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Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania
This is the fourth in a series of four executive summaries from the Clinical Year in Review Symposium presented at the 2006 International Meeting of the American Thoracic Society. The salient points of each talk have been abstracted by the session chair based on the annotated bibliography submitted by the presenters.
INTERSTITIAL LUNG DISEASE
Ulrich Costabel
Professor and Chief
University of Duisburg-Essen
RuhrlandklinikDepartment of Pneumology and Allergy
Essen Germany
Familial Pulmonary Fibrosis
Genetic factors play a role in the development of pulmonary fibrosis. Familial interstitial pneumonia fibrosis (FIP) is defined as the presence of two or more cases of idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. Steele and colleagues (1) identified 111 families with FIP, and studied 309 affected and 360 unaffected individuals. Twenty pedigrees had a vertical pattern of transmission, consistent with an autosomal dominant inheritance. Factors associated with the development of FIP included older age, male sex, and history of cigarette smoking. The predominant subtype of FIP was usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), although histologic confirmation was available for only one-quarter of patients. In 45% of families, there was more than one subtype among affected members. This study suggests a genetic basis for pulmonary fibrosis and confirms the association between cigarette smoking and fibrotic lung disease.
Antioxidant Therapy for IPF
There is no proven treatment for IPF, a progressive and devastating parenchymal lung disease. Oxidative stress and glutathione deficiency have been postulated to play a role in disease pathogenesis. The efficacy of N-acetyl-cysteine (NAC), a powerful antioxidant, was studied in a European multinational, randomized double-blind, placebo-controlled clinical trial by Demedts and colleagues (2). One hundred eighty-two patients with IPF were randomized to receive NAC (600 mg, three times daily) and standard therapy with prednisone and azathioprine (92 patients) versus placebo plus standard therapy (90 patients). Of these patients, 80 individuals in the NAC group and 75 in the placebo arm were confirmed to have IPF and included in the analysis. Subsequently, 71 and 68% of patients in the NAC and placebo arms completed 1 year of therapy, respectively. The primary endpoints were changes in vital capacity (VC) and diffusing capacity (DLCO) between values at baseline and 12 months of therapy. Treatment with NAC was associated with an absolute difference of 9% in VC and 24% in DLCO in the change from baseline compared with placebo. There was no difference in mortality between the groups, although the study was not powered to assess survival differences. Interestingly, there were no significant differences in adverse events, except for lower rate of myelosuppression in the NAC group. A larger clinical trial evaluating survival is warranted.
Hypersensitivity Pneumonitis: Histologic Subsets and Clinical Characteristics
The diagnosis of hypersensitivity pneumonitis (HP) can be elusive, and often confused with the idiopathic interstitial pneumonias. Ohtani and colleagues (3) studied the histopathologic and clinical features of 26 patients with chronic bird fancier's lung (BFL), a form of HP. Eleven patients were initially diagnosed with IPF, whereas others were believed to have nonspecific interstitial pneumonia (NSIP) or bronchiolitis obliterans organizing pneumonia (BOOP). The characteristics of chronic inflammatory and fibrotic lesions varied in BFL, but correlated with clinical features and prognosis. Patients with BOOP-like or cellular NSIP lesions, based on the 2002 American Thoracic Society/European Respiratory Society consensus classification of IIP, had the highest bronchoalveolar lavage (BAL) lymphocyte counts, recurrent acute episodes, better response to corticosteroids, and better prognosis.
Gene Expression Profiles: IPF versus HP
The diagnosis of interstitial lung diseases is currently based on clinical, radiographic, and pathologic features. Molecular biological techniques that establish gene expression signatures may lead to more accurate diagnosis. Selman and coworkers (4) compared gene expression patterns using custom oligonucleotide DNA microarray in lung biopsy specimens from patients with IPF, HP, and NSIP. They were able to identify gene expression signatures that characterize IPF and HP. In IPF, there was up-regulation of 354 genes that express tissue remodeling. In HP, 595 genes functionally associated with inflammation were up-regulated. The authors concluded that disease-specific genetic signatures may play a role in diagnosis.
CYSTIC FIBROSIS
Moira L. Aitken
Professor of Medicine
University of Washington
Division of Pulmonary and Critical Care Medicine
Seattle, Washington
Airway clearance measures, such as chest percussion, are critical in the treatment of patients with cystic fibrosis (CF). Elkins and colleagues (5) evaluated the safety and efficacy of aerosolized hypertonic saline (HS) in Australia. They treated 83 patients older than 6 years with clinically stable CF with 7% HS and 81 individuals with 0.9% saline for 12 months. Treatment with HS also resulted in a 4% improvement in FEV1 and 14% reduction in acute pulmonary exacerbations at 12 months. In another single-center trial of HS, Donaldson and colleagues (6) reported that HS improved mucociliary clearance at 1 hour and for at least 8 hours after therapy. The effect was found to persist for more than 11 days. The addition of amiloride appeared to prevent the therapeutic benefit of HS. HS was well tolerated in both studies and less costly than other accepted airway clearance treatments such as rhDNase.
