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.

[Resistance to second-line drugs in migrants with multidrug-resistant tuberculosis in the Berlin region]. / Resistenzen gegen Zweitlinienmedikamente bei Migranten mit multiresistenter Tuberkulose in der Region Berlin.

The empiric therapy of multidrug-resistant (MDR) tuberculosis (TB) after rapid molecular testing is rendered difficult by an often several weeks-long period of uncertainty, because results of susceptibility testing for second-line TB drugs are pending. The analysis of regional resistance patterns could lead to a more targeted empiric treatment for migrants depending on their country of origin. The results of the susceptibility testing from 2008 to 2013 of all mycobacteria sent to the Institute of Microbiology, working with the department of Pneumology, Heckeshorn Lung Clinic, Berlin, were reanalysed and tested for regional differences. We found 39 multidrug-resistant Mycobacterium tuberculosis strains among the examined strains. More than half of these strains tested susceptible to the following second line drugs namely, linezolid (97%), clofazimine (95%), cycloserine (95%), capreomycin (90%), p-aminosalicylic acid (82%), moxifloxacin (79%) and amikacin (79%). The proportion of strains susceptible to pyrazinamide (44%), ethambutol (28%), prothionamide (15%), rifabutin (8%) and streptomycin (8%) was lower. The mycobacterial cultures of the Chechen patients (n = 14) showed significantly different susceptibilities to amikacin (57%) and prothionamide (36%) compared to the strains from migrants of other regions. In this study, the regional differences in mycobacterial susceptibility to second line drugs suggest that the initial MDR TB therapy of migrants should be tailored to their country of origin.

A randomized controlled trial of acupuncture and receptive music therapy for sleep disorders in the elderly-ELAMUS: study protocol.

BACKGROUND: Globally, the demographic shift towards an aging population leads to significant challenges in healthcare systems, specifically due to an increasing incidence of multimorbidity resulting in polypharmacy among the elderly. Simultaneously, sleep disorders are a common complaint for elderly people. A treatment with pharmacological therapies often leads to side effects causing a high potential for dependency. Within this context, there is a high need to explore non-pharmacological therapeutic approaches. The purpose of this study is to evaluate the effectiveness of acupuncture and music therapy, both individually and combined as a multimodal therapy, in the treatment of sleep disorders in individuals aged 70 years and older. METHODS: We conduct a confirmatory randomized controlled trial using a two-factorial study design. A total of n = 100 elderly people receive evidence-based standard care information for age-related sleep disorders. Beyond that, patients are randomly assigned into four groups of n = 25 each to receive acupuncture, receptive music therapy with a monochord, multimodal therapy with both acupuncture and music therapy, or no further therapy. The study's primary outcome measurement is the improvement in sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) (global score), at the end of intervention. Additionally, depression scores (Geriatric Depression Scale), health-related quality of life (Short-Form-Health Survey-12), neurovegetative activity measured via heart rate variability, and safety data are collected as secondary outcomes. Using a mixed-methods approach, a qualitative process evaluation will be conducted to complement the quantitative data. DISCUSSION: The study is ongoing and the last patient in is expected to be enrolled in April 2024. The results can provide valuable insights into the effectiveness of non-pharmacological interventions for sleep disorders among the elderly, contributing to a more personalized and holistic approach in geriatric healthcare. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00031886).

[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.

Successful oral desensitization to i.v. para-aminosalicylic acid (PAS) using encapsulated PAS dry substance.

