1  Orphan Lung Diseases: From Defnition to Organization of Care	5

genetic origin, DNA mutations are being identi ed in an increasing proportion of familial interstitial lung diseases (ILDs) [13, 14].

Rare pulmonary diseases may be limited to the lungs or may result from pulmonary involvement of systemic diseases. Rare diseases limited to the lungs may be acquired (e.g., hypersensitivity pneumonitis) or of genetic origin (e.g., diffuse interstitial lung disease in children and young adults associated with mutations in surfactantor telomererelated genes).

Pulmonary involvement may occur in acquired rare systemic disorders (e.g., pulmonary manifestations of granulomatosis with polyangiitis) or in disorders of genetic origin (e.g., pulmonary lymphangioleiomyomatosis in tuberous sclerosis complex). In such conditions, solitary or dominant pulmonary involvement may be the presenting manifestation with only minor or silent systemic features (e.g., glomerulonephritis­ in microscopic polyangiitis with diffuse alveolar hemorrhage). Overlapping and distinct phenotypes of rare diseases are common: sporadic pulmonary lymphangioleiomyomatosis may be solitary or associated with kidney angiomyolipoma(s) or part of the systemic manifestations of tuberous sclerosis complex.

The spectrum of the rare pulmonary diseases presented in this book includes a variety of disorders, which themselves may present diagnostic challenges when similar clinical and/ or imaging features are present. This is especially the case for rare pulmonary tumors (e.g., primary pulmonary lymphomas) or rare infections (e.g., atypical mycobacterial infections), which can mimic a variety of conditions. The differential diagnosis of any rare pulmonary disease should thus always take into consideration the possibility of neoplastic or infectious disorders. Conversely, some rare conditions have a particularly protean presentation (e.g., sarcoidosis, lymphoproliferative lung disorders) [15] or have unusual presentations (e.g., lymphangioleiomyomatosis [16]), leading to diagnostic challenges.

Diagnostic Challenges

Diagnostic delays are a major complaint of patients with rare disorders, with a de nite diagnosis obtained only after several years in a large proportion of cases [17]. This issue is refected in the vast majority of surveys of patients and patient associations [18–21].

It is evident that a general practitioner cannot be aware of the thousands of rare diseases with their phenotypes and diverse presentations. However, medical education should emphasize the need for systematic consideration of a possible rare disease for any patient with atypical features of a suspected common disease (Box 1.1). Resources are now available online, allowing nonspecialist physicians to quickly

Box 1.1 Methodical Doubt for a Rare Disease

The main practical dif culty in the diagnosis of rare pulmonary diseases is that most of them present with common and not speci c features. Thus, an astute clinician has to raise the suspicion of a rare disease when faced with any atypical clinical features or unusualndings. The “methodical doubt” for the eventuality of a rare disease is a prerequisite for an accurate diagnosis of atypical common disorders, which eventually prove to be distinct rare diseases.

Some examples are as follows:

––Idiopathic bilateral lower lobe bronchiectasis in a 34-year-old man with further chronic rhinitis and sinusitis (could it primary be ciliary dyskinesia?)

––Rapidly progressive dyspnea with diffuse in ltrative lung disease on chest X-ray with severe worsening anemia (could it be alveolar hemorrhage?)

––Pneumothorax in a patient with polydipsia (could it be Langerhans cell histiocytosis?)

––Increasingly severe asthma with heart failure in a 25-year-old man (could it be eosinophilic granulomatosis with polyangiitis?)

––Relapsing episodes of hemoptysis, bruises of the lower limbs, and history of shoulder luxation in a 35-year-old man (could it be Ehlers–Danlos disease?)

––Bilateral, thin-walled, central, cystic bronchiectasis and a right apical bulla in a nonsmoking 56-year-­old man with repeated infections, cough, and wheezing (could it be Williams–Campbell syndrome?)

get synthetic information about most rare lung diseases (e.g., https://www.orpha.net/, https://www.ncbi.nlm.nih.gov/ guide/genetics-medicine/).

