A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults.

BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. METHODS: A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had âˆ¼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. CONCLUSION: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. CLINICALTRIALS: gov identifier: NCT01556945.

A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia.

RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.

Tuberculosis among foreign-born persons in New York City, 1992-1994: implications for tuberculosis control.

OBJECTIVE: To study the pattern of transmission of tuberculosis (TB) among foreign-born persons living in New York City. DESIGN: A retrospective multicenter study comparing 158 foreign-born patients to 231 US-born patients diagnosed with TB between 1992 and 1994. The patients were stratified according to their Mycobacterium tuberculosis isolate DNA fingerprint patterns. RESULTS: Nineteen (16%) of 122 isolates from foreign-born TB patients and 75 (42%) of 180 isolates from US-born TB patients had DNA fingerprint patterns (cluster patterns) indicative of recent exogenous transmission (P < 0.001). All cluster pattern strains from foreign-born cases were identical to those found among US-born patients. The likelihood of infection with a cluster pattern strain among foreign-born persons increased with duration of residence in the US, and was significantly associated with being homeless (P < 0.05), or having multidrug-resistant TB (P = 0.00072). CONCLUSION: Although most (84%) cases of TB among foreign-born persons in New York City appear to result from reactivation of infections they acquired abroad, the ones who acquire new infections become infected with strains that are already circulating among the US-born TB patients in New York City, and they have risk factors similar to those faced by US-born tuberculosis patients.

Ectopic enterobiasis: a case report and review.

Enterobius vermicularis ('pinworm') is rarely found outside the gastro-intestinal tract. We describe a case of extra-intestinal pinworm abscess associated with an inguinal hernia in an adult. A brief review of the literature is given and possible mechanisms of tissue invasion are discussed.

Infectious considerations in the world traveler.

Travel-associated dermatoses are among the six most frequent medical problems encountered by international travelers. Skin disorders caused by parasites previously confined to the tropics are seen with increasing frequency by physicians in nonendemic areas. Cutaneous manifestations may provide important clues to the underlying infection. This article describes the epidemiology, assessment, and management of important parasitoses with cutaneous involvement.

A single dose, combined vaccine against typhoid fever and hepatitis A: consistency, immunogenicity and reactogenicity.

BACKGROUND: Vaccines against hepatitis A and typhoid fever are well established and have an excellent safety and immunogenicity profile. Yet these diseases, which share the same geographic distribution, remain an important cause of morbidity in travelers to endemic countries. Combined vaccination provides dual protection and improves compliance and coverage for travelers. METHODS: This multicenter study evaluated the consistency of three lots of combined hepatitis A and typhoid fever vaccine. A total of 462 healthy subjects, aged 15-50 years, were enrolled and randomly allocated to 3 groups. The single dose of vaccine contains 25 microg typhoid Vi polysaccharide and at least 1,440 ELISA units of inactivated hepatitis A in a 1 mL dose. RESULTS: Bioequivalence of all production lots was shown in terms of safety and immunogenicity. Pain at injection site was the most frequent reported local symptom, and headache was the most frequent reported general symptom. As early as 14 days after immunization >95% of the subjects were positive for anti-Vi antibodies and >86% were positive for anti-HAV antibodies. The GMTs and seropositivity rates were maintained during the 6 month follow-up. CONCLUSION: The first combined vaccine against typhoid fever and hepatitis A was safe and elicited a very good immune response, with the majority of subjects seropositive at 1 month for both antigens. This combined vaccine offered more convenience and rapid seroconversion to travelers.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

BACKGROUND: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. OBJECTIVE: We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. METHOD: Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). RESULTS: The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Immunogenicity and safety of a combined hepatitis A and B vaccine administered concomitantly with either a measles-mumps-rubella or a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with a Haemophilus influenzae type b conjugate vaccine in infants aged 12-18 months.

Two studies were undertaken to investigate the concomitant administration of combined hepatitis A/B vaccine with a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with Haemophilus influenzae vaccine (DTPa-IPV/Hib), or with a measles-mumps-rubella vaccine (MMR), during the second year of life. On completion of the vaccination course, all subjects were seropositive or seroprotected against all antigens except for one subject who was seronegative for anti-PT. Seropositivity and seroprotection rates for all other antibodies were comparable to reference values for each vaccine component, indicating that the immunogenicity of MMR, DTPa-IPV/Hib and combined hepatitis A/B vaccines is not impaired by co-administration. All vaccines were well tolerated.

The gastroenterologist's approach to dysphagia.

