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man M, Back W, et al. Gas gangrene pyaemia with

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[12] Willis AT. Gas gangrene and clostridial cellulitis. In:

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Fatal Salmonella enteritidis septicaemia in a rheumatoid arthritispatient treated with a TNF-a antagonist

ANNEMIEKE RIJKEBOER1, ALEXANDRE VOSKUYL2 & MICHIEL VAN AGTMAEL1

From the Departments of 1Internal Medicine, 2Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands

AbstractWe report a patient with a rare presentation of extra-intestinal salmonellosis after infliximab therapy for rheumatoidarthritis. We discuss the increasing incidence of primary infections and reactivation of intracellular microorganisms aftertreatment with TNF-a blockage, with emphasis on salmonellosis.

Introduction

TNF-a is a pro-inflammatory cytokine that plays

an important role in the pathogenesis of many

inflammatory conditions, such as rheumatoid arthri-

tis (RA) and Crohn’s disease. TNF-a is also an

important cytokine in the defence against intracel-

lular microorganisms. It is essential for the forma-

tion and maintenance of granulomas, being key

components of host defences against intracellular

pathogens.

The use of TNF antagonists has resulted in

significant clinical benefits to large number of

patients with RA [1], but it has also resulted in

an increase of infections, especially infections of

intracellular pathogens such as Mycobacterium

tuberculosis, Histoplasma capsulatum, Listeria

monocytogenes, Pneumocystis jiroveci and Asper-

gillus fumigatus [2]. Considering the role of TNF-a,

blockage leads to an impaired cellular immune

response and inadequate granuloma maintenance,

causing atypical presentation of primary infections

with intracellular microorganisms or reactivation

of latent granulomatous infections as a result of

disintegration of granulomas [3,4].

In this case report we present a patient with

disseminated salmonellosis. The case illustrates the

consequences of blockage of TNF-a for the devel-

opment of a severe and fatal infection by Salmonella

enteritidis . To our knowledge, such a case has not yet

been published until now.

Case report

A 74-y-old male was diagnosed in 1998 with erosive,

rheumatoid factor positive rheumatoid arthritis, with

at that time symptoms of active polyarthritis and

pleuritis. He was a smoker and also had a history of a

transient ischaemic attack, hypertension and hy-

percholesterolaemia. He was treated with prednisone

and escalating doses of methotrexate without suffi-

cient effect. After 2 infusions with infliximab (3 mg/

kg) over 2 weeks, he was readmitted at our hospital,

4 weeks after the last infusion, with shortness of

breath and high fever (398C). No gastrointestinal

Correspondence: Dr. M. van Agtmael, Department of Internal Medicine, Room 4A40, VU University Medical Centre, De Boelelaan 1117, 1007 MB,

Amsterdam, The Netherlands. E-mail: agtmael@vumc.nl

80 Case reports

(Received 5 April 2006; accepted 18 April 2006)

ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis

DOI: 10.1080/00365540600786549

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signs were present. Laboratory results showed an

ESR of 88 mm/h, C-reactive protein of 133 mg/l and

leucocytes of 11.5�/10*9/l. A chest X-ray revealed

pleural fluid in the left chest cavity. Salmonella

enteritidis and Streptococcus orales were cultured

from the pleural fluid. Both pathogens were sensitive

for amoxicillin. Pleural empyema was diagnosed.

The chest cavity was rinsed and amoxicillin 1000 mg

4 times a d was given intravenously for 5 d. Fever

and shortness of breath disappeared and the ESR

and C-reactive protein normalized. He was dis-

charged from the hospital with amoxicillin

750 mg 3 times a d orally for an additional 2 weeks.

Two months later he presented himself at the

emergency room with abdominal and back pain.

On physical examination, he was moderately ill. His

blood pressure was 110/70 mmHg (with a known

blood pressure of 150/80 mmHg), heart rate 84/min,

and temperature 37.48C. The abdomen revealed a

painful pulsating mass in the mid-lower abdomen.

