Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans

Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon (IFN)- gamma axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23-component deficiency had a history of salmonella disease than did those with IFN- gamma -component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN- gamma -independent pathways. Investigation of the IL-12/IL-23-IFN- gamma axis should be considered in patients with invasive salmonella disease.     

Salmonella bacteremia in renal transplant recipients

Three cases of salmonella bacteremia in renal transplant recipients are reported. Two patients had prolonged salmonella infections with recurring bacteremia. The longest interval between bacteremic relapses was 15 years. 27 cases from the literature of salmonella bacteremia in renal transplant recipients are reviewed. The courses of salmonellosis in renal transplant recipients are more serious than in other non-compromised patients, being complicated by bacteremia in 70% of the cases. Renal transplant recipients have prolonged carrier states and frequent relapses or recurrences of salmonellosis. 45% of the salmonella bacteremias in renal transplant recipients are seen after a high dose methylprednisolone treatment for graft rejection episodes.     

Inherited IL-12p40 Deficiency: Genetic,Immunologic, and Clinical Features of 49 Patients From 30 Kindreds

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency.In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.     

A case of bacteremia due to Salmonella enteritidis in healthy man

Although bacteremia caused by non-typhoidal salmonella is frequently observed in immunocompromised hosts, it is rare to find this condition in healthy subjects. In this report, we present a case of bacteremia due to Salmonella enteritidis detected in a healthy man. A 59-year-old man was admitted to our hospital with a fifty-day history of fever on May 18, 1985. On admission, he showed no symptoms except high body temperature (38.8 degrees C). In the laboratory data, C-reactive protein was 3+, white- cell count was 9600, and erythrocyte sedimentation rate was 12 mm/h. Culture in blood and stool yielded Salmonella enteritidis. However, no abnormal findings were found in UGIS, barium enema, OC + DIC, abdominal CT and echography. As soon as Ampicillin was administered, the fever was gone and the blood culture yielded nothing. After six months, the stool culture was negative for pathological intestinal bacterial flora and he was in good physical condition. Generally, bacteremia develops mainly in the immunocompromised hosts, such as patients with neoplastic disease, AIDS, leukemia or collagen disease. The literature provides so far twenty three adult cases of bacteremia due to non-typhoidal salmonella in Japan. Only two of them had no systemic disease as well as our case. Although it is unknown why bacteremia developed in this healthy man, we reported that bacteremia developed rarely in subjects with healthy condition.     

Salmonella infections in patients with the acquired immunodeficiency syndrome

Defects in T-cell function have been seen in patients with the acquired immunodeficiency syndrome. Although the cellular immune system plays a key role in host defense against Salmonella, there have been no detailed reports of salmonellosis in patients with this syndrome. We report our experience with salmonella infections in six patients. Salmonellosis in these patients was unusually severe, characterized by widespread infection, bacteremia, and relapse, despite standard antibiotic treatment. Because of the difficulty in eradicating salmonella infection in patients with the acquired immunodeficiency syndrome, long-term suppressive treatment with antibiotics seems warranted.     

Salmonellosis in persons infected with human immunodeficiency virus: a report of seven cases from Malaysia

Persons infected with human immunodeficiency virus (HIV) have an increased risk of salmonellosis when compared to the general population. We describe seven such patients with Salmonella bacteremia, of whom two had recurrent salmonellosis. In the latter two cases the infection was unusually severe, characterized by widespread infection, bacteremia and relapse, despite standard antimicrobial therapy. HIV-infected individuals will benefit from education on the source of Salmonella, mode of acquisition and prevention through safe food handling and food preparation practices. Because of the difficulty of eradicating Salmonella infection in patients with acquired immunodeficiency syndrome, long-term suppressive treatment with antimicrobials is warranted.     

Non-typhoidal Salmonella bacteraemia without gastroenteritis: a marker of underlying immunosuppression. Review Of cases at St. Thomas' Hospital 1970-1999

OBJECTIVES: To classify non-typhoidal salmonella bacteraemia according to clinical presentation, and to study how this correlates with the presence of underlying immunosuppression. METHODS: We analysed data collected prospectively for all 82 cases of non-typhoidal salmonella bacteraemia presenting to St. Thomas' Hospital between 1970 and 1999. RESULTS: Patients presented with one of three syndromes: diarrhoea, an extra-intestinal focus of infection, or isolated fever with no focus. Only 18% of those with diarrhoea had underlying immunosuppression, compared with 80% of those with extra-intestinal focal infections (P= 0.001) and 80% of those with no focus (P= 0.0001). There was no significant association between salmonella serotype and underlying immunosuppression. Salmonella enteritidis isolates, especially phage type 4, increased significantly during the last decade (P= 0.001). The presentation of non-typhoidal salmonella bacteraemia in the absence of diarrhoea prompted the diagnosis of HIV in two patients. CONCLUSION: Underlying immunosuppression should be excluded in patients presenting with non-typhoidal salmonella bacteraemia in the absence of gastroenteritis. This may lead to an earlier diagnosis of HIV.     

