DTaP and Tdap)
and especially in those who never received, that is, were not “primed”
with, DTP (whole cell), which was replaced with DTaP down to dose
1 in 1997 in the United States. The more than 42,000 cases of pertussis
reported in 2012 was the highest number in more than 50 yr; increased
numbers of cases were reported in all except 1 state; 10 yr old children
had the highest age-related incidence after young infants.
Neither natural disease nor vaccination provides complete or life-
long immunity against pertussis reinfection or disease. Subclinical
reinfection undoubtedly contributed significantly to immunity against
disease ascribed previously to both vaccine and prior infection. The
resurgence of pertussis has been attributed to a variety of factors,
including partial control of pertussis leading to less continuous expo-
sure, increased awareness, improved diagnostics, suboptimal vaccines,
waning vaccine-induced immunity, and pathogen adaptation. Pertussis
is the only vaccine-preventable disease for which universal immuniza-
tion in the United States is recommended that continues to be endemic.
PATHOGENESIS
Bordetella organisms are small, fastidious, Gram-negative coccobacilli
that colonize only ciliated epithelium. The exact mechanism of disease
symptomatology remains unknown. Bordetella species share a high
degree of DNA homology among virulence genes. Only B. pertussis
expresses pertussis toxin (PT), the major virulence protein. PT has
numerous proven biologic activities (e.g., histamine sensitivity, insulin
secretion, leukocyte dysfunction). Injection of PT in experimental
animals causes lymphocytosis immediately by rerouting lymphocytes
to remain in the circulating blood pool but does not cause cough. PT
appears to have a central, but not a singular, role in pathogenesis. B.
pertussis produces an array of other biologically active substances,
many of which are postulated to have a role in disease and immunity.
After aerosol acquisition, filamentous hemagglutinin, some aggluti-
nogens (especially fimbriae [Fim] types 2 and 3), and a 69-kDa non-
fimbrial surface protein called pertactin (Prn) are important for
attachment to ciliated respiratory epithelial cells. Tracheal cytotoxin,
adenylate cyclase, and PT appear to inhibit clearance of organisms.
Tracheal cytotoxin, dermonecrotic factor, and adenylate cyclase are
postulated to be predominantly responsible for the local epithelial
damage that produces respiratory symptoms and facilitates absorption
of PT. Both antibody and cellular immune responses follow infection
and immunization. Antibody to PT neutralizes toxin, and antibody to
Prn enhances opsonophagocytosis.
Pertussis is extremely contagious, with attack rates as high as 100%
in susceptible individuals exposed to aerosol droplets at close range.
High airborne transmission rates were shown in a baboon model of
pertussis despite vaccinated with the acellular vaccine. B. pertussis does
not survive for prolonged periods in the environment. Chronic car-
riage by humans is not documented. After intense exposure as in
households, the rate of subclinical infection is as high as 80% in fully
immunized or previously infected individuals. When carefully sought,
a symptomatic source case can be found for most patients.
CLINICAL MANIFESTATIONS
Classically, pertussis is a prolonged disease, divided into catarrhal,
paroxysmal, and convalescent stages. The catarrhal stage (1-2 wk)
begins insidiously after an incubation period ranging from 3-12 days
with nondistinctive symptoms of congestion and rhinorrhea variably
accompanied by low-grade fever, sneezing, lacrimation, and conjunc-
tival suffusion. As initial symptoms wane, coughing marks the onset
of the paroxysmal stage (2-6 wk). The cough begins as a dry, intermit-
tent, irritative hack and evolves into the inexorable paroxysms that are
the hallmark of pertussis. A well-appearing, playful toddler with insig-
nificant provocation suddenly expresses an anxious aura and may
clutch a parent or comforting adult before beginning a machine-gun
burst of uninterrupted cough on a single exhalation, chin and chest
held forward, tongue protruding maximally, eyes bulging and water-
ing, face purple, until coughing ceases and a loud whoop follows as
inspired air traverses the still partially closed airway. Posttussive emesis
is common, and exhaustion is universal. The number and severity of
paroxysms escalate over days to a week and remain at that plateau for
days to weeks. At the peak of the paroxysmal stage, patients may have
more than 1 episode hourly. As the paroxysmal stage fades into the
convalescent stage (≥2 wk), the number, severity, and duration of
episodes diminish.
Infants younger than 3 mo of age do not display the classic stages.
The catarrhal phase lasts only a few days or is unnoticed, and then,
after the most insignificant startle from a draft, light, sound, sucking,
or stretching, a well-appearing young infant begins to choke, gasp, gag,
and flail the extremities, with face reddened. Cough may not be promi-
nent, especially in the early phase. Whoop infrequently occurs in
infants younger than 3 mo of age who at the end of a paroxysm lack
stature or muscular strength to create sudden negative intrathoracic
pressure. Apnea and cyanosis can follow a coughing paroxysm, or
apnea can occur without a cough. Apnea may be the only symptom.
Apnea and cyanosis both are more common with pertussis than with
neonatal infections from viruses, including respiratory syncytial virus.
The paroxysmal and convalescent stages in young infants are lengthy.
Paradoxically, in infants, cough and whooping may become louder and
more classic in convalescence. Convalescence includes intermittent
paroxysmal coughing throughout the 1st yr of life, including “exacer-
bations” with subsequent respiratory illnesses; these are not a result of
recurrent infection or reactivation of B. pertussis.
 Chapter 197 ◆ Pertussis (Bordetella pertussis and Bordetella parapertussis)
Adolescents and previously immunized children have foreshorten-
ing of all stages of pertussis. Adults have no distinct stages. Classically,
adolescents and adults describe a sudden feeling of strangulation fol-
lowed by uninterrupted coughs, feeling of suffocation, bursting head-
ache, diminished awareness, and then a gasping breath, usually without
a whoop. Posttussive emesis and intermittency of paroxysms separated
by hours of well-being are specific clues to the diagnosis in adolescents
and adults. At least 30% of older individuals with pertussis have non-
specific cough illness, distinguished only by duration, which usually is
longer than 21 days.
Findings on physical examination generally are uninformative. Signs
of lower respiratory tract disease are not expected unless complicating
secondary bacterial pneumonia is present. Conjunctival hemorrhages
and petechiae on the upper body are common.
DIAGNOSIS
Pertussis should be suspected in any individual who has a pure or
predominant complaint of cough, especially if the following features
are absent: fever, malaise or myalgia, exanthem or enanthem, sore
throat, hoarseness, tachypnea, wheezes, and rales. For sporadic cases,
a clinical case definition of cough of 14 days or longer duration with
at least 1 associated symptom of paroxysms, whoop, or posttussive
vomiting has a sensitivity of 81% and a specificity of 58% for confirma-
tion of pertussis. Pertussis should be suspected in older children whose
cough illness is escalating at 7-10 days and whose coughing episodes
are not continuous. Pertussis should be suspected in infants younger
than 3 mo of age with gagging, gasping, apnea, cyanosis, or an apparent
life-threatening event. Sudden infant death occasionally is caused by
B. pertussis.
Adenoviral infections usually are distinguishable by associated fea-
tures, such as fever, sore throat, and conjunctivitis. Mycoplasma causes
protracted episodic coughing, but patients usually have a history of
fever, headache, and systemic symptoms at the onset of disease as well
as more continuous cough and frequent finding of rales on ausculta-
tion of the chest. Epidemics of Mycoplasma and B. pertussis in young
adults can be difficult to distinguish on clinical grounds. Although
pertussis often is included in the laboratory evaluation of young infants
with afebrile pneumonia, B. pertussis is not associated with staccato
cough (breath with every cough), purulent conjunctivitis, tachypnea,
rales or wheezes that typify infection by Chlamydia trachomatis, or
predominant lower respiratory tract signs that typify infection by
respiratory syncytial virus. Unless an infant with pertussis has second-
ary pneumonia (and then appears ill), the findings on examination
between paroxysms including respiratory rate are entirely normal.
Leukocytosis (15,000-100,000 cells/µL) caused by absolute lympho-
cytosis is characteristic in the catarrhal stage. Lymphocytes are of T-
and B-lymphocyte origin and are normal small cells, rather than the
large atypical lymphocytes seen with viral infections. Adults, partially
immune children, and, occasionally, young infants may have less-
impressive lymphocytosis. Absolute increase in neutrophils suggests a
different diagnosis or secondary bacterial infection. Eosinophilia is not
a manifestation of pertussis. A severe course and death are correlated
with rapid-rise and extreme leukocytosis (median peak white blood
cell count in fatal vs nonfatal cases, 94,000 vs 18,000/µL, respectively)
and thrombocytosis (median peak platelet count in fatal vs nonfatal
cases, 782,000 vs 556,000/µL, respectively). Chest radiographic find-
ings are only mildly abnormal in the majority of hospitalized infants,
showing perihilar infiltrate or edema (sometimes with a butterfly
appearance) and variable atelectasis. Parenchymal consolidation sug-
gests secondary bacterial infection. Pneumothorax, pneumomediasti-
num, and subcutaneous emphysema can be seen occasionally.
Current methods for confirmation of infection by B. pertussis (i.e.,
culture, polymerase chain reaction [PCR], and serology) have limita-
tions in sensitivity, specificity, or practicality, and relative value depends
on the setting, phase of disease, and purpose of use (e.g., as clinical
diagnostic vs epidemiologic tool). For culture, careful attention must
be directed to specimen collection, transport, and isolation technique.
The specimen is obtained with deep nasopharyngeal aspiration or
with the use of a flexible swab, preferably a Dacron or calcium
1379
alginate–tipped swab, held in the posterior nasopharynx for 15-30 sec
(or until cough occurs). A 1% casamino acid liquid is acceptable for
holding a specimen up to 2 hr; Stainer-Scholte broth or Regan-Lowe
semisolid transport medium is used for longer transport periods, up
to 4 days. The preferred isolation media are Regan-Lowe charcoal agar
with 10% horse blood and 5-40 µg/mL cephalexin, and Stainer-Scholte
media with cyclodextrin resins. Cultures are incubated at 35-37°C in
a humid environment and examined daily for 7 days for slow-growing,
tiny, glistening colonies. Direct fluorescent antibody testing of poten-
tial isolates using specific antibody for B. pertussis and B. parapertussis
maximizes recovery rates. PCR testing on nasopharyngeal wash speci-
mens has a sensitivity similar to that of culture and averts difficulties
of isolation, but only standardized validated primers should be used.
Results of culture and PCR are expected to be positive in unimmu-
nized, untreated children during the catarrhal and early paroxysmal
stages of disease. However, fewer than 20% of culture or PCR tests have
positive results in partially or remotely immunized individuals tested
in the paroxysmal stage. Serologic tests for detection of change in
antibodies to B. pertussis antigens in acute and convalescent samples
are the most sensitive tests in immunized individuals and are useful
epidemiologically. A single serum sample showing immunoglobulin
(Ig) G antibody to PT elevated >2 SD above the mean of the immu-
nized population (>90 IU/mL) indicates recent symptomatic infection
and usually is positive in the mid paroxysmal phase. Tests for IgA and
IgM pertussis antibody, or antibody to antigens other than PT, are not
reliable methods for serologic diagnosis of pertussis.
TREATMENT
Infants younger than 3 mo of age with suspected pertussis usually are
admitted to hospital, as are many between 3 and 6 mo of age unless
witnessed paroxysms are not severe, as well as are patients of any age
if significant complications occur. Prematurely born young infants
have a high risk for severe, potentially fatal disease, and children with
underlying cardiac, pulmonary, muscular, or neurologic disorders have
increased risk of poor outcome beyond infancy. Table 197-1 lists
caveats in assessment and care of infants with pertussis. The specific,
limited goals of hospitalization are to: (1) assess progression of disease
and likelihood of life-threatening events at peak of disease; (2) maxi-
mize nutrition; (3) prevent or treat complications; and (4) educate
parents in the natural history of the disease and in care that will be
given at home. Heart rate, respiratory rate, and pulse oximetry are
monitored continuously with alarm settings so that paroxysms can be
witnessed and recorded by healthcare personnel. Detailed cough
records and documentation of feeding, vomiting, and weight change
provide data to assess severity. Typical paroxysms that are not life-
threatening have the following features: duration <45 sec; red but not
blue color change; tachycardia, bradycardia (not <60 beats/min in
Table 197-1 Caveats in Assessment and Care of Infants
with Pertussis
• Infants with potentially fatal pertussis may appear well between
episodes.
• A paroxysm must be witnessed before a decision is made
between hospital and home care.
• Only analysis of carefully compiled cough record permits
assessment of severity and progression of illness.
• Suctioning of nose, oropharynx, or trachea should not be
performed on a “preventive” schedule.
• Feeding in the period following a paroxysm may be more
successful than after napping.
• Family support begins at the time of hospitalization with empathy
for the child’s and family’s experience to date, transfer of the
burden of responsibility for the child’s safety to the healthcare
team, and delineation of assessments and treatments to be
performed.
• Family education, recruitment as part of the team, and continued
support after discharge are essential.
1380 Part XVII ◆ Infectious Diseases

