Salmonella Hepatitis: a Review Farzana Shafqat, Anwaar A

Home , Hepatitis A

Editorial Review Proceeding S.Z.P.G.M.I vol: 8(3-4) 1994, pp. 78-88. II II Salmonella Hepatitis: A Review Farzana Shafqat, Anwaar A. Khan, Zafar Iqbal Department of Medicine and Gastroenterology, Shaikh Zayed Hospital, Lahore

INTRODUCTION the identification of salmonella typhi in the laboratory and also for the serological diagnosis of he clinical picture of typhoid is extremely infection. These are O antigen, H antigen and Vi variable with increasing reports of atypical antigen. T 1 6 features · • Toxic manifestations like headache, step Somatic or O antigen is present within the ladder temperature, coated furred tongue, cough, bacterial cell wall. This is lipopolysaccharide, protein abdominal symptoms, malaise etc. may be observed and lipid complex. This constitutes the endotoxin. in only 50% of cases5. A special problem is the Group classification is done on the basis of this occurrence of typhoidhepatitis. antigen, Salmonella typhi belongs to 'Group D'. Typhoid hepatitis is one of the atypical Fu1ther typing of S. typhi is done on the basis of presentations of typhoid fever and can be defined as flagellar antigen called 'H' antigen. Surface antigen reversible involvement of liver during the course of which covers O antigen, is called Vi antigen. Vi typhoid fever. antigen increases the virulence of the organism. This Diagnosis of typhoid should always be antigen is also present in Paratyphi C, though their considered in patients presenting with fever and group factor and flagellar antigen are different. features of liver involvement especially in endemic These bacteria are readily killed by heat in one areas, because it can mimick other diseases hour at 55 ° C, in 15-20 minutes at 60 ° C and within occurring commonly in these areas, like acute viral 5 minutes by boiling. Baking also kills these hepatitis, amoebic hepatitis or malaria. organisms and other salmonellae. Growth stops below 55 ° C but survival is possible. Contamination Epidemiology during preparation of food or after cooking may not Involvement of liver in typhoid is more be harmful if the food is quickly cooled and kept af commonly seen in endemic areas but has also been refrigerator temperature below 5 ° C but if leftfor an reported from non-endemic areas7• hour or two before cooling, bacteria may multiply No age is exempt from typhoid hepatitis, but it rapidly and food becomes contaminated for safe is commonly seen between second and fourth consumption before it is put in the refrigerator. S. decade5 and in patients belonging to lower socio typhi and other Salmonellae can be destroyed by a economic class4• Complications like hepatitis occur number of chemicals including phenols, mercuric more in patients with depressed cellular immunity chloride, formaldehyde and quaternary ammonium and in those with relapse of typhoidfever1· 8•9 . compounds. Chlorine and potassium permanganate can be used for treating food. Bacteriology I,nfection in India and Pakistan occurs more Pathogenesis of salmonella hepatitis commonly with salmonella typhi as compared to The exact mechanism of hepatic damage in paratyphi A, B and C4• 10 • Similarly, liver involvement typhoid fever is not clear. It has been seen that this occurs more commonly with salmonella typhi complication, like other complications occurring in infection 11• Salmonella group of organisms belong to typhoid, is more commonly seen in malnourished the family enterobacteriaceae. Salmonella typhi are people belonging to lower socio-economic group4• gram negative, actively motile organisms. They do Bacteremia may be the cause of liver damage as not ferment lactose, sucrose and salicin. Salmonella bacteremia occurs in most patients with typhoid typhi only produce acid but no gas from dextn;>se and fever3. It definitely has a diagnostic significance but other carbohydrates. Their colonies stand out pale clinical severity and development of complications of against the coloured colonies of lactose fermenters in the disease have no significant association with the media containing lactose and a pH indicator. There concentration of bacteria in blood 12• are three groups of antigens that are important for Salmonella endotoxin has beeP implicated in

