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Clinical and Medical Reports
Case report ISSN: 2516-5283
Complicated enteric fever: challenges in identification,
reporting and inclusion in global burden of disease
estimates
Carlos Franco Paredes*
Hospital Infantil de México, Federico Gómez, México D.F., México
Abstract
Background: Enteric fever (typhoid fever and paratyphoid fever) remains an important public health problem in regions of the world where water and sanitation
conditions are compromised, particularly in South Asia, East Asia and Africa. The clinical presentation of enteric fever varies from an acute non-complicated disease
to a severe clinical form associated with intestinal or extra-intestinal manifestation. Currently available reports on the community-based burden of enteric fever
have not included assessments of the severity and complications of enteric fever at a population-based level. Herein, we present a case of a patient with intestinal
perforation and peritonitis caused by enteric fever. We also discuss the medical implications of typhoid fever including its persistent occurrence in high-risk areas,
as well as the devastating medical and socioeconomic consequences that individuals and their families face. This case illustrates that there is an important burden of
disease associated with complicated typhoid fever that it is often not captured in currently available assessments of the impact of this ancestral bacterial pathogen.
Introduction illness, an episode of high fever returned. Due to persistent fever, he
visited the neighborhood physician for the second time. The physician
Salmonella enterica infections are associated with three distinct prescribed intravenous fluids and an intramuscular injection (unknown
clinical syndromes: a) enteric fever resulting from infection by the medication). The patient experienced minimal improvement, and
typhoidal Salmonellae (Salmonella Typhi and Salmonella Paratyphi next day patient visited the physician for the third time due to the
A, B, and C; b) non-typhoidal Salmonella gastroenteritis; and c) non- persistence of fever and abdominal pain. This time the doctor advised
typhoidal Salmonella bacteremia (invasive disease caused by non- some laboratory tests and diagnosed him as having malaria (based on a
typhoidal Salmonellae) [1]. Enteric fever (EF) is an acute systemic “some” blood test) and prescribed medicine accordingly. Despite these
infection, representing two similar clinical illnesses, typhoid and interventions, the patient condition progressively deteriorated. The
paratyphoid fever, caused by different serotypes of the bacterium patient then visited another clinic at some distance despite financial
Salmonella enterica, serotypes Typhi (S. Typhi) and Paratyphi (S. challenges. This second physician consulted, recommended intravenous
Paratyphi A, B, and C), respectively. Combined morbidity and mortality fluids and antibiotics; and despite these interventions, by the third day
caused by infections of Salmonella enterica serovars is considerable of treatment (ten days from the onset of symptoms), his condition
since this group of bacterial pathogens are responsible for a global toll became grave with severe abdominal pain and persistent vomiting.
of approximately one million deaths annually [2,3]. At this point, the patient was transferred to a regional clinic where a
third physician evaluated him. By then, the patient was diagnosed with
Case presentation acute abdomen with associated hemodynamic instability and oliguria.
He was diagnosed with typhoid fever and intestinal perforation; and
A twenty-two-year-old single male, youngest of four siblings,
was referred to a tertiary care hospital for appropriate management. At
living in Karachi, Pakistan suffered from an illness consisting of fever,
this center, the patient underwent exploratory laparotomy confirming
headache and myalgias. He works as a helper receiving daily wages with
the diagnosis of intestinal perforation for which the surgeon stated that
a local construction contractor. He continued having pain until the next
it had the characteristic macroscopic signs of perforation peritonitis
morning when he noticed loss of appetite and nausea; and suffered an
caused by typhoid fever. The patient required surgical closure of the
episode of vomiting. He was unable to work that day, and by the second
day of his illness, his mother believed that his illness was caused by the
“evil eye” and requested the services of the neighborhood healer who
confirmed the “evil eye” effect. The local healer proceeded to read some *Correspondence to: Carlos Franco-Paredes, MD, MPH, Hospital Infantil de
“sacred” verses and to prescribe remedial water and powder; and also Mexico Federico Gomez, Mexico City, Mexico, Email: carlos.franco.paredes@
gmail.com
provided the patient with some written words in a piece of paper to be
burnt. He experienced some limited improvement but by the next day Key words: Typhoid perforation, paratyphoid fever, typhoid fever, Peyer’s
he continued to experience the same symptoms and his cousin took Patches, intestinal perforation, Salmonella, enteric fever, Pakistan, enteric fever
him to a physician in the neighborhood. His initial diagnosis was “low complications, case report
blood pressure” and the patient received intravenous fluids and received Received: February 20, 2018; Accepted: March 13, 2018; Published: March 16,
a dose of an unknown intravenous medication. By the fourth day of his 2018
Clin Med Rep, 2018 doi: 10.15761/CMR.1000114 Volume 2(2): 1-5Paredes CF (2018) Complicated enteric fever: challenges in identification, reporting and inclusion in global burden of disease estimates
perforation with an ileotransverse colostomy. The patient remained typhi infection (more than 100 cases per 100,000-person years) [5].
