A review of typhoid and its recent trends

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Typhoid fever caused by Salmonella entrica serovar typhi and paratyphi. It is characterized by sudden onset of fever, headache, nausea, weight loss, diarrheoa and many other cardiac and gastro intestinal disorders. It is endemic in several regions of the world mainly the developing nations. This article is totally based on literature survey. Much focus has been made on the salmonellae. In this article much stress was done on the epidemiology of the disease. The authors also focused on the treatment of this disease which can be done by use of antibiotics, vaccination and herbal drugs. Studies were also made on the diagnosis of typhoid which are more faster and cost effective. This article is also based on the effective vaccination which will prove to be useful for the prevention and treatment of the disease. It also deals with the future herbal treatment using plant extracts. This article will be beneficial for the people working in the field of infectious disease.

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Key words. Typhoid, Salmonellae, Vaccination, Diagnosis

Introduction

Typhoid is the major endemic disease which usually occurs in the developing nations by enteric organism Salmonella enteric serovar Typhi and Paratyphi. The Who estimates more than 600000 deaths each year. Typhoid fever is most common in school and pre school aged children i.e 19 years. It is mainly transmitted by contaminated food and water with faeces and urine of patients and carriers. Important vehicles include raw fruits, vegetables fertilized by night soil and eaten raw, contaminated milk and milk products usually by hands of carriers and missed cases. Flies may infect food in which the organisms then multiplies to achieve an infective dose. The incubation period depends upon the size of the infecting dose from 3 days to three months with an usual range of 1-3 weeks. For paratyphoid fever it is as low as 1-10 days. As long as bacilli appear in excreta, usually from the first week throughout convalescence; variable thereafter (commonly 1-2 weeks for parathyroid). About 10% of untreated typhoid fever patients will discharge bacilli for 3 months after onset of symptoms, and 2%- 5% become permanent carriers. The etiologic organisms can be isolated from the blood early in the disease and from urine and feaces after the first week; A fourfold rise in somatic (O) agglutination titers in paired sera appears during the second week in less than 70% of cases of typhoid fever; when it occurs, it supports the diagnosis, provided vaccine had not been given recently. Disease is characterized by insidious onset of sustained fever, severe headache, anorexia, a relative bradycardia, splenomegaly. Constipation more commonly than diarrhea (in adults). In typhoid fever, ulceration of Peyer patches in the ileum can produce intestinal hemorrhage or perforation (about 1% of cases), especially late in untreated cases. Severe forms have been described with cerebral dysfunction. Paratyphoid fever presents a similar clinical picture, but tends to be milder, and the case-fatality rate is much lower. Relapses may occur in approximately 3%- 4% of cases. The usual case-fatality rate of 10% can be reduced to <1% with prompt antibiotic therapy. It is much lower in Paratyphoid fevers. Intestinal perforation, Typhoid encephalopathy and chronic carrier states are some of the complications. For enteric fever, chloramphenicol, amoxicillin or TMP-SMX (particularly in children) have comparable high efficacy for acute infections. Quinolone derivatives especially Ciprofloxacin are quite effective, as are the third-generation cephalosporins. All isolates should be checked for drug resistance. The best method of prevention is consume food that is safe e.g. food and water that is either boiled, cooked or can be peeled. Vaccines (both oral and injectable) are available and are effective immunization. Ty21 a is an effective vaccine for age group 6 to be administered orally as capsule with the efficacy of 50-70% in age group >5 years. Booster doses are required every 3 years. Previously widal test gained momentum in the diagnosis bit now a days ELISA and other techniques based on serology are being administered like microarray, PCR and other which are costly but are useful for early diagnosis.

Epidemiology

The typhoid fever is endemic in various Asian and middle east countries, central and south America, India, Nigeria. Typhoid is also recently seen in places like Bangladesh, Indonesia , Hue, India, Netherland, UK , Africa (JohnA.Crump.,2010). Typhoid is also known as travelers disease which is transmitted from one place to another through food or trade and also through people who move from one place to another.

Salmonellae

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Salmonellae is an enteric gram negative pathogen belonging to the family Enterobacteriaceae. which are responsible for various enteric food borne disorders. The species entrica has serovar typhi and paratyphi are responsible for causing typhoid in humans. These has evolved to infect wide variety of reptiles, birds, mammals resulting in colonization and chronic diseases to death. There are around 2500 serovars responsible for pathogenesis. The MLST(Multi locus Sequence Typing) is an approach to discriminate between members of closely related collection of Salmonellae. The 72 strain collection is reffered to as typhimurium complex consisting of S.typhimurium and its 4 closest serological relatives. (Bell R.L,2010).