78 causing salmonella hypatitis like other features of hyperreactivity to catecholamines during typhoid typhoid fever. When these bacilli enter the fever is not clearly understood but it may represent a circulation after considerable multiplication in contributing mechanism to the pathogenesis of the lymphoid tissue of intestine, they undergo focal necrotic lesions and arteritis that occur m destructionwith the result of liberation of endotoxin typhoid11. 13 which produces the symptoms of typhoid fever • But Immune complexes and high ratio of rapid development of tolerance to endotoxin in an4trypsinto C3 have been seen in typhoidfever and volunteers can not explain the protracted course of more frequently in patients with complications 14 18 the disease . including hepatitis • Cell mediated immune Human volunteer studies showed that response (CMIR) appeared to play an important role 9 endotoxins did not play much role in the production in typhoid and its complications . It can be measured of sustained pyrexia and toxemia of typhoid by leucocyte migration test and delayed fever14, 15 • While evidence continues to accumulate hypersensitivity8. Recovery of the complicated cases that endotoxins do not play a major role in the was associated with change of negative L.M.T to 8 9 pathogenesis of typhoid fever and its complications, positive , • Mebel and Paniker19 found increased but in fact there are indicators favouring its local incidence of typhoid and severe toxemia in patients effectin the vicinityof the salmonella typhiinfection. with negative L.M. T cell mediated immune At these local sites, where salmonella typhi are response. Rajagopalan et al.9 also found intact CMIR multiplying, the highest concentration of endotoxins in uncomplicated cases of typhoid fever as compared might be expected14_ to complicated cases. The ratio of T lymphocyte sub Salmonella endotoxin is a potent inflammatory populations was grossly imbalanced in typhoid agent and is chemotactic for polymorphonuclear patients, the number of T lymphocytes and their leucocytes. Very minute concentration as low as 1 sub-population was further altered m the ng/ dl can produce local dermal responses during complicated cases as compared to uncomplicated .." , typhoid fever15. Therefore, sustained pyrexia and cases. Increased proportions of T suppressor cells toxemia may be explained by the ability of S. typhi and reduced population of T helper cells especially in and its endotoxin component to stimulate the complicated cases suggest that high levels of synthesis and release of endogenous pyrogens from suppressor T cells and circulating immune mononuclear cells and polymorphs accumulated at complexes may be responsible for a negative L.M.T. the site of inflammation.in tissues. Simultaneous presence of these two factors is to be Demonstration of salmonella bacilli within the expected since it has been reported that immune liver by indirect immunoflurescencestrongly favours complexes stimulate the formation of suppressor T the possibility of damage caused by locally released cells and other suppressor factors. Further endotoxins by the proliferating organisms and by confirmation of the involvement of circulating 16 ..... invoking local inflammatory reactions • Hepatic immune complexes and suppressor T cells in damage seen in patients with gut perforation and producing immunological abnormalities in typhoid peritonitis was considered to be due to ascending fever would help in deciding therapeutic approach to cholangitis17 • correct these abnormalities. Thus, there is found to Hornick et al.14 also considered the possibility of be a close correlation between the development of localized intravascular coagulation and arteritis in leucocyte migration test (L.M. T), recovery and the pathogenesis of dinical features of typhoid fever. inverse correlation with complications and a Hepatic injury in typhoid fever could be due to prolonged illness in typhoidfever. vascular hyperreactivity to catecholamines. In man '·-· and animals, intestinal mucosa possesses high Clinical features of salmonella hepatitis serotonin concentrations and a variety of Clinical features would be both of typhoid fever inflammatory lesions of the intestine cause vascular and that of hepatic involvement. Onset of fever in hyperactivity to catecholamines in man. Therefore, typhoid is slow and insidious in most of the cases3 release of serotonin from the inflammed intestinal but rapid onset "':ith or without chills has also been mucosa could be responsible for the vascular observed 17. hyperreactivityto the catecholamines. The most common prodromal symptoms which The clinical significance of the vascular precede the actual onset of fever were headache,

79 Shafqat et al. Salmonella Hepatitis: A Review

Table 1: Reports of liver involvement in typhoid fever (in percentage) � No. of' Jaundice Hrpalome11aly Abnormal Abnormal liver Study patirnts LFTs (t;I) histoloJ!y

