Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

[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.

Guidelines for the management of adult lower respiratory tract infections--summary.

This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.

Guidelines for the management of adult lower respiratory tract infections--full version.

This document is an update of Guidelines published in 2005 and now includes scientific publications through to May 2010. It provides evidence-based recommendations for the most common management questions occurring in routine clinical practice in the management of adult patients with LRTI. Topics include management outside hospital, management inside hospital (including community-acquired pneumonia (CAP), acute exacerbations of COPD (AECOPD), acute exacerbations of bronchiectasis) and prevention. Background sections and graded evidence tables are also included. The target audience for the Guideline is thus all those whose routine practice includes the management of adult LRTI.

Enhanced cost-benefit analysis of strategies for LTBI screening and INH chemoprevention in Germany.

OBJECTIVES: There is only limited economic data in head-to head comparison between a whole blood QuantiFERON TB Gold in tube (QFT) and the tuberculin skin test (TST) when screening and treating for latent tuberculosis infection (LTBI), and no published study to date that takes into account the predictive value of the two tests. METHODS: Health and economic outcomes of isoniazid preventive treatment (IPT) of close contacts were compared in a decision tree model to perform a cost-benefit analysis with respect to isoniazid related hepatotoxicity and early post-exposure TB over a 2-y period, using the QFT or TST alone or QFT as a confirmatory test for TST results. RESULTS: Cost of screening and treating for using the QFT alone amounted to euro215.79 per close contact, less than that of dual step-testing (euro227.89) or using TST alone (euro232.58). Savings amounted to euro12,200 or euro16,791 per 1000 close contacts, respectively. QFT based procedures were most sensitive to low compliance with IPT or increasing price. Costs of dual step screening was mostly influenced by cost of treating TB disease. When the progression rate for QFT was lowered to that for the TST in a sensitivity analysis, the relationship between the strategies remained robust. In addition, costs of the QFT strategy decreased to euro165.1, and those of the dual step strategy to euro218.4. CONCLUSION: IPT on the basis of using the QFT assay alone produces less cost and reduces more TB cases than other strategies in a low-incidence setting. These data have implications for the rational implementation of screening strategies in contact investigation.

Cost-optimisation of screening for latent tuberculosis in close contacts.

The aim of the present study was to perform cost-minimisation analysis of contact investigation from a public health perspective using the tuberculin skin test (TST) and a new blood assay, QuantiFERON-TB Gold (QFT-G). A decision-analysis model simulated the costs of investigating a cohort of adult close tuberculosis contacts by the public health service following the current German guidelines over a period of 2 yrs. The economic outcomes were compared with alternative screening strategies. These were: 1) QFT-G instead of TST; 2) TST followed by QFT-G; and 3) TST followed by QFT-G in vaccinated (bacille Calmette-Guérin (BCG)) subjects. In a base-case analysis, the costs of TST-based screening were 91.06 Euros (EUR).contact(-1), assuming a 1% tuberculosis-case-finding incidence. The least expensive strategy was TST screening plus subsequent QFT-G testing (52.05 EUR), resulting in a 43% cost reduction. Using QFT-G alone in BCG-vaccinated subjects who tested positive in the TST led to a 39% cost reduction. The savings using QFT-G alone instead of TST amounted to 29.77 EUR.contact(-1). The results depended on the acquisition costs assumed and the proportion of positive results in TST-based screening. Screening for tuberculosis by combining tuberculin skin testing and QuantiFERON-TB Gold markedly reduces public health costs compared with tuberculin skin test screening alone.

Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis.