infants), or oxygen desaturation that spontaneously resolves at the end
of the paroxysm; whooping or strength for brisk self-rescue at the end
of the paroxysm; self-expectorated mucus plug; and posttussive exhaus-
tion but not unresponsiveness. Assessing the need to provide oxygen,
stimulation, or suctioning requires skilled personnel who can watch-
fully observe an infant’s ability for self-rescue but who will intervene
rapidly and expertly when necessary. The benefit of a quiet, dimly
lighted, undisturbed, comforting environment cannot be overesti-
mated or forfeited in a desire to monitor and intervene. Feeding chil-
dren with pertussis is challenging. The risk of precipitating cough by
nipple feeding does not warrant nasogastric, nasojejunal, or parenteral
alimentation in most infants. The composition or thickness of formula
does not affect the quality of secretions, cough, or retention. Large-
volume feedings are avoided.
Within 48-72 hr, the direction and severity of disease are obvious
from analysis of recorded information. Many infants have marked
improvement upon hospitalization and antibiotic therapy, especially if
they are hospitalized early in the course of disease or have been
removed from aggravating environmental smoke, excessive stimula-
tion, or a dry or polluting heat source. Hospital discharge is appropriate
if over a 48-hr period disease severity is unchanged or diminished,
intervention is not required during paroxysms, nutrition is adequate,
no complication has occurred, and parents are adequately prepared for
care at home. Apnea and seizures occur in the incremental phase of
illness and in patients with complicated disease. Portable oxygen,
monitoring, or suction apparatus should not be needed at home.
Infants who have apnea, paroxysms that repeatedly lead to life-
threatening events despite passive delivery of oxygen, or respiratory
failure require intubation, pharmaceutically induced paralysis, and
ventilation.
Antibiotics
An antimicrobial agent always is given when pertussis is suspected or
confirmed, primarily to limit the spread of infection and secondarily
for possible clinical benefit. Macrolides are preferred agents and are
similar to one another in terms of in vitro activity (Table 197-2). Resis-
tance has been reported rarely. A 7-10–fold relative risk for infantile
hypertrophic pyloric stenosis has been reported in neonates treated
with orally administered erythromycin. Azithromycin is the preferred
agent in all age groups; rare cases of infantile hypertrophic pyloric
stenosis have followed its use in neonates. All young infants treated
with any macrolide should be monitored for symptoms of pyloric
stenosis. Benefits of postexposure prophylaxis for infants far outweigh
risk of infantile hypertrophic pyloric stenosis. The FDA also warns of
risk of fatal heart rhythms with use of azithromycin in patients already
at risk for cardiovascular events, especially those with prolongation of
the QT interval.
Adjunct Therapies
No rigorous clinical trial has demonstrated a beneficial effect of β2-
adrenergic stimulants such as salbutamol and albuterol. Fussing associ-
ated with aerosol treatment triggers paroxysms. No randomized,
blinded clinical trial of sufficient size has been performed to evaluate
the usefulness of corticosteroids in the management of pertussis; their
clinical use is not warranted. A randomized, double blind, placebo-
controlled trial of pertussis intravenous immunoglobulin was halted
prematurely because of expiration/lack of additional supply of study
product; there was no indication of clinical benefit. Standard intrave-
nous immunoglobulin has not been studied and should not be used
for treatment or prophylaxis.
Isolation
Patients with suspected pertussis are placed in isolation with droplet
precautions to reduce close respiratory or mucous membrane contact
with respiratory secretions. All healthcare personnel should wear a
mask upon entering the room. Screening for cough should be per-
formed upon entrance of patients to emergency departments, offices,
and clinics to begin isolation immediately and until 5 days after initia-
tion of macrolide therapy. Children and staff with pertussis in childcare
facilities or schools should be excluded until macrolide has been taken
for 5 days.
Care of Household and Other Close Contacts
A macrolide agent should be given promptly to all household contacts
and other close contacts, such as those in daycare, regardless of age,
history of immunization, and symptoms (see Table 197-2). The same
drugs and age-related doses used for treatment are used for prophy-
laxis. Visitation and movement of coughing family members in the

Table 197-2 Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis, By Age Group
Primary Agents Alternate Agent*
AGE GROUP AZITHROMYCIN ERYTHROMYCIN CLARITHROMYCIN TMP-SMZ
<1 mo Recommended agent Not preferred Not recommended Contraindicated for infants
10 mg/kg/day in a single Erythromycin is substantially (safety data <2 mo of age (risk for
dose for 5 days (only associated with infantile unavailable) kernicterus)
limited safety data hypertrophic pyloric stenosis
available) Use if azithromycin is
unavailable; 40-50 mg/kg/day
in 4 divided doses for 14 days
1-5 mo 10 mg/kg/day in a single 40-50 mg/kg/day in 4 divided 15 mg/kg/day in 2 Contraindicated at age <2 mo
dose for 5 days doses for 14 days divided doses for 7 For infants age ≥2 mo: TMP
days 8 mg/kg/day plus SMZ
40 mg/kg/day in 2 divided
doses for 14 days
Infants age 10 mg/kg in a single dose 40-50 mg/kg/day (maximum: 15 mg/kg/day in 2 TMP 8 mg/kg/day plus SMZ
≥6 mo and on day 1 (maximum: 2 g/day) in 4 divided doses divided doses 40 mg/kg/day in 2 divided
children 500 mg), then 5 mg/kg/ for 14 days (maximum: 1 g/day) doses (maximum TMP:
day (maximum: 250 mg) for 7 days 320 mg/day) for 14 days
on days 2-5
Adults 500 mg in a single dose on 2 g/day in 4 divided doses for 1 g/day in 2 divided TMP 320 mg/day, SMZ
day 1 then 250 mg/day 14 days doses for 7 days 1,600 mg/day in 2 divided
on days 2-5 doses for 14 days
*Trimethoprim-sulfamethoxazole (TMP-SMZ) can be used as an alternative agent to macrolides in patients age ≥2 mo who are allergic to macrolides, who cannot
tolerate macrolides, or who are infected with a rare macrolide-resistant strain of Bordetella pertussis.
From Centers for Disease Control and Prevention (CDC): Recommended antimicrobial agents for treatment and postexposure prophylaxis of pertussis: 2005 CDC
guidelines, MMWR Morb Mortal Wkly Rep 54:1–16, 2005.
 Chapter 197 ◆ Pertussis (Bordetella pertussis and Bordetella parapertussis)
hospital must be assiduously controlled until a macrolide has been
taken for 5 days. In close contacts younger than 7 yr of age who have
received fewer than 4 doses of pertussis-containing vaccines, DTaP
should be initiated or continued to complete the recommended series.
Children younger than 7 yr of age who received a 3rd dose more than
6 mo before exposure or a 4th dose 3 yr or more before exposure
should receive a DTaP booster dose. Individuals 9 yr of age or older
should be given Tdap if they have not received Tdap previously.
Unmasked healthcare personnel exposed to untreated cases should be
evaluated for postexposure prophylaxis and follow-up. Coughing
healthcare personnel with or without known exposure to pertussis
should be promptly evaluated for pertussis.
COMPLICATIONS
Infants younger than 6 mo of age have excessive mortality and morbid-
ity; infants younger than 2 mo of age have the highest reported rates
of pertussis-associated hospitalization (82%), pneumonia (25%), sei-
zures (4%), encephalopathy (1%), and death (1%). Infants younger
than 4 mo of age account for 90% of cases of fatal pertussis. Preterm
birth and young maternal age are significantly associated with fatal
pertussis. Neonates with pertussis have substantially longer hospital-
izations, greater need for oxygen, and greater need for mechanical
ventilation than neonates with viral respiratory tract infection.
The principal complications of pertussis are apnea, secondary infec-
tions (such as otitis media and pneumonia), and physical sequelae of
forceful coughing. Fever, tachypnea or respiratory distress between
paroxysms, and absolute neutrophilia are clues to pneumonia. Expected
pathogens include Staphylococcus aureus, Streptococcus pneumoniae,
and bacteria of oropharyngeal flora. Increased intrathoracic and
intraabdominal pressure during coughing can result in conjunctival
and scleral hemorrhages, petechiae on the upper body, epistaxis, hem-
orrhage in the central nervous system and retina, pneumothorax and
subcutaneous emphysema, and umbilical and inguinal hernias. Lacera-
tion of the lingual frenulum occurs occasionally.
The need for intensive care and mechanical ventilation usually is
limited to infants younger than 3 mo of age and infants with underly-
ing conditions. Respiratory failure from apnea may precipitate need for
intubation and ventilation through the days when disease peaks; prog-
nosis is good. Progressive pulmonary hypertension in very young
infants and secondary bacterial pneumonia are severe complications
of pertussis and are the usual causes of death. Pulmonary hypertension
and cardiogenic shock with fatal outcome are associated with extreme
elevations of lymphocyte and platelet counts. Autopsies in fatal cases
show luminal aggregates of leukocytes in the pulmonary vasculature.
Extracorporeal membrane oxygenation of infants with pertussis in
whom mechanical ventilation failed has been associated with >80%
fatality (questioning the advisability of this procedure). Exchange
transfusion or leukapheresis, however, is associated with drops in lym-
phocyte and platelet counts, with recovery in several reported cases.
Echocardiography should be performed in critically ill infants with
pertussis to detect presence of pulmonary hypertension and to inter-
vene expeditiously.
Central nervous system abnormalities occur at a relatively high fre-
quency in pertussis and are almost always a result of hypoxemia or
hemorrhage associated with coughing or apnea in young infants.
Apnea or bradycardia or both may result from apparent laryngospasm
or vagal stimulation just before a coughing episode, from obstruction
during an episode, or from hypoxemia following an episode. Seizures
usually are a result of hypoxemia, but hyponatremia from excessive
secretion of antidiuretic hormone during pneumonia can occur. The
only neuropathology documented in pertussis is parenchymal hemor-
rhage and ischemic necrosis.
Bronchiectasis has been reported rarely after pertussis. Children
who have pertussis before the age of 2 yr may have abnormal pulmo-
nary function into adulthood.
PREVENTION
Universal immunization of children with pertussis vaccine, begin­
ning in infancy with reinforcing dose(s) through adolescence and
1381
adulthood, is central to the control of pertussis. Prevention of pertussis
in young infants depends on universal maternal immunization during
every pregnancy and focused full immunization of contacts, both chil-
dren and adults of all ages (see Chapter 172).
DTaP Vaccines
Several diphtheria and tetanus toxoids combined with acellular pertus-
sis vaccines (DTaP) or combination products currently are licensed in
the United States for children younger than 7 yr of age. DTaP vaccines
have fewer adverse effects than the vaccines containing whole-cell per-
tussis (DTP), which are not available in the United States but are given
to infants and children in many other countries. Acellular pertussis
vaccines all contain inactivated PT and 2 or more other bacterial com-
ponents (filamentous hemagglutinin, Prn, and Fim 2 and 3). Clinical
efficacy against severe pertussis, defined as paroxysmal cough for
longer than 21 days, is approximately 85%. Mild local and systemic
adverse events as well as more serious events (including high fever,
persistent crying for 3 hr or longer, hypotonic hyporesponsive epi-
sodes, and seizures) occur significantly less frequently among infants
who receive DTaP than in those who receive DTP vaccine. DTaP-
containing vaccines can be administered simultaneously with any
other vaccines used in standard schedules for children.
Four doses of DTaP should be administered during the 1st 2 yr of
life, generally at ages 2, 4, 6, and 15-18 mo of age. The 4th dose may
be administered as early as 12 mo of age, provided that 6 mo have
elapsed since the 3rd dose. The 5th dose of DTaP is recommended for
children at 4-6 yr of age; a 5th dose is not necessary if the 4th dose in
the series is administered on or after the 4th birthday. DTaP should
not be given to a neonate because of interference with subsequent
infant immunizations, but commencement of vaccination at 6 wk of
age, with monthly doses through the 3rd dose, can be considered in
high-risk settings.
When feasible, the same DTaP product is recommended for all doses
of the primary vaccination series. Local reactions increase in rate and
severity with successive doses of DTaP, although never reaching the
magnitude of reactions following similar doses of DTP. Swelling of the
entire thigh or upper arm, sometimes accompanied by pain, erythema,
and fever, has been reported in 2-3% of vaccinees after the 4th or 5th
dose of a variety of DTaP products. Limitation of activity is less than
might be expected. Swelling subsides spontaneously without sequelae.
The pathogenesis is unknown. Extensive limb swelling after the 4th
dose of DTaP usually is not associated with a similar reaction to the
5th dose and is not a contraindication to subsequent dose(s) of pertus-
sis vaccines.
Exempting children from pertussis immunization should be
considered only within the narrow limits as recommended. Exemptors
have significantly increased risk for pertussis and play a role in out-
breaks of pertussis among immunized populations. Although well-
documented pertussis confers short-term protection, the duration of
protection is unknown; immunization should be completed on sched-
ule in children diagnosed with pertussis. Improper vaccine storage
reduces immunity.
Tdap Vaccines
Two tetanus toxoid, reduced-diphtheria toxoid, and acellular pertussis
antigen vaccine (Tdap) products were licensed in 2005 and were rec-
ommended universally in 2006 for use in individuals 11-18 yr of age
and in older individuals as a single-dose booster vaccine to provide
protection against tetanus, diphtheria, and pertussis. The preferred age
for Tdap vaccination is 11-12 yr. Recommendations for Tdap have
expanded through 2012. All adolescents and adults of any age (includ-
ing 65 yr of age and older) who have not received Tdap should receive
a single dose of Tdap regardless of interval since Td. Pregnant women
should be given Tdap during every pregnancy to provide passive anti-
body protection to the infant until administration of DTaP. Optimal
timing of maternal Tdap is 26 through 37 wk of gestation but Tdap can
be given at any time during pregnancy. Special effort should be made
to ensure that contacts of infants have received DTaP or Tdap as is
universally recommended. There is no recommendation for Tdap
revaccination of persons other than pregnant women. Relatively
lower burden of pertussis in older adolescents and adults, modest
Tdap effectiveness, and rapidly waning protection do not support
cost-effectiveness of routine revaccination. There is no contraindica-
tion to concurrent administration of any other indicated vaccine. A
single dose of Tdap is recommended for children 7-10 yr old who had
incomplete pertussis vaccination prior to age 7 yr.

