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1.  Lung Volumes and Emphysema in Smokers with Interstitial Lung Abnormalities 
The New England journal of medicine  2011;364(10):897-906.
BACKGROUND
Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known.
METHODS
We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema.
RESULTS
Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (−0.444 liters; 95% confidence interval [CI], −0.596 to −0.292; P<0.001) and a lower percentage of emphysema defined by lung-attenuation thresholds of −950 Hounsfield units (−3%; 95% CI, −4 to −2; P<0.001) and −910 Hounsfield units (−10%; 95% CI, −12 to −8; P<0.001). As compared with participants without interstitial lung abnormalities, those with abnormalities were more likely to have a restrictive lung deficit (total lung capacity <80% of the predicted value; odds ratio, 2.3; 95% CI, 1.4 to 3.7; P<0.001) and were less likely to meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking.
CONCLUSIONS
In smokers, interstitial lung abnormalities — which were present on about 1 of every 12 HRCT scans — were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation; ClinicalTrials.gov number, NCT00608764.)
doi:10.1056/NEJMoa1007285
PMCID: PMC3074462  PMID: 21388308
2.  019. Idiopathic interstitial pneumonias: clinico-radiologic-pathologic diagnosis 
Journal of Thoracic Disease  2015;7(Suppl 1):AB019.
Background
The idiopathic interstitial pneumonias (IIPs) represent a heterogeneous group of lung diseases with effects on the lung parenchyma and airways characterized by chronic inflammation and progressive fibrosis and share similar features (clinical, radiological). The idiopathic interstitial pneumonias are classified based on clinical, histopathological and radiological criteria in idiopathic pulmonary fibrosis-usual interstitial pneumonia (IPF-UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and lymphocytic interstitial pneumonia (LIP).
Objective
The importance of clinical-imaging-pathology findings correlation for the final diagnosis of two cases with idiopathic interstitial pneumonia.
Methods
1st case: 68-year-old male with dyspnea and interstitial thickening in the lower lobe of the left lung and radiologic characteristics of peripheral atelectasis and pulmonary fibrosis-CT guided lung biopsy. 2nd case: 56-year-old male with dyspnea and honeycomb changes in the lower lobe of the right lung-Partial lobectomy, 5, 8×5×2 cm3 in size, was performed.
Results
In both cases a variety of histopathological changes was noticed, such as: diffuse alveolar damage with confluent alveolar septal thickening; fibrosis with fibroblastic foci, smooth muscle hyperplasia and foci of ossification (2nd); dilated airspaces; bronchiolar or squamous metaplasia of alveolar epithelium; inflammation in the interstitium; dilated and congested blood vessels. The valuation of histological findings in accordance with history, clinical and imaging findings confirmed the diagnosis of usual interstitial pneumonia (UIP).
Conclusions
The diagnosis of idiopathic interstitial pneumonias is the result of collaboration between pulmonologists, radiologists and pathologists. The subtypes are important to distinguish because treatment and prognosis vary by subtype and ranges from excellent to nearly always fatal. The reasons of interstitial lung fibrotic lesions identification failure are: incomplete clinical information, inadequate radiological data, small or non-diagnostic biopsy sample, previous treatment which differentiates the clinical picture or histology and heterogeneity of histological changes from site to site.
doi:10.3978/j.issn.2072-1439.2015.AB019
PMCID: PMC4332053
Interstitial lung disease; radiology; pathology
3.  THE CORRELATION BETWEEN THE HISTOLOGICAL CHANGES AND THE FATE OF LIVING TUBERCLE BACILLI IN THE ORGANS OF TUBERCULOUS RABBITS 
It has been found that although there is some parallelism between the quantity of tubercle bacilli demonstrable histologically and the number of colonies that can be isolated from a given tissue, the culture method is far the more efficient in indicating quantitative relations. Tubercle bacilli were not perceived in the organs of rabbits 1 day after infection with the modified BCG although as many as 1,500 colonies were isolated from one of them. This may be solely because it is difficult to see widely dispersed single minute acid-fast rods in the diffuse infiltrations of mononuclears with their hyperchromatic nuclei and sparse cytoplasm. Later, with the formation of tubercle, the parallelism is much closer. The culture method gives evidence concerning the number of living tubercle bacilli in the tissue. The significance of the accumulation of acid-fast particles in the tissues has been discussed. It has been seen that from the beginning this accumulation is greater in the Kupffer cells of the liver, in the macrophages of the spleen and in the reticular cells of the bone marrow than within the mononuclears of the lung, the organ where the bacilli grow with the greatest rapidity and are destroyed with the greatest difficulty. Acid-fast particles are more prominent with the bovine than with the human bacillus or the BCG, the microorganism that is destroyed with the greatest difficulty thus leaving more incompletely digested bacillary debris at a given time within the cells. Thus it seems permissible to conclude from the presence of acid-fast material that some tubercle bacilli are undergoing destruction even 24 hours after infection. The initial accumulation of polynuclear leucocytes corresponds with the subsequent severity of the infection. Despite the greater primary localization of bacilli in the liver, this initial inflammatory reaction with all three infections is much greater in the lung than in the liver. In each organ it is more intense with the bovine than with the less virulent strains. The multiplication of the bacillus and its accumulation within large mononuclear and young epithelioid cells is accompanied by an intense formation of new mononuclears by mitosis. The more rapid the growth of the bacillus, the more conspicuous the regeneration of these cells. Thus with all strains mitosis is more intense in the more susceptible organ, as in the lung compared with the liver; with the most virulent strain the most extensive and diffuse accumulation of these new cells corresponds with the greater rise in the numbers of bovine bacilli after the lag of the 1st week. With the maturation of the epithelioid cells and the formation of tubercles the bacilli have already been greatly reduced numerically and the speed of this process diminishes with the virulence of the three strains used. The faster the development of tubercle the faster the destruction of the bacillus and the earlier the resorption of the tubercle. Tubercle bacilli never accumulate in such large numbers in the mononuclears of the liver as they do in the lung. Though at first the tubercles in the liver may be more numerous than those in the lung they never attain the same size. The formation of new mononuclears by mitosis is restricted and Langhans' giant cells appear very early (1st and 2nd weeks). In the lung, giant cells are not found until much later with the BCG and the human bacillus (4th week); they were not noted in the interstitial tubercles with the bovine type, but the extension of these tubercles was accompanied by an unabated mitosis of mononuclears until the death of the animal. The liver tubercles are resorbed early even with the bovine infection. Associated with these histological differences are the slow initial growth and the early and complete destruction of the tubercle bacilli even of bovine type in the liver, and the more rapid initial growth in the lung, with the later destruction of the BCG and the human bacillus and the unabated growth of the bovine