hospitalized for thirteen more days to receive supportive and specific Research conducted on enteric fever over the last decade in Asia, has
antimicrobial therapy. The patient’s mother and one of two cousins cared also documented high disease incidence of enteric fever with elevated
for him during his hospital stay. The patient and one of his cousins lost morbidity, particularly in the pediatric age group (< 5 years) [6]. Recent
their jobs due to their inability to continue working during the illness. reports too demonstrate a rising number of cases of S. Paratyphi A in
According to the patient, the out of pocket cost during the illness was South Asia with a presentation and severity similar to that of S. Typhi
approximately $100 USD in addition to the loss of productivity ($5 USD [7]. Studies to determine the burden of disease of typhoid fever in Asia
per day of the patient and his cousins). Transport cost to the tertiary have provided information on the incidence of the disease but little
care hospital was $10 USD per visit. Since the surgery took place in a information has been added on severity, complications, and clinical
public hospital, specific cost of surgery was not assessed. From a social outcomes such as mortality [8,9].
support perspective, the patient restricted mingling with his friends,
Many consider enteric fever a disease seen only in outpatient clinics
primarily due to the stigma of having a colostomy bag. The cost of
and only requiring treatment with inexpensive and oral antibiotics. The
supplies for colostomy bag was approximately of $20.00 USD per week.
reality for many individuals living in extreme poverty - those living in
Our team also met with the treating physician who was responsible poorly constructed dwelling with limited to no access to clean water;
for transferring the patient to the tertiary care hospital to obtain with no available sewage disposal system, poor nutrition, and low
additional information about his experiences in managing cases of education level - is that exposure to enteric pathogens is an inevitable
complicated enteric fever. The physician reported that the patient fate of their biological and social destinies [10]. Furthermore, once
presented with severe abdominal pain, vomiting, and with high-grade they are infected, the prevailing inequalities (i.e., insufficient access
fever (>103.50F). On physical examination, his abdomen was tender, to adequate health care services and insufficient financial resources
his blood pressure was low, and his urine output was significantly to travel to seek care) and socio-cultural determinants, influence
reduced. Based on his clinical course, his diagnosis was that of individuals’ health seeking behavior and thus grave consequences to
intestinal perforation caused by typhoid fever. He also reiterated that, the patients [11,12].
on a daily basis, many febrile patients with a possible diagnosis of
Available reports on typhoid fever have two dimensions; one
enteric fever seek care at his office. However, he is unable to perform
that presents the population level typhoid fever incidence and is
confirmatory diagnostic testing for typhoid fever or else, of any other
well documented through population-based studies, and the other
infectious disease contemplated supporting his provisional diagnosis.
that describes complicated/severe disease presenting to tertiary care
He further explained that blood culture testing is not performed locally
hospitals as case reports and hospital-based studies. The severe cases
and therefore patients and their families have to travel long distances.
reported by population-based studies are close to minimal, whereas
Furthermore, most patients evaluated at his office are extremely poor
hospital-based studies with a range of complicated cases fail to define
and are unable to afford the cost of any laboratory testing.
