Alvin S. Teirstein

Pulmonary Complications of the Acquired Immunodeficiency Syndrome: Report of a National Heart, Lung, and Blood Institute Workshop

Under the sponsorship of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, a two-day workshop on the pulmonary complications of the acquired immunodeficiency syndrome ...

Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4+ T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab′)2 fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150–160, 80, or 60–64 kD) but only 3 of 22 (14%) control tissues (all 62–64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase–peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)− (P = 0.0059) and 4 of 10 (40%) PPD+ (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase–peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

Cardiac Involvement in Patients with Sarcoidosis: Diagnostic and Prognostic Value of Outpatient Testing

BACKGROUND Cardiac sarcoidosis (CS) causes substantial morbidity and sudden death. Early diagnosis and risk stratification are warranted. METHODS Ambulatory patients with sarcoidosis were interviewed to determine whether they experienced palpitations, syncope, or presyncope, and were evaluated with ECG, Holter monitoring, and echocardiography (transthoracic echocardiogram [TTE]). Those with symptoms or abnormal results were studied with cardiac MRI (CMRI) or positron emission tomography (PET) scanning. The diagnosis of CS was based on abnormalities detected by these imaging studies. Patients with CS were referred for risk stratification by electrophysiology study (EPS). RESULTS Among the 62 patients evaluated, the prevalence of CS was 39%. Patients with CS had more cardiac symptoms than those without CS (46% vs 5%, respectively; p < 0.001), and were more likely to have abnormal Holter monitoring findings (50% vs 3%, respectively; p < 0.001) and TTE findings (25% vs 5%, respectively; p = 0.02). The degree of pulmonary impairment did not predict CS. Two of the 17 patients who underwent EPS had abnormal test findings and received implantable cardioverter-defibrillators. No patients died, had ventricular arrhythmias that triggered defibrillator therapy, or had heart failure develop during almost 2 years of follow-up. This diagnostic approach was more sensitive than the established criteria for identifying CS. CONCLUSION CS is common among patients with sarcoidosis. A structured clinical assessment incorporating advanced cardiac imaging with PET scanning or CMRI is more sensitive than the established criteria for the identification of CS. Sarcoidal lesions seen on CMRI or PET scanning do not predict arrhythmias in ambulatory patients with preserved cardiac function, who appear to be at low risk for short-term mortality.

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg·kg−1 body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

Genome-wide search for sarcoidosis susceptibility genes in African Americans

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman–Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Primary Prevention of Sudden Cardiac Death in Silent Cardiac Sarcoidosis: Role of Programmed Ventricular Stimulation

Background— Cardiac involvement in sarcoidosis is often silent and may lead to sudden death. This study was designed to assess the value of programmed electric stimulation of the ventricle (PES) for risk stratification in patients with sarcoidosis and evidence of preclinical cardiac involvement on imaging studies. Methods and Results— Patients with biopsy-proven systemic sarcoidosis but without cardiac symptoms who had evidence of cardiac sarcoidosis on positron emission tomography (PET) or cardiac MRI (CMR) were included. All patients underwent baseline evaluation, echocardiographic assessment of left ventricular function, and programmed electric stimulation of the ventricle. Patients were followed for survival and arrhythmic events. Seventy-six patients underwent PES of the ventricle. Eight (11%) were inducible for sustained ventricular arrhythmias and received an implantable defibrillator. None of the noninducible patients received a defibrillator. Left ventricular ejection fraction was lower in patients with inducible ventricular arrhythmia (36.4±4.2% versus 55.8±1.5%, P <0.05). Over a median follow-up of 5 years, 6 of 8 patients in the group with inducible ventricular arrhythmias had ventricular arrhythmia or died, compared with 1 death in the negative group ( P <0.0001). Conclusions— In patients with biopsy-proven sarcoidosis and evidence of cardiac involvement on PET or CMR alone, positive PES may help to identify patients at risk for ventricular arrhythmia. More importantly, patients in this cohort with a negative PES appear to have a benign course within the first several years following diagnosis. PES may help to guide the use of implantable cardioverter defibrillators in this population.Background—Cardiac involvement in sarcoidosis is often silent and may lead to sudden death. This study was designed to assess the value of programmed electric stimulation of the ventricle (PES) for risk stratification in patients with sarcoidosis and evidence of preclinical cardiac involvement on imaging studies. Methods and Results—Patients with biopsy-proven systemic sarcoidosis but without cardiac symptoms who had evidence of cardiac sarcoidosis on positron emission tomography (PET) or cardiac MRI (CMR) were included. All patients underwent baseline evaluation, echocardiographic assessment of left ventricular function, and programmed electric stimulation of the ventricle. Patients were followed for survival and arrhythmic events. Seventy-six patients underwent PES of the ventricle. Eight (11%) were inducible for sustained ventricular arrhythmias and received an implantable defibrillator. None of the noninducible patients received a defibrillator. Left ventricular ejection fraction was lower in patients with inducible ventricular arrhythmia (36.4±4.2% versus 55.8±1.5%, P<0.05). Over a median follow-up of 5 years, 6 of 8 patients in the group with inducible ventricular arrhythmias had ventricular arrhythmia or died, compared with 1 death in the negative group (P<0.0001). Conclusions—In patients with biopsy-proven sarcoidosis and evidence of cardiac involvement on PET or CMR alone, positive PES may help to identify patients at risk for ventricular arrhythmia. More importantly, patients in this cohort with a negative PES appear to have a benign course within the first several years following diagnosis. PES may help to guide the use of implantable cardioverter defibrillators in this population.