bacillus. Similar differences were observed between the splenic pulp and corpuscle. In the former the accumulation of acid-fast particles was much greater and the tubercles developed earlier. Mitosis of mononuclears was less frequent and giant cells appeared earlier. Tubercle bacilli, always intracellular, disappeared from the tubercles in the pulp sooner than from those in the corpuscle, and the tubercles themselves first disappeared from the pulp. Consequently with the persistence of bacilli mitosis continued in the tubercles of the corpuscle and these attained a much larger size. Moreover individual resistance is linked with the ability to form mature tubercles early. In two animals simultaneously infected with the same strain and killed at the same time, the destruction or retardation of the bacillus is greater in that rabbit in which maturation of the tubercle and of epithelioid cells has proceeded further (Figs. 15 and 16). These observations indicate that the mononuclears of different organs or even of the same organ, as in the different parts of the spleen, have a different capacity to destroy the tubercle bacillus, and that the transformation of the mononuclear into the mature epithelioid cell follows its destruction of the tubercle bacilli. In the lung the more virulent types of bacillus are destroyed within the epithelioid cells of interstitial tubercles but persist in foci of tuberculous pneumonia. In this organ in rabbits infected with the human strain and to a lesser degree in rabbits infected with the bovine strain, the parasite largely disappears from the epithelioid cells of interstitial tubercles. But with both strains tubercle bacilli in large numbers may accumulate within epithelioid cells lying free in the alveoli. With the human type they are numerous within the cells and free in caseous material in the localized foci of caseous pneumonia. With the bovine infection, this caseous pneumonia is more often widespread and in the areas of caseous pneumonia the greater part of the vast accumulation of bovine bacilli in the lungs is found; as many as 200,000 colonies have been isolated from 10 mg. of tissue (Fig. 11). Flooding of the respiratory passages by the caseation of tuberculous lesions into the bronchi plays an important rôle in dissemination of tubercle bacilli through the lung. The process on the contrary is predominantly interstitial when the bovine bacillus is held in check (Fig. 12). Thus there is apparently some factor acting in the alveoli that favors the growth of the parasite. The accumulation of tubercle bacilli is seen especially in the peripheral epithelioid cells in immediate contact with the alveolar space. In the same lung the bacilli are much fewer in the interstitial tubercles. The accumulation in human tuberculosis of large numbers of tubercle bacilli in the tissues lining cavities is well known. Novy and Soule (20) have shown that within certain limits the growth of the bacillus in vitro is proportional to the oxygen tension of its environment. Corper, Lurie and Uyei (21) have confirmed these observations and have noted further that a difference in the gaseous environment of the bacilli equal to the difference between the conditions existing in the alveolar air and the venous blood is sufficient to cause a considerable increase in the growth of the microorganism in vitro. Loebel, Shorr and Richardson (22) by the use of Warburg's manometer have found that the oxygen consumption of tuberculous tissue is such that a tubercle 0.5 mm. thick would completely exhaust the oxygen of the air before it reached the center. These observations suggest that a factor responsible for the greater multiplication of the bacillus in the cells of the alveoli may be the greater oxygen tension of the alveolar air. In the liver, spleen and bone marrow even with the bovine infection many instances were found of the effective destruction of the parasite synchronously with the maturation of epithelioid cells and the formation of tubercle. On the other hand, in the spleen and bone marrow of some rabbits, living bacilli persisted within the epithelioid cells of isolated tubercles even 2 months after infection, a condition never found with the human type or BCG infection. Thus the epithelioid cell is the means of defense for the rabbit against the bovine type bacillus, and as such it is usually adequate in the liver, spleen and bone marrow though ineffective in the lung and kidney. In the latter, descending infection, and the occasional colony-like multiplication of bacilli in unorganized material, tubular casts, determine the long persistence of large numbers of bacilli in this organ. In differentiating the mononuclear phagocyte of the connective tissues into the monocyte and clasmatocyte Sabin and her coworkers (23) have maintained that the clasmatocyte can efficiently destroy the tubercle bacillus but that the monocyte and its derivatives, the epithelioid and Langhans' giant cells, cannot. With the progress of the disease they have noted that the monocytes accumulate in great numbers in the foci of infection and overflow into general circulation (4). White (24) and Sabin and her coworkers have concluded that tuberculosis is specifically a disease of the monocyte, and that this cell and its derivatives act as incubators for the tubercle bacillus. Doan and Sabin (25) have therefore sought, with indecisive results, to protect the body against tuberculosis by an antimonocytic serum. However it has been shown here that although an intense multiplication of mononuclears is associated with the growth of the tubercle bacillus, their transformation into mature epithelioid cells is constantly associated with its destruction, and the rapidity of the destruction varies with the rapidity of the maturation of tubercle. Even in the bovine infection the epithelioid cells destroy the bacilli in the liver, spleen and bone marrow as a rule, and even in the lung, keep them in check in the interstitial tubercles. The appearance of giant cells is associated with cessation or diminution of mononuclear regeneration by mitosis, and is coincident with cessation of multiplication or marked reduction in the number of living bacilli. They therefore appear earlier and in larger numbers in these organs or parts of organs that first destroy the bacillus (Figs. 16 and 17). They were not observed even 2 months after the bovine infection in the interstitial tubercles in the lung. Their absence and the continued mitosis of mononuclears, which accounts for the massive pneumonic and interstitial consolidation of the lung with this infection, were associated with the failure of the lung to destroy effectively the bovine parasite. The formation of giant cells in the pneumonic foci in the bovine infection would seem to be an exception to this rule. The Langhans giant cells have often been considered an indication of the chronicity of the pathological process. It would appear that they are formed from existing epithelioid cells when the multiplication of the bacillus has ceased and the stimulus for the formation of new cells has decreased or stopped. Giant cells were most conspicuous in the liver and splenic pulp where, with the BCG infection, no caseation ever developed, and in the liver before caseation was seen anywhere in the body. In the human and bovine infections, giant cells formed in the liver before caseation appeared. Hence caseation is not a necessary requirement for giant cell formation, as maintained by Medlar (26), though these cells frequently form about caseous material. Lymphocytes and granulation tissue do not cause the destruction of tubercle bacilli, these being destroyed in their absence. They usually appear about tubercles due to all strains and in all organs, after the greater part of the microorganisms have been destroyed (Fig. 18). The bacilli are not