Sluarl and Pullen ]!)4(i :mo :u; 20 NR' NR Rowland l m; l fi30 I.I NR NR NR Gulati <'Lal. IDGS !JS 0 () NR NR \Vic.:ks <'l al. 1!)71 243 l.(i NR NR NR Rarnaehundran E'L al. 197-1 iiS 7.H 2!l Di Pm l'l al. I !l7G Iii 2(i.(i 10 !"13.3 100 Sa man lray PL al. I !)77 iiOO 0 18 NR NR Singhrlal.1!)78 4GO l NR NR NR Nasrallah and Nassar 1!)78 10-l 23 3:1 17 NR Johm,on and AderelP l !)8 I 117 (i 27 ii NR Guplu Pl al. 1!)85 125 fi.G 8.8 S.G NR Khnsla <'l al. I !l88 :m 8.:1 !iii fl:i ,10 bhaq PL al. I !)!JO :iO 0 (i:1 NR NR Arif ('l al. l !l!)O !) (i(i 77 100 1-1 Shafqal ('t al71'. ( HJ!l1) 31 ·l'l 70 NR :12

'Not n·rordPd.

3 17 malaise and anorexia • • Abdominal pain, benign course and may even be missed by the constipation, diarrhoea abdominal distension, body physician or it can be severe presenting with severe aches and pains and symptoms pertaining to chest bleeding syndrome, haematemesis, or hepatic 7 e.g. cough, sore throat may be present3• 1 •20 (Table 11. encephalopathy. Common physical signs are fever, toxaemia, Osler first repo1ted hepatomegaly in typhoid typhoid tongue, splenomegaly, hepatomegaly, fever in 1899 1 . Subsequently incidence of liver bronchitic signs, relative-bradycardia, rose spots and enlargement more than 14 cm was reported in 1 2 3 17 10 • abdominal tenderness • • · (Table 2). different series varing from 13-63% 1• Hepatomegaly is seen more commonly in patients with salmonella typhi infection as compared to Table 2: Common symptoms in typhoid. salmonella paratyphi, and in patients with relapse of typhoid fevere4• 11 • Hepatomegaly appears after the Headache Anorexia first week of illness and remains during the height of 1 Nausea and vomiting temperature and disappears with treatment' • Malaise Enlargement has been va1ying from 1-10 ems below Bodyache 23 Rigors right costal margin • It is usually non tender but Diarrhoea tender hepatomegaly has also been repo1ted�4. Constipation Patients with enteric hepatitis may or may not have Abdominal pain 1 1 Abdominal distension hepatomegaly. Ramachandran et al. described Cough hepatomegaly in all cases of enteric hepatitis Sore throat whereas it was absent in 15% of patients with biochemical evidence of hepatic damage repo1ted by 4 others . 3 Features indicative of hepatic involvement Jaundice in typhoid fever occurs rarely • which may be present alone or in combination are, Incidence repo1ted in various series ranges between hepatomegaly, jaundice, disturbed liver function 1% and 26.6%6·23 . This complication occurs earlier in tests and abnormal histology1,21.22. the illness, especially in people who are Salmonella hepatitis is usually mild and nms a malnourished. Rowland (1961) found jaundice in

80 Salmonella Hepatitis: A Review

Table 3: Frequency (in percentage) of different clinical featuresfor various reported series. �I

Signs Start and Huckstep Gulati et al. Samantary Gupta et al. Pullen 1946 1960 1968 1977 1985

Fever 100.00 100.00 100.00 100.00 100.00 Toxemia 51.0 37.0 15.(i GO.O Typhoid tongue 35.0 -13.(i GO.O Splenomegaly G3.l 11.0 38.0 (i5.0 ·11.0 Hcpatomegaly 25.2 G.3 18.0 8.8 Bronchitic signs 40.2 21.0 50.0 11.0 52.0 Rose spots 59.8 -15.0 .j 1.6 9.G Relative bradycardia 88.0 22 50.0 38.1 Abdominal tenderness 45.0 15.0 ·11.G 27.2

five (0.9%) of his patients at the time of admission6. Hemolysis can occur especially in people with Jaundice was also observed in 8% of patients in a glucose-6-phosphate dehydrogenase deficiency and 25 review of 214 patients in Ibadan. In 6% of cases it haemoglobinopathies ·28. Jaundice is usually mild was definitely due to hepatocellular damage25• Many but profound jaundice can occur indicating severity

