The prognostic value of quantitating and localizing F-18 FDG uptake in cardiac sarcoidosis.

BACKGROUND: There is no identified level of FDG uptake in cardiac sarcoidosis (CS) associated with increased risk of arrhythmias, conduction disease, heart failure, or death. We aim to utilize standardized uptake value (SUV) quantitation and localization to identify patients at increased risk of cardiac events. METHODS AND RESULTS: F18-FDG PET/CT with MPI was used in CS diagnosis (N = 67). Mean and max SUV were measured and grouped as basal, mid, and apical disease. Post-scan ventricular tachycardia, AICD placement, complete heart block, pacemaker placement, atrial fibrillation, heart failure, and cardiac-related hospital admissions were recorded (mean follow up 2.98 ± 2 years). Poisson regression analysis revealed that max SUV, mean SUV, as well as mean basal SUV, and LVEF were significantly associated with total cardiac events. Max SUV odds ratio (OR) = 1.068 (95% CI 1.024-1.114, P = 0.002), mean SUV OR = 1.059 (95% CI 1.008-1.113, P = 0.023), mean SUV OR = 1.061 (95% CI 1.012-1.112, P = 0.014), scan LVEF OR = 0.731 (95% CI 0.664-0.805, P < 0.001). CONCLUSIONS: SUV at time of CS diagnosis has significant associations with future cardiac events. Patients with higher SUV, particularly in basal segments, are at increased risk of events. Further studies are needed to identify treatment methods utilizing risk stratification of CS.

Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema.

The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (D(L,CO)) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n = 321), 6 months (n = 211) and 12 months (n = 144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p = 0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in D(L,CO) or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV(1) predicted mortality (HR 3.7, p = 0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in D(L,CO). For CPFE patients, change in FEV(1) was the best predictor of mortality.

Sex differences in physiological progression of idiopathic pulmonary fibrosis.

In idiopathic pulmonary fibrosis, incidence is higher in males, and females may have better survival. The aim of the present study was to determine whether the rate of increase in desaturation during serial 6-min walk testing would be greater, and survival worse, for males versus females. Serial changes in the percentage of maximum desaturation area (DA) over 1 yr were estimated using mixed models in 215 patients. DA was defined as the total area above the curve created using desaturation percentage values observed during each minute of the 6-min walk test. Multivariate Cox regression assessed survival differences. Adjusting for baseline DA, 6-min walk distance, change in 6-min walk distance over time and smoking history, the percentage of maximum DA increased by an average of 2.83 and 1.37% per month for males and females, respectively. Females demonstrated better survival overall, which was more pronounced in patients who did not desaturate below 88% on ambulation at baseline and after additionally adjusting for 6-month relative changes in DA and forced vital capacity. These data suggest that differences in disease progression contribute to, but do not completely explain, better survival of females with idiopathic pulmonary fibrosis.

Focal interstitial CC chemokine receptor 7 (CCR7) expression in idiopathic interstitial pneumonia.

BACKGROUND/AIMS: Idiopathic interstitial pneumonias (IIPs) are a diverse grouping of chronic pulmonary diseases characterised by varying degrees of pulmonary fibrosis. The triggers of the fibroproliferative process in IIP remain enigmatic but recent attention has been directed towards chemokine involvement in this process. METHODS: The expression of two chemokine receptors, CCR7 and CXCR4, and their respective ligands, CCL19, CCL21, and CXCL12, were examined in surgical lung biopsies (SLBs) from patients with IIP. Transcript and protein expression of these receptors and their ligands was compared with that detected in histologically normal margin SLBs. RESULTS: CCR7 and CXCR4 were detected by gene array and real time polymerase chain reaction analysis and CCR7, but not CXCR4, expression was significantly raised in usual interstitial pneumonia (UIP) relative to biopsies from patients diagnosed with non-specific interstitial pneumonia (NSIP) or respiratory bronchiolitis/interstitial lung disease (RBILD). CCR7 protein was expressed in interstitial areas of all upper and lower lobe UIP SLBs analysed. CCR7 expression was present in 50% of NSIP SLBs, and CCR7 was restricted to blood vessels and mononuclear cells in 75% of RBILD SLBs. Immune cell specific CXCR4 expression was seen in IIP and normal margin biopsies. CCR7 positive areas in UIP biopsies were concomitantly positive for CD45 (the leucocyte common antigen) but CCR7 positive areas in all IIP SLBs lacked the haemopoietic stem cell antigen CD34, collagen 1, and alpha smooth muscle actin. CONCLUSION: This molecular and immunohistochemical analysis showed that IIPs are associated with abnormal CCR7 transcript and protein expression.