destroyed in the lung with bovine infection where the tubercles are usually little permeated by lymphocytes and granulation tissue. There is however, no constant relation between granulation tissue and destruction of tubercle bacilli, for in the lung after the human infection and even in other organs after the bovine infection isolated tubercles may be surrounded and penetrated by lymphocytes and granulation tissue at a time when considerable numbers of living bacilli are still histologically demonstrable within the epithelioid cells. Caseation is usually not caused by the local accumulation of tubercle bacilli. At first, when the BCG (after 1 week) and the human microorganism (after 2 weeks) are present in the cells in very large numbers as demonstrated both histologically and by culture (Figs. 4 and 13) there is no necrosis of these cells. An exception to this rule found in the lung with the bovine infection is considered below. Later, after the bacilli have been destroyed to a great extent and even though the number of bacilli is small, caseation appears (Fig. 14). After this preliminary destruction the extent of caseation apparently varies with the number of residual bacilli. With the least virulent microorganism, the BCG, few bacilli remained in the liver in the 4th week and no caseation was seen. In the tubercles of the splenic corpuscle at the same time bacilli were somewhat more numerous and there was scant caseation. On the other hand with the human bacillus after 4 weeks more bacilli survived and caseation was more extensive in both organs; with the bovine microorganism tubercle bacilli were much more numerous and caseation was far advanced. In the lung, however, caseation appeared with the first considerable accumulation of the bovine bacilli present 2 weeks after inoculation. That the bovine bacillus is primarily more injurious to the lung of rabbits than the BCG or the human bacillus is suggested by the greater intensity of the initial inflammation and by the more conspicuous accumulation of cells in the alveoli evident from the very beginning of infection. Maximow (27) showed that bovine bacilli even in small numbers cause the death of cells in tissue cultures of rabbit lymph nodes whereas the BCG or the human bacillus may accumulate within the cells in tremendous numbers without injuring them. Nevertheless in the liver, spleen and bone marrow of the living animal, caseation does not appear at the time when bovine bacilli are most abundant, but after they have been greatly reduced in numbers. Large numbers of the less virulent types of tubercle bacilli accumulated in different organs a short time after infection do not cause caseation, and with the bovine infection caseation under the same conditions occurs only in the lung. Later when the animal is sensitized caseation occurs in various organs in the presence of the small numbers of tubercle bacilli that remain in the tissues after most of them have been destroyed, and the extent of this caseation varies with the numbers of residual bacilli. These observations suggest that a large number of bacilli fail to cause necrosis soon after infection whereas a few bacilli produce caseation in the animal that is sensitized. Many investigators have held that caseation is due to sensitization. Krause (28), Huebschman (29) and Pagel (30) think that caseation is caused by the action of tuberculin-like substances on the sensitized tissues of the allergic animal. Rich and McCordock (31) view the process in essentially the same light. Recently Schleussing (32) has suggested that caseation is a coagulation necrosis in Weigert's sense of an allergically inflamed tissue, and is similar to the necrosis of the Arthus phenomenon.
PMCID: PMC2132067  PMID: 19869977
4.  A retired shipyard worker with rapidly progressive pulmonary interstitial fibrosis. 
Environmental Health Perspectives  1999;107(4):321-327.
We present a case of progressive interstitial fibrosis in a retired shipyard worker who was exposed to asbestos during the postwar era of the late 1940s and 1950s, when asbestos exposures in the workplace were not regulated. Forty years later, at 63 years of age, the patient presented with restrictive lung disease. The patient was diagnosed with asbestos-related pleural disease and parenchymal asbestosis. He remained stable for the next 7 years, but then he began to manifest rapid clinical progression, which raised the possibility of an unusual variant of asbestosis, a concomitant interstitial process, or an unrelated disease. Lung biopsy was not undertaken because of the patient's low pulmonary reserve and limited treatment options. An empiric trial of oral steroids was initiated, but his pulmonary status continued to deteriorate and he died of pulmonary failure at 72 years of age. Many diseases result in pulmonary interstitial fibrosis. Ideally, open lung biopsy should be performed, but this procedure inevitably causes complications in many patients with end-stage restrictive lung disease. Furthermore, while the presence of asbestos bodies in tissue sections is a sensitive and specific marker of asbestos exposure, neither this finding nor any other charge is a marker indicative of asbestosis or the severity of asbestosis. With the enactment of the Asbestos Standard in the United States, asbestos exposures have been decreasing in this country. However, industries that produce asbestos products and wastes continue to expand in developing countries. Prevention of asbestos-related lung disease should be a global endeavor, and asbestos exposures should be regulated in both developed and developing countries.
Images
PMCID: PMC1566510  PMID: 10090713
5.  Desquamative alveolar disease (desquamative interstitial pneumonia): case report 1 
Thorax  1969;24(2):186-191.
Desquamative interstitial pneumonia is a disease characterized by massive alveolar cell proliferation and desquamation with sparse interstitial involvement. The reported case shows an unusually widespread radiographic reticulo-nodular image and abundant alveolar cells in the sputum. Functional studies reveal the expected diffusion defect with practically normal mechanical properties of the lung, in contrast with interstitial fibrosing lung diseases. On the basis of the pathological findings, especially the behaviour of alveolar cells, the individuality of this disease is discussed. We think that it is different from other diseases classed as varieties of a single disease or as different entities under the names of primary interstitial fibrosis or chronic fibrosing alveolitis.
Images
PMCID: PMC471939  PMID: 5822250
6.  Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer 
PLoS ONE  2015;10(10):e0140437.
Introduction
This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease.
Methods
Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis.
Results
Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29–155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06–20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0–37.4); p = 0.038).
Conclusions
Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.
doi:10.1371/journal.pone.0140437
PMCID: PMC4603947  PMID: 26460792
7.  Desquamative interstitial pneumonitis and systemic lupus erythematosus 
Desquamative interstitial pneumonia (DIP) is a rare form of interstitial lung disease (ILD) commonly found among healthy smokers. ILD is a rare manifestation of systemic lupus erythematosus (SLE), and typically associated with a histopathological pattern of nonspecific interstitial pneumonia (NSIP). The present article describes an unusual case of DIP in a non-smoking patient with SLE presenting as NSIP. DIP can occur in the context of SLE in patients with a negative smoking history, and clinicians should consider lung biopsy to correctly classify ILD with unusual presentation on computed tomography scan.