Salmonella meningitis and infection with HIV

Patients infected with HIV demonstrate increased susceptibility to serious infections with non-typhoidal salmonellae. However, no cases of salmonella meningitis have been reported in this population. We now report three cases of salmonella meningitis which occurred in a population of 1800 patients with AIDS or AIDS-related complex at our hospitals. The incidence of meningitis complicating salmonella infection in our HIV-infected population appears to be much higher than that reported in non-AIDS patients (7.5 versus 0.15%). All had cerebrospinal fluid parameters consistent with bacterial meningitis, and two of three revealed organisms on cerebrospinal fluid Gram stain. Two presented with a fulminant illness and died despite therapy; the third developed a brain abscess associated with a relapse of meningitis. Salmonella meningitis should be considered as a cause of acute neurological deterioration in patients at risk for HIV-related disease. Relapses may occur, and mortality is high.     

Salmonella arizonae bacteremia as the presenting manifestation of human immunodeficiency virus infection following rattlesnake meat ingestion

Recurrent nontyphoid salmonella septicemia is one of the opportunistic infections characteristic of AIDS. The increased incidence of severe salmonellosis in immunocompromised patients is due, in part, to defective cellular immunity. The literature contains reports of nine cases of extraintestinal Salmonella arizonae infections in patients ingesting rattlesnake capsules, all of whom had known underlying medical illnesses. We describe a previously healthy Hispanic man who developed S. arizonae bacteremia as his initial manifestation of infection with the human immunodeficiency virus (HIV). The patient ultimately stated that he had consumed rattlesnake meat for medicinal purposes--a relatively common practice among Hispanics. S. arizonae was cultured from the powder of all capsules remaining in his possession. To our knowledge, this represents the first reported case of S. arizonae bacteremia as the presenting manifestation of HIV infection following the ingestion of capsules containing rattlesnake meat.     

B27 Polymorphism and Peptide Repertoire

Summary Infections are a common cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. The primary disease process and complications of drug management may contribute to this increased susceptibility. A high incidence of salmonella infections have been reported in SLE patients. We report an unusual case of a SLE patient who developed recurrent salmonella sepsis. The first episode with salmonella typhimurium was followed a few months later by an episode of salmonella enteritides sepsis.     

Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries

Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.     

Non-thyphoidal salmonellosis in patients with systemic lupus erythematosus. A study of fifty patients and a review of the literature

The objective of this study was to characterize the clinical profile of lupus patients with non-typhoidal salmonellosis. A retrospective review of the clinical charts of lupus patients diagnosed with bacteriologically proven non-typhoidal salmonellosis over the last 20 y was undertaken, paying special attention to risk factors, clinical presentation and treatment outcome. Most episodes were bacteraemic without a localizing focus; and some patients were afebrile. They usually occurred in patients prone to opportunistic infections, and at times of increased immunosuppression given for lupus flares (especially nephritis). However, salmonellosis also occurred in some patients presenting with lupus. The C-reactive protein level was found to be significantly higher during the infective episodes compared to episodes of non-infective febrile lupus flare. All isolates were sensitive to the usual first-line antibiotics and eminently treatable with 3 weeks of appropriate antibiotics without recurrence/persistence or significant morbidity/mortality, the exceptions being spinal osteomyelitis and septic arthritis involving deformed joints requiring surgical debridement and prolonged antibiotic therapy for eradication. Mortality occurred in the setting of septic shock from mixed-microbial sepsis and major organ failure from active lupus. There is a high association of non-epidemic, non-typhoidal salmonellosis with SLE, especially in patients with active disease on intensified immunosuppression. The C-reactive protein value may be helpful in distinguishing between fever from a pure lupus flare and one complicated by infection.     

