Transcript Typhoid Fever

Enteric Fever
Richelle C Charles, MD.
Outline
• Definitions: Typhoid and Enteric fever
• Etiology
• Epidemiology
• Transmission and Pathogenesis
• Clinical manifestations
• Diagnosis and Management
• Prevention and control
Definition: Enteric and typhoid fever
• Enteric fever denotes typhoid or paratyphoid fever
• Salmonella enterica serotype Typhi causes
typhoid fever
• Salmonella enterica serotypes Paratyphi A, B and
C are the causative agents of paratyphoid fever
• The terms “enteric fever” and “typhoidal illness”
may sometimes be used to refer to syndrome of
high grade and prolonged fevers in the absence of
localizing symptoms or signs.
– Examples: Tularemia, Yersiniosis, Brucellosis
Etiologic agent and pathogenesis
Nomenclature of Salmonellae
• Salmonella enterica: Gram-negative
bacillus
• The multiple strata of clinical,
microbiologic, and serologic designations
applied to Salmonella infections lead to
confusion.
Nomenclature of Salmonellae
CLINICAL
• Salmonella strains are differentiated as typhoidal or non-typhoidal
– Typhoidal strains cause enteric fever in all human hosts
– Non-typhoidal Salmonella (NTS) are classically associated with
inflammatory diarrhea in human hosts
• Classically this distinction reflects systemic illness vs. gastroenteritis
but the lines can blur.
– NTS may cause invasive infection that includes prolonged bacteremia
(with or without pyogenic foci) that may mimic systemic illness with
typhoidal strains
– host factors influence susceptibility to invasive NTS (Specific
immunodeficiencies associated with systemic disease)
– characteristics of bacterial strain may influence likelihood for invasive
NTS
Figure 5
The Lancet 2012 379, 2489-2499DOI: (10.1016/S0140-6736(11)61752-2)
The Lancet 2012 379, 2489-2499DOI: (10.1016/S0140-6736(11)61752-2)
Nomenclature of Salmonellae
TAXONOMIC
Most pathogenic Salmonella belong to a single subspecies designated Salmonella
enterica subspecies enterica.
Nomenclature of Salmonellae
.
SEROLOGIC
Salmonella are usually classified serologically.
The serogroup is assigned based on the O antigen alone, while the serotype
designation, from which the name (eg….) is derived, is based on both the O and H
antigens.
Examples clinical and serologic
classification of pathogenic
Salmonella.
Clinical
Typhoidal
Nontyphoidal
Serotype
(O and H)
Formal Designation
Serogroup
(O)
S. enterica subsp. enterica ser. Typhi
D
Paratyphi A
S. enterica subsp. enterica ser. Paratyphi A
A
Paratyphi B
(schottmuelleri)
S. enterica subsp. enterica ser. Paratyphi B
B
Paratyphi C
(hirschfeldii)
S. enterica subsp. enterica ser. Paratyphi C
C
Typhimurium
S. enterica subsp. enterica ser. Typhimurium
B
S. enterica subsp. enterica ser. Enteriditis
D
S. enterica subsp. enterica ser. Newport
C
Typhi
Enteriditis
Newport
Epidemiology
Burden in high incidence areas
• Incidence of Enteric Fever annually
– 22-27 million S. Typhi
– 5 million S. Paratyphi A (Increasing-- 1:5
cases in Asia)
– S. Paratyphi B and C are less common
causes of enteric fever globally.
• In high incidence areas, most infection
occurs in young children
• Typically the leading cause of bacteremia
(> 75%) in such areas
Typhoid Fever: Distribution
Transmission, Risk Factors and
Patterns of Infection
Sources of Infection
• S. Typhi and Paratyphi A and B are human
restricted
– no environmental or animal reservoir (*S. Paratyphi C
can be shed by animals)
– Source of infection is organisms shed in the stool of
infected humans
• Pre-antibiotic era individuals shed bacteria during acute
illness and typically for weeks during convalescence
• 3-5% of infected individuals develop chronic asymptomatic
carriage (shedding bacteria > 1 year).
In endemic areas, what is the
proportion infection transmitted via
water source versus person-toperson transmission?
a) 50:50
b) 20:80
c) 80:20
Transmission, Risk Factors and
Patterns of Infection
Mode of transmission
• Typhoidal S. enterica are acquired
via ingestion of fecallycontaminated water or food.
