Am. J. Trop. Med. Hyg., 86(4), 2012, pp. 698–702doi:10.4269/ajtmh.2012.11-0750Copyright © 2012 by The American Society of Tropical Medicine and Hygiene

Factors Associated with Encephalopathy in Patients with Salmonella enterica

Serotype Typhi Bacteremia Presenting to a Diarrheal Hospital

in Dhaka, Bangladesh

Daniel T. Leung,* Jori Bogetz,{ Megumi Itoh,{ Lakshmi Ganapathi, Mark A. C. Pietroni,Edward T. Ryan,{ and Mohammod Jobayer Chisti{

Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School,Boston, Massachusetts; Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California; Department of Pediatrics,

Children’s Hospital Boston, Boston, Massachusetts; Dhaka Hospital and Centre for Nutrition and Food Security,International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh;

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts

Abstract. To characterize clinical correlates of typhoid fever-associated encephalopathy, we performed a retrospec-tive chart review of patients with Salmonella enterica serotype Typhi bacteremia who were hospitalized at the Interna-tional Centre for Diarrhoeal Disease Research, Bangladesh, from February of 2009 to June of 2011. Of 207 patientsbacteremic with Salmonella Typhi who were ³ 5 years of age, we identified 43 (21%) patients with encephalopathy.Univariate analysis revealed that patients with encephalopathy more often presented at ages of 10–24 years and hadsevere dehydration, low oxygen saturation, high respiratory rate, low leukocyte count, low platelet count, and Widalflagellar H agglutinin (TH) titer ³ 1:640 compared with typhoid patients without encephalopathy. Multivariate analysisusing logistic regression showed that age, dehydration, leukocyte count, and Widal TH titer were independently associatedwith encephalopathy. Our findings suggest that age, severity of disease, and immune responses are associated withencephalopathy during Salmonella Typhi bacteremia, perhaps reflecting the impact of prominent inflammatory responses.

INTRODUCTION

Typhoid fever is a systemic illness caused by infection withSalmonella enteric serotype Typhi. It affects over 21 millionpeople each year worldwide, with the highest incidence amonginfants and children living in southcentral and southeast Asia.1

Initial signs and symptoms include fever, chills, anorexia, mal-aise, headache, abdominal pain, and constipation. Althoughthe most-studied complications of severe typhoid fever includeintestinal perforation and hemorrhage,2,3 numerous extra-intestinal manifestations, including encephalopathy, can occur,especially in severe disease.4

The term typhoid originates from the Greek word typhosmeaning smoke, which refers to the apathy and confusionassociated with the disease.5 The work by Osler6 described the“typhoid state” as a semiconscious state characterized by ablank stare, “muttering” incoherent speech, and an arousablebut not interactive patient.6 Case series from the UnitedStates,7 Nigeria,8 India,9 and Bangladesh10 show that up to75% of patients hospitalized with typhoid fever may haveneuropsychiatric manifestations, mostly characterized as “stu-por,” “delirium,” or a “confusional state,” although myelitis,cerebellitis, parkinsonism, insomnia, and acute psychosis havealso been described.7–10 Historically, typhoid encephalopathy hasbeen associated with mortality rates of up to 50% even with anti-biotics, although recent surveys are lacking.11,12 The pathophysi-ology of the various neuropsychiatric manifestations of typhoidfever, including encephalopathy, remains to be elucidated.Although antibiotics remain the mainstay of treatment of

typhoid fever, several small studies suggest that concurrenthigh-dose dexamethasone therapy may have substantial bene-

fits in reducing mortality and morbidity of patients withtyphoid encephalopathy.11,13,14 Moreover, studies also suggestthat delaying steroid administration may result in increasedmortality13 or a higher rate of relapse.15 Thus, prompt recogni-tion of typhoid encephalopathy before availability of culturedata is important for initiation of appropriate therapy. Fewstudies have recently examined the clinical and demographiccharacteristics associated with encephalopathy in typhoidfever. Thus, we conducted a retrospective analysis of patientspresenting to our hospital with bacteremia-confirmed typhoidfever to identify factors associated with encephalopathy.

