Johannes M.A. Daniels

Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease.

RATIONALE The role of antibiotics in acute exacerbations is controversial and their efficacy when added to systemic corticosteroids is unknown. OBJECTIVES We conducted a randomized, placebo-controlled trial to determine the effects of doxycycline in addition to corticosteroids on clinical outcome, microbiological outcome, lung function, and systemic inflammation in patients hospitalized with an acute exacerbation of chronic obstructive pulmonary disease. METHODS Of 223 patients, we enrolled 265 exacerbations defined on the basis of increased dyspnea and increased sputum volume with or without increased sputum purulence. Patients received 200 mg of oral doxycycline or matching placebo for 7 days in addition to systemic corticosteroids. Clinical and microbiological response, time to treatment failure, lung function, symptom scores, and serum C-reactive protein were assessed. MEASUREMENTS AND MAIN RESULTS On Day 30, clinical success was similar in intention-to-treat patients (odds ratio, 1.3; 95% confidence interval, 0.8 to 2.0) and per-protocol patients. Doxycycline showed superiority over placebo in terms of clinical success on Day 10 in intention-to-treat patients (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.2), but not in per-protocol patients. Doxycycline was also superior in terms of clinical cure on Day 10, microbiological outcome, use of open label antibiotics, and symptoms. There was no interaction between the treatment effect and any of the subgroup variables (lung function, type of exacerbation, serum C-reactive protein, and bacterial presence). CONCLUSIONS Although equivalent to placebo in terms of clinical success on Day 30, doxycycline showed superiority in terms of clinical success and clinical cure on Day 10, microbiological success, the use of open label antibiotics, and symptoms. Clinical trial registered with www.clinicaltrials.gov (NCT00170222).

Procalcitonin vs C-Reactive Protein as Predictive Markers of Response to Antibiotic Therapy in Acute Exacerbations of COPD

BACKGROUND Rational prescription of antibiotics in acute exacerbations of COPD (AECOPD) requires predictive markers. We aimed to analyze whether markers of systemic inflammation can predict response to antibiotics in AECOPD. METHODS We used data from 243 exacerbations out of 205 patients from a placebo-controlled trial on doxycycline in addition to systemic corticosteroids for AECOPD. Clinical and microbiologic response, serum C-reactive protein (CRP) level (cutoffs 5 and 50 mg/L), and serum procalcitonin level (PCT) (cutoffs 0.1 and 0.25 μg) were assessed. RESULTS Potential bacterial pathogens were identified in the majority of exacerbations (58%). We found a modest positive correlation between PCT and CRP (r = 0.46, P < .001). The majority of patients (75%) had low PCT levels, with mostly elevated CRP levels. Although CRP levels were higher in the presence of bacteria (median, 33.0 mg/L [interquartile range, 9.75-88.25] vs 17 mg/L [interquartile range, 5.0-61.0] [P = .004]), PCT levels were similar. PCT and CRP performed similarly as markers of clinical success, and we found a clinical success rate of 90% in patients with CRP ≤ 5 mg/L. A significant effect of doxycycline was observed in patients with a PCT level < .1 μg/L (treatment effect, 18.4%; P = .003). A gradually increasing treatment effect of antibiotics (6%, 10%, and 18%), although not significant, was found for patients with CRP values of ≤ 5, 6-50, and > 50 mg/L, respectively. CONCLUSIONS Contrary to the current literature, this study suggests that patients with low PCT values do benefit from antibiotics. CRP might be a more valuable marker in these patients.

Splice-Site Mutations in the Axonemal Outer Dynein Arm Docking Complex Gene CCDC114 Cause Primary Ciliary Dyskinesia

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with laterality malformations involving complex heart defects. CCDC114 is homologous to DCC2, an ODA microtubule-docking complex component of the biflagellate alga Chlamydomonas. We show that CCDC114 localizes along the entire length of human cilia and that its deficiency causes a complete absence of ciliary ODAs, resulting in immotile cilia. Thus, CCDC114 is an essential ciliary protein required for microtubular attachment of ODAs in the axoneme. Fertility is apparently not greatly affected by CCDC114 deficiency, and qPCR shows that this may explained by low transcript expression in testis compared to ciliated respiratory epithelium. One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population.

DNA Copy Number Alterations in Endobronchial Squamous Metaplastic Lesions Predict Lung Cancer

RATIONALE Autofluorescence bronchoscopy (AFB) is a valid strategy for detecting premalignant endobronchial lesions. However, no biomarker can reliably predict lung cancer risk of subjects with AFB-visualized premalignant lesions. OBJECTIVES The present study set out to identify AFB-visualized squamous metaplastic (SqM) lesions with malignant potential by DNA copy number profiling. METHODS Regular AFB examinations in 474 subjects at risk of lung cancer identified six subjects with SqM lesions at baseline, and carcinoma in situ or carcinoma (carcinoma in situ or greater) at the initial SqM site at follow-up bronchoscopy. These progressive SqM lesions were compared for immunostaining pattern and array comparative genomic hybridization-based chromosomal profiles with 23 SqM lesions of subjects who remained cancer-free. Specific DNA copy number alterations (CNAs) linked to cancer risk were identified and accuracy of CNAs to predict endobronchial cancer in this series was determined. MEASUREMENTS AND MAIN RESULTS At baseline, p53, p63, and Ki-67 immunostaining were not predictive for a differential clinical outcome of SqM lesions. The mean number of CNAs in baseline SqM of cases was significantly higher compared with control subjects (P < 0.01). Chromosomal regions significantly more frequently altered in SqM of cases were 3p26.3-p11.1, 3q26.2-q29, 9p13.3-p13.2, and 17p13.3-p11.2 (family-wise error rate <0.10). CNAs were specifically detected at the site of future cancer. In cases, baseline-detected CNAs persisted in subsequent biopsies taken from the initial site, and levels increased toward cancer progression. In this series, a model based on CNAs at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3 predicted cancer with 97% accuracy. CONCLUSIONS The data suggest that the presence of specific CNAs in SqM lesions predict endobronchial cancer.

Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of both outer (ODA) and inner (IDA) dynein arms of cilia and sperm flagella. Loss-of-function mutations in PIH1D3 lead to absent ODAs and reduced to absent IDAs, causing ciliary and flagellar immotility. Further, PIH1D3 interacts and co-precipitates with cytoplasmic ODA/IDA assembly factors DNAAF2 and DNAAF4. This result has clinical and genetic counseling implications for genetically unsolved male case subjects with a classic PCD phenotype that lack additional phenotypes such as intellectual disability or retinitis pigmentosa.

Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia.

BACKGROUND Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. METHODS Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. RESULTS CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). CONCLUSION Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile.

High-risk human papillomavirus-positive lung cancer: molecular evidence for a pattern of pulmonary metastasis

Introduction: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital, and oropharyngeal cancers. Since a causal contribution of hrHPV infection to lung cancer (LC) is still a matter of debate, a comprehensive study was performed to delineate hrHPV involvement in LC, using a Dutch study population. Methods: Archival tissue specimens from 223 patients (145 men, 78 women, median age 65 years, range 27–87 years), who presented with cancer in the lungs, were subjected to GP5+/6+ polymerase chain reaction and p16INK4A immunohistochemistry. The series included primary lung carcinomas of patients without a history of cancer (n = 175), primary lung carcinomas of patients with an unrelated cancer in the past (n = 36), and carcinomas with primary presentation in the lungs of which the origin (i.e., primary or metastasis) was equivocal at the time of diagnosis (n = 12). GP5+/6+ polymerase chain reaction/p16INK4A double-positive carcinomas were subjected to HPV genotyping, HPVE7 transcript analysis, loss of heterozygosity analysis, and array-comparative genomic hybridization. Results: Whereas all primary lung carcinomas were hrHPV-negative (211 of 211, 100%), three hrHPV–positive equivocal carcinomas (3 of 12, 25%) were identified. These patients (1 male, 2 females) had a history of hrHPV-associated disease; one tonsillar and two cervical carcinomas. A clonal relationship between individual tumor pairs was supported by identical hrHPV genotype, pattern of p16INK4A expression, HPVE7 mRNA expression, and genomic aberrations. Conclusions: hrHPV presence in a tumor with primary presentation in the lungs signifies pulmonary metastasis from a primary hrHPV–positive cancer elsewhere in the body. No support was found for an attribution of hrHPV infection to the development of primary LC.

A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD). In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St Georges Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events. There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (−2.6 (−9.0–1.5)) and isotonic saline (−0.3 (−8.1–6.1)) in 22 patients (age range 22–73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild. 12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials. RCT in PCD: hypertonic saline does not improve SGRQ scores, but improves health perception http://ow.ly/uL6x306Dmzh

Close surveillance with long-term follow-up of subjects with preinvasive endobronchial lesions

RATIONALE Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear. OBJECTIVES To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions. METHODS In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS). MEASUREMENTS AND MAIN RESULTS During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05). CONCLUSIONS Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies.

Peak expiratory flow rate shows a gender-specific association with vitamin D deficiency

CONTEXT To our knowledge, no previous studies examined the longitudinal relationship between vitamin D status and pulmonary function in a population-based sample of older persons. OBJECTIVE Our objective was to examine the cross-sectional as well as the longitudinal relationship between vitamin D status and peak expiratory flow rate (PEFR) in a representative sample of the Dutch older population. DESIGN, SETTING, AND PARTICIPANTS Participants included men and women in the Longitudinal Aging Study Amsterdam, an ongoing cohort study in older people. MAIN OUTCOME MEASURE PEFR was measured using the mini-Wright peak flow meter. RESULTS Men with serum 25-hydroxyvitamin D (25-OHD) levels below 10 ng/ml (25 nmol/liter) had a significantly lower PEFR in the cross-sectional analyses, and men with serum 25-OHD levels below 20 ng/ml (50 nmol/liter) had a significantly lower PEFR in the longitudinal analyses as compared with men with serum 25-OHD levels above 30 ng/ml (75 nmol/liter) (cross-sectional: β = -47.0, P = 0.01 for serum 25-OHD <10 ng/ml; longitudinal: β = -45.0, P < 0.01 for serum 25-OHD <10 ng/ml; and β = -20.2, P = 0.03 for serum 25-OHD = 10-20 ng/ml in the fully adjusted models). Physical performance (β = -32.5, P = 0.08 for serum 25-OHD <10 ng/ml) and grip strength (β = -40.0, P = 0.03 for serum 25-OHD <10 ng/ml) partly mediated the cross-sectional associations but not the longitudinal associations. In women, statistically significant associations between 25-OHD and PEFR were observed in the cross-sectional analyses after adjustment for age and season of blood collection but not in the fully adjusted models or in the longitudinal analyses. CONCLUSIONS A strong relationship between serum 25-OHD and PEFR was observed in older men, both in the cross-sectional as well as longitudinal analyses, but not in older women. The association in men could partly be explained by physical performance and muscle strength.