INTRODUCTION: para-Aminosalicylic acid (PAS) is commonly used in the treatment of drug-resistant tuberculosis, including multidrug-resistant tuberculosis. Since its first use in the 1940s, hypersensitivity reactions frequently limit its use in clinical practice. Cases of successful desensitization against PAS using orally administered ascending doses are described in the literature. CASE REPORT: A 25-year-old patient with severe pulmonary multidrug-resistant tuberculosis developed drug fever with rash, acral cyanosis, and shivering immediately after the intravenous application of PAS. Hard gelatine capsules containing PAS dry substance were prepared in order to desensitize this patient. Encapsulated PAS was applied orally in rising doses starting with 10 mg/day and doubling the dose every 2 days until the half-maximal dose of 5,120 mg was reached. Desensitization covers a period of 21 days. Subsequent intravenous application of PAS at the full dose was well tolerated. In a 12-month follow-up period, no more allergic reactions appeared. CONCLUSIONS: PAS dry substance encapsulated in hard gelatine capsules and administered orally in rising concentrations may be useful to archive a successful desensitization for subsequent intravenous applications.

[Interferon-gamma release assays for hospital-based tuberculosis diagnostics in children and adolescents--a retrospective analysis]. / Interferon-gamma Release Assays in der klinikbasierten Tuberkulose-Diagnostik bei Kindern und Jugendlichen--eine retrospektive Analyse.

OBJECTIVE: Interferon-gamma release assays (IGRA) are well established for diagnosing latent tuberculosis infection in adults. Evidence for their diagnostic relevance in children is still insufficient. The aim of this study was to evaluate the sensitivity and specificity of IGRA compared to the tuberculin skin test (TST) in a local population of children and adolescents presenting to our lung clinic with a specialised outpatient department. METHODS: Records from all patients evaluated for tuberculosis at our centre between 2009 and 2011 were analysed retrospectively. Complete data sets were available for 80 children and adolescents (age 3 months to 17 years) in the following diagnostic groups: active pulmonary tuberculosis (MTB, n = 13), latent tuberculosis infection (LTBI, n = 15) and controls with tuberculosis exposure (n = 40), non-tuberculous mycobacterial disease (NTM, n = 2) or other lung diseases (n = 10). RESULTS: All 13 patients with MTB were positive on both IGRA and TST. Among the LTBI patients, 14 /15 had a positive IGRA and 14 /15 a positive TST result. In the control group 0 /52 exceeded the IGRA cut-off, while three patients had a positive TST due to a cross reaction with BCG or NTM. DISCUSSION: IGRA and TST results are highly correlated in paediatric patients with active or latent tuberculosis. IGRA sensitivity was comparable to that of the TST with a higher specificity as expected. The importance of IGRA in the hospital setting to guide diagnostic algorithms in an unselected population should be further evaluated in prospective studies.

Interferon-gamma release assays improve the diagnosis of tuberculosis and nontuberculous mycobacterial disease in children in a country with a low incidence of tuberculosis.

BACKGROUND: Diagnosis of childhood tuberculosis (TB) is challenging. The widely used tuberculin skin test (TST) may produce -positive results because of cross-reactivity with nontuberculous mycobacteria or bacille Calmette-Guerin vaccination, resulting in unnecessary treatment. Two recently developed interferon- gamma release assays (IGRAs) show good diagnostic accuracy for active TB in adults; pediatric data are limited, particularly in areas with a low incidence of TB. We assessed the diagnostic accuracy of IGRAs for TB in children in an area with a low incidence of TB. METHODS: In a hospital-based study, the diagnostic accuracy of the TST and 2 IGRAs (T SPOT-TB [T-SPOT; Oxford Immunotec] and QuantiFERON-TB Gold In-Tube [QFT-IT; Cellestis]) were assessed in a cohort of 73 children (median age, 39 months); 28 children with bacteriologically confirmed TB were compared with children without TB (23 with bacteriologically confirmed nontuberculous mycobacterial lymphadenitis and 22 with other nonmycobacterial respiratory tract infections). RESULTS: The specificity for TB of QFT-IT was 100% (95% confidence interval [CI], 91%-100%), and the specificity of T-SPOT was 98% (95% CI, 87%-100%), both of which were considerably higher than the specificity of TST (58%; 95% CI, 42%-73%). The specificity of the TST was 10.5% (95% CI, 1%-33%) in children with nontuberculous mycobacterial lymphadenitis and was 100% (95% CI, 83%-100%) in children with other nonmycobacterial respiratory tract infections. The sensitivity of both QFT-IT and T-SPOT was 93% (95% CI, 77%-99%), and the sensitivity of the TST was 100% (95% CI, 88%-100%). Agreement between the IGRAs was 95.6% ( kappa =0.91); 6.8% of the IGRAs showed indeterminate results. CONCLUSIONS: Both IGRAs showed high diagnostic value in bacteriologically confirmed childhood TB. Their advantage in this study, when performed in addition to the TST, was the ability to distinguish -positive TST results caused by nontuberculous mycobacterial disease, thereby reducing overdiagnosis of TB and guiding clinical management.

