Journal of Infection 81 (2020) 902–910

Contents lists available at ScienceDirect

Journal of Infection
journal homepage: www.elsevier.com/locate/jinf

Complications and mortality of typhoid fever: A global systematic

review and meta-analysis
Christian S. Marchello a, Megan Birkhold b, John A. Crump a,∗
a
Centre for International Health, University of Otago, PO Box 56, Dunedin 9016, New Zealand
b
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA

a r t i c l e i n f o s u m m a r y

Article history: Objectives: Updated estimates of the prevalence of complications and case fatality ratio (CFR) among
Accepted 29 October 2020 typhoid fever patients are needed to understand disease burden.
Available online 2 November 2020
Methods: Articles published in PubMed and Web of Science from 1 January 1980 through 29 January
Keywords: 2020 were systematically reviewed for hospital or community-based non-surgical studies that used cul-
Typhoid fever tures of normally sterile sites, and hospital surgical studies of typhoid intestinal perforation (TIP) with
Case fatality ratio intra- or post-operative findings suggestive of typhoid. Prevalence of 21 pre-selected recognized compli-
Meta-analysis cations of typhoid fever, crude and median (interquartile range) CFR, and pooled CFR estimates using a
Mortality random effects meta-analysis were calculated.
Intestinal perforation Results: Of 113 study sites, 106 (93.8%) were located in Asia and Africa, and 84 (74.3%) were non-surgical.
Among non-surgical studies, 70 (83.3%) were hospital-based. Of 10,355 confirmed typhoid patients, 2,719
(26.3%) had complications. The pooled CFR estimate among non-surgical patients was 0.9% for the Asia
region and 5.4% for the Africa region. Delay in care was significantly correlated with increased CFR in
Asia (r = 0.84; p<0.01). Among surgical studies, the median CFR of TIP was 15.5% (6.7–24.1%) per study.
Conclusions: Our findings identify considerable typhoid-associated illness and death that could be averted
with prevention measures, including typhoid conjugate vaccine introduction.
© 2020 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Introduction Timely and accurate diagnosis and treatment of typhoid fever

Typhoid fever is caused by the organism Salmonella enterica
subspecies enterica serovar Typhi (Salmonella Typhi); a systematic
infection transmitted predominantly through water or food con-
taminated by human feces.1–3 Typhoid fever presents clinically
across a spectrum of severity with a range of symptoms and signs
including fever, abdominal pain, nausea, and vomiting, that make
differentiating it from other febrile and gastrointestinal illnesses
challenging.2 The ‘gold standard’ diagnostic method for typhoid
fever is the culture of blood, bone marrow, or another normally
sterile site. However, clinical microbiology services are not widely
available in endemic areas and culture-based diagnosis has incom-
plete sensitivity.4 Additionally, delays in diagnosis and treatment
occur as a result of barriers to care, such as difficulty accessing
tertiary facilities because of delayed referral, distance, and the cost
of healthcare.5–7
∗
Corresponding author
E-mail address: john.crump@otago.ac.nz (J.A. Crump).
in the community is needed to avert complications requiring hos-
pitalization, and death.2 Typhoid complications include typhoid
intestinal perforation (TIP), gastrointestinal hemorrhage, hepatitis,
cholecystitis, myocarditis, shock, encephalopathy, pneumonia, and
anemia.1 , 2 TIP and gastrointestinal hemorrhage are serious com-
plications that are often fatal, even if managed surgically.8 , 9
Prevention of typhoid fever by improved sanitation and in-
creased access to clean, safe water and food remains critical,10–12
but requires substantial investment over long time scales. Typhoid
conjugate vaccine (TCV) has been pre-qualified and recommended
by the World Health Organization for routine use13 and repre-
sents a tool to prevent typhoid illness and deaths in a short time
horizon, complementing progress in sanitation, water, and food
safety improvements.14 In typhoid-endemic countries, TCV pre-
qualification allows for priority access and funding, removing im-
portant hurdles for vaccine introduction into routine immunization
schedules.15
While previous systematic reviews have examined the case fa-
tality ratio (CFR) of typhoid fever, they did not capture the substan-
tial number of observational studies on typhoid fever published in

https://doi.org/10.1016/j.jinf.2020.10.030
0163-4453/© 2020 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
C.S. Marchello, M. Birkhold and J.A. Crump Journal of Infection 81 (2020) 902–910

recent years. Furthermore, some past reviews were restricted by Table 1

Inclusion and exclusion criteria for search strategy of complications and mortality
location, population, or age.10 , 16–19 In order to support country-
of typhoid fever systematic review.
level decisions on typhoid control, including TCV introduction, and
to provide contemporary estimates of morbidity and mortality, we Inclusion
performed a systematic review and meta-analysis of the prevalence
of complications and case fatality ratio (CFR) among patients with
• Non-surgical studies using culture
typhoid fever. of normally sterile site specimens
• Surgical studies of intestinal
Methods perforation using either:
◦ Gross intraoperative findings
with the keywords ‘terminal
Search strategy
ileum’, ‘antimesenteric
perforation’, or ‘confirmed at
We systematically reviewed PubMed and Web of Science for laparotomy’
published articles on the complications and mortality of typhoid ◦ Postoperative findings using
histopathology stains or
fever. Each database was searched for key words of Salmonella
immunohistochemistry to
Typhi, mortality, case fatality, died, death, complications, perfora- differentiate alternative causes
tion, and hemorrhage (Supplementary Appendix A). Since a pre- for perforation
vious review reported on the mortality of typhoid fever prior to • Article published after 1980 but
Exclusion
• Case reports, case series, policy
reports, commentaries, editorials,
and conference abstracts
• Aggregate or summary data
estimating case fatality ratio
• Government passive surveillance
reports
• Used clinical indication (i.e.,
symptoms and signs), culture of a
non-sterile site (e.g., stool or
urine), or serology to classify a
case of typhoid fever
• Clear denominator was not
available to calculate proportions