Hypersensitivity pneumonitis and antigen identification--An alternate approach.

OBJECTIVES: Identification of the causal antigen for patients with hypersensitivity pneumonitis (HP) is challenging in a standard clinical setting. The purpose of this pilot study was to determine whether it was possible to evaluate the home/workplace of patients, and identify the causal antigen. METHODS: Using a case-control study design we compared the presence of antibody to antigen collected in the environment of individuals with HP and controls consisting of family members/co-workers. Based on patient interviews, homes/workplaces were evaluated and suspected sources of antigen collected for use in immunoassays. RESULTS: Nineteen individuals with HP participated with 15 classified as having fibrotic disease. Up to 54 bulk samples were collected from each patient's environment, with multiple isolates (antigens) cultured from each. Of the seven individuals who tested positive to one or more environmental samples, three had a positive response to more than 1 antigen from the environmental sample (range 1-9). Twelve individuals tested positive to antigen(s) on a standard panel, with only one overlapping with the antigen from the home/workplace sample. A significant association existed between results of interviews/site evaluations, and ability to collect antigen eliciting a positive response (p < 0.001). CONCLUSION: Antigen identification was successful for patients with 'active' disease. Antigens for which patients test positive on standard panels may not be present in their environment. One benefit to patient-centered testing is the ability to develop recommendations specific to their environment. As most individuals tested positive for >1 antigen, further investigation is warranted to determine the actual antigen responsible for disease.

Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival.

PURPOSE: We evaluated the risk and potential benefit of high-dose corticosteroid therapy in patients with idiopathic pulmonary fibrosis. SUBJECTS AND METHODS: We prospectively studied 41 patients with previously untreated, biopsy-proven idiopathic pulmonary fibrosis. Before treatment, we calculated clinical, radiographic, and physiologic severity-of-illness scores for each patient. We scored high-resolution computerized tomographic (CT) scans for ground glass and interstitial opacity. We determined the extent of cellular infiltration, interstitial fibrosis, desquamation, and granulation in open lung biopsy samples. Patients were monitored monthly for steroid-related side effects, response to therapy at 3 months, and mortality. RESULTS: All patients experienced at least one steroid-induced side effect. Eleven (27%) patients were nonresponders, 11 (27%) were responders, and 19 (46%) remained stable. Of the 19 patients who died during a mean (+/- SD) follow-up of 3.3 +/- 2.3 years, 8 (42%) lost weight during the initial 3 months of steroid therapy; only 3 (14%) of the 22 patients still living (P = 0.08) experienced weight loss. In a multivariate analysis, greater fibrosis (hazard ratio [HR] = 1.4 per unit increase; 95% confidence interval [CI]: 1.0 to 1.9; P = 0.03) and cellularity (RR = 1.9 per unit increase; 95% CI: 1.3 to 2.8; 3, P <0.001) in the biopsy sample and whether a patient was classified as a responder (RR = 0.4 versus nonresponder; 95% CI: 0.2 to 1.0; P = 0.05) or stable (RR = 0.2 versus nonresponder; 95% CI: 0.1 to 0.6, P <0.001) after steroid therapy were associated with mortality. CONCLUSION: Corticosteroid treatment for idiopathic pulmonary fibrosis is associated with substantial morbidity. Patients who remain stable or respond to corticosteroid therapy have better survival than those who fail to respond. Whether this difference reflects an effect of treatment or less severe disease can be determined only in a randomized trial.

Short-term and long-term outcomes after bilateral lung volume reduction surgery : prediction by quantitative CT.