Influence of ionizing radiation on nucleus 24 cochlear implants.

HYPOTHESIS: To evaluate the influence of conventional or hyperfractionated radiotherapy on Nucleus CI24M or CI24R(CS) implant systems. BACKGROUND: As a consequence of more than 70,000 cochlear implant recipients worldwide, the potential need for radiotherapy is an issue requiring consideration by both implantees and implantation centers. Conditions requiring radiotherapy of the head may include head, neck, or brain tumors. METHODS: The study examines the effect of ionizing radiation on cochlear implant function. The implanted devices examined were the Nucleus CI24M and Nucleus CI24R(CS). In a modeled study, two implants of each type were treated with fraction schemes most frequently used in clinical routine (e.g., conventional fractionation [total dose, 120 Gy] and hyperfractionation [total dose, 116 Gy]). Parameters quantified were the implant output amplitude changes at high and low current level (current levels 255 and 100, respectively), the charge balance of the biphasic pulse, and the accuracy of the impedance telemetry function. RESULTS: Within the clinically relevant dose range (< 80 Gy), implant function in all four devices was normal. Failure occurred in one Nucleus CI24R(CS) device treated with hyperfractionation. A dramatic drop in the output amplitude at 106 Gy was observed, and the impedance measurement failed at a total dose of 111 Gy. CONCLUSION: The results suggest that conventional or hyperfractionated radiotherapy can be applied safely at Nucleus CI24M or CI24R(CS) implant systems in a patient-like setting. Therefore, the authors propose that the results of the study can be applicable in clinical practice.

Analysis of a solid-phase radioimmunoassay for antibodies to cytoplasmic antigen fractions of Candida albicans.

An indirect solid-phase radioimmunoassay (SPRIA) in individual polystyrene microtiter cups has been adapted for measurement of antibody to various cytoplasmic and carbohydrate antigen fractions of Candida albicans. The assay was optimized for sensitivity, precision and linearization of serum dilution curves. The optimized procedure allows computerized measurement of anti-Candida antibodies and can be used for measurement of antibody over a wide concentration range. The procedure obviates variation due to changes in day-to-day counts as a result of isotope decay and end-point antibody dilutions. The assay has been used to demonstrate a Poisson-like distribution of antibody levels in the sera of persons showing no symptoms of candidiasis. The minimum antibody level detectable by the assay is about two orders of magnitude lower than the lowest level found in human serum and 4 orders of magnitude lower than the most sensitive test used hitherto, the hemagglutination test.

A long-lasting enhancing effect of anti-tuberculin antiserum on delayed-type hypersensitivity reaction in BCG-infected guinea pigs.

Anti-tuberculin serum and anti-BCG immunoglobulins from immunized guinea pigs were transferred into recipient guinea pigs which had been infected with BCG. An enhancement of tuberculin skin reactivity was observed 7 and 35 days after transfer of homologous antiserum in comparison to a control group. This indicates a modulating effect of humoral factors, presumably specific antibodies on the expression of delayed-type hypersensitivity reaction after immunostimulation with BCG.

Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function.