MATERIALS AND METHODS

Study site. We conducted a retrospective chart review atthe Dhaka Hospital of the International Center forDiarrhoeal Disease and Research, Bangladesh (icddr,b). Weobtained case records from the electronic charting system toidentify all patients admitted between February 15, 2009 (theinitiation date of the electronic system) and June 30, 2011 whohad blood cultures positive for S. enterica serotype Typhi. Asa negative comparator group, we also identified patientsbacteremic with Escherichia coli, Pseudomonas aeruginosa,andAcinetobacter baumanii complex, which are the three mostcommon non-Salmonella causes of Gram-negative bacteremiaamong patients aged 5 years and older at our institution.Case definition. Patients with encephalopathy were identi-

fied based on similar criteria as the criteria of previous stud-ies11,12 as patients with one or more of the followingmentioned in their chart: (1) confusion, disorientation, slurredspeech, or altered mental status or (2) Glasgow Coma Scale(GCS) < 15 without alternative diagnosis.16 We excluded fromour study all patients < 5 years of age because of the non-standardized mental status assessment of young childrenavailable in the charting system.Data abstraction. We collected admission demographic,

clinical, and laboratory data from the electronic charting

*Address correspondence to Daniel T. Leung, Division of InfectiousDiseases, Massachusetts General Hospital, 55 Fruit St., Jackson 504,Boston, MA 02114. E-mail: dleung@partners.org{These authors contributed equally.{These authors are co-senior authors.

698

system. The following variables were identified in each chart:age, gender, comorbid conditions, pre-admission antibiotics,presenting symptoms, duration of symptoms before admission,and physical examination findings, including neurologic exam,height, weight, and level of dehydration. We also collectedadmission laboratory data, including peripheral blood cellcounts, electrolytes, renal and liver function, Widal test, andculture data, including antimicrobial sensitivity of the isolate.Ethical review. The study was approved by the Ethical

Research Committee of the icddr,b and the InstitutionalReview Board of the Massachusetts General Hospital.Data analysis. We compared the characteristics of bacter-

emic patients with evidence of encephalopathy and bacteremicpatients without encephalopathy. For continuous variables, weused the Student t test (normally distributed data as assessed bythe Shapiro–Wilk test) or the Mann–Whitney U test (for non-parametric data) to compare groups. For categorical variables,we used Fisher exact tests. We used logistic regression to deter-mine multivariate predictors of encephalopathy. Gender plusvariables with P < 0.01 from univariate analysis that had < 25%missing data were entered into multivariate logistic regression.We performed statistical analyses using SPSS 17.0 (SPSS Inc.,Chicago, IL). Statistical significance was defined as a two-tailedP value < 0.05.

RESULTS

We identified a total of 323 patients who had blood culturespositive for Salmonella Typhi during the study period, includ-ing 207 patients ³ 5 years of age. Of these patients, we iden-tified 43 patients (21%) who fulfilled our clinical criteriafor encephalopathy at the time of admission (before availabilityof microbiologic analysis of blood). The age distributionof those patients with and without encephalopathy is depictedin Figure 1. Approximately 25–32% of those patients aged10–24 years had features of encephalopathy compared with5–12% of those patients in other age groups (P = 0.001). Weidentified 52 patients ³ 5 years of age with non-SalmonellaGram-negative bacteremia during the same period. Only three(6%) patients were identified with encephalopathy per ourdefinition, and no cases of encephalopathy occurred in individ-uals 10–24 years of age.Univariate comparisons of historical, clinical, and labora-

tory data are shown in Table 1. In addition to age association,we found that patients with encephalopathy were significantly

more likely to live in a slum or tin shed (P = 0.03) and havesevere dehydration on exam (P < 0.001), a high respiratory rateon admission (P = 0.03), a low oxygen saturation (P = 0.02), alow white blood cell count (P = 0.001), a low platelet count(P < 0.001), and a Widal flagella H agglutinin (TH) ³ 1:640(P < 0.001). The magnitude or duration of fever, water source,gender, antibiotic resistance pattern of the subsequent isolate,use of pre-admission antibiotics, and Widal somatic O aggluti-nin titer were not associated with encephalopathy.In multivariate logistic regression analysis (Table 2), we

found that age of 10–24 years, severe dehydration, low whiteblood cell count, and Widal TH ³ 1:640 were statistically signif-icant independent predictors of presence of encephalopathy.All patients received antibiotics and steroids at the dis-

cretion of the attending physician. Most patients receivedceftriaxone, and dexamethasone was administered to 1 of

FIGURE 1. Patients bacteremic with S. enterica serotype Typhi byage group and presence of encephalopathy.