PMCID: PMC3299041  PMID: 22332137
Connective tissue disease; Interstitial lung disease; Lupus
8.  Prediction of postoperative exacerbation of interstitial pneumonia in patients with lung cancer and interstitial lung disease 
Postoperative exacerbation of interstitial pneumonia in patients with lung cancer and interstitial lung disease has emerged as a serious problem. Therefore, the risk factors for postoperative exacerbation of interstitial pneumonia in patients with interstitial lung disease must be identified. We analyzed 22 patients diagnosed as having lung cancer with interstitial lung disease who underwent surgical treatment at the Kitasato University Hospital. Among the patients with lung cancer and interstitial lung disease, 5 patients (22.7%) had postoperative exacerbation of interstitial pneumonia. The prognosis of the patients with postoperative exacerbation was significantly poorer than that of patients without. Patients with postoperative exacerbation had a significantly higher age (≥75 years) and a significantly lower frequency of postoperative administration of steroid than patients without postoperative exacerbation. Almost all patients with postoperative exacerbation underwent lobectomy, had elevated KL-6 levels in the serum pre-operatively, and had significantly advanced stages of disease. Of the 5 patients with postoperative exacerbation, 2 had a history of inflammation prior to their exacerbation: 1 had a common cold and the other pyothorax. In patients with lung cancer and interstitial lung disease, advanced age, advanced stage disease, no postoperative administration of steroid and a pre-operative episode of inflammation are all risk factors for postoperative exacerbation of interstitial pneumonia.
doi:10.3892/etm.2011.342
PMCID: PMC3440811  PMID: 22977623
lung cancer; interstitial lung disease; postoperative exacerbation
9.  The benefits of exercise training in interstitial lung disease: protocol for a multicentre randomised controlled trial 
Background
Interstitial lung disease encompasses a diverse group of chronic lung conditions characterised by distressing dyspnoea, fatigue, reduced exercise tolerance and poor health-related quality of life. Exercise training is one of the few treatments to induce positive changes in exercise tolerance and symptoms, however there is marked variability in response. The aetiology and severity of interstitial lung disease may influence the response to treatment. The aims of this project are to establish the impact of exercise training across the range of disease severity and to identify whether there is an optimal time for patients with interstitial lung disease to receive exercise training.
Methods/Design
One hundred and sixteen participants with interstitial lung disease recruited from three tertiary institutions will be randomised to either an exercise training group (supervised exercise training twice weekly for eight weeks) or a usual care group (weekly telephone support). The 6-minute walk distance, peripheral muscle strength, health-related quality of life, dyspnoea, anxiety and depression will be measured by a blinded assessor at baseline, immediately following the intervention and at six months following the intervention. The primary outcome will be change in 6-minute walk distance following the intervention, with planned subgroup analyses for participants with idiopathic pulmonary fibrosis, dust-related interstitial lung disease and connective-tissue related interstitial lung disease. The effects of disease severity on outcomes will be evaluated using important markers of disease severity and survival, such as forced vital capacity, carbon monoxide transfer factor and pulmonary hypertension.
Discussion
This trial will provide certainty regarding the role of exercise training in interstitial lung disease and will identify at what time point within the disease process this treatment is most effective. The results from this study will inform and optimise the clinical management of people with interstitial lung disease.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12611000416998
doi:10.1186/1471-2466-13-8
PMCID: PMC3564686  PMID: 23369075
Interstitial lung diseases; Diffuse parenchymal lung diseases; Idiopathic pulmonary fibrosis; Idiopathic interstitial pneumonias; Asbestosis; Sarcoidosis; Hypersensitivity pneumonitis; Connective tissue diseases; Exercise; Rehabilitation
10.  MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis 
PLoS Medicine  2008;5(4):e93.
Background
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%).
Conclusions
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
Background.
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 http://dx.doi.org/10.1371/journal.pmed.0050093.
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
doi:10.1371/journal.pmed.0050093
PMCID: PMC2346504  PMID: 18447576
11.  Lung in Dengue: Computed Tomography Findings 
PLoS ONE  2014;9(5):e96313.
Background
Dengue is the most important mosquito-borne viral disease in the world. Dengue virus infection may be asymptomatic or lead to undifferentiated fever, dengue fever with or without warning signs, or severe dengue. Lower respiratory symptoms are unusual and lung-imaging data in patients with dengue are scarce.
Methodology/Principal Findings
To evaluate lung changes associated with dengue infection, we retrospectively analyzed 2,020 confirmed cases of dengue. Twenty-nine of these patients (11 females and 18 males aged 16–90 years) underwent chest computed tomography (CT), which yielded abnormal findings in 17 patients: 16 patients had pleural effusion (the sole finding in six patients) and 11 patients had pulmonary abnormalities. Lung parenchyma involvement ranged from subtle to moderate unilateral and bilateral abnormalities. The most common finding was ground-glass opacity in eight patients, followed by consolidation in six patients. Less common findings were airspace nodules (two patients), interlobular septal thickening (two patients), and peribronchovascular interstitial thickening (one patient). Lung histopathological findings in four fatal cases showed thickening of the alveolar septa, hemorrhage, and interstitial edema.
Conclusions/Significance
In this largest series involving the use of chest CT to evaluate lung involvement in patients with dengue, CT findings of lower respiratory tract involvement were uncommon. When abnormalities were present, pleural effusion was the most frequent finding and lung involvement was often mild or moderate and bilateral. Extensive lung abnormalities are infrequent even in severe disease and when present should lead physicians to consider other diagnostic possibilities.
doi:10.1371/journal.pone.0096313
PMCID: PMC4023925  PMID: 24836605
12.  Interstitial lung disease in classic and clinically amyopathic dermatomyositis: a retrospective study with screening recommendations 
Archives of dermatology  2010;146(7):729-738.
Objectives
(1) Determine the prevalence of interstitial lung disease and isolated low diffusing capacity for carbon monoxide (DLCO) in a large cohort of dermatomyositis outpatients. (2) Compare the pulmonary abnormalities of classic dermatomyositis (CDM) and clinically amyopathic dermatomyositis (CADM) patients.
Design
Retrospective cohort study.
Setting
University hospital outpatient dermatology referral center.