29 workers have reported typhoid patients presenting of illness • It is reversible with treatment and with profound jaundice as shown in Table 4. In a complete recove1y results• 1· 27. recent epidemic in India in 1989, 2.5% of patients This presentation creates diagnostic problem · .�..• came to hospital with jaundice26• Jaundice in typhoid and typhoid should always be considered in a patient fever could be due to ascending cholangitis. All 7 presenting with fever and jaundice of more than one 7 cases with jaundice repo1ted by Gupta et al. had gut week duration, even in non endemic areas . Rarely pe1foration and septic peritonitis and jaundice was patients with typhoid hepatitis can deteriorate and ascribed to ascending cholangitis 17 • Ramachandran can develop confusion, somnolence and asterixis et al. 11 repo1ted that cholangitis and bile stasis do along with presence of jaundice. Such cases have 7 not occur in hepatic involvement in typhoid fever. been repo1ted ·27·29 . Uncommonly, typhoid cholecystitis with bile duct Faierman et al.7 repo1ted a case of a young man obstruction may occur1 • Hepatic involvement and who migrated from Peru to the United States five icterus in typhoid fever can be due to suppurative weeks prior to his illness; developed typhoid pyelophlel?itis and Salmonella liver abscess27• hepatitis characterized clinically by profound Hemolysis in typhoid can occur and hemolytic jaundice and hepatic encephalopathy. He also had jaundice can result1 . other life threatening complications of typhoid like acute renal failure due to typhoid nephritis, and thrombocytopenia resulting in bleeding from Table 4: Case report of typhoid patients presenting as different sites. He recovered fully after treatment "fever with jaundice". and was discharged from hospital after six weeks. Another case of typhoid was reported from Reports Year Country No. of case India presenting with jaundice and encephalopathy29. This patient also recovered fully } 2 Ramachandran et al. Sri Lank after treatment. Singh et al 7. repo1ted 5 cases of 1974 1 Kar et a!. 1985 India typhoid fever presenting at the time of admission Faicrman et al. New York 1 19881972 1 with moderate jaundice and were toxic, deteriorated Gandapur et al. Pakistan during stay in hospital, developed hepatic Singh eta!. Hl78 India 5 Shankar and Kejriwal India 1 encephalopathy and hepatorenal syndrome and died. 1988 1 Rao et al. 1978 India Hematemesis, and epistaxis have been seen very Greig and Naidoo South Africa 1981 1 rarely in typhoid patients7,28 • Atypical presentations could also be due to

