Mary E. Strek

Churg-Strauss syndrome

Churg-Strauss syndrome is a rare diffuse vasculitis that is almost invariably accompanied by severe asthma. Although overall prognosis is good, and treatment with prednisone alone or in combination with immunosuppressive drugs is usually successful, severe asthma typically persists. Diffuse organ involvement of Churg-Strauss syndrome, especially cardiovascular and rare involvement of the CNS and renal system, suggests a poorer prognosis than usual, and can be fatal. The cause of Churg-Strauss syndrome is unknown, but its characteristic histological findings and association with asthma distinguish it from other vasculitides. Controversy surrounds the use of asthma drugs-especially antileukotrienes--and development of the disorder. We review the epidemiological evidence for an association of drug treatment with Churg-Strauss syndrome, the diverse diagnostic and pathological criteria for this syndrome, and treatment options.

An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features http://ow.ly/O7qao

Non–Cystic Fibrosis Bronchiectasis

There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use.

Autoimmune-Featured Interstitial Lung Disease: A Distinct Entity

BACKGROUND Patients with interstitial lung disease (ILD) may have features of an autoimmune disorder that do not meet the diagnostic criteria for connective tissue diseases. We determined the prevalence and characteristics of autoimmune-featured ILD (AIF-ILD) and compared these with those of idiopathic pulmonary fibrosis (IPF) and known connective tissue disease-related ILD (CTD-ILD). METHODS Patients with ILD who did not meet the criteria for a connective tissue disease were defined as having AIF-ILD if they had a sign or symptom suggestive of a connective tissue disease and a serologic test reflective of an autoimmune process. Clinical characteristics, high-resolution CT images, and lung biopsy specimens were analyzed and compared with those of patients with IPF and CTD-ILD. Survival was evaluated using a Kaplan-Meier curve. RESULTS Two hundred subjects completed the questionnaire and serologic testing. AIF-ILD was identified in 32%, IPF in 29%, and CTD-ILD in 19%. Gender, age, and race differed among groups (P < .01). Sixty-two percent of patients with AIF-ILD had a typical usual interstitial pneumonia (UIP) pattern on CT images. In 31 patients with AIF-ILD, lung biopsy specimens showed UIP in 81% and nonspecific interstitial pneumonia in 6%. Patients with AIF-ILD and IPF had similar survival, worse than those with CTD-ILD (P < .01). Antinuclear antibody (ANA) titers ≥ 1:1280 were associated with improved survival in patients with AIF-ILD (P = .02). CONCLUSIONS Systematic evaluation of symptoms and serologic tests in ILD can identify AIF-ILD. A UIP pattern on CT images and histopathology is common in AIF-ILD. Although survival for patients with AIF-ILD is poor, ANA titers ≥ 1:1280 are associated with improved survival.

Diagnosis and Treatment of Connective Tissue Disease-Associated Interstitial Lung Disease

Interstitial lung disease (ILD) is one of the most serious pulmonary complications associated with connective tissue diseases (CTDs), resulting in significant morbidity and mortality. Although the various CTDs associated with ILD often are considered together because of their shared autoimmune nature, there are substantial differences in the clinical presentations and management of ILD in each specific CTD. This heterogeneity and the cross-disciplinary nature of care have complicated the conduct of prospective multicenter treatment trials and hindered our understanding of the development of ILD in patients with CTD. In this update, we present new information regarding the diagnosis and treatment of patients with ILD secondary to systemic sclerosis, rheumatoid arthritis, dermatomyositis and polymyositis, and Sjögren syndrome. We review information on risk factors for the development of ILD in the setting of CTD. Diagnostic criteria for CTD are presented as well as elements of the clinical evaluation that increase suspicion for CTD-ILD. We review the use of medications in the treatment of CTD-ILD. Although a large, randomized study has examined the impact of immunosuppressive therapy for ILD secondary to systemic sclerosis, additional studies are needed to determine optimal treatment strategies for each distinct form of CTD-ILD. Finally, we review new information regarding the subgroup of patients with ILD who meet some, but not all, diagnostic criteria for a CTD. A careful and systematic approach to diagnosis in patients with ILD may reveal an unrecognized CTD or evidence of autoimmunity in those previously believed to have idiopathic ILD.

TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. OBJECTIVES To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. METHODS SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC. MEASUREMENTS AND MAIN RESULTS Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. CONCLUSIONS NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.

Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis

Hiatal hernia (HH) is associated with gastro-oesophageal reflux (GOR) and/or GOR disease and may contribute to idiopathic pulmonary fibrosis (IPF). We hypothesised that HH evaluated by computed tomography is more common in IPF than in asthma or chronic obstructive pulmonary disease (COPD), and correlates with abnormal GOR measured by pH probe testing. Rates of HH were compared in three cohorts, IPF (n=100), COPD (n=60) and asthma (n=24), and evaluated for inter-observer agreement. In IPF, symptoms and anti-reflux medications were correlated with diffusing capacity of the lung for carbon monoxide (DL,CO) and composite physiologic index (CPI). HH was correlated with pH probe testing in IPF patients (n=14). HH was higher in IPF (39%) than either COPD (13.3%, p=0.00009) or asthma (16.67%, p=0.0139). The HH inter-observer &kgr; agreement was substantial in IPF (&kgr;=0.78) and asthma (&kgr;=0.86), and moderate in COPD (&kgr;=0.42). In IPF, HH did not correlate with lung function, except in those on anti-reflux therapy, who had a better DL,CO (p<0.03) and CPI (p<0.04). HH correlated with GOR as measured by DeMeester scores (p<0.04). HH is more common in IPF than COPD or asthma. In an IPF cohort, HH correlated with higher DeMeester scores, confirming abnormal acid GOR. Presence of HH alone was not associated with decreased lung function.

Diagnosis and Treatment of Pulmonary Aspergillosis Syndromes

Both inherited and acquired immunodeficiency and chronic pulmonary disease predispose to the development of a variety of pulmonary syndromes in response to Aspergillus, a fungus that is ubiquitous in the environment. These syndromes include invasive aspergillosis, which is now recognized to occur in patients with critical illness without neutropenia and in those with mild degrees of immunosuppression, including from corticosteroid use in the setting of COPD. Chronic pulmonary aspergillosis includes simple aspergilloma, which is occasionally complicated by life-threatening hemoptysis, and progressive destructive cavitary disease requiring antifungal therapy. Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fibrosis. Recent advances in each of these syndromes include a greater understanding of the underlying pathophysiology and hosts at risk; improved diagnostic algorithms; and the availability of more effective and well-tolerated therapies. Improvement in outcomes for Aspergillus pulmonary syndromes requires that physicians recognize the varied and sometimes subtle presentations, be aware of populations at risk of illness, and institute potentially life-saving therapies early in the disease course.

Regulation of human eosinophil degranulation and activation by endogenous phospholipase A2.

The unique granular proteins of eosinophils may have a pathogenetic role in asthma and in the defense against parasitic infestations. However, the mechanisms regulating eosinophil degranulation are largely unknown. We examined the hypothesis that release of these proteins is regulated by endogenous activation of phospholipase A2. Human eosinophils (HE) were isolated from the peripheral blood of 42 subjects either by Percoll density separation or by negative-selection immunomagnetic fractionation. Eosinophil activation was initiated in vitro with 10(-6) M FMLP and 5 micrograms/ml cytochalasin B and was assessed by measurement of eosinophil peroxidase (EPO), leukotriene C4 (LTC4) and superoxide radical (.O2-) secretion. Treatment of HE with 100 microM mepacrine before activation blocked EPO release (2.0 +/- 0.2 vs 10.2 +/- 2.1% cell content for activated HE, P < 0.004, n = 9), .O2- generation (2.6 +/- 0.9 vs 44.2 +/- 10.8 nmol/ml per 10(6) HE, P < 0.002, n = 5), and LTC4 secretion (68.2 +/- 32.2 vs 1,125.2 +/- 526.8 pg/ml per 10(6) HE, P < 0.04, n = 8). Pretreatment of HE with 100 microM 4-bromophenacyl bromide before activation similarly blocked EPO release, .O2- generation and LTC4 secretion. Addition of AA to HE after treatment with 100 microM mepacrine and before subsequent activation reversed the inhibition of both EPO (10.4 +/- 2.2% with 1 microM AA vs 2.0 +/- 0.2% for mepacrine, n = 5, P < 0.02) and LTC4 secretion (695.1 +/- 412.9 with 10 microM AA vs 68.2 +/- 32.2 pg/ml per 10(6) HE for mepacrine, n = 8, P < 0.04), but did not reverse inhibition of .O2- generation by mepacrine. We demonstrate that secretion of preformed cytotoxic proteins and .O2- by eosinophils is regulated endogenously by phospholipase A2.

Characterisation of patients with interstitial pneumonia with autoimmune features.

Patients with interstitial lung disease (ILD) may have features of connective tissue disease (CTD), but lack findings diagnostic of a specific CTD. A recent European Respiratory Society/American Thoracic Society research statement proposed criteria for patients with interstitial pneumonia with autoimmune features (IPAF). We applied IPAF criteria to patients with idiopathic interstitial pneumonia and undifferentiated CTD-ILD (UCTD). We then characterised the clinical, serological and morphological features of the IPAF cohort, compared outcomes to other ILD cohorts and validated individual IPAF domains using survival as an endpoint. Of 422 patients, 144 met IPAF criteria. Mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis, but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD. IPAF is common among patients with idiopathic interstitial pneumonia and UCTD. Specific IPAF features can identify subgroups with differential survival. Further research is needed to replicate these findings and determine whether patients meeting IPAF criteria benefit from immunosuppressive therapy. IPAF is common among patients with IIP and has distinct subgroups that demonstrate differential survival http://ow.ly/Z0ShD