1980,20 our search was limited to articles published from 1 Jan-
uary 1980 through 29 January 2020. We placed no restrictions on
language, country, or demographics. We followed the Preferred Re-
porting Items for Systematic Reviews and Meta-Analyses (PRISMA;
Supplementary Appendix B)21 and the protocol was registered with
PROPSERO International Prospective Register of Systematic Reviews
on 10 July 2020 (CRD42020166998). Ours was a study of published
data and as such, institutional review board approval was not re-
quired.
Study selection
We selected ‘non-surgical studies’ reporting the proportion of
participants with Salmonella Typhi infection who had typhoid-
associated complications or who died. In such studies, Salmonella
Typhi infection was required to be ascertained by culture of a
normally sterile site (e.g., blood). We also selected ‘surgical stud-
ies’ of only participants undergoing surgery for intestinal perfo-
ration. Surgical studies were included if gross intraoperative find-
ings contained the keywords ‘terminal ileum,’ ‘antimesenteric per-
foration,’ or ‘confirmed at laparotomy’ to assign perforations as
TIP.8 , 9 We also accepted postoperative criteria including the use of
histopathology stains or immunohistochemistry to differentiate al-
ternative causes for perforation (e.g., tuberculosis) and to attribute
the cause of perforation to Salmonella Typhi. Consequently, we
considered participants from non-surgical studies as having ‘con-
firmed,’ and those from surgical studies as having ‘probable,’ ty-
phoid fever. Inclusion and exclusion criteria are summarized in
Table 1.
Titles and abstracts were downloaded from each database, im-
ported into Endnote X8 (Clarivate Analytics, Boston, MA, USA), and
combined into one reference list. Duplicates were removed by End-
note, and the de-duplicated list of articles was uploaded to the
online systematic review tool Rayyan (Qatar Computing Research
Institute, Doha, Qatar) for screening.22 Each subsequent process,
including title and abstract review, full text review, and data ab-
straction, was performed in parallel by two authors (CSM and MB).
A third author (JAC) was consulted when CSM and MB were un-
able to resolve discrepancies through discussion. The full text of 33
studies included in a systematic review on typhoid incidence were
additionally screened.23 Data were then abstracted into a shared
Google Sheets spreadsheet (Google LLC, Mountain View, CA, USA).
Data abstraction
Abstracted study characteristics included the first author, pub-
lication year, article identifier (e.g., PubMed ID), year data collec-
tion started and ended, the city, district, or locality of the study,
data collected at any point
• Hospital- or community-based
study designs of active household
or population-based surveillance,
prospective observational,
cross-sectional, case-control,
retrospective medical record, or
control arms of clinical trials
region and sub-region as classified by the United Nations (UN),24
type of normally sterile site cultured or study-specific TIP defini-
tion, whether participants were recruited from the community or
a hospital, and if the study was non-surgical or surgical.
Data were abstracted for the mean and median fever, illness,
or symptom duration prior to presentation; inclusion age and
age range of participants; total number of confirmed or proba-
ble typhoid cases; number and type of complications; and num-
ber of deaths attributed to typhoid fever. When reported, we ab-
stracted CFR data for MDR cases, defined by authors as infection
with Salmonella Typhi resistant to chloramphenicol, ampicillin, and
trimethoprim-sulfamethoxazole, and non-MDR cases, defined by
authors as susceptible to at least one of the first-line antimicro-
bials. We also noted the proportion of male and female partici-
pants with TIP.
Data on duration of fever, duration of illness, and duration of
symptoms prior to treatment were used as a proxy for delays in
accessing care and subsequently combined as one metric of ‘de-
lay in care.’ We categorized the ages of participants into three
groups based on inclusion age and age range: ‘children’ were ≤15
years old, ‘adults’ >15 years, and ‘mixed ages’ were studies of both
children and adult participants. Complications were classified two
ways. First, we used a pre-selected list of 21 complications defined
by Parry and colleagues.1 If a study mentioned any complication
from the list, regardless of whether the study defined it as a ty-
phoid complication, we abstracted the data. Second, we noted sep-
arately when a study specifically used the term ‘complication’ as-
sociated with typhoid fever. We did not abstract complications fol-
lowing surgery nor those attributed to the surgical procedure. If
a study described an initial diagnosis, including pneumonia, hep-
atitis, and other syndromes that overlapped with complications of
typhoid fever from our pre-selected list, it was not recorded as a
complication due to lack of attribution to typhoid by the authors
of the study. The final dataset was reviewed by a third author (JAC)
for completeness and accuracy.
Data analysis
For each non-surgical study, we divided the number of each
pre-selected complication by the number of confirmed typhoid

903
C.S. Marchello, M. Birkhold and J.A. Crump
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of search strategy and selection of articles for mortality and complications of
typhoid fever, 1965–2018.
cases to calculate the prevalence of the specific complication. We
divided the number of deaths attributed to typhoid fever by the
total number of confirmed typhoid cases to calculate a CFR. We
calculated the median and interquartile (IQR) range CFR for stud-
ies across each UN region and a pooled CFR estimate using a ran-
dom effects model meta-analysis with MetaXL (Epigear Interna-
tional version 5.3). For pooled CFR estimates, we also stratified by
UN sub-region and by age group. Among surgical studies of TIP,
we calculated the CFR of TIP among probable typhoid cases and
the prevalence of TIP among male and female participants.
Proportions were compared by X2 test, means by t-test, and
the relationship between delay in care and CFR by Pearson’s cor-
relation coefficient (r), in R version 4.0.2 (R Foundation for Sta-
tistical Computing, Vienna, Austria) and considered significant if
p <0.05. We assessed bias throughout the analyses by separating
non-surgical and surgical analyses, by stratifying by region, sub-
region, age, and study recruitment setting, and by heterogeneity
using I2 .
Results
Our search strategy returned 6,121 articles (Fig. 1). Of 513 full
text articles reviewed, 404 were excluded. An unclear or inappro-
904
Journal of Infection 81 (2020) 902–910
priate diagnostic method due to inadequate description of how
a confirmed or probable typhoid case was defined was the most
common reason for exclusion. We were unable to translate the lan-
guage of 11 articles and we were unable to locate the full text of 10
articles. A total of 109 articles were included for analysis.20 , 25–132
Study characteristics
Among the 109 articles, one (0.9%) collected data in five coun-
tries,90 resulting in 113 study sites (Supplementary Appendix C).
Among 113 study sites, data were collected from 1965 through
2018 and from every UN region; 62 (54.9%) in Asia, 44 (38.9%) in
Africa, four (3.5%) in the Americas, two (1.8%) in Oceania, and one
(0.9%) in Europe. Eighty-four (74.3%) sites recruited non-surgical
typhoid fever participants and 29 (25.7%) were surgical studies of
TIP. Among 84 non-surgical studies, 70 (83.3%) were hospital-based
and 14 (16.7%) were community-based. There were 14,007 con-
firmed cases of typhoid fever with a median (IQR) of 64 (25–190)
cases per study; 12,889 (92.0%) were from hospital-based and 1,118
(8.0%) from community-based studies. Among 29 surgical study
sites, there were 2,926 probable cases of typhoid with a median
of 58 (46–104) cases per study. Of the 16,933 total confirmed or
probable cases, 11,973 (70.7%) were from Asia, 3,642 (21.5%) from
C.S. Marchello, M. Birkhold and J.A. Crump Journal of Infection 81 (2020) 902–910

Table 2
Complications of typhoid fever, by United Nations region, 1965–2018.

Complicationsa Africa Americas Asia Oceania Totalb

n/ N (%) n/ N (%) n/ N (%) n/ N (%) n/ N (%)

Abdominal
Intestinal perforation 37 / 486 (7.6) 4/ 217 (1.8) 34 / 4,622 (0.7) 5/ 739 (0.7) 80 / 6,064 (1.3)
Gastrointestinal 11 / 320 (3.4) 0/ 0 — 87 / 2,809 (3.1) 21 / 739 (2.8) 119 / 3,868 (3.1)
hemorrhage
Hepatitis 10 / 157 (6.4) 1/ 9 (11.1) 104 / 2,389 (4.4) 17 / 739 (2.3) 132 / 3,294 (4.0)
Cholecystitis 1/ 55 (1.8) 0/ 0 — 10 / 913 (1.1) 0/ 365 (0.0) 11 / 1,333 (0.8)
Cardiovascular
Asymptomatic ND ND ND ND ND
electrocardiographic
changes
Myocarditis 2/ 191 (1.0) 0/ 0 — 30 / 1,979 (1.5) 1/ 365 (0.3) 33 / 2,535 (1.3)
Shock 0/ 14 (0.0) 0/ 0 — 59 / 3,580 (1.6) 17 / 365 (4.7) 76 / 3,959 (1.9)
Neuropsychiatric
Encephalopathy 0/ 0 — 0/ 0 — 98 / 2,460 (4.0) 4/ 365 (1.1) 102 / 2,825 (3.6)
Delirium 34 / 277 (12.3) 0/ 0 — 650 / 2,027 (32.1) 21 / 344 (5.8) 705 / 2,648 (26.6)
Psychotic states 2/ 50 (4.0) 2/ 217 (0.9) 28 / 1,438 (1.9) 0/ 0 — 32 / 1,705 (1.9)
Meningitis 6/ 347 (1.7) 1/ 9 (11.1) 13 / 1,625 (0.8) 0/ 0 — 20 / 1,981 (1.0)
Impairment of ND ND ND ND ND
coordination
Respiratory
Bronchitis 0/ 0 — 0/ 0 — 32 / 407 (7.9) 0/ 0 — 32 / 407 (7.9)
Pneumonia 4/ 191 (2.1) 7/ 226 (3.1) 43 / 1,416 (3.0) 18 / 374 (4.8) 72 / 2,207 (3.3)
Hematologic
Anemia 132 / 311 (42.4) 52 / 226 (23.0) 683 / 3,516 (19.4) 150 / 703 (21.3) 1,017 / 4,756 (21.4)
Disseminated 0/ 0 — 0/ 0 — 98 / 660 (14.8) 1/ 374 (0.3) 99 / 1,034 (9.6)
intravascular
coagulation
Other
Focal abscess 1/ 47 (2.1) 0/ 0 — 0/ 0 — 0/ 0 — 1/ 47 (2.1)
Pharyngitis ND ND ND ND ND
Miscarriage 0/ 0 — 0/ 0 — 1/ 6 (16.7) 0/ 0 — 1/ 6 (16.7)
Relapse 6/ 171 (3.5) 2/ 129 (1.6) 71 / 2,166 (3.2) 0/ 0 — 79 / 2,466 (3.2)
Chronic carriage ND ND ND ND ND
Seizure or 14 / 125 (11.2) 0/ 0 — 94 / 4,224 (2.2) 0/ 0 — 108 / 4,349 (2.5)
convulsionsc
Total complications 260 / 689 (37.7) 69 / 226 (30.5) 2,135 / 8,681 (24.6) 255 / 739 (34.5) 2,719 / 10,335 (26.3)
Total Complications 116 / 348 (33.3) 24 / 327 (7.3) 401 / 3,028 (13.2) 128 / 739 (17.3) 669 / 4,442 (15.1)
as described by study
∗a
Complications from Parry et al. Table 11 ND = No data. Data could not be abstracted as these complications were not described in any of the included articles.
∗∗b
Europe not shown due to the single study from Europe including participants diagnosed with stool and urine cultures, therefore it was not possible to distinguish
complications among those diagnosed by culture of a normally sterile site. 101 .
^cComplication not listed by Parry et al