81 Shafqat et al. neurological disturbances like encephalopathy5 patients, bone marrow cultures were positive in 56 30 meningitis6 intracerebral or subdural abscess , (90%) while S. typhi was recovered from blood in 11 8 32 35 myocarditis- , or acute renal failure2 • • only 25 (45%) • Most of these patients had taken Severe bleeding syndrome occurred in a young antibiotics. Bone marrow aspirate culture was found female due to deficiencies of factors II, VII, IX and X to be superior to strepotkinase clot culture and 8 ml resulting from defective synthesis in a patient with 1:10 blood:broth ratio of blood culture34. It was also 33 typhoid hepatitis . Other serious complications of found to give better results as compared to duodenal 36 typhoid are intestinal haemorrhage, intestinal string capsule culture and rectal swab culture • 7 pe1forationor peripheral circulatoryfailure2· 1 • Diagnosis can also be confirmed by changes in biopsy specimens from liver or kidney. Changes Diagnosis characteristic of typhoid were seen in 100% of cases Diagnosis of salmonella hepatitis is based on by some workers22 ·23 • Calva and Ruiz-Palacios confirmation of typhoid fever and that of liver observed histological changes in 88% of their 16 involvement. patients suffering from typhoid hepatitis • Typhoid fever can be confirmed by isolation of Fluorescein stained bacilli can be seen in the tissues. the organisms from culture of different media, e.g., Intact fluorescent bacilli were seen to be spread blood, bone marrow aspirate, rose spots, urine, through out the parenchyma of the liver in numbers 36 faeces and bile. Most important of these are blood of four to six bacteria in all (8) biopsy specimens • and bone marrow cultures. Changes of acute tubulo-interstitial nephritis Blood is the most important and accessible have been seen in patients with acute renal failure 7 media for the isolation of organisms. Therefore, it is due to typhoid fever • Salmonella typhi VI antigen important to take two, three specimens before have been demonstrated in three consecutive starting any treatmenP. In the absence of typhoid patients who did not have any symptoms antimicrobial therapy, blood cultures are positive in pertaining to urinary tract involvement. They only 37 over 80% of patients during first week of illness\ had mild proteinuria • Bacteremia persists even after the first week and in SerologicaJ tests e.g., widal test may help in most severe cases it may not reach its height till the diagnosis though with ce1tain resei'vations. third week, while it may persist till the end in Formation of agglutinins (antibodies) against their patients dying from toxemia. Positive cultures have antigens within the body, form the basis of this test. been obtained in high percentage of patients In developing countries, where facilities for presenting with two or three weeks history of isolation and culture are not freely available fever5•20 . During clinical relapse orgaisms can be especially in smaller hospitals, diagnosis depends isolated as frequentlyas from the acute case but may upon clinical features and the detection of 26 be for a shorter period • Blood cultures should not agglutinating antibodies to S. typhi Le. the widal be discarded for 10-12 days, as the number of test. Numerous studies, however, have produced organisms in blood may be ve1y small, even as low as data which have resulted in serious doubts on the one organism per ml resulting in delayed positivity. value of the Widal test in the diagnosis of typhoid Blood should be diluted as it contains bacteric\dal fever1•3•28 • Several factors have contributed to this substances. It is, therefore, diluted at least four problem. These include poorly standarized antigens, times by the culture medium to reduce its the sharing of antigenic determinants with other bactericidal properties. Ten times dilution of 8 ml. salmonellae, the effect of .treatment with antibiotics 31 have been recommended . Blood from patients, and previous immunization with TAB vaccine. already, on chloramphenicol may have to be diluted Another major problem relates to the difficulty of further to obtain better results. In some cases bile interpreting Widal test results where the disease is and liquid (Sodium polyanethol sulphonate) have endemic and where the antibody titres of the normal been added to the medium which helps to counteract population are often not known. Also possibility of the action of blood. false positive reactions to non-typhoid fevers exists Bone marrow culture is considered to be the in areas where fever due to infectious causes is a most sensitive single method for isolating these common occurrence39• organisms especially in patients who have already Therefore, the diagnostic value of the widal test used antibiotics. In a comparative study of 62 in any given case varies considerat.iy wit�:t!2� ;,,-�dud//� ,,.1 � ""i-;,\ ·:'."