In the gastroenterological diagnostic armamentarium, dysphagia is considered as an important symptom for diseases of the esophagus. Concerning the history of illness, symptoms such as retrosternal pain and heartburn are often associated with gastroesophageal reflux disease. Morphological changes of the mucosa can be diagnosed by flexible endoscopy and radiographic examinations. Investigation with 24-h pH monitoring, manometry, and pharmacological tests is necessary for the diagnosis of functional disorders. Additionally, dysphagia can be associated with multiple internal diseases, including muscular diseases such as dermatomyositis, progressive systemic sclerosis, as well as lupus erythematosus. Difficulties in swallowing associated with hypo- and hyperthyroidism can also be interpreted as muscular lesions. Metabolic disorders such as alcoholism, and diabetes mellitus can be the cause of dysphagia. Increasing importance in the differential diagnosis of dysphagia is attached to infections of the upper GI tract. Especially in immunocompromised patients, infections of Candida albicans, mycobacterias, herpes, varicella zoster, and cytomegaloviruses can produce dysphagia and odynophagia. The differential diagnosis of the "angina-like chest pain" has to differentiate between cardiac disease and a noncardiac genesis. Therefore, besides the cardiac diagnostic investigation, endoscopy, radiography, and manometry are often indicated.

Identification of enteropathogenic Escherichia coli by PCR-based detection of the bundle-forming pilus gene.

A rapid and simple method of detecting enteropathogenic Escherichia coli (EPEC) was developed. The procedure is based on amplifying by the PCR method a 326-bp region of the bundle-forming pilus gene of EPEC. The oligonucleotide DNA primers used in this procedure did not amplify DNA of any other bacterial enteropathogens tested. The procedure was 100% specific for EPEC strains that exhibit a characteristic pattern of attachment (localized adherence) to HeLa cells.

[Autochthonous pulmonary dirofilariasis in Europe]. / Autochthone pulmonale Dirofilariose in Europa.

The chest X-ray of a 39-year-old woman who had an acute onset of fever, cough, dyspnoea and thoracic pain revealed two peripheral round opacities (about 1.5 cm in diameter) in the right lower lobe. Extensive further studies having failed to discover the cause, a diagnostic thoracotomy was performed and the two pleura-adjacent tumours were removed. Histological examination revealed granulomatous encapsulated filariae, species Dirofilaria immitis. This was confirmed by a positive ELISA test with Dirofilaria immitis antigen. As the patient had been on holiday in Corsica three months before onset of symptoms, it is most likely that the pulmonary dirofilariasis was acquired autochthonously in Europe.

A prophylactic hepatitis B vaccine with a novel adjuvant system.

Studies with recombinant hepatitis B vaccines show seroprotection rates varying between 91 and 100%. Thus, a limited risk may remain for non-responding populations (e.g. non-responders, haemodialysis patients, elderly) who could benefit from a more immunogenic hepatitis B vaccine. One strategy to enhance the immune response is the use of novel adjuvants. SmithKline Beecham has developed a new adjuvant system containing alum and 3-deacylated monophosphoryl lipid A: SBAS4 (SmithKline Beecham Adjuvant System 4). Pilot studies showed that SBAS4 improved in vivo humoral and in vitro cellular immune responses compared to the response to classical recombinant hepatitis B vaccines and was safe and well-tolerated. Several studies assessed the profile of the HBsAg/SBAS4 vaccine in a healthy population, non-responders or elderly. In general the HBsAg/SBAS4 vaccine was well tolerated. Compared to an established recombinant hepatitis B vaccine, we observed an increased local reactogenicity but few symptoms were reported as severe. The HBsAg/SBAS4 vaccine elicits a strong immune response: subjects are protected faster and the GMTs are usually much higher. HBsAg/SBAS4 thus has the potential to protect those subjects who fail to be protected by well established hepatitis B vaccines.

An unusual case of active tuberculosis of the oesophagus in an adult.

A case is reported of a 56-year-old woman of Libyan origin presenting with dysphagia, retrosternal pain and weight loss. Oesophago-gastroduodenoscopy revealed an ulcerated tumor in the upper oesophagus strongly suggesting a malignancy. A positive Mendel-Mantoux test along with histological evidence of epitheloid cell granulomas and clinical findings consistent with pulmonary and lymph node tuberculosis led to the presumptive diagnosis of oesophageal tuberculosis. The diagnosis was later confirmed by positive bacteriological cultures of oesophageal biopsies and gastric washings. It is very unusual for dysphagia to be the presenting symptom of active adult tuberculosis. Oesophageal tuberculosis is extremely rare and must be distinguished predominantly from oesophageal carcinoma.

Russell's viper venom: effects on coagulating whole blood in vitro.

