Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

[Pathogenicity of Mycobacterium kansasii]. / Pathogenität von Mycobacterium kansasii.

BACKGROUND: In a recent prospective study on pulmonary infections with non-tuberculous mycobacteria (NTM) led by the WATL group, disease rates in patients with M. kansasii infection were found to be 100 %. In the present study we re-evaluated the pathogenicity of M. kansasii infections in a large lung diseases treatment center in Berlin (Lungenklinik Heckeshorn). METHODS: All patients in whose respiratory specimen cultures M. kansasii was detected between January 2003 and June 2013 were included. The 2007 ATS diagnostic criteria were applied to differentiate disease from asymptomatic infection. The strains were further investigated by sequencing of the 16S-23S rDNA internal transcribed spacer (ITS) region. RESULTS: We evaluated 43 consecutive cases. Complete patient data were available in 38 cases. In one patient, no culture results were obtained, in 37 patients M. kansasii was isolated and patient data could be retrieved. In 25/37 patients (68 %) clinical disease was present so that a specific treatment was initiated (underlying diseases were COPD in 8/25 (32 %), bronchiectasis in 5/25 (20 %), TB scar or scar due to prior chest surgery in 3/25 (12 %) and alcohol abuse in 4/25 (16 %)). Twelve out of 37 patients (32 %) were found to be colonized or asymptomatically infected (underlying diseases were COPD in 7/12 (58 %), bronchiectasis in 3/12 (25 %) and TB scar or scar due to prior chest surgery in 3/12 (25 %)). Sequencing results identified 30 strains as genotype I, and 2 strains as genotype II. In 22/30 cases (73 %) genotype I was considered pathogenic. CONCLUSIONS: In our cohort, we could not confirm the high M. kansasii pathogenicity of 100 % found in a previous multi-center study; we therefore support the clinical and semiquantitative microbiologic diagnostic criteria also for infection with M. kansasii.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC).

BACKGROUND: Continuous hyperfractionated accelerated radiotherapy (CHART) counteracts repopulation and may significantly improve outcome of patients with non-small-cell lung cancer (NSCLC). Nevertheless high local failure rates call for radiation dose escalation. We report here the final results of the multicentric CHARTWEL trial (CHART weekend less, ARO 97-1). PATIENTS AND METHODS: Four hundred and six patients with NSCLC were stratified according to stage, histology, neoadjuvant chemotherapy and centre and were randomized to receive 3D-planned radiotherapy to 60Gy/40 fractions/2.5weeks (CHARTWEL) or 66Gy/33 fractions/6.5weeks (conventional fractionation, CF). RESULTS: Overall survival (OS, primary endpoint) at 2, 3 and 5yr was not significantly different after CHARTWEL (31%, 22% and 11%) versus CF (32%, 18% and 7%; HR 0.92, 95% CI 0.75-1.13, p=0.43). Also local tumour control rates and distant metastases did not significantly differ. Acute dysphagia and radiological pneumonitis were more pronounced after CHARTWEL, without differences in clinical signs of pneumopathy. Exploratory analysis revealed a significant trend for improved LC after CHARTWEL versus CF with increasing UICC, T or N stage (p=0.006-0.025) and after neoadjuvant chemotherapy (HR 0.48, 0.26-0.89, p=0.019). CONCLUSIONS: Overall, outcome after CHARTWEL or CF was not different. The lower total dose in the CHARTWEL arm was compensated by the shorter overall treatment time, confirming a time factor for NSCLC. The higher efficacy of CHARTWEL versus CF in advanced stages and after chemotherapy provides a basis for further trials on treatment intensification for locally advanced NSCLC.

[Significance of local and general risk factors for the pathogenesis of pulmonary, non-tuberculous mycobacteriosis in non-AIDS patients]. / Bedeutung der lokalen und allgemeinen Risikofaktoren für die Pathogenese der pulmonalen nicht-tuberkulösen Mykobakteriosen bei Nicht-AIDS-Patienten.