OBJECTIVES: To evaluate selection criteria and duration of benefit for patients undergoing lung volume reduction surgery (LVRS). METHODS: Eighty-nine consecutive patients with severe emphysema who underwent bilateral LVRS were prospectively followed up for up to 3 years. Patients underwent preoperative pulmonary function testing, 6-min walk, chest CT, and answered a baseline dyspnea questionnaire. CT scans in 65 patients were analyzed for emphysema extent and distribution using the percentage of emphysema in the lung, percentage of normal lower lung, and the CT emphysema ratio (CTR, an index of the craniocaudal distribution of emphysema). All patients underwent at least 6 weeks of pulmonary rehabilitation prior to surgery. Outcome measures were FEV(1), 6-min walk distance, and transitional dyspnea index (TDI). RESULTS: Compared to baseline, FEV(1) was significantly increased at 3, 6, 12, 18, 24, and 36 months after surgery (p < or = 0.008). The 6-min walk distance increased from 871 feet (baseline) to 1,110 feet (3 months), 1,214 feet (6 months), 1,326 feet (12 months), 1,342 feet (18 months), 1,371 feet (24 months), and 1,390 feet (36 months) after surgery. Despite a decline in FEV(1) over time, 6-min walk distance was preserved. Dyspnea as measured by TDI improved at 3, 6, 12, 18, 24, and 36 months after surgery. A high CTR was the best predictor of a 12% increase over baseline and an absolute increase of 200 mL in FEV(1), although with a low area under the receiver operating characteristic curve. In addition, the sensitivity and negative predictive value of the CTR were limited. No radiographic or physiologic predictor was able to consistently predict a successful increase in walk distance or TDI. CONCLUSION: LVRS improves pulmonary function, decreases dyspnea, and enhances exercise capacity in many patients with severe emphysema, although improvement wanes 36 months after surgery.

Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia.

BACKGROUND: Some idiopathic interstitial pneumonias (IIPs) are characterised by fibroproliferation and deposition of extracellular matrix. Because efficacious treatment options are limited, research has been directed towards understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. AIMS: To examine the expression of interleukin 4 (IL-4), IL-13, and their corresponding receptor subunits in the various forms of IIP and normal patient groups. METHODS: Molecular and immunohistochemical analysis of IL-4, interferon gamma (IFNgamma), IL-13, IL-4 receptor (IL-R), and IL-13 receptor subunits in surgical lung biopsies (SLBs) from 39 patients (21 usual interstitial pneumonia (UIP), six non-specific interstitial pneumonia (NSIP), eight respiratory bronchiolitic interstitial lung disease (RBILD), and five normal controls). RESULTS: Molecular analysis demonstrated that IL-13Ralpha2, IL-13Ralpha1, and IL-4Ralpha were present in a greater proportion of upper and lower lobe biopsies from patients with UIP than patients with NSIP and RBILD. Immunohistochemical analysis of patients with UIP, NSIP, and RBILD revealed interstitial staining for all three receptor subunits, whereas such staining was only seen in mononuclear cells present in normal SLBs. Fibroblastic foci in patients with UIP strongly stained for IL-4Ralpha and IL-13Ralpha2. Localised expression of IL-4Ralpha was also seen in SLBs from patients with NSIP but not in other groups. CONCLUSION: Some histological subtypes of IIP are associated with increased pulmonary expression of receptor subunits responsive to IL-4 and IL-13. These findings may be of particular importance in understanding the pathogenesis of IIP and, more importantly, may provide important novel therapeutic targets.

Acute exacerbation of chronic bronchitis: disease-specific issues that influence the cost-effectiveness of antimicrobial therapy.

