Efecto experimental de las radiaciones ionizantes en el pulmón:

Mini-Review Article

Epidemiology of typhoid and paratyphoid fever in India

Suman Kanungo1, Shanta Dutta2, and Dipika Sur1
1Division of Epidemiology, National Institute of Cholera and Enteric Diseases, Kolkata, India
2Division of Microbiology, National Institute of Cholera and Enteric Diseases, Kolkata, India


Abstract
Enteric fever (typhoid and paratyphoid fever) is a major human bacterial infection. Although the disease is not common in industrialised
countries, it remains an important and persistent health problem in developing nations. Hospital-based studies and outbreak reports from
India indicate that enteric fever is a major public health problem in this country, with Salmonella enterica serovar Typhi (S. Typhi) the most
common aetiologic agent but with an apparently increasing number of cases due to S. Paratyphi A (SPA). Because risk factors such as poor
sanitation, lack of a safe drinking water supply and low socio economic conditions in resource-poor countries are amplified by the evolution
of multidrug resistant salmonellae with reduced susceptibility to fluoroquinolone, treatment failure cases have been reported in India, which
is associated with increased mortality and morbidity. Vaccination, which requires strict planning and proper targeting of the vulnerable age
groups, is considered to be an effective tool in controlling this disease in endemic areas, given there is development of a conjugate vaccine
against both serovars (S. Typhi and S. Para A).

Key Words: Typhoid, multidrug resistance, Salmonella Typhi and Paratyphi, antimicrobials, vaccination
J Infect Developing Countries 2008; 2(6):454-460.
Received 14 June 2008 - Accepted 19 September 2008
Copyright 2008 Kanungo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction
persistent health problem in developing nations [2]. Clinical syndromes caused by Salmonella infection Hospital-based studies and outbreak reports from India in humans are broadly divided into two groups. The indicate that enteric fever is a major public health first, enteric fever, is transmitted by contaminated water problem in this country, with Salmonella Typhi (S. or food, and is caused mainly by Salmonella enterica Typhi) the most common aetiologic agent but with an serovar Typhi (typhoid fever) or Salmonella enterica apparently increasing number of cases due to S. serovar Paratyphi A, B or C (paratyphoid fever). The Paratyphi A. S. Paratyphi B and S. Paratyphi C are secondly, a range of clinical syndromes including relatively uncommon in India. There have been two diarrhoeal disease, is caused by a large number of non- large-scale studies in India on the incidence of blood typhoidal Salmonella serovars (NTS) [1]. Salmonellae culture confirmed typhoid fever, one among individuals under 40 years old [3] and another among children 6 to facultative anaerobic bacilli that ferment glucose, 17 years old [4], but as yet, none on paratyphoid fever. reduce nitrate to nitrite, and synthesise peritrichous Thus, the actual burden of paratyphoid fever in India flagella when motile. Salmonella is a genus in the and its incidence and characteristics relative to typhoid family Enterobacteriaceae that has more than 2,300 fever are poorly understood. In a study conducted in serotypes, based on the presence of three main antigens: Punjab that examined 340 enteric fever cases, 334 S. somatic O antigen (lipopolysaccharide cell wall Typhi and 6 Paratyphi A isolates were identified [5]. component), surface Virulent (Vi) antigen (S. Typhi and This scenario, however, has changed as recent studies S. Paratyphi C only), and flagellar H antigen. Here we have highlighted the increasing occurrence of will restrict our description to the epidemiology of Typhoid fever incidence varies substantially in Asia. Very high typhoid fever incidence has been found Burden of enteric fever in India
in India and Pakistan [11]. In comparison, typhoid fever frequency was moderate in Vietnam and China and industrialised countries, it remains an important and intermediate in Indonesia. [12]. Worldwide, the Kanungo et al. – Typhoid and paratyphoid fever in India J Infect Developing Countries 2008; 2(6): 454-460. emergence of multidrug resistant S. Typhi and S. Researchers from New Delhi, India, reported that S. Paratyphi A strains has been shown to be Typhi (75.7%) was the predominant serovar isolated geographically heterogeneous [12-13], underscoring the during the study period followed by S. Paratyphi A importance of continuing microbiological surveillance (23.8%) [17]. The maximum number of enteric fever cases occurred during April to June (dry season) antimicrobial resistance profile at the country level. followed by July to September (monsoon season) [19]. Studies completed in Kolkata urban slums show a Transmission, seasonality and risk factors of