The hypercoagulable states

Patients are considered to have hypercoagulable states if they have laboratory abnormalities or clinical conditions that are associated with an increased risk of thrombosis (prethrombotic states) or if they have recurrent thrombosis without recognizable predisposing factors (thrombosis-prone). The number of specific primary hypercoagulable states that are recognized is growing. These disorders are generally inherited abnormalities of coagulation in which a physiologic anticoagulant mechanism is defective: for example, antithrombin III deficiency, protein C and protein S deficiency, abnormalities of the fibrinolytic system, and dysfibrinogenemias. Secondary hypercoagulable states are generally acquired disorders in patients with underlying systemic diseases or clinical conditions known to be associated with an increased risk of thrombosis: for example, malignancy, pregnancy, use of oral contraceptives, myeloproliferative disorders, hyperlipidemia, diabetes mellitus, and abnormalities of blood vessels and rheology. The complex pathophysiologic features of these secondary hypercoagulable states are discussed, and a framework is provided for the laboratory investigation and systematic clinical approach to the patient.     

Salmonella infections in immunocompromised adults

Clinical syndromes caused by Salmonella infection in humans are divided into typhoid fever, caused by Salmonella typhi and Salmonella paratyphi, and a range of clinical syndromes, including diarrhoeal disease, caused by a large number of non-typhoidal salmonella serovars (NTS). Typhoid is a human-restricted and highly adapted invasive disease, but shows little association with immunocompromise. In contrast, NTS have a broad vertebrate host range, epidemiology that often involves food animals, and have a dramatically more severe and invasive presentation in immunocompromised adults, in particular in the context of HIV. Immunocompromise among adults, including underlying severe or progressive disease, chronic granulomatous disease, defects or blockade of specific cytokines (particularly IL-12/IL-23/IL-17 and TNF), and HIV, is associated with suppurative foci and with primary bacteraemic disease, which may be recurrent. These patients have markedly increased mortality. Worldwide, invasive recurrent NTS bacteraemia associated with advanced HIV disease is a huge problem, and the epidemiology in this context may be more human-restricted than in other settings. This review will describe the presentation and pathogenesis of NTS in different categories of immunocompromised adults, contrasted to typhoid fever.     

Invasive non-typhoidal salmonellosis in immunocompetent infants and children.

OBJECTIVE: To investigate the extraintestinal manifestations of non-typhoidal Salmonellae (NTS) infection in immunocompetent infants and children. METHOD: The study took place at the University General Hospital at Heraklion, Crete. Over a 10-year period from 1993-2002 we studied 1087 patients, of whom 443 were children less than 14 years old, with a culture-proven diagnosis of NTS infection. Stool and blood cultures were routinely obtained in patients presenting with fever and diarrhea. The cases of invasive infection in otherwise well children, including bacteremia and/or extraintestinal focal infections were further analyzed. RESULTS: Invasive cases were less common in children than adults (4.06% vs. 8.7%; relative risk 0.467; 95% confidence intervals (CI) 0.279-0.784; p=0.0033). Furthermore, invasive cases were much less common in the otherwise well than in immunocompromised children (3.5% vs. 21.4%; relative risk 0.163; 95% CI 0.053-0.500; p=0.0008). The 15 otherwise well children with invasive NTS infection were aged from 3 weeks to 7.5 years, and nine were aged less than 12 months. Among them, 11 presented with bacteremia, and four with focal extraintestinal infections (rectal abscess, deep neck abscess, urinary tract infection, elbow arthritis). Salmonella enterica subsp. enterica serovars Enteritidis and Virchow were the most common invasive serotypes. All invasive strains were susceptible to beta-lactams including ampicillin, and to cotrimoxazole. All patients made a complete recovery with intravenous antibiotics and did not present with relapses or major infections during long-term follow-up. CONCLUSION: Invasive non-typhoidal salmonellosis in immunocompetent children is less frequent than in both immunocompromised children and in adulthood. However, invasive cases may well occur in otherwise healthy children, especially during infancy. In these patients, prompt appropriate treatment leads to favorable outcomes.     

Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins

Third-generation cephalosporins have been considered for the treatment of systemic salmonelloses because of emerging resistance among Salmonella species to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Twelve patients with typhoid/paratyphoid fever, nine with nontyphoid salmonella bacteremia, and two with Salmonella meningitis were treated with cefotaxime; one leukemic patient with Salmonella dublin bacteremia received ceftizoxime. All infections were cured except for one in a patient with sickle cell anemia; this patient's illness recurred but was cured with a second course of cefotaxime followed by ceftriaxone. A review of the literature documented cures with cefotaxime in 50 of 61 patients with typhoid/paratyphoid fever, all of four with salmonella osteomyelitis, 12 of 14 with salmonella meningitis, and 44 of 49 with non-typhoid salmonella bacteremia. Ceftriaxone and cefoperazone cured, respectively, 23 of 25 and 32 of 33 patients with typhoid/paratyphoid fever. The relapse rates of typhoid fever treated with cefotaxime, ceftriaxone, and cefoperazone were 6%, 4%, and 0%, respectively. Cefotaxime, ceftriaxone, and cefoperazone are acceptable alternative antibiotics for the treatment of salmonelloses caused by multiresistant organisms.     

Salmonellosis during infection with human immunodeficiency virus

Salmonella bacteremia is being identified with increasing frequency in persons infected with the human immunodeficiency virus. Salmonellosis may occur in patients with an established diagnosis of acquired immunodeficiency syndrome (AIDS), or it may be the first manifestation of this disorder. In patients with AIDS, salmonellosis is characterized by recurrent bacteremia despite treatment and a relative paucity of gastrointestinal manifestations. Treatment regimens may be limited by antimicrobial resistance, poor penetration of antibiotics into phagocytes, and drug intolerance; optimal therapy remains to be established. Possible mechanisms to account for this increased frequency and severity of salmonellosis include altered cell-mediated immunity, hemolysis, prior use of antibiotics, and increased exposure to the pathogen. Salmonellae should be considered among the pathogens associated with human immunodeficiency virus infection.     

Extra-intestinal manifestations of salmonella infections

While salmonellosis is often considered to affect primarily the gastrointestinal tract, infection at other sites may occur, producing characteristic clinical syndromes. We reviewed cases from our institutions and the literature on focal manifestations of salmonella infections. In the past, most extra-intestinal salmonella infections were caused by S. choleraesuis; however, we found S. typhimurium to be the predominant serotype. The mortality rate for patients in our series was considerably lower than the rate described for focal infections in other reviews. This may in part be due to lower proportion of infections due to S. choleraesuis, improved microbiologic and diagnostic techniques, increased use of ampicillin, and improved surgical techniques. Salmonella endocarditis usually occurs in patients with preexisting heart disease. Unlike other salmonella infections, S. choleraesuis is the most frequent serotype. Salmonella endocarditis is often very destructive, with a fatality rate of 70%. Nonvalvular (mural) endocarditis occurs in one-fourth of patients and survival has not been reported. While antibiotic therapy should be tried initially, if response is not prompt the clinician should look for an associated site of infection (intra- or extra-cardiac abscess), which will often require surgery. Salmonella pericarditis often presents with cardiac or pulmonary symptoms, but typical signs of pericardial disease (pulsus paradoxus, friction rub) or characteristic electrocardiographic changes (low voltage, elevated ST segments) are uncommon. Early diagnosis, before infection involves other areas of the heart, is crucial for survival. In addition to antibiotic therapy, pericardiocentesis or pericardiectomy is required. Salmonella may infect the peripheral or visceral arteries, but the abdominal aorta is the most frequent site of vascular infection. Most patients are men over age 50 with preexisting atherosclerosis of the aorta who do not have a previous history of gastroenteritis. About one-fourth of patients have associated lumbar osteomyelitis. No patients have been reported to survive with medical therapy alone. Specific guidelines for surgical removal of infected aneurysms have been proposed and these (in addition to increased use of ampicillin) may be responsible for higher survival rates in recent years. Due to the high incidence of relapses, postoperative blood cultures should be done routinely. Arterial infection should be considered in any elderly patient with salmonella bacteremia especially with prolonged fever or bacteremia after an "adequate course" of antibiotic therapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Primary gluteal abscess due to Salmonella typhimurium: a case report and review of the literature

Infections due to nontyphoidal salmonellae are common, and their incidence has been increasing in the last few years. In this case report, we document the unusual finding of a gluteal abscess caused by Salmonella typhimurium in the absence of detectable bacteremia. Fluoroquinolones remain an important treatment option for salmonellosis, and to avoid potential treatment failures, we underscore the importance of routine screening for nalidixic acid susceptibility with all extraintestinal Salmonella isolates. To our knowledge, this is the first published case of S typhimurium gluteal abscess in the absence of bacteremia and risk factors for salmonellosis.