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1.  Impact of a disease-management program on symptom burden and health-related quality of life in patients with idiopathic pulmonary fibrosis and their care partners 
Patients were recruited from the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, located within the University of Pittsburgh Medical Center. Idiopathic pulmonary fibrosis results in scarring of the lung and respiratory failure, and has a median survival of 3 to 5 years from the time of diagnosis. The purpose of this study was to determine whether patients with idiopathic pulmonary fibrosis and their care partners could be more optimally managed by a disease-management intervention entitled “Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management,” which nurses delivered using the format of a support group. We hypothesized that participation would improve perceptions of health-related quality of life (HRQoL) and decrease symptom burden.
Subjects were 42 participants randomized to an experimental (10 patient/care partner dyads) or control (11 patient/care partner dyads) group. Experimental group participants attended the 6-week program, and controls received usual care. Before and after the program, all participants completed questionnaires designed to assess symptom burden and HRQoL. Patients and care partners in the intervention group were also interviewed in their home to elicit information on their experience after participating in the Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management.
After the intervention, experimental group patients rated their HRQoL less positively (P = .038) and tended to report more anxiety (P = .077) compared with controls. Care partners rated their stress at a lower level (P = .018) compared with controls. Course evaluations were uniformly positive. Post-study qualitative interviews with experimental group participants suggested benefits not exemplified by these scores. Patient participants felt less isolated, were able to put their disease into perspective, and valued participating in research and helping others.
Further exploration of the impact of disease-management interventions in patients with advanced lung disease and their care partners is needed using both qualitative and quantitative methodology. Disease-management interventions have the potential to positively affect patients with advanced lung disease and their care partners.
PMCID: PMC3467095  PMID: 20561836
2.  Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study 
Pulmonary Circulation  2013;3(1):89-94.
Survival rates for patients with idiopathic pulmonary arterial hypertension (IPAH) have improved with the introduction of PAH-specific therapies. However, the time between patient-reported onset of symptoms and a definitive diagnosis of IPAH is consistently delayed. We conducted a retrospective, multi-center, descriptive investigation in order to (a) understand what factors contribute to persistent diagnostic delays, and (b) examine the time from initial symptom onset to a definitive diagnosis of IPAH. Between January 2007 and December 2008, we enrolled consecutively diagnosed adults with IPAH from four tertiary referral centers in Australia. Screening of patient records and “one-on-one” interviews were used to determine the time from patient-described initial symptoms to a diagnosis of IPAH, confirmed by right heart catheterization (RHC). Thirty-two participants (69% female) were studied. Mean age at symptom onset was 56 ± 16.4 years and 96% reported exertional dyspnea. Mean time from symptom onset to diagnosis was 47 ± 34 months with patients subsequently aged 60 ± 17.3 years. Patients reported 5.3 ± 3.8 GP visits and 3.0 ± 2.1 specialist reviews before being seen at a pulmonary hypertension (PH) center. Advanced age, number of general practitioner (GP) visits, heart rate, and systolic blood pressure at the time of diagnosis were significantly associated with the observed delay. We found a significant delay of 3.9 years from symptom onset to a diagnosis of IPAH in Australia. Exertional dyspnea is the most common presenting symptom. Current practice within Australia does not appear to have the specific capacity for timely, multi-factorial evaluation of breathlessness and potential IPAH.
PMCID: PMC3641745  PMID: 23662179
diagnosis; epidemiology; pulmonary hypertension; pulmonary arterial hypertension
3.  Healthcare-seeking behavior, treatment delays and its determinants among pulmonary tuberculosis patients in rural Nigeria: a cross-sectional study 
Nigeria ranks fourth among 22 high tuberculosis (TB) burden countries. Although it reached 99% DOTS coverage in 2008, current case detection rate is 40%. Little is known about delays before the start of TB therapy and health-seeking behaviour of TB patients in rural resource-limited settings. We aimed to: 1) assess healthcare-seeking behaviour and delay in treatment of pulmonary TB patients, 2) identify the determinants of the delay in treatment of pulmonary TB.
We conducted a cross-sectional study of adult new pulmonary TB patients notified to the National Tuberculosis Control Programme (NTP) by three rural (two mission/one public) hospitals. Data on health-seeking and delays were collected using a standardised questionnaire. We defined patient delay as the interval (weeks) between the onset of cough and the first visit to any health provider, and health system delay as the time interval (weeks) between patient's first attendance to any health provider, and the onset of treatment. Total delay is the sum of both delays. Multiple linear regression models using nine exposure variables were built to identify determinants of delays.
Of 450 patients (median age 30 years) enrolled, most were males (55%), subsistent farmers (49%), rural residents (78%); and 39% had no formal education. About 84% of patients reported first consulting a non-NTP provider. For such patients, the first facilities visited after onset of symptoms were drug shops (79%), traditional healers (10%), and private hospitals (10%). The median total delay was 11 (IQR 9–16) weeks, patient delay 8 (IQR 8–12) and health system (HS) delay 3 (IQR 1–4) weeks. Factors associated with increased patient delay were older age (P <0.001) longer walking distance to a public facility (<0.001), and urban residence (P <0.001). Male gender (P = 0.001) and an initial visit to a non-NTP provider (P = 0.025) were independent determinants of prolonged HS delay. Those associated with longer total delay were older age (P <0.001), male gender (P = 0.045), and urban residence (P<0.001).
Overall, TB treatment delays were high; and needs to be reduced in Nigeria. This may be achieved through improved access to care, further education of patients, engagement of informal care providers, and strengthening of existing public-private partnerships in TB control.