Such patients should be referred to a respiratory specialist for either con rming an atypical presentation of a common disease or seeking assistance in the diagnosis of a rare pulmonary disease. Because of the complexity involved, we recommend that any patient suspected of having a rare disease should be offered the bene t of a second opinion at an expert center, for con rmation (or making) of a precise and de nitive diagnosis and for outlining a program of specialized care. In the eld of interstitial lung diseases, for example, referral to an expert center frequently corrects the diagnosis or suggests a diagnosis or investigation when no diagnosis has yet been contemplated [22], and early referral to an expert center is associated with an improved outcome [23]. Such patients must be advised to contact patient organizations and especially meet expert patients [24]. They should further be informed about possible participation in studies and clinical trials.

6	V. Cottin

Expert Centers

In rare disease care, the experience of any single physician is limited, and a well-organized, multidisciplinary approach at an expert center leads to better outcomes than more traditional models [25–27]. The goals of a specialized center are multifold and are centered around providing timely access to an accurate diagnosis and an effective care plan. Other deliverables include management of treatment side effects and patient comorbidities, patient education and support groups, medical education of both practicing clinicians and trainees, and access to clinical trials, lung transplant, and end-of-life care. Organization models for the care of orphan lung diseases are exempli ed by those employed for the care of interstitial lung diseases. A multidisciplinary team is integral to providing such complex care delivery and requires access to pulmonology, rheumatology, pathology, thoracic surgery/ interventional pulmonology, radiology, palliative care, lung transplant, pharmacy, nursing, social work, and administrative support (both clinical and research), with expertise in orphan lung diseases [26]. The key components of the role of a specialized center are presented in Fig. 1.2.

Facilitating multidisciplinary discussions is a key function of expert centers, and such discussions are the current gold standard for the diagnosis of interstitial lung diseases. They integrate clinical, radiological, and, where available, pathological features in order to reach a consensus diagnosis [28–31] and further incorporate a variety of information that contribute to the diagnosis, including autoimmune serology,

	Medical
	community
Patients’	Clinical
associations
and	research
advocacy

Patient

	Regulators	Translational
		research

	Payers	Pharmaceuti-
		cal industry

Fig. 1.2  The key components of the role of a specialized center for orphan lung diseases

precipitins, clinical or molecular biology genetic information, molecular classi ers, or reports from other health-care providers (e.g., occupational medicine specialist, domiciliary visit looking for exposures that may cause hypersensitivity pneumonitis, etc.). Diagnoses of interstitial lung diseases in multidisciplinary discussions have been shown to improve diagnostic con dence and decrease interobserver variability [22, 32–34]. The expertise of an ILD center allows for better assessment of the risk inherent in diagnostic procedures and may reduce the number of cases in which a biopsy is contemplated and performed [35], as compared to centers with less familiarity with interstitial lung diseases [36].

There is signi cant heterogeneity in the conduct of multidisciplinary meetings in interstitial lung disease centers and no established composition of the panel of participants. Multidisciplinary discussions, at minimum, include a pulmonologist and a radiologist with expertise in the eld [31, 37]. Specialized diagnostic resources, including extensive autoimmune serology and histopathology obtained by videothoracoscopic surgical lung biopsy or cryobiopsy, may be needed to make an accurate diagnosis. Depending on the individual case, other specialty involvement, such as pathology, rheumatology, or genetics, may be useful [31, 38]. A quiet setting with a visual projection system, high-quality high-resolution computed tomography of the chest, and a standardized template summarizing collated patient data are the essential components [31]. Multidisciplinary groups that do not include all interstitial lung disease-speci c experts bene t from access to larger and better versed panels for their more complex cases [39]. Innovative strategies are needed to overcome geographic barriers and facilitate access to multidisciplinary discussions and expert diagnostic testing for patients with rare diseases [40].

