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Chronic Salmonella Typhi carriage at sites other than the gallbladder [1]

['Seth A. Hoffman', 'Center For Vaccine Development', 'Global Health', 'University Of Maryland School Of Medicine', 'Baltimore', 'Maryland', 'United States Of America', 'Department Of Medicine', 'Michael J. Sikorski', 'Institute For Genome Sciences']

Date: 2023-05

Typhoid fever caused by infection with Salmonella enterica subspecies enterica serotype Typhi (S. Typhi), an important public health problem in many low- and middle-income countries, is transmitted by ingestion of water or food contaminated by feces or urine from individuals with acute or chronic S. Typhi infection. Most chronic S. Typhi carriers (shedding for ≥12 months) harbor infection in their gallbladder wherein preexisting pathologies, particularly cholelithiasis, provide an environment that fosters persistence. Much less appreciated is the existence of non-gallbladder hepatobiliary chronic S. Typhi carriers and urinary carriers. The former includes parasitic liver flukes as a chronic carriage risk factor. Chronic urinary carriers typically have pathology of their urinary tract, with or without renal or bladder stones. Even as the prevalence of multidrug-resistant and extensively drug-resistant S. Typhi strains is rising, global implementation of highly effective typhoid vaccines is increasing. There is also renewed interest in identifying, monitoring, and (where possible) treating chronic carriers who comprise the long-term reservoir of S. Typhi.

Funding: This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (OPP1161058 to MML; INV-000049 to MML; INV-029806 to MML), the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK067872 to MJS), and the National Institute of Allergy and Infectious Diseases (F30AI156973 to MJS). MML is supported in part by the Simon and Bessie Grollman Distinguished Professorship at the University of Maryland School of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

Copyright: © 2023 Hoffman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Introduction

Typhoid fever, the human host-restricted infection caused by Salmonella enterica subspecies enterica serotype Typhi (S. Typhi), remains a cardinal health burden for residents of many low- and middle-income countries (LMICs) who lack potable water and improved sanitation. Residents of high-income countries (HICs) mainly acquire typhoid fever by travel to typhoid-endemic LMICs and occasionally by transmission from chronic carriers residing in HICs (including immigrants from typhoid-endemic countries). During acute typhoid infection, S. Typhi that are shed in the feces and urine of the infected individual may lead to transmission to proximal contacts (“short cycle transmission”) via contamination of food during preparation or handling by temporary or chronic carriers with improper hygiene practices [1–3]; “long cycle transmission” mainly ensues via consumption of water sources contaminated with human feces or by crops irrigated with untreated sewage [4,5].

In the pathogenesis of acute S. Typhi infection, ingested bacilli that survive gastric transit translocate from the lumen of the small intestine (mainly via M cells overlying gut-associated lymphoid tissue) to reach the mucosal lamina propria [6], enter the lymphatic drainage system, and access the blood circulation via the thoracic duct [7,8]. During this primary bacteremia [9], when typhoid bacilli are filtered from the circulation by mononuclear phagocytic cells of the spleen, liver, and bone marrow [7,8], they also reach the gallbladder hematogenously at that point or shortly thereafter by infected hepatic bile entering the gallbladder [7]. After an incubation period of approximately 8 to 14 days, the acute stage of clinical illness commences, characterized by a low-level secondary bacteremia [10,11]. Bile and bile-containing duodenal fluid yield S. Typhi at this stage, with the latter providing a useful clinical specimen for diagnostic purposes [12]. Early investigators reported that clinical specimens besides blood and stool can also serve to isolate S. Typhi from patients with acute typhoid fever including bile, urine, and skin snips of the evanescent rose spots [13]. Decades later, bone marrow, if obtainable, was ultimately confirmed as the gold standard clinical specimen [14].

Soon after the initial report of isolation of typhoid bacilli in the pre-antibiotic era [15], studies revealed that patients with acute typhoid and convalescents excrete the pathogen in their stools, and some contacts of typhoid cases shed the pathogen asymptomatically [16]. To control typhoid in endemic areas of Southwest Germany, Robert Koch established “Bacteriological Stations” to identify the source of infection (typhoid fever cases) and to render them innocuous by disinfecting their excreta [17]. Koch’s teams looked for unhygienic conditions during household visits (e.g., human feces used for fertilizer, unkempt privies) and repeatedly examined stools and urine of convalescents to determine when they ceased shedding typhoid bacilli, to reduce the risk of them transmitting the disease [17]. Less compliant cases were sent to a hospital to isolate them until their stool excretion ceased, while more compliant patients were followed in their domiciles [17]. Investigators in other countries followed Koch’s example and undertook to monitor the duration of S. Typhi excretion in stools by convalescents (reviewed by Ledingham and Arkwright) [18]. They found that a small percentage (2% to 5%) of individuals excrete typhoid bacilli for more than one year and persist in excreting for decades thereafter (Table 1) [18–20]. Most chronic stool excretors had gallbladder disease and the female:male ratio was approximately 2:1 to 4:1 (Table 1) [10,18,19]. It became recognized that chronic urinary carriers also exist [18,21], as reported by investigators who performed repetitive cultures of convalescents’ urine over time (Table 1) [13,18,22]. Urinary carriers can also shed S. Typhi for many years or decades (Table 1) [13,18,19,23–27].