PMCID: PMC3560225  PMID: 23327613
Tuberculosis; Health-seeking delays; Private sector; Public sector; Rural; Low-resource setting
4.  MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis 
PLoS Medicine  2008;5(4):e93.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.
Methods and Findings
We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins—MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A—that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%–100%) and specificity of 98.1% (95% CI 89.9%–100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%–100%) and specificity of 87.2% (95% CI 72.6%–95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%).
Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.
Naftali Kaminski and colleagues find increased levels of specific proteins in the bloodstream of individuals with idiopathic pulmonary fibrosis, and suggest that these proteins may ultimately provide a biomarker for the disease.
Editors' Summary
Idiopathic pulmonary fibrosis (IPF) is a serious disease in which the lungs become progressively scarred or thickened for unknown reasons. In healthy people, air is taken in through the mouth or nose and travels down the windpipe into tubes in the lungs called the airways. Each airway has many small branches that end in alveoli, tiny air sacs with thin walls that are surrounded by small blood vessels called capillaries. When air reaches the alveoli, the oxygen in it passes into the bloodstream and is taken to the organs of the body to keep them working. In IPF, the alveoli and the space around them (the “interstitial” area) gradually become scarred and thickened, which stops oxygen's movement into the bloodstream. When only small areas of the lung are scarred, IPF may cause no symptoms. But, as more of the lung becomes damaged, IPF eventually causes breathlessness, even when resting. There is no effective treatment for IPF, although steroids and drugs that suppress the body's immune system are often tried in an attempt to slow its progression. On average, half of the people with IPF die within three years of diagnosis, often from respiratory or heart failure.
Why Was This Study Done?
It can be difficult to diagnose IPF—there are many lung diseases with similar symptoms, including numerous other interstitial lung diseases—and currently, physicians can only follow the progression of IPF by repeatedly testing their patients' lung function or by doing multiple chest X-rays. If proteins could be identified whose level in blood indicated disease activity (so-called “peripheral blood biomarkers”), it would be easier to diagnose and monitor patients. In addition, the identification of such biomarkers might suggest new drug targets for the treatment of IPF. In this study, the researchers look for peripheral blood biomarkers in IPF by using a “multiplex analysis” system to measure the level of several proteins in patient blood samples simultaneously.
What Did the Researchers Do and Find?
The researchers measured the levels of 49 plasma proteins (plasma is the fluid part of blood) in 74 patients with IPF and 53 healthy people (controls) and used a technique called “recursive partitioning” to define a five-protein signature that distinguished patients from unaffected study participants (controls). Matrix metalloproteinase 7 (MMP7) and MMP1—the two plasma proteins whose levels were most increased in patients with IPF compared to controls—were key components of this signature. Concentrations of MMP7 and MMP1 were higher in bronchoalveolar lavage samples (fluid obtained by washing out the lungs with saline) and in lung tissue samples from patients with IPF than in similar samples taken from healthy individuals. Plasma concentrations of MMP7 and MMP1 were significantly higher in patients with IPF than in patients with hypersensitivity pneumonitis, an interstitial lung disease that mimics IPF, but not increased in patients with chronic obstructive pulmonary disease or sarcoidosis, two other lung diseases. In an independent validation group, patients with IPF and familial pulmonary fibrosis had increased plasma concentrations of MMP7 and MMP1 that correlated with the severity of their disease. In addition, MMP7 concentrations were raised in close relatives of people with familial pulmonary fibrosis who had normal lung function tests but some lung scarring.
What Do These Findings Mean?
These findings provide evidence for a protein signature in the blood for IPF and suggest MMP1 and MMP7 may be useful as biomarkers for IPF. These two matrix metalloproteinases have previously been suggested to be involved in the development of IPF. However, additional work is probably needed to confirm that increased plasma concentrations MMP7 and MMP1 are specific for IPF, since it may be that these markers will not distinguish IPF from other interstitial lung diseases.
Additional Information.
Please access these Web sites via the online version of this summary at
Read a related PLoS Medicine Perspective article
The MedlinePlus Encyclopedia has a page on idiopathic pulmonary fibrosis (in English and Spanish) and on pulmonary fibrosis
The US National Heart Lung and Blood Institute and the British Lung Foundation also provide information on IPF for patients and relatives
Some of the researchers involved in this study provide more details about what might go wrong in IPF in a recent PLoS Medicine article
PMCID: PMC2346504  PMID: 18447576
5.  Pulmonary rehabilitation in idiopathic pulmonary fibrosis: A call for continued investigation☆ 
Respiratory medicine  2008;102(12):1675-1680.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that afflicts patients with relentlessly progressive shortness of breath [Joint Statement of the American Thoracic Society and the European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med 2000;161:646–641]. Despite nearly 30 years of intense investigation, effective therapy for IPF remains elusive; median survival rates have stubbornly remained less than five years from the time of diagnosis [Bjoraker JA, Ryu JH, Edwin MK, Meyers J, Tazelaar H, Schroeder D, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199–2032, Flaherty KR, Thwaite E, Kazerooni EA, Gross B, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003;58:143–483], and no medical therapy has been proved to be in any way effective for the treatment of this disease. Without medications that help IPF patients live longer, an important question to ask is whether there are interventions that might allow these people to live better—to be more active; to experience less dyspnea, less depression, less anxiety; to possess a greater sense of control over their disease; and to have better quality of life. Pulmonary rehabilitation helps to accomplish many of these goals in patients with chronic obstructive pulmonary disease, and emerging data suggest that it may do the same for patients with IPF.
