Gut 1995; 37: 136-139

Recurrent Salmonella enteritidis sepsis and hepatictuberculosis

M Trauner, E Grasmug, R E Stauber, H F Hammer, G Hoefler, E C Reisinger

Department ofMedicineM TraunerE GrasmugR E StauberH F HammerE C Reisinger

Institute of PathologyG Hoefler

Karl FranzensUniversity, Graz,Austria

Correspondence to:Dr E C Reisinger,Department of InternalMedicine, Karl FranzensUniversity, Auenbruggerplatz15, A-8036 Graz, Austria.Accepted for publication23 September 1994

AbstractA 33 year old woman with recurrentSalmonella enteritidis sepsis is described.Penicillins, ceftriaxone, ciprofloxacin,and chloramphenicol could not eradicatethe salmonellas but a combination ofhigh dose ciprofloxacin and ceftriaxonefor the eighth episode successfully curedthe infection. The combination of cipro-floxacin and ceftriaxone may be a valuabletherapeutic regimen in patients withrecurrent salmonella sepsis. Prolongedintrahepatic cholestasis resulting fromgranulomatous hepatitis in this patientimproved considerably with empiricursodeoxycholic acid treatment. A liverbiopsy specimen showing non-caseating

A

Figure 1: Histological examination of the patient's first liver biopsy specimen. (A) Twosmall epitheloid granulomas within the liver parenchyma; (B) larger epitheloid granuloma,note the absence of caseation necrosis. Haematoxylin and eosin, original magnificationX200.

epitheloid granulomas was positive formycobacterial DNA by polymerase chainreaction. Repeated bronchoscopy withmultiple biopsies eventually revealedcaseating granulomas with acid fast bacilliin the lung biopsy specimens. Therefore,tuberculosis was diagnosed as the under-lying disease and the cause of granulo-matous hepatitis in this patient andtuberculostatic treatment was started.Polymerase chain reaction for myco-bacterial DNA may be helpful in the dif-ferential diagnosis of hepatic granulomaswhen routine histological examinationand culture of biopsy specimens arenot diagnostic. Tuberculosis should beconsidered as one of the diseases pre-disposing to recurrent salmonella sepsis.(Gut 1995; 37: 136-139)

Keywords: Salmonella enteritidis, hepatic tuberculosis.

The incidence of non-typhoidal salmonellainfections and septicaemias has increasedduring the past years resulting from the grow-ing rate of food contamination by salmonellasand the increasing number of patients withimmunosuppression.' Some recent importantoutbreaks were caused by Salmonella enteritidisand the frequency of S enteritidis isolates fromblood cultures in patients with non-typhoidalsalmonella septicaemia has risen sharply.2Standard antibiotic treatment can fail becauseof antibiotic resistance, impaired access ofantibiotics to sites where salmonellas persist, orimmune dysfunction in patients with under-lying diseases.3 4 Relapsing salmonella sepsis inthese patients raises important diagnostic andtherapeutic problems.We present a 33 year old woman with

granulomatous hepatitis and S enteritidissepticaemia recurring eight times.

Case reportOne year before presentation to our hospital a33 year old white female nurse had beengiven tuberculostatic triple therapy (isoniazid,ethambutol, rifampin) because of a clinicalsuspicion of pulmonary tuberculosis (drycough, subfebrile temperatures, miliar shad-owing in the chest x ray, positive tuberculinskin testing); no granulomas or mycobacteriawere found at bronchoscopy. Tuberculostatictherapy was stopped after three months forunknown reasons. Two months after the inter-ruption of tuberculostatic treatment thepatient had a short episode of febrile diarrhoea(negative stool cultures) followed by relapsing

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Recurrent Salmonella enteritidis sepsis and hepatic tuberculosis

TABLE I Antibiotic treatment of the salmonella septicaemias

Sepsis Drugs, dose, and route

1* Piperacillin 4 g intravenouslyCeftriaxone 1-5 g twice daily intravenously+gentamicin 160 mg intravenously

2* Penicillin G 10 MU twice daily intravenously+gentamicin 240 mgintravenously

Penicillin V 1-5 g thrice daily by mouth3 Ciprofloxacin 200 mg twice daily intravenously

Ciprofloxacin 250 mg twice daily by mouth4 Imipenem 1 g thrice daily intravenously+netilmicin 200 mg intravenously

