[Recommendations for therapy, chemoprevention and chemoprophylaxis of tuberculosis in adults and children. German Central Committee against Tuberculosis (DZK), German Respiratory Society (DGP)]. / Empfehlungen zur Therapie, Chemoprävention und Chemoprophylaxe der Tuberkulose im Erwachsenen- und Kindesalter. Deutsches Zentralkomitee zur Bekämpfung der Tuberkulose (DZK), Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Several new international recommendations have been published since the German Central Committee against Tuberculosis (DZK) published its recommendations for drug treatment of tuberculosis (TB) in 2001 and for chemoprevention of latent tuberculosis infection (LTBI) in 2004. These international publications have been integrated in the present new recommendations which describe both the treatment of active TB and preventive treatment, pointing out specific adaptations for Germany. Separate sections deal with the current management of mono-, poly-, and multiresistance or drug intolerance, of TB in children, of different forms of extrapulmonary TB, of LTBI and of special situations such as HIV infection, renal or hepatic insufficiency, infection following BCG instillation in bladder cancer or in case of adverse drug reactions. The following aspects differ from the previous recommendations: A three-drug regimen for the so-called fully susceptible minimal TB is no longer recommended in adults. A dosage of 15 mg/kg body weight of ethambutol for adults is regarded as sufficient. Four secondline drugs (supplemented by pyrazinamide, where appropriate) are recommended for multidrug-resistant tuberculosis (MDR-TB). MDR-TB should be treated over a period of at least 20 months, with an injectable drug administered for a minimum of 8 months (initial phase). Ciprofloxacine and ofloxacine are no longer used to treat TB. It is also recommended to offer an HIV test to all TB patients to complement antiretroviral therapy, if necessary, and to adapt the antituberculous therapy accordingly.

[Clinical features and diagnosis of tuberculosis]. / Klinik und Diagnose der Tuberkulose.

Recently, major advances have been accomplished in the diagnosis of active tuberculosis. A comprehensive diagnostic approach for a patient with possible tuberculosis includes a detailed medical history and clinical examination as well as the results of radiological, microbiological, immunological, molecular-biological and histological methods. In concert, these results enable the clinician to rapidly develop a decision with a high probability for the diagnosis or exclusion of active tuberculosis. Therapeutic intervention can thus be made early, even though corrections in these decisions need to be considered depending on the results of Mycobacterium tuberculosis culture and sensitivity testing.

Local immunodiagnosis of pulmonary tuberculosis by enzyme-linked immunospot.

Lymphocytes are crucial in the immune defence against Mycobacterium tuberculosis (MTB) infection. The aim of the present study was to ascertain whether or not MTB-specific lymphocytes are selectively compartmentalised in the lungs of patients with minimal active pulmonary tuberculosis (PTB). Patients with smear-negative MTB-culture-confirmed PTB were prospectively recruited. Differential cell counts, immunophenotyping with monoclonal antibodies directed against the cell surface markers CD4, CD8, CD4CD45RA, CD4CD45R0, CD38, human leukocyte antigen DR, CD19, CD3, CD57 and CD16 and MTB-specific enzyme-linked immunospot assays of peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) mononuclear cells with 6-kDa early secretory antigenic target and culture filtrate protein 10 were performed. Among 12 patients with culture-confirmed smear-negative PTB, no differences were found in the distribution of total CD4 or CD8 T-cells in peripheral blood or BAL fluid (BALF). Activated human leukocyte antigen-DR-positive cells, as well as memory CD4CD45R0-positive T-cells, were expanded among cells of the BALF. Compared with a group of control patients with alternative pulmonary pathologies, there was no significant difference in lymphocyte subpopulations. However, 6-kDa early secretory antigenic target- and culture filtrate protein 10-specific lymphocytes were more concentrated, with a median BALF:peripheral blood ratio of 9.9 and 8.9, respectively, in patients with PTB. Mycobacterium tuberculosis-specific T-cells are highly selectively compartmentalised at the site of infection in active pulmonary tuberculosis.

Use of a T-cell interferon-gamma release assay for the diagnosis of tuberculous pleurisy.