Table 1

Univariate correlates of encephalopathy in patients with SalmonellaTyphi encephalopathy

Variable at presentation

Noencephalopathy

(N = 164)Encephalopathy

(N = 43) P value

Age (years) N (%)5–9 35 (21%) 2 (5%) 0.00110–24 90 (55%) 37 (86%)³ 25 39 (24%) 4 (9%)

Female N (%) 72 (44%) 15 (35%) 0.30Residence N (%)

Slum or tinshed dwelling

52/96 (54%) 26/34 (76%) 0.03

Building 44/96 (46%) 8/34 (24%)Water source N (%)

Tube well 29/99 (29%) 9/32 (28%) 1.00City supply 70/99 (71%) 23/32 (72%)

Pre-admissionantibiotic use, N (%) 50/164 (30%) 9/43 (21%)

0.26

Days of diarrheamedian (range) 4 (0–15) 3 (1–14)

0.69

Days of vomitingmedian (range) 2 (0–10) 2 (0–12)

0.70

Days of fevermedian (range) 7 (1–15) 5 (1–15)

0.30

Severe dehydrationstatus, N (%) 34/164 (21%) 23/41 (56%)

< 0.001

Temperature ( °C)median (range) 39.2 (36–41) 39.5 (35–42)

0.48

Heart rate(beats/minute)median (range)

108 (60–170) 112 (62–150)0.49

Respiratory rateper minutemedian (range)

28 (18–68) 32 (16–50)0.03

Oxygen saturation (%)median (range) 97 (80–100) 96 (72–100)

0.02

Hematocrit (%)mean (SD)

34.6 (4.6) 33.1 (4.2) 0.19

WBC median(range)

6.6 (2.0–18.2) 5.1 (1.7–18.4) 0.001

Plateletsmedian (range)

140 (44–353) 66 (23–208) < 0.001

Multidrug-resistantSalmonella TyphiN (%)

58/164 (35%) 13/43 (30%)0.59

Widal TO titer³ 1:160 (%)

73/137 (53%) 16/34 (47%) 0.57

Widal TH titer³ 1:640 (%)

46/137 (34%) 25/34 (74%) < 0.001

Multidrug-resistant Salmonella Typhi is defined as resistant to chloramphenicol, amoxi-cillin, and cotrimoxazole (trimethoprim/sulfamethoxazole). WBC = admission peripheralblood white blood cell count.

TYPHOID ENCEPHALOPATHY IN BANGLADESH 699

164 bacteremic patients without encephalopathy and 30 of43 patients with encephalopathy. Of 207 total patients, therewas only one death, which occurred in a patient with enceph-alopathy. This patient was 18 years old, had a GCS of 4 onadmission, and died within 24 hours of admission because ofshock. All others recovered.

DISCUSSION

Typhoid fever is a major cause of mortality and morbidityin developing countries worldwide, with the highest geo-graphic burden of disease in Asia, especially in major urbancenters.17–19 Encephalopathy is a potentially fatal compli-cation of typhoid fever, and here, we describe clinical anddemographic factors associated with this disease entity inDhaka, Bangladesh.We show that older children and young adults have higher

rates of encephalopathy among those patients hospitalizedwith Salmonella Typhi bacteremia than younger children andolder adults. In multivariate analysis, age of 10–24 years wasindependently associated with encephalopathy. Studies haveshown that differences in mean age of patients with typhoidvary by region, and they are likely related to burden ofdisease, with lower ages in countries with high incidence.20 Inpopulation-based surveillance from endemic areas, ratesof Salmonella Typhi bacteremia are highest in those patientsaged < 5 years.17,18,20,21 However, hospital-based surveillancestudies have shown that older children and young adultsaccount for the majority of hospitalizations for typhoidfever,10,19 and they suggest that younger adults have greaterneuropsychiatric morbidity during typhoid fever comparedwith older adults.22 The reasons behind these findings areunclear. Because encephalopathy may be associated withsevere typhoid and because Gram-negative bacteremia isuncommon in older children and young adults, it is possiblethat this finding may be a response of this age group to Gram-negative bacteremia itself; however, we were unable to iden-tify any cases of encephalopathy in adolescents and youngadults with non-Salmonella Typhi Gram-negative bacteremiaat the icddr,b during the same period using the same criteria.It is also possible that older children and young adults are ableto mount more prominent inflammatory responses than youn-ger children and that encephalopathy may be associated withsuch responses. This possibility is also supported by the obser-vation that intestinal perforation during typhoid is also morecommon in older children and adults than young children andthat perforation may be associated with hyperplasia of intes-tinal lymphoidal tissue caused by previous antigenic expo-sure.3,10 Although other investigators have also hypothesizedthat a greater inflammatory response is responsible for path-ogenesis of severe typhoid, including encephalopathy,11,23 the