Ciprofloxacin 250 mg twice daily by mouth5 Ciprofloxacin 200 mg twice daily intravenously

Ciprofloxacin 250 mg twice daily by mouth6 Ciprofloxacin 200 mg twice daily intravenously

Amoxycillin 2 g thrice daily by mouthAmoxycillin 750 mg thrice daily by mouth

7 Chloramphenicol total 20 g intravenously8 Ciprofloxacin 200 mg four times daily intravenously+ceftriaxone 2 g twice

daily intravenously

*Before presentation to our hospital; tdiscontinued by the patient.

fever attacks lasting three to four dayzfour to six weeks. Five months later septiand considerable abdominal tendernessexploratory laparotomy in another h(Intraoperative needle biopsy of the erliver showed non-caseating epitheloidlomas (Fig 1). Staining for acid fast bacnegative. Four days after discharge thehad another septic episode, whichresolved quickly with intravenous anti(Table I).Four weeks later she developed he

episode of septic temperatures of up t(and was transferred to our hospital i1992. Blood cultures were positive foritidis (antigen formula: 1, 9, 12:phagetyping: RDNC). The isolatesusceptible to penicillins, cephalos]tetracyclines, sulphonamides, quiniaminoglycosides, and chloramphenicoland urine cultures were negative. Thleucocyte count was 51 00/pAl with Ineutrophilia (4% bands, 74% segmand toxic granulation. The aspartatetransferase was 29 IU/1 (normalalanine aminotransferase 52 IU/1y-glutamyltransferase 371 IU/l (6-28)line phosphatase 2788 IU/l (60-170),aminopeptidase 240 U/l (11-35),angiotensin converting enzyme 82(18-55). The Gruber-Widal reactiospecific serum antibodies to salmonellapositive.5 Chest x ray showed minimalnode calcifications. Abdominal ultrmand computed tomography of the abshowed hepatosplenomegaly. Theresolved within 24 hours with intra'ciprofloxacin (Table I).The patient was readmitted to our h

with additional septic episodes one, six,10, and 11 months after presentation.cultures were positive for S enteritidissame antigen formula and phage typtime. Stool culture during the fourth c

TABLE II Antibiotic treatment of the eighth episode

Time (h)

6 9 12 15 18 21

Ciprofloxacin 200 mg 200 mg 200 mgCeftriaxone 2 g 2 g

and duodenal bile aspiration before antibioticDuration treatment of the eighth episode were positive(days) for the same S enteritidis. All other cultures2 of stool, duodenal aspirates, and urine were

7 negative. The fever resolved quickly with7 antibiotic therapy at each septic episode (Table7 I). The eighth episode was treated with high73 dose intravenous ciprofloxacin (200 mg3t6 four times daily) and ceftriaxone (2 g twice10 daily) for 14 days (Table II). This regimen73t successfully prevented further septicaemias.7 An extensive search for underlying disorders8

28 was carried out after the third salmonella14 episode. High resolution computed tomo-14 graphy of the chest showed minimal subpleural

thickening in the posterior segment of the rightupper lobe. Gallium scintigraphy showed[67Ga]citrate uptake in liver and spleen, both

s every lacrimal glands (panda sign) and intrathoracicic fever hilar lymph nodes (lambda sign). Two bron-led to choscopies with transbronchial biopsy speci-

ospital. mens showed chronic interstitial pneumonianlarged without granulomas and a normal CD4/CD8granu- ratio in the bronchoalveolar lavage. The:illi was gallium scintigraphy findings, increased serumpatient angiotensin converting enzyme concentrationsagain and granulomatous hepatitis first led us to

ibodies suspect sarcoidosis as the underlying disease.The patient was given a 10 week course of oral

r third prednisolone. Serum alkaline phosphatase) 41 C concentrations began to fall even before pred-in July nisolone was begun and started to rise duringS enter- treatment (Fig 2). Repeat liver biopsy showedg, m; non-specific reactive hepatitis and mildc was steatosis without granulomas. Endoscopicporins, retrograde cholangiography, oral cholecysto-olones, graphy, intravenous urography, bone scan, and1. Stool echocardiography were normal. Liver functionie total tests remained raised after the last salmonellarelative episode and ultrasound showed persistentlented) hepatosplenomegaly. The patient was givenamino- empirically ursodeoxycholic acid (UDCA;0-18), 10 mg/kg body weight) and serum alkaline'0-22), phosphatase dropped considerably (Fig 2)., alka- Fluorescence activated cell sorting analysisleucin of peripheral white blood cells performed fiveand days before the sixth and ninth months afterIU/1 the last salmonella episode showed increased

