Respiratory

The Rare Responsibility: Every Breath Matters

Dear Impossible Readers,

Cystic fibrosis is the most widely recognised rare respiratory disease, but it is far from the only one. Rare respiratory diseases form a diverse group of conditions that, although uncommon individually, collectively affect thousands of patients worldwide. Unlike more common lung illnesses like asthma or COPD, these conditions often have unique genetic, immunological, or developmental origins. They frequently pose diagnostic challenges, progress unpredictably, and lack standardised care pathways. Understanding rare respiratory diseases is essential not only for improving patient outcomes but also for providing insights into fundamental biological processes that could transform medicine more broadly.

Lymphangioleiomyomatosis (LAM) involves abnormal smooth muscle–like cell growth that destroys lung tissue, primarily in women. Autoimmune pulmonary alveolar proteinosis (aPAP), by contrast, is caused by immune system dysfunction leading to surfactant accumulation in the lungs. Pulmonary veno-occlusive disease (PVOD) is a vascular condition where pulmonary veins and capillaries become blocked, often misdiagnosed as pulmonary arterial hypertension. Meanwhile, primary ciliary dyskinesia (PCD) results from inherited defects in the microscopic cilia that clear the airways, causing lifelong infections. Finally, congenital central hypoventilation syndrome (CCHS) is a neurological control disorder, where the brain fails to signal adequate breathing during sleep or wakefulness. Together, these examples demonstrate the wide biological spectrum covered by rare respiratory diseases, from genetic and autoimmune to vascular and neurological mechanisms.

Treatments today are often supportive rather than curative. For LAM, sirolimus (an mTOR inhibitor) can slow lung decline, but many patients eventually require oxygen or lung transplants. aPAP is usually managed with whole-lung lavage and, in some cases, inhaled or injected GM-CSF therapy. PVOD remains particularly challenging, as standard pulmonary hypertension drugs may worsen symptoms. Supportive care and lung transplants continue to be the only options. In PCD, airway clearance and antibiotics are the main treatments, alongside ENT care. CCHS patients rely on lifelong ventilatory support, either via tracheostomy, non-invasive ventilation, or diaphragm pacing. While these treatments help extend life and improve quality of life, they often fall short of addressing the root cause of the disease.

Future approaches may shift the paradigm. In LAM, researchers are exploring combination therapies beyond mTOR inhibition, as well as gene-based interventions targeting TSC mutations. For aPAP, antibody-depleting strategies such as rituximab or plasma cell–targeted drugs may provide longer-term relief, while gene therapy could address hereditary forms. PVOD research is looking towards earlier, non-invasive diagnostics and antifibrotic therapies to delay progression. For PCD, mutation-specific treatments inspired by cystic fibrosis drug development (e.g., read-through agents, splice-correcting oligonucleotides, and gene therapy) are on the horizon. CCHS may benefit from advanced ventilatory technologies, closed-loop breathing systems, and even gene-editing strategies for PHOX2B mutations. Collectively, these advances hold the promise of moving from symptomatic management to disease modification or even cure.

In summary, rare respiratory diseases emphasise the extensive variety of mechanisms that can impair breathing. While cystic fibrosis demonstrates what can be achieved when science and innovation come together, transforming a once-fatal disease into one manageable with targeted therapy, most other rare respiratory diseases remain in an era of supportive care.

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Further Reading

Bell, S.C., Mall, M.A., Gutierrez, H., Macek, M., Madge, S., Davies, J.C., Burgel, P.R., Tullis, E., Castaños, C., Castellani, C. and Byrnes, C.A., 2020. The future of cystic fibrosis care: a global perspective. The Lancet Respiratory Medicine, 8(1), pp.65-124.
Chen, W., Feng, X., Yao, L.K., Li, X., Yang, Z.M., Qin, X.Y., Li, Y. and Qiu, Y., 2025. Exogenous GM-CSF therapy for autoimmune pulmonary alveolar proteinosis: a systematic literature review. Frontiers in Medicine, 12, p.1552566.
Cottin, V., Richeldi, L., Brown, K. and McCormack, F.X. eds., 2023. Orphan lung diseases: a clinical guide to rare lung disease. Springer Nature.
Eyries, M., Montani, D., Girerd, B., Perret, C., Leroy, A., Lonjou, C., Chelghoum, N., Coulet, F., Bonnet, D., Dorfmüller, P. and Fadel, E., 2014. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nature genetics, 46(1), pp.65-69.
Johnson, S.R., Cordier, J.F., Lazor, R., Cottin, V., Costabel, U., Harari, S., Reynaud-Gaubert, M., Boehler, A., Brauner, M., Popper, H. and Bonetti, F., 2009. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. European Respiratory Journal, 35(1), pp.14-26.
Kuehni, C.E. and Lucas, J.S., 2017. Diagnosis of primary ciliary dyskinesia: summary of the ERS Task Force report. Breathe, 13(3), p.166.
Lucas, J.S., Davis, S.D., Omran, H. and Shoemark, A., 2020. Primary ciliary dyskinesia in the genomics age. The Lancet Respiratory Medicine, 8(2), pp.202-216.
McCarthy, C., Carey, B.C. and Trapnell, B.C., 2022. Autoimmune pulmonary alveolar proteinosis. American Journal of Respiratory and Critical Care Medicine, 205(9), pp.1016-1035.
McCarthy, C., Gupta, N., Johnson, S.R., Yu, J.J. and McCormack, F.X., 2021. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. The Lancet Respiratory Medicine, 9(11), pp.1313-1327.
McCormack, F.X., 2008. Lymphangioleiomyomatosis: a clinical update. Chest, 133(2), pp.507-516.
Montani, D., Price, L.C., Dorfmuller, P., Achouh, L., Jaïs, X., Yaici, A., Sitbon, O., Musset, D., Simonneau, G. and Humbert, M., 2008. Pulmonary veno-occlusive disease. European Respiratory Journal, 33(1), pp.189-200.
Porcaro, F., Paglietti, M.G., Cherchi, C., Schiavino, A., Chiarini Testa, M.B. and Cutrera, R., 2021. How the management of children with congenital central hypoventilation syndrome has changed over time: two decades of experience from an Italian center. Frontiers in Pediatrics, 9, p.648927.
Ratjen, F., Bell, S.C., Rowe, S.M., Goss, C.H., Quittner, A.L. and Bush, A., 2015. Cystic fibrosis (Primer). Nature Reviews. Disease Primers, 1(1).
Shteinberg, M., Haq, I.J., Polineni, D. & Davies, J.C., 2021. Cystic fibrosis. Lancet, 397(10290), pp.2195–2211.
Tai, J., Liu, S., Yan, X., Huang, L., Pan, Y., Huang, H., Zhao, Z., Xu, B. and Liu, J., 2024. Novel developments in the study of estrogen in the pathogenesis and therapeutic intervention of lymphangioleiomyomatosis. Orphanet Journal of Rare Diseases, 19(1), p.236.
Trapnell, B.C., Whitsett, J.A. and Nakata, K., 2003. Pulmonary alveolar proteinosis. New England Journal of Medicine, 349(26), pp.2527-2539.
Weese-Mayer, D.E., Patwari, P.P., Rand, C.M., Diedrich, A., Kuntz, N.L. and Berry-Kravis, E.M., 2012. Congenital central hypoventilation syndrome (CCHS) and PHOX2B mutations. In Primer on the autonomic nervous system (pp. 445-449). Academic Press.