BACKGROUND: Pre-existing underlying bronchopulmonary diseases and relative impairments of the immune system are risk factors that predispose to the development of pulmonary infections with non-tuberculous mycobacteria (NTM), even if the impairment is not severe. METHODS: In a prospective study n = 111 patient diagnoses between 1992 and 2004 were included. The criterion for inclusion was laboratory evidence of non-tuberculous mycobacteria. The local risk factors and general risks were recorded for each case and the total number of risks for each patient was counted. Risk profiles were drawn up and risk scores calculated for different groups. RESULTS: N = 66 patients met the ATS criteria for NTM disease. The disease rates for the most frequent species varied widely ( M. AVIUM complex 57 %, M. KANSASII 100 %, M. XENOPI 73 %). Older women (> 65 years) with M. AVIUM complex were rarely ill. The risk factors were almost equally frequent for patients meeting criteria for disease status and those who did not and patients under 65 years of age had fewer local risk factors than older patients. Patients with M. GORDONAE showed fewer local risk factors than patients with M. AVIUM complex or M. XENOPI. CONCLUSIONS: Even local risk factors predispose towards infections with mycobacteria and do not only lead to disease after infection. Bullous changes of the lungs, cavities and bronchiectasis are local risk factors, but can also develop as sequelae of mycobacteriosis. There is sufficient evidence to support the continued use of the concept of colonisation alongside those of infection with and infection without disease status. In our region, a thorough evaluation is needed to establish whether older women with M. AVIUM complex actually have mycobacteriosis.

[Extramedullary hematopoiesis -- a differential diagnosis of intrathoracic paravertebral tumors]. / Extramedulläre Blutbildung als Differenzialdiagnose einer paravertebralen Raumforderung.

BACKGROUND: Intrathoracic tumors always suggest a malignant clinical picture in the first instance. Especially in the case of paravertebral masses an extramedullary hematopoiesis is possible. It is regarded as compensation mechanism for reduced blood cell formation. PATIENTS: In four patients' radiographic examination of the lung partially bilateral paravertebral masses where detected by chance. In two cases, a chronic anemia existed, one patient suffered from an extended hemangiomatosis of the right brachium and the right hemithorax. In one case, no hematological disease could be diagnosed. RESULTS: The computed tomography revealed malignancy-simulating tumors with partially necrotic pattern. In all cases, transthoracal biopsy showed cytological evidence of typical differentiated bone marrow with a regular hematopoiesis. As the extramedullary hematopoiesis of these four patients was diagnosed by chance and no symptoms or local complications existed, no specific therapy was necessary. In one of these cases a stable radiographic outcome for more than ten years is evident. CONCLUSIONS: Especially in the case of patients with chronic anemia the existence of extramedullary hematopoiesis has to be considered upon occurrence of paravertebral tumors. An hematological disorder as cause may as well be absent. Due to the suspicion of malignancy a morphologic diagnosis is always necessary, but some clinical and radiologic features may indicate a benign process. A progression of the size can be unrecognized for ten years, so a therapeutic intervention is needed only in case of symptoms like myelocompression.

[How are interstitial lung diseases diagnosed in Germany? Results of the scientific registry for the exploration of interstitial lung diseases ("Fibrosis registry") of the WATL]. / Wie werden interstitielle Lungenerkrankungen in Deutschland diagnostiziert? Ergebnisse des wissenschaftlichen Registers zur Erforschung von interstitiellen Lungenerkrankungen ("Fibroseregister") der WATL.

From 1995 to 1999 we evaluated questionnaires sent by pulmonologists and departments of pulmonology in order to register interstitial lung diseases. On the whole 1142 patients (579 males, 563 females, mean age 51.1 +/- 15.3 years, sarcoidosis, n = 511, extrinsic allergic alveolitis, n = 145, idiopathic pulmonary fibrosis, n = 308, bronchiolitis obliterans organizing pneumonia (BOOP), n = 93, others, n = 85) were recorded in the registry. With reference to the mean age sarcoidosis occurred most frequently in the fourth decade and idiopathic pulmonary fibrosis in the sixth decade. In all these diseases bronchoscopy with bronchoalveolar lavage and transbronchial biopsy was predominantly used for further diagnosis. It was striking that high-resolution computed tomography of the thorax was still rarely used when diagnosing these diseases. Apart from the group with BOOP the number of non-smokers in men and women was decisively higher than the average of the population of Germany.

Detection of M. tuberculosis DNA in sarcoidosis: correlation with T-cell response.