Symptoms

Symptoms starts with the onset of continued fever, headache, rose spots on trunk, loss of appetite, toxic look, coated tongue, splenic enlargement, non productive cough. Severe disease with complications including meningitis, psychosis, pneumonia, myocarditis, hepatitis, pancreatitis, nephritis, osteomyeletis (Crump,2010). There are also several reports of complications of acute pancreatics, Disseminated intravascular coagulation (DIC) and lower gastrointestinal bleeding (Huang et al,2005). Biopsies taken from the upper small intestine as early as three days post experimental infection of volunteers with serotype Typhi reveal diffuse enteritis caused predominantly by a mononuclear leukocyte infiltrate. Similarly, mucosal thickening of the ileum due to a polymorphonuclear-poor, mono nuclear rich infiltrate is characteristic in typhoid fever patients. Tissue colonization of serotype Typhi may produce capillary thrombosis in Peyer's patches of the terminal ileum which can result in hemorrhage, necrosis (usually observed in the second week of infection), ulceration and intestinal perforation. Enlargement of mesenteric lymph nodes, liver and spleen is accompanied by granulomatous lesions (Santos et al,2010). The delayed antibiotic treatment can even lead to relapses. (Clark et al,2010).

Mode of transmission

The food trade has open the ways for the movement of Salmonella species over the globe. Contaminated food and water are the main reason for the transference of the disease. Cultural and individual food handling practices, cooking preferences, hygiene routines and environmental differences may put individuals at different risk of typhoid fever. (Tran et al,2005). Salmonella are more subjected to food in fresh fruits, vegetables, spices, cheese that are subjected to trade market. Various raw molluscan shell fishs also act as the carrier for the salmonella pathogen. (Khan et al,2008)

DIAGNOSIS

WHO states that "the diagnosis, treatment, & prevention of typhoid, the method used as the gold standard for the laboratory diagnosis should approach 100% each for sensitivity, specificity & positive & negative predictive values (Baker et al,2010). Serological tests predominately are used as a very common method are also present such as PCR which serve as very fast way of diagnosis. Blood is the main sample for culture of Salmonella serovar Typhi since 1900 (Parry CM et.al,2002).

The first typhoid diagnosis is the widal test was developed in 1896. It is based on agglutination where S.typhi are used to detect antibodies in blood. This monitors antibodies that reacts with S.typhi. The major problem problem associated with this test is the S.typhi is a member of Enterobacteriaceae which have many conserved surfaces antigens and induce antibodies that are cross reactive. There are several commercial serological test developed which include Typhidot M & Tubex with sensitivity of 80% and 70%. The typhidot and tubex both are economic. In comparision of the sensitivity & sensitivity of Typhidot M and Widal test is 92.6% & 37.5% in Typhidot M and 34.1% &42.3% in Widal test. (NarayanappD et.al,2010).

The semi automated blood culture is used as a major diagnostics tool for typhoid. In this blood is taken from patient is inoculated into vessel that contains specialized media. This are very costly so is limited to only major hospitals in the cities. The culturing of bone marrow biopsies are more sensitive than blood culture.(Gilman RH et.al,1975)

DNA analysis techniques holds good. PCR methods are very specific and very fast for diagnosis of S.Typhi. Since the first evolution of PCR as a diagnostic tool for typhoid in the year 1993 by the amplification of flagellin gene (fliC-d) of S.Typhi (Song JH et.al,1993). Large volume of human DNA does not cause problem for PCR based pathogen detection in blood, particularly in samples with low bacterial number. Small volumes of blood are often used for DNA extraction or as template in PCR with sensitivity >90%. A new method for detection of serovar which is highly sensitive uses optimized ox-bile containing medium in blood culture of enrichment of bacteria combined with PCR assay. (Zhou&Pollard,2010). There are other types of PCRs also used like Nested PCR. It is used for the detection of Salmonella serovars, typhi and Paratyphi with sensitivity of 10 bacteria/ml. Regular PCRs detect 10^6bacteria/ml. The turn around time for the assay is less than 8 hours rather than several days in conventional blood culture. Thus, new TSB bile blood culture PCR system is superior. (Zhou & Pollard,2010).

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Curently there is no precise correlate of infection or biomarker for typhoid is identified. Human microarray option is also there which is expensive. Microarray datas are publically available and comparative analysis can be done with the help online available data bases(Ali A et al,2009) . Mass spectroscopy, proteomics could be applied to identify particular genes that are activated during typhoid.

