NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations.

The proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) has a central role in host defence against pneumococcal disease. Both rare mutations and common polymorphisms in the NFKBIA gene encoding the NF-kappaB inhibitor, IkappaB-alpha, associate with susceptibility to bacterial disease, but the possible role of polymorphisms within the related IkappaB-zeta gene NFKBIZ in the development of invasive pneumococcal disease (IPD) has not been reported previously. To investigate this further, we examined the frequencies of 22 single-nucleotide polymorphisms spanning NFKBIZ in two case-control studies, comprising UK Caucasian (n=1008) and Kenyan (n=723) individuals. Nine polymorphisms within a single UK linkage disequilibrium (LD) block and all four polymorphisms within the equivalent, shorter Kenyan LD block displayed either a significant association with IPD or a trend towards association. For each polymorphism, heterozygosity was associated with protection from IPD when compared with the combined homozygous states (for example, for rs600718, Mantel-Haenszel 2 x 2 chi(2)=7.576, P=0.006, odds ratio (OR)=0.67, 95% confidence interval (95% CI) for OR: 0.51-0.88; for rs616597, Mantel-Haenszel 2 x 2 chi(2)=8.715, P=0.003, OR=0.65, 95% CI: 0.49-0.86). We conclude that multiple NFKBIZ polymorphisms associate with susceptibility to IPD in humans. The study of multiple populations may aid in fine mapping of associations within extensive regions of strong LD ('transethnic mapping').

Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. METHODS: 100 men with moderate-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon gamma (IFNgamma) and anti-inflammatory adiponectin. RESULTS: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes -0.24 mg/l (95% CI -0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNgamma did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and -0.07 pg/ml (95% CI -0.72 to +1.94 and -0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI -0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNgamma and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. CONCLUSIONS: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate-severe obstructive sleep apnoea.

Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea-hypopnoea syndrome: a systematic review and economic analysis.

OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of continuous positive airway pressure (CPAP) devices for the treatment of obstructive apnoea-hypopnoea syndrome (OSAHS), compared with the best supportive care, placebo and dental devices. DATA SOURCES: The main search was of fifteen electronic databases, including MEDLINE, EMBASE and the Cochrane Library, up to November 2006. REVIEW METHODS: Randomised controlled trials (RCTs) comparing CPAP with best supportive/usual care, placebo, and dental devices in adults with a diagnosis of OSAHS were included. The primary outcomes of interest were subjective daytime sleepiness assessed by the Epworth Sleepiness Scale (ESS) and objective sleepiness assessed by the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT). A new economic model was developed to assess incremental cost per quality-adjusted life-year (QALY). The cost-effectiveness of CPAP was compared with that of the use of dental devices and conservative management. The costs and QALYs were compared over a lifetime time horizon. Effectiveness was based on the RCT evidence on sleepiness symptoms (ESS), which was 'mapped' to utilities using individual patient data from a subset of studies. Utilities were expressed on the basis of generic HRQoL instruments [the EQ-5D (EuroQoL-5 Dimensions) in the base-case analysis]. The base-case analysis focused on a male aged 50. A series of subgroup and scenario analyses were also undertaken. RESULTS: The searches yielded 6325 citations, from which 48 relevant clinical effectiveness studies were identified, 29 of these providing data on daytime sleepiness. The majority of the included RCTs did not report using an adequate method of allocation concealment or use an intention-to-treat analysis. Only the studies using a sham CPAP comparator were double blinded. There was a statistically significant benefit with CPAP compared with control (placebo and conservative treatment/usual care) on the ESS [mean difference (MD) -2.7 points, 95% CI -3.45 to -1.96]. However, there was statistical heterogeneity, which was reduced when trials were subgrouped by severity of disease. There was also a significant benefit with CPAP compared with usual care on the MWT. There was a non-statistically significant difference between CPAP and dental devices (six trials) in the impact on daytime sleepiness (ESS) among a population with moderate symptom severity at baseline (MD -0.9, 95% CI -2.1 to 0.4). A review of five studies evaluating the cost-effectiveness of CPAP was undertaken. All existing cost-effectiveness studies had limitations; therefore a new economic model was developed, based on which it was found that, on average, CPAP was associated with higher costs and benefits than dental devices or conservative management. The incremental cost per QALY gained of CPAP was below 20,000 pounds in the base-case analysis and most alternative scenarios. There was a high probability of CPAP being more cost-effective than dental devices and conservative management for a cost-effectiveness threshold of 20,000 pounds per QALY gained. CONCLUSIONS: CPAP is an effective and cost-effective treatment for OSAHS compared with conservative/usual care and placebo in populations with moderate to severe daytime sleepiness, and there may be benefits when the disease is mild. Dental devices may be a treatment option in moderate disease but some uncertainty remains. Further research would be potentially valuable, particularly investigation of the effectiveness of CPAP for populations with mild sleepiness and further trials comparing CPAP with dental devices.