STUDY OBJECTIVE: In patients with severe COPD, acute infective exacerbations are frequent. Streptococcus pneumoniae and Haemophilus influenzae are the most commonly isolated bacteria in sputum cultures from these patients. We hypothesized that in patients with advanced disease, Gram-negative bacteria other than H influenzae play at least an equally important role. METHODS: We evaluated clinical data and sputum culture results from 211 unselected COPD patients admitted to our hospital with an acute infective exacerbation of COPD. One hundred twelve patients fulfilled our protocol criteria of reliable microbiologic results and reproducible lung function tests; the patients were categorized according to the recently published three stages of severity. RESULTS: Lung function tests revealed an FEV1 of > or =50% of the predicted value in 30 patients (stage I), an FEV1 of 35% to <50% of the predicted value in 30 patients (stage II), and an FEV1 of < or =35% of the predicted value in 34 patients (stage III). Bacteria were classified into three groups: group 1 contained S pneumoniae and other Gram-positive cocci; group 2, H influenzae and Moraxella catarrhalis; and group 3, Enterobacteriaceae and Pseudomonas spp. For all patients together, the most frequently isolated bacteria were group 3 organisms (Enterobacteriaceae and Pseudomonas spp, 48.2%), followed by group 1 organisms (S pneumoniae and other Gram-positive cocci, 30.4%), and group 2 organisms (H influenzae and M catarrhalis, 21.4%). In stage I patients, 14 of 30 had bacteria from group 1, seven of 30 had group 2, and nine of 30 had group 3. In stage II patients, eight of 30 had group 1 bacteria, 10 of 30 had group 2, and 12 of 30 had group 3. In stage III patients, 12 of 52 had group 1 bacteria, seven of 52 had group 2, and 22 of 52 had group 3. The three groups of bacteria causing infective exacerbations were unevenly distributed among the three severity stages of lung function (p=0.016). CONCLUSION: There is a correlation between deterioration of lung function and the bacteria isolated from patients with infective exacerbations of COPD. In acute infective exacerbations, Enterobacteriaceae and Pseudomonas spp are the predominant bacteria in patients with an FEV1 < or =35% of the predicted value.

Diagnostic value of monitoring kinetics of antibody responses in candidiasis by a solid-phase radioimmunoassay.

A solid-phase radioimmunoassay was used to monitor antibody binding to cytoplasmic antigens of Candida albicans in sera from patients with superficial or deep-seated candidiasis over extended observation periods. Healthy persons showed a constant level of Candida antibodies. Patients with superficial candidiasis or colonization generally had a slow, but significant rise; patients with presumptive and proven systemic candidiasis, however, developed rapid rises (up to forty-fold) of antibody levels within a few days. This method permitted the kinetics of antibody response to be followed and, thus, appeared to aid in the differentiation among the various forms of candidiasis.

Lower respiratory tract infections in the intensive care unit: consequences of antibiotic resistance for choice of antibiotic.

Pneumonia in the intensive care unit (ICU) has been associated with highly virulent pathogens that often exhibit resistance to multiple antibiotics and mortality rates of 30-70%. Pseudomonas aeruginosa and Enterobacteriaceae are the leading pathogens, followed by Staphylococcus aureus and polymicrobial etiologies. Recent clinical studies using monotherapy for nosocomial pneumonias resulted in low eradication rates for P. aeruginosa and staphylococci. An additional problem of these studies was the development of resistance by P. aeruginosa during the antibiotic treatment; also the selection of highly resistant strains like Xanthomonas maltophilia and Acinetobacter species was a major concern. However, several prospective studies comparing monotherapy versus combination therapy in nosocomial pneumonia of ICU patients have shown that a response rate of 60% is achievable, which is comparable to historic rates for combination therapy regimens. Only infections induced by P. aeruginosa, S. aureus, or other highly resistant pathogens (Acinetobacter, X. maltophilia, etc.) should be treated with well-defined antibiotic combinations.

Ampicillin + sulbactam vs clindamycin +/- cephalosporin for the treatment of aspiration pneumonia and primary lung abscess.