PMCID: PMC3673288  PMID: 18848771
Pulmonary fibrosis; Pulmonary rehabilitation; Dyspnea
6.  Idiopathic pulmonary fibrosis: New insights to functional characteristics at diagnosis 
Although idiopathic pulmonary fibrosis is the most severe of the idiopathic lung diseases, it has not been characterized in detail. This retrospective study analyzed lung function data collected from 93 patients at a tertiary care centre in Kingston, Ontario, in an attempt to more clearly delineate the physiological abnormalities present in the condition.
The lung function of patients with idiopathic pulmonary fibrosis (IPF) has not been characterized in detail.
To characterize the heterogeneous physiological abnormalities that exist in patients with IPF during their initial clinical evaluation.
Lung function tests from 93 patients, performed within six months of the initial diagnosis of IPF, were obtained from a referral pulmonary function laboratory at a tertiary care hospital in Canada. A restrictive pattern was defined as total lung capacity (TLC) <95th percentile of predicted value. Patients with obstructive lung disease, lung cancer, emphysema and other restrictive lung diseases were excluded.
On diagnosis, 73% of patients with IPF had a restrictive pattern, with a mean TLC of 72% of predicted. Mean forced vital capacity (FVC) was 71% and 44% of patients had an FVC <95th percentile. Mean diffusing capacity for carbon monoxide (DLco) was 60% and DLco/alveolar volume (VA) 92% of predicted. Increased severity of restriction – based on TLC – was associated with lower DLco (74% of predicted in mild restriction and 39% of predicted in severe restriction) and higher forced expiratory volume in 1 s (FEV1)/FVC ratio (82% of predicted in mild restriction and 90% of predicted in severe restriction) but not with age (76 years in mild restriction and 69 years in severe restriction). Regardless of severity of restriction, the average DLco/VA (≥86% of predicted) remained within normal limits.
One in four patients with IPF had normal TLC and more than one-half had a normal FVC during initial evaluation. As the severity of the restriction increased, FEV1/FVC increased, DLco decreased but DLco/VA remained normal.
PMCID: PMC4128468  PMID: 24712014
Idiopathic pulmonary fibrosis; Lung function; Restrictive disease
7.  Delayed diagnosis and associated factors among new pulmonary tuberculosis patients diagnosed at the emergency department of a tertiary care hospital in Porto Alegre, South Brazil: a prospective patient recruitment study 
BMC Infectious Diseases  2013;13:538.
Control of tuberculosis (TB) depends on early diagnosis and treatment at the primary health care level. However, many patients are still diagnosed late with TB at hospitals. The present study aimed to investigate the delay in diagnosis of TB patients at the emergency department.
This was a prospective study in a general, tertiary care, university-affiliated hospital of a city with a high prevalence of TB in Brazil. New TB patients ≥ 14 years diagnosed with pulmonary TB at the emergency department of Hospital de Clínicas de Porto Alegre were prospectively recruited between February 2010 and January 2012. The consenting patients meeting our inclusion criteria were interviewed using a pre-tested questionnaire. We evaluated the delay in time until diagnosis and identified factors associated with delayed diagnosis (patient and health care system delays).
We included 153 patients. The median total time of delay, patient delay, and health care system delay were 60 (interquartile range [IQR]: 30–90.5 days), 30 (lQR: 7–60 days), and 18 (IQR: 9–39.5 days) days, respectively. The factors that were independently associated with patient delay (time ≥ 30 days) were crack (odds ratio [OR] = 4.88, p = 0.043) and cocaine (OR = 6.68, p = 0.011) use. The factors that were independently associated with health care system delay (time ≥ 18 days) were weight loss (OR = 2.76, p = 0.025), miliary pattern (OR = 5.33, p = 0.032), and fibrotic changes (OR = 0.12, p = 0.013) on chest X-ray.
Patient delay appears to be the main problem in this city with a high prevalence of TB in Brazil. The main factor associated with patient delay is drug abuse (crack and cocaine). Our study shows substance abuse programs need to be aware of control of TB, with health interventions focusing on TB education programs.
PMCID: PMC3840591  PMID: 24219185
Tuberculosis; Risk factors; Patient delay; Health care system delay; Diagnosis
8.  A Common MUC5B Promoter Polymorphism and Pulmonary Fibrosis 
The New England Journal of Medicine  2011;364(16):1503-1512.
The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk.
Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue.
Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10−15; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10−37). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis.
A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dys-regulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3379886  PMID: 21506741
9.  Idiopathic pulmonary fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.
PMCID: PMC2330030  PMID: 18366757
10.  Does delay in diagnosing colorectal cancer in symptomatic patients affect tumor stage and survival? A population-based observational study 
BMC Cancer  2010;10:332.
Diagnosing colorectal cancer (CRC) at an early stage improves survival. To what extent any delay affects outcome once patients are symptomatic is still unclear.
Our objectives were to evaluate the association between diagnostic delay and survival in symptomatic patients with early stage CRC and late stage CRC.
Prospective population-based observational study evaluating daily clinical practice in Northern Holland. Diagnostic delay was determined through questionnaire-interviews. Dukes' stage was classified into two groups: early stage (Dukes A or B) and late stage (Dukes C or D) cancer. Patients were followed up for 3.5 years after diagnosis.
In total, 272 patients were available for analysis. Early stage CRC was present in 136 patients while 136 patients had late stage CRC. The mean total diagnostic delay (SE) was 31 (1.5) weeks in all CRC patients. No significant difference was observed in the mean total diagnostic delay in early versus late stage CRC (p = 0.27).
In early stage CRC, no difference in survival was observed between patients with total diagnostic delay shorter and longer than the median (Kaplan-Meier, log-rank p = 0.93).