The pathogenetic role of Mycobacterium tuberculosis (M. tuberculosis) in tuberculosis is well defined, whereas its role in sarcoidosis is controversial. In sarcoidosis, activation of T-helper cells is observed, which is comparable to tuberculosis. The aim of this study was first to investigate whether M. tuberculosis DNA could be retrospectively detected in samples of patients with clinically verified sarcoidosis by polymerase chain reaction (PCR) and second, to analyze the relationship between M. tuberculosis DNA positive samples and T-cell response in sarcoidosis patients. Formalin fixed paraffin-embedded lung tissues or cell sediments of bronchoalveolar lavage, respectively, from 65 patients with sarcoidosis and lung tissues from 40 tuberculosis patients were investigated by means of different PCR assays in comparison to control samples. The primers used were derived from insertion sequence IS 986/6110 specific for the M. tuberculosis complex (123 bp PCR) and from the gene encoding the 38 kDa protein antigen b (419 bp PCR). The 123 bp assay yielded a specificity of 97% and a sensitivity of 95%. In contrast, the 419 bp PCR method showed a lower sensitivity of only 8% likely because of possible DNA degradation during fixation and embedding procedures of the tissue and the fact that this PCR uses a single copy element as target. We amplified the M. tuberculosis complex specific 123 bp fragment in 64% of samples from sarcoidosis patients. The specificity of PCR products in these cases was confirmed by DNA sequencing. Interestingly in the M. tuberculosis positive sarcoidoses, we found increased serum levels of soluble interleukin-2 receptor in correlation to the sarcoidosis stages (p < 0.05). In conclusion, the determination of M. tuberculosis by PCR alone does not permit a differentiation between sarcoidosis and tuberculosis. However these results support the contention that M. tuberculosis may play a pathogenetic role at least in the part of sarcoidosis patients with elevated interleukin-2 receptor values.

[CHARTWEL-Bronchus (ARO 97-1): a randomized multicenter trial to compare conventional fractionated radiotherapy with CHARTWEL radiotherapy in inoperable non-small-call bronchial carcinoma]. / CHARTWEL-Bronchus (ARO 97-1). Eine randomisiert multizentrische Studiezum Vergleich einer konventionell fraktionierten Strahlentherapie mit CHARTWEL-Bestrahlung bei inoperablen nichtkleinzelligen Bronchialkarzinomen. CHARTWEL-Bronchus-Protokollkomittee.

BACKGROUND: The CHART-bronchus trial sponsored by the Medical Research Council showed an improvement in survival of 10% compared to conventional fractionation to 60 Gy when patients with inoperable non-small-cell lung cancer (NSCLC) were treated with CHART to 54 Gy. At present it is not known whether this survival advantage holds when the dose of conventional treatment is increased and whether CHART can be replaced by the more practicable CHARTWEEL (CHART-weekend less). PROTOCOL OF THE TRIAL: A randomized multicenter trial of definite radiotherapy in locally advanced inoperable NSCLC was designed (ARO 97-1, Arbeitsgemeinschaft Radioonkologie der Deutschen Krebsgesellschaft). Conventional fractionation to 66 Gy (5 weekly fractions of 2 Gy) is compared with CHARTWEEL to 60 Gy (15 weekly fractions of 1.5 Gy, Monday to Friday, interval between fractions > or = 6 hours, overall treatment time 2.5 weeks). The main endpoint of the trial is overall survival. It was calculated that an entry of 665 patients is needed to detect an improvement in 2-year survival of 10%, the actual time is estimated to be 5 years or less. The trial was activated on 1.9.1997.

[Nontuberculous mycobacteriosis as a complication of the Swyer-James syndrome]. / Nicht-tuberkulöse Mykobakteriose als Komplikation eines Swyer-James-Syndroms.

The chest radiograph of a 35-year-old man with fatigue, exertional dyspnoea and haemoptyses revealed a cavity in the left upper lobe and a shrunken left lung with radiolucency greater than that on the right. Acid-fast rods in sputum were identified as Mycobacterium kansasii on culture. Scintigraphy showed a 9% residual perfusion on the left and abnormal ventilation, compatible with Swyer-James syndrome. This had favoured the development of a mycobacterial infection. There was also a decrease in ciliary function (rate of 4-7 Hz, normal: 10-11). Treatment, begun when tuberculosis had been suspected, was after sensitivity tests changed to a combination of rifampicin (600 mg), ethambutol (1600 mg) and protionamide (500 mg) daily. There was marked regression of the findings within 4 weeks, but treatment was prematurely stopped after 11 months. Two years later there was a recurrence which again responded well to the same drug regimen with additional sulphamethoxazole (1600 mg/d).