Aspiration pneumonia, necrotising pneumonia and primary lung abscess are complications arising from the aspiration of infectious material from the oral cavity or stomach. There is limited information on optimal antibacterial therapeutic regimens. Patients with pulmonary infection following aspiration (n = 95) were included in a prospective, open, randomised, comparative multicentre trial to compare the safety, clinical and bacteriological efficacy of ampicillin + sulbactam vs. clindamycin +/- cephalosporin. Treated patients (n = 70) received sequential antibiotic therapy with either ampicillin + sulbactam (n = 37) or clindamycin (n = 33), with or without a second- or third-generation cephalosporin, administered until the complete resolution of clinical and radiological abnormalities. Definite or presumptive pathogens were isolated from 58 patients. Mean duration of therapy was 22.7 days for ampicillin + sulbactam and 24.1 days for clindamycin. In patients treated with ampicillin + sulbactam, the clinical response was 73.0% at the end of therapy and 67.5% 7-14 days after therapy. For clindamycin, the rates were 66.7% and 63.5%, respectively. Bacteriological response was similar in both treatment arms. Nine patients died (12.9%), with a Simplified Acute Physiology Score of > 30 points being the only significant predictive factor for therapeutic failure. Ampicillin + sulbactam and clindamycin +/- cephalosporin were both well-tolerated and proved equally effective in the treatment of aspiration pneumonia and lung abscess.

Acute and long-term efficacy of antituberculous treatment in HIV-seropositive patients with tuberculosis: a study of 36 cases.

Thirty-six consecutively observed HIV-seropositive patients with tuberculosis, including 31 patients with AIDS, who received antituberculous treatment, were followed up to evaluate its efficacy. Treatment with standard antituberculous regimens was intended except when an individual's condition required a modified therapeutic approach. Therapeutic failure occurred in five patients (14%) while on treatment, one also had a post-treatment relapse. Treatment failure was associated with drug resistance and non-compliance in three patients and in another two, both of whom died early in the course of their disease, with HIV-related conditions other than tuberculosis. The median relapse-free post-treatment follow-up time in 24 patients in whom treatment did not fail was 13 months (range 4-67). Standard antituberculous treatment is highly effective in the immediate and long-term treatment of HIV-related tuberculosis provided that drug susceptibility and treatment compliance are confirmed.

Nosocomial pneumonia in the critical care unit.

Nosocomial pneumonia poses a major threat to the recovery of patients receiving mechanical ventilation. In addition, nosocomial pneumonia is often difficult to diagnose. This article examines the extent of the threat and some of the difficulties facing the critical care physician when diagnosing nosocomial pneumonia.

A prediction model for bacterial etiology in acute exacerbations of COPD.

OBJECTIVES: Bacteria play a leading role in acute exacerbations of chronic obstructive pulmonary disease (COPD), but we lack predictors of bacterial etiology. We developed a prediction model for infection with gram-negative enteric bacteria (GNEB) and Pseudomonas aeruginosa. METHODS: Clinical presentation, sputum characteristics, microbial sputum patterns, lung function and previous and concomitant medication were prospectively recorded in patients with moderate to severe exacerbation of COPD. Risk factors for a specific bacterial etiology were calculated and a prediction model developed. RESULTS: A total of 193 patients with acute exacerbation were included. In 121 (62.6%) of them a microbial etiology could be identified, most frequently Haemophilus influenzae (32 strains), Streptococcus pneumoniae (22 strains) and P. aeruginosa (12 strains). Multivariate analysis identified severe airflow obstruction and use of systemic steroids as predictors for exacerbation due to gram-negative enteric bacilli and P. aeruginosa. A prediction model including FEV1 < 35% of predicted value, systemic steroid use and prior antibiotic therapy within preceeding 3 months had a negative predictive of 89%, being a helpful tool in excluding patients at risk of exacerbation due to gram-negative enteric bacilli and P. aeruginosa when all criteria are absent. CONCLUSION: A simple prediction model based on three factors may identify COPD patients at low risk for exacerbations with gram-negative enteric bacilli and P. aeruginosa. Bacterial Etiology in COPD Exacerbations.