association of age with inflammatory response against typhoidhas yet to be investigated in detail.The Widal test is the oldest and most widely used serologic

test for typhoid fever, although its use is complicated by sig-nificant cross-reactivity with other Salmonella spp. and non-Salmonella pathogens and considerable interlaboratoryvariability.24 The Widal TH is an agglutination test, primarilyrepresenting immunoglobulin G (IgG) directed against the fla-gella antigen (H antigen) of Salmonella Typhi. Our multivariateanalysis showed that a Widal TH titer of ³ 1:640 was indepen-dently associated with encephalopathy. However, theWidal TOtiter, thought to represent an IgM response against the lipopoly-saccharide (O) antigen, was not associated with encephalopa-thy. It is thought that the TH titer develops after titer of the TOand persists for a longer duration.25,26 As such, markedly highTH responses without similarly elevated TO responses duringtyphoid encephalopathy may reflect previous exposure andprominent anamnestic responses to Salmonella Typhi.Other factors that were associated with encephalopathy in

this retrospective study were likely a reflection of the increasedseverity of disease in encephalopathic patients. Severe dehy-dration was independently associated with encephalopathy,and it may be related to decreased oral intake in the confusedpatient, a marker of more severe disease and higher insensiblelosses resulting in circulatory compromise or alternatively, adirect cause of encephalopathy. Of note, we did not find anassociation with hyper- or hyponatremia and encephalopathy.Similarly, the low oxygen saturation and high respiratory ratefound to be associated with encephalopathy on univariate anal-ysis may be related to a compromised airway in patients withaltered mental status, capillary leak in early sepsis, or pneumo-nia.10 Leucopenia and thrombocytopenia were also associatedwith encephalopathy in our analysis, perhaps again reflectingthe severity of disease or the effect of Salmonella Typhi infec-tion on bone marrow progenitor cells.27

Typhoid encephalopathy is thought to occur in the thirdweek of illness,5 although it is now rare for individuals toremain untreated for this duration. In our study, the medianduration of fever did not differ significantly between thosepatients with (5 days) and without (7 days) encephalopathy.This finding is consistent with a previous report from Indone-sia that showed that patients with encephalopathy presentedwith 7–9 days of symptoms.13 However, our observation islimited by the inclusion of only culture-positive patients.Because culture yield is thought to decrease over time, wemay have missed those patients who presented later in theirdisease course and were culture-negative.Of note, we did not find an association of encephalopathy

with multidrug-resistant Salmonella Typhi, despite drug resis-tance being associated with higher mortality and morbidity ina study of Pakistani children infected with SalmonellaTyphi.28 One of the limitations of this study is that we wereunable to assess the colony count, time to culture positivity,and strain type of Salmonella Typhi isolated, and it is possiblethat differences in bacterial burden or virulence play a role indetermining central nervous system (CNS) involvement.The pathogenesis of typhoid encephalopathy remains

unknown. Salmonella Typhi is rarely found in the CNS,isolated in only 2% of patients with blood culture-positivesevere typhoid fever.13 It has been proposed that steroidsdecrease mortality in typhoid encephalopathy by reducingthe production and release of prostaglandins and free oxygen

Table 2

Multivariate correlates of encephalopathy in patients with SalmonellaTyphi encephalopathy

Variable Adjusted OR 95% CI P value

Age 10–24 years 3.7 1.1–12 0.03Female 0.7 0.3–1.8 0.49Severe dehydration 4.5 1.8–11.2 0.001WBC count 0.8 0.7–0.99 0.04Widal TH titer ³ 1:640 5.4 1.9–15.2 0.001

CI = confidence interval; OR = odds ratio; WBC count = admission peripheral blood whiteblood cell count.

