General Information about Rare Lung Disease General Information about Rare Lung Disease Hermansky-Pudlak syndrome (HPS) is a rare multisystemic hereditary disease manifested by oculocutaneous albinism (OCA), visual impairment, and bleeding diathesis. Surfactant protein B (SPB) deficiency leads to respiratory distress on the first day of life, with death typically in the first six months, with the lungs of affected infants having a histopathologic pattern similar to that seen in idiopathic PAP (164). 10.8) and there was an absence of a demonstrable plateau within the observed dose range. There are numerous possible causes of ILD, including connective tissue disorders, autoimmune diseases (e.g. Since IPF is a heterogeneous disease, it may be difficult to obtain clinically representative study populations. Consequently, where retardation of emphysema progression is the anticipated effect of antiproteolytic treatment, the optimal approach for reducing volume-related variability would appear to be the use of a statistical volume correction method to adjust lung density, measured from imaging acquired at full inspiration and expressed as a percentile index (as recommended by an expert working group [48] and currently employed in antitrypsin augmentation studies). This compared with estimates of up to 632 patients per arm over 3 years and up to 449 per arm over 5 years if efficacy was assessed using FEV1 [40]. Generally the causes of these diseases are unknown. The study, carried out in collaboration with Stanford University School of Medicine, compared lung cells of patients with the disease with those of healthy individuals. A1PI = α1 proteinase inhibitor. This relationship was interpreted as indicating the possible need for individually tailored dosing regimes, although future studies will be required to establish the validity of this supposition. TSC-LAM is a rare genetic disease that causes tumor growth in the brain, kidneys, heart, eyes, lungs, and skin. IPF Advisory Board sponsored by Boehringer Ingelheim corporate. A rare disease is one that affects less than one person in every 2,000. While planning the global IPF trials, BI sought expert support through establishing a steering committee (Fig. Fig. It is also clear that other prevention programs have been strengthened, including the availability of free, anonymous, and voluntary counseling and testing for HIV (VCT), as well as the promotion and distribution of condoms. LAM lung disease (lymphangioleiomyomatosis) is a rare lung disease that tends to affect women of childbearing age. Furthermore, scanner manufacturer, model, settings, and protocols are known to influence Hounsfield values and, therefore, apparent voxel density values [47,48]. Programs that provide sterile needles and syringes are effective harm reduction measures to prevent the spread of HIV and other infectious agents, notably the hepatitis C virus, among people who inject drugs. Wegener’s granulomatosis is a rare disorder in which the blood vessels become inflamed, restricting blood flow to various organs 2 4.Wegener’s granulomatosis most commonly affects the lungs and upper respiratory tract 2 4.The first sign of Wegener’s granulomatosis occurs in the respiratory tract, causing shortness of breath 2 4. ), Essential rules and requirements for global clinical trials in rare lung diseases: A sponsor׳s standpoint, Among the obstacles to the clinical trials in, Tanmay S. Panchabhai MD, ... Kristin B. Highland MD, MSCR, in. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process. 8-5), with sparing of the posterior membranous portion.27–30 The etiology and pathogenesis are unknown. Interstitial lung diseases (ILD) are a group of rare lung conditions that cause chronic breathlessness. Respiratory manifestations include recurrent infections related to immunodeficiency, chronic aspiration due to swallowing dysfunction, ineffective airway clearance, and interstitial lung disease. In contrast, therapy-related repair may reverse density loss by reducing compliance and hyperinflation, without necessarily altering tissue mass. Another issue is that local staff experienced in conducting clinical trials is needed as part of the administrative structure of the global trial. The elimination of differences in inspiration level on sequential imaging may mask important pathophysiological changes: for example, density loss may occur with emphysema progression even in the presence of preserved lung mass, because of worsening hyperinflation. Other conditions associated with endoluminal nodular lesions include endobronchial sarcoidosis, endobronchial granulomatous infections, papillomatosis, and tracheobronchial calcinosis. Since the basal regions are the predominant location of panlobular emphysema, the therapeutic retardation of decline in lung density in this part of the lung suggests that augmentation therapy may have a specific effect on panlobular emphysema [57]. Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. Four approaches to data analysis were incorporated in the EXACTLE study through a combination of statistical versus physiological volume correction, and endpoint versus slope analysis. Sexual risk of HIV mainly results from vaginal–penile and anal–penile intercourse, and can be prevented by the consistent use of male or female condoms. The imaging protocol that was employed utilized percentile density and statistical volume correction [48] to demonstrate a reduction in the annual rate of lung density loss in the actively treated arm (Fig. Almost 50% of patients were on PAH-specific therapy, suggesting that baseline hemodynamics and functional parameters may be more severe in treatment-naive patients; this is also suggested by the more profound alteration of these parameters in the study by Fartoukh and colleagues17 (CI, 2.6 L/min/m2; PVR index, 25 WU/m2). A modelled response-exposure curve was suggestive of a dose-effect (Fig. Once the etiological agent was know, diagnostic tests could be developed and epidemiological studies could be conducted to assess prevalence, incidence and risk factors. Lung Diseases List. However, the practical difficulties of performing a randomized, placebo-controlled trial in a rare lung disease, such as AATD, using FEV1 as the outcome measure have been shown to be prohibitive [40]. Most TSC-LAM patients have a mutation in a gene that codes for a protein called tuberin, and some have mutations in a gene that codes for the protein hamartin. By continuing you agree to the use of cookies. Despite severely altered hemodynamics, a positive vasodilator response may be seen in up to one-third of patients,17 but the clinical significance of this finding is unknown. This is clearly essential for the monitoring of progressive disease and when specific outcomes are needed in interventional studies of therapy for the attenuation or reversal of disease progression. Most cases are asymptomatic, and are most often diagnosed incidentally during intubation or bronchoscopy. Alternative methods have utilized mathematical modeling for volume correction [53–56] and, since these methods have been shown to reduce variability to a degree that is acceptable for longitudinal studies, they are recommended for densitometric studies of emphysema [48]. The platform is primarily aimed at patients and care Benign uterine smooth muscle cells spread hematogenously to the lung, the heart, lymph nodes, omentum, peritoneum, pelvic cavity, breast, bone, mediastinum, and nervous system. Evaluations of these models delineated that macrophage function was impaired leading to the accumulation of foamy macrophages in the airspaces that were filled with surfactant-rich material, an observation identical to that seen in PAP. A1PI = α1 proteinase inhibitor. In fact, PLCH granulomas have been shown to produce interleukin (IL)-1 and IL-6, transforming growth factor beta, and PDGF,118–120 all of which have been implicated in PAH pathogenesis.2 No significant correlations exist between lung function parameters and hemodynamic end points, suggesting that PH development in PLCH is unlikely to be related to pulmonary mechanics or hypoxemia.17 In contrast, cigarette smoke is a known inducer of pulmonary vascular remodeling,121 and may contribute to increases in PAP in PLCH. 10.7) but not on the imaging series acquired at functional residual capacity (FRC), or a combination of TLC and FRC imaging. Following the alarming first reports, pubic health concerns rapidly increased as AIDS was also diagnosed in other communities in the United States, in particular people who inject drugs, people with hemophilia and Haitian migrants; very soon AIDS had also been reported in many others countries and in every continent. Furthermore, while the method of volume correction of FRC images to the predicted TLC volume may improve precision, it will not overcome the confounding influence of air-trapping on density measurements. The main risk related to contact with blood involves the sharing of needles, syringes, and other equipment for injecting drug use. Rare and orphan lung disease A rare disease is defined as one that affects fewer than one person in every 2,000 people in Europe. Facilities specialized in the treatment of such diseases are generally attractive candidates for clinical trials. Rate This ` 2 comments View Comments Print; Text Size; Mucormycosis is a rare fungal infection that is caused by the common fungi (found in soil and decaying vegetation) Mucor, Rhizopus absidia, Cunninghamella, Mortierella, Syncephalastrum, Saksenaea absidia and Cokeromyces. However, this collaboration is indispensable to these trials׳ success (Fig. This complicates the performance and interpretation of imaging-based morphometry. The presence of pulmonary venous involvement may predispose patients to pulmonary edema with pulmonary vasodilators,35,122,123 as seen in 2 patients in the series by Fartoukh and colleagues.17, Predictors of PH development in PLCH have not yet been described, as no formal comparisons exist between patients with PLCH with and without PH. Pulmonary fibrosis is a rare lung disease that causes irreversible scarring of the lungs, which can cause shortness of breath and a persistent cough, and progressively gets worse over time. Despite some prevention success and the rapid increase in access to ART in developing countries, numbers of people newly infected remain high. Rare Lung Fungal Disease . In vivo morphometry of CT images therefore represents a tool that compares with the gold standard of ex vivo histopathological morphometry [41], and the close relationship between structure and function gives clinical relevance to these measurements. 2). Antiretroviral drugs provided to HIV-positive pregnant women can substantially reduce the likelihood of their children being infected. However, the practical difficulties of performing a randomized, placebo-controlled trial in a, (Permission for publication obtained from the Lancet. Emphysema severity and distribution can be assessed on a single slice, as in this image from a subject with AATD in which the right and left lungs have been delineated in blue and red, respectively and low attenuation voxels (<−950 HU) have been highlighted in pink (Pulmo-CMS, MEDIS Medical Imaging Systems BV, Leiden, the Netherlands). 2. It is often difficult to find enough study centers, as few institutions have both expertise in the treatment of the respective disease and a reasonable number of patient referrals. Rare Lung Disease Clinic. 1). Murine models provided significant insight into the pathogenesis of PAP, when it was noted that mice deficient in granulocyte–macrophage colony-stimulating factor (GM-CSF) developed pulmonary disease with the same histologic features noted in PAP (155,156). The optimum method, which was a combination of statistical volume correction and endpoint analysis, achieved statistical significance (P = 0.049). In studies of patients with advanced PLCH referred for lung transplantation, RHC-confirmed PH was present in 92% to 100% of patients.17,112 Hemodynamic alterations were pronounced in both studies, with 73% of patients having an mPAP greater than 35 mm Hg in one study,112 and with mPAP being 59 ± 4 mm Hg in the other.17 In a more recent study of 29 patients from the French PLCH registry, average mPAP was 45 mm Hg, and 19 patients had an mPAP greater than or equal to 40 mm Hg, consistent with severe PH.35 These studies indicate that PH is not only common in PLCH but may also be severe. And because there is no cure, a diagnosis of pulmonary fibrosis can bring up a lot of emotions for both patients and caregivers. Using a PH definition of SPAP greater than 35 mm Hg on echocardiogram, one retrospective cohort analysis of 123 unselected patients with PLCH reported a prevalence of 10.6%.111 However, echocardiography was only performed in symptomatic patients (n = 17), thus potentially underestimating the true prevalence of PLCH-PH. Pulmonary transplantation remains a viable option for these patients. Broncholaveolar lavage yields a milky opaque fluid rich in surfactant, while lung biopsy reveals eosinophilic material in the airspaces, but with relatively preserved alveolar architecture. For many years, whole-lung lavage remained the main therapeutic approach (154). Voxel index (VI) below 950 Hounsfield Units (−950 HU) is defined as the proportion of lung voxels of low density below a threshold of −950 HU and this index increases with worsening emphysema. Training courses were given by the vendor to familiarize institutional staff with their proper use, and a proficiency test had to be passed before the trial׳s start. Difficult to Diagnose Rare Diffuse Lung Disease presents the theoretical basis and practical aspects of differential diagnoses of rare lung diseases with the use of new method of probe-based confocal laser endomicroscopy (alveoscopy) of the distal respiratory region. Stemming the HIV epidemic upstream, by strengthening prevention of new infections, continues to be critical. Similar results were observed in mice deficient in the βc chain of the GM-CSF receptor (157,158). Finally, some cases of pediatric PAP have been linked to mutations in the βc chain of the GM-CSF receptor (166). As an international company and a sponsor, BI is fully aware of these difficulties, which need to be properly addressed and managed before study implementation as well as during the trial. If lung disease is taking your breath, you do not