Africa, 739 (4.4%) from Oceania, 554 (3.3%) from the Americas, and
25 (0.1%) from Europe. Sixty-seven (59.3%) of 113 study sites re-
cruited participants of a mixed age, 35 (31.0%) recruited only chil-
dren, and 11 (9.7%) only adults.
Typhoid fever complications
Of the 84 non-surgical study sites, 56 (66.7%) reported at least
one complication occurring from the list of pre-selected complica-
tions. Among 10,335 cases of confirmed typhoid fever, there were
2,719 (26.3%) complication events (Table 2). Delirium and anemia
were the most prevalent complications, occurring in 705 (26.6%)
of 2,648 and 1,017 (21.4%) of 4,756 confirmed cases, respectively.
Eighty (1.3%) of 6,064 participants had TIP; 34 (0.7%) of 4,622
participants in Asia and 37 (7.6%) of 486 participants in Africa.
Twenty-seven (32.1%) of 84 sites described unspecified complica-
tions for 669 (15.1%) of 4,442 confirmed cases. Asymptomatic elec-
trocardiographic changes, impairment of coordination, pharyngitis,
and chronic carriage were not reported from any of the included
non-surgical study sites. Data on miscarriage were available in one
study of pregnant women,42 occurring in one (16.7%) of six with
confirmed typhoid fever. Although not in the Parry et al. list of ty-
phoid complications, seizures or convulsions were reported among
108 (2.5%) of 4,349 typhoid patients.
Outcomes of typhoid intestinal perforation
We identified 29 articles reporting surgical studies of TIP and
an additional seven non-surgical studies provided data on CFR of
TIP. Among the 36 combined surgical and non-surgical studies, 12
(33.3%) were in Asia, 23 (63.9%) in Africa, and one (2.8%) in the
Americas. There were a total of 2,971 TIP cases, of which 2,921
(98.3%) were from surgical studies and 50 (1.7%) were from non-
surgical studies. Of 2,971 TIP cases, 999 (33.6%) were in Asia, 1,967
(66.2%) in Africa, and 5 (0.2%) in the Americas. Of 2,971 TIP cases,
433 (14.6%) died. The median CFR of TIP across the 36 studies was
15.5% (6.7–24.1%).
Of 999 TIP cases in Asia, 46 (4.6%) died. The median CFR of TIP
across 12 studies in Asia was 1.0% (0.0–8.4%). Of 1,967 TIP cases in
Africa, 387 (19.7%) died. The median CFR of TIP across 23 stud-
ies in Africa was 20.0% (13.7–28.0%). Sex was available for 996
(99.7%) of 999 TIP cases in Asia; 704 (70.7%) were male compared
to 292 (29.3%) female (X2 =170.4; p<0.01). Sex was available for
1,826 (92.8%) of 1,967 TIP cases in Africa; 1,210 (66.3%) were male
compared to 616 (33.7%) female (X2 =193.2; p<0.01).
Typhoid fever mortality
Seventy-nine (94.0%) of 84 non-surgical study sites reported on
mortality. Among 13,303 confirmed typhoid cases from studies re-

