Parry et al.

BMC Infectious Diseases 2014, 14:73

http://www.biomedcentral.com/1471-2334/14/73

RESEARCH ARTICLE

Open Access

Risk factors for the development of severe

typhoid fever in Vietnam
Christopher M Parry1,2*, Corinne Thompson1,3, Ha Vinh4, Nguyen Tran Chinh4, Le Thi Phuong5, Vo Anh Ho5,
Tran Tinh Hien1,4, John Wain1,6, Jeremy J Farrar1,3 and Stephen Baker1,3,7

Abstract
Background: Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. Age,
sex, prolonged duration of illness, and infection with an antimicrobial resistant organism have been proposed risk
factors for the development of severe disease or fatality in typhoid fever.
Methods: We analysed clinical data from 581 patients consecutively admitted with culture confirmed typhoid fever
to two hospitals in Vietnam during two periods in 19931995 and 19971999. These periods spanned a change in
the antimicrobial resistance phenotypes of the infecting organisms i.e. fully susceptible to standard antimicrobials,
resistance to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole (multidrug resistant, MDR), and
intermediate susceptibility to ciprofloxacin (nalidixic acid resistant). Age, sex, duration of illness prior to admission,
hospital location and the presence of MDR or intermediate ciprofloxacin susceptibility in the infecting organism
were examined by logistic regression analysis to identify factors independently associated with severe typhoid at
the time of hospital admission.
Results: The prevalence of severe typhoid was 15.5% (90/581) and included: gastrointestinal bleeding (43; 7.4%);
hepatitis (29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12; 2.1%); intestinal perforation (6; 1.0%); haemodynamic
shock (5; 0.9%), and death (3; 0.5%). Severe disease was more common with increasing age, in those with a longer
duration of illness and in patients infected with an organism exhibiting intermediate susceptibility to ciprofloxacin.
Notably an MDR phenotype was not associated with severe disease. Severe disease was independently associated
with infection with an organism with an intermediate susceptibility to ciprofloxacin (AOR 1.90; 95% CI 1.18-3.07;
p = 0.009) and male sex (AOR 1.61 (1.00-2.57; p = 0.035).
Conclusions: In this group of patients hospitalised with typhoid fever infection with an organism with intermediate
susceptibility to ciprofloxacin was independently associated with disease severity. During this period many patients
were being treated with fluoroquinolones prior to hospital admission. Ciprofloxacin and ofloxacin should be used
with caution in patients infected with S. Typhi that have intermediate susceptibility to ciprofloxacin.
Keywords: Salmonella enterica serovar Typhi, Severe typhoid, Antimicrobial resistance, Multidrug resistance,
Intermediate ciprofloxacin susceptibility

* Correspondence: [email protected]
1
Wellcome Trust Major Overseas Programme, Oxford University Clinical
Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho
Chi Minh City, Vietnam
2
Department of Clinical Sciences, Liverpool School of Tropical Medicine,
Pembroke Place, Liverpool, L3 5QA, UK
Full list of author information is available at the end of the article
2014 Parry et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication
waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise
stated.