BACKGROUND: Acute exacerbation of chronic bronchitis (AECB) is a common condition, with substantial associated costs and morbidity. Research efforts have focused on innovations that will reduce the morbidity associated with AECB. Health care payers increasingly expect that the results of evidence-based economic evaluations will guide practitioners in their choice of cost-effective interventions. OBJECTIVES: To provide a framework on which to base effective and efficient antimicrobial therapy for AECB, we present a concise clinical review of AECB, followed by an assessment of the available data on the economic impact of this disease. We then address several AECB-specific issues that must be considered in cost-effectiveness analyses of AECB antimicrobial interventions. METHODS: Published literature on the clinical and economic impact of AECB was identified using MEDLINE, pre-MEDLINE, HealthSTAR, CINAHL, Current Contents/All Editions, EMBASE, and International Pharmaceutical Abstracts databases. Other potential sources were identified by searching for references in retrieved articles, review articles, consensus statements, and articles written by selected authorities. RESULTS: In evaluating cost-effectiveness analyses of AECB antimicrobial therapy it is critical to (1) use the disease-free interval as an outcome measure, (2) evaluate the sequence of multiple therapies, (3) address the impact of both current and future antibiotic resistance, and (4) measure all appropriate AECB-associated costs, both direct and indirect. CONCLUSIONS: Incorporating these approaches in economic analyses of AECB antimicrobial therapy can help health care organizations make evidence-based decisions regarding the cost-effective management of AECB.

Lung volume reduction surgery for emphysema.

Over the past decades, extensive literature has been published regarding surgical therapies for advanced COPD. Lung-volume reduction surgery would be an option for a significantly larger number of patients than classic bullectomy or lung transplantation. Unfortunately, the initial enthusiasm has been tempered by major questions regarding the optimal surgical approach, safety, firm selection criteria, and confirmation of long-term benefits. In fact, the long-term follow-up reported in patients undergoing classical bullectomy should serve to caution against unbridled enthusiasm for the indiscriminate application of LVRS. Those with the worst long-term outcome despite favourable short-term improvements after bullectomy have consistently been those with the lowest pulmonary function and significant emphysema in the remaining lung who appear remarkably similar to those being evaluated for LVRS. With this in mind, the National Heart, Lung and Blood Institute partnered with the Health Care Finance Administration to establish a multicenter, prospective, randomized study of intensive medical management, including pulmonary rehabilitation versus the same plus bilateral (by MS or VATS), known as the National Emphysema Treatment Trial. The primary objectives are to determine whether LVRS improves survival and exercise capacity. The secondary objectives will examine effects on pulmonary function and HRQL, compare surgical techniques, examine selection criteria for optimal response, identify criteria to determine those who are at prohibitive surgical risk, and examine long-term cost effectiveness. It is hoped that data collected from this novel, multicenter collaboration will place the role of LVRS in a clearer perspective for the physician caring for patients with advanced emphysema.

Diagnosing interstitial lung disease: a practical approach to a difficult problem.

Interstitial lung disease has a variety of causes: environmental, infectious, autoimmune, and drug-related. Accurate diagnosis is essential because the prognosis and treatment of the disease varies widely depending on the cause. However, the respiratory symptoms and pulmonary radiographic picture of these various causes of interstitial lung disease are often similar, making the diagnosis of its cause confusing and frustrating. The practical, algorithmic approach to diagnosis outlined here identifies key diagnostic clues in the patient's history, physical exam, and radiographic findings.

The spectrum of acute bronchitis. Using baseline factors to guide empirical therapy.

The optimal therapy for acute bronchitis depends on the causative pathogen and the presence or absence of underlying lung disease. Because there is no fast, reliable way to identify the pathogen, physicians have to rely on clinical judgment and epidemiologic characteristics. In this article, Drs Flaherty, Saint, Fendrick, and Martinez discuss how an evidence-based approach to treatment may help ensure that efficacious therapy is available in the future.

TLR9 is expressed in idiopathic interstitial pneumonia and its activation promotes in vitro myofibroblast differentiation.