In late stage CRC, patients with a diagnostic delay shorter than the median had a shorter survival than patients with a diagnostic delay longer than the median (log-rank p = 0.01). In the multivariate Cox regression model with survival as dependent variable and median delay, age, open access endoscopy, number and type of symptoms as independent variables, the odd's ratio for survival in patients with long delay (>median) versus short delay (≤median) was 1.8 (95% confidence interval (CI) 1.1 to 3.0; p = 0.01). Tumor-site was not associated with patient survival. When separating late stage CRC in Dukes C and Dukes D tumors, a shorter delay was associated with a shorter survival in Dukes D tumors only and not in Dukes C tumors.
In symptomatic CRC patients, a longer diagnostic and therapeutic delay in routine clinical practice was not associated with an adverse effect on survival. The time to CRC diagnosis and initiation of treatment did not differ between early stage and late stage colorectal cancer.
PMCID: PMC2907342  PMID: 20584274
11.  Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis 
The European Respiratory Journal  2011;39(2):359-365.
The supplemental oxygen flow rate is a common bedside measure of gas exchange impairment. We aimed to determine whether a titrated oxygen requirement predicted mortality in idiopathic pulmonary fibrosis.
We examined 104 adults with idiopathic pulmonary fibrosis enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The titrated oxygen requirement was defined as the lowest oxygen flow rate required to maintain an oxyhemoglobin saturation of 96% while standing. Cox proportional hazards models and time-dependent receiver operating characteristic curves were used to examine survival time.
A higher titrated oxygen requirement was associated with a greater mortality rate independent of forced vital capacity and six-minute walk test results in idiopathic pulmonary fibrosis (adjusted hazard ratio per 1 L/min = 1.10, 95% confidence interval 1.01 to 1.20). The titrated oxygen requirement was at least as accurate as pulmonary function and six-minute walk testing at predicting 1-year mortality. Findings were similar in other interstitial lung diseases.
The titrated oxygen requirement is a simple, inexpensive bedside measurement that aids prognostication in idiopathic pulmonary fibrosis.
PMCID: PMC3236811  PMID: 21885386
Idiopathic pulmonary fibrosis; Interstitial lung diseases; Outcome prediction; Pulmonary fibrosis; Pulmonary gas exchange
12.  Patient-reported outcome 2 years after lung transplantation: does the underlying diagnosis matter? 
Transplantation has the potential to produce profound effects on survival and health-related quality of life (HRQL). The inclusion of the patient’s perspective may play an important role in the assessment of the effectiveness of lung transplantation. Patient perspectives are assessed by patient-reported outcome measures, including HRQL measures. We describe how patients’ HRQL among different diagnosis groups can be used by clinicians to monitor and evaluate the outcomes associated with transplantation.
Consecutive lung transplant recipients attending the lung transplant outpatient clinic in a tertiary institution completed the 15-item Health Utilities Index (HUI) questionnaire on a touchscreen computer. The results were available to clinicians at every patient visit. The HUI3 covers a range of severity and comorbidities in eight dimensions of health status. Overall HUI3 scores are on a scale in which dead = 0.00 and perfect health = 1.00; disability categories range from no disability = 1 to severe disability <0.70. Single-attribute and overall HUI3 scores were used to compare patients’ HRQL among different diagnosis groups. Random-effect models with time since transplant as a random variable and age, gender, underlying diagnoses, infections, and broncholitis obliterans syndrome as fixed variables were built to identify determinants of health status at 2-years posttransplantation.
Two hundred and fourteen lung transplant recipients of whom 61% were male with a mean age of 52 (19–75) years were included in the study. Chronic obstructive pulmonary disease and cystic fibrosis patients displayed moderate disability, while pulmonary fibrosis and pulmonary arterial hypertension patients displayed severe disability. Patients with chronic obstructive pulmonary disease had the worst pain level, whereas patients with pulmonary fibrosis had the worst emotion and cognition levels. A random-effect model confirmed that development of broncholitis obliterans syndrome was the most important determinant of health status (P = 0.03) compared to other variables, such as cytomegalovirus infections and underlying diagnoses.
Descriptions of patients’ HRQL among different diagnosis groups could be used by clinicians to assist individualized patient care.
PMCID: PMC3508652  PMID: 23204877
patient-reported outcomes; health-related quality of life measures; underlying diagnoses in lung transplant recipients; health utilities index
13.  International collaboration: a retrospective study examining the survival of Irish citizens following lung transplantation in both the UK and Ireland 
BMJ Open  2012;2(2):e000605.
Prior to 2005, Irish citizens had exclusively availed of lung transplantation services in the UK. Since 2005, lung transplantation has been available to these patients in both the UK and Ireland. We aimed to evaluate the outcomes of Irish patients undergoing lung transplantation in both the UK and Ireland.
We retrospectively examined the outcome of Irish patients transplanted in the UK and Ireland. Lung allocation score (LAS) was used as a marker of disease severity.
A total of 134 patients have undergone transplantation. 102 patients underwent transplantation in the UK and 32 patients in Ireland. In total, 52% were patients with cystic fibrosis, 19% had emphysema and 15% had idiopathic pulmonary fibrosis. In Ireland, 44% of the patients suffered from idiopathic pulmonary fibrosis, 31% had emphysema and 16% had cystic fibrosis. A total of 96 double sequential transplants and 38 single transplants have been performed. LAS of all patients undergoing lung transplantation was 37.8 (±1.02). The mean LAS for patients undergoing lung transplantation in Ireland was 44.7 (±3.1), and 35 (±0.4) for patients undergoing lung transplantation in the UK (p<0.05). The 5-year survival of all Irish citizens who had undergone lung transplantation was 73%. The 5-year survival of Irish patients transplanted in the UK was 69% and in Ireland was 91% and 73% at 5.01 years.