tn and T suppressor and normal T helper cellsas were (CD4/CD8 ratio 0.32 and 0.46, respectively).lymph Antibody testing and polymerase chain reac-asound tion in the serum were negative for HIV. Skindomen testing was positive for tuberculosis and

fever tetanus. Phagocytosis capacity and oxidativevenous burst in macrophages and granulocytes were

normal.lospital Six months after the last salmonella episodeseven, fever up to 38 5°C recurred. The patient hadBlood lost 12 kg within six weeks. All routineof the bacteriological cultures including multiple

ie each stool cultures for S enteritidis remained-pisode negative. Chest x ray showed a subsegmental

infiltrate in the posterior left lower lobe thatpersisted for two weeks with intravenousdoxycycline followed by imipenem. Repeatedbronchoscopy with multiple biopsies event-

24 ually showed epitheloid cell granulomas withcentral caseating necrosis and acid fast bacilli.

200 mg When the polymerase chain reaction method6became available both liver biopsy specimens

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Trauner, Grasmug, Stauber, Hammer, Hoefler, Reisinger

1~~~~~~~~~~~~~C

~~ ~ ~ ~ ~ ~ ~ ~

.i p* _ t o .. .. v x I;

Figure 2: Clinical profile of the patient. Eight arrows indicate the eight S enteritidis

septicaemias, LBx-liver biopsy. GGT- y-glutamyltransferase, alk phos-alkaline

phosphatase. Bars indicate the medical treatment:. IPredn=prednisolone,UDCA ursodeoxycholic acid, Th=tuberculostatic therapy (isoniazid, r;fampicin.pyrazinamide for eight weeks, followed by isoniazid and ethambutol).

were positive for mycobacterial DNA (Fig 3).

The fever and pulmonary infiltrate resolved

quickly with tuberculostatic therapy (isoniazid,

rifampin, pyrazinamide). Serum angiotensin

converting enzyme concentrations became

normal and the liver function tests continued

to improve (Fig 2). More than one year after

the last S enteritidis episode the patient is

asymptomatic and in a good clinical condition.

Discussion

We report a case of S enteritidis sepsis relapsing

eight times within one year. Underlying dis-

orders favouring salmonella septicaemia that

had to be ruled out in our patient were

Figure 3: Polymerase chainreaction (PCR) formycobacterial DNA in thepatient's liver biopsyspecimens. Amplification ofmycobacterial DNA byPCR (3% agarose gel) wascarried out using primersthat amplify a 143 bp longfragment (arrow) of thegenefor the 65 kDmembrane antigen. Bothliver biopsy specimens werepositive for mycobacterialDNA. Lanes: 1=molecularweight marker, 2=firstliver biopsy, 3=second liverbiopsy, 4=negative control(normal liver tissue,necropsy material),5=positive control(tuberculosis of the lung,biopsy specimen). Thesecond DNA bands at thetop of lanes 2-4 representnon-specific high molecularweight DNA (larger than20 kD).

haemolytic conditions,3 histoplasmosis,7schistosomiasis,8 neoplasias,9 collagenosis,10sarcoidosis, and AIDS.4 Particularly inAIDS, relapsing episodes of septicaemia mayoccur.4 Immunosuppressive therapy, longtermhaemodialysis, and splenectomy are furtherimportant conditions predisposing to recurrentsalmonella sepsis.'1 Fluorescence activated cellsorting analysis of peripheral white blood cellsshowed increased T suppressor cells with areduced CD4/CD8 ratio; such findings havebeen reported in patients with prolongedsalmonella and mycobacterial infections.12 13An intensive search for chronic salmonella

carriage in the gastrointestinal and urinarytract was negative in our patient. The presenceof S enteritidis in duodenal aspirate during thelast episode was considered a secondaryphenomenon because salmonellas may haveentered the biliary tract from blood duringsepticaemia.14 Persistence of S enteritidis in thereticuloendothelial system could explainrecurrent endogenous septicaemias in ourpatient. 15