a denominator and hence are unaccounted for in efforts to measure
Discussion global burden of disease. The disadvantage thus, is that severity
estimates are based on “expert opinion” resulting in less confidence by
This case illustrates that typhoid fever and its associated global scientific community. Historically when typhoid fever related
complications remain as an important public health problem in hospitalizations and mortality were frequently reported, typhoid fever
Pakistan. Typhoid fever is associated with a plethora of complications derived significant policy makers’ attention at national and international
and sequelae that impose a substantial burden of disease in terms of the fora, and thus was a priority disease for control measures. For example,
economic hardship to those affected. A constellation of factors can also typhoid vaccine development and use during Anglo-Bohr war, as well
be directly linked to poor clinical outcomes including inappropriate as in Spanish-American war was a result of alarming case fatality rates
health seeking behavior of those affected with enteric fever, financial [13-14]. In contrast since 2000 studies have repeatedly and regularly
constraints, and misconceptions about the disease. From a healthcare reported high typhoid and paratyphoid fever incidence in Asia and
standpoint, the undifferentiated clinical presentation of typhoid Africa with no minimal policy derive for typhoid vaccine use, instead
fever in conjunction with the unavailability of quality laboratory finding reasons for delaying vaccine use in developing countrie. Typhoid
facilities to confirm the diagnosis in highly endemic settings often incidence is high [15], it affects all age groups with a peak incidence in
leads to unnecessary delays in diagnosis. These factors often result in children four to twelve years [16,17], cost of illness is very high [18],
burdensome complications and long-term sequelae such as in the case existing vaccines are efficacious with population impact [19], and a
illustrated herein. These complications and the suffering caused by WHO pre-qualified vaccine is available and cost effective; public health
affected individuals and their families are not often captured in most use of typhoid vaccines and other control measures to combat enteric
of the estimates of disease burden. More importantly, complications fever burden has been negligible [20]. Factors causing hindrance for the
of typhoid fever and it sequelae create a vicious cycle of destitution by large-scale typhoid vaccine use have been differences in comparative
affecting the already disenfranchised populations living in endemic lower incidence in rural areas, vaccine immune response in younger
settings without access to clean water and sewage. children (younger than five years), a clear vaccine delivery strategy
and vaccine cost. Despite Gavi, the vaccine alliance’s commitment to
The persistent burden of enteric fever support a typhoid vaccine, the above factors have played a major role in
the absence of typhoid vaccine financing in typhoid endemic countries.
Across South and Southeast Asia, some areas in Latin America and
Africa, typhoid fever remains the most commonly identified clinical The two drivers of vaccine policy are disease specific mortality and
syndrome caused by S. enterica [4]. Worldwide, it is most common in severity resulting to a burden on health care system. Data on severe
impoverished areas that are overloaded with poor access to sanitation. typhoid is not systematically collected and presented, and if it is, it comes
Non-epidemic incidence estimations suggest that south-central Asia, from hospital-based case reports with many years of data. The above
south-east Asia, and southern Africa are areas with high rates of S. factors have thus resulted in minimal vaccine manufacturers’ interest in
Clin Med Rep, 2018 doi: 10.15761/CMR.1000114 Volume 2(2): 2-5Paredes CF (2018) Complicated enteric fever: challenges in identification, reporting and inclusion in global burden of disease estimates
vaccine development and production, and country licensure leading to to capillary thrombosis resulting in necrosis by the second week and
WHO prequalification. In the presence of high antimicrobial resistance, ulceration. If continued ulcerations persist it may lead to hemorrhage
global complication and mortality data are an under-estimate [21-23]. and/or intestinal perforation that usually occurs by the third week of
illness as it occurred in this patient [32].
Discussion
Typhoid fever remains a life-threatening multi systemic infectious
The patient was diagnosed with complicated typhoid fever as disease in many parts of the world where poor sanitation and unsafe
perforation peritonitis with severe sepsis. Undifferentiated febrile food and water access is highly prevalent [25]. Intestinal perforation
syndromes in resource-poor settings usually in tropical or subtropical with secondary bacterial peritonitis remains an important cause of
settings with prevailing low sanitation and insufficient access to safe morbidity and mortality in patients with typhoid fever [26]. The natural
water include a broad differential diagnosis of infectious diseases history of untreated typhoid fever is associated with intestinal or extra-
including enteric fever, dengue, tuberculosis, brucellosis, leptospirosis, intestinal complications that tend to occur within the second and fourth
rickettsiosis, chikungunya, and others [24]. Clinical judgment by week of illness, but mainly identified by early during the third week
the treating physician is often, the only way to care for patients, and of illness as it occurred in this patient (Table 1). Intestinal perforation
therefore it is commonplace to institute concomitant empiric therapies from typhoid fever was documented for centuries but this complication
for patient management. As this case illustrates, the true number was clearly described by Pierre Charles Alexander Louis (1787-1872)
of patients with severe and complicated enteric fever is difficult to [26]. His description of cases of perforation demonstrated that it was
ascertain in these communities where the lack of infrastructure, usually a single perforation located in the ileum in the center of an
disorganized urban or peri-urban settlements leading to poor hygienic ulcer. While intestinal perforation and mortality rates declined after
practices combined with lack of clean water result in a high rate of the availability of chloramphenicol in 1949 and other antimicrobials
enteric transmitted illnesses including typhoid fever and paratyphoid afterwards, this condition continues to occur in highly endemic places
fever [25-28]. The combination of undifferentiated febrile illnesses among disenfranchised populations with prevailing health inequities
with often atypical clinical presentations; and insufficient availability and inequalities; and often leading to catastrophic consequences [27] as
of laboratories performing blood cultures converge with a plethora of shown in this case. These complications are a result of undifferentiated
social, cultural, and economic determinants to synergistically produce febrile illness or non-specific clinical presentations, challenges with cost
poor clinical outcomes. Therefore, we can conclude that at this point in and unavailability of diagnostic techniques, and patient health seeking
time, the occurrence of complicated typhoid is almost exclusively seen behavior [28]. A major challenge is the non-specific presentation of
in highly-endemic areas of enteric fever which not coincidentally, are typhoid fever earlier during the course of the disease that makes it
communities living in extreme poverty. difficult to differentiate from other febrile illnesses [4]. In the current
case report, we highlight the challenges in under reporting and
Complications of Enteric Fever: Intestinal Perforation and difficulties that patients undergo as undifferentiated febrile illness
Peritonitis leading to a complicated clinical course.