- \ 82 t. : L1 :t· ' I -. \..' '( Salmonella Hepatitis: A Review knowledge and experience of the interpreter39 • In an been found raised indicating billiary stasis4. area where typhoid fever is uncommon, a titre of Prolonged prothrombin time can occur. Profound 1/40 for either H or O antibodies, or both, in an deficiencies of clotting factors, II, VII and X have 3 uninoculated febrile patient should suggest the been repo1ted:i . 23 possibility of acute infection, titres over that levels Diem et al • described histological changes in have increasing diagnostic significance. In endemic 100% of their culture proven typhoid cases. These areas where antibodies due to previous infection will changes consisted of hepatocyte swelling. Kupffer be common in the population, it is impo1tant to cell hyperplasia, mononuclear infiltrations of know the average level of antibodies in normal, presinusoidal space and po1tal space and fatty 8 healthy people in that area 3 • High O antibody titres degeneration of liver cells. Spotty necrosis was especially rising titres have greater significance. In a observed in eight out of fifteen patients. Ayhan et 22 previously inoculated person, within six months, al. from Turkey also described sii:nilar type of interpretation should be made carefully. Clinical changes in all of their 16 patients. These changes picture of the patient and a rising titre would be were found to be reversible after treatment. Absence helpful in such cases. Widal test still remains the of diffuse inflammation is the characteristic feature vital investigation in developing countries where of salmonella hepatitis. typhoidis endemic. Other serological tests have been tried but none Treatment of these has been accepted as a routine test in Treatment of salmonella hepatitis is the same microbiology laboratories in endemic areas. These as that of typhoid fever. The management of typhoid 9 include passive agglutination test3 , counter immuno patients remained symptomatic and supportive until 39 13 electrophoresis , (ELISA) enzyme linked the discove1y of specific chemotherapy in 1948 . ° 41• immunosorbent assay4 , and DNA probes Before the antibiotic era, the disease used to run a ·-.,, Another test of great diagnostic value especially long and protracted course lasting for several weeks in the absence of laboratory facilities is diazo to several months and the mortality was high·1. reaction in urine1 • Involvement of liver in typhoid fever can be Chloramphenicol confirmed by clinical, biochemical, and histological Chloramphenicol was the specific therapy 13 abnormalities. There should be high index of discovered in 1948 . It is still the drug of choice in suspicion in patients with prolonged fever and patients sufferingfrom typhoid fever due to sensitive showing features of liver involvement like strains of salmonella typhi44• Treatment with hepatomegaly, jaundice, hepatic encephalopathy and chloramphenicol has definitely shortened the course 1 bleeding fromany site. of the acute illness • Mo1tality and complications Liver mJury in typhoid 1s usually especially intestinal haemorrhage have decreasedf\ hepatocellular. But mixed cholestatic and Complications primarily due to a long and severe hepatocellular and pure cholestatic type can also be febrile illness, like pneumonia, seconda1y infections, 42 seen • Raised levels of bilirubin with increased bed sores, parotitis and venous thrombosis are also 6 conjugated bilirubin is the characteristic feature of less common . patients with jaundice in typhoid. Levels of bilirubin Relapse rate and carriers are found to be increase during the course of illness but decrease increasing with chloramphenicol treatment2. But and finally return to normal with improvement of this problem is attributed by some workers to 27 17 patient aftertreatment • . inadequate dosages and sh01t course of treatment -.' Rise in transaminases especially serum (SGPT) Bone marrow damage and sensitivity to ,,, aminotransferases (ALT) indicates definite chloramphenicol can occur but the incidence of both hepatocellular damage. Sometimes their rise is the these side effects is ve1y low6. only indication of liver damage in typhoid, there may Major problem which has created difficulties is not be any othe1· feature present like hepatomegaly the emergence of chloramphenicol resistant strains, 4 10 45 4 s or jaundice • Biochemical alteration suggestive of and now occurrence of multiple drug resistance . • _ hepatic damage and dysfunction have been repo1ted Different drug regimens have been tried depending 4 11 1 6 in 23-60% of the cases in various series · • Alkaline upon the need and availability of the drug • • It phosphatase and 5-adenosine nucleotidase have also should be used in adequate doses and for a sufficient