Bibliography is available at Expert Consult.

 Chapter 197 ◆ Pertussis (Bordetella pertussis and Bordetella parapertussis)
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1382 Part XVII ◆ Infectious Diseases
Chapter 198
Salmonella
Zulfiqar Ahmed Bhutta
Salmonellosis is a common and widely distributed foodborne disease
that is a global major public health problem affecting millions of indi-
viduals and resulting in significant mortality.
Salmonellae live in the intestinal tracts of warm- and cold-blooded
animals. Some species are ubiquitous, whereas others are specifically
adapted to a particular host.
The sequencing of the Salmonella enterica serovar Typhi (previously
called Salmonella typhi) and Salmonella typhimurium genomes indi-
cates an almost 95% genetic homology between the organisms.
However, the clinical diseases caused by the 2 organisms differ consid-
erably. Orally ingested salmonellae survive at the low pH of the stomach
and evade the multiple defenses of the small intestine so as to gain
access to the epithelium. Salmonellae preferentially enter M cells,
which transport them to the lymphoid cells (T and B) in the underlying
Peyer patches. Once across the epithelium, Salmonella serotypes that
are associated with systemic illness enter intestinal macrophages and
disseminate throughout the reticuloendothelial system. By contrast,
nontyphoidal Salmonella (NTS) serovars induce an early local inflam-
matory response, which results in the infiltration of polymorphonu-
clear leukocytes into the intestinal lumen and diarrhea. The NTS
serovars cause a gastroenteritis of rapid onset and brief duration, in
contrast to typhoid fever, which has a considerably longer incubation
period and duration of illness and in which systemic illness predomi-
nates and only a small proportion of children get diarrhea. These dif-
ferences in the manifestations of infection by the 2 groups of pathogens,
1 predominantly causing intestinal inflammation and the other leading
to systemic disease, may be related to specific genetic pathogenicity
islands in the organisms. NTS serovars are unable to overcome defense
mechanisms that limit bacterial dissemination from the intestine to
systemic circulation in immunocompetent individuals and produce a
self-limiting gastroenteritis. In contrast, S. typhi may possess unique
Table 198-1 Salmonella Species, Subspecies, and Serotypes and Their Usual Habitats
SALMONELLA SPECIES AND SUBSPECIES NO. OF SEROTYPES WITHIN SUBSPECIES
S. enterica subsp. enterica (I)
S. enterica subsp. salmae (II)
S. enterica subsp. arizonae (IIIa)
S. enterica subsp. diarizonae (IIIb)
S. enterica subsp. houtenae (IV)
S. enterica subsp. indica (VI)
S. bongori (V)
Total
*Isolates of all species and subspecies have occurred in humans.
Data from Popoff MY, Bockemühl J, Gheesling LL. Supplement 2002 (No. 46) to the Kauffmann-White scheme. Res Microbiol 155:568-570, 2004.
virulence traits that allow it to overcome mucosal barrier functions in
immunocompetent hosts, resulting in a severe systemic illness. Inter-
estingly, the frequencies of typhoid fever in immunocompetent and
immunocompromised individuals do not differ. Nonetheless, invasive
nontyphoidal salmonellae strains have been noted in Africa among
HIV-positive adults and among children with either HIV, malaria, or
malnutrition. The presentation may be more like typhoid fever than
gastroenteritis.
The nomenclature of Salmonella reflects the species name Salmo-
nella enterica with a number of serovars. Salmonella nomenclature has
undergone considerable alterations. The original taxonomy was based
on clinical syndromes (S. typhi, Salmonella choleraesuis, Salmonella
paratyphi). With adoption of serologic analysis, a Salmonella species
was defined subsequently as “a group of related fermentation phage-
type,” with the result that each Salmonella serovar was regarded as a
species in itself. Although this classification is simplistic, its use until
2004 resulted in identification of 2,501 serovars of Salmonella, which
led to the need for further categorization to aid communication among
scientists, public health officials, and the public.
All Salmonella serovars form a single DNA hybridization group, a
single species called S. enterica composed of several subspecies (Table
198-1). Each subspecies contains various serotypes defined by the
O and H antigens. To further simplify the nomenclature for physicians
and epidemiologists, the names for the common serovars are kept for
subspecies I strains, which represent >99.5% of the Salmonella strains
isolated from humans and other warm-blooded animals.
198.1 Nontyphoidal Salmonellosis
Zulfiqar Ahmed Bhutta
ETIOLOGY
Salmonellae are motile, nonsporulating, nonencapsulated, Gram-
negative rods that grow aerobically and are capable of facultative anaer-
obic growth. They are resistant to many physical agents but can be
killed by heating to 54.4°C (130°F) for 1 hr or 60°C (140°F) for 15 min.
They remain viable at ambient or reduced temperatures for days and
may survive for weeks in sewage, dried foodstuffs, pharmaceutical
agents, and fecal material. Like other members of the family Entero-
bacteriaceae, Salmonella possesses somatic O antigens and flagellar H
antigens.
With the exception of a few serotypes that affect only 1 or a few
animal species, such as Salmonella dublin in cattle and S. choleraesuis
in pigs, most serotypes have a broad host spectrum. Typically, such
strains cause gastroenteritis that is often uncomplicated and does
not need treatment but can be severe in the young, the elderly, and
patients with weakened immunity. The causes are typically Salmonella
Enteritidis (Salmonella enterica serotype Enteritidis) and Salmonella
Typhimurium (S. enterica serotype Typhimurium), the 2 most impor-
tant serotypes for salmonellosis transmitted from animals to humans.
USUAL HABITAT
1504 Warm-blooded animals
502 Cold-blooded animals and the environment*
95 Cold-blooded animals and the environment*
333 Cold-blooded animals and the environment*
72 Cold-blooded animals and the environment*
13 Cold-blooded animals and the environment*
22 Cold-blooded animals and the environment*
2541