Parry et al. BMC Infectious Diseases 2014, 14:73

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Background
Typhoid fever, caused by Salmonella enterica serovar Typhi
(S. Typhi) and Salmonella enterica serovar Paratyphi A
(S. Paratyphi A), has been estimated to cause approximately
27 million infections each year worldwide [1]. The disease
is common in parts of Asia particularly among children [2].
Fatality rates in the pre-antimicrobial era ranged from 7
26% of hospitalised cases [3-5]. The introduction of chloramphenicol, and subsequently, other antimicrobial agents,
led to a marked reduction in the occurrence of severe and
fatal disease [4,5]. Despite improvements in treatment,
some patients, particularly the very young and elderly, and
those receiving inadequate antimicrobial therapy, continue
to develop severe and life threatening disease [5-7].
Since the early1990s multidrug-resistant (MDR) strains
of S. Typhi and S. Paratyphi A (resistant to chloramphenicol, trimethoprim/sulphamethoxazole and ampicillin)
have not only caused epidemics, but have become endemic
across some parts of Asia [2,8]. Similarly, isolates of S.
Typhi and S. Paratyphi A with intermediate susceptibility to
ciprofloxacin (formerly called decreased susceptibility and
indicated in the laboratory by resistance to nalidixic acid or
with a minimum inhibitory concentration (MIC) between
0.1 and 0.5 g/mL against ciprofloxacin) are now common
in endemic areas and in imported infections in industrialised countries [8,9]. Intermediate susceptibility to ciprofloxacin has been associated with longer fever clearance
time and treatment failures when either ciprofloxacin or
ofloxacin are used for treatment [10,11].
Severe or fatal typhoid fever has been reported to be associated with extremes of age, female and male sex and
prolonged illness [4,6,7,12-16]. Infection with antimicrobial resistant isolates (MDR and nalidixic acid resistant)
has also been proposed to correlate with the development
of severe infection [6,16,17]. The association of antimicrobial resistance with severe disease may result from a delay
in the initiation of appropriate antimicrobial therapy, but
may also potentially be the result of a genotypic association that increases the pathogenic potential of infecting
organism.
We aimed to determine microbiological and clinical factors associated with increased risk of severe typhoid fever,
hypothesising that the changing antimicrobial resistance
phenotypes throughout the selected study periods in
Vietnam were associated with a shift in disease severity.
We used a logistic regression model to assess the influence
of age, sex, duration of illness prior to hospital admission,
and the antimicrobial resistance profile of the infecting isolate on the clinical severity of typhoid.
Methods
Patients studied

This analysis was performed on data from patients at

two hospitals in southern Vietnam between May 1993-

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July 1995 and April 1997-February 1999. The two hospitals were The Hospital for Tropical Diseases (HTD) in
Ho Chi Minh City (HCMC) and Dong Thap Provincial
Hospital (DTPH) in Cao Lanh, Dong Thap Province.
HTD is a 500-bed infectious disease hospital with a
catchment area encompassing HCMC and is a referral
hospital for the surrounding province and DTPH is a
400-bed general hospital, serving the population of Cao
Lanh and is a referral centre for the province of Dong
Thap in the Mekong Delta. During these time periods
consecutive patients with blood or bone marrow culture
confirmed typhoid were included in antimicrobial treatment, diagnostic, pathophysiology and surveillance
studies at the two hospitals [17-27]. There were only a
small number of patients with paratyphoid and they
were excluded from this analysis.
Each individual study independently received approval
from the scientific and ethical committee of the respective hospital prior to the initiation of the study. Patients,
or the parent or guardian for children, gave informed
verbal consent before entry into the studies. The studies
were conducted in accordance with the Declaration of
Helsinki. This was a post-hoc analysis of the existing
prospectively collected anonymised patient and laboratory data from these studies. No additional data collection or laboratory analysis was performed.
Clinical data

Demographic, clinical and laboratory data was prospectively gathered on standardised case report forms at the
time of hospital admission. For continuous variables
patients were categorised according to the presence with
in the first 24 hours of admission of; a peak temperature
of > 40.0C, a systolic blood pressure of < 90 mmHg, a
haematocrit of < 30%, an elevated white cell count (defined
as > 15 109/L), a low white cell count (defined as < 4
109/L), a low platelet count (defined as < 100 109/L), an
elevated SGOT (defined as > 200 IU/L which was approximately five times upper limit of normal) and an elevated
SGPT (defined as > 200 IU/L which was approximately five
times upper limit of normal). Clinical outcomes (death or
resolution) were recorded for all patients. Patients who
were readmitted as relapse cases were only included for
the initial admission. Information concerning antimicrobial
agents used for treatment prior to hospital admission was
not reliably available.
Severe disease was defined by the presence of one or
more of the following features: gastrointestinal bleeding
(the presence of visible blood in the stool), intestinal perforation (confirmed at surgery), encephalopathy (delirium,
obtundation or coma), haemodynamic shock (systolic
blood pressure < 90 mmHg and/or diastolic blood pressure < 60 mmHg associated with tissue hypoperfusion),
myocarditis (tachycardia or bradycardia with an associated

