Infectious Diseases in Clinical Practice:
Typhoid Fever: Current Concepts
Bhutta, Zulfiqar A. MB, BS, FRCP, FRCPCH, PhD
Department of Pediatrics and Child Health, The Aga Khan University, Karachi, Pakistan.
Address correspondence and reprint requests to Zulfiqar A. Bhutta, MB, BS, FRCP, FRCPCH, PhD, Chairman, Department of Paediatrics and Child Health, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. E-mail: Zulfiqar.email@example.com.
Abstract: Infectious diseases account for most of the 10 million annual deaths globally in children younger than 5 years. In recent years, data indicating that typhoid fever is a major cause of morbidity among the urban and periurban populations and the single most important cause of febrile bacteremia in febrile children has emerged. In several community-based studies from south Asia, the incidence rate seems to be especially high among young children, with rates exceeding 500 to 1000 cases per 100,000 population. In contrast, nontyphoidal salmonella infections in Africa seem to be an important cause of community-acquired bacteremia, especially among HIV-infected populations.
Although isolated cases of chloramphenicol resistance in Salmonella typhi have been known for a long time, the mid 1980s saw the emergence of strains of S. typhi resistant to all the 3 primary oral antibiotics. In recent years, there has also been a marked increase in quinolone-resistant isolates. Although the exact determinants and factors associated with endemic disease and outbreaks of drug-resistant cases of typhoid are uncertain, there does seem to be an association with crowding, lack of sanitation and hygiene, and access to street foods.
The appropriate and rapid diagnosis of typhoid remains a challenge with a variety of serological diagnostic tests and polymerase chain reaction-based techniques. Given the limited resources available for case management, appropriate antimicrobial therapy of multidrug- and quinolone-resistant typhoid poses particular problems in developing countries, especially because of the rapid emergence of resistant strains in recent years. Therefore, it is imperative that the focus clearly remain on preventive strategies for typhoid, including safe water, hygiene, and appropriate vaccination strategies.
Despite the vast advances in public health and hygiene in much of the developed world, enteric fever (more commonly termed typhoid fever) remains endemic in many developing countries. Typhoid fever is caused by Salmonella enterica serovar Typhi (S. typhi), a Gram-negative bacterium. A very similar but often less severe disease is caused by S. paratyphi A and, less commonly, by S. paratyphi B (Schotmulleri) and S. paratyphi C (Hirschfeldii).
Human volunteer experiments established an infecting dose of about 105 to 109 organisms with an incubation period ranging from 4 to 14 days, depending on the inoculating dose of viable bacteria.1 After ingestion, S. typhi are thought to invade the body through the gut mucosa in the terminal ileum, possibly through specialized antigen-sampling cells, known as M cells, which overlie gut-associated lymphoid tissues, through enterocytes, or via a paracellular route. After attachment to the microvilli, S. typhi crosses the intestinal mucosal barrier by an intricate mechanism involving membrane ruffling, actin rearrangement, and internalization in an intracellular vacuole. After passing through the intestinal mucosa, S. typhi enters the mesenteric lymphoid system, and then passes into the bloodstream via the lymphatics. This primary bacteremia is usually symptomless, and blood cultures are frequently negative at this stage of the disease. The blood-borne bacteria are disseminated throughout the body and are thought to colonize the organs of the reticuloendothelial system, where they may replicate within macrophages. After a period of bacterial replication, S. typhi are shed back into the blood, causing a secondary bacteremia, which coincides with the onset of clinical symptoms and marks the end of the incubation period (Fig. 1).
