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The untreated typhoid fever can be divided into four individual stages, each with the duration of approximately one week. In general in the first week of infection, body temperature rises slowly with fever fluctuations and relative bradycardia, malaise, headache along with cough. Bloody nose or epistaxis is also observed in a quarter of cases with the high frequency of abdominal pain. The number of circulating white blood cells decrease markedly resulting in the condition known as leukopenia followed by eosinopenia along with lymphocytosis. With the appearance of these symptoms the blood cultures show positive reaction for the bacteria viz., Salmonella typhi or paratyphi. In general, the Widal test comes to be negative in the first week of infection. The second week of the infection is characterized by high fever with the temperature reaching to 40 ï¿½C (104 ï¿½F) and the patient lies prostrate. Bradycardia or phygmothermic dissociation or Faget sign, is also noticed with a dicrotic pulse wave. Delirium is although frequent but sometimes it gets agitated and due to this condition typhoid is alos known as "nervous fever". Rose spots are also seen on the lower portion of chest and abdomen majority of patients. Rhonchi also appear in the lung bases of the patients (Weinberg, 2008).
The abdomen becomes distended and painful in the right lower quadrant. Diarrhea can be suspected to occur in this stage with six to eight stools in a day with prominent green colour comparable to the pea soup and a characteristic smell. Constipation also occurs frequently. The spleen and liver get enlarged and the condition is termed as hepatosplenomegaly. Elevation of liver transaminases is also noticed. The Widal test is strongly positive at this stage with higher accumulation of anti-O and anti-H antibodies. Blood cultures are sometimes observed positive at this stage. The major symptom of this fever is that it usually rises in the afternoon in the first and second week. In the third week, a number of serious complications make their appearance. These complications are characterized by intestinal hemorrhage due to bleeding in congested Peyer's patches and this condition can become very serious but is usually not considered fatal. Intestinal perforation in the distal ileum also occurs and it is a very serious complication which is frequently fatal. It may occur without alarming symptoms until septicaemia or diffuse peritonitis occur. Encephalitis is also at risk. Neuropsychiatric symptoms also known as "muttering delirium" or "coma vigil" with picking at bedclothes or imaginary objects are also observed. Metastatic abscesses, cholecystitis, endocarditis and osteitis are also seen. The fever at this stage is still very high and oscillates very little over 24 hours. Dehydration also ensues and the patient is delirious or in a typhoid state. By the end of third week the fever starts subsiding or undergoes defervescence leading into the fourth and final week of the infection (Ryan and Ray, 2004).
The bacterium responsible for typhoid fever may spread via poor hygiene habits and public sanitation conditions, and sometimes also by the agency of flying insects feeding on faeces. Public education campaigns play important role as they encourage people to wash their hands after defecating and before handling any food item as it is an important component in controlling spread of typhoid fever. The data obtained from the United States Centers for Disease Control and Prevention (CDC) suggests that chlorination of drinking water results in dramatic decreases in the transmission of typhoid fever in U.S.A. However, a person may become an asymptomatic carrier of typhoid fever with no symptoms of the disease but bears the potential of infecting other individuals of the community.
The CDC predicts that approximately 5% of people who come across typhoid continue to carry the disease even after their recovery. The most famous asymptomatic carrier was Mary Mallon also known as "Typhoid Mary", was a young cook who infected at least 53 people with typhoid and three of them died because of the disease (New York Times, 1938). Mallon has been reported as the first perfectly healthy person responsible for "epidemic" of the typhoid. In early 20th century, many carriers of typhoid were kept under isolation ward and never released to in order to prevent further new typhoid cases. These infected people were often deteriorated mentally and they became mad by the conditions they were exposed to (BBC on Long Grove Hospital Surrey GB).
Typhoid fever still remains a devastating disease in developing countries and is still prevalent in areas with inadequate sanitation and poor hygiene conditions (Singh and Mcfeters, 1992). The causative agent or the Salmonella enterica serovar typhi is pathogenic both to man and animals with associable inflammatory reaction observed in the intestinal tract. Like other enteric pathogens, S. enterica serovar Typhi is transmitted through food or water contaminated with faeces from acutely infected person suffering from or diarrhea or chronic asymptomatic carriers (Rajiv et al. 2007). The disease is a serious systemic disease, spreading via faecal-oral route. According to a survey conducted by WHO, the annual global burden of typhoid is of 22 million new cases cases reported every year among which 5% are fatal (Ivanoff, 2003; Crump et al. 2004). Salmonella enterica subsp. enterica serovar Typhi is primarily etiological agent of a systemic infection among humans with the name enteric fever or typhoid fever (Selander et al. 1990; Kidgell et al. 2002).
Salmonella enterica serovar Typhi continues its potential to cause severe disease in many parts of the world till now and its most feared complication is perforation of ulcerated Peyerï¿½s patches in the small intestine, resulting in peritonitis with associated mortality. The disease is identified by prolonged fever, bacterial replication in the reticulo-endothelial system (RES) with significant inflammation of the lymphoid organs associated with the small intestine (Everest et al. 2001). In the developing countries, typhoid fever accounts for 5% of all deaths, with markedly different rates where typhoid fever is considered endemic. The reasons for such differences in disease severity are not known but differences in health care facilities, host immune responses, genetic factors, and perhaps in the strains of Salmonella enterica serovar Typhi circulating in areas of endemicity may play major role (Zhu et al. 1996; Everest et al. 2001).