CPAP and measures of cardiovascular risk in males with OSAS.

Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.

A case of empyema necessitatis.

We present a case of empyema necessitatis presenting with an inflammatory cellulitis of the chest wall. Most of the cases previously reported were due to tuberculosis, pneumococcus or actinomycosis, with only a few cases being due to Staphylococcus aureus, as in this case. Early treatment with antibiotics and surgical drainage can prevent further complications.

Advanced techniques in medical thoracoscopy.

For expert pulmonologists, advanced procedures in medical thoracoscopy are the nonroutine and more complex applications of the method. The main current indications are the treatment of infected pleural space, forceps lung biopsy and sympathectomy. In parapneumonic effusions and empyema, medical thoracoscopy is as a drainage procedure, intermediate between tube thoracostomy and video-assisted thoracoscopic surgery (VATS), which is efficient, significantly lower in cost and avoids surgical thoracoscopy under general anaesthesia. It is essential that it is performed early in the course of the disease and is particularly advisable for frail patients at high surgical risk. The efficacy of forceps lung biopsy has been demonstrated in diffuse lung diseases, whereas results in localised lung diseases and chest-wall lesions have been less positive. However, VATS is currently the preferred approach for these indications. The technique still maintains its efficacy for visceral pleura and peripheral lung biopsy, in particular in the presence of pleural effusion and lung disorders. At the present time, thoracoscopic sympathectomy is minimally invasive and is an accepted intervention for patients with a variety of autonomous nervous system disturbances. Essential hyperhidrosis patients, and well-selected patients with other disorders, can be helped with this procedure, which can also be performed by interventional pulmonologists.

Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients.

Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Several randomised controlled trials have shown that continuous positive airway pressure (CPAP) treatment of OSA reduces blood pressure (BP). This randomised, sham-placebo controlled crossover trial assesses whether CPAP produces a similar clinically significant fall in BP in hypertensive OSA patients, but without hypersomnolence. Thirty-five, nonsleepy, hypertensive patients with OSA were treated with CPAP for 1 month, randomised first to either therapeutic or sham-placebo (subtherapeutic CPAP, about 1 cmH(2)O pressure). The second months' alternative treatment followed a 2-week washout period. BP was measured over 24 h, before and at the end of the two treatment periods: mean 24-h BP was the primary outcome variable. There was no overall significant difference in mean 24-h BP: the change in mean 24-h BP on therapeutic CPAP was -2.1 mmHg (sd 8.1), and -1.1 mmHg (sd 8.1) on subtherapeutic CPAP, with a difference of 0.7 mmHg (95% confidence interval (CI) +2.9- -4.4). There was a small significant fall in Epworth Sleepiness Score, therapeutic (-1.4) versus sham (-0.3), and difference -1.2 (95% CI -2.0- -0.4), but no change in objective sleepiness. In nonhypersomnolent hypertensive patients with obstructive sleep apnoea, there is no significant fall in mean 24-h blood pressure with continuous positive airway pressure, in contrast to the fall seen in hypersomnolent patients with obstructive sleep apnoea.

Genotypic variation in Pneumocystis jirovecii isolates in Britain.

BACKGROUND: Pneumocystis jirovecii is the cause of Pneumocystis pneumonia (PCP) in immunosuppressed humans. Asymptomatic colonisation with P jirovecii may occur in patients with minor immunosuppression or chronic lung disease. The aim of this study was to describe the molecular epidemiology of P jirovecii in Britain over a period of 12.5 years. METHODS: Between January 1989 and July 2001 161 samples of P jirovecii were obtained from patients with PCP (n = 119), patients colonised by P jirovecii (n = 35), and from air spora (n = 6). Genotyping of samples was performed at the mitochondrial large subunit rRNA (mt LSU rRNA). RESULTS: Genotype 1 (38%) was the most frequently identified genotype: genotypes 2 (26.6%), 3 (20.3%), and 4 (5%) were less common. Mixed infection (more than one genotype) was identified in 10% of samples. While genotype 1 was the most frequently detected type in both patients with PCP and those colonised by P jirovecii (38% and 42%, respectively), these groups differed in the relatively lower rate of detection of genotype 4 (2% v 17%) and the higher detection of mixed infection in those with PCP (13% v 3%). Detection of specific genotypes of P jirovecii was associated with the patient's place of residence (p = 0.02). There was no association between specific genotypes and severity of PCP as measured by arterial oxygen tension (p = 0.3). CONCLUSIONS: The evidence of clustering of specific genotypes with patient's postcode of residence is consistent with the hypothesis of person to person transmission of P jirovecii via the airborne route. The lack of association between specific mt LSU rRNA genotypes and severity of PCP suggests that this locus is not implicated in the virulence of the organism.