Infectious diseases can be cofactors in idiopathic interstitial pneumonias (IIP) pathogenesis; recent data suggests that toll-like receptors 9 (TLR9) ligands contribute to experimental chronic tissue remodeling. Real-time TAQMAN and immunohistochemical analysis of IIP normal surgical lung biopsies (SLBs), primary fibroblast lines grown from both IIP and normal SLBs indicate that TLR9 is prominently and differentially expressed in a disease-specific manner. TLR9 expression was increased in biopsies from patients with IIP compared with normal lung biopsies and its expression is localized to areas of marked interstitial fibrosis. TLR9 in fibroblasts appeared to be increased by profibrotic Th2 cytokines (IL-4 and IL-13) and this was true in fibroblasts cultured from the most severe form of IIP, idiopathic pulmonary fibrosis (IPF) SLBs, in non-specific interstitial pneumonia fibroblast lines, and in normal fibroblasts. Finally, confocal microscopy studies have shown that TLR9 activation by its synthetic agonist CpG-ODN significantly increased the expression of alpha smooth muscle actin, the main marker of myofibroblast differentiation. These data indicate that TLR9 expression may drive the abnormal tissue healing response in severe forms of IIP and its activation can have a key role in myofibroblast differentiation promoting the progression of disease during the terminal phase of IPF.

Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.

Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia.

OBJECTIVE: To compare disease progression and mortality between idiopathic interstitial pneumonia (IIP) and interstitial lung disease (ILD) due to connective tissue diseases (CTD) including scleroderma, rheumatoid arthritis, systemic lupus, polymyositis, dermatomyositis, Sjögren's syndrome, and mixed CTD. METHODS: A case-control study of patients with CTD-ILD (n = 46) and IIP controls (n = 51), seen at the University of Michigan between July 1,1998 and June 30,1999 and followed until March 30, 2002, was conducted. Survival analysis and Cox regression were performed to estimate survival, accounting for demographic and clinical parameters, including pulmonary function tests and high resolution computed tomography (HRCT) diagnosis and scoring. RESULTS: Median followup time was 4.4 person-years. Five-year survival in the IIP group was 51.9% (95% confidence interval [95% CI] 30.8-69.4) versus 43.4% (95% CI 21.1-63.9) in the CTD-ILD group. There were no significant differences among HRCT diagnostic categories between IIP and CTD-ILD. A fibrotic score > or = 2 was associated with decreased survival among the entire group. Age at diagnosis and most recent forced vital capacity were significant predictors of mortality when adjusted for IIP versus CTD-ILD diagnosis, sex, and interstitial score. CONCLUSION: Contrary to expectation, CTD-ILD compared with IIP appears to be associated with a worse prognosis when adjusted for age. A higher fibrotic score is suggestive of decreased survival.

The role of pulmonary function testing in pulmonary fibrosis.

Interstitial lung diseases are characterized by disruption of the distal pulmonary parenchyma. The clinical history manifestations, cough and dyspnea, and physical exam manifestations, inspiratory crackles, are nonspecific. Pulmonary function testing aids in the evaluation and management of patients with interstitial lung disease although the pattern of abnormality is nonspecific. Pulmonary function testing can provide an estimate of histologic severity but not a definitive quantification of histologic fibrosis or inflammation. Pulmonary function tests can provide a baseline estimation of prognosis and be used to monitor disease progression or response to therapy. The forced vital capacity and diffusion capacity are the most valuable serial measurements, but further data are required to examine composite scoring and exercise gas exchange.

Differential diagnosis of chronic airflow obstruction.

Chronic obstructive pulmonary disease is a syndrome including illnesses such as asthma, chronic bronchitis, and emphysema. Although these diseases share a common obstructive component, their optimal treatment and prognosis differ. This article examines the salient features of the history, physical exam, pulmonary function tests, and radiological evaluation which may allow the clinician to differentiate the various diseases that make up COPD; thus allowing the clinician to better target the multiple therapeutic modalities available.

Nonspecific interstitial pneumonia (NSIP).

Nonspecific interstitial pneumonia (NSIP) represents one histologic subtype of idiopathic interstitial pneumonia (IIP). NSIP is typified by temporal homogeneity and less profusion of fibroblastic foci than is seen with usual interstitial pneumonia (UIP), the most common IIP. Clinically patients with NSIP present with similar symptoms (cough and dyspnea) when compared to patients with UIP. The duration of these symptoms prior to presentation is variable. The finding of fever may be more common in NSIP and clubbing may be more common in UIP; however, both findings can be seen in either UIP or NSIP. Physiological findings typically demonstrate a restrictive ventilatory defect with decreased gas transfer; little difference exists between UIP and NSIP. High resolution computed tomography (HRCT) scans are more likely to show honeycombing with UIP and a ground-glass pattern with NSIP, however, either of these findings can be seen with UIP or NSIP. The most striking differential feature between NSIP and UIP is the markedly better prognosis for patients with NSIP, a finding that cannot be explained by baseline differences in physiology or radiographic features. In this article we explore the clinical, physiological, and radiographic features of NSIP. We also review available information regarding response to therapy and prognosis.