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abnormality of the ECG or ultrasound evidence of a pericardial effusion), hepatitis (as indicated by jaundice and/or
hepatomegaly with abnormal levels of SGOT (> 400 IU/L)
and/or SGPT (>400 IU/L)), a clinical diagnosis of cholecystitis (right upper quadrant pain and tenderness without
evidence of hepatitis), pneumonia (respiratory symptoms
with abnormal chest X-ray infiltrates) or pleural effusion,
severe anaemia (haematocrit 20%), the need for a blood
transfusion, or death.
Microbiological methods

Blood or bone marrow aspirates was added to brain

heart infusion broth containing sodium polyethanolsulphonate (1:10) and incubated at 35-37C for seven
days. Sub-cultures were performed after one, two and
seven days or when the broth went turbid. Alternatively, blood was inoculated into BACTEC bottles
(Becton-Dickenson, USA) and cultured for five days in
a BACTEC 9050 automated incubator. Bottles that
gave a positive signal were sub-cultured. Salmonella
isolates were identified by standard biochemical tests
and agglutination with Salmonella specific antisera
(Murex diagnostics, Dartford, United Kingdom). Antimicrobial sensitivities were performed at the time of
isolation by a modified Bauer-Kirby disc diffusion
method and inhibition zone sizes were recorded. Interpretations of the zone sizes were based on the current
(2013) CLSI guidelines [28]. The antimicrobials tested
(Unipath, Basingstoke, United Kingdom) were chloramphenicol (30g), ampicillin (10g), trimethoprimsulphamethoxazole (1.25/23.75g), ceftriaxone (30g),
ofloxacin (5g), azithromycin (15g) and nalidixic acid
(30g). Isolates were stored in Protect beads (Prolabs,
Oxford, United Kingdom) at 20C.
Stored bacterial isolates were later sub-cultured onto
nutrient agar and the MICs for the isolates were determined by the standard agar plate dilution method
according to CLSI guidelines or using E- test strips according to the manufacturers guidelines (AB Biodisk,
Solna, Sweden). The evaluated antimicrobials were ciprofloxacin (0.008 g/mL to 4 g/mL), ofloxacin (0.008
g/mL to 4 g/mL) and nalidixic acid (0.5g/mL to 512
g/mL). Antimicrobial powders were purchased from
Sigma, United Kingdom, except for ofloxacin, which
was donated from Hoescht Marion Roussel. Escherichia
coli ATCC 25922 and Staphylococcus aureus ATCC
25923 were used as control strains for these assays. An
isolate was defined as MDR if it was resistant to chloramphenicol ( 32g/ml), trimethoprim/sulphamethoxazole ( 8/152 g/ml) and ampicillin ( 32g/ml). An
isolate was defined as having intermediate ciprofloxacin
susceptibility if it was resistant to nalidixic acid ( 32g/ml)
and/or had a ciprofloxacin MIC of 0.1-0.5 g/ml and/or
ofloxacin MIC of 0.25-1.0 g/ml.

Page 3 of 9

Analysis

Demographic and clinical features were described for

the whole cohort and within the stratified age categories
of < 5 years, 515 years and 16 years. Continuous data
was described using median and inter-quartile range and
compared using the Mann Whitney U-test. Proportions
were compared with the Chi squared test or the Fishers
exact test as appropriate. Age, sex, duration of illness
prior to admission to hospital, the presence of an MDR
phenotype and intermediate susceptibility to ciprofloxacin were evaluated for association with severe or fatal
typhoid fever through a univariate analysis. A multivariate logistic regression model controlling simultaneously for the effects of confounding included variables
associated with the outcome of severity (p < 0.10) as well
as a priori factors age, sex and site. Statistical analysis
was performed using STATA version 11 (StataCorp,
Texas, USA).

Results
Demographic data and diagnostic test results

Data was available for analysis on a total of 581 patients

with culture confirmed typhoid fever. There were 347
typhoid patients during 1993 and 1995 and 234 during
1997 and 1999. The final dataset included 355 (61.1%)
children (< 16 years), with 44 (7.6%) under the age of
5 years, and 226 (38.9%) adults ( 16 years) (Figure 1).
There were 296 (50.9%) males, comprised of 196 (55.2%)
male children and 100 (43.2%) male adults. A blood and
bone marrow culture was performed with material from
193 (33%) patients and blood culture alone was performed

Figure 1 The age distribution and severity in 581 hospitalised

Vietnamese patients with typhoid fever between 1993 and 1999.