Sleep . 6: obstructive sleep apnoea/hypopnoea syndrome and hypertension.

The use of CPAP to control excessive daytime sleepiness in OSAHS probably also produces a substantial reduction in vascular risk. This is reviewed with particular reference to hypertension.

Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment. METHODS: Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA. RESULTS: Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%. CONCLUSION: A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.

Sleep. 1: Obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history.

Arguments over the definition of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) have still not been satisfactorily resolved. As a result, robust estimates of the prevalence of OSAHS are not possible. New approaches are needed to identify those who have "CPAP responsive" disease, enabling more accurate estimates to be made of the prevalence of the sleep apnoea syndrome in the community.

Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea.

OBJECTIVE: Obstructive sleep apnoea (OSA) is a relatively common condition producing disabling somnolence and profound physiological responses to hypoxaemic episodes during sleep, including significant oscillations in blood pressure. This study aimed to provide controlled data on the interaction between OSA and endocrine axes to establish whether overrepresentation of pathology such as hypertension and hypogonadism in OSA subjects might have an endocrine basis. DESIGN, SETTING AND SUBJECTS: Parallel randomized sham placebo controlled 1-month trial of nasal continuous positive airway pressure (nCPAP) in 101 male subjects with OSA presenting to a respiratory sleep clinic. METHODS: Analysis of gonadotrophins, testosterone, sex hormone binding protein (SHBG), prolactin, cortisol, thyroid stimulating hormone (TSH), free thyroxine (free T4), insulin-like growth factor-1 (IGF-1), renin and aldosterone were performed at baseline and after 1 month's active or placebo nCPAP intervention. Quality of life questionnaire scoring was also recorded over the same time period. RESULTS: Testosterone and SHBG showed significant negative correlations with baseline OSA severity. Active treatment of OSA produced SHBG elevation and TSH reduction (P< or =0.03). Both groups showed an increase in aldosterone (P<0.001) and IGF-1 (P< or =0.03), associated with a large improvement in subjective quality of life scoring. CONCLUSIONS: These findings demonstrate significant changes in endocrine axes not previously reported in a placebo-controlled trial. OSA is a recognized reversible cause of testosterone reduction; SHBG suppression correlating to baseline OSA severity supports a diagnosis of secondary hypogonadism. Significant rises in aldosterone and IGF-1 on treatment coincide with increased physical activity and an improved quality of life score.

Caffeine levels following treatment of obstructive sleep apnoea.

BACKGROUND: Randomised trials show that treatment of obstructive sleep apnoea (OSA) with nasal continuous positive airway pressure (CPAP) greatly improves sleepiness and also lowers diurnal systemic blood pressures (BP). Such patients consume more coffee than controls (presumably to combat their sleepiness) and might reduce their consumption following effective treatment, thus lowering BP by this mechanism rather than via a direct effect of alleviating OSA. METHODS: Plasma caffeine levels before and after treatment with either therapeutic (n=52) or subtherapeutic (control, n=49) CPAP were measured in stored blood samples from a previous randomised controlled trial of CPAP for 4 weeks in patients with OSA. RESULTS: There was a small significant rise in caffeine levels when the two groups were analysed as a whole (p=0.02), but not individually. Despite the fall in sleepiness measured objectively in the therapeutic CPAP group, there was no difference in absolute (or change in) caffeine levels between the two groups (mean (SE) micro mol/l; therapeutic CPAP 9.2 (1.2), 10.2 (1.0), subtherapeutic 6.7 (0.9), 8.6 (0.9) before and after treatment, respectively). CONCLUSION: Reduced coffee consumption is unlikely to be the explanation for the falls in BP following treatment of OSA.

Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study.

BACKGROUND: The opportunistic fungus Pneumocystis jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy. METHODS: A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P jiroveci. Polymerase chain reaction for detection of P jiroveci specific DNA was also performed. RESULTS: Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P jiroveci DNA. In contrast, P jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher's exact test). CONCLUSIONS: P jiroveci colonisation, as determined by detection of P jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.