905
C.S. Marchello, M. Birkhold and J.A. Crump
Table 3
Confirmed and probable cases of typhoid fever and case fatality ratio of confirmed typhoid fever, by United Nations region, 1965–2018.
Africa Americas
Confirmed and probable typhoid fever
Study locations 44 4 62
Confirmed and probable cases 3,642 554
Median (IQR) cases per study 50 (26–102.5) 113.5 (9.8–242.3)
Mortality among confirmed cases
Study locations 22 3 51
Confirmed cases 1,700 544
Number of deaths 77 23
CFR confirmed typhoid fever 4.5 4.2
Median CFR (IQR) 4.2 (0.0–7.1) 9.2 (4.8–15.7)
Pooled CFR (95% CI) 5.4% (2.7–8.9%) 6.7% (0.0–19.9%)
∗a
No median; IQR = interquartile range; CI = confidence interval.
porting mortality, 250 died, for a CFR of 1.9% (Table 3). The pooled
CFR estimate (95% CI; heterogeneity I2 ) among 79 studies report-
ing on mortality of confirmed typhoid fever was 2.0% (1.4–2.8%;
83.9%). The pooled CFR estimates for the Asia, Africa, Oceania, the
Americas, and Europe regions were 0.9% (0.6–1.3%; 63.4%), 5.4%
(2.7–8.9%; 83.4%), 7.2% (0.0–20.4%; 97.2%), 6.7% (0.0–19.9%; 94.4%),
and 1.0% (0.0–6.8%; incalculable), respectively. Data on outcomes
for multi-drug resistant Salmonella Typhi infection, outcomes and
sub-regions and sub-regional forest plots for South-eastern Asia,
Southern Asia, Eastern Africa, and Western Africa, including strat-
ification in these sub-regions by age groups, are provided in Sup-
plementary Appendix D and E, respectively.
Sixty-seven (84.8%) of 79 non-surgical study sites were
hospital-based, and 12 (15.2%) were population or community-
based studies.37 , 38 , 60 , 73 , 84 , 90 , 96 , 118 Ten (83.3%) of 12 non-hospital
study sites were located in Asia and two (16.7%) in Africa; one each
in Kenya37 and Burkina Faso.60 No deaths were reported among
866 confirmed typhoid cases in the 12 non-hospital sites compared
to 250 (2.0%) of 12,437 hospital-based confirmed cases (X2 =16.7;
p<0.01). The pooled CFR estimate for non-surgical hospital-based
study sites was 2.4% (1.6–3.3%; 85.9%) compared to 0.2% (0.0–
0.7%; 0.0%) for non-hospital sites. The pooled CRF estimate among
hospital-based sites in Asia was 1.0% (0.6–1.5%; 69.7%) compared
to 6.2% (3.2–10.2%; 83.5%) among hospital-based sites in Africa
(Fig. 2).
Care delays and outcome
Of 84 non-surgical studies, 20 (23.8%) reported a mean or me-
dian duration of fever, illness, or symptoms prior to care, as well
as CFR. Two studies stratified duration of fever, one by age38
and the other by sex,66 for a total of 22 estimates. Of 22 esti-
mates, seven (31.8%) were from Africa,30 , 37 , 59 , 66 , 81 , 122 12 (54.6%)
from Asia,36 , 38 , 41 , 72 , 84 , 96 , 98 , 102 , 105 , 109 , 131 and one each (4.5%) were
from the Americas,97 Europe,101 and Oceania.108 Among all 22 es-
timates, there was a statistically non-significant positive correla-
tion of longer delay in care with increased CFR (r = 0.11; p = 0.64).
Among the 12 estimates from Asia, there was a significant positive
correlation between delay in care and CFR (r = 0.84; p<0.01) and a
non-significant negative correlation between delay in care and CFR
(−0.42; p = 0.35) among seven estimates from Africa. Scatterplots
for delay in care are shown in Supplementary Appendix F.
Among 19 estimates in Asia and Africa, the mean (range) delay
in care was 7.5 (2.0–16.4) days in Asia and 9.4 (6.7–11.0) days in
Africa (p = 0.19). Among the 17 hospital-based estimates reporting
delay in care metrics, the mean (range) delay was 9.3 (5.0–16.4)
days, compared with 5.3 (2.0–10.4) days among five community-
based estimates (p = 0.03).
906
Journal of Infection 81 (2020) 902–910
Asia Europe Oceania All regions
1 2 113
11,973 30 739 16,938
a
79 (40–189) 369.5 (367.3–371.8) 63 (30–163)
1 2 84
10,295 25 739 13,303
90 0 60 250
0.9 0.0 8.1 1.9
0.0 (0.0–1.5) 0.0 (0.0) 8.1 (5.3–10.8) 0.2 (0.0–4.2)
0.9% (0.6–1.3%) 0.8% (0.0–5.7%) 7.2% (0.0–20.4%) 2.0% (1.4–2.8%)
Discussion
Our systematic review of published literature from 1980
through 2020 of predominantly hospitalized typhoid fever patients
demonstrates a substantial prevalence of typhoid complications
and death. We estimated a CFR of 2.0%, with significant variation
by UN region. A considerable proportion of hospitalized patients
with typhoid experienced complications. At the same time, delays
in care, as measured by duration of fever or illness before pre-
sentation, were associated with increased CFR. However, we also
identified significant differences in prevalence of complications and
CFR between community-based and hospital-based studies, sug-
gesting a bias towards poorer outcomes in hospital-based studies.
Among hospital-based non-surgical studies, the CFR of typhoid
fever was significantly higher in Africa compared to Asia. Although
there was no association between delay in care and CFR in Africa,
our ability to detect an association was influenced by fewer data
from Africa compared with Asia, where a statistically significant
positive correlation was identified. Despite Africa comprising 39%
of included study sites, it accounted for only 12% of all confirmed
typhoid cases in our review. The limited data available on con-
firmed typhoid fever cases and smaller sample sizes of African
studies may be due to lower typhoid incidence,23 compounded by
the lack of capacity of many health care centers in Africa to obtain
and perform blood cultures.133–135 Delays were longer in hospital-
based sites compared to community-based sites, and such delays
in diagnosis, appropriate treatment, and management of complica-
tions may contribute to the higher CFR identified among hospital
studies. Others have linked duration of illness prior to hospitaliza-
tion with increased prevalence of typhoid complications.19
Intestinal perforation was a common complication and an im-
portant contributor to typhoid mortality, especially in African stud-
ies where one in five patients with TIP died. A lack of access to
surgical services and resources for post-operative management and
intensive care, if needed, likely contribute to the high CFR seen
among TIP patients.48 , 123 , 133 , 136 The prevalence of TIP as a compli-
cation of typhoid fever in non-surgical studies may be underesti-
mated by our review, as some such studies were often done solely
on medical wards or in hospitals that lacked surgical facilities.
A substantial limitation of our review was the preponderance
of hospital-based studies. This introduced a bias towards higher
prevalence of complications and higher CFR. However, care seeking
behavior for febrile illnesses is not driven exclusively by severity.
In some settings, poor transportation infrastructure, cost of health-
care, and difficulty in obtaining referrals can result in the sick-
est patients not reaching care.5–7 Alternatively, community-based
studies alter the outcome towards the null by enhancing typhoid
diagnosis and management, allowing early treatment before pro-
C.S. Marchello, M. Birkhold and J.A. Crump Journal of Infection 81 (2020) 902–910

Fig. 2. Forest plot of typhoid case fatality ratio among non-surgical hospital-based study sites in Asia and Africa, by year, 1978–2018.