The ESR was 100 mm/h, CRP 161 mg/l with

leucocytes of 8.3�/10*9/l. A symptomatic aneurysm

was suspected. A CT angiogram was performed and

2 aneurysms were observed. One supra-renal aneur-

ysm with a diameter of 4.8 cm was seen extending

from the diaphragm to the celiac truncus. A second

infra-renal aneurysm had a diameter of 7.2 cm and

extended to the bifurcation. Because signs of leakage

were found on the angiogram, the vascular surgeon

placed an endovascular prosthesis in the lower

abdominal aorta the same day.

With the recent history of Salmonella empyema, 1

dose of amoxicillin 1000 mg i.v. was given prior to

the implantations of stents. After surgery the blood

cultures revealed Salmonella enteritidis , with an

equivalent antibiogram to the Salmonella cultured

from the pleural fluid, sensitive for amoxicillin. A

mycotic aneurysm with Salmonella enteritidis was

suspected. Considering therapy failure or relapse

under amoxicillin, ceftriaxone 2 g i.v. once daily was

immediately started and after 2 weeks switched to

ciprofloxacin 750 mg orally twice daily. Fever

disappeared and the CRP and ESR normalized and

the patient was discharged with ciprofloxacin main-

tenance therapy at the same dose. After 4 weeks of

therapy he was readmitted with fever and a rise of

ESR to 100 mm/h and CRP to 130 mg/l. A CT

angiogram now revealed air surrounding the endo-

prosthesis. With clinical and radiological deteriora-

tion, surgical replacement of the infected aorta with

stents was discussed, but it was decided not to

operate expecting major technical difficulties and

concomitant high perioperative mortality. He was

discharged with ciprofloxacin but deteriorated in

2 months and returned with abdominal pain caused

by a ruptured suprarenal aneurysm. An emergency

endoprosthesis was placed, but he died 2 d later due

to a new bleeding aneurysm.

Discussion

We have described a rare case of systemic salmonel-

losis in a rheumatoid arthritis patient after infliximab

treatment. We questioned whether this patient was

simply a rare case or related to the treatment with

infliximab. The first presentation of an empyema

caused by Salmonella enteritidis , and despite ade-

quate treatment, followed by bacteraemia causing a

fatal mycotic aneurysm, is an extra-ordinary, extra-

intestinal manifestation of a Salmonella infection.

In the United States the incidence rate of salmo-

nellosis in 2002 was 17.7 per 100,000 population.

The most common serotypes were S. typhimurium

and S. enteritidis , together accounting for 42% of all

laboratory-confirmed cases of human salmonellosis.

Salmonella enteritidis infections are most often asso-

ciated with food products, but also waterborne

outbreaks and transmission by infected exotic pets

(snakes, turtles) or health care workers have been

described.

Infection with non-typhoidal Salmonella most

often presents itself with acute self-limiting gastro-

enteritis. In 1�4% of the immunocompetent patients

with gastroenteritis there are positive blood cultures.

In immunocompromized patients the incidence of

bacteraemia is higher. Localized infections develop

in approximately 5% to 10% in persons with a

Salmonella bacteraemia. Other extra intestinal man-

ifestations are summarized in Table I. Salmonella

bacteraemia is prone to develop vascular infections

in 10% to 25% of patients over 50 y old. It usually

involves the aorta, especially if there is a pre-existent

aneurysm or atherosclerotic plaque [5,6].

Salmonellae are Gram-negative bacilli and facul-

tative intracellular organisms. After crossing the

intestinal epithelial barrier through ‘bacteria-

mediated endocytosis’, Salmonella invades macro-

phages. The ability to invade and multiply in

Airsurroundingtheprosthesis

Figure 1. An abdominal CT shows an endovascular prosthesis in

the abdominal aorta, surrounded with air.

Case reports 81

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macrophages is essential for dissemination and for

causing systemic disease. The host recognizes in-

vasive Salmonella using receptors such as Toll-like

receptor 2 (TLr-2) and TLr-4 and TLr-5. Recogni-

tion leads to activation of cytokines such as IFN-g,

IL-12 and tumour necrosis factor-a and activation of

phagocytes. Final clearance and immunity to rechal-

lenge new encounters requires a Th1-type CD4 T-

cell response and production of specific antibodies

by B-lymphocytes [5].