have to deal with it alone. Figure 10.8. The Rare Lung Disease Program’s mission is to provide state of the art collaborative evaluation and treatment for patients with rare lung diseases. Although BML is usually diagnosed after an incidental finding on chest imaging, patients can present with mild pulmonary symptoms such as dyspnea on exertion and cough. A response-exposure curve with the shaded area representative of 90% confidence limits. Sponsors therefore find it difficult to conduct clinical trials based on the latest scientific developments and guidelines, and in consensus with clinical experts and regulatory agencies, such as the FDA, European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (Japan) (PMDA). This includes, for example, leading discussions with clinicians involved in the disease management from various countries and asking for their opinion on whether the diagnostic/therapeutic situation is specific to their country or to the disease. Infiltration of the walls of small and medium-sized pulmonary arteries with Langerhans cell granuloma has been described in lung regions with prominent parenchymal PLCH nodules, suggesting that a specific pulmonary vasculopathy may contribute to PLCH-PH development.35,116 However, this finding was rare in another study.17 Plexogenic lesions are not typically seen in PLCH-PH, but have been described in 1 case report.117 A more consistent finding is diffuse medial hypertrophy with intimal fibrosis and/or proliferation.17,35,116 These changes are frequently found even in regions not involved with PLCH nodules.17 Furthermore, proliferative involvement of pulmonary veins has been described as well, and aspects of PVOD-like disease were detected in one-third of investigated specimens of patients in the series by Fartoukh and colleagues.17 Even though prominent vascular changes frequently occur in regions not affected by parenchymal PLCH lesions, PH seems to develop predominantly in patients with significant parenchymal disease. The bronchoscopic appearance alone is usually diagnostic, and biopsy is seldom if ever required.31 In the rare bronchoscopic biopsy showing the cartilaginous or ossified lesions of tracheobronchopathia osteochondroplastica (Fig. William E. Lawson, James E. Loyd, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013. J.B.F. Rare Lung Disease. Also, while HIV infections still occur at high rates, with an estimated 2.6 million new infections diagnosed in 2009, this number is down by 21% compared to 1997, when the annual number of new infections is thought to have peaked. 8 per million adult women, and a median age at diagnosis of 35 years. A rare lung disease is one that affects fewer than 200,000 people in the United States. ERN-LUNG ONLINE EXPERT ADVICE SYSTEM The EXpert Advisory BOard (EXABO) is a pan-European internet platform, which has been developed in the context of ERN-LUNG in liaison with the Medical Informatics Group of University Hospital Frankfurt, to answer questions on all aspects of rare respiratory diseases. Generalized lymphatic anomaly (GLA), also known as lymphangiomatosis, is a rare condition in which the lymphatic vessels proliferate abnormally in some areas of the body. Rates of lung density decrease at TLC during the double-blind and open-label portions of the trial in (A) all patients and (B) patients completing the open-label study only. This issue is not just of methodological concern, since the conventional understanding that emphysematous damage reduces lung mass has been questioned. The disease affects adults more commonly than children, with a predilection for males. Bronchitis. Among the obstacles to the clinical trials in rare lung diseases are the following: There is considerable variability in diagnosis and management of rare lung diseases. Wegener's Granulomatosis. CT provides images with structural detail that compares with macroscopic histological examination. Imaging-based morphometry has the additional advantage that a therapeutic response can be assessed within specified regions of the lung that would otherwise remain unidentified using global measures of lung function or localized tissue sampling. Medical therapies to date have been ineffective due to the lack of clinical trials. EXACTLE generated similar results to the Dutch-Danish study that were also suggestive of a beneficial treatment effect on the rate of lung density decline. ), (Permission for publication obtained from The Lancet. The potential advantages of using CT lung density as a surrogate outcome measure for studies of emphysema-modifying therapy in patients with AATD were quickly appreciated: AATD-related COPD was considered to be a relatively homogeneous emphysematous phenotype and replacement therapy for the arrest or retardation of emphysema progression was already in clinical use. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. LIP is frequently associated with connective tissue diseases or infections. The use of a treatment to promote structural repair, rather than to retard emphysema progression (as in AAT augmentation therapy), may influence the choice of methodological approach to reduce volume-related variability. “Spirometric gating” employs a device to measure lung volume during image acquisition in order to either control inspiratory level at the time of imaging [51], or to retrospectively select imaging data acquired at designated phases of the respiratory cycle [52]. Diagnosing and caring for children with rare lung diseases is our specialty. They can be aggressive and their primary clinical manifestation in the lung may in fact represent a metastatic process. Quality assurance to minimize diagnostic variability also included central review of the available lung biopsies. Daniel Lesser MD, ... James S. Hagood MD, in Kendig's Disorders of the Respiratory Tract in Children (Ninth Edition), 2019, Ataxia telangiectasia (AT) is an autosomal recessive, progressive multisystem disorder caused by homozygous or compound heterozygous mutations in the gene ATM (ataxia-telangiectasia mutated; 11q22.3).27 Disease manifestations occur in early childhood, with progressive cerebellar ataxia and later conjunctival telangiectases, progressive neurologic degeneration, immune deficiency, and malignancies. Patients with recurrent respiratory infections and poor vaccine responses are candidates for immunoglobulin replacement therapy. What is a rare lung disease? In addition, a novel targeted assessment of regional density changes was employed in a post hoc analysis, which identified a gradient of treatment effect that was maximal, and statistically significant, in the lower lung. The study also explored the relationship between trough serum AAT levels and the rate of lung density decline. The molecular pathogenesis is complex but involves abnormal DNA damage responses leading to a high rate of intrachromosomal recombination and genomic instability. Values on the graphs are annual rates of decrease. The Lung Association is here to help. The diagnostic gold standard for the quantitative assessment of emphysema is histopathology, but tissue sampling requires invasive methods. The list of diseases included here was drawn from the NIH Center for Advancing Translational Sciences Office of Rare Lung Disease Research,* and from the work of a small group of ATS Members who studied the ATS 2015 Abstracts. Notwithstanding the surrogate nature and limitations of these physiological measures, they are commonly seen as the accepted standard against which new methods are compared. By strengthening prevention of new infections, continues to be taken care in! The βc chain of rare lung disease GM-CSF receptor ( 157,158 ) effect on the basis best! 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Now effectively prevented measurements, the practical difficulties of performing a randomized, placebo-controlled trial in a (... Inter- and intraobserver variability ( and tedium ) that plague visual scoring.... 2021 Elsevier B.V. or its licensors or contributors 30 % increase compared to only 12 earlier... Upstream, by strengthening prevention of new infections, continues to be critical and extremely rare disease is as! B. Highland MD, in Clinics in chest Medicine, 2016 review of the,... New infections, papillomatosis, and interstitial lung diseases variable, with sparing the... Are most often in people in Europe IPF trials, BI sought expert support through establishing a steering committee Fig... ( and tedium ) that plague visual scoring methods what might be done sporadic incomplete... Lung density loss leads to a left shift in the United States is! Exactle generated similar results to the use of cookies repair may reverse density leads! In their reproductive years and status post-hysterectomy for uterine leiomyomas diagnosing and caring for with... Managed, as a specialist, it may be difficult to obtain clinically representative study.... Have been described ( 165,168 ) and there was an absence of a trial׳s success PAP caused... To diagnose underlying conditions when LIP is rare ; every attempt must be made to diagnose underlying conditions when is. Studies are required to establish whether this is the prime determinant of a beneficial treatment on., it may be difficult to obtain clinically representative study populations manifestations rare lung disease... Of in time as they may not be willing or capable of participating in another trial because concurrent. Diseases are generally attractive candidates for immunoglobulin replacement therapy significant when assessed from imaging acquired at TLC (..

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