In addition to the virulence of the infecting organisms, host factors and immunity may also play an important role in predisposition to infection. Similar to studies in murine models, a recent study has indicated an association between susceptibility to typhoid fever and genes within the major histocompatibility complex class II and class III loci.2 To illustrate, carriers pass a large number of virulent bacilli into the intestine daily, which are then excreted in the stool, without entering the epithelium of the host. Patients who are infected with HIV are at significantly increased risk of clinical infection with S. typhi and S. paratyphi.3 Similarly, patients with Helicobacter pylori infection also have increased risk of acquiring typhoid.4
EPIDEMIOLOGY AND RECENT BURDEN ESTIMATES
There are few established surveillance systems for typhoid in the developing world, especially in community settings; as a result, the true problem is difficult to estimate. Recent estimates indicate that there may be at least 21.7 million typhoid cases annually (with an estimated 5.4 million cases due to paratyphoid). However, the global mortality estimates of about 200,000 deaths have been revised 3-fold downward from previous estimates.5,6 The incidence rate of typhoid fever in developed countries is lower than 15 cases per 100,000 population, with most cases occurring among travelers. In contrast, the incidence varies considerably in the developing world, with estimated incidence rates ranging from 100 to 1000 cases per 100,000 population. Several population-based studies from south Asia7-9 also indicate that, contrary to previous views, the age-specific incidence of typhoid may be highest in children younger than 5 years, with comparatively higher rates of complications and hospitalization. In contrast with previous studies in Latin America10 and Africa11 suggesting that S. typhi infection may cause either a benign bacteremia or mild disease in infancy and childhood, the consistency of data between the south Asian studies may reflect the risk of early exposure to relatively large infecting dose of the organisms in these populations.
There may be other factors that affect the changing epidemiology of typhoid. Although the overall ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10:1, the proportion of S. paratyphi infections is increasing in some parts of the world12 (Dong Mei Tan personal communication, 2005). In addition, in contrast with the Asian situation, the HIV and AIDS epidemic in Africa has also been associated with a concomitant increase in community-acquired bacteremia caused by nontyphoidal salmonellae, such as S. typhimurium,3,13 and an illness that may be clinically indistinguishable from typhoid. The exact reasons for these differences in the spectrum of salmonella infections between Asia and Africa remain unclear.
Another worrying development in typhoid has been the emergence of drug-resistant typhoid. After the sporadic outbreaks of chloramphenicol-resistant typhoid between 1970 and 1985, many strains of S. typhi developed plasmid-mediated multidrug resistance (MDR) to all the 3 primary antimicrobials (ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole).14 Although this was countered by the availability and advent of oral quinolones, the chromosomally acquired quinolone resistance in S. typhi has been recently described in recent years from various parts of Asia15 and may be related to the widespread and indiscriminate use of these agents in population settings.16
The incubation period is usually 7 to 14 days but is also dependent on the infecting dose (range, 3-30 days). The clinical presentation of typhoid fever varies from a mild illness with low-grade fever, malaise, and slight dry cough to a severe clinical condition with abdominal discomfort and multiple complications. The advent and availability of antibiotic therapy has changed the presentation of typhoid fever; the classic mode of presentation with a slow and "stepladder" rise in fever and toxicity is now rare.17
Many factors influence the severity and overall clinical outcome of the infection. These include the duration of illness before the initiation of appropriate therapy, the choice of antimicrobial treatment, age, exposure or vaccination history, the virulence of the bacterial strain, the quantity of inoculum ingested, and several host factors affecting the immune status.
The presentation of typhoid fever may also differ according to age. Although previous data from South America and other parts of Africa suggested that typhoid may present as a mild illness in young children,10,11 this may vary in different parts of the world. There is emerging evidence from south Asia that the presentation of typhoid may be more dramatic in children younger than 5 years, with comparatively higher rates of complications and hospitalization.7-9 Diarrhea, toxicity, and complications, such as disseminated intravascular complications, are also more common in infancy, with higher case fatality rates. However, some of the other features and complications of typhoid fever observed in adults, such as relative bradycardia, neurological manifestations, and gastrointestinal bleeding, are relatively rare in childhood.