Nontyphoidal salmonellae have emerged as a major cause of bactere-
mia in Africa, especially among populations with a high incidence of
HIV infection.
EPIDEMIOLOGY
Salmonellosis constitutes a major public health burden and represents
a significant cost to society in many countries. Typhoid fever caused
by this organism is a global problem, with more than 27 million cases
worldwide each year, culminating in an estimated 217,000 deaths.
Although there is little information on the epidemiology and the
burden of Salmonella gastroenteritis in developing countries, Salmo-
nella infections are recognized as major causes of childhood diarrheal
illness. With the growing burden of HIV infections and malnutrition
in Africa, NTS bacteremic infections have emerged as a major cause
of morbidity and mortality among children and adults.
NTS infections have a worldwide distribution, with an incidence
proportional to the standards of hygiene, sanitation, availability of safe
water, and food preparation practices. In the developed world, the
incidence of Salmonella infections and outbreaks has increased several-
fold over the past few decades, which may be related to modern prac-
tices of mass food production that increase the potential for epidemics.
The incidence of infections with NTS serovars, such as S. enterica
serovar Typhimurium and S. Enteritidis cause a significant disease
burden, with an estimated 93.8 million cases worldwide and 155,000
deaths each year. Salmonella gastroenteritis accounts for more than
half of all episodes of bacterial diarrhea in the United States, with
incidence peaks at the extremes of ages, among young infants and the
elderly. Most human infections have been caused by S. Enteritidis; the
prevalence of this organism has decreased over the past decade, with
S. Typhimurium overtaking it in some countries.
The rise in Salmonella infections in many parts of the world over the
past 3 decades may also be related to intensive animal husbandry
practices, which selectively promote the rise of certain strains, espe-
cially drug-resistant varieties that emerge in response to the use of
antimicrobials in food animals. Poultry products were traditionally
regarded as a common source of salmonellosis, but consumption of a
range of foods is now associated with outbreaks, including fruits and
vegetables. Although this change in epidemiology may be related to
selective pressure from the use of antimicrobials, there may be other
factors, such as the rise of strains with a selective propensity to develop
resistance and virulence. It appears that multidrug-resistant strains of
Salmonella are more virulent than susceptible strains and that poorer
outcome does not simply relate to the delay in treatment response
because of empirical choice of an ineffective antibiotic. Strains of
multidrug-resistant Salmonella, such as S. Typhimurium phage type
DT104, harbor a genomic island that contains many of the drug-
resistance genes. It is possible that these integrons also contain genes
that encode virulence factors. The global spread of multidrug-resistant
S. Typhimurium phage type DT104 in animals and humans may be
related to the growing use of antimicrobials and may be facilitated by
international and national trade of infected animals.
Several risk factors are associated with outbreaks of Salmonella
infections. Animals constitute the principal source of human NTS
disease, and cases have occurred in which individuals have had contact
with infected animals, including domestic animals such as cats, dogs,
reptiles, pet rodents, and amphibians. Specific serotypes may be associ-
ated with particular animal hosts; children with S. enterica serovar
Marina typically have exposure to pet lizards. NTS serovars usually
cause self-limiting diarrhea with secondary bacteremia occurring in
less than 10% of patients. The NTS serovars have a broad host range,
including poultry and cattle, and NTS infection is commonly from
food poisoning in developed countries.
Domestic animals probably acquire the infection in the same way
that humans do, through consumption of contaminated raw meat,
poultry, or poultry-derived products. Animal feeds containing fish-
meal or bone meal contaminated with Salmonella are an important
source of infection for animals. Moreover, subtherapeutic concentra-
tions of antibiotics are often added to animal feed to promote growth.
Such practices promote the emergence of antibiotic-resistant bacteria,
Chapter 198 ◆ Salmonella 1383
including Salmonella, in the gut flora of the animals, with subsequent
contamination of their meat. There is strong evidence to link resistance
of S. Typhimurium to fluoroquinolones with the use of this group of
antimicrobials in animal feeds. Animal-to-animal transmission can
occur, but most infected animals are asymptomatic.
An increasing number of produce-associated foodborne outbreaks
in the United States that are associated with bacterial contamination
are primarily from Salmonella. Although almost 80% of Salmonella
infections are discrete, outbreaks can pose an inordinate burden on
public health systems. During 1998-2008, a total of 1,491 outbreaks of
Salmonella infections were reported to the Foodborne Disease Out-
break Surveillance System, and 80% of these were caused by a single
serotype. Of the single-serotype outbreaks, 50% had an implicated food
and 34% could be assigned to a single food commodity. Of the 47
serotypes reported, the 4 most common, causing more than two-thirds
of the outbreaks, included Enteritidis, Typhimurium, Newport, and
Heidelberg. Overall, eggs were the most commonly implicated food,
followed by chicken, pork, beef, fruit, and turkey. Salmonella infections
in chickens increase the risk for contamination of eggs, and both
poultry and eggs are regarded as a dominant cause of common-source
outbreaks. However, a growing proportion of Salmonella outbreaks are
also associated with other food sources. The food sources include many
fruits and vegetables, such as tomatoes, sprouts, watermelon, canta-
loupe, lettuce, and mangoes.
In addition to the effect of antibiotic use in animal feeds, the rela-
tionship of Salmonella infections to prior antibiotic use among chil-
dren in the previous month is well recognized. This increased risk for
infection in people who have received antibiotics for an unrelated
reason may be related to alterations in gut microbial ecology, which
predispose them to colonization and infection with antibiotic-resistant
Salmonella isolates. These resistant strains of Salmonella are also more
virulent. The Centers for Disease Control and Prevention (CDC)
reports resistance to ceftriaxone in approximately 3% of NTS tested
and some level of resistance to ciprofloxacin in approximately 3% of
isolates. Approximately 5% of NTS tested by the CDC are resistant to
5 or more types of drugs. Consequently, costs are also expected to be
higher for resistant than for susceptible infections because of the sever-
ity of the former. Those patients are more likely to be hospitalized, and
treatment is rendered less effective. The CDC is seeing some level of
resistance to ciprofloxacin in two-thirds of Salmonella Typhi tested.
The CDC has not yet detected resistance to ceftriaxone or azithromycin
in the United States, but resistance to these antibiotics has been seen
in other parts of the world.
Given the ubiquitous nature of the organism, nosocomial infections
with NTS strains can also occur through contaminated equipment and
diagnostic or pharmacologic preparations, particularly those of animal
origin (pancreatic extracts, pituitary extracts, bile salts). Hospitalized
children are at increased risk for severe and complicated Salmonella
infections, especially with drug-resistant organisms.
PATHOGENESIS
The estimated number of bacteria that must be ingested to cause symp-
tomatic disease in healthy adults is 106-108 Salmonella organisms. The
gastric acidity inhibits multiplication of salmonellae, and most organ-
isms are rapidly killed at gastric pH ≤2.0. Achlorhydria, buffering
medications, rapid gastric emptying after gastrectomy or gastroenter-
ostomy, and a large inoculum enable viable organisms to reach the
small intestine. Neonates and young infants have hypochlorhydria and
rapid gastric emptying, which contribute to their increased vulnerabil-
ity to symptomatic salmonellosis. In infants who typically take fluids,
the inoculum size required to produce disease is also comparatively
smaller because of faster transit through the stomach.
Once they reach the small and large intestines, the ability of Salmo-
nella organisms to multiply and cause infection depends on both the
infecting dose and competition with normal flora. Prior antibiotic
therapy may alter this relationship, as might factors such as coadmin-
istration of antimotility agents. The typical intestinal mucosal response
to NTS infection is an enterocolitis with diffuse mucosal inflammation
and edema, sometimes with erosions and microabscesses. Salmonella
1384 Part XVII ◆ Infectious Diseases
Figure 198-1 Overlapping and distinct virulence systems in Salmonella typhi and nontyphoidal Salmonella. (From de Jong HK, Parry CM, van
der Poll T, Wiersinga WJ. Host-pathogen interaction in invasive Salmonellosis. PLoS Pathog 2012;8(10):e1002933.)
organisms are capable of penetrating the intestinal mucosa, although
destruction of epithelial cells and ulcers are usually not found. Intesti-
nal inflammation with polymorphonuclear leukocytes and macro-
phages usually involves the lamina propria. Underlying intestinal
lymphoid tissue and mesenteric lymph nodes enlarge and may dem-
onstrate small areas of necrosis. Such lymphoid hypertrophy may cause
interference with the blood supply to the gut mucosa. Hyperplasia of
the reticuloendothelial system is also found within the liver and spleen.
If bacteremia develops, it may lead to localized infection and suppura-
tion in almost any organ.
Both S. Typhi and NTS possess overlapping and distinct virulence
systems (Fig. 198-1). Although S. Typhimurium can cause systemic
disease in humans, intestinal infection usually results in a localized
enteritis that is associated with a secretory response in the intestinal
epithelium. Intestinal infection also induces secretion of interleukin
(IL)-8 from the basolateral surface and other chemoattractants from
the apical surface, directing recruitment and transmigration of neutro-
phils into the gut lumen and thus preventing the systemic spread of
the bacteria (Fig. 198-2).
Central to S. Typhimurium pathogenesis are 2 type III secretion
systems encoded within the pathogenicity islands SPI-1 and SPI-2 that
are responsible for the secretion and translocation of a set of bacterial
proteins termed effectors into host cells with the intention of altering
host cell physiology for bacterial entry and survival. Thus, once deliv-
ered by the type III secretion systems, the secreted effectors play critical
roles in manipulating the host cell to allow for bacterial invasion,
induction of inflammatory responses, and the assembly of an intracel-
lular protective niche created for bacterial survival and replication. The
type III secretion system encoded on SPI-1 mediates invasion of the
intestinal epithelium, whereas the type III secretion system encoded
on SPI-2 is required for survival within macrophages. In addition, the
expression of strong agonists of innate pattern recognition receptors
(lipopolysaccharide and flagellin) is important for triggering a Toll-like
receptor (TLR)–mediated inflammatory response. These observations
suggest that S. Typhimurium must have acquired additional factors
that further modulate the host response during infection.
Salmonella species invade epithelial cells in vitro by a process of
bacteria-mediated endocytosis involving cytoskeletal rearrangement,
disruption of the epithelial cell brush-border, and the subsequent for-
mation of membrane ruffles (Fig. 198-3). An adherent and invasive
phenotype of S. Enterica is activated under conditions similar to those
found in the human small intestine (high osmolarity, low oxygen). The
invasive phenotype is mediated in part by SPI-1, a 40-kb region that
encodes regulator proteins such as HilA, the type III secretion systems
involved in invasion of epithelial cells, and a variety of other products.
In humans the Toll-like receptor–dependent IL-12/interferon (IFN)-λ
is a major immunoregulatory system that bridges innate and adaptive
immunity and is responsible for restricting the systemic spread of
nontyphoidal Salmonella.
Shortly following invasion of the gut epithelium, invasive Salmonella
organisms encounter macrophages within the gut-associated lymphoid
tissue. The interaction between Salmonella and macrophages results in
alteration in the expression of a number of host genes, including those
encoding proinflammatory mediators (inducible nitric oxide synthase,
chemokines, IL-1β), receptors or adhesion molecules (tumor necrosis
factor [TNF]-α receptor, CD40, intercellular adhesion molecule 1),
and antiinflammatory mediators (transforming growth factor-β1 and
transforming growth factor-β2). Other upregulated genes include
those involved in cell death or apoptosis (intestinal epithelial cell pro-
tease, TNF-R1, Fas) and transcription factors (early growth response
1, IFN regulatory factor 1). S. Typhimurium can induce rapid macro-
phage death in vitro, which depends on the host cell protein caspase-1
and is mediated by the effector protein SipB (Salmonella invasion
protein B). Intracellular S. Typhimurium is found within specialized
vacuoles that have diverged from the normal endocytic pathway. This
ability to survive within monocytes/macrophages is essential for S.
Typhimurium to establish a systemic infection in the mouse. The
mucosal proinflammatory response to S. Typhimurium infection and
the subsequent recruitment of phagocytic cells to the site may also
facilitate systemic spread of the bacteria.
Some virulence traits are shared by all salmonellae, but others are
serotype restricted. These virulence traits have been defined in tissue
 Chapter 198 ◆ Salmonella 1385

Membrane
Tight ruffle
junction
Salmonella
spp.

Actin

Epithelial SopE SipA SopA

cell SopE2 SipC SptP
SopB
SopB Rho GTPases

Rho GTPases MAPK Cl– MAPK SspH1

AvrA
Cl–
NF-B
NF-B
AP-1

IL-8 IL-1
IL-18

Macrophage
SipB
PMN

Figure 198-2 On contact with the epithelial cell, salmonellae assemble the Salmonella pathogenicity island 1-encoded type III secretion system
(TTSS-1) and translocate effectors (yellow spheres) into the eukaryotic cytoplasm. Effectors such as SopE, SopE2, and SopB then activate host Rho
guanosine triphosphatase (GTPase), resulting in the rearrangement of the actin cytoskeleton into membrane ruffles, induction of mitogen-activated
protein kinase (MAPK) pathways, and destabilization of tight junctions. Changes in the actin cytoskeleton, which are further modulated by the
actin-binding proteins SipA and SipC, lead to bacterial uptake. MAPK signaling activates the transcription factors activator protein-1 (AP-1) and
nuclear factor-κB (NF-κB), which turn on production of the proinflammatory polymorphonuclear leukocyte (PMN) chemokine interleukin (IL)-8. SipB
induces caspase-1 activation in macrophages, with the release of IL-1β and IL-18, augmenting the inflammatory response. In addition, SopB stimu-
lates Cl– secretion by its inositol phosphatase activity. The destabilization of tight junctions allows the transmigration of polymorphonuclear leu-
kocytes (PMNs) from the basolateral to the apical surface, paracellular fluid leakage, and access of bacteria to the basolateral surface. However,
the transmigration of PMNs also occurs in the absence of tight-junction disruption and is further promoted by SopA. The actin cytoskeleton is
restored, and MAPK signaling is turned off by the enzymatic activities of SptP. This also results in the down-modulation of inflammatory responses,
to which SspH1 and AvrA also contribute by inhibiting activation of NF-κB. (From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host
cells, Nat Rev Microbiol 6:53–66, 2008.)

culture and murine models, and it is likely that clinical features of

human Salmonella infection will eventually be related to specific DNA Table 198-2 Host Factors and Conditions Predisposing
sequences. With most diarrhea-associated nontyphoidal salmonello- to the Development of Systemic Disease
ses, the infection does not extend beyond the lamina propria and the with Nontyphoidal Salmonella Strains
local lymphatics. Specific virulence genes are related to the ability to Neonates and young infants (≤3 mo of age)
cause bacteremia. These genes are found significantly more often in
strains of S. Typhimurium isolated from the blood than in strains HIV/AIDS
recovered from stool. Although both S. dublin and S. choleraesuis have Other immunodeficiencies and chronic granulomatous disease
a greater propensity to rapidly invade the bloodstream with little or no
Immunosuppressive and corticosteroid therapies
intestinal involvement, the development of disease after infection with
Salmonella depends on the number of infecting organisms, their viru- Malignancies, especially leukemia and lymphoma
lence traits, and several host defense factors. Various host factors may Hemolytic anemia, including sickle cell disease, malaria, and
also affect the development of specific complications or clinical syn- bartonellosis
dromes (Table 198-2) and of these, HIV infections are assuming greater
importance in Africa in all age groups. Collagen vascular disease
Bacteremia is possible with any Salmonella serotype, especially in Inflammatory bowel disease
individuals with reduced host defenses and especially in those with
Achlorhydria or use of antacid medications
altered reticuloendothelial or cellular immune function. Thus, children
with HIV infection, chronic granulomatous disease, and leukemia are Impaired intestinal motility
more likely to develop bacteremia after Salmonella infection, although Schistosomiasis, malaria
the majority of children with Salmonella bacteremia in Africa are HIV-
negative. Children with Schistosoma mansoni infection and hepato- Malnutrition
splenic involvement, as well as chronic malarial anemia, are also at a
1386 Part XVII ◆ Infectious Diseases

Salmonella spp.