Patients
Records of 91 outpatients with adult-onset dermatomyositis seen between May 26, 2006 and May 25, 2009 were reviewed.
Main Outcome Measures
Presence of interstitial lung disease on thin slice chest computed tomography (CT) scans and DLCO.
Results
Of the 71 dermatomyositis patients who had CT or DLCO data, 23% (16/71, 95% confidence interval [CI] = 13–33%) had interstitial lung disease as defined by CT results. All interstitial lung disease patients had a reduced DLCO, and the interstitial lung disease prevalence was not different between CADM (29% [10/35]) and CDM (17% [6/36]) patients (p=0.27). Twenty-five percent (18/71, 95% CI = 15–36%) of patients (20% [7/35], CADM; 31% [11/36], CDM; p=0.41), had an isolated low DLCO in the absence of CT findings showing interstitial lung disease.
Conclusions
Established interstitial lung disease and isolated reductions in DLCO, which may signify early interstitial lung disease or pulmonary hypertension, are very common in both classic and clinically amyopathic dermatomyositis dermatology outpatients. As the DLCO is an inexpensive test that is sensitive for pulmonary disease, it may be appropriate to screen all dermatomyositis patients with serial DLCO measurements and base further testing on DLCO results.
doi:10.1001/archdermatol.2010.134
PMCID: PMC3010864  PMID: 20644033
13.  Bronchoalveolar Lavage Fluid Characteristics of Patients With Sarcoidosis and Nonsarcoidosis Interstitial Lung Diseases: Ten-Year Experience of a Single Center in Turkey 
Background:
Bronchoalveolar lavage (BAL) is a noninvasive and useful technique for evaluating interstitial lung diseases (ILDs). Flow cytometric analysis of BAL fluid reveals specific diagnostic information in some unusual ILDs, and helps to narrow down the possible causes of interstitial diseases in most patients with more common disorders. A high BAL CD4/CD8 ratio is highly specific for sarcoidosis but can also be seen in other ILDs.
Objectives:
In this retrospective, descriptive, cross-sectional study, we compared BAL fluid characteristics and clinical variables in patients with sarcoidosis and non-sarcoidosis ILDs in a large cohort.
Patients and Methods:
The study was conducted in a tertiary university hospital in Zonguldak, the biggest city of the western Black Sea region of Turkey. Between 2004 and 2014, all patients who underwent both fiberoptic bronchoscopy and BAL with a suspicion of ILD were included in the study, retrospectively. Patients were divided into two main groups: sarcoidosis and non-sarcoidosis ILDs. Non-sarcoidosis ILDs were further divided into subgroups: pneumoconiosis, tuberculosis (TB), collagen vascular diseases, idiopathic interstitial pneumonias, malignancies, and unclassified ILDs. The clinical data of patients, including age, gender, smoking status, pulmonary function tests, and BAL flow cytometric analysis results, were compared among groups.
Results:
In total, 261 patients (119 sarcoidosis and 142 non-sarcoidosis ILDs) were enrolled. The median (interquartile range) BAL CD4/CD8 ratio and lymphocyte fraction were significantly higher in sarcoidosis than in non-sarcoidosis ILDs: 3.88 (3.76) versus 0.88 (1.01), respectively, and 20.6 (28.3) versus 6.0 (13.7), respectively. T cell receptor γ delta, CD16+56+, CD103+, CD8+103+, and CD3+16+56+ cells were significantly lower in sarcoidosis than in non-sarcoidosis ILDs. The median BAL CD4/CD8 ratios were significantly higher in patients with TB (1.87, P = 0.01) and malignancies (1.69, P = 0.03) than in other non-sarcoidosis ILDs.
Conclusions:
Among BAL fluid flow cytometric parameters, CD4/CD8 and lymphocyte fraction may be helpful for distinguishing sarcoidosis from other ILDs, but they are neither specific nor diagnostic for any lung disease. Thus, a multidisciplinary diagnostic discussion is required to differentiate various ILDs.
doi:10.5812/ircmj.31103
PMCID: PMC4636855  PMID: 26566455
Bronchoalveolar Lavage; CD4/CD8 Ratio; Lung Diseases, Interstitial; Pneumoconiosis; Flow Cytometry
14.  Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease. 
Thorax  1990;45(8):591-596.
The reported prevalence of interstitial lung disease in patients with rheumatoid arthritis has varied from 10% to 50%, yet less than 5% of patients with arthritis develop severe fibrosing interstitial lung disease. This suggests that subclinical disease may not always presage progressive disease. Bronchoalveolar lavage fluid from patients with rheumatoid arthritis and either clinically evident interstitial lung disease or subclinical disease was examined for the presence of factors with a putative role in the development of interstitial fibrosis. Patients with subclinical disease were identified by prospective radiographic and lung function screening of 93 patients with rheumatoid arthritis. Fourteen patients were identified in this manner and an association between subclinical disease and smoking history was noted. Eleven patients with established interstitial lung disease had increased neutrophils (p less than 0.05), collagenase, and type III procollagen N terminal peptide levels (p less than 0.01) in the bronchoalveolar lavage fluid. Preliminary characterisation of the bronchoalveolar lavage collagenase suggested that it originated from neutrophils. Ten patients with subclinical interstitial lung disease underwent bronchoalveolar lavage. Of these, one had increased neutrophils and two had increased collagenase concentrations--abnormalities associated with advanced interstitial lung disease and a poor prognosis. These results suggest that in arthritis patients with evidence of subclinical pulmonary interstitial disease bronchoalveolar lavage might be useful in identifying those who may require careful monitoring in the hope that early treatment will prevent severe fibrosis.
PMCID: PMC462634  PMID: 2169654
15.  Coronary Artery Disease Is Under-diagnosed and Under-treated in Advanced Lung Disease 
The American journal of medicine  2012;125(12):1228.e13-1228.e22.
BACKGROUND
Coronary artery disease is a potentially treatable comorbidity observed frequently in both chronic obstructive pulmonary disease and interstitial lung disease. The prevalence of angiographically proven coronary artery disease in advanced lung disease is not well described. We sought to characterize the treatment patterns of coronary artery disease complicating advanced lung disease and to describe the frequency of occult coronary artery disease in this population.
METHODS
We performed a 2-center, retrospective cross-sectional study of patients with either chronic obstructive pulmonary disease or interstitial lung disease evaluated for lung transplantation. Medications and diagnoses before the transplant evaluation were recorded in conjunction with left heart catheterization results.