BACKGROUND: The MOSAIC study compared moxifloxacin with three standard antibiotic regimens in patients with Anthonisen type 1 acute exacerbations of chronic bronchitis (AECB). Further exploratory analyses were performed to identify prognostic factors of short and long term clinical outcomes and their value for clinical research. METHODS: Outpatients aged > or =45 years were screened between AECB episodes, randomised to treatment upon presenting with an AECB, assessed 7-10 days after study treatment, and followed monthly until a new AECB or for up to 9 months. Logistic regression assessed the predictive factors for clinical cure (return to pre-AECB status) and clinical success (cure or improvement), and a stepwise Cox regression model time to a composite event (failure of study treatment, new AECB, or further antibiotic treatment for AECB). RESULTS: In multivariate analyses, clinical cure was positively influenced by treatment with moxifloxacin (odds ratio (OR) 1.49; 95% CI 1.08 to 2.04) while cardiopulmonary disease (OR 0.59; 95% CI 0.38 to 0.90), forced expiratory volume in 1 second (FEV1) <50% predicted (OR 0.48; 95% CI 0.35 to 0.67), and > or =4 AECBs in the previous year (OR 0.68; 95% CI 0.48 to 0.97) predicted a poorer outcome. For clinical success, treatment with moxifloxacin had a positive influence (OR 1.57; 95% CI 1.03 to 2.41) while cardiopulmonary disease (OR 0.41; 95% CI 0.25 to 0.68) and use of acute bronchodilators (OR 0.50; 95% CI 0.30 to 0.84) predicted a poorer outcome. The occurrence of the composite event was influenced by antibiotic treatment (hazard ratio (HR) 0.82; 95% CI 0.68 to 0.98), age > or =65 years (HR 1.22; 95% CI 1.01 to 1.47), FEV1<50% predicted (HR 1.27; 95% CI 1.05 to 1.53), > or =4 AECBs in previous year (HR 1.63; 95% CI 1.34 to 1.99), and acute bronchodilator use (HR 1.48; 95% CI 1.17 to 1.87). For the composite event the beneficial effect of moxifloxacin was primarily seen in patients aged > or =65 years. CONCLUSION: Despite selection of a homogeneous population of patients with chronic bronchitis, between group differences relating to antibiotic treatment could still be confounded by factors related to medical history, severity of disease, and use of concomitant medications. The design of future clinical trials should take these factors into account.

Cost-effectiveness of isoniazid chemoprevention in close contacts.

The aim of the present study was to perform a cost-effectiveness analysis in young and middle-aged adults with latent tuberculosis (TB) infection in Germany. A Markov model simulated the progression of 20- and 40-yr-old close contacts of active TB cases over 20 yrs. Health and economic outcomes of isoniazid (INH) chemoprevention versus no intervention were compared. The analysis determined the incremental cost-effectiveness ratio in terms of cost per quality-adjusted life year and the difference between numbers of TB cases and of TB-related deaths. INH chemoprevention prevented 79% of expected TB cases in both age groups, and saved 9,482 and 9,142 in the lower and higher age groups, respectively, per case prevented. Quality-adjusted life expectancy was slightly extended by 8 days in the lower age group and 7 days in the higher age group, at a cost saving of 417 and 375, respectively, per person. Annual savings were 20,862 and 18,742 per 1,000 contacts, respectively. The number needed to be treated to prevent one TB case in the lower age group was 23 and 25 in the higher age group. The programme also prevented three TB-related deaths in the younger and two in the older cohort. The results are highly sensitive to treatment-cost assumptions. In conclusion, isoniazid chemoprevention in Germany is a highly cost-effective approach for reducing the burden of tuberculosis in recently converted young and middle-aged adults.

[Chronic cough and pulmonary infiltration]. / Chronischer Husten und pulmonales Infiltrat.

HISTORY: A 56-year-old man complain of chronic cough for 6 months without further clinical problems. The patient was otherwise in good health and showed only a moderate bronchial sound at the left ventral paracordial region. INVESTIGATIONS: Thorax X-ray revealed an infiltrate in the lingula with segmental borders. The CT scan showed air bronchogramms and bilateral more small infiltrates. DIAGNOSIS, TREATMENT, CLINICAL COURSE: Bronchoscopic transbronchial biopsies revealed a BALT-lymphoma. A seven years old chest X-ray showed the lingual infiltrate in nearly the same extension as the current X-ray. Because of the disseminated manifestation, the slow course and the good performance status we did not start a palliative chemotherapy so far. CONCLUSION: Any pulmonary infiltrate which looks like pneumonia must be given a definite diagnosis if there are no clinical signs of infection.

[Pleural effusion in pneumonia]. / Pleuraerguss bei Pneumonie.

Parapneumonic effusions are frequent (40%) but normally no clinical problem. If a parapneumonic effusion is seen on chest X-ray or by ultrasonic investigation, a thoracocentesis should be done whenever possible without risk. Investigations of the pleural fluid should include: aspect, pH-value, protein, glucose, microbiology (gram stain and culture, and cytology. Based on the extent of the effusion, the finding of free floating or loculated effusion and the results of pleura fluid investigation patients could be categorized in four risk groups. Very low and low risk for poor outcome is normally characterized by a small or moderately free floating effusion, clear pleural fluid and a pH > 7.2. In these risk groups no further intervention seems to be necessary. For patients with moderate or high risk (pus, large effusion (> 1/2 hemithorax), loculated effusion, pH < 7.2 a drainage therapy is recommended. For larger parapneumonic effusions and for complicated parapneumonic free floating effusion tube drainage therapy seems to be sufficient. However, for empyema or large lobulated effusions video-assisted thoracoscopy surgery followed by local fibrinolytic treatment might produce the best results.