International collaboration can be achieved, as evidenced by the favourable outcomes seen in Irish citizens who undergo lung transplantation in both the UK and Ireland. Irish citizens undergoing lung transplantation in Ireland have a higher LAS score. Despite excellent outcomes, an intention-to-treat analysis of the treatment utility (transplant) indicates the limited effectiveness of lung transplantation in Ireland and emphasises the need for increased rates of lung transplantation.
Article summary
Article focus
Determine the survival outcomes following lung transplantation for Irish patients undergoing lung transplantation in experienced UK programmes and a newly established transplant programme in Ireland.
Compare recipient lung allocation scores (a marker of disease severity) between programmes.
Key messages
International collaboration for complex medical services can be achieved, as demonstrated by the favourable outcomes seen in Irish citizens who undergo lung transplantation in both in the UK and Ireland.
Irish citizens undergoing lung transplantation in Ireland have a higher LAS (44.7 (±3.1) vs 37.8 (±1.02)), suggesting that local services can accommodate patients with a greater disease burden.
Despite excellent outcomes, an intention-to-treat analysis of the treatment utility (transplant) indicates the limited effectiveness of lung transplantation in Ireland and emphasises the need for increased rates of lung transplantation.
Strengths and limitations of this study
This study is unique in that it gives insight into an Anglo-Irish collaboration delivering a successful highly complex service to severely ill patients. It shows excellent outcomes and offers a platform on which further development may result in increase levels of transplant activity benefiting both Ireland and the UK. A limitation of the study is the modest number of lung transplants in Ireland.
PMCID: PMC3317140  PMID: 22457478
14.  Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation 
Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17–dependent cellular immunity after lung transplantation.
Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD.
Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. PaO2/FiO2 index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity.
Measurements and Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4+ T-cell and monocyte mediated, and dependent on IL-17, IL-1β, and tumor necrosis factor (TNF)-α. PaO2/FiO2 indices were impaired significantly 6–72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower PaO2/FiO2, increased local TNF-α and IL-1β production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts.
Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.
PMCID: PMC2267340  PMID: 18174545
lung transplantation; primary graft dysfunction; collagen type V; autoimmunity; memory T cell
15.  Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature 
BMC Pulmonary Medicine  2014;14:139.
Idiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival.
A systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients.
Median survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival.
IPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse.
PMCID: PMC4151866  PMID: 25127540
Idiopathic pulmonary fibrosis; Systematic review; Survival; Lung transplantation
16.  Idiopathic Systemic Capillary Leak Syndrome (Clarkson's Disease): The Mayo Clinic Experience 
Mayo Clinic Proceedings  2010;85(10):905-912.
OBJECTIVE: To determine clinical features, natural history, and outcome of a well-defined cohort of 25 consecutive patients with idiopathic systemic capillary leak syndrome (SCLS) evaluated at a tertiary care center.
PATIENTS AND METHODS: Records of patients diagnosed as having SCLS from November 1, 1981, through April 30, 2008, were reviewed. Descriptive statistics were used to analyze patient demographics, clinical features, complications, and therapeutic interventions.
RESULTS: Of the 34 patients whose records were reviewed, 25 fulfilled all diagnostic criteria for SCLS. The median age at diagnosis of SCLS was 44 years. Median follow-up of surviving patients was 4.9 years, and median time to diagnosis from symptom onset was 1.1 years (interquartile range, 0.5-4.1 years). Flulike illness or myalgia was reported by 14 patients (56%) at onset of an acute attack of SCLS, and rhabdomyolysis developed in 9 patients (36%). Patients with a greater decrease in albumin level had a higher likelihood of developing rhabdomyolysis (p=.03). Monoclonal gammopathy, predominantly of the IgG-κ type, was found in 19 patients (76%). The progression rate to multiple myeloma was 0.7% per person-year of follow-up. The overall response rate to the different therapies was 76%, and 24% of patients sustained durable (>2 years) complete remission. The estimated 5-year overall survival rate was 76% (95% confidence interval, 59%-97%).
CONCLUSION: Systemic capillary leak syndrome, a rare disease that occurs in those of middle age, is usually diagnosed after a considerable delay from onset of symptoms. The degree of albumin decrement during an attack correlates with development of rhabdomyolysis. A reduction in the frequency and/or the severity of attacks was seen in nearly three-fourths of patients who were offered empirical therapies. The rate of progression to multiple myeloma appears to be comparable to that of monoclonal gammopathy of undetermined significance.
A review of records of patients with this rare disease, which occurs during middle age, showed that systemic capillary leak syndrome is usually diagnosed after a considerable delay from onset of symptoms.
PMCID: PMC2947962  PMID: 20634497
17.  Disparities in Access to Lung Transplantation for Patients with Cystic Fibrosis by Socioeconomic Status 
Rationale: Although previous studies suggest that access to care for patients with cystic fibrosis (CF) does not vary appreciably by socioeconomic status (SES), disparities with respect to access to lung transplantation for patients with CF are largely unknown.
Objectives: To determine whether access to lung transplantation for patients with CF differs according to SES.
Methods: Observational study involving 2,167 adult patients with CF from the CF Foundation Patient registry who underwent their first lung transplant evaluation between 2001 and 2009. The primary outcome was acceptance for lung transplant after initial evaluation. The main SES indicator was Medicaid status. Alternate SES indicators included race, educational attainment, ZIP code–level median household income, and driving time from residence to closest lung transplant center.