RESULTS
Of 473 subjects, 351 had chronic obstructive pulmonary disease, and 122 had interstitial lung disease. In subjects diagnosed clinically with coronary artery disease, medical regimens included a statin in 78%, antiplatelet therapy in 62%, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in 42%, and a beta-blocker in 37%. Ten percent were on no medication from these 4 classes. Fifty-seven percent of these subjects were on an antiplatelet agent as well as a statin, and 13% were on neither. Beta-blockers were less frequently prescribed in chronic obstructive pulmonary disease than interstitial lung disease (23% vs 58%, P = .007). Coronary angiography was available in 322 subjects. It demonstrated coronary artery disease in 60% of subjects, and severe coronary artery disease in 16%. Occult coronary artery disease and severe occult coronary artery disease were found in 53% and 9%, respectively. There were no significant differences in angiographic results between chronic obstructive pulmonary disease and interstitial lung disease, despite imbalanced risk factors.
CONCLUSIONS
Coronary artery disease is common in patients with advanced lung disease attributable to chronic obstructive pulmonary disease or interstitial lung disease and is under-diagnosed. Guideline-recommended cardioprotective medications are suboptimally utilized in this population.
doi:10.1016/j.amjmed.2012.05.018
PMCID: PMC3732035  PMID: 22959785
COPD; Coronary artery disease; Interstitial lung disease; Lung transplantation; Pulmonary fibrosis
16.  Association Between Interstitial Lung Abnormalities and All-Cause Mortality 
JAMA  2016;315(7):672-681.
IMPORTANCE
Interstitial lung abnormalities have been associated with decreased six-minute walk distance, diffusion capacity for carbon monoxide and total lung capacity; however to our knowledge, an association with mortality has not been previously investigated.
OBJECTIVE
To investigate whether interstitial lung abnormalities are associated with increased mortality.
DESIGN, SETTING, POPULATION
Prospective cohort studies of 2633 participants from the Framingham Heart Study (FHS) (CT scans obtained 9/08–3/11), 5320 from the Age Gene/Environment Susceptibility (AGES)-Reykjavik (recruited 1/02–2/06), 2068 from COPDGene (recruited 11/07–4/10), and 1670 from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) (between 12/05–12/06).
EXPOSURES
Interstitial lung abnormality status as determined by chest CT evaluation.
MAIN OUTCOMES AND MEASURES
All cause mortality over approximately 3 to 9 year median follow up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
RESULTS
Interstitial lung abnormalities were present in 177 (7%) of the participants from FHS, 378 (7%) from AGES-Reykjavik, 156 (8%) from COPDGene, and in 157 (9%) from ECLIPSE. Over median follow-up times of ~3–9 years there were more deaths (and a greater absolute rate of mortality) among those with interstitial lung abnormalities compared to those without interstitial lung abnormalities in each cohort; 7% compared to 1% in FHS (6% difference, 95% confidence interval [CI] 2%, 10%), 56% compared to 33% in AGES-Reykjavik (23% difference, 95% CI 18%, 28%), 16% compared to 11% in COPDGene (5% difference, 95% CI −1%, 11%) and 11% compared to 5% in ECLIPSE (6% difference, 95% CI 1%, 11%). After adjustment for covariates, interstitial lung abnormalities were associated with an increase in the risk of death in the FHS (HR=2.7, 95% CI, 1.1–65, P=0.030), AGES-Reykjavik (HR 1.3, 95% CI 1.2–1.4, P<0.001), COPDGene (HR=1.8, 95% CI, 1.1, 2.8, P=0.014), and ECLIPSE (HR=1.4, 95% CI, 1.1–2, P=0.022) cohorts. In the AGES-Reykjavik cohort the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
CONCLUSIONS AND RELEVANCE
In four separate research cohorts, interstitial lung abnormalities were associated with a higher risk of all-cause mortality. The clinical implications of this association require further investigation.
doi:10.1001/jama.2016.0518
PMCID: PMC4828973  PMID: 26881370
Idiopathic pulmonary fibrosis; interstitial lung disease; interstitial lung abnormalities (ILA); undiagnosed; subclinical
17.  Rare lung diseases I – Lymphangioleiomyomatosis 
The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia.
LAM is a rare, progressive and (without intervention) often fatal interstitial lung disease that predominantly affects women of childbearing age. LAM is characterized by progressive interstitial infiltration of the lung by smooth muscle cells, resulting in diffuse cystic changes of the lung parenchyma. The molecular basis of this disorder has been delineated over the past five years and LAM is now known to be a consequence of mutations in the tuberous sclerosis genes. This knowledge, combined with advances in our understanding of the signalling pathways regulated by these genes, has given rise to potential molecular therapies that hold great promise for treating this devastating disease.
PMCID: PMC2683291  PMID: 17036091
Chylothorax; Lymphatic channels; Molecular therapy; Pneumothorax; Sirolimus; Tuberous sclerosis
18.  Eosinophil-mediated injury to lung parenchymal cells and interstitial matrix. A possible role for eosinophils in chronic inflammatory disorders of the lower respiratory tract. 
Journal of Clinical Investigation  1984;74(1):269-278.
Eosinophils are a common component of the inflammation of the lower respiratory tract that characterizes the interstitial lung disorders. Bronchoalveolar lavage analyses (n = 680) of 251 patients with interstitial lung disease demonstrated that eosinophils represented greater than 5% of the effector cells comprising the alveolitis in 20% of all lavages. In contrast, lavage of normal individuals (n = 117) showed that eosinophils were never greater than 5% of the total effector cells recovered. To evaluate a possible role for eosinophils in mediating some of the cellular and connective tissue matrix derangements of the lung parenchyma found in interstitial disease, eosinophils were evaluated for the presence of proteases capable of cleaving connective tissue proteins found in the lung and for the ability to mediate cytotoxicity to lung parenchymal cells. Evaluation of guinea pig and human eosinophils demonstrated that eosinophil granules contained a collagenase that specifically cleaved human collagen types I and III, the two major connective tissue components of the human lung parenchyma. In contrast, the eosinophil did not contain an elastase or a nonspecific neutral protease. The eosinophil collagenase appeared to be a metalloprotease, as it was inhibited by ethylenediaminetetraacetate but not by phenylmethanesulfonyl-fluoride or alpha 1-antitrypsin. The eosinophil also has the capacity to injure lung parenchymal cells. Without further stimulation, eosinophils purified from peritoneal exudates of guinea pigs demonstrated spontaneous cytotoxicity for human lung fibroblasts (HFL-1), cat lung epithelial cells (AK-D) and rat lung mesothelial cells (I6B). Under identical conditions, the epithelial cells were more sensitive to eosinophil-mediated cytotoxicity than the fibroblasts or mesothelial cells (P less than 0.01), consistent with the clinical observation that in the interstitial disorders, the alveolar epithelial cells are damaged more commonly than fibroblasts or pleural cells. The eosinophil-mediated cytotoxicity could be partially inhibited by the antioxidants catalase and dimethylsulfoxide suggesting that toxic oxygen radicals play a role in mediating the cellular damage. Importantly, eosinophils purified from bronchoalveolar lavage of human interstitial lung disease also demonstrated spontaneous cytotoxicity for lung epithelial cells. These observations demonstrate that eosinophils are frequent participants of the alveolitis of the interstitial lung disorders and suggest that these cells have the potential to damage the parenchymal cells and collagen matrix of the lower respiratory tract.