SspH2 SifA
SpvB PipB2 s
Spacious Ssel otor
phagosome
ulem
otub
M icr
SCV Sif

Actin SseJ
Epithelial cell

Microtubules

Nucleus

SseF
SseG

Golgi Secretory vesicles

Figure 198-3 Formation of the Salmonella-containing vacuole (SCV) and induction of the Salmonella pathogenicity island 2 (SPI-2) type III secre-
tion system (TTSS) within the host cell. Shortly after internalization by macropinocytosis, salmonellae are enclosed in a spacious phagosome that
is formed by membrane ruffles. Later, the phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium, and
is called the SCV. It contains the endocytic marker lysosomal-associated membrane protein 1 (LAMP-1; purple). The Salmonella SPI-2 is induced
within the SCV and translocates effector proteins (yellow spheres) across the phagosomal membrane several hours after phagocytosis. The SPI-2
effectors SifA and PipB2 contribute to formation of Salmonella-induced filament along microtubules (green) and regulate microtubule motor (yellow
star shape) accumulation on the Sif and the SCV. SseJ is a deacylase that is active on the phagosome membrane. SseF and SseG cause microtubule
bundling adjacent to the SCV and direct Golgi-derived vesicle traffic toward the SCV. Actin accumulates around the SCV in a SPI-2 dependent
manner, in which SspH2, SpvB, and SseI are thought to have a role. (From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells,
Nat Rev Microbiol 6:53–66, 2008.)

greater risk for development of chronic salmonellosis. Children with
sickle cell disease are at increased risk for Salmonella septicemia and
osteomyelitis. This risk may be related to the presence of numerous
infarcted areas in the gastrointestinal tract, bones, and reticuloendo-
thelial system, as well as reduced phagocytic and opsonizing capacity
of patients, which allow the organism to flourish.
Some inherited defects, such as IL-12 deficiency (IL-12β1 chain
deficiency, IL-12p40 subunit deletion) are associated with increased
risk for Salmonella infections, suggesting a key role for IL-12 in the
clearance of Salmonella. IL-12 is produced by activated macrophages
and is a potent inducer of IFN-γ by natural killer cells and T lympho-
cytes. Given the putative protective role of IL-12 against malarial infec-
tion, Salmonella infection of phagocytes may secondarily affect IL-12
production and thus produce a vicious circle of chronic malaria and
Salmonella coinfection.
CLINICAL MANIFESTATIONS
Acute Enteritis
The most common clinical presentation of salmonellosis is acute enter-
itis. After an incubation period of 6-72 hr (mean: 24 hr), there is an
abrupt onset of nausea, vomiting, and crampy abdominal pain, located
primarily in the periumbilical area and right lower quadrant, followed
by mild to severe watery diarrhea and sometimes by diarrhea contain-
ing blood and mucus. A large proportion of children with acute enteri-
tis are febrile, although younger infants may exhibit a normal or
subnormal temperature. Symptoms usually subside within 2-7 days in
healthy children, and fatalities are rare. However, some children
experience severe disease with a septicemia-like picture (high fever,
headache, drowsiness, confusion, meningismus, seizures, abdominal
distention). The stool typically contains a moderate number of poly-
morphonuclear leukocytes and occult blood. Mild leukocytosis may be
detected.
Bacteremia
Although the precise incidence of bacteremia following Salmonella
gastroenteritis is unclear, transient bacteremia can occur in 1-5% of
children with Salmonella diarrhea. Bacteremia can occur with minimal
associated symptoms in newborns and very young infants, but in older
infants it typically follows gastroenteritis and can be associated with
fever, chills, and septic shock. In patients with AIDS, recurrent septi-
cemia appears despite antibiotic therapy, often with a negative stool
culture result for Salmonella and sometimes with no identifiable focus
of infection. NTS gastrointestinal infections commonly cause bactere-
mia in developing countries. High rates of invasive disease with S.
Typhimurium and S. Enteritidis reported from Africa (38-70% of iso-
lates) suggest an association with HIV infections and malaria.
Extraintestinal Focal Infections
Following bacteremia, salmonellae have the propensity to seed and
cause focal suppurative infection of many organs. The most common
focal infections involve the skeletal system, meninges, intravascular
sites, and sites of preexisting abnormalities. The peak incidence of
Salmonella meningitis is in infancy, and the infection may be

associated with a florid clinical course, high mortality, and neurologic
sequelae in survivors.
COMPLICATIONS
Salmonella gastroenteritis can be associated with acute dehydration
and complications that result from delayed presentation and inade-
quate treatment. Bacteremia in younger infants and immunocompro-
mised individuals can have serious consequences and potentially fatal
outcomes. Salmonella organisms can seed many organ systems, leading
to osteomyelitis in children with sickle cell disease, among other infec-
tions. Reactive arthritis may follow Salmonella gastroenteritis, usually
in adolescents with the HLA-B27 antigen.
In certain high-risk groups, especially those with impaired immu-
nity, the course of Salmonella gastroenteritis may be more complicated.
Neonates, infants younger than 6 mo, and children with primary or
secondary immunodeficiency may have symptoms that persist for
several weeks. The course of illness and complications may also be
affected by coexisting pathologies. In children with AIDS, Salmonella
infection frequently becomes widespread and overwhelming, causing
multisystem involvement, septic shock, and death. In patients with
inflammatory bowel disease, especially active ulcerative colitis, Salmo-
nella gastroenteritis may lead to rapid development of toxic megacolon,
bacterial translocation, and sepsis. In children with schistosomiasis,
the Salmonella may persist and multiply within schistosomes, leading
to chronic infection unless the schistosomiasis is effectively treated.
Prolonged or intermittent bacteremia is associated with low-grade
fever, anorexia, weight loss, diaphoresis, and myalgias and may occur
in children with underlying problems and a reticuloendothelial system
dysfunction such as hemolytic anemia or malaria.
DIAGNOSIS
Clinical features that are specific to Salmonella gastroenteritis and
thus would allow differentiation from other bacterial causes of
diarrhea are few. Definitive diagnosis of Salmonella infection is based
on clinical correlation of the presentation and culture of and subse-
quent identification of Salmonella organisms from feces or other
body fluids. In children with gastroenteritis, cultures of stools have
higher yields than rectal swabs. In children with NTS gastroenteritis,
prolonged fever lasting 5 or more days and young age should be rec-
ognized as risk factors closely associated with development of bactere-
mia. In patients with sites of local suppuration, aspirated specimens
should be Gram-stained and cultured. Salmonella organisms grow
well on nonselective or enriched media, such as blood agar, chocolate
agar, and nutrient broth, but stool specimens containing mixed bacte-
rial flora require a selective medium, such as MacConkey, xylose-
lysine-deoxycholate, bismuth sulfite, or Salmonella-Shigella (SS) agar
for isolation.
Although other rapid diagnostic methods, such as latex agglutina-
tion and immunofluorescence, have been developed for rapid diagno-
sis of Salmonella in cultures, there are few comparable tests for rapid
serologic detection. Polymerase chain reaction techniques may offer a
rapid alternative to classic cultures but are as yet not in widespread use
in clinical settings.
TREATMENT
Appropriate therapy relates to the specific clinical presentation of Sal-
monella infection. In children with gastroenteritis, rapid clinical assess-
ment, correction of dehydration and electrolyte disturbances, and
supportive care are key (see Chapter 340). Antibiotics are not generally
recommended for the treatment of isolated uncomplicated Salmonella
gastroenteritis because they may suppress normal intestinal flora and
prolong both the excretion of Salmonella and the remote risk for creat-
ing the chronic carrier state (usually in adults). However, given the risk
for bacteremia in infants (<3 mo of age) and the risk of disseminated
infection in high-risk groups with immune compromise (HIV, malig-
nancies, immunosuppressive therapy, sickle cell anemia, immunodefi-
ciency states), these children must receive an appropriate empirically
chosen antibiotic until culture results are available (Table 198-3). The
S. Typhimurium phage type DT104 strain is usually resistant to the
Chapter 198 ◆ Salmonella 1387
Table 198-3 Treatment of Salmonella Gastroenteritis
ORGANISM AND DOSE AND DURATION
INDICATION OF TREATMENT
Salmonella infections in Cefotaxime 100-200 mg/kg/day every
infants <3 mo of age or 6-8 hr for 5-14 days
immunocompromised or
persons (in addition to Ceftriaxone 75 mg/kg/day once daily
appropriate treatment for 7 days
for underlying disorder) or
Ampicillin 100 mg/kg/day every
6-8 hr for 7 days
or
Cefixime 15 mg/kg/day for 7-10 days
following 5 drugs: ampicillin, chloramphenicol, streptomycin, sulfon-
amides, and tetracycline. An increasing proportion of S. Typhimurium
phage type DT104 isolates also have reduced susceptibility to fluoro-
quinolones. Given the higher mortality associated with multidrug-
resistant Salmonella infections, it is necessary to perform susceptibility
tests on all human isolates. Infections with suspected drug-resistant
Salmonella should be closely monitored and treated with appropriate
antimicrobial therapy.
PROGNOSIS
Most healthy children with Salmonella gastroenteritis recover fully.
However, malnourished children and children who do not receive
optimal supportive treatment (see Chapters 58 and 340) are at risk for
development of prolonged diarrhea and complications. Young infants
and immunocompromised patients often have systemic involvement,
a prolonged course, and extraintestinal foci. In particular, children
with HIV infection and Salmonella infections can have a florid course.
After infection, NTS are excreted in feces for a median of 5 wk. A
prolonged carrier state after nontyphoidal salmonellosis is rare (<1%)
but may be seen in children with biliary tract disease and cholelithiasis
after chronic hemolysis. Prolonged carriage of Salmonella organisms is
rare in healthy children but has been reported in those with underlying
immune deficiency. During the period of Salmonella excretion, the
individual may infect others, directly by the fecal–oral route or indi-
rectly by contaminating foods.
PREVENTION
Control of the transmission of Salmonella infections to humans
requires control of the infection in the animal reservoir, judicious
use of antibiotics in dairy and livestock farming, prevention of con-
tamination of foodstuffs prepared from animals, and use of appropriate
standards in food processing in commercial and private kitchens
(Table 198-4). Because large outbreaks are often related to mass food
production, it should be recognized that contamination of just 1 piece
of machinery used in food processing may cause an outbreak; meticu-
lous cleaning of equipment is essential. Clean water supply and educa-
tion in handwashing and food preparation and storage are critical to
reducing person-to-person transmission. Salmonella may remain
viable when cooking practices prevent food from reaching a tempera-
ture greater than 65.5°C (150°F) for longer than 12 min. Parents
should be advised of the risk of reptiles as pets in households with
young infants.
In contrast to developed countries, relatively little is known about
the transmission of NTS infections in developing countries, and it is
likely that person-to-person transmission may be relatively more
important in some settings. Although some vaccines have been used
in animals, no human vaccine against NTS infections is currently avail-
able. Infections should be reported to public health authorities so that
outbreaks can be recognized and investigated. Given the rapid rise of
antimicrobial resistance among Salmonella isolates, it is imperative that
there is rigorous regulation of the use of antimicrobials in animal feeds.
Bibliography is available at Expert Consult.