[Tumor simulating primary pulmonary cryptococcosis in an immunocompetent patient. A contribution to differential diagnosis]. / Als Tumor imponierende primäre pulmonale Kryptokokkose bei einer immunkompetenten Patientin. Ein Beitrag zur Differentialdiagnose.

Case report of a primary cryptococcosis of the lung in a 78-year old non-immunocompromised female. The patient presented with a mass in the right upper lobe, highly suspicious of lung cancer. Cryptococcus finally was detected on repeated biopsies from ulcerated and necrotic bronchial mucosa. A clinical work-up showed no evidence of dissemination and no signs of immunoinsufficiency. Mass reduction in the lung was achieved under therapy with fluconazol.

Phenotypically activated gammadelta T lymphocytes in the peripheral blood of patients with tuberculosis.

Surface molecules with the potential relevance for resistance against Mycobacterium tuberculosis were investigated. The expression of lymphocyte function antigen-1, very late antigen (VLA)-4, l-selectin, intercellular adhesion molecule (ICAM)-1, major histocompatibility complex class II, Fas, and CD40 on alphabeta T cells, gammadelta T cells, NK cells, and monocytes of healthy donors and patients with tuberculosis were analyzed. A high activation status of gammadelta T cells and increased levels of soluble ICAM-1 in plasma of patients with tuberculosis versus healthy individuals was detected. Tuberculosis patients with and without an underlying systemic disease could be segregated by differential expression of VLA-4 and ICAM-1 on gammadelta T cells and on monocytes. The composition of peripheral blood mononuclear cells varied slightly, whereas the proportion of monocytes decreased significantly in patients with tuberculosis, compared with healthy controls. The activation phenotype of peripheral gammadelta T cells in patients with tuberculosis emphasizes the role of these T cells in controlling the inflammatory process during tuberculosis and perhaps other microbial infections.

[Invasive and non-invasive home ventilation--changes between 1982 and 1996]. / Invasive und nichtinvasive intermittierende Selbstbeatmung--Wandel zwischen 1982 und 1996.

PATIENTS AND METHODS: In our centre, 111 patients with chronic ventilatory insufficiency (33 females, 78 males, age 48 +/- 18 years, range 3 to 76 years) were treated by intermittent positive pressure ventilation between 1982 and 1996. Underlying diseases were neuromuscular diseases in 29%, sleep-related hypoventilation in 26%, kyphoscoliosis in 15%, chronic obstructive airway disease in 15%, and post-tuberculosis syndromes in 12%. Singular indications were 1 bronchiectasis, 1 lung fibrosis and 1 cystic fibrosis. RESULTS: Until 1991, most patients were ventilated via tracheostoma (10 of 16), in the following years 87 of 95 patients could be ventilated via a nasal or facial mask. Ventilation mode was a controlled one in 80 patients and an assisted one in 31 patients, average ventilation time during night was 6 to 8 hours. In the majority of patients hypercapnia was not only removed during ventilation but also at daytime as an indicator of improvement of ventilatory insufficiency accomplished by a clearly better quality of life and daytime activity. Ten patients (9%) died due to their underlying diseases, 5 of them in the first year of intermittent ventilation.

Lung function tests in patients with idiopathic pulmonary fibrosis. Are they helpful for predicting outcome?

STUDY OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) varies widely in its course. To evaluate predictive parameters at presentation to the hospital, we investigated 99 patients with IPF (47 women), focusing on extensive lung function tests. METHODS: Standard tests of lung volumes, arterial oxygen tension, and gas exchange at rest and during bicycle exercise were performed. Survival rates in relation to functional parameters were calculated using the actuarial method. Differences in survival proportions were summarized as hazard ratios, and significance levels were determined by log-rank test. RESULTS: At presentation, most patients showed a reduced total lung capacity (TLC) of 79.2 +/- 21.1%, an arterial oxygen tension (PaO2) considered pathologic in 63%, when related to age, a significant decrease of PaO2 with 11.8 +/- 12.1 mm Hg and an increase of the alveolar-arterial oxygen pressure difference with 46.4 +/- 16.4 (12.2 to 76.8) mm Hg during bicycle exercise. Diminished survival was associated with an age older than 50 years, a reduced value to more than 2 SDs below the predicted values of both, TLC alone, or in combination with a reduced vital capacity. Factors not influencing survival were gender, parameters of gas exchange at rest, and PaO2 at rest and during bicycle exercise. CONCLUSIONS: We conclude that standard lung function tests make it possible to assess the prognosis of patients with IPF, while extensive tests like gas exchange measurements at rest and during bicycle exercise do not contribute additional information to make the prognostic estimations more precise.

Lymphocyte subsets in peripheral blood and smoking habits.