• Molecular epidemiologic studies
based on high resolution
genotyping show waterborne
transmission as the most likely
route of transmission in majority of
cases of enteric fever.
– Despite spatial and temporal case
clustering, the distribution of S.
typhi genotypes was random
– Households with multiple cases of
enteric fever, only 20% shared a
common bacterial genotype
Baker S, Open Biol 2011
Transmission, Risk Factors and
Patterns of Infection
• S. Typhi may persist for weeks after passage in
water, and may persist in a variety of
contaminated food items (e.g. dehydrated
formula and iced beverages)
• ID50 in human volunteers ~ 107 bacteria (as few
as 103 organisms can cause disease)
• Contact with a known case in <20%
• Consistent risk factors include drinking nonboiled water and foods prepared outside the
home
Typhoid fever in the U.S.
• Sporadic disease
(<1/100,000 personyears)
• In the U.S. ~80% of
reported cases occur in
returned travelers.
• Risk dependent on
location, approaching 1
per 1000 in travelers
arriving from India.
Lynch MF, JAMA. 2009;302(8):859.
Typhoid fever in the U.S.
• Most published
outbreaks between
1960-1999 are
foodborne
– Majority associated with
asymptomatic chronic carriers
employed as food handlers
(Olsen SJ (2003) Epidemiol Infect 130: 1321).
• In the U.S. 0.2%
fatalities in reported
cases.
Mary Mallon
Clinical Pathogenesis
• Invasion:
– Asymptomatic (80-90%) or transient
diarrhea (10-20%).
• Intracellular infection which
disseminates throughout
reticuloendothelial system
• Low grade bacteremia.
– Median of 1 culturable bacteria per mL
blood
– Median of 10 culturable bacteria per mL
bone marrow
• Pre-patent phase (Latency) of infection
lasts ~1-2 weeks (3-60 days depending
on number of organisms ingested)
Modified from Monack, D. 2004 Nature Reviews
Microbiology 2, 747-765.
Clinical Manifestations
• Non-specific
– 90% - mild,
require outpatient
treatment
– 10% - severe,
classic ‘enteric
fever’
Clinical Feature
Flu-like
symptoms
Abdominal
symptoms
Physical
signs
Fever
Approx. Frequency*
> 95 %
Headache
80 %
Chills
40 %
Cough
30 %
Myalgia
20 %
Arthralgia
<5%
Anorexia
50 %
Abdominal pain
30 %
Diarrhea
20 %
Constipation
20 %
Hepatomegaly
10 %
Splenomegaly
10 %
Abdominal tenderness
5%
Rash
<5%
Generalized
adenopathy
<5%
Clinical Manifestations
• Classic descriptions of enteric fever are based on
series of hospitalized patients
– Classically the first week is relatively indolent
– By the second week of illness patients become toxic
– Some degree of abdominal pain, diarrhea, or
constipation is common
– Some suggestion of encephalopathy is common
– Life threatening complications around third week (i.e.
encephalopathy, GI hemorrhage or perforation
– Resolution over 3-4 weeks. Relapse in 10-20%.
– Severe disease in adolescents and young males.
– Life threatening complications typically after 1 week of
escalating fevers and include intestinal perforation
and encephalopathy.
Diagnosing Enteric Fever
• Currently there is no optimal assay for
diagnosing patients with acute typhoid or
paratyphoid fever
• This deficiency limits our ability to do the
following:
– To diagnose acute cases required for clinical
management
– Target administration of appropriate antimicrobials
– Measure disease burden within a defined area
– Measure the effectiveness of various intervention
strategies.