It is not surprising that impairments in this

cascade lead to an increase in invasive infections

with Salmonella species. Studies in mice with

targeted disruptions of TLr-4 response or genes

coding for IFN-g, IL-12 or TNF-a [7�9], and

humans with mutations in receptors for IFN-g and

IL-12 [10], have demonstrated increased suscept-

ibility for Salmonella infections. Also, patients with a

decreased cellular immunity, such as patients with

HIV, have an increased risk of salmonellosis with and

without bacteraemia [6].

It is conceivable that patients being treated with

anti-TNF agents also have an increased risk of

serious infections with this microorganism, consider-

ing the steps in the immune response to Salmonella.

Case reports have been published, but a convincing

increasing incidence of invasive Salmonella infec-

tions has not yet been reported [3,11,12].

What are the arguments for the role of infliximab

leading to this severe Salmonella infection in this

patient?

Recent studies from Netea et al. and Popa et al.

have demonstrated that patients with RA treated

with anti-TNF agents have reduced TLr-4-positive

dendritic cells and have decreased levels of INF-g in

response to infections compared to RA patients

without treatment with anti-TNF agents, or healthy

controls [11,13].

Hess et al. demonstrated in his article a decreased

adherence of S. typhimurium to cultured intestinal

cell lines after the cells were pretreated with TNF-a.

This augmented bacteria-enterocyte interaction

could be another factor for the increased risk of

salmonellosis after treatment with anti-TNF agents

[14].

TNF-a is essential for the forming and mainte-

nance of granulomas. Mastroeni et al. observed in

mice that after anti-TNF the Salmonella infection

worsened with an increase in bacterial numbers

accompanied by a lack of granulomas formation.

Furthermore, extensive growth of bacteria in macro-

phages, polymorphonuclear phagocytes and hepato-

cytes was seen. They suggest that lack of recruitment

of inflammatory macrophages rather than the im-

pairment of bacterial killing by phagocytes accounts

for the exacerbation of Salmonella infection in the

absence of TNF-a [15].

Summarizing, TNF blockage leads to greater

adherence of Salmonella in the intestinal wall, with

decline of TLR-4 dendritic phagocytic cells, de-

creased production of IFN-g and less granulomas

formation and maintenance, causing an impaired

immune response to Salmonella species with, as

result, severe invasive infections. As seen in infec-

tions with mycobacteria, it is expected that TNF

blockage will result in more disseminated Salmonella

infections.

In conclusion, it is conceivable that treatment

with an anti-TNF agent has played an essential role

in the clinical course of our patient. We hypothesize

that anti-TNF increases the change in bacteraemia

and therefore enhances the risk for endovascular

and deep-seated infections. The risks of complica-

tions should be weighed against the benefits in

certain groups of patients (e.g. with prosthetic

joints, vascular aneurysms) before biologicals such

as TNF blockers are given. In countries with a high

prevalence of Salmonella infections (and Salmonella

carriers) a stool culture before anti-TNF treatment

should be considered (and if positive treated). Due

to the increase of anti-TNF-a treatment strategies

in the coming y, we will probably see a rise in

invasive salmonellosis. More awareness is needed

for the treatment of patients with a cardiovascular

history.

Table I. Extra-intestinal manifestations of salmonellosis.

Site Incidence Complications Mortality

Endocarditis 0.2%�0.4% Valve perforations 70%

Pericarditis

Arteritis Rare Mycotic aneurysm 14%�60%

Aneurysm rupture

Central nervous

system

0.1%�0.9% Meningitis brain

abscess

20%�60%

Pulmonary Rare Pneumonia 25%�60%

Empyema

Bone B/1% Osteomyelitis Very low

Joint-reactive 0.6% �/3 joints involved Negligible

Joint-septic 0.1%�0.2% Osteomyelitis Very low

Muscle/soft tissue Rare Pyomyositis 33%

Abscess

Hepatobiliary Rare Hepatomegaly 10%

Abscess

Splenic Rare Splenomegaly B/10%

Abscess

Urinary 0.6% Cystitis 20%

Pyelonephritis

Abscess

Genital Rare Abscess Very low

Soft tissue B/1% Thrombophlebitis 15%

Endophthalmitis

82 Case reports

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Weisman M, et al. Anti-Tumour Necrosis Factor Trial in

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patients receiving concomitant methotrexate: a randomised

phase III study. Lancet 1999;/354:/1932�9.