907
C.S. Marchello, M. Birkhold and J.A. Crump
gression to severe and complicated disease.137 We attempted to
limit other selection biases in non-surgical studies by stratifying
by setting type, region and sub-region, and age, and by including
only those that used culture of normally sterile sites to confirm
typhoid fever. Among surgical studies, misclassification of non-
typhoid causes of intestinal perforation as TIP are increasingly rec-
ognized.138 We were limited by the use of intra- and postopera-
tive findings in classifying ileal perforations as TIP. We attempted
to address this limitation by abstracting and presenting the criteria
defining a case of TIP by study. Heterogeneity was high for pooled
estimates of all studies. This was anticipated given the range of
years, study designs, location, and age groups of included studies.
However, when stratified by sub-region and by age group, hetero-
geneity was much lower.
Although our understanding of typhoid fever morbidity and
mortality could be improved with more robust, community-based
active surveillance studies, we demonstrate considerable typhoid
fever morbidity and mortality that could be averted with preven-
tion efforts. TCV represents a means to make rapid gains in pre-
vention of typhoid fever complications and death.
Author contributions
JAC conceived the study. CSM and JAC developed the research
protocol. CSM submitted the review to PROSPERO and performed
the literature search. CSM and MB screened titles and abstracts,
reviewed full texts, and performed data abstraction. JAC resolved
discrepancies and reviewed the final dataset. CSM performed data
analyses and prepared the first manuscript draft. MB prepared the
abstract, ‘Research in Context’, and gave feedback on the first and
subsequent drafts. JAC provided major revisions and comments to
the first draft. All authors contributed to final edits and revisions
prior to submission.
Declaration of Competing Interest
None.
Funding
This work was supported by Bill & Melinda Gates Foundation
(BMGF) [grant OPP1151153], to JAC and CSM. JAC also received sup-
port from BMGF [grant numbers OPP1125993 and OPP1158210],
the US National Institutes of Health [grant number R01AI121378],
and the New Zealand Health Research Council through the e-ASIA
Joint Research Program [grant number 16/697]. MB received sup-
port from the US National Institutes of Health [grant number T32
DK067872].
Role of the funder
The funders of the study had no role in study design, data col-
lection, data analysis, data interpretation, or writing of the report.
The corresponding author had full access to all the data in the
study and had final responsibility for the decision to submit for
publication.
Acknowledgments
The authors would like to thank Dr Leonardo Martinez, Stanford
University, for his assistance in translating articles in Spanish text.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jinf.2020.10.030.
908
Journal of Infection 81 (2020) 902–910
References
1. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med
2002;347(22):1770–82.
2. Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, clini-
cal presentation, laboratory diagnosis, antimicrobial resistance, and antimi-
crobial management of invasive Salmonella infections. Clin Microbiol Rev
2015;28(4):901–37.
3. Wain J, Hendriksen RS, Mikoleit ML, Keddy KH, Ochiai RL. Typhoid fever. The
Lancet 2015;385(9973):1136–45.
4. Antillon M, Saad NJ, Baker S, Pollard AJ, Pitzer VE. The relationship between
blood sample volume and diagnostic sensitivity of blood culture for typhoid
and paratyphoid fever: A systematic review and meta-analysis. J Infect Dis
2018;218(suppl_4):S255–SS67.
5. Snavely ME, Maze MJ, Muiruri C, Ngowi L, Mboya F, Beamesderfer J, et al. So-
ciocultural and health system factors associated with mortality among febrile
inpatients in Tanzania: a prospective social biopsy cohort study. BMJ Glob
Health 2018;3(1):e0 0 0507.
6. Snavely ME, Oshosen M, Msoka EF, Karia FP, Maze MJ, Blum LS, et al. "If you
have no money, you might die": A qualitative study of sociocultural and health
system barriers to care for decedent febrile inpatients in northern Tanzania.
Am J Trop Med Hyg 2020.
7. Moyer CA, Johnson C, Kaselitz E, Aborigo R. Using social autopsy to understand
maternal, newborn, and child mortality in low-resource settings: a systematic
review of the literature. Glob Health Action 2017;10(1):1413917.
8. Birkhold M, Coulibaly Y, Coulibaly O, Dembélé P, Kim DS, Sow S, et al. Mor-
bidity and mortality of typhoid intestinal perforation among children in Sub-
Saharan Africa 1995-2019: A scoping review. World J Surg 2020.
9. Mahajan G, Kotru M, Sharma R, Sharma S. Usefulness of histopathological ex-
amination in nontraumatic perforation of small intestine. J Gastrointest Surg
2011;15(10):1837–41.
10. Crump JA. Progress in typhoid fever epidemiology. Clin Infect Dis 2019;68(Sup-
plement_1):S4–9.
11. Pitzer VE, Feasey NA, Msefula C, Mallewa J, Kennedy N, Dube Q, et al. Math-
ematical modeling to assess the drivers of the recent emergence of typhoid
fever in Blantyre, Malawi. Clin Infect Dis. 2015;61(suppl_4):S251–S2S8.
12. Luby SP, Faizan MK, Fisher-Hoch SP, Syed A, Mintz ED, Bhutta ZA, et al. Risk
factors for typhoid fever in an endemic setting, Karachi, Pakistan. Epidemiol
Infect. 1998;120(2):129–38.
13. World Health O. Typhoid vaccines: WHO position paper, March 2018 - Recom-
mendations. Vaccine 2019;37(2):214–16.
14. Pitzer VE, Bowles CC, Baker S, Kang G, Balaji V, Farrar JJ, et al. Predict-
ing the impact of vaccination on the transmission dynamics of typhoid in
South Asia: a mathematical modeling study. PLOS Neglected Tropical Diseases
2014;8(1):e2642.
15. World Health Organization (WHO). Typhoid vaccine prequalified. 3 January
2018.
16. Buckle GC, Walker CLF, Black RE. Typhoid fever and paratyphoid fever: System-
atic review to estimate global morbidity and mortality for 2010. J Glob Health.
2012;2(1):010401.
17. Mogasale V, Maskery B, Ochiai RL, Lee JS, Mogasale VV, Ramani E, et al. Burden
of typhoid fever in low-income and middle-income countries: a systematic,
literature-based update with risk-factor adjustment. The Lancet Global health
2014;2(10):e570–ee80.
18. Pieters Z, Saad NJ, Antillón M, Pitzer VE, Bilcke J. Case fatality rate of enteric
fever in endemic countries: A systematic review and meta-analysis. Clin Infect
Dis 2018;67(4):628–38.
19. Cruz Espinoza LM, McCreedy E, Holm M, Im J, Mogeni OD, Parajulee P,
et al. Occurrence of Typhoid Fever Complications and Their Relation to Du-
ration of Illness Preceding Hospitalization: A Systematic Literature Review and
Meta-analysis. Clin Infect Dis 2019;69(Suppl 6):S435–SS48.
20. Butler T, Knight J, Nath SK, Speelman P, Roy SK, Azad MA. Typhoid fever com-
plicated by intestinal perforation: a persisting fatal disease requiring surgical
management. Rev Infect Dis 1985;7(2):244–56.
21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med
2009;6(7).
22. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan—a web and