Enteric Fever: Diagnostics
• Cultured based diagnostics
– Blood cultures are limited by low number of organisms
• Sensitivity 40%-80% dependent on volume of culture
– stool cultures positive in 50% of children, 30% of adults
– BM culture gold standard but invasive – 80 to 95% sensitivity
• Serologic based diagnostics
– Widal test most commonly used but lacks sensitivity and
specificity
– Rapid serologic tests (e.g. Tubex® or Typhidot® ) suffer similar
problems
• Often left with need for empiric treatment
Selected diagnostic tests
Microbiologic
Genomic
Host response
Test
(culture site)
Sensitivity
Specificity
Comments
Blood
30-70%
100%
A number of advantages
Sensitivity increases with volume
Bone marrow
80-95%
100%
Considered gold standard but impractical
Stool
30-50%
Urine
15-50%
PCR
50-95%
variable
Issues of sensitivity not solved
Widal
70-100%
30-85%
Specificity decreases in endemic zones
IDL Tubex®
(Anti-LPS IgM)
60-85%
55-80%
Typhidot®
(Anti-OMP
IgG/IgM)
75-90%
50-90%
TPTest
IgA Assay
>90%
>90%
Many small studies in general less sensitive
but more specific than Widal
Sensitive, specific, minimal laboratory
requirements
Management
• Antibiotic management
– reduces the mortality rate of enteric fever from
10-15% to less than 1%
– shortens the duration of fever from 3-4 weeks
to 3-5 days
Antibiotics
• Ciprofloxacin (and ofloxacin) remain effective for
nalidixic-acid susceptible strains.
– Short courses of 5-7 days are acceptable in uncomplicated
cases.
• Third generation cephalosporins
– Longer time to fever clearance and more clinical failures and
rates of relapse with courses <7 days
• Azithromycin
– Only rare reports of resistance
– Excellent oral drug for uncomplicated infection caused by NaR
strains.
– Excellent response and low failure rates
– Low rates of relapse after seven day course
Emergence of antibiotic
resistance
Wain (2015)Lancet 385:1136-45
Complications and mortality both are higher in cases of MDR strains (resistant to
chloramphenicol, ampicillin, and co-trimoxazole) of Salmonella Typhi or Salmonella
Paratyphi
Asymptomatic carriage
• 3-5% of infected
individuals develop
chronic infection in
the gall bladder
which may persist for
decades
• May be reservoirs of
infection within a
community
Asymptomatic Carriage
• Gallstones are thought to be the principal
risk factor for developing chronic carriage.
– Gallstones detected in approximately 90% of
chronic carriers.
– Gallstones allow attachment of the bacteria
and biofilm formation, which in turn protects
the bacteria from the antimicrobial and
emulsifying action of bile.
Asymptomatic carriage
• May contribute to transmission of infection
• May act as vehicles for introducing S.
Typhi or S. Paratyphi A into previously
uninfected communities.
Prevention and Control
Typhoid Control
• Major preventative strategy is the provision of safe water
and adequate sanitation.
– Municipal public infrastructure level
• Development of appropriate facilities for waste disposal and sewage
treatment
• Development of safe water supplies
– Household level – washing hands, food and water safety
• Reportable, control in areas where disease is sporadic
includes identification of carriers (from household
contacts) and restriction of carriers from food handling
Typhoid Vaccines
Table 4: Vaccines for Typhoid Fever (11,22).
Vacc.
Type
Protection
against S.
Typhi
Boosting
Interval
in
Travelers
Licensed
in #
Nations
Route
Dose and Interval
Minimum
Age
5*
50-80%
every 5
years
56**
2
50-80%
every 2
years
> 90**
Ty21a
liveattenuated
Oral
4 doses
Administer one dose
every other day until
complete
Vi
capsule
antigen
Polysacch.
IM
1
*5 years and older per WHO, 6 years and older per Advisory Committee on Immunization Practices.
**As of March 2010
Typhoid Vaccines
• WHO recommends vaccination in highly
endemic areas but not adopted into NIP.
• Vaccines are primarily used by persons
from non-endemic areas
Limitations of current vaccines
• Limited immunity in young children (<2 years)
• Lack of cross protection against other causes of
enteric fever, primarily S. Paratyphi A
• A number of conjugate Vi vaccines are in
various stages of development to improve both
immunogenicity in young children under 2 years
of age and to induce longer lasting protection,
• A paratyphoid A conjugate vaccine containing
the O-specific polysaccharide of S. Paratyphi A
has also recently been reported
Obstacles to typhoid control
• Currently there is no optimal assay for
diagnosing patients with acute typhoid or
paratyphoid fever
• Limited data to assess true burden of disease
• Increasing antimicrobial resistance
• Lack of effective vaccines for children under the
age of 2