Although there are no established criteria of expertise, there is informal agreement that expert centers should have ample expertise, infrastructure, and resources for a given rare disease (or for a group of rare diseases, e.g., interstitial lung diseases), associating clinical experience with an adequate volume of patients with the disorder together with active clinical research (international scienti c publications), commitment to education and training, and open collaboration with translational research laboratories in the eld. European countries including France have pioneered the formal identi-cation of expert centers, with advantages of greater visibility of centers and more ef cient referrals of patients to experienced physicians, data collection [41], and initiation of a virtuous circle with larger patient cohorts, increased physician experience, improved medical education, and greater participation in research. As an example, the designation of expert centers in France has validated renewable 5-year mandates of national “reference centers” with further “regional competence (referral) centers” in the specialty departments of large university hospitals. The role of these

1  Orphan Lung Diseases: From Defnition to Organization of Care	7

reference centers, especially, comprises the production of diagnostic and management procedures and guidelines, evaluation of referred individual complex cases, development of registries, design and coordination of clinical research, and epidemiological studies. These “competence (referral)” centers together with their “reference” centers form a tight network, allowing equity in the access to care and clinical research for all patients in the country. One further layer of organization of care by organ involved (e.g. all expert centers in the respiratory eld) ensures that the care pathway to the respective expert centers (reference or competence centers) is smooth and ef cient. This ensures especially, that some centers be designated to organize the care of the rarest of conditions (e.g., referral of a patient with alveolar microlithiasis to a national reference center that specializes in all rare interstitial lung diseases including genetic conditions).

The European Union Committee of Experts on Rare Diseases (EUCERD), entrusted with aiding the European Commission (EU), has laid down the foundation for the rare disease community regarding the centers of expertise, European Reference Networks, patient registries and databases, newborn screening, and indicators for national rare disease plans/strategies [42]. The overarching aim of the European Reference Networks is to facilitate access to highly specialized health care for patients requiring a concentration of resources or expertise [43]. The European Reference Network for the lungs (ERN-LUNG, https://ern-lung.eu/) is one of the 24 established European Reference Networks. It has been established for patients with rare respiratory diseases seeking care and advice on all aspects of rare respiratory diseases and facilitates collaboration of expert centers throughout Europe for exchange of knowledge [44], cross-­ border cooperation, and health-care organization [43].

Patient Organizations

National patient organizations and advocacy groups have been developed for most rare diseases throughout the world [45, 46]. These, most often, have resulted from the efforts of obstinate pioneering individuals (or members of their family), progressively aggregating the skills of both patients and their families. The partnership of patients, clinicians, and scientists has resulted in major advances in the diagnosis and treatment of many rare diseases. The raising of funds, organization of annual meetings where patients (and their families) and doctors from expert centers meet, and national and international cooperation of patients have dramatically increased in the last few decades [24].

Often, these organizations work only with patients in a single country, limited in many cases by language barriers. However, international federations of patient associations are increasingly overcoming this limitation. One example for

this is the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation (EU-IPFF), which federates 21 member organizations representing countries all over Europe (https://www.eu-ipff.org). Further alliances of patients’ organizations have been developed at the international level, especially in the USA (National Organization for Rare Disorders, NORD, https://rarediseases.org/) and in Europe (European Organization for Rare Diseases, EURORDIS, www.eurordis.org). The EURORDIS website contains the contact details of dozens of organizations that work on individual diseases or rare diseases in general.

The LAM Foundation is a clear example of how advances can be made when patients and researchers work together toward a common goal [47]. Founded in 1995 and driven by the tremendous motivation of a mother of a young patient with lymphangioleiomyomatosis and the networking power of the Internet, the LAM Foundation has funded landmark studies that have substantially improved our knowledge of the disease pathobiology [48] and has been instrumental in the conduct of a randomized controlled trial that demonstrated the bene t of targeting mammalian target of rapamycin, providing patients with an effective treatment [49].