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on 388 (67%) patients. Notably, in the patients receiving

both blood and bone marrow cultures, S. Typhi was isolated from both samples on 145 (25%) occasions and from
the bone marrow alone on 28 (5%) occasions.
The clinical and microbiological features of typhoid on
hospital admission

The signs and symptoms of the enrolled patients at the

time of admission are summarised in Table 1 and classified by age range. Children under 16 years old were
more likely than adults to have a shorter duration of
illness, constipation and a cough. Abdominal pain and
vomiting was most commonly recorded in school-aged
children, and adults were more likely than children to
have a headache. More than half of all enrolled subjects
had diarrhoea and a peak temperature in excess of 40C.
Children under 16 years old were more likely to have
hepatopslenomegaly and were more frequently infected
with an MDR or intermediate ciprofloxacin susceptibility
organism.
Clinical outcomes and the prevalence of severe typhoid

The clinical outcomes of the enrolled typhoid patients are

summarised in Table 2 and classified by age range. The
prevalence of severe or fatal typhoid at the time of admission in this group of patients was 15.5% (90/581). The
most common complications associated with severe
disease were gastrointestinal bleeding (43; 7.4%); hepatitis
(29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12;
2.1%); pneumonia or pleural effusion (11; 1.9%); intestinal
perforation (6; 1.0%); and haemodynamic shock (5; 0.9%).
Severe disease was slightly more frequent in adults (39/
226; 17.3%) than in children under 16 years (51/355;
14.4%) (Figure 1). The overall case fatality rate was 3/581
(0.5%). All these three fatal cases were adults with combined encephalopathy and haemodynamic shock. The six
patients with intestinal perforation, all male, were managed successfully with surgery and antimicrobial therapy.
The clinical and laboratory features associated with severe
disease are shown in Table 3.
Risk factors associated with severe typhoid infections

Associations between age, sex, duration of illness prior to

admission, hospital site and infection with an organism
with an MDR or intermediate ciprofloxacin susceptibility
phenotype with severe disease are shown in Table 4. All of
these variables were evaluated for associations with severe
typhoid through a logistic regression model. After controlling for the effects of confounding, severe disease was
independently associated with infection with an organism
with intermediate resistance to ciprofloxacin (AOR 1.90;
95% CI 1.18-3.07; p = 0.009) and male sex (AOR 1.04
(1.00-2.57; p = 0.048).

Page 4 of 9

We hypothesised that the observed association between

infection with an organism exhibiting intermediate resistance to ciprofloxacin and disease severity may be related
to these individuals having a longer duration of illness before hospital admission, as a result of initially receiving ineffective treatment. However, the median duration of illness
prior to hospitalisation for patients infected with an organism with intermediate ciprofloxacin resistance was 8 (IQR:
610) days and for patients infected with a ciprofloxacin
susceptible organism was also 8 (IQR: 613) days (p =
0.081).

Discussion
In this study of 581 Vietnamese patients hospitalised with
acute typhoid we identified an independent association of
infection with isolates with intermediate susceptibility to
ciprofloxacin with severe typhoid. Our research and the
research of other groups have previously discussed an impaired response to ofloxacin and ciprofloxacin among patients infected with a ciprofloxacin intermediate isolate
[10,11]. A retrospective report in children and adults from
New Dehli, India showed an association between severe
disease and MDR strains and strains with a decreased susceptibility to fluoroquinolones [16]. In the multivariate
analysis in the New Dehli study this relationship with
severe disease remained significant for strains exhibiting a
decreased susceptibility to fluoroquinolones (OR 3.96,
95% CI 1.39-11.24, p = 0.004). During the period of the
study fluoroquinolones, such as ofloxacin and ciprofloxacin, became widely available for treating typhoid infections
caused by MDR organisms in outpatients, private clinics
and hospitals. Such treatment would be less effective initial treatment for strains with intermediate susceptibility
to ciprofloxacin. We anticipated that this might result in a
delayed presentation to hospital for patients infected with
such strains. In fact there was no significant difference in
the duration of illness before admission in these patients
compared with those infected with ciprofloxacin susceptible strains.
Our analyses found that severe or fatal disease was
slightly more common in adults than children. Previous
data regarding the severity of typhoid in children and
adults demonstrates variability. Some studies describe
typhoid as a severe disease in young children [6,7,13,14],
but others characterise it as a comparatively mild, even
benign, illness [29-31]. This feature of our findings may
lack some generalisability, as severely ill children resident
in HCMC may be admitted to one of two specialist paediatric hospitals rather than HTD. Furthermore, typhoid
in very young children (< 5 years) may present with
unspecific clinical features such as syndromic sepsis,
pneumonia, diarrhoea or a viral syndrome and may not be
recognised as clinical typhoid [31]. We also found that
that severe disease was more common in males and all