[Complications of pulmonary involvement in Bechterew's disease]. / Komplikationen der pulmonalen Beteiligung beim M. Bechterew.

Fibrocystic changes in the upper lung lobes are a rare visceral manifestation of ankylosing spondylitis. The impaired bronchopulmonary clearance in bronchial, pulmonary or pleural cavities predisposes to secondary microbial colonisation. Two cases are reported--one patient proved to have non-tuberculous mycobacterial disease caused by M. kansasii, the other developed an aspergilloma.

[Combined cytostatic chemotherapy of advanced non-small-cell bronchial carcinoma with doxorubicin and ifosfamide]. / Kombinierte zytostatische Chemotherapie des fortgeschrittenen nicht-kleinzelligen Bronchialkarzinoms mit Doxorubicin und Ifosfamid.

Fifty-three patients with inoperable non-small cell bronchial carcinoma were treated at four-weekly intervals with two cytostatic drugs, doxorubicin (50 mg/m2 on day 1) and ifosfamide (2000 mg/m2 on days 1-3). To avoid urotoxicity of ifosfamide, mesna, a uroprotective drug, was additionally given intravenously at a dose of three times 400 mg/m2 on days 1-3. All diagnoses had been histologically and/or cytologically confirmed. Adenocarcinoma was present in 22, large-cell undifferentiated carcinoma in 18, and squamous-cell carcinoma in 13. Distant metastases were present in 46, seven had a regionally localized tumour growth. There were one complete and 20 partial remissions (response rate 40%). Among a further 19 patients temporary growth arrest was registered. The remissions occurred in seven with adenocarcinoma, nine with large-cell carcinoma and five with squamous-cell carcinoma. Median remission was 8.3 months, mean survival time 10.5 months. Patients without response survived a mean of 5.5 months, patients with tumour progression for 1.3 months (Kaplan-Meier method). Most prominent among side-effects were cardiotoxicity and infection during the leukopenic phase. Urotoxicity was minor, due to treatment with mesna. The results suggest that doxorubicin and ifosfamide in combination can be considered an effective means, with acceptable toxicity, of treating advanced non-small cell bronchial carcinoma.

Chromosomal aberrations in the peripheral lymphocytes of cancer patients treated with high-energy electrons and bleomycin.

5 patients with inoperable bronchogenic carcinomas on a weekly therapy with a low dose of bleomycin (BL) plus irradiation with high-energy electrons, were analysed cytogenetically by cultivating peripheral lymphocytes taken immediately before the BL treatments and some hours before the irradiations. For the induction of dicentric chromosomes, linear dose-effect relationships were found: 3 of the patients responded with similar dose-effect relationships. The other 2 were different: they were not comparable with those 3 or with each other. These results were unexpected because all 5 patients received similar types of treatment.

[A pilot and a controlled study of the influence of ethambutol on serum urate concentration and uric acid clearance (author's transl)]. / Orientierende Untersuchung und kontrollierte Prüfung über den Einfluss von Ethambutol auf die Harnsäurekonzentration im Serum und die renale Harnsäureclearance.

Ethambutol is said to be capable of elevating serum urate concentration. This statement was reconsidered in three investigations using strictly supervised administration of ethambutol in a single daily dose of 25 mg. per kg. of body weight: (1) In short term administration 10 healthy subjects received ethambutol for eight days. (2) In a pilot study 13 patients suffering from pulmonary tuberculosis were treated with a triple combination including thambutol for six months. (3) In a controlled trial 23 patients were randomly allocated to one of the following regiments: In the first group patients received ethambutol plus isoniazid plus rifampicin for six months. In the second group patients received streptomycin plus isoniazid plus PAS for three months and thereafter streptomycin plus isoniazid plus ethambutol for another three months. Serum urate concentrations and clearances of uric acid and of creatinine were determined periodically in all subjects. A slight increase in serum urate concentration occurring in long term therapy showed no relation to ethambutol administration, but was obviously dependant on parameters related to the course of the disease in form of increase in body weight and physical activity, or related to the well known syntropy of chronic alcoholism and tuberculosis.