S. Typhi usually enters the human host through ingestion of Enteric Fever is a Neglected Disease of Poverty
contaminated water or food that subsequently survive the gastric acid Case studies such as the one illustrated in this report provide
milieu to then gain access to the micro-fold cells (M cells) of the intestinal information in assisting health practitioners in the clinical management
epithelium through the activity of bacterial proteins delivered into host of individuals with similar clinical presentations. However, its most
cells by a type III secretion system which is encoded the pathogenicity important value resides in understanding the landscape of determinants
island SP-1 [29]. Subsequently, after forming an intracellular replicative of clinical outcomes at the individual level, at the community level,
niche, there is activation of a second type-III secretion system, but and at the healthcare level. Thus, these factors assist in designing
this time encoded by SPI-2. Some of the bacilli arrive into the lamina surveillance studies to document the true burden of disease and hence
propria, where an influx of macrophages ingests the bacilli; and it is guide population-based public health interventions. Certainly, this
believed that typhoid bacilli reach the bloodstream mainly through case of intestinal perforation highlights multiple issues ranging from
lymph drainage from mesenteric nodes to then reaching the systemic individual behavior, household social and economic capacity, health
circulation. As a result of this primary bacteremia, the pathogen care provider behavior, and health system performance. The purpose of
reaches the intracellular sanctuary of the reticuloendothelial system reporting this case is to document the challenges involved in quantifying
where it replicates and spearheads to a secondary bacteremia that such information in large population-based studies. Salmonella enterica
coincides with the onset of clinical symptoms [30]. Some of the typhoid subspecies I include the most common bloodstream bacterial isolates
bacilli remains or gain secondary access to the intestinal lymphoid in Asia and in Africa [33]. This patient would have been missed easily
tissue in the small intestine. Molecules involved in recognition of the in a surveillance study even if there were surveillance activities in the
typhoidal and non-typhoidal Salmonellas determine the activation of area where the patient resided due to the following two factors: a) the
innate immune responses including the type and degree of involvement patient was 22 years-old and typhoid fever is considered less common
of the complement system, neutrophilic versus monocytic infiltration in older populations; b) the patient’s health care seeking ranged from
of the intestinal lining resulting in a variety of immunopathogenic “evil eye” healers to tertiary care hospital surgeons; and in the course
of the disease (15-days) the patient was evaluated by five different
expressions of disease including bacteremia, gastroenteritis, enteric
health care providers. Therefore, this case study brings to the surface
fever, and focal or metastatic infections [31].
the importance of adapting surveillance efforts to the community-level
The Peyer’s patches, as they are termed, are organized lymphoid and contemplating all potential scenarios of health seeking behaviors.
regions that function in immune surveillance and the generation of In addition, information from these sources should be able identify
localized immune responses. When S. Typhi infects these mucosal unique cases, otherwise, cases like the one described may be counted
patches in the terminal ileum produces hyperplasia during the first more than once or not counted at all depending on participation of
week of illness, which may resolve without scarring or may progress these health care providers with the surveillance system.
Clin Med Rep, 2018 doi: 10.15761/CMR.1000114 Volume 2(2): 3-5Paredes CF (2018) Complicated enteric fever: challenges in identification, reporting and inclusion in global burden of disease estimates
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Copyright: ©2018 Paredes CF. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
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