mobile app for systematic reviews. Systematic Reviews 2016;5(1):210.
23. Marchello CS, Hong CY, Crump JA. Global typhoid fever incidence: a
systematic review and meta-analysis. Clin Infect Dis 2019;68(Supple-
ment_2):S105–SS16.
24. United Nations Statistics D. Standard country or area codes for statistical use
(M49). 2020.
25. Abantanga FA. Complications of typhoid perforation of the ileum in children
after surgery. East Afr Med J 1997;74(12):800–2.
26. Abdool Gaffar MS, Seedat YK, Coovadia YM, Khan Q. The white cell count in
typhoid fever. Trop Geogr Med 1992;44(1-2):23–7.
27. Abraham G, Teklu B. Typhoid fever: clinical analysis of 50 Ethiopian patients.
Ethiop Med J 1981;19(2):41–6.
28. Abucejo PE, Capeding MR, Lupisan SP, Arcay J, Sombrero LT, Ruutu P,
et al. Blood culture confirmed typhoid fever in a provincial hospital in the
Philippines. Southeast Asian J Trop Med Public Health 2001;32(3):531–6.
29. Adesunkanmi AR, Ajao OG. The prognostic factors in typhoid ileal perforation:
a prospective study of 50 patients. J R Coll Surg Edinb 1997;42(6):395–9.
C.S. Marchello, M. Birkhold and J.A. Crump
30. Afifi S, Earhart K, Azab MA, Youssef FG, El Sakka H, Wasfy M, et al. Hospi-
tal-based surveillance for acute febrile illness in Egypt: a focus on communi-
ty-acquired bloodstream infections. Am J Trop Med Hyg 2005;73(2):392–9.
31. Agu K, Nzegwu M, Obi E. Prevalence, morbidity, and mortality patterns of ty-
phoid ileal perforation as seen at the University of Nigeria Teaching Hospital
Enugu Nigeria: an 8-year review. World J Surg 2014;38(10):2514–18.
32. Ahmad Hatib NA, Chong CY, Thoon KC, Tee NW, Krishnamoorthy SS, Tan NW.
Enteric fever in a tertiary paediatric hospital: A retrospective six-year review.
Ann Acad Med Singap 2016;45(7):297–302.
33. Ali G, Rashid S, Kamli MA, Shah PA, Allaqaband GQ. Spectrum of neuropsy-
chiatric complications in 791 cases of typhoid fever. Trop Med Int Health
1997;2(4):314–18.
34. Atamanalp SS, Aydinli B, Ozturk G, Oren D, Basoglu M, Yildirgan MI.
Typhoid intestinal perforations: twenty-six year experience. World J Surg
2007;31(9):1883–8.
35. Aziz S, Malik L. Emergence of multi-resistant enteric infection in a paediatric
unit Of Karachi, Pakistan. J Pak Med Assoc 2018;68(12):1848–50.
36. Bhutta ZA. Impact of age and drug resistance on mortality in typhoid fever.
Arch Dis Child 1996;75(3):214–17.
37. Breiman RF, Cosmas L, Njuguna H, Audi A, Olack B, Ochieng JB, et al. Popula-
tion-based incidence of typhoid fever in an urban informal settlement and a
rural area in Kenya: implications for typhoid vaccine use in Africa. PLoS ONE
2012 2012;7(1):e29119.
38. Brooks WA, Hossain A, Goswami D, Nahar K, Alam K, Ahmed N, et al. Bac-
teremic typhoid fever in children in an urban slum, Bangladesh. Emerging In-
fect Dis. 2005;11(2):326–9.
39. Carmeli Y, Raz R, Schapiro JM, Alkan M. Typhoid fever in Ethiopian immi-
grants to Israel and native-born Israelis: a comparative study. Clin Infect Dis
1993;16(2):213–15.
40. Chalya PL, Mabula JB, Koy M, Kataraihya JB, Jaka H, Mshana SE, et al. Typhoid
intestinal perforations at a University teaching hospital in Northwestern Tan-
zania: A surgical experience of 104 cases in a resource-limited setting. World J
Emerg Surg 2012;7:4.
41. Chandra R, Srinivasan S, Nalini P, Rao RS. Multidrug resistant enteric fever. J
Trop Med Hyg 1992;95(4):284–7.
42. Chansamouth V, Thammasack S, Phetsouvanh R, Keoluangkot V, Moore CE,
Blacksell SD, et al. The aetiologies and impact of fever in pregnant inpatients
in Vientiane, Laos. PLOS Neglected Tropical Diseases 2016;10(4):e0 0 04577.
43. Chaudhary P, Kumar R, Munjewar C, Bhadana U, Ranjan G, Gupta S, et al. Ty-
phoid ileal perforation: a 13-year experience. Healthc Low Resour Settings
2015;3(1).
44. Chen YH, Chen TP, Tsai JJ, Hwang KP, Lu PL, Cheng HH, et al. Epidemiological
study of human salmonellosis during 1991-1996 in southern Taiwan. Kaohsiung
J Med Sci 1999;15(3):127–36.
45. Chheng K, Carter MJ, Emary K, Chanpheaktra N, Moore CE, Stoesser N, et al. A
prospective study of the causes of febrile illness requiring hospitalization in
children in Cambodia. PLoS ONE 2013;8(4):e60634.
46. Choo KE, Razif A, Ariffin WA, Sepiah M, Gururaj A. Typhoid fever in hospital-
ized children in Kelantan, Malaysia. Ann Trop Paediatr 1988;8(4):207–12.
47. Contreras R, Ferreccio C, Sotomayor V, Astroza L, Berríos G, Ortiz E, et al. [Ty-
phoid fever in school children: by what measures is the modification of the
clinical course due to oral vaccination?]. Rev Med Chil 1992;120(2):134–41.
48. Conventi R, Pellis G, Arzu G, Nsubuga JB, Gelmini R. Intestinal perforation due
to typhoid fever in Karamoja (Uganda). Ann Ital Chir 2018;89:138–48.
49. Crump JA, Ramadhani HO, Morrissey AB, Msuya LJ, Yang L-Y, Chow S-C,
et al. Invasive bacterial and fungal infections among hospitalized HIV-infected
and HIV-uninfected children and infants in northern Tanzania. Trop Med Int
Health 2011;16(7):830–7.
50. Crump JA, Ramadhani HO, Morrissey AB, Saganda W, Mwako MS, Yang L-Y,
et al. Invasive bacterial and fungal infections among hospitalized HIV-infected
and HIV-uninfected adults and adolescents in northern Tanzania. Clin Infect Dis
2011;52(3):341–8.
51. Dheer G, Kundra S, Singh T. Clinical and laboratory profile of enteric fever in
children in northern India. Trop Doct. 2012;42(3):154–6.
52. Dworkin J, Saeed R, Mykhan H, Kanan S, Farhad D, Ali KO, et al. Burden of
typhoid fever in Sulaimania. Iraqi Kurdistan. Int J Infect Dis. 2014;27:70–3.
53. Edino ST, Mohammed AZ, Uba AF, Sheshe AA, Anumah M, Ochicha O,
et al. Typhoid enteric perforation in north western Nigeria. Niger J Med
2004;13(4):345–9.
54. Ganesh R, Janakiraman L, Vasanthi T, Sathiyasekeran M. Profile of typhoid
fever in children from a tertiary care hospital in Chennai-South India. Indian J
Pediatr 2010;77(10):1089–92.
55. Gbadoé AD, Lawson-Evi K, Dagnra AY, Guédénon K, Géraldo A, Djadou E,
et al. [Pediatric salmonellosis at the Tokoin’s teaching hospital, Lomé (Togo)].
Med Mal Infect 2008;38(1):8–11.
56. Gedik E, Girgin S, Taçyildiz IH, Akgün Y. Risk factors affecting morbidity in
typhoid enteric perforation. Langenbecks Arch Surg 2008;393(6):973–7.
57. González Ojeda A, Pérez Ríos A, Rodríguez M, de la Garza Villaseñor L. [The
surgical complications of typhoid fever: a report of 10 cases]. Rev Gastroenterol
Mex 1991;56(2):77–81.
58. Gordon MA, Walsh AL, Chaponda M, Soko D, Mbvwinji M, Molyneux ME,
et al. Bacteraemia and mortality among adult medical admissions in Malaw-
i–predominance of non-Typhi Salmonellae and Streptococcus pneumoniae. J In-
fect 2001;42(1):44–9.
59. Green SD, Cheesbrough JS. Salmonella bacteraemia among young children at a
rural hospital in western Zaire. Ann Trop Paediatr 1993;13(1):45–53.
909
Journal of Infection 81 (2020) 902–910
60. Guiraud I, Post A, Diallo SN, Lompo P, Maltha J, Thriemer K, et al. Pop-
ulation-based incidence, seasonality and serotype distribution of invasive
salmonellosis among children in Nanoro, rural Burkina Faso. PLoS ONE 2017
2017;12(7):e0178577.
61. Harichandran D, Dinesh KR. Antimicrobial susceptibility profile, treatment out-