Typhoid fever usually presents with high-grade fever with a wide variety of associated features, such as generalized myalgia, abdominal pain, hepatosplenomegaly, abdominal pain, and anorexia. In younger children, diarrhea may be a more common presentation in the earlier stages of the illness and may be followed by constipation. In the absence of localizing signs, the early stage of the disease may be difficult to differentiate from other endemic diseases, such as malaria or dengue fever. In about 25% of cases, a macular or maculopapular rash (rose spots) may be visible around the 7th to the 10th day of the illness, and lesions may appear in crops of 10 to 15 on the lower chest and abdomen and may last 2 to 3 days. These lesions may be difficult to see in dark-skinned children. Table 1 shows some of the common clinical features observed among children with typhoid fever in south Asia based on a longitudinal series of culture-proven cases presenting to ambulatory settings in either community or hospital settings.9,18 These data highlight the fact that hospital-based series may represent more severe disease than that presenting in community settings.
The presentation of typhoid fever may be tampered by coexisting morbidities and early administration of antibiotics. In malaria-endemic areas and in parts of the world where schistosomiasis is common, the presentation of typhoid may also be atypical.19,20 It is also recognized that MDR typhoid is a more severe clinical illness with higher rates of toxicity, complications, and case fatality rates.21 This may be related to the increased virulence of MDR S. typhi and to the higher number of circulating bacteria.22 These findings may have implications for treatment algorithms, especially in endemic areas with high rates of MDR typhoid.
If no complications occur, the symptoms and physical findings gradually resolve within 2 to 4 weeks; however, the illness may be associated with malnutrition in a number of affected children. Although the enteric fever caused by S. paratyphi organisms (paratyphoid) has been classically regarded as a milder illness, recent reports of infections with drug-resistant isolates indicate that paratyphoid fever may also be severe with significant morbidity and complications.23
Although altered liver function is found in many patients with enteric fever, clinically significant hepatitis, jaundice, and cholecystitis are relatively rare and may be associated with higher rates of adverse outcome.
Intestinal perforation may be preceded by marked increase in abdominal pain (usually in the right lower quadrant), tenderness, vomiting, and features of peritonitis. Intestinal perforation and peritonitis may be accompanied by a sudden rise in pulse rate, hypotension, marked abdominal tenderness and guarding, and subsequent abdominal rigidity. A rising white blood cell count with a left shift and free air on abdominal radiographs may be seen in such cases. The relatively infrequent gastrointestinal perforations and hemorrhage in childhood compared with adults may be related to the higher frequency of intestinal lymphoid hyperplasia.24,25
Rarer complications include toxic myocarditis (which may be manifested by arrhythmias, sinoatrial block, or cardiogenic shock). Neurological complications are also relatively uncommon among children and may include delirium, psychosis, increased intracranial pressure, acute cerebellar ataxia, chorea, deafness, and Guillain Barré syndrome. Although case fatality rates may be higher with neurological manifestations, recovery usually occurs with no sequelae. Other reported complications include fatal bone marrow necrosis, disseminated intravascular coagulation, hemolytic uremic syndrome, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis.
The propensity to become a carrier follows the epidemiology of gallbladder disease, increasing with age and antibiotic resistance of the prevalent strains. Although limited data is available, the rates of chronic carriage are generally lower in children than in adults.26
DIAGNOSIS OF TYPHOID
The basis of the diagnosis of typhoid fever is a positive culture from the blood or another anatomical site. Results of blood cultures are positive in 40-60% of the patients seen early in the course of the disease, and stool and urine cultures become positive after the 1st week. The stool culture result is also occasionally positive during the incubation period. However, the sensitivity of blood cultures in diagnosing typhoid fever in many parts of the developing world is limited as widespread antibiotic prescribing may render bacteriological confirmation difficult. Although bone marrow cultures may increase the likelihood of bacteriological confirmation of typhoid, these are difficult to obtain and relatively invasive. In recent years, the development of sensitive nested PCR diagnostic techniques have made it possible to detect typhoid fever with greater sensitivity than blood cultures, thus raising questions as to whether blood cultures can be regarded as the "gold-standard" for its diagnosis.27
Other laboratory investigations are nonspecific. Although blood leukocyte counts are frequently low in relation to the fever and toxicity, there is a wide range in counts; in younger children, leukocytosis is a common association and may reach 20,000 to 25,000 cells per cubic millimeter.18,28 Thrombocytopenia may be a marker of severe illness and may accompany disseminated intravascular coagulation. Although liver function test results may be deranged, significant hepatic dysfunction is rare.