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Page 5 of 9

Table 1 The demographics and clinical features of 581 typhoid fever patients categorised by age
All ages

<5 years

5-15 years

16 years

n = 581

n = 44

n = 311

n = 226

1993-1995

347 (59.7)

26 (7.5)

177 (51.0)

144 (41.5)

1997-1999

234 (40.3)

18 (17.7)

134 (57.3)

82 (35.0)

Covariate

p
value1

p
value2

0.785

0.117

0.177

<0.001

Baseline
Year3

Site4
Ho Chi Minh City

350 (60.2)

24 (6.9)

136 (38.9)

190 (54.3)

Dong Thap

231 (39.8)

20 (8.7)

175 (75.6)

36 (15.6)

Male sex

296 (50.9)

28 (63.6)

168 (53.8)

100 (45.3)

0.230

0.010

8 (611)

7 (610)

7 (610)

9 (714)

0.813

<0.001

Abdominal pain

178 (30.6)

9 (20.5)

129 (41.5)

40 (17.7)

0.007

<0.001

Constipation

134 (23.1)

10 (22.7)

107 (34.4)

17 (7.5)

0.123

<0.001

Diarrhoea

321 (55.2)

26 (59.1)

177 (56.9)

118 (52.2)

0.785

0.240

116 (20)

5 (11.4)

75 (24.1)

36 (15.9)

0.081

0.052

131 (22.5)

15 (34.1)

79 (25.4)

37 (16.4)

0.221

0.004

Days ill prior to admission5

Signs & symptoms

Vomiting
Cough
Headache

220 (37.9)

5 (11.4)

117 (37.6)

98 (43.4)

<0.001

0.029

Temperature >40C

318 (54.7)

27 (61.4)

180 (58.6)

111 (53.1)

0.730

0.175

SBP <90 mmHg

Hepatomegaly
Jaundice
Splenomegaly
Rash

25 (4.3)

2 (4.5)

14 (4.5)

9 (4.0)

1.000

0.761

303 (52.2)

31 (70.5)

222 (71.4)

50 (22.1)

0.899

<0.001

17 (2.9)

0 (0)

11 (3.5)

6 (2.7)

0.372

0.757

101 (17.4)

10 (22.7)

72 (23.2)

19 (8.4)

0.950

<0.001

15 (2.6)

1 (2.3)

10 (3.2)

4 (1.8)

1.000

0.426

Laboratory
7

Haematocrit <30%

72 (12.4)

7 (18.4)

52 (17.4)

13 (7.2)

0.875

0.001

White cell count <4109/L

40 (6.9)

2 (4.5)

19 (6.1)

19 (8.4)

1.000

0.251

White cell count > 1510 /L

11 (1.9)

2 (4.5)

6 (1.9)

3 (1.3)

0.261

0.541

Platelet count <100109/L

27 (4.6)

2 (5.7)

13 (5.3)

12 (9.0)

1.000

0.165

10

63 (10.8)

3 (21.4)

43 (32.8)

17 (22.7)

0.549

0.159

10

44 (7.6)

0 (0)

26 (19.8)

18 (24.0)

0.075

0.286

Fully susceptible organism

75 (12.9)

4 (9.1)

30 (9.7)

41 (18.1)

1.000

0.003

MDR

469 (80.7)