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1388 Part XVII ◆ Infectious Diseases
Table 198-4 Recommendations for Preventing
Transmission of Salmonella from Reptiles
and Amphibians to Humans
Pet store owners, healthcare providers, and veterinarians should
provide information to owners and potential purchasers of reptiles
and amphibians about the risks for and prevention of
salmonellosis from these pets.
Persons at increased risk for infection or serious complications from
salmonellosis (e.g., children <5 yr of age and
immunocompromised persons) should avoid contact with reptiles
and amphibians and any items that have been in contact with
reptiles and amphibians.
Reptiles and amphibians should be kept out of households that
include children <5 yr of age or immunocompromised persons. A
family expecting a child should remove any pet reptile or
amphibian from the home before the infant arrives.
Reptiles and amphibians should not be allowed in childcare
centers.
Persons should always wash their hands thoroughly with soap and
water after handling reptiles and amphibians or their cages.
Reptiles and amphibians should not be allowed to roam freely
throughout a home or living area.
Pet reptiles and amphibians should be kept out of kitchens and
other food preparation areas. Kitchen sinks should not be used to
bathe reptiles and amphibians or to wash their dishes, cages, or
aquariums. If bathtubs are used for these purposes, they should
be cleaned thoroughly and disinfected with bleach.
Reptiles and amphibians in public settings (e.g., zoos and exhibits)
should be kept from direct or indirect contact with patrons except
in designated animal contact areas equipped with adequate
handwashing facilities. Food and drink should not be allowed in
animal contact areas.
From the Centers for Disease Control and Prevention (CDC): Reptile-associated
salmonellosis—selected states, 1998-2002, MMWR Morb Mortal Wkly Rep
52:1206–1210, 2003.
198.2 Enteric Fever (Typhoid Fever)
Zulfiqar Ahmed Bhutta
Enteric fever (more commonly termed typhoid fever) remains endemic
in many developing countries. Given the ease of modern travel, cases
are regularly reported from most developed countries, usually from
returning travelers.
ETIOLOGY
Typhoid fever is caused by S. enterica serovar Typhi (S. Typhi), a Gram-
negative bacterium. A very similar but often less-severe disease is
caused by Salmonella Paratyphi A and rarely by S. Paratyphi B (Schot-
mulleri) and S. Paratyphi C (Hirschfeldii). The ratio of disease caused
by S. Typhi to that caused by S. Paratyphi is approximately 10 : 1,
although the proportion of S. Paratyphi A infections is increasing in
some parts of the world for reasons that are unclear. Although S. Typhi
shares many genes with Escherichia coli and at least 95% of genes with
S. Typhimurium, several unique gene clusters known as pathogenicity
islands and other genes have been acquired during evolution. The
inactivation of single genes, as well as the acquisition or loss of single
genes or large islands of DNA, may have contributed to host adaptation
and restriction of S. Typhi.
One of the most specific gene products is the polysaccharide capsule
Vi (virulence), which is present in approximately 90% of all freshly
isolated S. Typhi and has a protective effect against the bactericidal
action of the serum of infected patients.
EPIDEMIOLOGY
It is estimated that more than 26.9 million typhoid fever cases occur
annually, of which 1% result in death. The vast majority of this disease
burden is witnessed in Asia. Additionally, an estimated 5.4 million
cases caused by paratyphoid occur each year. In 2010, 13.5 million
cases of typhoid fever were recorded, and both typhoid and paraty-
phoid fevers together accounted for more than 12 million disability-
adjusted life years. The mortality caused by typhoid fever in the same
year was found to be 7.2 per 100,000 population for the sub-Saharan
region of Africa. Given the paucity of microbiologic facilities in devel-
oping countries, these figures may be more representative of the clini-
cal syndrome rather than of culture-proven disease. In most developed
countries, the incidence of typhoid fever is <15 cases per 100,000
population, with most cases occurring in travelers. In contrast, the
incidence may vary considerably in the developing world, with esti-
mated rates ranging from 100-1,000 cases per 100,000 population.
There are significant differences in the age distribution and population
at risk. Population-based studies from South Asia also indicate that the
age-specific incidence of typhoid fever may be highest in children
younger than 5 yr of age, in association with comparatively higher rates
of complications and hospitalization.
Typhoid fever is notable for the emergence of drug resistance. Fol-
lowing sporadic outbreaks of chloramphenicol-resistant S. Typhi infec-
tions, many strains of S. Typhi have developed plasmid-mediated
multidrug resistance to all 3 of the primary antimicrobials: ampicillin,
chloramphenicol, and trimethoprim-sulfamethoxazole. There is also a
considerable increase in nalidixic acid–resistant isolates of S. Typhi, as
well as the emergence of fluoroquinolone-resistant isolates. Nalidixic
acid–resistant isolates first emerged in Southeast Asia and India, and
now account for the majority of travel-associated cases of typhoid fever
in the United States.
S. Typhi is highly adapted to infection of humans to the point that
it has lost the ability to cause transmissible disease in other animals.
The discovery of the large number of pseudogenes in S. Typhi suggests
that the genome of this pathogen has undergone degeneration to facili-
tate a specialized association with the human host. Thus, direct or
indirect contact with an infected person (sick or chronic carrier) is a
prerequisite for infection. Ingestion of foods or water contaminated
with S. Typhi from human feces is the most common mode of trans-
mission, although waterborne outbreaks as a consequence of poor
sanitation or contamination have been described in developing coun-
tries. In other parts of the world, oysters and other shellfish cultivated
in water contaminated by sewage and the use of night soil as fertilizer
may also cause infection.
PATHOGENESIS
Enteric fever occurs through the ingestion of the organism, and a
variety of sources of fecal contamination have been reported, including
street foods and contamination of water reservoirs.
Human volunteer experiments established an infecting dose of
about 105-109 organisms, with an incubation period ranging from 4-14
days, depending on the inoculating dose of viable bacteria. After inges-
tion, S. Typhi organisms are thought to invade the body through the
gut mucosa in the terminal ileum, possibly through specialized
antigen-sampling cells known as M cells that overlie gut-associated
lymphoid tissues, through enterocytes, or via a paracellular route. S.
Typhi crosses the intestinal mucosal barrier after attachment to the
microvilli by an intricate mechanism involving membrane ruffling,
actin rearrangement, and internalization in an intracellular vacuole. In
contrast to NTS, S. Typhi expresses virulence factors that allow it to
downregulate the pathogen recognition receptor–mediated host
inflammatory response. Within the Peyer patches in the terminal
ileum, S. Typhi can traverse the intestinal barrier through several
mechanisms, including the M cells in the follicle-associated epithe-
lium, epithelial cells, and dendritic cells. At the villi, Salmonella can
enter through the M cells or by passage through or between compro-
mised epithelial cells.
On contact with the epithelial cell, S. typhi assembles type III secre-
tion system encoded on SPI-1 and translocates effectors into the cyto-
plasm. These effectors activate host Rho guanosine triphosphatases,
resulting in the rearrangement of the actin cytoskeleton into mem-
brane ruffles, induction of mitogen-activated protein kinase pathways,

and destabilization of tight junctions. Changes in the actin cytoskele-
ton are further modulated by the actin-binding proteins SipA and SipC
and lead to bacterial uptake. Mitogen-activated protein kinase signal-
ing activates the transcription factors activator protein-1 and nuclear
factor-κB, which turn on production of IL-8. The destabilization of
tight junctions allows the transmigration of polymorphonuclear leu-
kocytes from the basolateral surface to the apical surface, paracellular
fluid leakage, and access of bacteria to the basolateral surface. Shortly
after internalization of S. Typhi by macropinocytosis, salmonellae are
enclosed in a spacious phagosome that is formed by membrane ruffles.
Later, the phagosome fuses with lysosomes, acidifies, and shrinks to
become adherent around the bacterium, forming the Salmonella-
containing vacuole. type III secretion system encoded on SPI-2 is
induced within the Salmonella-containing vacuole and translocates
effector proteins SifA and PipB2, which contribute to Salmonella-
induced filament formation along microtubules. The S. Typhi toxin has
been isolated and characterized composed of 2 A subunits, PltA and
CdtB, which are homologs of the A subunits of the pertussis and cyto-
lethal distending toxins, respectively. Its single B subunit, PltB, is a
homolog of 1 of the components of the heteropentameric B subunit
of pertussis toxin. Although the cellular targets of the adenosine
diphosphate–ribosyl transferase activity of PltA have not yet been
identified, CdtB is a DNase that inflicts DNA damage and induces
cell-cycle arrest. S. Typhi produces typhoid toxin only within mam-
malian cells, and the toxin is then ferried to the extracellular environ-
ment by a unique transport mechanism that involves vesicle carrier
intermediates (Fig. 198-4). These findings open the door to future
opportunities for developing diagnostic and preventive strategies.
After passing through the intestinal mucosa, S. Typhi organisms
enter the mesenteric lymphoid system and then pass into the blood-
stream via the lymphatics. This primary bacteremia is usually asymp-
tomatic, and blood culture results are frequently negative at this stage
of the disease. The bloodborne bacteria are disseminated throughout
the body and are thought to colonize the organs of the reticuloendo-
thelial system, where they may replicate within macrophages. After a
period of bacterial replication, S. Typhi organisms are shed back into
the blood, causing a secondary bacteremia that coincides with the
onset of clinical symptoms and marks the end of the incubation period.
Pathogenesis of typhoid fever
Salmonella
typhi
M cell
Enterocytes lining
terminal ileum
Peyer patch
and resident
macrophage
Mesenteric
lymph nodes
Primary
bacteremia
Figure 198-4 Pathogenesis of typhoid fever. RES, reticuloendothelial system. (Adapted from Richens J: Typhoid fever. In Cohen J, Powderly
WG, Opal SM, editors: Infectious diseases, ed 2, London, 2004, Mosby, pp. 1561–1566.)
Chapter 198 ◆ Salmonella 1389
In vitro studies with human cell lines have shown qualitative and
quantitative differences in the epithelial cell response to S. Typhi and
S. Typhimurium with regard to cytokine and chemokine secretion.
Thus, by avoiding the triggering of an early inflammatory response in
the gut, S. Typhi could instead colonize deeper tissues and organ
systems. Infection with S. Typhi produces an inflammatory response
in the deeper mucosal layers and underlying lymphoid tissue, with
hyperplasia of Peyer patches and subsequent necrosis and sloughing
of overlying epithelium. The resulting ulcers can bleed but usually
heal without scarring or stricture formation. The inflammatory lesion
may occasionally penetrate the muscularis and serosa of the intestine
and produce perforation. The mesenteric lymph nodes, liver, and
spleen are hyperemic and generally have areas of focal necrosis as well.
A mononuclear response may be seen in the bone marrow in associa-
tion with areas of focal necrosis. The morphologic changes of S.
Typhi infection are less prominent in infants than in older children
and adults.
It is thought that several virulence factors, including type III secre-
tion system encoded on SPI-2, may be necessary for the virulence
properties and ability to cause systemic infection. The surface Vi poly-
saccharide capsular antigen found in S. Typhi interferes with phagocy-
tosis by preventing the binding of C3 to the surface of the bacterium.
The ability of organisms to survive within macrophages after phagocy-
tosis is an important virulence trait encoded by the PhoP regulon
and may be related to metabolic effects on host cells. The occasional
occurrence of diarrhea may be explained by the presence of a toxin
related to cholera toxin and E. coli heat-labile enterotoxin. The clinical
syndrome of fever and systemic symptoms is produced by a release
of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) from the
infected cells.
In addition to the virulence of the infecting organisms, host factors
and immunity may also play an important role in predisposition to
infection. There is an association between susceptibility to typhoid
fever and human genes within the major histocompatibility complex
class II and class III loci. Patients who are infected with HIV are at
significantly higher risk for clinical infection with S. Typhi and S.
Paratyphi. Similarly, patients with Helicobacter pylori infection have an
increased risk of acquiring typhoid fever.
Widespread
dissemination
Peyer patches
re-exposed to
S. typhi via bile
Secondary
bacteremia
Seeding of RES:
liver, spleen,
gall bladder,
bone marrow
1390 Part XVII ◆ Infectious Diseases

