Georg Härter

Anti-TNF immunotherapy reduces CD8+ T cell–mediated antimicrobial activity against Mycobacterium tuberculosis in humans

The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell-directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell-mediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosis-reactive CD8+CCR7-CD45RA+ effector memory T cells (TEMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, TEMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8+ TEMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8+ TEMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8+ TEMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis.

Intravenous Zanamivir for Patients with Pneumonitis due to Pandemic (H1N1) 2009 Influenza Virus

We report on 2 critically ill patients with pneumonitis and acute respiratory distress syndrome due to pandemic (H1N1) 2009 influenza A virus who were treated with intravenous zanamivir and had favorable clinical outcomes. Zanamivir given intravenously may be a therapeutic option in patients with critical illness and mechanical ventilation.

In vitro activities of itraconazole, methiazole, and nitazoxanide versus Echinococcus multilocularis larvae.

ABSTRACT Albendazole (ABZ) and mebendazole are the only drugs licensed for treatment of human alveolar echinococcosis. In order to augment the armamentarium against this deadly disease, we tested a series of drugs for their efficacy against Echinococcus multilocularis larvae. E. multilocularis larvae grown intraperitoneally in Mongolian gerbils were transferred into tissue culture. Vesicles budded from the tissue blocks and after 6 weeks, drugs were added, and the effect on the vesicles was observed. We tested the following drugs at various concentrations: ABZ, artemether, caspofungin, itraconazole (ITZ), ivermectin, methiazole (MTZ), miltefosine, nitazoxanide (NTZ), rifampin, and trimethoprim-sulfamethoxazole. ABZ, ITZ, MTZ, and NTZ effectively destroyed parasite vesicles in this in vitro culture system. At high NTZ doses of 10 μg/ml, disintegration of all vesicles was observed after 7 days and was significantly more rapid than with ABZ at equal concentrations (21 days). After drug discontinuation, regrowth of vesicles occurred between 7 and 14 days for all four drugs, indicating a parasitostatic effect. Combination treatment with NTZ-ABZ at concentrations between 1 and 10 μg/ml for either 3 weeks, 3 months, or 6 months yielded no vesicle regrowth during 8 months after drug discontinuation. The treated larval tissue was injected intraperitoneally into gerbils, and no regrowth of larval tissue was observed, suggesting a parasitocidal effect after combined treatment. ITZ, MTZ, and NTZ are potent inhibitors of larval growth, although they proved to be parasitostatic only. The combination of NTZ plus ABZ was parasitocidal in vitro. Animal experiments are warranted for studies of dose, toxicity, and drug interactions.

CD4+ T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4+ T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B–expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B–dependent degradation of the TCR-ζ–chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21+CD40L− Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21–dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.

Fecal Transplant in Refractory Clostridium difficile Colitis

BACKGROUND Clostridium difficile infections are becoming more common, more severe, and more likely to recur. Conventional treatment with antibiotics often fails to eradicate the infection; even when it succeeds, recurrent infection is common. Complementary treatment with probiotic agents to reconstitute the physiological intestinal flora does not yield any consistent benefit. In recent years, fecal transplantation has been used in the English-speaking countries with cure rates of about 87%, but the available evidence is limited to large case series. No randomized controlled trials have been performed. We present the case of a 73-year-old woman with intractable, recurrent enterocolitis due to Clostridium difficile who was successfully treated with fecal transplantation via colonoscopy. CASE DESCRIPTION Upon the completion of antibiotic treatment for a second recurrence of enterocolitis, stool in liquid suspension was introduced into the patients colon through a colonoscope. Prior testing had shown the stool donor to be free of acute infection or stool pathogens. The patient was given loperamide to prolong contact of the stool transplant with the colonic mucosa. She was also treated with Saccharomyces cerevisiae for four weeks. COURSE There was no clinical or microbiological evidence of a further recurrence of enterocolitis for 6 months after transplantation. Stool transplantation had no adverse effects. CONCLUSION This patient had a lasting remission of enterocolitis due to Clostridium difficile after the treatment described above. Fecal transplantation seems to be a safe and highly effective treatment for recurrent Clostridium difficile infection. It is unclear whether the administration of Saccharomyces cerevisiae confers any additional benefit.