come and serotype distribution of clinical isolates of Salmonella enterica sub-
species enterica: a 2-year study from Kerala. South India. Infect Drug Resist.
2017 2017;10:97–101.
62. Hosoglu S, Aldemir M, Akalin S, Geyik MF, Tacyildiz IH, Loeb M. Risk fac-
tors for enteric perforation in patients with typhoid Fever. Am J Epidemiol
2004;160(1):46–50.
63. Kadhiravan T, Wig N, Kapil A, Kabra SK, Renuka K, Misra A. Clinical out-
comes in typhoid fever: adverse impact of infection with nalidixic acid-resis-
tant Salmonella Typhi. BMC Infect Dis 2005;5:37.
64. Keddy KH, Sooka A, Smith AM, Musekiwa A, Tau NP, Klugman KP, et al. Ty-
phoid fever in South Africa in an endemic HIV setting. PLoS ONE 2016
2016;11(10):e0164939.
65. Keenan JP, Hadley GP. The surgical management of typhoid perforation in chil-
dren. Br J Surg 1984;71(12):928–9.
66. Khan M, Coovadia YM, Connolly C, Sturm AW. Influence of sex on clinical fea-
tures, laboratory findings, and complications of typhoid fever. Am J Trop Med
Hyg 1999;61(1):41–6.
67. Khan MI, Soofi SB, Ochiai RL, Khan MJ, Sahito SM, Habib MA, et al. Epidemiol-
ogy, clinical presentation, and patterns of drug resistance of Salmonella Typhi
in Karachi, Pakistan. J Infect Dev Ctries. 2012;6(10):704–14.
68. Kurlberg G, Frisk B. Factors reducing mortality in typhoid ileal perforation.
Trans R Soc Trop Med Hyg 1991;85(6):793–5.
69. Laditan AA, Alausa KO. Problems in the clinical diagnosis of typhoid fever in
children in the tropics. Ann Trop Paediatr 1981;1(3):191–5.
70. Lepage P, Bogaerts J, Van Goethem C, Ntahorutaba M, Nsengumuremyi F, Hiti-
mana DG, et al. Community-acquired bacteraemia in African children. Lancet
1987;1(8548):1458–61.
71. Leung DT, Bogetz J, Itoh M, Ganapathi L, Pietroni MAC, Ryan ET, et al. Factors
associated with encephalopathy in patients with Salmonella enterica serotype
Typhi bacteremia presenting to a diarrheal hospital in Dhaka. Bangladesh. Am
J Trop Med Hyg. 2012;86(4):698–702.
72. Limpitikul W, Henpraserttae N, Saksawad R, Laoprasopwattana K. Typhoid out-
break in Songkhla, Thailand 2009-2011: clinical outcomes, susceptibility pat-
terns, and reliability of serology tests. PLoS ONE 2014;9(11):e111768.
73. Lin FY, Vo AH, Phan VB, Nguyen TT, Bryla D, Tran CT, et al. The epidemiology
of typhoid fever in the Dong Thap Province, Mekong Delta region of Vietnam.
Am J Trop Med Hyg. 20 0 0;62(5):644–8.
74. Magsi AM, Iqbal M, Khan S, Parveen S, Khan MI, Shamim M. Frequency, pre-
sentation and outcomes of typhoid ileal perforation. Indo American Journal of
Pharmaceutical Sciences 2019;6(6):1–5.
75. Malik AS. Complications of bacteriologically confirmed typhoid fever in chil-
dren. J Trop Pediatr 2002;48(2):102–8.
76. Maltha J, Guiraud I, Kaboré B, Lompo P, Ley B, Bottieau E, et al. Frequency of
severe malaria and invasive bacterial infections among children admitted to a
rural hospital in Burkina Faso. PLoS ONE 2014;9(2):e89103.
77. Mathura KC, Gurubacharya DL, Shrestha A, Pant S, Basnet P, Karki DB. Clinical
profile of typhoid patients. Kathmandu Univ Med J (KUMJ) 2003;1(2):135–7.
78. Mishra S, Patwari AK, Anand VK, Pillai PK, Aneja S, Chandra J, et al. A clinical
profile of multidrug resistant typhoid fever. Indian Pediatr 1991;28(10):1171–4.
79. Mock C, Visser L, Denno D, Maier R. Aggressive fluid resuscitation and broad
spectrum antibiotics decrease mortality from typhoid ileal perforation. Trop
Doct. 1995;25(3):115–17.
80. Mock CN, Amaral J, Visser LE. Improvement in survival from typhoid ileal per-
foration. Results of 221 operative cases. Ann Surg 1992;215(3):244–9.
81. Mtove G, Amos B, von Seidlein L, Hendriksen I, Mwambuli A, Kimera J,
et al. Invasive salmonellosis among children admitted to a rural Tanzanian
hospital and a comparison with previous studies. PLoS ONE 2010;5(2):e9244.
82. Mukherjee P, Mukherjee S, Dalal BK, Haldar KK, Ghosh E, Pal TK. Some
prospective observations on recent outbreak of typhoid fever in West Bengal.
J Assoc Physicians India 1991;39(6):445–8.
83. Muthumbi E, Morpeth SC, Ooko M, Mwanzu A, Mwarumba S, Mturi N, et al. In-
vasive salmonellosis in Kilifi, Kenya. Clin Infect Dis. 2015;61(Suppl 4):S290–301.
84. Naheed A, Ram PK, Brooks WA, Hossain MA, Parsons MB, Talukder KA,
et al. Burden of typhoid and paratyphoid fever in a densely populated urban
community, Dhaka, Bangladesh. Int J Infect Dis. 2010;14(Suppl 3):e93–9.
85. Ndayizeye L, Ngarambe C, Smart B, Riviello R, Majyambere JP, Rickard J. Peri-
tonitis in Rwanda: Epidemiology and risk factors for morbidity and mortality.
Surgery 2016;160(6):1645–56.
86. Nesbitt A, Mirza NB. Salmonella septicaemias in Kenyan children. J Trop Pediatr
1989;35(1):35–9.
87. Nilsson E, Olsson S, Regner S, Polistena A, Ali A, Dedey F, et al. Surgical inter-
vention for intestinal typhoid perforation. G Chir 2019;40(2):105–11.
88. Nuhu A, Dahwa S, Hamza A. Operative management of typhoid ileal perfora-
tion in children. Afr J Paediatr Surg 2010;7(1):9–13.
89. Obaro S, Lawson L, Essen U, Ibrahim K, Brooks K, Otuneye A, et al. Community
acquired bacteremia in young children from central Nigeria–a pilot study. BMC
Infect Dis 2011;11:137.
90. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Ag-
tini MD, et al. A study of typhoid fever in five Asian countries: disease burden
and implications for controls. Bull World Health Organ 2008;86(4):260–8.
C.S. Marchello, M. Birkhold and J.A. Crump
91. Oh HM, Masayu Z, Chew SK. Typhoid fever in hospitalized children in Singa-
pore. J Infect 1997;34(3):237–42.
92. Oheneh-Yeboah M. Postoperative complications after surgery for typhoid ileal
perforation in adults in Kumasi. West Afr J Med 2007;26(1):32–6.
93. Ollé-Goig JE, Ruiz L. Typhoid fever in rural Haiti. Bull Pan Am Health Organ
1993 1993;27(4):382–8.
94. Osifo OD, Ogiemwonyi SO. Typhoid ileal perforation in children in Benin city.
Afr J Paediatr Surg 2010;7(2):96–100.
95. Ouedraogo S, Ouangre E, Zida M. Epidemiological, clinical, and therapeutic fea-
tures of typhoid intestinal perforation in a rural environment of Burkina Faso.
Med Sante Trop 2017;27(1):67–70.
96. Owais A, Sultana S, Zaman U, Rizvi A, Zaidi AKM. Incidence of typhoid bac-
teremia in infants and young children in southern coastal Pakistan. Pediatr In-
fect Dis J 2010;29(11):1035–9.
97. Palacios Malmaceda PG, Vela Acosta JJ, Gutiérez Arrasco W. [Typhoid fever in
children under 2 years of age]. Bol Med Hosp Infant Mex 1981;38(3):473–83.
98. Parry CM, Thompson C, Vinh H, Chinh NT, Phuong LT, Ho VA, et al. Risk fac-
tors for the development of severe typhoid fever in Vietnam. BMC Infect Dis
2014;14:73.
99. Petersiel N, Shresta S, Tamrakar R, Koju R, Madhup S, Shresta A, et al. The epi-
demiology of typhoid fever in the Dhulikhel area, Nepal: A prospective cohort
study. PLoS ONE 2018;13(9):e0204479.
100. Phoba MF, De Boeck H, Ifeka BB, Dawili J, Lunguya O, Vanhoof R, et al. Epi-
demic increase in Salmonella bloodstream infection in children, Bwamanda, the
Democratic Republic of Congo. Eur J Clin Microbiol Infect Dis 2014;33(1):79–87.