39 (88.6)

261 (83.9)

169 (74.8)

0.510

0.004

Reduced susceptibility to FLQ

215 (37.0)

17 (38.6)

127 (40.8)

71 (31.4)

0.781

0.026

SGOT >200 IU/L

SGPT >200 IU/L

Isolate

Comparison of children < 5 years with children 515 years and of children < 16 years with adults 16 years by chi square, Fishers exact or MannWhitney
U test as appropriate.
Denominators for age groups are the total for each period.
4
Denominators for age groups are the total for each site.
5
median (IQR).
6
SBP systolic blood pressure.
7
n = 518.
8
n = 580.
9
n = 414.
10
n = 220.
FLQ: Fluoroquinolone.
1

the cases of intestinal perforation were in males. Previous

studies have suggested that disease severity between sexes
can vary geographically and has been found to be more

common in females [7,15] but also with males, particularly

intestinal perforation [4]. It is noteworthy that anaemia
was significantly more common among patients with

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Table 2 Outcome in the 581 patients with confirmed typhoid categorised by age group
5-15 years

16 years

p value1

p value2

0.363

0.348

Covariate

All ages

<5 years

n = 581

n = 44

n = 311

n = 226

Severe or fatal disease

90 (15.5)

4 (9.1)

47 (15.1)

39 (17.3)

Gastrointestinal bleeding

43 (7.4)

1 (2.3)

22 (7.1)

20 (8.9)

0.334

0.287

Intestinal perforation

6 (1.0)

0 (0)

2 (0.6)

4 (1.8)

1.000

0.214

Encephalopathy

16 (2.8)

1 (2.3)

7 (2.3)

8 (3.5)

1.000

0.437

Myocarditis

12 (2.1)

0 (0)

9 (2.9)

3 (1.3)

0.609

0.384

Haemodynamic shock

5 (0.9)

0 (0)

0 (0)

5 (2.2)

0.009

Renal impairment

4 (0.7)

0 (0)

0 (0)

4 (1.8)

0.023

Hepatitis

29 (5.0)

1 (2.3)

18 (5.8)

10 (4.4)

0.488

0.617

Cholecystitis

4 (0.7)

0 (0)

3 (1.0)

1 (0.4)

1.000

1.000

Pneumonia

5 (0.9)

1 (2.3)

2 (0.6)

2 (0.9)

0.328

1.000

Pleural effusion

6 (1.0)

1 (2.3)

3 (1.0)

2 (0.9)

0.412

1.000

Severe anaemia

6 (1.0)

0 (0)

5 (1.6)

1 (0.4)

1.000

0.413

Blood transfusion

3 (0.5)

0 (0)

2 (0.6)

1 (0.4)

1.000

1.000

Death

3 (0.5)

0 (0)

0 (0)

3 (1.3)

0.058

Comparison of children < 5 years with children 515 years and 2 of children < 16 years with adults 16 years by chi square, Fishers exact or MannWhitney U test
as appropriate.

severe disease. We speculate that the reasons for this are

multi-factorial including intestinal bleeding, haemolysis
and nutritional.
In this analysis severe disease occurred in 15.5% of all
typhoid patients and fatal disease in 0.5%. These figures
are comparable with studies conducted in Pakistan,
Bangladesh, India and the United States [6-8,16]. As only
approximately 10% of patients with blood culture
confirmed typhoid are hospitalised in this region, these
figures likely do not reflect the true frequency of severe
disease in the population [32]. The threshold for hospital
admission, the availability of antimicrobials in the
community without prescription and their use prior to
admission will vary between different localities and undoubtedly bias who is admitted to hospital. All the fatal
cases from this analysis were adults with encephalopathy
and haemodynamic shock; these symptoms have previously been identified as markers of particularly severe
disease [33-35].
We found no association of disease severity with an
MDR phenotype. In a prospective study of 1,158 children
with culture confirmed typhoid fever in Karachi, Bhutta
and co-workers found that MDR infections in children in
Karachi were associated with higher rates of toxicity,
hepatomegaly and hypotensive shock [6]. The 2% mortality in children with an MDR infection in the study from
Pakistan was not significantly higher than the 1.4% mortality in those infected with an antimicrobial susceptible
strain (OR 1.6, 95% CI; 0.5 - 4.6, p = 0.34). Notably, intermediate susceptibility to fluoroquinolones was not documented in the study from Pakistan. In a previous
investigation in Vietnam, which incorporated some data

