Richard Dekhuijzen

Antituberculosis drug‐induced hepatotoxicity: Concise up‐to‐date review

The cornerstone of tuberculosis management is a 6‐month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug‐induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug‐induced hepatotoxicity. The reported incidence of antituberculosis drug‐induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre‐existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug‐induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug‐induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

The PI3-K/AKT-Pathway and Radiation Resistance Mechanisms in Non-small Cell Lung Cancer

The phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (AKT) pathway is associated with all three major radiation resistance mechanisms: intrinsic radiosensitivity, tumor cell proliferation, and hypoxia. In cell signaling cascades, the PI3-K/AKT signaling pathway is a key regulator of normal and cancerous growth and cell fate decisions by processes such as proliferation, invasion, apoptosis, and induction of hypoxia-related proteins. Activation of this pathway can be the result of stimulation of receptor tyrosine kinases such as epidermal growth factor receptor or vascular endothelial growth factor receptor or from mutations or amplification of PI3-K or AKT itself which are frequently found in non-small cell lung cancer (NSCLC). Furthermore, several treatment modalities such as radiotherapy can stimulate this survival pathway. Monitoring and manipulation of this signal transduction pathway may have important implications for the management of NSCLC. Strong and independent associations were found between expression of activated AKT (pAKT) and treatment outcome in clinical trials. Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade. To successfully implement these treatments in daily practice, there is a need for molecular predictors of sensitivity to inhibitors of PI3-K/AKT activation. In conclusion, the PI3-K/AKT pathway plays a crucial role in cellular defense mechanisms. Therefore, quantification of the activation status is a potential parameter for predicting treatment outcome. More importantly, specific targeting of this pathway in combination with radiotherapy or chemotherapy may enhance tumor control in NSCLC by antagonizing cellular defense in response to treatment.

Diaphragm adaptations in patients with COPD

Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD.

Lung function in idiopathic pulmonary fibrosis - extended analyses of the IFIGENIA trial

BackgroundThe randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.MethodsWe analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.ResultsIn trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.ConclusionThis descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.Trial RegistrationRegistered at http://www.ClinicalTrials.gov; number NCT00639496.

Region of Difference 1 in Nontuberculous Mycobacterium Species Adds a Phylogenetic and Taxonomical Character

The esat-6 and cfp-10 genes are essential for virulence in Mycobacterium tuberculosis. Among nontuberculous mycobacteria, we found these genes only in M. kansasii, M. szulgai, M. marinum, and M. riyadhense, with unique sequences. This adds a phylogenetic and taxonomical characteristic and may represent a virulence factor for nontuberculous mycobacteria.

Mycobacterium xenopi clinical relevance and determinants, the Netherlands.

Clinical isolation of M. xenopi represents true infection in 51% of cases; genotype is a major determinant.

In vitro drug susceptibility of 2275 clinical non-tuberculous Mycobacterium isolates of 49 species in The Netherlands.

In this study, 2275 clinical isolates of 49 species of non-tuberculous mycobacteria isolated in The Netherlands were subjected to standardised drug susceptibility testing using the Middlebrook 7H10 agar dilution method. Clarithromycin and rifabutin were most active, with 87% and 83% of all isolates, respectively, being susceptible. Susceptibility to ciprofloxacin (44%) and amikacin (32%) was limited and was mostly restricted to Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium fortuitum and phylogenetically related species. Susceptibility to isoniazid (0.5%), rifampicin (37%), ethambutol (35%) and streptomycin (33%) was rare; susceptibility to cycloserine, clofazimine and prothionamide was generally restricted to slow growers, although prothionamide also had activity against M. fortuitum and related species. Significant discrepancies between in vitro and in vivo activity exist. To improve the utility of drug susceptibility testing, the selection of drugs should be changed to more drugs with proven clinical efficacy correlating with in vitro susceptibility.

Clinical relevance of Mycobacterium chelonae-abscessus group isolation in 95 patients.

OBJECTIVES To determine the clinical relevance of Mycobacterium chelonae-abscessus group isolation from clinical samples. METHODS We retrospectively reviewed medical files of all patients from whom these mycobacteria were isolated between January 1999 and January 2005 and re-identified the isolates by rpoB sequencing. We applied the American Thoracic Society (ATS) diagnostic criteria to establish clinical relevance. RESULTS Ninety-five patients were traced (56 M. chelonae, 25 Mycobacterium abscessus, 8 Mycobacterium massiliense, 6 Mycobacterium bolletii). Most isolates were cultured from pulmonary samples in patients with pre-existing pulmonary disease. Among patients with pulmonary isolates, 27% (20/74) meets ATS criteria; M. abscessus is most relevant (50%; 9/18), followed by M. massiliense (29%; 2/7), M. bolletii (20%; 1/5) and M. chelonae (18%; 8/44). Extrapulmonary disease presented as disseminated skin disease, eye disease specific for M. chelonae and otomastoiditis for M. abscessus. Treatment, especially for pulmonary M. abscessus disease, yielded limited results. CONCLUSIONS One-fourth of the patients with pulmonary M. chelonae-abscessus group isolates met the ATS criteria; this percentage differs by species. Species distribution and clinical relevance differ from other regions. M. abscessus isolation in cystic fibrosis patients warrants special attention. Current ATS criteria might be too lenient to diagnose M. chelonae-abscessus group disease.

Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis

BACKGROUND Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD. AIM To investigate whether treatment with the inhaled corticosteroid fluticasone propionate (FP) or the anti-oxidative agent N-acetylcysteine (NAC) are effective in primary care patients. METHODS The study was a 3-year placebo-controlled randomised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment. Patients were (ex-)smokers with chronic bronchitis or COPD. Interventions were inhaled FP 500microg b.i.d., oral NAC 600mg o.d., or placebo. Exacerbation rate and quality of life measured with the Chronic Respiratory Questionnaire (CRQ) were the primary outcomes, FEV(1) decline and respiratory symptoms secondary outcomes. RESULTS 286 patients recruited from 44 general practices were randomised. Exacerbation rate was 1.35 times higher for NAC (p=0.054) and 1.30 times higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo. CONCLUSION No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis.

Pulmonary Mycobacterium szulgai infection and treatment in a patient receiving anti-tumor necrosis factor therapy

Background A 54-year-old man with a 22-year history of rheumatoid arthritis and an 8-year history of chronic obstructive pulmonary disease presented with dyspnea on exertion, nonproductive cough and fatigue of 1 months duration. His medication at presentation consisted of etanercept, azathioprine, naproxen and inhaled fluticasone and salbutamol.Investigations At presentation, the patient underwent physical examination, chest X-ray and high-resolution CT, blood tests, and bronchoalveolar lavage fluid analysis including auramine stains and gene sequence analysis of cultured Mycobacterium szulgai. The patient underwent minithoracotomy after 6 months, and bronchoalveolar lavage fluid analysis, culture and chest X-ray after 18 months. Further chest imaging and culture of sputum samples were performed another year later.Diagnosis Pulmonary M. szulgai infection.Management Triple drug therapy with rifampicin, ethambutol hydrochloride and clarithromycin. Anti-tumor necrosis factor treatment was continued.