Table 198-5 Common Clinical Features of Typhoid

Fever in Children*
FEATURE RATE (%)
High-grade fever 95
Coated tongue 76
Anorexia 70
Vomiting 39
Hepatomegaly 37
Diarrhea 36
Toxicity 29 A
Abdominal pain 21
Pallor 20
Splenomegaly 17
Constipation 7
Headache 4
Jaundice 2
Obtundation 2
Ileus 1
Intestinal perforation 0.5
*Data collected in Karachi, Pakistan, from 2,000 children.
B
Figure 198-5 A, A rose spot in a volunteer with experimental typhoid
fever. B, A small cluster of rose spots is usually located on the abdomen.
CLINICAL FEATURES These lesions may be difficult to identify, especially in dark-skinned
The incubation period of typhoid fever is usually 7-14 days but depends people. (From Huang DB, DuPont HL: Problem pathogens: extra-
on the infecting dose and ranges between 3 and 30 days. The clinical intestinal complications of Salmonella enterica serotype Typhi infec-
presentation varies from a mild illness with low-grade fever, malaise, tion, Lancet Infect Dis 5:341–348, 2005.)
and slight, dry cough to a severe clinical picture with abdominal dis-
comfort and multiple complications.
Many factors influence the severity and overall clinical outcome of
the infection. They include the duration of illness before the initiation splenomegaly, and myalgias than patients who require admission to
of appropriate therapy, choice of antimicrobial treatment, age, previous the hospital.
exposure or vaccination history, virulence of the bacterial strain, quan- The presentation of typhoid fever may be tempered by coexisting
tity of inoculum ingested, and several host factors affecting immune morbidities and early diagnosis and administration of antibiotics. In
status. malaria-endemic areas and in parts of the world where schistosomiasis
The presentation of typhoid fever may also differ according to age. is common, the presentation of typhoid may also be atypical. It is also
Although data from South America and parts of Africa suggest that recognized that multidrug-resistant S. Typhi infection is a more severe
typhoid may manifest as a mild illness in young children, presentation clinical illness with higher rates of toxicity, complications, and case
may vary in different parts of the world. There is emerging evidence fatality rates, which may be related to the greater virulence as well as
from south Asia that the presentation of typhoid may be more dramatic higher numbers of circulating bacteria. The emergence of typhoid
in children younger than 5 yr of age, with comparatively higher rates infections resistant to nalidixic acid and fluoroquinolones is associated
of complications and hospitalization. Diarrhea, toxicity, and complica- with higher rates of morbidity and treatment failure. These findings
tions such as disseminated intravascular coagulopathy are also more may have implications for treatment algorithms, especially in endemic
common in infancy, resulting in higher case fatality rates. However, areas with high rates of multidrug-resistant and nalidixic acid– or
some of the other features and complications of typhoid fever seen in fluoroquinolone-resistant typhoid.
adults, such as relative bradycardia, neurologic manifestations, and If no complications occur, the symptoms and physical findings
gastrointestinal bleeding, are rare in children. gradually resolve within 2-4 wk; however, the illness may be associated
Typhoid fever usually manifests as high-grade fever with a wide with malnutrition in a number of affected children. Although enteric
variety of associated features, such as generalized myalgia, abdominal fever caused by S. Paratyphi organisms has been classically regarded as
pain, hepatosplenomegaly, abdominal pain, and anorexia (Table a milder illness, there have been several outbreaks of infection with
198-5). In children, diarrhea may occur in the earlier stages of the drug-resistant S. Paratyphi A, suggesting that paratyphoid fever may
illness and may be followed by constipation. In the absence of local- also be severe, with significant morbidity and complications.
izing signs, the early stage of the disease may be difficult to differentiate
from other endemic diseases such as malaria and dengue fever. The COMPLICATIONS
fever may rise gradually, but the classic stepladder rise of fever is rela- Although altered liver function is found in many patients with enteric
tively rare. In approximately 25% of cases, a macular or maculopapular fever, clinically significant hepatitis, jaundice, and cholecystitis are
rash (rose spots) may be visible around the 7th-10th day of the illness, relatively rare and may be associated with higher rates of adverse
and lesions may appear in crops of 10-15 on the lower chest and outcome. Intestinal hemorrhage (<1%) and perforation (0.5-1%) are
abdomen and last 2-3 days (Fig. 198-5). These lesions may be difficult infrequent among children. Intestinal perforation may be preceded by
to see in dark-skinned children. Patients managed as outpatients a marked increase in abdominal pain (usually in the right lower quad-
present with fever (99%) but have less emesis, diarrhea, hepatomegaly, rant), tenderness, vomiting, and features of peritonitis. Intestinal
 Chapter 198 ◆ Salmonella 1391

Table 198-6 Extraintestinal Infectious Complications of Typhoid Fever Caused By Salmonella enterica Serotype Typhi
ORGAN SYSTEM
INVOLVED
Central nervous system
Cardiovascular system
Pulmonary system
Bone and joint
Hepatobiliary system
Genitourinary system
Soft-tissue infections
Hematologic
From Huang DB, DuPont HL: Problem pathogens: extra-intestinal complications of Salmonella enterica serotype Typhi infection, Lancet Infect Dis 5:341–348, 2005.
PREVALENCE (%) RISK FACTORS
3-35 Residence in endemic region,
malignancy, endocarditis,
congenital heart disease,
paranasal sinus infections,
pulmonary infections, meningitis,
trauma, surgery, and
osteomyelitis of the skull
1-5 Cardiac abnormalities—e.g.,
existing valvular abnormalities,
rheumatic heart disease, or
congenital heart defects
1-6 Residence in endemic region, past
pulmonary infection, sickle cell
anemia, alcohol abuse, diabetes,
HIV infection
<1 Sickle cell anemia, diabetes,
systemic lupus erythematosus,
lymphoma, liver disease,
previous surgery or trauma,
extremes of age, and steroid use
1-26 Residence in endemic region,
pyogenic infections, intravenous
drug use, splenic trauma, HIV,
hemoglobinopathy
<1 Urinary tract, pelvic pathology, and
systemic abnormalities
At least 17 cases reported in the Diabetes
English language literature
At least 5 cases reported in the
English language literature
COMPLICATIONS
Encephalopathy, cerebral edema,
subdural empyema, cerebral
abscess, meningitis, ventriculitis,
transient parkinsonism, motor
neuron disorders, ataxia, seizures,
Guillain-Barré syndrome, psychosis
Endocarditis, myocarditis,
pericarditis, arteritis, congestive
heart failure
Pneumonia, empyema,
bronchopleural fistula
Osteomyelitis, septic arthritis
Cholecystitis, hepatitis, hepatic
abscesses, splenic abscess,
peritonitis, paralytic ileus
Urinary tract infection, renal abscess,
pelvic infections, testicular abscess,
prostatitis, epididymitis
Psoas abscess, gluteal abscess,
cutaneous vasculitis
Hemophagocytosis syndrome

perforation and peritonitis may be accompanied by a sudden rise in
pulse rate, hypotension, marked abdominal tenderness and guarding,
and subsequent abdominal rigidity. A rising white blood cell count
with a left shift and free air on abdominal radiographs may be seen in
such cases.
Rare complications include toxic myocarditis, which may manifest
as arrhythmias, sinoatrial block, or cardiogenic shock (Table 198-6).
Neurologic complications are also relatively uncommon among
children; they include delirium, psychosis, increased intracranial pres-
sure, acute cerebellar ataxia, chorea, deafness, and Guillain-Barré syn-
drome. Although case fatality rates may be higher with neurologic
manifestations, recovery usually occurs with no sequelae. Other
reported complications include fatal bone marrow necrosis, dissemi-
nated intravascular coagulopathy, hemolytic–uremic syndrome, pyelo-
nephritis, nephrotic syndrome, meningitis, endocarditis, parotitis,
orchitis, and suppurative lymphadenitis.
The propensity to become a carrier follows the epidemiology of
gallbladder disease, increasing with patient age and the antibiotic resis-
tance of the prevalent strains. Although limited data are available, rates
of chronic carriage are generally lower in children than adults.
DIAGNOSIS
The mainstay of the diagnosis of typhoid fever is a positive result of
culture from the blood or another anatomic site. Results of blood
cultures are positive in 40-60% of the patients seen early in the course
of the disease, and stool and urine culture results become positive after
the 1st wk. The stool culture result is also occasionally positive during
the incubation period. However, the sensitivity of blood cultures in
diagnosing typhoid fever in many parts of the developing world is
limited because widespread liberal antibiotic use may render
bacteriologic confirmation difficult. Although bone marrow cultures
may increase the likelihood of bacteriologic confirmation of typhoid,
collection of the specimens is difficult and relatively invasive.
Results of other laboratory investigations are nonspecific. Although
blood leukocyte counts are frequently low in relation to the fever and
toxicity, there is a wide range in counts; in younger children leukocy-
tosis is common and may reach 20,000-25,000 cells/µL. Thrombocy-
topenia may be a marker of severe illness and may accompany
disseminated intravascular coagulopathy. Liver function test results
may be deranged, but significant hepatic dysfunction is rare.
The classic Widal test measures antibodies against O and H antigens
of S. Typhi but lacks sensitivity and specificity in endemic areas.
Because many false-positive and false-negative results occur, diagnosis
of typhoid fever by Widal test alone is prone to error. Other relatively
newer diagnostic tests using monoclonal antibodies have been devel-
oped that directly detect S. Typhi–specific antigens in the serum or S.
Typhi Vi antigen in the urine. However, few have proved sufficiently
robust in large-scale evaluations. A nested polymerase chain reaction
analysis using H1-d primers has been used to amplify specific genes of
S. Typhi in the blood of patients; it is a promising means of making a
rapid diagnosis, especially given the low level of bacteremia in enteric
fever. Despite these innovations, the mainstay of diagnosis of typhoid
remains clinical in much of the developing world, and several diagnos-
tic algorithms have been evaluated in endemic areas.
DIFFERENTIAL DIAGNOSIS
In endemic areas, typhoid fever may mimic many common febrile ill-
nesses without localizing signs. In children with multisystem features
and no localizing signs, the early stages of enteric fever may be con-
fused with alternative conditions, such as acute gastroenteritis,
1392 Part XVII ◆ Infectious Diseases