seasonal variation of the incidence of both typhoid and enteric fever
paratyphoid fever, with monsoon months being the Humans are the only reservoir for these organisms. The main source of infection is the stool of infected persons; other sources are contaminated water, food, Figure 1. Month-wise variation of typhoid and paratyphoid
and possibly flies. Lack of sanitation and clean running water cause contamination for long periods of time in resource-poor countries. Contaminated surface water further contaminates the water supply. In addition, it is seldom possible for the population in poor countries either to boil their drinking water, or to sterilise the Enteric disease is caused by both waterborne and food-borne infectious agents which gain access via the gastrointestinal tract. The onset depends mainly on the virulence of the organism and the infective dose. Humans can be both cases and carriers. They usually secrete the organism for an average of 6 to 8 weeks and 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 5 5 5 5 5 5 6 6 6 6 6 6 6 6 carrier status usually diminishes after 6 to 8 months [1]. In India, enteric disease is most prevalent in urban areas, with incidence approaching one percent of the Exposure of the individual to contaminated food or population annually in some endemic areas [15]. water correlates closely with the risk for enteric fever. Usually children 15 years of age and younger are more Since public health interventions, such as water susceptible, most probably because adults develop improvement or vaccination campaigns, are usually immunity from recurrent infection and sub-clinical implemented for groups of individuals, a large enteric cases. A large-scale community study performed in an fever surveillance study was conducted and factors were Indian urban slum showed incidence as high as 2 per analysed which correlate with enteric fever on an 1,000 population per year for children under five, and individual level alongside factors associated with high- 5.1 per 1,000 population per year for children under ten and low-risk areas with enteric fever incidence [18]. [16]. Another study in Northern India showed that the Thus the individual level data were linked to a majority of cases occurred in children aged 5 to 12 population-based geographic information system. In the years and 24.8% of cases were in children up to 5 years study, individual and household level variables were of age [17]. Salmonella serovars showed an age-related fitted in Generalized Estimating Equations (GEE) with bias, with paratyphoid fever more common in adults. the logit link function to take into account the likelihood One study from Kolkata showed the incidence of that household factors correlated within household paratyphoid fever was lower (0.8/1000/year), and the members. Over a 12-month period, 80 typhoid fever mean age of paratyphoid patients was older (17.1 years) cases and 47 paratyphoid fever cases were detected compared to typhoid fever (incidence 1.4/1000/year, among 56,946 residents in two bustees (slums) of Kolkata, India. Residents in areas with a high risk for Typhoid fever is usually observed throughout the typhoid and paratyphoid fever had lower literacy rates year. Some studies show a peak of the disease from July and economic status, a bigger household size, and to September, as it coincides with the rainy season resided closer to water bodies and study treatment when the chance of water contamination is high, centres than residents in low-risk areas. Predictors for both typhoid and paratyphoid fever were found to be Kanungo et al. – Typhoid and paratyphoid fever in India J Infect Developing Countries 2008; 2(6): 454-460. similar [18]. In contrast, a study conducted in Jakarta, pattern) a range of nonspecific symptoms may be Indonesia, showed that the risk factors are more associated with typhoid fever. These include chills, prevalent outside the household in paratyphoid rather constipation, diarrhoea, weakness, dizziness, nausea and Chronic carriers of typhoid play a crucial role in cough. Diarrhoea may be a presenting feature especially spreading the disease throughout the community. The in immunocompromised cases and infants. Classical first essential factor in carrier prevention of infection clinical features of the disease were comparable among includes educating the general public as well as patients under and above 5 years of age but other identifying all possible carriers and sources of manifestations, such as hepatomegaly, anaemia and complications, are generally more frequent in children Invasive salmonellosis due to NTS in India