The classic Widal test measures antibodies against the O and the H antigens of S. typhi but lacks sensitivity and specificity in endemic areas. Because many false-positive and false-negative results occur, diagnosis of typhoid fever by Widal test alone is prone to error. Other relatively newer diagnostic tests using monoclonal antibodies have been developed, directly detecting S. typhi-specific antigens in the serum or S. typhi Vi antigen in the urine.29,30 However, only a few have proved sufficiently robust in large-scale evaluations. A nested polymerase chain reaction using H1-d primers has been used to amplify specific genes of S. typhi in the blood of patients; given the low level of bacteremia in enteric fever, it is a promising means of making a rapid diagnosis.28 Despite these new developments in most of the developing world, the basis of diagnosis of typhoid remains clinical, and several diagnostic algorithms have been evaluated in endemic areas.
In endemic areas, typhoid fever may mimic many common febrile illnesses without localizing signs. In children with multisystem features, the early stages of enteric fever may be confused with alternative conditions, such as acute gastroenteritis, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosis includes malaria, sepsis with other bacterial pathogens, infections caused by intracellular microorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsial diseases, and viral infections, such as dengue fever, acute hepatitis, and infectious mononucleosis. There are preliminary efforts underway to develop diagnostic tests, such as a "fever stick," that may allow the rapid diagnosis of a variety of febrile illnesses in developing countries.31
Early diagnosis of typhoid fever and institution of appropriate treatment are essential for optimal management and outcome, especially in children. The vast majority of cases can be managed at home with oral antibiotics and close medical follow-up for complications or failure to respond to therapy. However, patients with persistent vomiting, severe diarrhea, and abdominal distension may require hospitalization and parenteral antibiotic therapy. The general principles of management of typhoid include (1) general nursing and supportive care, and (2) antibiotic therapy.
General Nursing and Supportive Care
Close attention must be given to adequate rest, hydration, and correction of fluid-electrolyte imbalance. Soft, easily digestible diet should be continued unless the patient has abdominal distension or ileus. This is especially important in children because inadequate nutrition and dietary restrictions can trigger acute malnutrition and increased risk of complications.
Antipyretics (acetaminophen, 120-750 mg every 4 to 6 hours PO) should be administered as required, recognizing that despite clinical improvement, defervescence may take several days. Given the importance of overall clinical improvement, a composite typhoid morbidity score has been recommended for monitoring recovery in typhoid.32
Antibiotic therapy (the right choice, dosage, and duration) is critical to curing typhoid with minimal complications and has made an enormous contribution to the reduction of morbidity and mortality.33 Traditional therapy with either chloramphenicol or amoxicillin is associated with relapse rates of 5% to 15% and 4% to 8%, respectively, whereas the newer quinolones and third-generation cephalosporins are associated with higher cure rates. The antibiotic treatment of typhoid fever in children is also influenced by the prevalence of antimicrobial resistance. Over the last 2 decades, the emergence of MDR strains of S. typhi (ie, isolates fully resistant to amoxicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) has necessitated treatment with second-line agents, such as fluoroquinolones or cephalosporins. In recent years, the emergence of resistance to quinolones has placed tremendous pressure on public health systems because therapeutic options are limited.