bronchitis, and bronchopneumonia. Subsequently, the differential
diagnosis includes malaria; sepsis with other bacterial pathogens;
infections caused by intracellular microorganisms, such as tuberculo-
sis, brucellosis, tularemia, leptospirosis, and rickettsial diseases; and
viral infections such as Dengue fever, acute hepatitis, and infectious
mononucleosis.
TREATMENT
An early diagnosis of typhoid fever and institution of appropriate treat-
ment are essential. The vast majority of children with typhoid fever can
be managed at home with oral antibiotics and close medical follow-up
for complications or failure of response to therapy. Patients with per-
sistent vomiting, severe diarrhea, and abdominal distention may
require hospitalization and parenteral antibiotic therapy.
There are general principles of typhoid fever management. Adequate
rest, hydration, and attention are important to correct fluid and elec-
trolyte imbalance. Antipyretic therapy (acetaminophen 10-15 mg/kg
every 4-6 hr PO) should be provided as required. A soft, easily digest-
ible diet should be continued unless the patient has abdominal disten-
tion or ileus. Antibiotic therapy is critical to minimize complications
(Table 198-7). It has been suggested that traditional therapy with either
chloramphenicol or amoxicillin is associated with relapse rates of
5-15% and 4-8%, respectively, whereas use of the quinolones and third-
generation cephalosporins is associated with higher cure rates. The
antibiotic treatment of typhoid fever in children is also influenced by
the prevalence of antimicrobial resistance. Over the past 2 decades,
emergence of multidrug-resistant strains of S. Typhi (i.e., isolates fully
resistant to amoxicillin, trimethoprim-sulfamethoxazole, and chlor-
amphenicol) has necessitated treatment with fluoroquinolones, which
are the antimicrobial drug of choice for treatment of salmonellosis
in adults, with cephalosporins as an alternative. The emergence of
resistance to quinolones places tremendous pressure on public health
systems because alternative therapeutic options are limited.
Although some investigators suggest that children with typhoid
fever should be treated with fluoroquinolones like adults, others ques-
tion this approach on the basis of the potential development of further
resistance to fluoroquinolones and the fact that quinolones are still not
approved for widespread use in children. A Cochrane systematic
review of the treatment of typhoid fever also indicates that there is little
evidence to support the carte blanche administration of fluoroquino-
lones in all cases of typhoid fever. Azithromycin may be an alternative
antibiotic for children with uncomplicated typhoid fever.
In addition to antibiotics, the importance of supportive treatment
and maintenance of appropriate fluid and electrolyte balance must be
underscored. Although additional treatment with dexamethasone
(3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hr for 48 hr)
is recommended for severely ill patients with shock, obtundation,
stupor, or coma; corticosteroids should be administered only under
strict controlled conditions and supervision, because their use may
mask signs of abdominal complications.
PROGNOSIS
The prognosis for a patient with enteric fever depends on the rapidity
of diagnosis and institution of appropriate antibiotic therapy. Other
factors are the patient’s, age, general state of health, and nutrition, the
causative Salmonella serotype, and the appearance of complications.
Infants and children with underlying malnutrition and patients
infected with multidrug-resistant isolates are at higher risk for adverse
outcomes.
Despite appropriate therapy, 2-4% of infected children may experi-
ence relapse after initial clinical response to treatment. Individuals who
excrete S. Typhi for 3 mo or longer after infection are regarded as
chronic carriers. The risk for becoming a carrier is low in children
(<2% for all infected children) and increases with age. A chronic
urinary carrier state can develop in children with schistosomiasis.
PREVENTION
Of the major risk factors for outbreaks of typhoid fever, contamination
of water supplies with sewage is the most important. Other risk factors
for development of typhoid fever are congestion, contact with another
patient or a febrile individual, and lack of water and sanitation services.
During outbreaks, central chlorination as well as domestic water puri-
fication is important. In endemic situations, consumption of street
foods, especially ice cream and cut fruit, is recognized as an important
risk factor. The human-to-human spread by chronic carriers is also
important, and attempts should be made to target food handlers and

Table 198-7 Treatment of Typhoid Fever in Children

Optimal Therapy Alternative Effective Drugs
DAILY DOSE DAILY DOSE
SUSCEPTIBILITY ANTIBIOTIC (mg/kg/day) DAYS ANTIBIOTIC (mg/kg/day) DAYS
UNCOMPLICATED TYPHOID FEVER
Fully sensitive Chloramphenicol 50-75 14-21 Fluoroquinolone, e.g., 15 5-7*
ofloxacin or ciprofloxacin
Amoxicillin 75-100 14
Multidrug-resistant Fluoroquinolone 15 5-7 Azithromycin 8-10 7
or
Cefixime 15-20 7-14 Cefixime 15-20 7-14
Quinolone-resistant† Azithromycin 8-10 7 Cefixime 20 7-14
or
Ceftriaxone 75 10-14
SEVERE TYPHOID FEVER
Fully sensitive Fluoroquinolone, e.g., ofloxacin 15 10-14 Chloramphenicol 100 14-21
Amoxicillin 100
Multidrug-resistant Fluoroquinolone 15 10-14 Ceftriaxone 60 10-14
or
Cefotaxime 80 10-14
Quinolone-resistant Ceftriaxone 60 10-14 Azithromycin 10-20 7
Cefotaxime 80 10-14 Fluoroquinolone 20 7-14
*A 3-day course is also effective, particularly for epidemic containment.
†
The optimum treatment for quinolone-resistant typhoid fever has not been determined. Azithromycin, third-generation cephalosporins, or high-dose
fluoroquinolones for 10-14 days is effective.
Modified from World Health Organization: Treatment of typhoid fever. In: World Health Organization: Background document: the diagnosis, prevention and
treatment of typhoid fever. Communicable disease surveillance and response: vaccines and biologicals, Geneva, 2003, World Health Organization, pp. 19–23.
Available at: http://whqlibdoc.who.int/hq/2003/WHO_V&B_03.07.pdf
high-risk groups for S. Typhi carriage screening. Once identified,
chronic carriers must be counseled as to the risk for disease transmis-
sion and the importance of handwashing.
The classic heat-inactivated whole-cell vaccine for typhoid is associ-
ated with an unacceptably high rate of side effects and has been largely
withdrawn from public health use. Globally, 2 vaccines are currently
available for potential use in children. An oral, live-attenuated prepara-
tion of the Ty21a strain of S. Typhi has good efficacy (67-82%) for up
to 5 yr. Significant adverse effects are rare. The Vi capsular polysac-
charide can be used in people 2 yr of age and older. It is given as a
single intramuscular dose, with a booster every 2 yr, and has a protec-
tive efficacy of 70-80%. The vaccines are currently recommended for
anyone traveling into endemic areas, but a few countries have intro-
duced large-scale vaccination strategies. Previous studies in South
America have demonstrated protection against typhoid fever among
schoolchildren with the use of an oral attenuated Ty21 strain vaccine.
Several large-scale demonstration projects using the Vi polysaccha-
ride vaccine in Asia have demonstrated protective efficacy against
typhoid fever across all age groups, but the data on protection among
young children (<5 yr) showed important differences between studies.
The recent Vi-conjugate vaccine has a protective efficacy exceeding
90% in younger children and may offer protection in parts of the world
where a large proportion of preschool children are at risk for the
disease enteric or typhoid fever.

Bibliography is available at Expert Consult.


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Chapter 199
Shigella
Theresa J. Ochoa and Thomas G. Cleary
Shigella causes an acute invasive enteric infection clinically manifested
by diarrhea that is often bloody. The term dysentery is used to describe
the syndrome of bloody diarrhea with fever, abdominal cramps, rectal
pain, and mucoid stools. Bacillary dysentery is a term often used to
distinguish dysentery caused by Shigella from amoebic dysentery
caused by Entamoeba histolytica.
ETIOLOGY
Four species of Shigella are responsible for bacillary dysentery: Shigella
dysenteriae (serogroup A), Shigella flexneri (serogroup B), Shigella
boydii (serogroup C), and Shigella sonnei (serogroup D). There are 15
serotypes in group A, 19 serotypes in group B, 19 serotypes in group
C, and one serotype in group D. Species classification has important
therapeutic implications because the species differ in both geographic
distribution and antimicrobial susceptibility.
EPIDEMIOLOGY
It is estimated that there are approximately 80-165 million cases of
shigellosis each year worldwide, resulting in more than 1 million
deaths; most of these cases and deaths occur in developing countries.
Studies estimate similar illness rates but fewer deaths because of a
decrease in the case-fatality rates. In the United States, approximately
14,000 cases per year are documented, although it is thought that the
actual frequency of infection is 450,000 cases annually. Shigella is the
third most important pathogen identified in the Foodborne Disease
Active Surveillance Network in the United States. Although infection
can occur at any age, it is most common in the 2nd and 3rd yr of life.
Approximately 70% of all episodes and 60% of all Shigella-related
deaths involve children younger than 5 yr of age. Infection in the 1st
6 mo of life is rare for reasons that are not clear. Breast milk from
Chapter 199 ◆ Shigella 1393
women living in endemic areas contains antibodies to both virulence
plasmid-coded antigens and lipopolysaccharides, and breastfeeding
might partially explain the age-related incidence.
Asymptomatic infection of children and adults occurs commonly in
endemic areas. Infection with Shigella occurs most often during the
warm months in temperate climates and during the rainy season in
tropical climates. Both sexes are affected equally. In industrialized soci-
eties, S. sonnei is the most common cause of bacillary dysentery, with
S. flexneri second in frequency; in preindustrial societies, S. flexneri is
most common, with S. sonnei second in frequency. S. boydii is found
primarily in India. S. dysenteriae serotype 1 tends to occur in massive
epidemics, although it is also endemic in Asia and Africa, where it is
associated with high mortality rates (5-15%). However, Shigella has
shown temporal procession in serogroup dominance. Recently, epide-
miologic transition has favored the emergence of S. sonnei as the domi-
nant serogroup in some countries, although the reason for this is
not clear.
Contaminated food (often a salad or other item requiring extensive
handling of the ingredients) and water are important vectors. Exposure
to both fresh and saltwater is a risk factor for infection. Rapid spread
within families, custodial institutions, and childcare centers demon-
strates the ability of shigellae to be transmitted from 1 individual to
the next and the requirement for ingestion of very few organisms to
cause illness. As few as 10 S. dysenteriae serotype 1 organisms can cause
dysentery. In contrast, ingestion of 108-1010 Vibrio cholerae is necessary
to cause cholera.
PATHOGENESIS
Shigella has specialized mechanisms to survive the low gastric pH.
Shigella survives the acid environment in the stomach and moves
through the gut to the colon, its target organ. The basic virulence trait
shared by all shigellae is the ability to invade colonic epithelial cells by
turning on a series of temperature-regulated proteins. This invasion
mechanism is encoded on a large (220 kb) plasmid that at body tem-
perature synthesizes of a group of polypeptides involved in cell inva-
sion and killing. Shigellae that lose the virulence plasmid are no longer
pathogenic. Enteroinvasive Escherichia coli that harbor a closely related
plasmid containing these invasion genes behave clinically like shigellae.
The virulence plasmid encodes a type III secretion system required to
trigger entry into epithelial cells and apoptosis in macrophages. This
secretion system translocates effector molecules from the bacterial
cytoplasm to the membrane and cytoplasm of target host cells. The
type III secretion system is composed of approximately 50 proteins,
including the Mxi and Spa proteins involved in assembly and regula-
tion of the type III secretion system, chaperones (IpgA, IpgC, IpgE, and
Spa15), transcription activators (VirF, VirB, and MxiE), translocators
(IpaB, IpaC, and IpaD), and approximately 30 effector proteins. In
addition to the major plasmid-encoded virulence traits, chromosom-
ally encoded factors are also required for full virulence.
Shigella passes the epithelial cell barrier by transcytosis through M
cells and encounters resident macrophages. The bacteria evade degra-
dation in macrophages by inducing apoptosis, which is accompanied
by proinflammatory signaling. Free bacteria invade the epithelial cells
from the basolateral side, move into the cytoplasm by actin polymer-
ization, and spread to adjacent cells. Proinflammatory signaling by
macrophages and epithelial cells further activates the innate immune
response involving natural killer cells and attracts polymorphonuclear
leukocytes (PMNs). The influx of PMNs disintegrates the epithelial cell
lining, which initially exacerbates the infection and tissue destruction
by facilitating the invasion of more bacteria. Ultimately, PMNs phago-
cytose and kill Shigella, thus contributing to the resolution of the
infection.
Some shigellae make toxins, including Shiga toxin and enterotoxins.
Shiga toxin is a potent exotoxin that inhibits protein synthesis and is
produced in significant amounts by S. dysenteriae serotype 1, by a
subset of E. coli, which are known as enterohemorrhagic or Shiga
toxin–producing E. coli, and occasionally by other organisms. Shiga
toxin inhibits protein synthesis to injure vascular endothelial cells
to trigger the severe complication of hemolytic-uremic syndrome.