Measurements and Main Results: The odds that Medicaid recipients were not accepted for lung transplant were 1.56-fold higher (95% confidence interval [CI], 1.27–1.92) than patients without Medicaid, after multivariate adjustment for demographic characteristics, disease severity, and potential contraindications to lung transplant, and before or after use of the lung allocation score. This association was independent of other SES indicators, including race, educational attainment, ZIP code–level median household income, and driving time to closest transplant center (odds ratio [OR] = 1.37; 95% CI, 1.10–1.72). Patients not completing high school (OR = 2.37; 95% CI, 1.49–3.79) and those residing in the lowest (vs. highest) ZIP code median household income category (OR = 1.39; 95% CI, 1.01–1.93) also experienced a higher odds of not being accepted for lung transplant in multivariate analysis.
Conclusions: In this nationally representative study of adult patients with CF, multiple indicators of low SES were associated with higher odds of not being accepted for lung transplant.
PMCID: PMC3530210  PMID: 22983958
cystic fibrosis; lung transplantation; socioeconomic status; health status disparities; health care access
18.  Lung transplant for interstitial lung disease: outcomes for single versus bilateral lung transplantation† 
This study was undertaken to evaluate outcomes for single (SLT) vs. bilateral lung transplantation (BLT) in patients with interstitial lung disease (ILD). One hundred and eleven patients with ILD who underwent lung transplantation between January 1993 and March 2009 were evaluated. Recipients with BLT were younger (43 ± 12 vs. 57 ± 7 years), and significantly more patients with non-idiopathic pulmonary fibrosis (IPF) received BLT (50%) vs. patients with IPF (18%). BLT recipients had a significantly longer mean waitlist time (240 vs. 125 days), significantly higher systolic (51 ± 18 vs. 40 ± 11 mmHg) pulmonary artery pressures, were placed on cardiopulmonary bypass more frequently (67 vs. 31%), had a higher incidence of primary graft dysfunction (63 vs. 17%), more frequently were given prolonged peri-operative inhaled nitric oxide and more frequently required prolonged post-operative mechanical ventilatory support (6.0 vs. 1.7 days). Additionally, BLT recipients had a significantly longer intensive care unit (8 vs. 4 days) and hospital (24 vs. 15 days) length of stay. We did not detect a difference in survival (Kaplan–Meier) for SLT vs. BLT. Our findings suggest that outcomes for SLT for patients with ILD are comparable or somewhat superior to those for BLT, and short- and long-term survival are not significantly different for the two procedures.
PMCID: PMC3290370  PMID: 22180607
Lung transplantation; Idiopathic pulmonary fibrosis; Interstitial lung disease; Lung allocation score; Single lung transplant; Bilateral lung transplant
19.  Patient and heath system delays in the diagnosis and treatment of new and retreatment pulmonary tuberculosis cases in Malawi 
BMC Infectious Diseases  2014;14:132.
Tuberculosis (TB) control remains a challenge in Malawi despite the National TB Control Program since 1984. This study aimed at measuring patient and health system delays and identifying factors associated with these delays.
A cross-sectional survey of 588 pulmonary TB patients was conducted in three TB centres in Blantyre, Lilongwe, and Mzuzu, between July and December 2011 using a semi-structured questionnaire. Patient delay was defined as the time interval between the onset of TB symptom(s) (a common symptom being coughing) to the first visit to any health provider. Health system delay was the interval from the first care-seeking visit at any health provider to the initiation of anti-tuberculosis treatment. Participants were invited to participate in the study during intensive phase of treatment. The characteristics associated with patient and health system delays were analyzed.
The median patient delay was 14 days for both new and retreatment TB cases (interquartile range [IQR] 14 – 28 and 7 – 21, respectively). The median health system delay was 59 days (IQR 26 – 108) for new and 40.5 days (IQR 21–90) for retreatment cases. Factors associated with longer patient delay in new cases included primary education (adjusted odds ratio [AOR] 2.2, 95% CI 1.3 – 3.9) and knowledge that more than three weeks of coughing is a sign of TB (AOR 1.9, 1.1 – 3.3). In retreatment cases, distance >10 Km (AOR 3.3, 1.1 – 9.6) and knowledge that more than three weeks of coughing is a sign of TB (AOR 3.7, 1.3 – 10.7; p < 0.05) were significant factors. Making the first visit to a health centre (OR 1.9, 0.9 – 3.8) or a drug store/ traditional healer (OR 5.1, 1.1 – 21.7) in new TB cases were associated with a longer health system delay (p < 0.05) while smear negative (OR 6.4, 1.5 – 28.3), and smear unknown or not done (OR 6.1, 1.3 – 26.9) among retreatment cases were associated with a longer health system delay (p < 0.05).
Effective management and new diagnostic techniques are needed especially among retreatment cases. It is also needed to address geographic barriers to accessing care and increasing TB awareness in the community.