Ventilatory failure due to asbestos pleurisy

Seven patients are described who had a distinctive syndrome of chest wall restriction caused by asbestos-induced pleural fibrosis. All had severe dyspnea and predominant pleural disease on radiographic examination, with pulmonary function findings of reduced vital capacity, total lung capacity (measured in five patients), and maximal voluntary ventilation. Five patients had ventilatory failure with carbon dioxide retention; four of these have died and one is close to death. Examination of the thoracic organs in five patients showed minimal or no parenchymal fibrosis in three and less severe involvement of the parenchyma than of the pleura in the remaining two. Neoplasms were suspected in three patients because of extension of the pleural fibrosis into the lung. Two of these patients had pleural uptake of 67-gallium citrate attributable to the inflammatory reaction. With the increasing duration since onset of exposure in the nine million workers who have been exposed to asbestos, as well as in other exposed persons, it is expected that additional cases of ventilatory failure caused by asbestos-induced pleural fibrosis will be encountered.

Job and industry classifications associated with sarcoidosis in a case-control etiologic study of sarcoidosis (ACCESS)

Objectives: Objective: To determine whether specific occupations and industries may be associated with sarcoidosis. Methods: A Case Control Etiologic Study of Sarcoidosis (ACCESS) obtained occupational and environmental histories on 706 newly diagnosed sarcoidosis cases and matched controls. We used Standard Industrial Classification (SIC) and Standard Occupational Classification (SOC) to assess occupational contributions to sarcoidosis risk. Results: Univariable analysis identified elevated risk of sarcoidosis for workers with industrial organic dust exposures, especially in Caucasian workers. Workers for suppliers of building materials, hardware, and gardening materials were at an increased risk of sarcoidosis as were educators. Work providing childcare was negatively associated with sarcoidosis risk. Jobs with metal dust or metal fume exposures were negatively associated with sarcoidosis risk, especially in Caucasian workers. Conclusions: In this study, we found that exposures in particular occupational settings may contribute to sarcoidosis risk.

MACC (METHOTREXATE, ADRIAMYCIN, CYCLOPHOSPHAMIDE AND CCNU) IN ADVANCED LUNG CANCER

Eighty‐three patients (53 men, 30 women) with advanced lung cancer were treated with a four‐drug combination (MACC) consisting of methotrexate, adriamycin, cyclophosphamide and CCNU given once every 3 weeks. The overall objective response rate (complete response and partial response >50%) was 52% with a median duration of therapy of 29 weeks. Response rate was highest for small cell carcinoma (87%) followed by adenocarcinoma (58%) and squamous cell carcinoma (36%). There was a significant prolongation of median survival for responders vs. nonresponders: 48 weeks vs. 17 weeks for the whole group (p < 0.005), 48 weeks vs. 19 weeks for small cell carcinoma, 48 weeks vs. 15 weeks for adenocarcinoma, 40 weeks vs. 20 weeks for squamous cell carcinoma, and 56 weeks vs. 17 weeks for large cell carcinoma. Prolongation of survival was also apparent when analyzed by extent of the disease (limited vs. extensive) and by performance status. Major toxic effects included bone marrow depression (leukopenia in 36 and thrombocytopenia in 12 patients), mucositis (13 patients), fever and/or sepsis (11 patients), renal toxicity (4 patients) and skin rash (4 patients), There was only one case of cardiotoxicity, and one treatment‐related death from septic shock during leukopenia. This regimen has shown activity in all cell types of lung cancer and is easy to administer on an out‐patient basis.

Sarcoidosis Diagnosed After September 11, 2001, Among Adults Exposed to the World Trade Center Disaster

Objective: Explore relationships between World Trade Center (WTC) exposures and sarcoidosis. Methods: Sarcoidosis has been reported after exposure to the WTC disaster. We ascertained biopsy-proven post-9/11 sarcoidosis among WTC Health Registry enrollees. Cases diagnosed after Registry enrollment were included in a nested case–control study. Controls were matched to cases on age, sex, race or ethnicity, and eligibility group (eg, rescue or recovery worker). Results: We identified 43 cases of post-9/11 sarcoidosis. Twenty-eight incident cases and 109 controls were included in the case–control analysis. Working on the WTC debris pile was associated with sarcoidosis (odds ratio 9.1, 95% confidence interval 1.1 to 74.0), but WTC dust cloud exposure was not (odds ratio 1.0, 95% confidence interval 0.4 to 2.8). Conclusions: Working on the WTC debris pile was associated with an elevated risk of post-9/11 sarcoidosis. Occupationally exposed workers may be at increased risk.