Images
PMCID: PMC425209  PMID: 6330175
19.  Pulmonary Tuberculosis Confirmed by Percutaneous Transthoracic Needle Biopsy: Analysis of CT Findings and Review of Correlations with Underlying Lung Disease 
Balkan Medical Journal  2014;31(3):208-213.
Background:
Pulmonary tuberculosis (TB) can produce unusual radiographic findings. Further, negative sputum and bronchoscopic results are common. Early diagnosis is equally as significant as treatment in the reduction of morbidity and mortality associated with pulmonary TB.
Aims:
The aim of this study was to assess computed tomography (CT) findings of pulmonary TB, confirmed via percutaneous transthoracic needle biopsy (PTNB), and to correlate these findings with coexisting, underlying, lung diseases if present.
Study Design:
Cross sectional study.
Methods:
We selected eighty-four patients who were diagnosed with pulmonary TB by way of PTNB. Initially, acid-fast bacilli smear test results from these patients were negative. CT findings were reviewed to detect the presence of parenchymal abnormalities as follows: nodule(s) (<3 cm in diameter), mass (any masses ≥3 cm), daughter nodules, air-space consolidation, cavitation, calcification, lymphadenopathy, mediastinal lymphadenopathy, and associated lung parenchymal disease.
Results:
The CT findings of pulmonary TB confirmed by PTNB included nodules in 44 of 84 (52.4%) cases; 15 of these 44 cases (34.1%) had daughter nodules. The second most common finding was masses in 24 cases (28.6%), nine of which also had daughter nodules. 16 cases (19.0%) displayed nonsegmental consolidation. Of these 16 cases, four had coexisting usual interstitial pneumonia; four others had emphysema. Two patients with a mass had underlying pneumoconiosis.
Conclusion:
Nodules or a mass mimicking lung cancer were the most common findings on CT scans in patients with pulmonary TB, confirmed via PTNB. The second most common finding was airspace consolidation. Therefore, PNTB is useful for the accurate diagnosis of pulmonary TB in the following cases: airspace consolidation or mass associated with underlying usual interstitial pneumonia, emphysema mimicking lung malignancy or cases of bacterial pneumonia.
doi:10.5152/balkanmedj.2014.13187
PMCID: PMC4299964  PMID: 25625018
Percutaneous transthoracic needle biopsy; pulmonary; tuberculosis
20.  Interstitial Lung Disease in Systemic Scleroderma, Complicated with Bilateral Pulmonary Aspergilloma: An Unusual Association 
Aspergilloma or mycetoma is a saprophytic fungal infection that colonizes pre-existing excavated lung lesion. However, its association with systemic sclerosis related interstitial lung disease is unusual and scarcely found in literature. We report a middle aged female with long standing systemic sclerosis, who was on immunosuppressive therapy for many years, presented with repeated haemoptysis. Although provisionally pulmonary tuberculosis was suspected, imaging investigations showed presence of bilateral masses inside bullous air spaces along with air-crescent sign suggestive of fungal ball. Subsequent Computed tomography guided needle aspiration from lung mass confirmed Aspergillus fumigatus as aetiologic agent on fungal culture. Patient was treated conservatively for haemoptysis and with oral antifungal drug as surgical removal of fungal ball was not an option due to poor pulmonary reserve. Although she had been treated with itraconazole for more than three years, she had recurrent haemoptysis during this period without any significant regression of size of the aspergilloma. Management of aspergilloma in a background of extensive interstitial lung disease remains poorly defined and complicated. Thereby, overall prognosis is unfavourable and depends on evolution of both underlying scleroderma as well as aspergilloma.
doi:10.7860/JCDR/2015/15340.6926
PMCID: PMC4717821  PMID: 26816937
Breathlessness; Recurrent haemoptysis; Systemic sclerosis
21.  Accuracy of mortality data for interstitial lung diseases in New Mexico, USA. 
Thorax  1996;51(7):717-720.
BACKGROUND: The sensitivity and accuracy of death certificates and mortality data as sources of population based data on the occurrence of interstitial lung diseases has received limited attention. To determine the usefulness of these data sources, death certificates and mortality data from patients in New Mexico were examined. METHODS: Patients with an interstitial lung disease were identified from a population based registry. For subjects who had died, diagnostic information from their death certificates and from mortality data was compared with the clinical diagnoses made before death. RESULTS: Of 385 patients with a clinical diagnosis of an interstitial lung disease, 134 died between October 1988 and August 1994. Death certificates were obtained for 96% of these patients. An interstitial lung disease was listed somewhere on the death certificate for only 46% of the patients, and as an immediate cause of death for only 15%. For the patients with an interstitial lung disease listed somewhere on the death certificate the overall concordance between the diagnoses before death and those on the death certificate was 76%. Mortality data for the State of New Mexico showed a diagnosis of interstitial lung disease to be the assigned cause of death for only 22% of the patients. The overall agreement between the diagnoses made before death and those of the state mortality data was only 21%. CONCLUSIONS: These results suggest that death certificates and state mortality data are neither sensitive nor accurate for describing the occurrence of interstitial lung diseases. This finding may partly explain the apparently low mortality rates from idiopathic pulmonary fibrosis in the USA compared with other countries.