83 Shafqat et al.

period. Divided doses are not recommended1• 17 • illustrates potential for epidemic spread of these Doses recommended by Huckstep varies with the strains26•45• severity of disease. In severe cases, one gram 6 The resistance appears as a result of either hourly can be given initially forthree days and then mutation or acquisition of R factor. The frequency of can be reduced to 500 mg 6 hourly for at least 12 infection due to resistant strains is likely to increase days. In ordinary acute or subacute cases 0.5 g 6 in countries where typhoid is endemic and hourly for three days and then 0.25 g 6 hourly for 12 chloramphenicol is used indiscriminately. For days have been recommended. treatment of the highly resistant strains of salmonella typhi, quinolones or third generation 6 46 Cotrimoxazole cephalosporins are the drugs of choice2 • • Cotrimoxazole is also considered to be an effective drug in the treatment of typhoid fever10• Quinolones The carrier state seems less common but frequency Quinolones are synthesized chemically. These of relapses after treatment with this drug is not agents are bactericidal against salmonella typhi and clear. Again the danger is because of its effect on penetrate into phagocytes54. In comparative clinical blood cells formation and development of resistance trials, ciprofloxacin, ofloxacin, pefloxacin or to it10• The mean duration of fever in typhoid after fleroxacin have been found to be equivalent or co-trimoxazole therapy varies between 5 and 8 days, superior to standard anti typhoid therapy54• longer as compared to that of chloramphenicol 17. The Ciprofloxacin have been found to be effective dosage schedule in adults is 960 mg twice daily for 2 in patients with multi drug resistant typhoid fever 55 weeks. Children are given a dose according to their by many workers . Seven days sho1t course 56 body weight, with a recommended average daily dose ciprofloxacintherapy has been recommended • of 6 mg to 8 mg of trimethoprim and 30 to 40 mg of Ofloxacin, another antibiotic belonging to sulphamethoxazole per kg of body weight. quinolones, has been tested in Pakistan for its efficacy against salmonella typhi in vitro. Amoxycillin Salmonellae typhi responsible for causing typhoid Amoxycillin has been used successfully in the fever was found to be highly susceptible to ofloxacin treatment of typhoid. It was also found to be useful and this antibiotic possessed a low and very narrow in children who had glucose 6-phosphate range of minimum inhibitory concentrations57• It has dehydrogenase deficiency and typhoid fever4R. been used effectively in resistant cases of typhoid Recommended dose is 1 g 6 hourly for 14 days, 2 g a fever. When a dose of 400 mg twice a day of ofloxacin day for 21 days gave better results than was given, fever subsided within 72 hours after chloramphenicol with no carriers and a 2% relapse administration of this therapy. Treatment was rate49. Relapses are apparently infrequent and continued for 14 days, without any untoward carrier rate is not much after treatment with effects1°. Major problem with these drugs is high cost amoxycillin. and their contraindication in children and pregnant women. Second line of treatment in resistant cases Emergence of resistant strains of salmonella Cephalosporins typhi have created a lot of difficulties. After isolation Numerous third generation cephalosporins of bacteria, sensitivity of the organism has also to be have demonstrated good results against S. typhi. 10 checked • Chloramphenicol resistance in salmonella These are cefotaxime, ceftriaxone, moxalactam, and 50 typhi was apparently first repo1ted in England • ceftizoxime. Cure rates with these have been 53 Subsequently it was observed in other countiies. considerably high and relapses low • Ceftriaxone in First epidemic due to chloramphenicol resistant a dose of 1 g every 12 hours for 14 days have been 51 strains of salmonella typhi occurred in Mexico • found to be a reasonable alternative to quinolones Until recently, resistance was seen only to for the treatment of highly resistant cases of typhoid chloramphenicol but now incidence of multiple durg fever, especially in patients under 16 years of age resistance of salmonella typhi strains had been and in pregnant or lactating women. An alternative increasing52• Recently an outbreak of multi-resistant regimen commonly used in endemic areas is typhoid has occurred in Eastern India. This administration of ceftriaxone 3 g once a day for 7

