of disorders of surfactant production (A) and clearance

(B)—collectively referred to as “disorders of surfactant homeostasis” [34]. The former group (i.e., A) includes conditions secondary to mutations in genes encoding surfactant proteins (SPs)-B and -C [35] or proteins involved in surfactant lipid metabolism (i.e., ABCA3) [36, 37]. Conversely, PAP syndrome belongs to the second category of disorders (i.e., B) and is classi ed as “primary,” which can be either autoimmune (accounting for more than 90% of all cases) or hereditary, or as “secondary” to inhalation of dust, such as silica, or underlying immunological or hematological ­diseases that alter macrophage function. Autoimmune PAP is characterized by the presence of neutralizing autoantibodies directed against granulocyte macrophage colony-stimulating factor (GM-CSF) [38]. Conversely, hereditary PAP cases carry autosomal recessive mutations within the CSF2RA or CSF2RB gene, which encode the alpha and beta subunits of the GM-CSF receptor, thus resulting in decreased protein expression on the cell surface [39]. Defective GM-CSF activity, in turn, results in altered function of alveolar macrophages, which are unable to maintain surfactant homeostasis and display defective phagocytic and antigen-presenting capabilities [40], leading to increased susceptibility to lung infections [41]. Despite the complexity of the different conditions that are included under the “disorders of surfactant homeostasis” umbrella, this is a nice example of how basic, animal-based research can facilitate the understanding of the basis of human disease that, in turn, stimulates the development of an effective, novel treatment strategy.

Lack of Access to a Correct Diagnosis

Delay in Diagnosis

For many individuals with a rare disease, the period between the emergence of the rst symptoms and the appropriate diagnosis often involves unacceptable and highly risky delays; in addition, in many instances, a wrong diagnosis leads to the administration of inappropriate, if not dangerous, treatments. The European Organization for Rare Diseases (EURORDIS), in collaboration with 67 European rare disease organizations, has conducted a survey about the delay in diagnosis for 8 rare diseases in Europe [3]. One of the main ndings of this survey was that 25% of patients had to wait between 5 and 30 years from emergence of early symptoms to a con rmatory diagnosis of their disease. Before receiving a secure diagnosis, 40% of patients rst received an erroneous one and others received none. In all, 25% of patients had to travel to a different region to obtain the nal diagnosis and 2% had to travel to a different country. The diagnosis was announced in unsatisfactory terms or conditions in 33% of cases and in unacceptable conditions in

12.5% of cases. The genetic nature of the disease was not communicated to the patient or family in 25% of cases. Intuitively, the consequences of a misdiagnosis include clinical worsening of the patient’s health—even leading to death—and loss of con dence in the health-care system. This is utterly unacceptable—imagine if this had occurred to a member of one’s own family—and should not continue.

Clinical features alone usually do not allow discrimination between rare and common lung diseases. In fact, the diagnostic delay of a rare disease is mainly accounted for by the fact that in early stages symptoms may be absent, masked, misunderstood, or confused with other more common diseases [42]. This implies that the goal of primary care should be the early recognition that a rare lung disease might be present and the determination of an appropriate threshold for referral to centers with speci c expertise. The need for more global, accessible educational tools is clear. “You only see what you look for and you only look for what you know.”

From a research perspective, these delays present barriers to recruitment, whereas from a clinical perspective, they contribute to patient morbidity. For instance, most patients suffer from several episodes of pneumothorax before being diagnosed with LAM. In addition, a misdiagnosis not only leads to inappropriate—and ineffective—treatments but also to unnecessary risks, such as pregnancy or air travel in the case of LAM. Similarly, in patients with Hermansky–Pudlak syndrome, invasive procedures should be avoided because of the patient’s tendency to bleed. In the latter case, a correct diagnosis allows other family members to be screened for the syndrome, with the demonstration of absent dense bodies on whole mount electron microscopy of platelets being diagnostic. Diseases caused by a single, mutated gene—such as alpha-1 antitrypsin de ciency, surfactant protein disorders, and cystic brosis—lend themselves to family screening. This is essential as diseases diagnosed at an early stage are more likely to be properly treated, and, with the knowledge that a rare disease is present in the family, other individuals are less likely to fall victim to an erroneous diagnosis.

Challenges But Not Negativity

These challenges should not be seen as insurmountable and, in some cases, have been successfully overcome (Table 2.1). This requires a clear appreciation of the fundamental pathological aspects of the disease in order to identify how to best deal with it; an ivory tower, purely mechanistic research, without keeping an eye on the disease that gave rise to the research question, can lead to false dawns (see excellent reviews in Moeller et al. [43] and Jenkins et al. [44], on the bleomycin model of lung brosis as a purported “model” for IPF and how this has failed to provide any novel therapy for this disease).