S. typhi has a combination of characteristics that make it an effective pathogen. The disease initiates when Salmonella typhi enters gastrointestinal epithelial cells for the purpose of submucosal translocation. The organism uses Cystic fibrosis trans-membrane conductance regulator (CFTR) for entering regulatory proteins (Pier et al. 1998). The species houses an endotoxin typical of Gram negative organisms, as well as the Vi antigen which is believed to increase virulence. The Vi antigen of Salmonella typhi, is actually a capsular polysaccharide controlled by two widely separated loci, viaA and viaB. Salmonella typhi also produces and excretes a protein ï¿½invasinï¿½ that allows non-phagocytic cells to take up the bacterium, where it can survive intra-cellularly. It is also inhibits the oxidative burst of leukocytes, setting up the innate immune response ineffective. Virulence genes of Gram negative and Gram-positive bacteria are very organized in clusters termed as ï¿½Pathogenicity Islandsï¿½, located either on the bacterial chromosome or on large virulence-associated plasmids (Groisman and Ochman, 1996; Hacker et al. 1997). A DNA region of 40 kb is also located at the centisome 63 of the Salmonella chromosome which is required for the entry of the pathogen into the host cells (Galan, 1994; Groisman, 1997; Mills et al. 1995). It is also involved in macrophage cytotoxicity (Chen et al. 1996). This region is also known as ï¿½Salmonella pathogenicity island 1ï¿½ (SPI-1), as it bears the genetic information for a large number of proteins of the type-III secretion system (Mills et al. 1995). A second 40-kb pathogenicity island or SPI-2, has been also described in S. tyhimurium (Ochman et al. 1996; Hensel et al. 1997). Both these SPIï¿½s are reported to be important for different stages of the infectious life cycle of Salmonella. Virulence genes encode for the products assisting the organism in expressing its virulence inside the host cells. Some genes namely, sef, pef, spv or inv are known to be involved in adhesion and invasion, while sop, stn, pip A, B, D are responsible for survival inside the host system or in the actual manifestation of pathogenic processes (Murugkar et al. 2003).
The antibiotics commonly prescribed used for the treatment typhoid fever include chloramphenicol, ampicillin while B-lactams, sulphademidine, gentamicin, aminoglycosides, nalidixic acid, ciprofloxacin and the fluoroquinolones (norfloxacin and ofloxacin) are also in use (Girgis et al. 1999; Kadhiravan et al. 2005). In early 1990ï¿½s, multidrug resistant (MDR) strain of S. enterica serovar Typhi, resistant towards chloramphenicol, amoxicillin and cotrimoxazole, emerged and become endemic in the developing countries. The spread of this multi-drug resistance caused therapeutic and public health problems in the African continent, South East Asia and Middle East since 1987 (Samuel et al. 2000; Well, 2003).
Until mid-1970s chloramphenicol was the most preferable drug of choice for typhoid fever responsible for marked reduction in mortality from 10% to <2% in the developed countries. Unfortunately, a few sporadic isolations of chloramphenicol-resistant Salmonella enterica serotype Typhi reported from Chile and Kuwait before 1970, and multi-drug resistance of S. enterica Typhi emerged in the Indian subcontinent in 1987 (Rowe and Ward, 1997). Ciprofloxacin was then used extensively for the treatment of typhoid both in the developing and developed countries. Recent emergence of S. enterica Typhi isolates with decreased susceptibility to ciprofloxacin is now gaining worldwide attention (Herikstad et al. 1997; Threlfall et al. 1999).
Enteric fever is of grave concern in the present scenario due to the development of multidrug resistance (MDR) in Salmonella enterica serovar Typhi. The emergence and reemergence of MDR S. enterica serovar Typhi isolates was reported by Mandal et al. (2002). The emergence of MDR S. enterica serovar Typhi is due to indiscriminate use of antibiotics in the treatment of enteric fever. Under such selective pressure of antibiotics, the antibiotic-sensitive bacteria can acquire resistance traits from antibiotic-resistant strains belonging to same or different genera becoming resistant to one or more antibiotics. The R-plasmid is clinically important in the acquisition and spread of antibiotic resistance among bacteria. In Salmonella enterica serovar Typhi, R-plasmid-encoded resistance to ampicillin (A), chloramphenicol (C), cotrimoxazole (Co), and tetracycline (T) is transferable (Jevanand et al. 1997). Plasmid-mediated transferable drug resistance is also known among E. coli isolates (Bauernfeind et al. 1987). Therefore, the surveillance of R-factor among bacterial isolates is essential to trace the source of infection. Further, identification and characterization of virulence factors will provide new insights into the evolution of bacterial pathogens which could lead to the development of novel therapeutic strategies.