Rare symptoms, including ―Rose spots‖, relative Typhoid is a highly adapted invasive disease that is bradycardia and—in severe cases—neuropsychiatric restricted to humans and shows little association with symptoms such as muttering and delirium have also the immunocompromised. In contrast, non-typhoidal been reported [15]. Late diagnosis or failure to respond salmonelloses have a broad vertebrate host range, an to treatment may lead to serious complications, epidemiology that often involves foods and animals, including gastrointestinal hemorrhage, perforation of and a dramatically more severe and invasive the gut, and shock. There is evidence of pancreatitis [23]; splenic infarction [24] in some cases due to particular in those with HIV. The prevalence of non- typhoid. There is also evidence of vertical transmission typhoidal Salmonella (NTS) bacteraemia has risen in of the pathogen with high mortality and morbidity in many countries and is probably related to the increase in HIV infection [21]. Although invasive disease caused by NTS has been recently reported from many African Treatment
and Asian countries, the infection is relatively unknown Antibiotic therapy is the only effective treatment for in India. One study from Thailand [22] reported a total enteric fever. In the past, the drug of choice was of 135 patients with NTS bacteraemia. Salmonella chloramphenicol. It was the standard treatment until group C was predominant. The most common plasmid-mediated resistance to this drug emerged. underlying disease was HIV infection. Up to 30% of Because of severe adverse effects, a high relapse rate NTS isolates were identified as multidrug resistant. In and widespread bacterial resistance to chloramphenicol, one disease burden study from Kolkata, only one isolate ampicillin (1g given orally every 6 hours) and of S. Typhimurium and one isolate of S. Dublin were trimethoprim-sulfamethoxazole (TMP-SMX; double identified (not published) from 1,500 blood culture strength tablet given twice a day) became the mainstay With the emergence of multidrug resistant S. Typhi Clinical Features
in the late 1980s, typhoid disease was found to be Typhoid fever is a severe, contagious and life- resistant to treatment with most of the commonly used threatening systemic disease caused by Salmonella antibiotics such as chloramphenicol, ampicillin, TMP- Typhi which may result in persistent fever with or SMX, streptomycin and tetracycline. A study in the without severe complications. Typhoid often presents mid-1990s in Bangalore showed resistance to with misleading symptoms, thus making it extremely difficult to diagnose. Paratyphoid fever relates to a nalidixic acid to be as high as 95% with 90% sensitivity group of enteric illnesses caused by strains of to norfloxacin and ciprofloxacin [26]. Multidrug Salmonella Paratyphi A, B and C. Paratyphoid fever resistant outbreaks have been reported in 1995 from bears similarities with typhoid fever, but its course is Bangalore with 76% resistance to ampicillin, 64% to more benign with fewer complications [1]. chloramphenicol, and 75% to tetracycline [27]. Another Hallmarks of enteric fever include abdominal pain study in Karnataka completed in 1999 showed very and high fever, with fever being the main presenting high resistance to chloramphenicol and cotrimoxazole feature (as high as 75% of the cases) in the initial [28]. Recently multidrug resistance was seen in S. stages. Usually the incubation period is 1 to 14 days. In Typhi but less in S. Paratyphi A isolates. However, addition to fever up to 39°C, (with a typical step-ladder resistance to nalidixic acid was comparable in both Kanungo et al. – Typhoid and paratyphoid fever in India J Infect Developing Countries 2008; 2(6): 454-460. Ciprofloxacin for adults, excluding pregnant women, is presently the treatment of choice. There is a Diagnosis and Treatment of Chronic Carriers of