VACCINATIONS

Salmonella is a facultative intra macrophage pathogen leads to Th1 response for macrophage activation which leads to production of IFN Gamma (Interferon) by CD4 T cells but in vivo studies report efficient activation of polyclonal Salmonella specific Th1 cells are activated rapidly and secrete IFN gamma but do not contribute to bacterial clearance until several weeks after infection. Salmonella infection causes depletion of Salmonella specific CD4 cells such that very few of these survive to enter the CD4 effector /memory pool. Type III secretory system (T3SS) encoded by Salmonella Pathogenicity Island-1 (SPI-1) allows Salmonella to invade host epithelial cells, induce intestinal inflammation, and cause macrophage death , the SPI-2-encoded T3SS expressed in the intracellular environment interferes with vesicular trafficking and promotes bacterial survival , and SPI-7 encodes a capsule that enables S. Typhi to resist phagocytosis and complement killing and suppresses innate inflammatory responses. The inhibition of CD4T cell development of Salmonella is beneficial for the development of effective cellular immunity to typhoid and may therefore aid the development of live vaccine strains (Aparna Srinivasan,2010). Immunization is one of the most important method of the morden era to prevent any infection. Vaccination against typhoid is an effective way as a treatment. The design of new Salmonella vaccines are based on the identification of virulence genes and on the knowledge of the immunological mechanisms of resistance to disease. Control and clearance of vaccine strain rely on the phygocyte oxidative burst, reactive nitrogen intermediates, inflammatory cytokines, CD4(+) T cells and are controlled by genes NRAMPI and class II MHC. (K.H.Khan et.al,2008).

There are basically two kinds of vaccines developed for Typhoid. Several other upcoming vaccines are also predicted which prove to be effective against S. paratyphi A. The two commonly used vaccines include Typhium Vi vaccine which is a polysaccharide and is taken via needle. The efficacy of these vaccines decreases year by year so booster doses are given after 1-7 year. According to WHO recommendation in U.S, Vi vaccine booster diseases should be given every 2 years. (Froeschle, Decker, 2009).

Live , Attenuated, orally taken vaccine Ty21a formulation addresses to Vi negative S.typhi and S.paratyphi B infections with efficacy of 49%. It includes vaccine strains CVD 908 which is highly immunogenic, inducing impressive serum antibody , Mucosal IgA and cell mediated responses. A derivative of CVD908 in htr A deletion leads of other strain CVD 908 htr A are very well used vectors to deliver foreign antigens to immune system. (KH.Khan, 2008).

Genetically modified probiotics also can be given as vaccines for typhoid. Genitically modified Bifodobacterium longum antigen delivery system offers a promising vaccine platform for inducing efficient mucosal immunity. It contains glt A gene which encodes for galacto-N-biose binding protein (GLBP) of ABC transporter (Yamamoto et.al, 2010).

The two prokaryotic recombinant antigens r SpaO, r H1a genes of S.paratyphi A are conserved sequences. This when tested on mice proves to be effective against S.paratyphi A caused typhoid fever (Ping Ruan et.al,2008).

Traditional treatment

The traditional typhoid treatment of typhoid was obtained with Chloramphenicol, Ampicillin, Trimethoprim and Sulphamethoxazole. Chloramphenicol reduced mortality rate from 25% to 1% first generation therapy ( K H Khan et al,2008). These drugs have become resistant so a Fluoroquinolones and cephalosporin act as third generation drug. (John, 1996). Uncomplicated typhoid was cured by Norfloxacin, pefloxacin and afloxacin. The treatment with Azithromycin has been reported against typhoid. (Duran and Amsden,2000).

FUTURE TREATMENT

S.typhi & paratyphi infections has a lot of herbal remedy for protection and treatment of typhoid fever. Anti Salmonella activity of Terminalia belerica, an ingredient of "triphala" has been observed. Fruits of T.belerica were extracted with petroleum ether, chloroform, acetone, alcohol and water showed anti Salmonella activity and MIC was 12.5 mg/ml. (Madani A, Jain SK, 2008).The crude ethanolic extract and n-Hexane dichloromethane, ethyl acetate, n butanol and aqueous fraction of Dodonaea viscose had also showed invitro anti Salmonella activity. (Khurram et al,2009).Chloroform crude extract of leaf and stem of Nephelium longan showed an excellent antibacterial activity including Salmonella typhi. (Ripa FA et al,2010). Carica papaya is also proving to be one of the herbal remedy. It is used in traditional medicine for variety of purposes in treating infectious and non infectious diseases. MIC concentration of papaya seed extract for 50% of the test bacteria, MIC for S.typhi was 11.8 mg/ml of extract. So could be used as an effective antibacterial agent (Yismaw G,2008). All these above have proved to be doing good for invitro studies and is assumed to even work well for invivo.

Conclusion

Typhoid is the major health issue in many tropical nations. In large areas morbidity from typhoid fever has been increasing and local epidemics have occurred. Sanitation and health education are the main tool for the control of typhoid fever. But it requires time. Mass immunization can help to tackle the problem while a safer water supply can be implemented. Now effective oral live attenuated vaccines are available which can control the outbreak. In non endemic areas it occurs through food carriers. The disease survillence is needed to be very fast so that the morbidity can be prevented at an early rate with the administration of medications. Researches are going on to deduce alternate therapies like use of plant products for long term treatment may prove effective for the treatment of the disease.