PMCID: PMC3976046  PMID: 24606967
Patient delay; Health system delay; Tuberculosis; Case detection
20.  The Genetic Approach in Pulmonary Fibrosis 
Multiple investigators have undertaken genetic studies in idiopathic pulmonary fibrosis populations in attempts to define genetic links to disease in hopes that this would improve understanding of disease pathogenesis and target pathways for therapy. Multiple genes have been evaluated using a candidate gene approach with limited success, with results suggesting a disease modifier effect rather than a disease causing effect. Using this approach, associations have been observed between idiopathic pulmonary fibrosis and specific polymorphisms in genes encoding interleukin-1 receptor antagonist, tumor necrosis factor-α, and complement receptor 1. Recently investigators have used familial pulmonary fibrosis cohorts to evaluate for genetic mutations associated with idiopathic pulmonary fibrosis. Using one pulmonary fibrosis kindred, a mutation in the gene encoding surfactant protein C was identified as the cause of pulmonary fibrosis in this family. Subsequently, another individual with idiopathic pulmonary fibrosis was identified with a different mutation in surfactant protein C. Though rarely found in patients with idiopathic pulmonary fibrosis, these surfactant protein C mutations highlight the importance of the alveolar epithelium in disease pathogenesis. A recent collaboration between investigators at three major centers has resulted in the largest collection of families with pulmonary fibrosis to date, with hopes that this effort will identify genetic mutations associated with idiopathic pulmonary fibrosis. If genetic links to idiopathic pulmonary fibrosis are defined in this study, then the pathways involved with these genes and gene products can be targeted by investigators to help identify potential treatment options for this disease.
PMCID: PMC2658686  PMID: 16738199
familial pulmonary fibrosis; idiopathic pulmonary fibrosis; surfactant protein C
21.  Lung transplantation in telomerase mutation carriers with pulmonary fibrosis 
The European Respiratory Journal  2014;44(1):178-187.
Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined.
We gathered an international series of telomerase mutation carriers who underwent lung transplant in the USA, Australia and Sweden.
The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001).
Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.
Telomerase mutation carriers with IPF may be prone to complications from their underlying telomere syndrome after LTx
PMCID: PMC4076528  PMID: 24833766
22.  Bilateral Lung Transplantation Offers Better Long-Term Survival, Compared With Single-Lung Transplantation, for Younger Patients With Idiopathic Pulmonary Fibrosis 
The Annals of Thoracic Surgery  2011;91(1):244-249.
Single-lung transplantation (SLT) and bilateral lung transplantation (BLT) are both good options for patients with end-stage lung disease secondary to idiopathic pulmonary fibrosis. It is, however, unclear whether BLT offers any survival advantage over SLT. The purpose of our study was to evaluate a large group of patients to determine if either SLT or BLT officered a long-term survival advantage for patients with IPF.
This was an Institutional Review Board-approved retrospective analysis of the United Network of Organ Sharing database from 1987 to 2008. Survival was determined using Kaplan-Meir estimates and the effect of laterality was determined by Cox proportional hazards and propensity analyses.
Lung transplantation for idiopathic pulmonary fibrosis was performed in 3,860 patients (2,431 SLTs and 1429 BLTs). Multivariate and propensity analysis failed to show any survival advantage for BLT (hazard ratio = 0.90, 95% confidence interval = 0.78 to 1.0, p = 0.11). One-year conditional survival favored BLT (hazard ratio 0.73, 95% confidence interval 0.60 to 0.87, p = 0.00064). Risk factors for early death included recipient age over 57 and donor age over 36 years.
Bilateral lung transplantation should be considered for younger patients with idiopathic pulmonary fibrosis and results may be optimized when younger donors are used.
PMCID: PMC3395073  PMID: 21172522
23.  Long-Term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at:
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website:
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website:
The objective of this health technology assessment was to determine the effectiveness, cost-effectiveness, and safety of long-term oxygen therapy (LTOT) for chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Oxygen therapy is used in patients with COPD with hypoxemia, or very low blood oxygen levels, because they may have difficulty obtaining sufficient oxygen from inspired air.
Long-term oxygen therapy is extended use of oxygen. Oxygen therapy is delivered as a gas from an oxygen source. Different oxygen sources are: 1) oxygen concentrators, electrical units delivering oxygen converted from room air; 2) liquid oxygen systems, which deliver gaseous oxygen stored as liquid in a tank; and 3) oxygen cylinders, which contain compressed gaseous oxygen. All are available in portable versions. Oxygen is breathed in through a nasal cannula or through a mask covering the mouth and nose. The treating clinician determines the flow rate, duration of use, method of administration, and oxygen source according to individual patient needs. Two landmark randomized controlled trials (RCTs) of patients with COPD established the role of LTOT in COPD. Questions regarding the use of LTOT, however, still remain.
Research Question
What is the effectiveness, cost-effectiveness, and safety of LTOT compared with no LTOT in patients with COPD, who are stratified by severity of hypoxemia?
Research Methods
Literature Search
Search Strategy
A literature search was performed on September 8, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Library, and INAHTA for studies published from January 1, 2007 to September 8, 2010.
A single clinical epidemiologist reviewed the abstracts, obtained full-text articles for studies meeting the eligibility criteria, and examined reference lists for additional relevant studies not identified through the literature search. A second clinical epidemiologist and then a group of epidemiologists reviewed articles with an unknown eligibility until consensus was established.
Inclusion Criteria
patients with mild, moderate, or severe hypoxemia;
English-language articles published between January 1, 2007 and September 8, 2010;
journal articles reporting on effectiveness, cost-effectiveness, or safety for the comparison of interest;
clearly described study design and methods;
health technology assessments, systematic reviews, RCTs, or prospective cohort observational studies;
any type of observational study for the evaluation of safety.
Exclusion Criteria
no hypoxemia
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
studies comparing different oxygen therapy regimens
studies on nocturnal oxygen therapy
studies on short-burst, palliative, or ambulatory oxygen (supplemental oxygen during exercise or activities of daily living)
Outcomes of Interest
forced expiratory volume in 1 second (FEV1)
forced vital capacity (FVC)
pulmonary hypertension
arterial partial pressure of oxygen (PaO2)
arterial partial pressure of carbon dioxide (PaCO2)
end-exercise dyspnea score
endurance time
health-related quality of life
Note: Outcomes of interest were formulated according to existing studies, with arterial pressure of oxygen and carbon dioxide as surrogate outcomes.
