Typhoid fever is a major cause of mortality and morbidity in developing countries worldwide, with the highest geographic burden of disease in Asia, especially in major urban centers.17–19
Encephalopathy is a potentially fatal complication of typhoid fever, and here, we describe clinical and demographic factors associated with this disease entity in Dhaka, Bangladesh.
We show that older children and young adults have higher rates of encephalopathy among those patients hospitalized with Salmonella
Typhi bacteremia than younger children and older adults. In multivariate analysis, age of 10–24 years was independently associated with encephalopathy. Studies have shown that differences in mean age of patients with typhoid vary by region, and they are likely related to burden of disease, with lower ages in countries with high incidence.20
In population-based surveillance from endemic areas, rates of Salmonella
Typhi bacteremia are highest in those patients aged < 5 years.17,18,20,21
However, hospital-based surveillance studies have shown that older children and young adults account for the majority of hospitalizations for typhoid fever,10,19
and they suggest that younger adults have greater neuropsychiatric morbidity during typhoid fever compared with older adults.22
The reasons behind these findings are unclear. Because encephalopathy may be associated with severe typhoid and because Gram-negative bacteremia is uncommon in older children and young adults, it is possible that this finding may be a response of this age group to Gram-negative bacteremia itself; however, we were unable to identify any cases of encephalopathy in adolescents and young adults with non-Salmonella
Typhi Gram-negative bacteremia at the icddr,b during the same period using the same criteria. It is also possible that older children and young adults are able to mount more prominent inflammatory responses than younger children and that encephalopathy may be associated with such responses. This possibility is also supported by the observation that intestinal perforation during typhoid is also more common in older children and adults than young children and that perforation may be associated with hyperplasia of intestinal lymphoidal tissue caused by previous antigenic exposure.3,10
Although other investigators have also hypothesized that a greater inflammatory response is responsible for pathogenesis of severe typhoid, including encephalopathy,11,23
the association of age with inflammatory response against typhoid has 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 significant cross-reactivity with other Salmonella
spp. and non-Salmonella
pathogens and considerable interlaboratory variability.24
The Widal TH is an agglutination test, primarily representing immunoglobulin G (IgG) directed against the flagella antigen (H antigen) of Salmonella
Typhi. Our multivariate analysis showed that a Widal TH titer of ≥ 1:640 was independently associated with encephalopathy. However, the Widal TO titer, thought to represent an IgM response against the lipopolysaccharide (O) antigen, was not associated with encephalopathy. It is thought that the TH titer develops after titer of the TO and persists for a longer duration.25,26
As such, markedly high TH responses without similarly elevated TO responses during typhoid encephalopathy may reflect previous exposure and prominent anamnestic responses to Salmonella
Other factors that were associated with encephalopathy in this retrospective study were likely a reflection of the increased severity of disease in encephalopathic patients. Severe dehydration was independently associated with encephalopathy, and it may be related to decreased oral intake in the confused patient, a marker of more severe disease and higher insensible losses resulting in circulatory compromise or alternatively, a direct cause of encephalopathy. Of note, we did not find an association with hyper- or hyponatremia and encephalopathy. Similarly, the low oxygen saturation and high respiratory rate found to be associated with encephalopathy on univariate analysis may be related to a compromised airway in patients with altered mental status, capillary leak in early sepsis, or pneumonia.10
Leucopenia and thrombocytopenia were also associated with encephalopathy in our analysis, perhaps again reflecting the severity of disease or the effect of Salmonella
Typhi infection on bone marrow progenitor cells.27
Typhoid encephalopathy is thought to occur in the third week of illness,5
although it is now rare for individuals to remain untreated for this duration. In our study, the median duration of fever did not differ significantly between those patients with (5 days) and without (7 days) encephalopathy. This finding is consistent with a previous report from Indonesia that showed that patients with encephalopathy presented with 7–9 days of symptoms.13
However, our observation is limited by the inclusion of only culture-positive patients. Because culture yield is thought to decrease over time, we may have missed those patients who presented later in their disease course and were culture-negative.
Of note, we did not find an association of encephalopathy with multidrug-resistant Salmonella
Typhi, despite drug resistance being associated with higher mortality and morbidity in a study of Pakistani children infected with Salmonella
One of the limitations of this study is that we were unable to assess the colony count, time to culture positivity, and strain type of Salmonella
Typhi isolated, and it is possible that differences in bacterial burden or virulence play a role in determining 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-positive severe typhoid fever.13
It has been proposed that steroids decrease mortality in typhoid encephalopathy by reducing the production and release of prostaglandins and free oxygen species by macrophages induced by Salmonella
Unfortunately, there has been a lack of studies to confirm this suspicion. Small studies of encephalopathy associated with non-typhoidal Salmonella
infection have shown that proinflammatory cytokines are elevated in both cerebrospinal fluid (CSF) and serum,29–31
and cytokine-induced neurotoxicity has been suggested as the cause. No studies to date have measured CSF cytokines in Salmonella
Typhi infection. Studies from plasma of acute typhoid patients have shown elevations in proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-R, and IL-1RA in acute disease that decrease with therapy.32
Interestingly, a study of ex vivo
lipopolysaccharide (LPS)-stimulated whole blood from patients with Salmonella
Typhi infection showed that those patients with complicated disease had lower levels of the proinflammatory cytokines IL-1β and TNF-α in the acute phase than those patients with uncomplicated disease.33
IFN-γ cellular responses are also elevated during early typhoid fever, with the majority of this response reflecting CD4 cells.34
As such, it is possible that encephalopathy may reflect a poorly understood 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 clinical record. Second, complete data were not available for all patients. Third, we did not include children less than 5 years of age in our analysis. Fourth, we limited our analysis to patients with confirmed Salmonella Typhi bacteremia. Despite these limitations, however, our analysis suggests that typhoid encephalopathy may still be common in this urban area and that prospective evaluation and standardized characterization of encephalopathy during Salmonella Typhi bacteremia may be warranted.
In conclusion, we show that 21% of patients hospitalized at a diarrheal hospital in Bangladesh with Salmonella Typhi bacteremia showed features of encephalopathy and that most of these cases occur in individuals aged 10–24 years. We also show that age, a Widal TH ≥ 1:640, leucopenia, and severe dehydration are independently associated with encephalopathy, and we hypothesize that encephalopathy in typhoid fever may be associated with an overabundant inflammatory response.