There are no therapeutic standards forpatients with recurrent salmonella sepsis.The antibiotic treatment regimens for thepatient's first to seventh septicaemia includingpenicillins, ceftriaxone, ciprofloxacin, andchloramphenicol were not successful inpreventing relapsing sepsis (Table I). Theseantibiotics were highly effective against S enter-itidis in vitro, but they may have failed in vivobecause of limited concentrations in intra-cellular compartments where salmonellas canpersist.3 Recent data suggest that quinolonesor third generation cephalosporins are moreeffective in the treatment of salmonellainfections than penicillins, cotrimoxazole,or chloramphenicol.1 16 Although bothciprofloxacin and ceftriaxone show excellentintracellular activity,16 standard doses ofciprofloxacin (200 mg twice daily intra-venously or 250 mg twice daily by mouth) orceftriaxone (2 g intravenously per day) seemto be inadequate in treating patients withrecurrent salmonella sepsis. Combined highdose ciprofloxacin (200 mg four times dailyintravenously) and ceftriaxone (2 g twicedaily intravenously) for 14 days (Table II) wasfinally successful in eradicating the salmonellasin our patient. Eradication by a combination ofciprofloxacin and ceftriaxone has beenreported in an immunodeficient 8 year old boywith relapsing S dublin septicaemia.17 Thecombination of ciprofloxacin and ceftriaxonemay be a valuable therapeutic regimen inpatients with recurrent salmonella sepsis. Highdose oral ciprofloxacin (750 mg twice daily)and intravenous ciprofloxacin (200 mg fourtimes daily)18 have similar pharmacokineticsand are of comparable therapeutic efficacy.19The liver finction tests with considerably

raised serum alkaline phosphatase concentra-tions were caused by granulomatous hepatitis(Figs 1 and 2).20 The differential diagnosis ofhepatic granulomas includes an extensive listof infectious and non-infectious conditions.21 22Positive lambda and panda signs at galliumscintigraphy and increased serum angiotensin

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Recurrent Salmonella enteritidis sepsis and hepatic tuberculosis 139

converting enzyme concentrations initially ledus to suspect sarcoidosis.23 Another explana-tion for granulomatous hepatitis considered inour patient was continued infection withS enteritidis. In typhoid fever histologicallynon-specific reactive hepatitis is common,24whereas granulomatous hepatitis is rare.25Non-typhoidal salmonellas have been shownto induce liver granulomas in mice underexperimental conditions.26 However, Gramstaining could not show rods within livergranulomas in our patient. We decided to startan empiric course of UDCA (Fig 2) because itis effective in the treatment of a wide variety ofcholestatic conditions and has no serious sideeffects.27

Repeated bronchoscopy with multiple biop-sies finally showed caseating granulomas andacid fast bacilli thus pointing to tuberculosis asthe underlying disease and the most probablecause of liver granulomas in this patient.28 Apositive polymerase chain reaction formycobacterial DNA obtained from both liverbiopsies further supported the diagnosis ofhepatic tuberculosis. The histopathologicalpatterns of tuberculous liver granulomas varywidely.29 As caseation necrosis may be absentand stains for acid fast bacilli are usuallynegative,2' the diagnosis of hepatic tuber-culosis needs a high index of clinical suspi-cion.30 Fever of unknown origin, positivetuberculin skin testing, anaemia, and weightloss clinically suggest tuberculosis rather thanother causes of hepatic granulomas.21Polymerase chain reaction for mycobacterialDNA may be helpful in the differential diag-nosis of hepatic granulomas when routinehistological tests and cultures of biopsyspecimens are not diagnostic. MycobacterialDNA, however, has also been detected in somecases of pulmonary sarcoidosis.6

Tuberculosis itselfmay impair cell mediatedimmunity,31 thus explaining our patient'ssusceptibility to recurrent S enteritidis septi-caemia. Infection of macrophages by myco-bacteria might interfere with their ability to killother intracellular pathogens such as salmo-nellas.7 Because mycobacteria are susceptibleto quinolones,32 repeated ciprofloxacintreatment of salmonellosis may have maskedtuberculosis, thus delaying the diagnosis of theunderlying disease in our patient.

We thank Professor G J Krejs, Graz, for critical review of themanuscript.

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