PMCID: PMC472495  PMID: 8882079
22.  Development of imatinibmesylate-induced interstitial lung disease 2 weeks after discontinuation of the treatment: a case report 
Background
Imatinibmesylate (imatinib) is a small molecule tyrosine kinase inhibitor administered to patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. Although imatinib-associated interstitial lung disease is uncommon, a few cases have been reported so far. However, in all these cases interstitial lung disease developed during the use of imatinib. The present case is the first report of imatinib-induced interstitial lung disease developing after discontinuation of the drug.
Case presentation
A 51-year-old woman was administered oral imatinib for gastrointestinal stromal tumor. Ten weeks later, imatinib was discontinued because of facial edema. On this occasion, chest radiography showed no abnormal findings. However, 2 weeks after discontinuation of imatinib, she developed fever, dry cough, and dyspnea. Chest radiography and computed tomography showed diffuse interstitial infiltrates in both lungs. Examination of bronchoalveolar lavage fluid showed an increased proportion of lymphocytes. Imatinib-induced interstitial lung disease was suspected, because no other cause was evident. After administration of corticosteroids, her clinical condition and chest radiographic findings improved.
Conclusion
We report a unique case of imatinib-induced interstitial lung disease that developed 2 weeks after discontinuation of the drug. Physicians should consider occurrence of imatinib-induced interstitial lung disease even after discontinuation of the drug.
doi:10.1186/2049-6958-7-48
PMCID: PMC3537559  PMID: 23174134
Drug-induced interstitial lung disease; Drug-induced lung injury; Drug induced pneumonitis; Drug lymphocyte-stimulating test; Imatinibmesylate
23.  Pulmonary Diffuse Alveolar Septal Amyloidosis 
Diffuse alveolar septal involvement is a rare form of pulmonary amyloidosis. Ante-mortem diagnosis is unusual, and most of the reported cases were diagnosed at autopsy. It has recently been reported that transbronchial lung biopsy via a flexible fiberoptic bronchoscope was a relatively safe method to confirm diffuse alveolar septal amyloidosis.
We report a case of pulmonary diffuse alveolar septal amyloidosis confirmed by transbronchial lung biopsy. The patient’s chief complaints were dyspnea on exertion and epigastric pain aggravated over a one-year period, while a chest roentgenogram showed bilateral diffuse interstitial infiltration. This case also showed nephrotic syndrome, cardiac arrhythmia, congestive heart failure, a tingling sensation in both hands and multiple nodules in the gastrointestinal tracts, suggesting involvement of the kidney, heart, peripheral nerves and gastrointestinal tracts.
We propose that when diffuse interstitial lung disease is present with systemic signs such as nephrotic syndrome or cardiac arrhythmia, amyloidosis should be considered as a possible diagnosis. Also, transbronchial lung biopsy may be a useful confirmative diagnostic tool.
doi:10.3904/kjim.1990.5.1.63
PMCID: PMC4534991  PMID: 2271513
Pulmonary amyloidosis; Diffuse alveolar septal; Transbronchial biopsy
24.  Lymphocytic interstitial pneumonia as a manifestation of SLE and secondary Sjogren's syndrome 
BMJ Case Reports  2013;2013:bcr2013009598.
A 47-year-old woman with systemic lupus erythematosus (SLE) diagnosed at age of 35years was admitted for dyspnoea, substernal chest pain, dry mucosas and difficulty in swallowing. Physical examination revealed vesicular breath sounds bilaterally. Laboratory work showed antinuclear antibody (ANA) (speckled pattern, 1:40), positive anti-Sjogren’s syndrome antigen (SSA) and antisingle side band (SSB) and negative double-strand DNA (dsDNA), with normal C3,C4,C50. A high-resolution chest CT scan demonstrated multiple bronchial cysts and diffuse interstitial infiltrates. Surgical lung biopsy revealed emphysematous changes and mild lymphocytic infiltrate around the bronchioles compatible with lymphocytic interstitial pneumonia diagnosis. This case illustrates a patient with primary SLE overlapped by initial manifestations of secondary Sjogren’s syndrome (SS) presenting with associated autoimmune interstitial lung disease. Antibody markers, high-resolution chest CT scan and surgical lung biopsy were essential in evaluating this patient, confirming the interstitial lymphocytic infiltration of the lung. Primary SS (pSS) is the most commonly associated disease to lung interstitial pneumonia (LIP) (25%). High-resolution chest CT scan demonstrates areas of ground-glass attenuation, suggestive of interstitial disease. Surgical lung biopsy shows pathologic increase of mature lymphocyte cells and histiocytes. Most of the cases have a benign presentation and shortly relapse. Superimposed infection, pulmonary fibrosis and lymphoma develop in less than 20% of cases. Corticosteroids are the primary therapy. While pSS is commonly associated with interstitial lung involvement, secondary Sjogren's syndrome (sSS) is only rare. It has been described the initial sSS presentation by Sica symptoms development only, and our case is the first report of LIP presentation as initial manifestation of sSS. Our patient remained stable after corticosteroids and hydoxychloroquine therapy and no progression of disease after 6 months follow-up.
doi:10.1136/bcr-2013-009598
PMCID: PMC3762176  PMID: 23912652
25.  Statin Use Is Associated with Reduced Mortality in Patients with Interstitial Lung Disease 
PLoS ONE  2015;10(10):e0140571.
Introduction
We hypothesized that statin use begun before the diagnosis of interstitial lung disease is associated with reduced mortality.
Methods
We studied all patients diagnosed with interstitial lung disease in the entire Danish population from 1995 through 2009, comparing statin use versus no statin use in a nested 1:2 matched study.
Results
The cumulative survival as a function of follow-up time from the date of diagnosis of interstitial lung disease (n = 1,786+3,572) and idiopathic lung fibrosis (n = 261+522) was higher for statin users versus never users (log-rank: P = 7·10−9 and P = 0.05). The median survival time in patients with interstitial lung disease was 3.3 years in statin users and 2.1 years in never users. Corresponding values in patients with idiopathic lung fibrosis were 3.4 versus 2.4 years. After multivariable adjustment, the hazard ratio for all-cause mortality for statin users versus never users was 0.73 (95% confidence interval, 0.68 to 0.79) in patients with interstitial lung disease and 0.76 (0.62 to 0.93) in patients with idiopathic lung fibrosis. Results were robust in all sensitivity analyses.
Conclusion
Among patients with interstitial lung disease statin use was associated with reduced all-cause mortality.
doi:10.1371/journal.pone.0140571
PMCID: PMC4608706  PMID: 26473476

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