84 Salmonella Hepatitis: A Review

58 36 days • macrophages unresponsive to lymphokines • Cefoperazone is another cephalosporin found In addition to rece1vmg treatment with to be as effective as chloramphenicol in the antibiotics, patients with severe typhoid fever should treatment of severe typhoid fever. It can also be receive dexamethasone in a dosage of 3 mg/kg .5 given to children with severe typhoid fevei 9• initially, foUowed by eight doses of 1 mg/kg eve1y 6 Defervescencewas found to be more rapid and blood hours. The use of dexamethasone decreased cultures tended to become negative faster with m01tality from 55% in the placebo group to 10% in cefoperazone as compared to chloramphenicol59. This the treatment group in a randomized double blind .J drug is, however, expensive and can only be given trial in severe typhoid feve1 6. intravenously, it should be reserved for the treatment of S. typhi strains resistant to standard Treatment of carriers therapy. Dosage is 100 mgjkg/day IV 12 hourly till For the control of typhoid fever, identification daily temperature is below 38 ° C then 50 and treatment of chronic carriers is ve1y mgjkg/day/IM 12 hourly forupto 14 days. impo1tant6:i. Carrier state is usually associated with Cefixime has also been found ve1y effective in underlying bilia1y tract or urinary tract abnormality. typhoid fever caused by multiple drug resistant Chloramphenicol does not help in the treatment of strains in childern. It was given orally in a dose of 20 carriers. Ampicillin is the drug of choice. Larger mg/kg/day in two divided doses 12 hourly for a doses for longer period should be used 18• Amoxicillin minimum of 12 days. All patients responded rapidly given for a 28 day course cured the carrier state even to treatment and were . cured clinically and in the presence of gallstones64 . bacteriologically. No serious adverse reactions Trimethoprim sulphamethoxazole (co- 60 attributable to the drug were observed . trimoxazole) seems to be effective in the clearing of carriers4ll. Salmonella typhi carriers have also been Corticosteroids in typhoid fever treated successfuUy with 750 mg of ciprofloxain Co1ticosteroids have been used in cases of given for 28 days in a patient with associated severe typhoid fever but their role has been gallbladder disease who refused surge1y and was 6 controve1tial since it was first described in 195P • sensitive to ampicillin and co-trimoxazole65. Typhoid Steroid therapy definitely shortens the duration of carrier state when associated with chronic fever and improves the sense of well being of the cholclithiasis can only be cured in most cases by 1 patient6 • cholecystectomy with or without antibiotics 66 Initially they were used in smaller doses and for supplementation . Schistosomiasis also favours a sho1ter period i.e. 300 mg co1tisone or equivalent carrier state and eradication of S. typhi needs dose of prednisolone for 3-5 days. Such sho1t term treatment of schistosomal infection along with steroid therapy has not been associated with higher treatment of S. typhi infection67• incidence of perforation or haemorrhage from 1 intestinal ulcer6 • But the use of steroids in severe Prevention typhoid fever in small doses have not been found to Typhoid fever is a serious illness and can lead to decrease mo1tality6, but on the contra1y it has been life threatening complications, therefore, needs to be found to increase the relapse rate especially when controUed. Incidence in developed countries has used later in the course of the disease62. Steroids in decreased during this centu1y because of small doses, therefore, are not recommended in improvement in their hygienic conditions. Control of typhoid fever. the disease in endemic areas requires supply of clean Co1ticosteroids used in high doses have been water, effective sewage disposal, early diagnosis, and found beneficial in patients suffering from severe treatment of patients and of asymptomatic carriers. typhoid fever. They reduce mo1tality significantly Achievement of these ideal conditions is not possible 16 without any increase in complications: • The in the near future therefore the only alternative for mechanisms in decreasing fatality rate is not weU the control of disease is by vaccination. understood. Steroid therapy is found to reduce the Commonly used parentral vaccines consist of production of arachidonic acid and its metabolites, inactivated bacilli. Out of the available vaccines, heat act as antioxidant, reduce the level of macrophage killed phenol preserved (Phenolized), alcohol killed derived lysosomal enzymes, and render normal and acetone killed, acetone dried (Acetone vaccine),

85 Shafqat et al. the acetone vaccine is found to be superior to polysacharide of S. typhi (vi) has been found to 69 others • These vaccines are efficacious in preventing produce specific immune response and confer typhoid fever but they have three major limitations. immunity, in a pilot study followedby a large clinical 69 They are 70% effective, immunity produced does not trial in Nepal • The efficacy of vi was 75%, only one persist for more than three to five years and injection was given and adverse reactions were rare. vaccination results in local and systemic reactions in most recipientst4. CONCLUSION The development of a safe effective oral vaccine has been considered the ultimate goal. This vaccine Salmonella hepatitis is a well recognized entity is made from an attenuated mutant strain of S. typhi and has variable clinical features. It should always be Ty21a which lacks the enzyme UDP-galactose-4 considered in patients with fever and hepatic epimerase. This live oral vaccine has been evaluated dysfunction especially in endemic areas, as earlier for its efficacyin human volunteers. The ingestion of recognition and management results in complete 10 75 five to eight doses of vaccine (equivalent to 3-10xl0 recovery • live organisms) caused no significant side effects, gave a protection rate of 87% against a dose that REFERENCES caused typhoid fever in 53% of unimmunized control 69 volunteers • In earlier studies, parenteral vaccines 1. Huckstep RL. Recrnt advances in the surgery of typhoid fever. Ann R Coll Surg Engl 1960; 207-30. that had been found effective in the field 2. Gulati PD, Saxena SN, Gupta PS, Chuttani HK. demonstrated no protection against such a high Changing pattrrn of typhoid fever. Am J Med 1968; 45: 14 challenge dose • The large field trials in Egypt and 511--18. 3. Stuart BM, Pullen RL. Typhoid: Clinical analysis of 3GO Chile also provided favourable information regarding cases. 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