Antibiotic-resistant gram-negative pathogens, particularly Pseudomonas aeruginosa, pose formidable challenges in the treatment of CF pulmonary exacerbations. Intravenous tobramycin is often used in antimicrobial regimens. Smyth and colleagues (7) compared once- versus thrice-daily tobramycin (10 mg/kg) in 219 patients from 21 centers in the United Kingdom. All patients were treated for 14 days with a regimen that also included ceftazidime. There was no difference in the primary outcome, mean change in FEV1, in the two groups. There was no overall difference in serum creatinine; subgroup analysis of 125 children, however, revealed a 3.7% rise in serum creatinine. The impact on creatinine clearance or audiometry was not reported. The authors concluded that once-daily tobramycin is equally efficacious and more convenient overall, and possibly less nephrotoxic in children.
The impact of in vitro antibiotic susceptibility testing on clinical outcomes in patients with CF with acute pulmonary exacerbations remains controversial. Aaron and coworkers (8) compared conventional antibiotic susceptibility testing to multiple combination bacterial (MCB) antibiotic testing in 251 patients with CF with multidrug-resistant (MDR) gram-negative bacteria. These patients from Canada and Australia provided sputum samples for susceptibility testing every 3 months over 4.5 years. When an acute exacerbation occurred, they were randomized to receive a 14-day course of antibiotics based on either conventional or MCB testing. Acute exacerbations developed in 132 patients in the study period; there were no differences in pulmonary function, symptoms, time to next exacerbation, or rate of treatment failure between the two groups. MCB testing did not result in better outcomes than conventional testing.
Macrolide antibiotics have potent antiinflammatory properties in addition to their antimicrobial effects. Azithromycin was previously shown to improve FEV1 in patients with CF over a 6-month course of therapy. In a follow-up to the previous trial, Saiman and colleagues (9) examined a database of 186 patients with CF treated with azithromycin to determine if there was heterogeneity in the FEV1 treatment response. They also evaluated the possible relationship between change in FEV1 and risk of pulmonary exacerbations. They did, in fact, identify heterogeneity in FEV1 response to azithromycin, ranging from –15 to greater than +15% from baseline. The majority of patients were in the –5 to +5% range. Interestingly, azithromycin appeared to decrease exacerbation rate regardless of impact on FEV1. This study supports the efficacy of macrolide therapy in CF.
Because patients with CF with the same genetic mutations may have different clinical phenotypes, Drumm and colleagues (10) addressed the role of genetic modifiers of lung disease in CF in a cohort study. In the first cohort, they examined 808 individuals homozygous for the DF 508 mutation, and who were in the highest and lowest quartile based on FEV1. In the replication cohort of 498 patients, all CF genotypes and all lung function were evaluated. They found that genetic variation in the transforming growth factor-ß1 polymorphism, –509 promoter, and codon 10 with specific alleles T and C, respectively, was associated with greater pulmonary disease severity in CF. The authors comment that the dataset from this study may be useful in studying more genetic modifiers on a genomewide basis.
PULMONARY INFECTIONS
Michael S. Niederman
Chairman, Department of Medicine
Winthrop University Hospital
Department of Medicine
Mineola, New York
Professor of Medicine and Vice-Chairman
Department of Medicine
SUNY at Stony Brook
Stony Brook, New York
Hospital-acquired Pneumonia
Defining the natural history of health care–associated pneumonia.
Health care–associated pneumonia (HCAP) is a newly defined category of pneumonia. It refers to pneumonia occurring in patients from nursing homes or other health care facilities, or who have been hospitalized in the past 30 days, or who are on hemodialysis. A positive respiratory culture within 2 days of admission is required for the diagnosis. Kollef and colleagues (11) used a retrospective database from 59 hospitals in the United States to assess the epidemiology and natural history of HCAP. Of the 4,543 patients with pneumonia and positive cultures, 988 had HCAP. Patients with HCAP had a mortality rate of 19.8%, significantly higher than that for community-acquired pneumonia (CAP; 10%), but less than that for ventilator-associated pneumonia (VAP; 29.3%). The most common pathogen in HCAP was Staphylococcus aureus; 56.8% of isolates were methicillin-resistant S. aureus (MRSA). In addition, P. aeruginosa was the pathogen identified in 25.3%. Patients with HCAP were older, had more comorbidities, and had longer lengths of stay than those with CAP. In general, the epidemiology of HCAP is more similar to that of VAP.