Tables 2 and 3 indicate the recommended therapy for typhoid fever in uncomplicated and severe cases based on current recommendations by the World Health Organization.34 A number of additional studies have evaluated the potential of short-course treatment with newer antibiotics for the treatment of typhoid fever,35-37 although this may not succeed in MDR typhoid.38 Although it has been recommended that children with typhoid, like adults, should also be treated with fluoroquinolones, some have questioned this approach on the bases of the potential development of further resistance to fluoroquinolones after widespread use in community settings and of the fact that quinolones are still not approved by the Food and Drug Administration for use in children.39 A recent systematic review of the treatment of typhoid fever also indicates that there is little evidence to support the carte blanche administration of fluoroquinolones to all cases of typhoid;40 thus, as much as possible, treatment regimen that restricts the use of second- and third-line antibiotics for the treatment of typhoid in primary care settings must be devised.
In addition to antibiotics, the importance of supportive treatment and maintenance of appropriate nutrition and hydration must be underscored. Although additional treatment with dexamethasone (dosage, 3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hours for 48 hours) has been recommended among severely ill patients with shock, obtundation, stupor, or coma,41 this must only be done under strict, controlled conditions and supervision, and signs of abdominal complications may be masked.
The prognosis for a patient with enteric fever depends on the rapidity of diagnosis and institution of appropriate antibiotic therapy. Other factors include the age of the patient, the general state of health and nutrition, the causative salmonella serotype, and the appearance of complications. Infants and children with underlying malnutrition and those infected with MDR isolates are at higher risk of adverse outcomes.
Despite appropriate therapy, between 2% and 4% of infected children can relapse after initial clinical response to treatment. Individuals who excrete S. typhi for 6 months or longer after infection are regarded as long-term carriers. The risk of becoming a carrier is low in children and increases with age but, generally, is in less than 2% of all infected children. However, it must be emphasized that there is little recent epidemiological information on the true burden of typhoid carriers in developing countries. According to recent World Health Organization recommendations,34 proven carriers can be treated with amoxicillin or ampicillin (dosage, 100 mg/kg per day) plus probenecid (dose, 1 g orally or 23 mg/kg for children) or trimethoprim-sulfamethoxazole (dosage, 160-800 mg twice a day) for 6 weeks, with clearance rates of about 60%. Higher clearance of long-term carriers can be achieved with the administration of 750 mg of ciprofloxacin twice a day for 28 days or other quinolones.
Children with schistosomiasis can develop a chronic urinary carrier state. If cholelithiasis or schistosomiasis is present, then additional cholecystectomy or antiparasitic medication may also be required for eradication.
Of the major risk factors for outbreaks of typhoid, contamination of water supplies with sewage is the most important. Therefore, a combination of central chlorination and domestic water purification is important during outbreaks. In endemic situations, consumption of street foods, especially ice cream and cut fruits, and lack of proper hand washing have been recognized as important risk factors (Table 4).42-50 The human-to-human spread of the organisms by the long-term carriers is also an important risk factor, and attempts should therefore be made to target food handlers and high-risk groups for S. typhi carriage screening. Once identified, long-term carriers must be counseled regarding the risk of disease transmission and given advice on hand washing and preventive strategies. Recent studies on community-based strategies for hand washing promotion indicate that these can be effective in reducing the problem on diarrheal diseases and acute respiratory infections.51,52
The classic heat-inactivated whole cell vaccine is associated with an unacceptably high rate of adverse effects and has been largely withdrawn from public health use. Globally, 2 vaccines are currently available for potential use in children. An oral, live-attenuated preparation of the Ty21a strain of S. typhi has been shown to have good efficacy (range, 67%-82%) for up to 5 years.5 Significant adverse effects are rare. The Vi capsular polysaccharide can be used in people aged 2 years or older. It is administered as a single intramuscular dose, with a booster every 2 years, and has a protective efficacy of 70% to 80%. The vaccines are currently recommended for traveling into endemic areas, but a few countries have introduced large-scale vaccination strategies. Given the age spectrum and the distribution of cases in south Asia, it is important that the strategies for vaccinating preschool children be explored. The recent Vi-conjugate vaccine has been shown to have a protective efficacy exceeding 90% in younger children and may offer protection in parts of the world where a large proportion of preschool children are at risk of the disease.53
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