Diagnosis of neuroschistosomiasis by antibody specificity index and semi-quantitative real-time PCR from cerebrospinal fluid and serum.

We describe the case of a 16-year-old German male expatriate from Ghana who presented with obstipation, dysuria, dysaesthesia of the gluteal region and the lower limbs, bilateral plantar hypaesthesia and paraesthesia without pareses. A serum-cerebrospinal fluid (CSF) Schistosoma spp. specific antibody specificity index of 3.1 was considered highly suggestive of intrathecal synthesis of anti-Schistosoma spp. specific antibodies, although standardization of this procedure has not previously been described. Diagnosis was confirmed by detection of Schistosoma DNA in CSF by semi-quantitative real-time PCR at 100-fold concentration compared with serum. Accordingly the two diagnostic procedures, which have not previously been applied for routine diagnosis, appear to be useful for the diagnosis of neuroschistosomiasis. Clinical symptoms resolved following anthelmintic and anti-inflammatory therapy.

Direct-acting antiviral agents in the treatment of chronic Hepatitis C – “Real-life” experience from an academic centre and two specialized clinical practices

The introduction of the new direct antiviral agents has revolutionized the therapy of chronic hepatitis C. Today we are able to cure the vast majority of our patients with an 8- to 12-week therapy course of an antiviral combination therapy with an excellent safety profile. Real-life data are very important to further develop our experience with the new therapeutics and help us to improve the care of our patients in our everyday clinical practice.In our study, we present the retrospective analysis of a representative German cohort of 344 patients with chronic hepatitis C treated with the new direct antiviral agents. The patients were recruited in an academic center of southern Germany (University Clinic of Ulm, Clinic of Internal Medicine I) and in 2 highly specialized clinical practices in the city center and the near region of Ulm. Within this in-detail characterized study cohort, we analyzed the efficacy and safety of antiviral therapy under real-life conditions.In 322 patients, we could document SVR12 data and found an excellent overall SVR12 rate of 97.8 % across all genotypes. In more detail, we could show comparable SVR12 results of 99 % and 99.2 % in patients with the hepatitis C virus subtypes 1a and 1b of and an excellent SVR12 rate of 93.1 % in genotype 3 patients without liver cirrhosis. Nevertheless, SVR12 rates tend to be lower in patients with the presence of liver cirrhosis, especially in genotype 3 patients with the lowest SVR12 rate in the whole study group of only 80 %. In general, there were no major safety issues except of 1 patient treated with a protease-inhibitor-based regimen who developed a generalized skin reaction and needed hospitalization and premature end of antiviral therapy.In summary, our analysis of this well characterized representative cohort of 344 patients adds more information in the field of real-life experience with the new antiviral therapeutics and could therefore contribute to improve the care of our patients. Together with the existing real-life data, we now can proceed in achieving the aim of viral eradication of hepatitis C virus within our population.

Reisemedizinische Beratung für HIV-Patienten@@@Vaccinations and prophylaxis: what to consider

Eine HIV-Infektion ist prinzipiell kein Hinderungsgrund für eine Fernreise. Bei der reisemedizinischen Beratung dieser Patienten gilt es, auch den Immunstatus und die antiretrovirale Medikation zu berücksichtigen. Mehr dazu im folgenden Beitrag.

Reisemedizinische Beratung für HIV-Patienten

Eine HIV-Infektion ist prinzipiell kein Hinderungsgrund für eine Fernreise. Bei der reisemedizinischen Beratung dieser Patienten gilt es, auch den Immunstatus und die antiretrovirale Medikation zu berücksichtigen. Mehr dazu im folgenden Beitrag.