Changing patterns of bacteria.
Gaynes and colleagues (12) reviewed the data for nosocomial infections in the United States using the National Nosocomial Surveillance System (NNIS) from 1975 onward. The article focused specifically on data in intensive care unit (ICU) patients collected by the NNIS since 1986. In nosocomial pneumonia, gram-negative rods (GNRs) accounted for 65.9% of pathogens. The frequency of GNRs did not increase overall in the years studied, although the frequency of Acinetobacter increased from 4 to 7%. Disturbing trends in antibiotic resistance were noted. Resistance of Escherichia coli and Klebsiella pneumonia to third-generation cephalosporins increased; resistance to carbapenems in P. aeruginosa and Acinetobacter also increased. The authors postulated that antibiotic usage patterns contributed to ICU resistance patterns.
Patient management with surveillance cultures.
The use of surveillance respiratory cultures to guide antimicrobial therapy in VAP has not been well demonstrated. Michel and colleagues (13) performed a prospective observational study of 299 patients mechanically ventilated for at least 48 hours. Endotracheal aspirate (EA) cultures were collected twice weekly. The patients were started on antibiotics based on the most recent EA results when VAP was suspected; BAL was performed to confirm the diagnosis. VAP was suspected in 75 patients and confirmed in 41 patients. EA identified the same pathogen as BAL in 34 of 41 patients, and antibiotic choice based on EA was correct in 95% of patients. Fewer patients (45%) received broad-spectrum antibiotics than those reported in previously published clinical algorithms. This study suggests that surveillance cultures may have value in guiding the therapy of VAP.
Impact of recent antibiotic therapy on antimicrobial resistance.
The impact of fluoroquinolone (FQ) therapy for pneumonia in ICU patients on the emergence of MDR bacteria was evaluated by Nseir and coworkers (14) in a prospective cohort and case-control trial. Of 239 ICU patients with no prior antibiotic exposure, 135 were subsequently treated with FQs (ofloxacin or ciprofloxacin). These patients were subsequently screened for MDR bacteria. MDR bacteria emerged in 77 patients; 40% of the organisms were MRSA, 24% P. aeruginosa, and 19% extended spectrum ß-lactamases. In multivariate analysis, FQ use (odds ratio [OR], 3.3) and duration of antibiotics (OR, 1.1) were most strongly correlated with MDR bacteria acquisition. Patients with MRB had longer ICU stays and higher mortality. This study suggests that FQ use can lead to resistance not only to FQ but to other classes of antibiotics as well, and that perhaps FQ should be reserved for subsequent rather than initial infections when possible.
Community-acquired Pneumonia
Predicting pneumococcal resistance.
Pneumococcal resistance represents an increasingly important clinical challenge. Using data from 3,339 patients with invasive pneumococcal infection from the Toronto Bacterial Network from 1995 to 2002, Vanderkooi and colleagues (15) examined the impact of recent antibiotic exposure on subsequent pneumococcal resistance. Of these individuals, 563 had received a known antibiotic within 3 months of the invasive infection, whereas 1,576 had received no recent antibiotic therapy. In addition, 282 had received an unidentified antibiotic; in 917 individuals, antibiotic use could not be determined. The most commonly used antimicrobial agents were penicillins, cephalosporins, trimethoprim–sulfamethoxazole, macrolides, and quinolones. The investigators found that use of any agent predicted subsequent resistance to it. Quinolone resistance was more likely if the patients were receiving corticosteroids (OR, 6.0), from a nursing home (OR, 5.4), or acquired infection in a nosocomial setting (OR, 5.8). The case fatality rate was 19.4%. This study is important because it documents that recent antimicrobial therapy predicts pneumococcal resistance, and implies that patients should be treated with a different antibiotic than previously received.
Impact of diagnostic testing in CAP.
Current guidelines for CAP recommend empiric therapy. The role of diagnostic studies in guiding therapy remains uncertain. Van der Eerden and colleagues (16) performed a prospective, randomized, open study of 262 adults admitted with CAP from 1998 to 2000 in the Netherlands. Empiric therapy according to 1993 American Thoracic Society guidelines was compared with pathogen-directed therapy (PDT) based on sputum Gram stain and Legionella urinary antigen analysis. All patients had extensive testing (including blood cultures), but was not used to choose therapy in the empiric group. Empiric therapy consisted of a ß-lactam/ß-lactam inhibitor plus erythromycin in non-ICU patients or ceftazidime plus erythromycin in ICU patients. In the PDT group, treatment was directed at Pneumococcus (penicillin), atypical pathogens (erythromycin), mixed infection (amoxicillin–clavulinic acid), or postinfluenza pneumonia (flucloxacillin with or without gentamicin). Pneumococcus was the dominant pathogen in both groups; interestingly, no penicillin or macrolide resistance was encountered. No pathogen was identified in 37% of patients in the PDT group, and in 46% in the empiric treatment group. Fewer than 10% of patients required ICU admission. There were no differences in length of stay, 30-day mortality, resolution of fever, or clinical failure in the two study groups. In the subset of patients admitted to the ICU, mortality was higher in the empiric group (91 vs. 45%).