The diagnosis of pleural tuberculosis (plTB) by the analysis of pleural effusions (PEs) with standard diagnostic tools is difficult. In routine clinical practice, the present authors evaluated the performance of a commercially available Mycobacterium tuberculosis (MTB)-specific enzyme-linked immunospot assay on peripheral blood mononuclear cells (PBMCs) and pleural effusion mononuclear cells (PEMCs) in patients with suspect plTB. The T-SPOT.TB test (Oxford Immunotec Ltd, Abingdon, UK) was performed on PBMCs and PEMCs in 20 patients with a clinical and radiological suspect of plTB and in 21 control subjects with a diagnosis of PE of nontuberculous origin at four centres participating in the European Tuberculosis Network. In total, 18 (90%) out of 20 patients with plTB tested T-SPOT.TB-positive on PBMCs and 19 (95%) out of 20 on PEMCs. Among controls, T-SPOT.TB was positive in seven out of 21 (33%) patients when performed on PBMCs (these patients were assumed to be latently infected with MTB) and five (23%) out of 21 when performed on PEMCs. Sensitivity and specificity of T-SPOT.TB for the diagnosis of active plTB when performed on PEMCs were 95 and 76%, respectively. Enumerating Mycobacterium tuberculosis-specific T-cells in pleural effusion mononuclear cells by ELISPOT is feasible in routine clinical practice and may be useful for a rapid and accurate diagnosis of pleural tuberculosis.

Avoiding the effect of BCG vaccination in detecting Mycobacterium tuberculosis infection with a blood test.

Bacille Calmette-Guérin (BCG) vaccination can confound tuberculin skin test (TST) reactions in the diagnosis of latent tuberculosis infection (LTBI). The TST was compared with a Mycobacterium tuberculosis (MTB)-specific enzyme-linked immunospot (ELISPOT) assay during an outbreak of MTB infection at a police academy in Germany. Participants were grouped according to their risk of LTBI in close (n = 36) or occasional (n = 333) contacts to the index case. For the TST, the positive response rate was 53% (19 out of 36) among close and 16% (52 out of 333) among occasional contacts. In total, 56 TST-positive contacts (56 out of 71 = 78.9%) and 27 TST-negative controls (27 out of 298 = 9.1%) underwent ELISPOT testing. The odds ratio (OR) of a positive test result across the two groups was 29.2 (95% confidence interval (CI) 3.5-245.0) for the ELISPOT and 19.7 (95% CI 2.0-190.2) for the TST with a 5 mm cut-off. Of 369 contacts, 158 (42.8%) had previously received BCG vaccination. The overall agreement between the TST and the ELISPOT was low, and positive TST reactions were confounded by BCG vaccination (OR 4.8 (95% CI 1.3-18.0)). In contrast, use of a 10-mm induration cut-off for the TST among occasional contacts showed strong agreement between TST and ELISPOT in nonvaccinated persons. In bacille Calmette-Guérin-vaccinated individuals, the Mycobacterium tuberculosis-specific enzyme-linked immunospot assay is a better indicator for the risk of latent tuberculosis infection than the tuberculin skin test.

[Tuberculosis-current therapeutic principles]. / Tuberkulose-gegenwärtige Therapieprinzipien.

Chemotherapy for tuberculosis is indicated in case of disease as well as in latent tuberculosis infection. Standard medication for drug-susceptible tuberculosis consists of isoniazid and rifampicin for six months with additional pyrazinamide and ethambutol for the first two months. Prolonged treatment is necessary in cases of cavernous pulmonary tuberculosis with lack of negative cultures by two months of therapy, in tuberculosis of the central nervous system and in some cases of superficial lymph node disease. Especially in multiple-drug resistant tuberculosis prolonged treatment with three or more drugs, that have been proven to be effective by susceptability testing, is mandatory. Attention must be payed to reliable delivery of chemotherapy as well as to side effects of antituberculosis medications. The classical treatment for latent tuberculosis infection is isoniazid. Multidrug short-course therapy, which has been shown to be equally effective, enhances patients' compliance, but toxicity is increased.

Interleukin-12 as successful adjuvant in tuberculosis treatment.

Interleukin-12 (IL-12) proved to be an effective and successful adjuvant to a standard antituberculotic medication in a patient suffering from progressive clinical tuberculosis (TB). IL-12 is a potent enhancer of interferon-gamma production which is necessary for killing intracellular bacteria like mycobacteria. This patient's TB was progressive, although sensitivity to first-line antituberculotics was proven and medication was given as directly observed therapy over more than 8 months. The 3-month adjuvant therapy with IL-12 significantly and convincingly improved results. It is believed that this case, the first in the literature to describe adjuvant interleukin-12 therapy in tuberculosis, strongly encourages the study of adjuvant interleukin-12 therapy on a more systematic basis.