dramatic increase in nalidixic acid-resistant isolates with reduced susceptibility to fluoroquinolones (FQs), In developed countries where adequate medical although all isolates are susceptible to third-generation facilities exist, it is important to screen all patients, cephalosporins. Patients infected with such strains may suspects and contacts. Three negative stool cultures and not be responsive to treatment with ciprofloxacin, one negative Vi antigen blood test should be the which could lead to reports of treatment failure minimum requirements before a proven case of typhoid cases[15]. One study from Kolkata reported the fever is determined non-infectious. However, the Vi test isolation of one S. Typhi strain which demonstrated is of little use in tropical and subtropical countries high-levels of ciprofloxacin and norfloxacin resistance with 16 ug/mL of MIC [29]. Indian studies showing evidence of emergence of fluoroquinolone resistance The treatment of the chronic carrier is a difficult [30] are similar in pattern to results from other Asian problem. Trials with ampicillin have shown some success but even prolonged ampicillin administration in Pregnant women and children most often receive the convalescent stage may not prevent the carrier state ceftriaxone injections. However, all these drugs can cause adverse effects and long-term use can lead to the development of antibiotic resistance. Together, these aureomycin in patients who were excreting the typhoid constitute about 80% of the world’s typhoid burden, bacillus showed that about 25% continued to excrete the where various rates of multi drug resistance (16 to 37%) bacillus after completion of the treatment. Presently, it and nalidixic acid resistance (5 to 51%) were found still appears that prophylaxis remains the best method during 2002-2004 [30]. However, there is now evidence for preventing the spread of typhoid fever by chronic that strains previously resistant to chloramphenicol have carriers who have not responded to both conservative become sensitive to treatment with chloramphenicol and operative treatment. To date, ciprofloxacin and [31]. Another study showed a change in resistance norfloxacin are found to be more effective drugs than patterns to conventional anti-typhoid microbials such as prolonged courses of ampicillin or co-trimoxazole [14]. ampicillin and chloramphenicol from 84% to 14% [32]. A study conducted in Kolkata observed that recent Prevention and Control
S. Paratyphi A isolates from Kolkata, India, were As the main route of typhoid transmission (enteric fever as a whole) is faeco-oral by contaminated food chloramphenicol, to which this organism was sensitive and water, the disease remains a serious problem in the in earlier years [33]. There was also evidence of an developing world where it is confounded by low socio- upsurge of S. Paratyphi A in Kolkata [34]. In the global economic conditions and overcrowding. Cost-of-illness context, there is evidence of increased incidence of studies have shown that the burden of disease increases enteric infections due to S. Typhi Vi-phage- type E1 in most countries upon the emergence of multi-drug and S. Paratyphi A phage type PT1 in the western world resistant forms of enteric fever (unpublished data). among those who had traveled to India and Pakistan in Hence, a need for prevention and control has gained enormous importance in recent years. As humans are The latest studies showed evidence of significant the only reservoir of this faeco-orally transmitted resistance to ciprofloxacin and early evidence of disease, preventive measures include improvement of resistance to ceftriaxone [36]. These observations correspond with the global picture. In Vietnam, However, instituting these measures requires a huge uncomplicated typhoid fever cases due to MDR S. investment, making it an almost unachievable task, Typhi with reduced susceptibility to fluoroquinolones especially in resource-poor countries where they are have been shown to be successfully treated with a 7-day needed most. For comprehensive control measures, course of azithromycin [37]. There have been reports cases need to be diagnosed early followed by provision of isolation and emergence of S. Paratyphi A since 1996 of prompt and appropriate treatment. Carriers need to be from across India, especially from central India and identified efficiently and early treatment instituted. Orissa. The isolates were sensitive to chloramphenicol Additionally, a strong surveillance system should be in Kanungo et al. – Typhoid and paratyphoid fever in India J Infect Developing Countries 2008; 2(6): 454-460. place for early detection of both cases and carriers. the efficacy of the Vi vaccine bound to nontoxic Most policy makers in developing countries resort to a recombinant Pseudomonas aeruginosa exotoxin A comprehensive approach to prevent typhoid through (rEPA) among children 2 to 5 years of age showed that immunisation, thus combining a short-term measure it is safe and immunogenic and has more than 90% with long-term solutions. An effective vaccine against efficacy in this age group [42]. A large-scale, S. Para A is not available to date. community-based demonstration trial of the Vi vaccine has recently been concluded in Kolkata, India, among a Vaccines