from the first period of this study, higher bacterial

counts in the blood were associated with an MDR
phenotype [17].
The reason for more severe disease in those infected
with strains with intermediate susceptibility to ciprofloxacin may be more complex than merely a poor response to
antimicrobial therapy. We speculate that the genotype of
the relevant S. Typhi organisms may also play an important role in regulating disease severity. Specifically, we
suggest an association between bacterial haplotype
(assessed by chromosomal single nucleotide polymorphisms (SNPs)) and the pathogenic potential of the strain.
There is currently no SNP/disease severity data to support
this theory. However, S. Typhi isolates originating in
Papua New Guinea in the late 1980s and early 1990s
exhibited extensive genetic diversity using an insensitive genotyping method (Pulsed field gel electrophoresis
(PFGE)), yet a single clone appeared to associated with 11
cases of fatal disease [36]. A further study of 81 S. Typhi
isolates from 19971999, also in Papua New Guinea,
showed increased genetic divergence in S. Typhi with
PFGE, but only a restricted range of PFGE types were
found in seven patients with severe or fatal disease [37].
Furthermore, recent studies have shown an association of
the ciprofloxacin intermediate phenotype and the IncH1
MDR plasmid with H58 haplotype [38-40]. We have
found that this particular haplotype has undergone widespread emergence in the Mekong Delta of Vietnam in the
last 10 years [41]. Whether this haplotype is associated
with more severe disease requires further investigation.
Our investigation has limitations that need to be considered. Firstly, we only studied hospital admitted cases

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Table 3 Clinical and haematological characteristics of 90 severe and 491 non-severe typhoid fever patients
Characteristic

Severe or fatal n = 90

Non-severe n = 491

OR

95% CI

p value

Signs & symptoms

Abdominal pain

45 (50.0)

133 (27.1)

2.69

1.70-4.26

<0.001

Constipation

29 (32.2)

105 (21.4)

1.75

1.07-2.86

0.025

Diarrhoea

62 (68.9)

259 (52.7)

1.98

1.23-3.21

0.005

Vomiting

30 (33.3)

86 (17.5)

2.36

1.43-3.87

0.001

Cough

21 (23.3)

110 (22.4)

1.05

0.62-1.80

0.846

Headache

42 (46.7)

178 (36.3)

1.54

0.98-2.42

0.061

Temperature >40C

50 (58.1)

268 (56.5)

1.07

0.67-1.70

0.783

Systolic blood pressure <90 mmHg

9 (10.0)

16 (3.3)

3.30

1.41-7.72

0.004

Hepatomegaly

62 (68.9)

241 (49.1)

2.30

1.42-3.71

0.001

Splenomegaly

19 (21.1)

82 (16.7)

1.34

0.76-2.33

0.310

5 (5.6)

10 (2.0)

2.83

0.94-8.48

0.053

Haematocrit <30%1

23 (26.7)

49 (11.3)

2.85

1.63-5.01

<0.001

White cell count <4109/L2

10 (11.1)

30 (6.1)

1.92

0.90-4.07

0.086

Rash
Haematology

White cell count >1510 /L

5 (5.6)

6 (1.2)

4.75

1.42-15.90

0.006

Platelet count <100109L 3

7 (9.9)

20 (5.8)

1.77

0.72-4.35

0.211

SGOT > 200 IU/L

33 (63.5)

30 (17.9)

7.99

4.01-15.91

<0.001

SGPT > 200 IU/L4

28 (53.8)

16 (9.5)

11.08

5.24-23.47

<0.001

n = 518.
2
n = 580.
3
n = 414.
4
n = 220.

and our data are, therefore, biased by factors that determine hospital admission such as pre-hospital treatment
and access to healthcare. The lack of reliable data concerning pre-hospital antimicrobial therapy is a further
drawback. The data are recorded from a period more
than ten years ago and, therefore, may not represent the
contemporary situation in Vietnam or in other parts of
Asia. However, we selected this period as it covered a
period of changing antimicrobial susceptibility patterns
and strains. In many locations, which are currently endemic for typhoid, antimicrobial resistant strains now

dominate the local epidemiology, making it difficult to

determine any potential link between resistance and disease severity [41].