Two cases of Mycobacterium microti derived tuberculosis in HIV-negative immunocompetent patients.

We describe two cases of Mycobacterium microti infection causing pulmonary tuberculosis (TB) in HIV-seronegative immunocompetent patients in Germany. The isolates were identified as M. microti of the llama and vole types, according to spoligotype patterns. Our data demonstrate that M. microti can cause severe pulmonary TB in immunocompetent patients.

Double infection with a resistant and a multidrug-resistant strain of Mycobacterium tuberculosis.

An immunocompetent patient was dually infected with a resistant and a multidrug-resistant strain of Mycobacterium tuberculosis (TB). The multidrug-resistant strain, which belongs to the W- strain/Beijing family, was first isolated after 3 months of therapy. Inappropriate treatment led to further drug resistance and unsuccessful therapy. Thus, additional infections with resistant M. tuberculosis strains should be considered when tuberculosis therapy fails.

Bird Keeper's lung without bird keepinge

The identification of disease inducing allergens in hypersensitivity pneumonitis can be very problematic, and only by a thorough analysis of anamnestic data the source of allergen can be identified. We report a case of a 32-year-old female diagnosed with hypersensitivity pneumonitis caused by the inhalation of budgerigar antigen in her home. She had been living there for two years and had never been a bird keeper at all. The former proprietor of the house was a budgerigar keeper for years. When we detected precipitating antibodies against different antigens including pigeon and budgerigar antigens as well as hay and Aureobasidium pullulans, the source of antigen exposition was not definitely clear. In the serum of our patient we found precipitating antibodies against protein structures extracted from dust samples from the patient's home, which were not detected in the serum of her husband. Using Western blots of budgerigar serum and of the dust sample from the patient's home we could demonstrate an IgG reactive banding pattern in our patient's serum. The banding pattern against budgerigar serum correlated very closely to that of a control patient, who was a budgerigar keeper with hypersensitivity pneumonitis. The patient's husband reacted neither against budgerigar serum nor against the dust sample, while he and his wife showed double banding at about 9 kDA, when their serum was exposed to dust from a home free of bird keeping. These results point to the fact, that the house dust sample of our patient contained budgerigar antigen, leading to an indirect antigen expositon causing hypersensitivity alveolitis. However, the positive reaction of the patient serum against the protein extract from the dust sample of her home needs further confirmation by inhibition experiments using budgerigar antigen. - Our patient received a prolonged treatment with corticosteroids, and after about one year the vital capacity of the lungs, which was reduced by 50% at the beginning of the treatment, returned to normal. The patient is still living in her home. Although she has been off medication for one year, lung function has not deteriorated. This fact points to a reduction of the amount of antigen in the patient's home.

Low in vitro production of interferon-gamma and tumor necrosis factor-alpha in HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria.

We studied 32 HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria (NTM). Immunologic studies included lymphocyte subset analysis by flow cytometry, measurement of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production following in vitro stimulation of diluted whole blood (DWB) and peripheral blood mononuclear cells (PBMC) by phytohemagglutinin (PHA), anti-CD3 as well as purified protein derivative of tuberculin (PPD), and in four cases with different amounts of the very mycobacterium, which caused disease in these patients. Data were compared to those of 30 HIV-seronegative patients with disease by Mycobacterium tuberculosis (MTb). Following alpha-CD3-stimulation of PBMC, NTM patients showed lower IFN-gamma (P < 0.00005) and lower TNF-alpha (P < 0.02). For a subgroup of tuberculin skin test-positive NTM patients we found significantly lower PPD-induced IFN-gamma releases in cultured DWB (P < 0.0002) and PBMC (P < 0.0004) compared to MTb patients. Data for PPD-induced TNF-alpha release for this subgroup were also significant (P < 0.001 and P < 0.05, respectively). The four NTM patients with poor PPD-induced IFN-gamma response hardly showed increased cytokine production on stimulation with their specific mycobacterium. The lower production capacity of IFN-gamma and TNF-alpha of NTM patients compared to the MTb patients points to an immunologic imbalance forming the basis for their increased susceptibility to pulmonary infections by nontuberculous mycobacteria.

Extensive mediastinal lymphadenopathy in an adult immunocompetent woman caused by Mycobacterium avium complex.