Timing of lung transplantation for patients with fibrotic lung diseases.

Idiopathic pulmonary fibrosis (IPF) is typically a fatal disease that fails to respond to medical therapy. For these patients lung transplantation offers the promise of improved quality and duration of life. The initial reports of successful transplantation for IPF date back to the mid-1980s although recent data suggest IPF patients make up nearly 20% of all single lung transplants. The survival rates following lung transplantation for IPF are estimated at 67% for 1 year, 52% for 3 years, and 35% for 5 years. Mortality rates following lung transplantation for IPF are higher than emphysema, but are generally comparable to primary pulmonary hypertension. Given the relatively high mortality following transplant the decision of when to transplant a patient is of paramount importance. Although individual patients differ, generalizations predicting a poor prognosis include the diagnosis of usual interstitial pneumonia (UIP), a forced vital capacity or total lung capacity of less than 65% predicted, a diffusion capacity for carbon monoxide (DL(CO)) less than 45% of predicted, and the presence of extensive honeycombing on high-resolution computed tomographic scans. The presence of any of these features should prompt the patient and physician to consider lung transplantation as a potential therapeutic modality. Patients with interstitial lung disease related to collagen vascular diseases or other causes need to be considered on an individual basis; their prognosis is usually better than patients with IPF, and the potential for systemic involvement may preclude listing for lung transplantation.

Respiratory response during arm elevation in isolated diaphragm weakness.

Upper extremity exercise is associated with a significant metabolic and ventilatory cost that is particularly evident in patients with severe chronic airflow obstruction. In these patients abnormal ventilatory muscle recruitment has been hypothesized to relate to impaired diaphragm function resulting from hyperinflation. Similar data have never been reported in patients with isolated diaphragm weakness but without airflow obstruction or hyperinflation, a group that would ideally define the role of diaphragm function during arm elevation (AE). We prospectively studied 15 patients with isolated diaphragm weakness of varying severity (Pdi(sniff), 31.74 +/- 3.75 cm H(2)O) as contrasted with eight normal subjects (Pdi(sniff), 111. 77 +/- 13.35 cm H(2)O) of similar age. Patients with diaphragm weakness demonstrated significant lung volume restriction with normal DL(CO)/VA. There was no difference in resting oxygen consumption (V O(2)), carbon dioxide production (V CO(2)), minute ventilation (V E), and tidal volume (VT) between the two groups; however, a borderline difference in resting breathing frequency (f(b)) (p = 0.056) was evident. Both groups demonstrated a rise in V O(2), V CO(2), and V E during 2 min of AE anteriorly. Normal subjects demonstrated a statistically significant rise in VT but a statistically insignificant rise in f(b) during AE. In contrast, patients with diaphragm weakness demonstrated a statistically significant rise in f(b) during AE but a statistically insignificant rise in VT. In patients the observed rise in VT directly correlated with baseline Pdi(sniff) (r = 0.59, p = 0.02) and Pdi(max) (r = 0.81, p = 0.002). Both groups demonstrated a rise in Pdi during AE. The rise in Pdi during AE directly correlated to Pdi(sniff) in the patients (r = 0.69, p = 0.004). Observed end-expiratory Ppl rose during arm elevation in both the patient group and in the normal control group, but no evidence of a differential response to AE was found. In those patients with greater diaphragm weakness (Pdi(sniff) < 30 cm H(2)O), abnormal respiratory muscle function (lesser rise in Pdi) and a lesser increase in VT during AE were more evident. These data highlight the importance of diaphragm function in determining the metabolic and respiratory muscle response to arm elevation.