Prior to 1948, there was no specific treatment for typhoid fever and the case fatality rate was 10% to 20% [28,29]. Woodward and colleagues made a historic breakthrough when in 1948 they reported that chloramphenicol could markedly curtail the course of typhoid fever and convert a potentially fatal infection into a relatively short febrile illness [30]; however, 10% to 30% of cases treated with chloramphenicol experienced relapses of milder clinical typhoid that required another course of treatment [31]. From 1950 to 1971, when oral chloramphenicol was used worldwide and S. Typhi were almost universally susceptible, this antibiotic dropped the case fatality rate to approximately 1% and became a therapeutic intervention that controlled typhoid mortality globally. However, despite its efficacy in ameliorating the duration and severity of clinical typhoid, reducing complications, and diminishing case fatality, chloramphenicol did not prevent chronic carriage [29], nor could it terminate the chronic carrier state [31].

Following large epidemics of chloramphenicol-resistant typhoid fever in Latin America and Southeast Asia in the 1970s due to S. Typhi carrying an R factor plasmid encoding resistance genes [32], newer oral antibiotics shown to be efficacious in treating chloramphenicol-resistant infections, including trimethoprim/sulfamethoxazole and amoxicillin, became the new drugs of choice [32–34]. These new effective oral antibiotics did not prevent or reliably treat the carrier state [35]. In small clinical trials conducted in the late 1980s, oral fluoroquinolone antibiotics showed promising efficacy in curing the chronic carrier state [36,37]; one study reported a chronic carrier cure rate of 92% with a 28-day regimen of ciprofloxacin [36]. Since around 1990, S. Typhi circulating in South Asia, where most of the global burden of typhoid fever exists, has become multidrug resistant (MDR), and since 2016 extensively drug-resistant (XDR) S. Typhi strains have emerged and spread; the XDR strains offer few practical options for treatment [38,39].

The diminishing ability to treat typhoid in endemic areas and among travelers has renewed interest in controlling typhoid fever morbidity and mortality burden worldwide by preventing disease with vaccines, including World Health Organization–prequalified Vi conjugate vaccines, as well as water, sanitation, and hygiene (WASH) improvements. The most widely studied licensed Vi conjugate vaccine consists of S. Typhi Vi polysaccharide linked to tetanus toxoid as the carrier protein (Typbar TCV, Bharat Biotech) [40], which has been evaluated in post-licensure effectiveness trials in Nepal [41], Malawi [42], and Bangladesh [43]. Mass immunizations to assess the impact of administration of a single dose of this vaccine to control endemic and epidemic typhoid have been carried out in Pakistan [44], India [45], Zimbabwe [46], and Samoa [47]. Results from these extensive field assessments support widespread use of Vi conjugate vaccines in typhoid-endemic areas. Should the typhoid disease burden markedly decrease in previously hyperendemic areas following high levels of vaccination coverage (and possible herd effects), one upshot will be an increased interest in identifying and monitoring the chronic carriers within the population who will constitute the long-term reservoir of infection [48–51]. Some carriers may be amenable to treatment if their isolates are fluroquinolone-susceptible [36]. Other carriers will die off within the population over several decades, once amplified transmission has been reliably interrupted [48,50,51]. This evolving global epidemiologic situation has reawakened interest in the various types of chronic S. Typhi carriers that constitute the long-term reservoir.

Since the classic physiological niche for chronic S. Typhi infection is the gallbladder, most modern studies have understandably focused on biliary carriers, the role of cholelithiasis, and S. Typhi’s ability to create biofilms on gallstones [50,52]. The prevalence of chronic S. Typhi carriers in endemic populations parallels the prevalence of cholelithiasis and chronic gallbladder disease [50,53]. Thus, chronic carriage is several-fold higher in females than males, and in older adults (>40 years of age) than younger adults and teenagers (Table 1) [50,53].

This review focuses on the less appreciated, less frequent chronic S. Typhi carriers who harbor foci of infection outside the gallbladder, including the intra- and extrahepatic bile ducts and the urinary tract. Herein, we review chronic carriage in these other anatomic sites. Although much information presented is also relevant to S. Paratyphi A and B infections, we have limited our scope to S. Typhi as the main new specific intervention becoming available, Vi conjugate vaccines, applies only to prevention and control of typhoid fever.

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[1] Url: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0011168

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