We report a case of extensive mediastinal lymphadenopathy in a 29-year-old immunocompetent woman, which was thought to be caused by Mycobacterium tuberculosis (MTB). Chest radiographs showed deterioration while the patient was receiving antituberculous medication for 8 months. After isolation of Mycobacterium avium complex (MAC) from a lymph node aspiration biopsy and switch to a MAC-specific therapeutic regimen, the lesion almost completely disappeared within 1 year. To our knowledge, this is the first report of an extensive mediastinal lymphadenopathy caused by MAC in an immunocompetent adult.

[Diagnosis of chronic berylliosis]. / Diagnostik der chronischen Berylliose.

The diagnostic value of the lymphocyte transformation test (BeLT) and the intracutaneous skin test with berylliumsulfate was addressed in 13 patients with chronic berylliosis, and 15 individuals with occupational exposure. Additionally, patients with sarcoidosis (n = 21), tuberculosis (n = 14) and healthy controls (n = 25) were tested with BeLT and yielded negative results. In chronic berylliosis the BeLT was positive in 10/13. In 3/13 the BeLT was negative, but the skin test positive. 6/15 exposed individuals exhibited a positive BeLT. The time course of the skin test differed markedly between the individual berylliosis patients. Typical granulomas were present in 4/10 cases. In 9 exposed individuals BeLT tested negative. Additionally, skin tests were negative in 7 exposed patients, however, unspecific skin reactions were observed in 3 cases. The diagnostic value of Beryllium IT requires further investigation. At present, BeLT appears to be a suitable test to prove beryllium sensitisation.

Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs.

The usefulness of the lymphocyte transformation test (LTT) for the analysis of adverse reactions to antituberculous drugs was evaluated. - The LTT was performed with isoniazid and rifampicin in 15 tuberculosis and 2 MOTT (Mycobacteria other than tuberculosis)-infection patients who suffered drug reactions, in 23 patients without any adverse reactions, in 7 controls previously exposed to antituberculous drugs, and in 14 controls who had never been exposed. 4/15 of the hepatotoxic reactions only showed a positive LTT with rifampicin, 3/15 only with isoniazid, and in 8/15 the LTT was negative. In an anaphylactoid shock reaction the LTT was extremely exaggerated for both rifampicin and isoniazid. In patients without any side effects only one slightly increased LTT due to isoniazid was observed. Two healthy controls with previous contact to these drugs showed a positive LTT for isoniazid, one of those with both rifampicin and isoniazid. The LTT was negative in all control persons without any former contact to antituberculous medications. In most cases hepatotoxicity seems to be a pure toxic reaction without the participation of cellular immune mechanisms. LTT can be useful for identifying the drug responsible for immunological side effects.

Assessment of mycobacterial DNA in cells and tissues of mycobacterial and sarcoid lesions.

In this study we applied a polymerase chain reaction (PCR) assay for the detection and species-specific identification of mycobacteria to samples from patients with sarcoidosis and mycobacterial infections and from control patients. The PCR-technique is based on the amplification of mycobacterial DNA coding for 16S rRNA, which is present in all mycobacterial species, and on the additional sequencing of the PCR fragment to determine the species. Mycobacterial DNA could be detected in lung tissues and bronchoalveolar lavage cells from cases of tuberculosis and infections with atypical mycobacteria. On the other hand, mycobacterial DNA was amplified only in lung tissue from one patient with sarcoidosis. Twenty-three samples from patients with sarcoidosis were negative for mycobacterial DNA. From our results we conclude that the granulomatous lesions in sarcoidosis may not be due to mycobacterial infections.

[Clinical atypical mycobacterial infections]. / Klinik atypischer Mykobakteriosen.

In adults atypical mycobacteria usually cause pulmonary disease, lymphadenitis in children and disseminated disease in the course of the acquired immunodeficiency syndrome. Apart from that atypical mycobacteria lead to cutaneous lesions as well as to local abscess formation and necrotic tissue lesions following accidental or iatrogenic trauma of the skin or the soft tissues. Whereas well-established and upcoming microbiologic procedures easily allow an exact classification of the organism, clinical diagnosis is sometimes problematic.

[Immunologic parameters in lung tuberculosis]. / Immunologische Parameter bei Lungentuberkulose.

In patients with pulmonary tuberculosis serum immunoglobulin levels are found to be increased, quantitative deviations from the norm are observed on analysis of the mononuclear cells, there is an increase in the number of circulating immune complexes, and, in the event of extensive pulmonary involvement, an attenuation of cell-mediated cutaneous reactions is seen. In accordance with the chronic course of the disease, a return to normalcy of these parameters in the healing phase occurs only gradually.