Clinical Trials

De nitive clinical trials of drugs and procedures for patients with rare diseases are challenging because patients are geographically dispersed and the recruitment of an adequate number of subjects is dif cult. In addition to the rarity of patients, a major challenge is the recruitment of patients early enough in their disease course to be amenable to improvement (or at least stabilization) of their condition (e.g., idiopathic pulmonary brosis, which is too often diagnosed only at a late stage when characteristic end-stage irreversible honeycombing is present) [17].

In highly rare diseases, standard, randomized, double-­ blind, placebo-controlled trials for the evaluation of new drugs may be logistically impossible, often leading to adoption of alternative suboptimal study designs and methods and less clinically meaningful end points. However, innovative adaptive designs and statistical approaches are increasingly being developed to overcome the barriers due to small sample sizes [50–56].

Research in Orphan Lung Diseases

Patients with orphan lung diseases seek global access to a de nite diagnosis and expert management as well as to cutting-­edge clinical and basic research.

Advances in rare diseases often begin with early observations in curious single cases initially based on dysmorphol-

8	V. Cottin

ogy. Over time, morphological and pathological features of single cases or short series of patients can lead to characterization of speci c syndromes or diseases. Advances in morphological studies may be followed by basic research that often includes extended genetic analysis. The identi cation of the pathophysiological mechanisms of diseases supported by public and private institutions, furthered by the advocacy of patients and patient groups [24], forge the path to comprehensive care from onset symptoms to ef cient treatment.

as well as academic involvement including knowledge of the disease and its treatment, academic training as an educator/ teacher with health professionals in patient education (including self-management), willingness to take into account patient values and priorities for decision-making, collaborative relationships with academic specialists, responsibilities in patients’ associations (e.g., as a board member), attendance and active participation in regional/national/ international patient meetings, and participation as a partner in the design of clinical studies/therapeutic trials [47].

Orphan Drugs

Orphan drugs are speci cally designed to treat rare diseases. The US Orphan Drug Act was signed into law in 1983, providing incentives to the pharmaceutical industry to improve the development of drugs for rare diseases [46]. The “orphan” status allows sponsors to bene t from incentives, research subsidies, and extended patent protection, for the development of drugs (and further medical devices or drug products). More than 500 new orphan therapies have been approved since passing the Act. In Europe, the regulations for orphan medical products were adopted in 1999. Marketing exclusivity for orphan drugs spans 7 years in the USA and 10 years in the EU.

Although these regulations have been effective in supporting the development of new drugs for rare diseases, they also have some downsides, with fewer drugs going through the traditional process, less rigorous trials conducted for orphan drugs, and unaffordable prices for orphan disease therapies. Some authors, therefore, believe that the Orphan Drug Act and the approach to orphan drug development may need to be updated [57, 58].

Orphanet

Orphanet (www.orpha.net) is a portal for rare diseases and orphan drugs. It provides comprehensive information about the classi cation of rare diseases and an encyclopedia of rare diseases, and offers services including assistance-to-­ diagnosis tools, emergency guidelines, inventory of orphan drugs, directory of expert centers and patient organizations, directory of professionals and institutions, etc..

Empowerment of Patients

The empowerment of patients is a necessity in rare diseases because these are chronic and dif cult-to-manage disorders that require coordinated efforts to make progress [45, 47]. The ideal expert patient with a rare disease should have both personal and collective experiential knowledge of the illness

Conclusions

Comprehensive care delivery for orphan lung diseases has several key components including diagnosis, treatment, monitoring, support/advocacy, education, and research. The overarching goal of improving patient care and advancing the eld of orphan lung diseases can only be achieved in specialized centers with multifaceted care delivery models. With the exponential pace of knowledge generation, orphan lung diseases including interstitial lung diseases have become a subspecialty. Effective knowledge translation and dissemination have become more complex, bene ting from sharing of expertise, and international collaborations are the key to facilitate research. Creative and innovative strategies are needed to nd ways to deliver optimal care to the highest possible number of patients with orphan lung diseases.

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