Summary of Findings
Based on low quality of evidence, LTOT (~ 15 hours/day) decreases all-cause mortality in patients with COPD who have severe hypoxemia (PaO2 ~ 50 mm Hg) and heart failure.
The effect for all-cause mortality had borderline statistical significance when the control group was no LTOT: one study.
Based on low quality of evidence, there is no beneficial effect of LTOT on all-cause mortality at 3 and 7 years in patients with COPD who have mild-to-moderate hypoxemia (PaO2 ~ 59-65 mm Hg)1
Based on very low quality of evidence, there is some suggestion that LTOT may have a beneficial effect over time on FEV1 and PaCO2 in patients with COPD who have severe hypoxemia and heart failure: improved methods are needed.
Based on very low quality of evidence, there is no beneficial effect of LTOT on lung function or exercise factors in patients with COPD who have mild-to-moderate hypoxemia, whether survivors or nonsurvivors are assessed.
Based on low to very low quality of evidence, LTOT does not prevent readmissions in patients with COPD who have severe hypoxemia. Limited data suggest LTOT increases the risk of hospitalizations.
Limited work has been performed evaluating the safety of LTOT by severity of hypoxemia.
Based on low to very low quality of evidence, LTOT may have a beneficial effect over time on health-related quality of life in patients with COPD who have severe hypoxemia. Limited work using disease-specific instruments has been performed.
Ethical constraints of not providing LTOT to eligible patients with COPD prohibit future studies from examining LTOT outcomes in an ideal way.
PMCID: PMC3384376  PMID: 23074435
24.  Exacerbation of Lung Radiation Injury by Viral Infection: The Role of Clara Cells and Clara Cell Secretory Protein 
Radiation research  2013;179(6):617-629.
Viral infections have been associated with exacerbation of disease in human cases of idiopathic pulmonary fibrosis. Since pulmonary fibrosis is a common outcome after irradiation to the lung, we hypothesized that viral infection after radiation exposure would exacerbate radiation-induced lung injury. Epithelial injury, a frequent outcome after infection, has been hypothesized to contribute to the pathogenesis of pulmonary fibrosis and bronchiolar epithelial Clara cells participate in epithelial repair. Therefore, it was further hypothesized that altered responses after irradiation involve the bronchiolar epithelial Clara cells. C57BL/6J or CCSP−/− mice were irradiated with 0 (sham), 5, 10 or 15 Gy to the whole thorax. At ten weeks post-irradiation, animals were mock infected or infected with influenza A virus and body weight and survival were monitored. Pulmonary function was assessed by whole-body plethysmography. The Clara cell markers, CCSP and Cyp2f2, were measured in the lung by qRT-PCR, and protein expression was visualized in the lung by immunofluorescence. Following pulmonary function tests, mice were sacrificed and tissues were collected for pathological analysis. In 15 Gy irradiated animals infected with influenza A virus, accelerated respiratory rates, reduced pulmonary function, and exacerbated lung pathology occurred earlier post-irradiation than previously observed after irradiation alone, suggesting infection accelerates the development of radiation injury. After irradiation alone, CCSP and Cyp2f2 mRNA levels were reduced, correlating with reductions in the number of Clara cells lining the airways. When combined with infection, these markers further declined and an apparent delay in recovery of mRNA expression was observed, suggesting that radiation injury leads to a chronic reduction in the number of Clara cells that may potentiate the epithelial injury observed after influenza A virus infection. This novel finding may have considerable therapeutic implications with respect to both thoracic tumor patients and recipients of bone marrow transplants.
PMCID: PMC3725325  PMID: 23621375
25.  Estimates of delays in diagnosis of cervical cancer in Nepal 
BMC Women's Health  2014;14:29.
Cervical cancer is the leading cause of cancer related deaths among women in Nepal. The long symptom to diagnosis interval means that women have advanced disease at presentation. The aim of this study was to identify, estimate and describe the extent of different delays in diagnosis of cervical cancer in Nepal.
A cross-sectional descriptive study was conducted in two tertiary cancer hospitals of Nepal. Face to face interview and medical records review were carried out among 110 cervical cancer patients. Total diagnostic delay was categorized into component delays: patient delay, health care providers delay, referral delay and diagnostic waiting time.
Total 110 patients recruited in the study represented 40 districts from all three ecological regions of the country. Median total diagnostic delay was 157 days with more than three fourth (77.3%) of the patients having longer total diagnostic delay of >90 days. Out of the total diagnostic delay, median patient delay, median health care provider delay, median referral delay and median diagnostic waiting time were 68.5 days, 40 days, 5 days and 9 days respectively. Majority of the patients had experienced longer delay of each type except referral delay. Fifty seven percent of the patients had experienced longer patient delay of >60 days, 90% had suffered longer health care provider delay of >1 week, 31.8% had longer referral delay of >1 week and 66.2% had waited >1 week at diagnostic center for final diagnosis. Variation in each type of delay was observed among women with different attributes and in context of health care service delivery.
Longer delays were observed in all the diagnostic pathways except for referral delay and diagnostic waiting time. Among the delays, patient delay is of crucial importance because of its longer span, although health care provider delay is equally important. In the context of limited screening services in Nepal, the efforts should be to reduce the diagnostic delay especially patient and health care provider delay for early detection and reduction of mortality rate of cervical cancer.
PMCID: PMC3932513  PMID: 24533670
Alarming symptoms; Cervical cancer; Delays; Health care provider; Nepal

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