The investigation of peripheral blood lymphocyte (PBL) subpopulations is of interest in a wide variety of inflammatory diseases. Since the number of circulating lymphocytes has been shown to be affected by smoking habits, it seems useful to know how PBL subpopulations are influenced. We therefore determined percentages and absolute numbers of a wide range of PBL subpopulations in smokers (n = 14) and nonsmokers (n = 14). PBLs were obtained from healthy volunteers and analyzed by flow cytometry using antibodies for the detection of CD3, CD4, CD8, CD19, CD56, CD57, CD45RO, CD45RA, alpha/beta and gamma/delta T cell receptor epitopes. With the exception of CD3+ cells, no differences between smokers and nonsmokers were found regarding percentages of PBL subpopulations. Smokers were found to have higher absolute numbers of PBLs in the following subpopulations compared with nonsmokers: CD3+, CD4+, CD3+ alpha/beta +, CD45RO+/CD4+, and CD45RA+/CD4+. Cytotoxic lymphocytes, natural killer cells, and B cells did not differ in number between smokers and nonsmokers. There was likewise no difference in the number of the CD8+ alpha/beta + and all cells bearing the gamma/delta T cell receptor. Smoking increased the number of T cells and mainly CD4+ PBLs. The smoking habits of healthy control groups should therefore be taken into account when comparing lymphocyte subpopulations in different diseases.

An analysis of decisions by European general practitioners to admit to hospital patients with lower respiratory tract infections. The European Study Group of Community Acquired Pneumonia (ESOCAP) of the European Respiratory Society.

BACKGROUND: The purpose of this study was to identify factors on which European general practitioners (GPs) base their decisions to admit to hospital patients with lower respiratory tract infections (LRTI). METHODS: A survey was carried out from December 1993 to January 1994 to identify factors that affect GPs' decisions to admit to hospital patients with LRTI by collecting data on 2056 patients from 605 GPs in France, Germany, Italy, Spain, and the UK. RESULTS: Only 93 (4.5%) of the patients included in the study were admitted to hospital. Univariate analysis showed that age > 60 years, institutionalisation of the patient, concomitant diseases, cardiac insufficiency, asthma, a diagnosis of pneumonia, and clinical signs such as chest pain, cyanosis, tachypnoea and hypotension significantly (odds ratio (OR) > 2.0, p < 0.002) influenced the decision to admit to hospital. No influence could be shown for sex, smoking habits, history of bronchiectasis or chronic bronchitis, the presence of fever, chills, myalgia, cough or purulent sputum, and the diagnoses of acute bronchitis, influenza or exacerbation of chronic bronchitis. In the multivariate analysis only the presence of chest pain (OR 2.3, 95% confidence interval (CI) 1.5 to 3.5), cyanosis (OR 4.1, 95% CI 2.4 to 7.1), dyspnoea (OR 4.9, 95% CI 3.1 to 7.9), and hypotension (OR 2.9, 95% CI 1.6 to 5.2), as well as a diagnosis of pneumonia (OR 6.6, 95% CI 4.3 to 10) (all p < 0.00001) remained as factors that significantly affected the decision to admit to hospital. CONCLUSIONS: Clinical signs of severe infection and a diagnosis of pneumonia are the main factors that induce GPs to admit patients with LRTI to hospital in Europe.

[MRSA (methicillin-resistant Staphylococcus aureus) infections in patients with pulmonary diseases]. / MRSA-Infektionen bei pneumologisch erkrankten Patienten.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a major nosocomial pathogen. We investigated MRSA-infections in patients with pulmonary diseases referring to epidemiological aspects. Between 9/92 and 2/92 we found MRSA-infections in our hospital in 24 patients (11 female, 13 male, average age 54.6 years). Clinical presentation, main and accompanying disorders and previous antibiotic therapy regimens were registered. Strains were typed using DNA-RFLP and lysotyping. MRSA detection were done in specimen from sputum (12/24) and from the bronchial secret (9/24). In 18/24 cases the MRSA-colonisation was associated with infection. In 15/24 cases the first acquisition of MRSA happened in our hospital, 6/24 times the germ was carried off other institutions and in 3/24 cases it was possibly community acquired. Most frequently patients suffered from bronchial cancer (6/24), from chronical bronchitis (5/24), from pneumonia (4/24) or Cystic fibrosis (4/24). Usually the patients showed other severe comorbidity. 13/24 patients had an antibiotic course before detecting MRSA. Typing revealed a strain already known in different hospitals of Berlin, another known strain of northern Germany and two so far unknown strains. Of interest was a different behaviour of resistance and the lost of resistance of strains in the course. MRSA-infection in pulmonary medicine emerged as a problem mostly in patients with multimorbidity and severe underlying diseases. Change of resistance in strains and new strains were observed.