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species by macrophages induced by Salmonella Typhi endo-toxin.11 Unfortunately, there has been a lack of studies to con-firm this suspicion. Small studies of encephalopathy associatedwith non-typhoidal Salmonella infection have shown thatproinflammatory cytokines are elevated in both cerebrospinalfluid (CSF) and serum,29–31 and cytokine-induced neurotoxicityhas been suggested as the cause. No studies to date have mea-sured CSF cytokines in Salmonella Typhi infection. Studiesfrom plasma of acute typhoid patients have shown elevationsin proinflammatory cytokines interleukin (IL)-6, interferon(IFN)-g, tumor necrosis factor (TNF)-R, and IL-1RA inacute disease that decrease with therapy.32 Interestingly, a studyof ex vivo lipopolysaccharide (LPS)-stimulated whole bloodfrom patients with Salmonella Typhi infection showed thatthose patients with complicated disease had lower levels ofthe proinflammatory cytokines IL-1b and TNF-a in the acutephase than those patients with uncomplicated disease.33 IFN-gcellular responses are also elevated during early typhoid fever,with themajority of this response reflectingCD4 cells.34As such,it is possible that encephalopathy may reflect a poorly under-stood effect of a prominent inflammatory response on the CNS.There are several limitations to this study. First, this study is

a retrospective chart review study extracting data from a clini-cal record. Second, complete data were not available for allpatients. Third, we did not include children less than 5 years ofage in our analysis. Fourth, we limited our analysis to patientswith confirmed Salmonella Typhi bacteremia. Despite theselimitations, however, our analysis suggests that typhoidencephalopathy may still be common in this urban area andthat prospective evaluation and standardized characterizationof encephalopathy during Salmonella Typhi bacteremia maybe warranted.In conclusion, we show that 21% of patients hospitalized at

a diarrheal hospital in Bangladesh with Salmonella Typhi bac-teremia showed features of encephalopathy and that most ofthese cases occur in individuals aged 10–24 years. We also showthat age, a Widal TH ³ 1:640, leucopenia, and severe dehydra-tion are independently associated with encephalopathy, and wehypothesize that encephalopathy in typhoid fever may be asso-ciated with an overabundant inflammatory response.

Received December 2, 2011. Accepted for publication January 26,2012.

Acknowledgments: This research study was funded by InternationalCentre for Diarrhoeal Disease Research, Bangladesh and its donors,which provide unrestricted support to International Centre forDiarrhoeal Disease Research, Bangladesh for its operations andresearch. Current donors providing unrestricted support include theAustralian Agency for International Development (AusAID), theGovernment of the People’s Republic of Bangladesh, the CanadianInternational Development Agency (CIDA), the Swedish Interna-tional Development Cooperation Agency (Sida), and the Departmentfor International Development, United Kingdom (DFID). This studywas also supported by grants from the National Institutes of Health,including Fogarty International Center Grant D43-TW005572,American Recovery and Reinvestment Act Supplement (to D.T.L.), aPostdoctoral Research Fellowship in Global Infectious Diseasesfrom the Harvard Global Health Institute (D.T.L.), a PostdoctoralFellowship in Tropical Infectious Diseases from the American Soci-ety of Tropical Medicine and Hygiene/Burroughs Wellcome Fund(D.T.L.), and National Institute of Allergy and Infectious DiseasesGrant U01-AI077883 (to E.T.R.).

Authors’ addresses: Daniel T. Leung and Edward T. Ryan, Divisionof Infectious Diseases, Massachusetts General Hospital, Boston,MA, E-mails: dleung@partners.org and etryan@partners.org. Jori

Bogetz and Megumi Itoh, Department of Pediatrics, Stanford Univer-sity School of Medicine, Palo Alto, CA, E-mails: jbogetz@stanford.edu and mitoh@stanford.edu. Lakshmi Ganapathi, Department ofPediatrics, Children’s Hospital Boston, Boston, MA, E-mail: Lakshmi.Ganapathi@childrens.harvard.edu. Mark A. C. Pietroni andMohammod Jobayer Chisti, Dhaka Hospital and Centre for Nutri-tion and Food Security, Intensive Care Unit and Respiratory Ward,International Centre for Diarrhoeal Disease Research, Bangladesh,Mohakhali, Dhaka, Bangladesh, E-mails: markp@icddrb.org andchisti@icddrb.org.

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