Russell's viper venom (RVV) leads to a strong activation of the coagulation system with consumptive coagulopathy and thrombopenia. For better comprehension of the pathophysiologic process, the effect of RVV was examined in an in vitro model of hemostasis. The stimulation of the coagulation system and of platelet activity can be discriminated by sequential measuring of fibrinopeptide A (FPA) generation and platelet factor 4 (PF 4) release, respectively. In coagulating whole blood both parameters show a parallel response curve in the control series (n = 6) with an initial slow phase followed by a rapid phase after 4.7 +/- 0.8 min (FPA) and 6.0 +/- 0.9 min (PF 4) of the incubation period. Varying concentrations of RVV (15, 50, 100 and 1,000 ng/ml; n = 6 each) cause a dose-dependent stimulation of FPA generation as well as of PF 4 secretion. Clot formation time shows a decrease from 9 min (controls) to 6.3 +/- 2.0 min (100 ng/ml RVV) and 2.7 +/- 0.5 min (1,000 ng/ml), respectively. The concomitant addition of antithrombin III (AT III, 20 U/ml) and RVV (100 ng/ml) leads to a nearly complete normalization of hemostasis in vitro. The beginning of the rapid activation phase is comparable to that of the control group, clot formation does not occur during the 10-min incubation period. Heparin (1 IU/ml) acts as an antagonist not only of the venom-induced FPA generation, but also of the PF 4 release. Prostaglandin E1 (PGE1) (150 ng/ml) does not inhibit the RVV-stimulated FPA generation, but causes a moderate inhibition of PF 4 secretion, especially during the rapid phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic portal hypertension in a renal transplant patient after long-term azathioprine therapy.

We report the case of a patient with renal insufficiency who was admitted for the evaluation of splenomegaly. He had received a kidney allograft 6 1/2 years ago. Treatment with azathioprine and prednisolone for immunosuppression had been discontinued 1 year before admission. The underlying cause of the splenomegaly appeared to be an idiopathic portal hypertension. Until now, this disease has been described in only 13 kidney transplant patients receiving long-term immunosuppressive therapy with azathioprine. For the first time we demonstrate that azathioprine can cause this chronic liver disease even if the drug has been withdrawn some time before. Therefore, the indication for azathioprine must be considered very carefully.

Risk factors associated with vancomycin-resistant Enterococcus faecium infection or colonization in 145 matched case patients and control patients.

Risk factors and mortality associated with vancomycin-resistant Enterococcus faecium (VREF) infection or colonization were examined at a tertiary care hospital by comparing 145 patients who had VREF isolates (cases) to 145 patients with vancomycin-susceptible Enterococcus faecium (VSEF) isolates (controls). The number of deaths per 100 person-days of hospitalization after diagnosis did not differ significantly between VREF patients (1.2) and VSEF patients (0.8). Multivariate analyses found that the duration of hospitalization ( > or = 7 days), intrahospital transfer between floors, use of antimicrobials (i.e., vancomycin and third-generation cephalosporins), and duration of vancomycin use ( > or = 7 days) was independently associated with VREF infection or colonization. This study, which has a large sample size, confirms some earlier observations regarding risks for VREF infection or colonization and identifies factors that may be potentially exploited to develop interventional strategies for the control of this emerging nosocomial problem.

Substitution of factor XIII: a therapeutic approach to ulcerative colitis.

Three patients with ulcerative colitis in the active stage demonstrated reduced levels of F XIII activity and F XIII subunit A (61 and 80.3%, respectively). Because of the lack of clinical improvement during conservative therapy, the patients were treated additionally with F XIII concentrate (Fibrogammin HS, Behring, FRG) for 10 days. The substitution resulted in an increase in F XIII activity (144.3%) and F XIII subunit A (238%) as well as in a marked improvement in symptoms.

[Disseminated histoplasmosis after a tropical visit in a patient with known sarcoidosis]. / Disseminierte Histoplasmose nach Tropenaufenthalt bei bekannter Sarkoidose.

A 40-year-old man with grade II sarcoidosis went on a two-week visit to Ecuador. Afterwards he was treated with low-dose corticosteroids because of slight deterioration on the X-ray film. Unilateral hilar enlargement followed by bouts of high fever and a greatly increased erythrocyte sedimentation rate, suggested an acute exacerbation of the sarcoidosis and was, therefore, treated with an increase in steroid dosage plus azathioprine. Bronchoalveolar lavage fluid and tissue samples from lung, bone-marrow and spleen were suggestive of an infection with Histoplasma capsulatum. There was now bilateral hilar enlargement with right upper lobe infiltration, marked hepatosplenomegaly and thrombocytopenia (17,000/microliters), but serological tests remained negative. The fulminant course with dissemination could not be arrested despite administration of fluconazole (400 mg/d) and amphotericin B (total dosage 1.14 g). Histoplasma capsulatum was cultured from lung and spleen tissue post-mortem.

Risk and aetiology of diarrhoea at various tourist destinations.

Almost two of three tourists developed traveller's diarrhoea during 2-week stays at high-risk destinations. Large differences in infection rates between hotels were seen. Patients with milder forms of diarrhoea show a similar chronology to those more severely affected. Although enterotoxigenic Escherichia coil was the most frequent cause, viral pathogens were detected more often than in other studies.

Differentiation of pathogenic Escherichia coli strains in Brazilian children by PCR.

A PCR technique to differentiate pathogenic enteric Escherichia coli strains in a field setting was evaluated. Among 76 children with acute diarrhea, this technique identified 12 children (16%) with enterotoxigenic E. coli, 6 (8%) with enteropathogenic E. coli, and 1 (1%) with enteroinvasive E. coli infection. Compared with the conventional assays, the PCR method proved to be simpler, more rapid, and inexpensive and therefore suitable for application in a developing-country field setting.