Conclusion
In this large dataset on clinical typhoid and disease severity we found an independent association between infections with strains with intermediate susceptibility to
ciprofloxacin and severe typhoid fever. This may reflect
the widespread use of fluoroquinolones, particularly ciprofloxacin and ofloxacin, in this area during this period

Table 4 Factors associated with severe or fatal typhoid fever

Covariate

Severe or fatal n = 90

Non severe n = 491

OR

95% CI

p value

AOR

95% CI

p value

14 (1023)

12 (721)

1.01

0.99-1.03

0.243

1.02

0.99-1.04

0.122

Male

54 (60.6)

242 (49.3)

1.54

0.98-2.44

0.062

1.61

1.00-2.57

0.048

Days ill prior to admission1

10 (714)

8 (610)

1.03

0.99-1.07

0.081

1.04

.99-1.08

0.065

Age (years)1

Fully susceptible organism

9 (10.0)

66 (13.4)

0.72

0.34-1.49

0.371

NI

MDR

78 (86.7)

391 (79.6)

1.66

0.87-3.17

0.123

1.41

0.72-2.75

0.316

Intermediate ciprofloxacin resistance

45 (50.0)

170 (34.6)

1.89

1.20-2.97

0.005

1.90

1.18-3.07

0.009

Ho Chi Minh City

52/350 (14.9)

298/350 (85.1)

1.00

1.00

Dong Thap

38/231 (16.5)

193/231 (83.5)

1.13

0.72-1.78

0.603

1.19

0.72-1.98

0.501

Site

1
Median (IQR).
AOR: adjusted odds ratio; NI: Not included.

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that are not fully effective against these infections.

Whether additional host and bacterial factors are implicated in severe disease requires further investigation.
Ciprofloxacin and ofloxacin should be used with caution
in patients infected with S. Typhi that have intermediate
susceptibility to ciprofloxacin. Although the newer generation fluorquinolone gatifloxacin is effective for treating
such infections it is now unavailable in many countries
because of safety concerns. Other alternatives for treating
infections with isolates that are MDR and have intermediate susceptibility to ciprofloxacin are extended spectrum
cephalosporins and azithromycin [42].

Page 8 of 9

7.

8.

9.

10.

Competing interests
The authors declare that they have no competing interests.
Authors contribution
CMP, CT, JJF and SB designed the study. CMP, HV, NTC, LTP, VAH, TTH, JW
participated in data collection. CMP and CT analysed the data and wrote the
first draft. All authors revised the manuscript for important intellectual
content and read and approved the final version.
Acknowledgements
We thank the Directors, clinical and laboratory staff of the Hospital for
Tropical Diseases and Dong Thap Provincial Hospital for their support of this
study and the patients for their agreement to participate.
Financial disclosure
This work was supported by The Wellcome Trust of Great Britain. Stephen
Baker is supported by a Sir Henry Dale Fellowship from the Royal Society
and the Wellcome Trust. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Author details
1
Wellcome Trust Major Overseas Programme, Oxford University Clinical
Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho
Chi Minh City, Vietnam. 2Department of Clinical Sciences, Liverpool School of
Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. 3Nuffield
Department of Clinical Medicine, Centre for Tropical Medicine, Churchill
Hospital, Oxford, UK. 4Hospital for Tropical Diseases, 764 Vo Van Kiet, District
5, Ho Chi Minh City, Vietnam. 5Dong Thap Provincial Hospital, Cao Lanh,
Dong Thap Province, Vietnam. 6Department of Medical Microbiology,
University of East Anglia, Norwich, UK. 7London School of Hygiene and
Tropical Medicine, Keppel Street, WC1E 7HT, London, UK.

11.

12.
13.
14.
15.

16.

17.

18.

19.

Received: 7 October 2013 Accepted: 30 January 2014

Published: 10 February 2014
20.
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