[2] Crum NF, Lederman ER, Wallace MR. Infections associated

with tumour necrosis factor-a antagonists. Medicine 2005;/

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[3] Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer

DO. Granulomatous infectious diseases associated with

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[4] Wallis RS, Broder M, Wong J, Lee A, Hoq L. Reactivation of

latent granulomatous infections by infliximab. Clin Infect

Dis 2005;/41:/S194�8.

[5] Pegues DA, Ohl ME, Miller SI. Principles and Practice of

Infectious Diseases, Chapter 220. In: Mandell GL, Bennett

JE, Dolin R, editors. Salmonellae. Elsevier, Churchill

Livingstone; 2004. p. 2636�54.

[6] Hohmann EL. Non-typhoidal salmonellosis. Clin Infect Dis

2001;/32:/263�9.

[7] Mastroeni P, Harrison JA, Robinson JH, Clare S, Khan S,

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monellae in BALB/c mice: role of gamma-interferon and

macrophage activation. Infect Immun 1998;/66:/4767�76.

[8] Everest P, Roberts M, Dougan G. Susceptibility to Salmo-

nella typhimurium infection and effectiveness of vaccination

in mice deficient in the tumour necrosis necrosis factor alpha

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[9] Hess J, Ladel C, Miko D, Kaufmann SH. Salmonella

typhimurium aroA-infection in gene-targeted immunodefi-

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Immunol 1999;/11:/346�51.

[11] Netea MG, Radstake T, Joosten LA, van der Meer JWM,

Barrera P, Kullberg BJ. Salmonella septicaemia in rheuma-

toid arthritis patients receiving anti-tumour necrosis factor

therapy. Arthritis Rheum 2003;/48:/1853�7.

[12] Fu A, Bertouch JV, McNeil HP. Disseminated Salmonella

typhimurium infection secondary to infliximab treatment.

Arthritis Rheum 2004;/50:/3049�60.

[13] Popa C, Netea MG, Barrera P, Radstake TRDS, Riel PL,

Kullberg BJ, van der Meer JWM. Cytokine production of

stimulated whole blood cultures in rheumatoid arthritis

patients receiving short-term infliximab therapy. Cytokine

2005;/30:/72�7.

[14] Hess DJ, Henry-Stanley MJ, Erickson EA, Wells CL. Effect

of tumour necrosis factor a, interferon g, and interleukin-4

on bacteria-enterocyte interactions. J Surg Research 2002;/

104:/88�94.

[15] Mastroeni P, Skepper JN, Hormaeche CE. Effect of anti-

tumour necrosis factor alpha antibodies on histopathology

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Neurological morbidity and the pertussis vaccine: An old story revisited

AVIV SCHUPPER & AVINOAM SHUPER

From the Department of Neurology, Schneider Children’s Medical Centre of Israel, Petah Tiqva, Sackler Faculty of Medicine,

Tel Aviv University, Tel Aviv, Israel

AbstractWe describe 3 children with neurological disorders that developed in association with their receipt of the whole-cell pertussisvaccine. Newer studies supported the ability of the wP vaccine to adversely affect the CNS. The possibility that it worsenedtheir clinical course in infancy by causing additional damage should not be disregarded.

Introduction

The potential of the whole-cell pertussis vaccine (wP)

to cause long-term neurological damage in children

has been debated for over 4 decades. Findings

reported after administration of the vaccine include

high fever, persistent crying, unusual high-pitched

cry, excessive somnolence, convulsions, hypotonic-

hyporesponsive state, encephalitis, encephalopathy

(including onset of epilepsy with retardation, infan-

tile spasms, Reye syndrome), Guillain-Barre syn-

drome, transverse myelitis, cerebellar ataxia, and

sudden infant death syndrome. The medical com-

munity today favours a coincidental rather than a

cause-and-effect relationship between the wP vaccine

Correspondence: A. Shuper, Neurology Service, Schneider Children’s Medical Centre of Israel, Petah Tiqva 49202, Israel. Tel: �/972 3 925 3879. Fax: �/972

3 925 3871. E-mail: AVINOAMS@clalit.org.il

Case reports 83

(Received 24 April 2006; accepted 25 April 2006)

ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis

DOI: 10.1080/00365540600786556

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