Monotherapy of severe CAP.
Because of the absence of definitive data, current guidelines for the treatment of severe CAP do not recommend monotherapy, including use of an FQ. In a prospective, randomized, open trial of 398 patients admitted to the ICU with severe CAP, Leroy and coworkers (17) compared monotherapy using levofloxacin (500 mg every 12 hours) with ofloxacin plus cefotaxime. Patients with septic shock were excluded. Fifty-one percent required mechanical ventilation. Pneumococcus was the most common pathogen. In two well-matched groups, there were no differences in clinical cure (79.1% in monotherapy group, 79.5% in the two-drug group), mortality, or bacteriologic response. In the subset of patients requiring mechanical ventilation, however, there was a trend toward lower clinical cure in the levofloxacin group. The authors concluded that monotherapy with levofloxacin may be efficacious in severe CAP, except in those needing mechanical ventilation. Given the exclusion of patients with shock, and no use of macrolides in the two-drug group, the answer to the question of monotherapy for severe CAP remains elusive.
MYCOBACTERIAL DISEASE
Michael D. Iseman
Professor of Medicine
University of Colorado Health Sciences Center
Division of Pulmonary Sciences and Critical Care Medicine
Denver, Colorado
Recurrent Tuberculosis: Can You Fool Some of the Lymphocytes All of the Time?
It has been postulated for many years that prior infection with tuberculosis (TB) may protect against subsequent reinfection. Verver and coworkers (18) performed a surveillance study in Cape Town, South Africa, where there is a very high rate of unexplained recurrent TB, to address this issue. They identified 1,007 patients with non-MDR TB, 897 of whom were successfully treated. DNA fingerprints of the TB isolate were available for 612 of the treated patients. Reinfection TB was defined as a recurrent TB episode in which the strains of the separate episodes differed by more than four bands by DNA fingerprinting. They reported a risk of reinfection, during a 5.2-year median duration of follow-up, of 2.2 per 100 person-years in adequately treated patients. This rate was fourfold higher than that for a control group of new patients with TB. The authors suggest that there may be a subgroup of individuals who are intrinsically vulnerable to TB not altered by prior infection. If confirmed, the findings of this study may warrant long-term surveillance of patients who have been previously treated for TB.
TB in Health Care Workers: Safety Begins at Home
Three articles published in the past year (19–21) document the very high risk of TB infection in health care workers (HCWs) in Uganda, Thailand, and Brazil. Factors contributing to this risk include high TB rates in the populations served by these HCWs, insensitive tools available for diagnosis, and limited resources to prevent nosocomial transmission. The implications are far-reaching.
The Centers for Disease Control and Prevention (CDC) published a document (22) updating the 1994 Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health Care Facilities. This report is designed to assist institutions in the United States in minimizing infection of HCWs with TB. The publication reviews the history of TB in HCWs from 1900 to 1960 when TB was an important occupational hazard, to 1960–1990 when this risk plummeted. From 1990 to 2000, there was an increasing risk due to HIV and MDR TB, which has again diminished in the past few years. The CDC recommends systematic measures, based on sound scientific practices, to prevent transmission of TB in health care settings, primarily to protect patients (especially the immunosuppressed) and HCWs.
Better TB Therapy: Of Mice and Men
Using a murine model that mimics the treatment of high-risk patients with TB, Rosenthal and colleagues (23) compared novel TB regimens with the "Denver regimen," which has been widely used in the United States. The Denver regimen consists of 2 weeks of daily isoniazid (INH), rifampin, pyrazinamide, and ethambutol, followed by 6 weeks of twice-weekly administration of these four drugs, and ending with a continuation phase of 18 weeks of twice-weekly INH and rifampin. In this study, this regimen was compared with those using once-weekly moxifloxacin plus rifapentine (15 mg/kg), both of which have long serum half-lives, or once-weekly INH plus rifapentine (15 mg/kg) in the continuation phase. After 2 months of treatment, lung TB colony-forming unit counts were much lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, once-weekly moxifloxacin plus rifapentine was significantly more effective in sterilizing mice tissues than the twice-weekly Denver regimen of INH plus rifampin. No significant difference in sterilizing activity was noted between once-weekly INH plus rifapentine and the Denver regimen. These results suggest that there may be a role for newer agents in the treatment of TB.
FOOTNOTES
Conflict of Interest Statement: G.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
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