101. Prieto López I, de la Fuente Aguado J, González Díaz I, López Myragalla I,
Martínez Vázquéz C, Sopeña Pérez-Argüelles B, et al. [Infection by Salmonella
Typhi in the southern area of Ponteverde]. An Med Interna 1994;11(2):71–3.
102. Punjabi NH, Taylor WRJ, Murphy GS, Purwaningsih S, Picarima H, Sisson J,
et al. Etiology of acute, non-malaria, febrile illnesses in Jayapura, northeast-
ern Papua, Indonesia. Am J Trop Med Hyg. 2012;86(1):46–51.
103. Qamar FN, Yousafzai MT, Sultana S, Baig A, Shakoor S, Hirani F, et al. A
retrospective study of laboratory-based enteric fever surveillance, Pakistan,
2012-2014. J Infect Dis 2018 2018;218(suppl_4):S201–S2S5.
104. Rao PS, Rajashekar V, Varghese GK, Shivananda PG. Emergence of mul-
tidrug-resistant Salmonella Typhi in rural southern India. Am J Trop Med Hyg
1993;48(1):108–11.
105. Rasaily R, Dutta P, Saha MR, Mitra U, Lahiri M, Pal SC. Multi-drug resistant
typhoid fever in hospitalised children. Clinical, bacteriological and epidemio-
logical profiles. Eur J Epidemiol 1994;10(1):41–6.
106. Rodrigues C, Mehta A, Mehtar S, Blackmore PH, Hakimiyan A, Fazalbhoy N,
et al. Chloramphenicol resistance in Salmonella Typhi. Report from Bombay. J
Assoc Physicians India 1992;40(11):729–32.
107. Rogerson SJ, Spooner VJ, Smith TA, Richens J. Hydrocortisone in chlorampheni-
col-treated severe typhoid fever in Papua New Guinea. Trans R Soc Trop Med
Hyg 1991;85(1):113–16.
108. S AG, Parry CM, Crump JA, Rosa V, Jenney A, Naidu R, et al. A retrospective
study of patients with blood culture-confirmed typhoid fever in Fiji during
2014-2015: epidemiology, clinical features, treatment and outcome. Trans R Soc
Trop Med Hyg 2019;113(12):764–70.
109. Saeed N, Usman M, Khan EA. An overview of extensively drug-resis-
tant Salmonella Typhi from a tertiary care hospital in Pakistan. Cureus
2019;11(9):e5663.
110. Saha S, Islam MS, Sajib MSI, Saha S, Uddin MJ, Hooda Y, et al. Epidemiology of
typhoid and paratyphoid: Implications for vaccine policy. Clin Infect Dis 2019
2019;68(Suppl 2):S117–SS23.
111. Seçmeer G, Kanra G, Cemeroğlu AP, Ozen H, Ceyhan M, Ecevit Z. Salmonella Ty-
phi infections. A 10-year retrospective study. Turk J Pediatr. 1995;37(4):339–41.
112. Shahunja KM, Leung DT, Ahmed T, Bardhan PK, Ahmed D, Qadri F, et al. Fac-
tors associated with non-typhoidal Salmonella bacteremia versus typhoidal
Salmonella bacteremia in patients presenting for care in an urban di-
arrheal disease hospital in Bangladesh. PLOS Neglected Tropical Diseases
2015;9(9):e0 0 04066.
113. Shetty AK, Mital SR, Bahrainwala AH, Khubchandani RP, Kumta NB. Typhoid
hepatitis in children. J Trop Pediatr 1999;45(5):287–90.
114. Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, et al. Typhoid fever
in children aged less than 5 years. Lancet 1999;354(9180):734–7.
910
Journal of Infection 81 (2020) 902–910
115. Sucindar M, Kumaran SS. Profile of culture positive enteric fever in children
admitted in a tertiary care hospital. Journal of Evolution of Medical and Dental
Sciences 2017;6(88):6112–17.
116. Sulaiman K, Sarwari AR. Culture-confirmed typhoid fever and pregnancy. Int J
Infect Dis 2007;11(4):337–41.
117. Sur D, Barkume C, Mukhopadhyay B, Date K, Ganguly NK, Garrett D. A retro-
spective review of hospital-based data on enteric fever in India, 2014-2015. J
Infect Dis 2018 2018;218(suppl_4):S206–SS13.
118. Sur D, von Seidlein L, Manna B, Dutta S, Deb AK, Sarkar BL, et al. The malaria
and typhoid fever burden in the slums of Kolkata, India: data from a prospec-
tive community-based study. Trans R Soc Trop Med Hyg 20 06;10 0(8):725–33.
119. Tade AO, Ayoade BA, Olawoye AA. Pattern of presentation and management of
typhoid intestinal perforation in Sagamu, South-West Nigeria: a 15 year study.
Niger J Med. 2008;17(4):387–90.
120. Talabi AO, Etonyeaku AC, Sowande OA, Olowookere SA, Adejuyigbe O. Predic-
tors of mortality in children with typhoid ileal perforation in a Nigerian ter-
tiary hospital. Pediatr Surg Int 2014;30(11):1121–7.
121. Thisyakorn U, Mansuwan P, Taylor DN. Typhoid and paratyphoid fever in 192
hospitalized children in Thailand. Am J Dis Child 1987;141(8):862–5.
122. Topley JM. Mild typhoid fever. Arch Dis Child 1986;61(2):164–7.
123. Uba AF, Chirdan LB, Ituen AM, Mohammed AM. Typhoid intestinal perfora-
tion in children: a continuing scourge in a developing country. Pediatr Surg Int
2007;23(1):33–9.
124. Ugochukwu AI, Amu OC, Nzegwu MA. Ileal perforation due to typhoid fever -
review of operative management and outcome in an urban centre in Nigeria.
Int J Surg 2013;11(3):218–22.
125. Ugwu BT, Yiltok SJ, Kidmas AT, Opaluwa AS. Typhoid intestinal perforation in
north central Nigeria. West Afr J Med 2005;24(1):1–6.
126. Usang UE, Inyang AW, Nwachukwku IE, Emehute J-DC. Typhoid perforation
in children: an unrelenting plague in developing countries. J Infect Dev Ctries
2017;11(10):747–52.
127. Vala S, Shah U, Ahmad SA, Scolnik D, Glatstein M. Resistance patterns of ty-
phoid Fever in children: A longitudinal community-based study. Am J Ther
2016;23(5):e1151–4.
128. van den Bergh ET, Gasem MH, Keuter M, Dolmans MV. Outcome in three
groups of patients with typhoid fever in Indonesia between 1948 and 1990.
Trop Med Int Health. 1999;4(3):211–15.
129. van der Werf TS, Cameron FS. Typhoid perforations of the ileum. A review of
59 cases, seen at Agogo Hospital, Ghana, between 1982 and 1987. Trop Geogr
Med. 1990;42(4):330–6.
130. Weeramanthri TS, Corrah PT, Mabey DC, Greenwood BM. Clinical experience
with enteric fever in The Gambia, West Africa 1981-1986. J Trop Med Hyg
1989;92(4):272–5.
131. Wongsawat J, Pancharoen C, Thisyakorn U. Typhoid fever in children:
experience in King Chulalongkorn Memorial Hospital. J Med Assoc Thai
2002;85(12):1247–50.
132. Yu AT, Amin N, Rahman MW, Gurley ES, Rahman KM, Luby SP. Case-fatality
ratio of blood culture-confirmed typhoid fever in Dhaka, Bangladesh. J Infect
Dis. 2018 2018;218(suppl_4):S222–S2S6.
133. GlobalSurg C. Management and outcomes following surgery for gastrointesti-
nal typhoid: An international, prospective, multicentre cohort study. World J
Surg 2018;42(10):3179–88.
134. Anyanwu L-J, Mohammad A, Abdullahi L, Farinyaro A, Obaro S. Determinants of
postoperative morbidity and mortality in children managed for typhoid intesti-
nal perforation in Kano Nigeria. Journal of Pediatric Surgery 2018;53(4):847–52.
135. Abantanga FA, Nimako B, Amoah M. Perforations of the gut in children as a
result of enteric fever: A 5-years single institutional review. Annals of Pediatric
Surgery 2009;5(1):1–10.
136. Ekenze SO, Anyanwu PA, Ezomike UO, Oguonu T. Profile of pediatric abdominal
surgical emergencies in a developing country. Int Surg 2010;95(4):319–24.
137. Crump JA, Youssef FG, Luby SP, Wasfy MO, Rangel JM, Taalat M, et al. Esti-
mating the incidence of typhoid fever and other febrile illnesses in developing
countries. Emerging Infect Dis 2003;9(5):539–44.
138. Poornima R, Venkatesh KL, Nirmala MVG, Hassan N. Clinicopathological study
of Ileal perforation: study in tertiary center. Int Surg J. 2017;4(2):543.