population of 60,000 with a coverage of 69%. The Vaccination of high-risk populations is considered results are awaited. If proven effective, this vaccine can the most promising strategy for the control of typhoid be incorporated in India’s public health program. fever. The concept of vaccination against typhoid began Despite the availability of these vaccines and the in the 1960s when field trials showed the effectiveness WHO’s recommendation for the use of vaccines among of a killed vaccine, reporting a protection rate of school children in endemic areas, the use is quite approximately 70% after two doses [39]. It was a heat- limited because of cost, lack of proper data, and the inactivated, phenol preserved, whole cell typhoid and vaccine’s ineffectiveness in children under 2 years of paratyphoid vaccine constituting S. Typhi, S Paratyphi age. In view of the increasing number of infections with A and S. Paratyphi B. The vaccine had a reasonable S. Paratyphi A, development of a suitable vaccine protection level but severe reactogenicity due to the against S. Paratyphi A is urgently needed. presence of extra protein components from S. Paratyphi A and B. The World Health Organization (WHO) Conclusion
recommended discontinuation of this vaccine as it The existence of multidrug-resistant bacteria is a evoked unacceptable adverse effects; it was thereafter serious and growing problem in the treatment of typhoid, especially in the developing world. This In the 1980s, two licensed, newer generation, well- situation has been further complicated by the emergence tolerated typhoid vaccines were available, which of quinolone resistant strains with reduced susceptibility promised protection without significant adverse effects: to FQs, which is a major concern of clinicians who treat the live, attenuated oral vaccine, Ty21a, and the enteric fever. When bacteria prove to be resistant to injectable subunit Vi polysaccharide vaccine. Studies standard antibiotics, morbidity and mortality rates conducted in Chile showed that 3 doses of Ty21a increase. Failure to treat an infection properly leads to conferred a protection of around 62% over a 7-year prolonged illness, thus increasing the chance of period and almost 80% protection against typhoid fever developing a carrier state in which persons are over a surveillance span of 5 years. [40]. The same trial contagious and able to spread the resistant strain to showed that the vaccine conferred significant protection others. As plasmid-mediated mutagenesis among against paratyphoid B fever using pool data from two circulating strains occurs much more quickly than the different sites [41]. Both the Ty21a and Vi development of new drugs, there is always a fear that polysaccharide (PS) vaccine provide significant highly lethal strains of resistant bacteria will evolve, protection against typhoid by distinctly different leaving physicians with no effective way to combat immune mechanisms. Vi stimulates the IgG antibody them. Therefore, vaccination has been proven to be an while Ty21a induces humoral and cell-mediated effective way of controlling typhoid in resource-poor immune responses but not the Vi antibody [42]. countries, especially in vulnerable age groups, mainly The Vi vaccine has been targeted for accelerated introduction into public health programs, due to several However, the proportion of prevalence of typhoid advantages it has over Ty21a, including consistent and paratyphoid around the globe is changing due to efficacy results (64-77%) even in areas of high typhoid altered urbanisation and food habits. As the risk factors incidence [ 43]; a single-dose regimen; the lack of for both diseases may not coincide, the typhoid vaccine is not found to be protective against paratyphoid. Some requirements. A review article showed that both the other strategy, such as the development of a suitable Ty21a and Vi vaccines are less toxic and equally conjugate vaccine against both serovars, is required to effective than the conventional vaccine [40]. In South control the endemicity of the disease in developing Africa, Vi provided a protection coverage of 55% over a 3-year period [44]. A study done in Vietnam to elicit Kanungo et al. – Typhoid and paratyphoid fever in India J Infect Developing Countries 2008; 2(6): 454-460. predictors for typhoid and paratyphoid fever in Kolkata, India. References
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Conflict of interest: No conflict of interest is declared.
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