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time to onset of chronic lung allograft dysfunction [42]. Comparison of the <tenth percentile telomere length group with the >tenth percentile group showed a higher rate of primary graft dysfunction, but there were no differences in the incidence of acute rejection, cytopenia, infection, or renal dysfunction [42].

Interestingly, among the patients included in the PANTHERIPF trial (prednisone/azathioprine/N-acetylcysteine), patients with the shorter telomere length (<tenth percentile) had the worse outcome (death, lung transplantation, hospitalization, or FVC decline) and a post hoc analysis showed an interaction between immunosuppression and telomere length [73], suggesting that azathioprine and prednisone are particularly harmful for patients with short telomeres and probably also for TRG mutations carriers.

Surfactant Pathway

Surfactant functions to alter surface tension to prevent alveolar collapse. Surfactant is secreted by type II epithelial alveolar cells and is composed of 90% lipids and 10% proteins. The main surfactant proteins are SP-A, SP-B, SP-C, and SP-D and the corresponding genes are called SFTPA, SFTPB, SFTPC, and SFTPD [7]. ABCA3 transporter (ATB Binding Cassette family A, member 3) encoded by ABCA3 is critical for pulmonary surfactant synthesis and processing [74]. Among surfactant gene mutations, SFTPA1, SFTPA2, and SFTPC mutations have been implicated in FPF.

Surfactant Protein Genes

Although SFTPC mutations were rst linked to pediatric cases of ILD, the contribution of SFTPC mutations in adult FPF has been also established in 1–5% of FPF cohorts [8, 75, 76]. De novo mutations are frequent in children and may explain as much as 50% of cases [77].

Heterozygous mutation in SFTPA2, or SFTPA1, has been identi ed in subjects with FPF and/or lung adenocarcinoma [78, 79].

ABCA3 is expressed in Type II AEC lamellar bodies and is important in surfactant processing. Although homozygous ABCA3 mutations are usually associated with respiratory failure in newborns [80], several adult patients carriers of

mutations of ABCA3 with pulmonary brosis and emphysema have been reported [81].

NKX2.1 encodes a transcription factor closely related to surfactant protein transcription [82]. Heterozygous mutations are classically associated with the triad of ILD, hypothyroidism, and neurologic anomalies (hypotonia, delayed development, chorea) [83]. However, thyroid abnormalities and neurologic anomalies may be subtle and easily overlooked, or even absent, in up to 1/3 of cases, including adult cases [83].

Pulmonary Involvement

Biallelic ABCA3 mutations and heterozygous NKX2.1, SFTPA1 SFTPA2, and SFTPC mutations in adults may share similar clinical and radiological presentation (Fig. 24.5). The most frequent radiological pattern associates diffuse ground-­glass opacities, septal thickening, and cysts of variable size with a preferential distribution in the upper lobes and in subpleural areas (Fig. 24.3). Differentiating emphysema from cysts is sometimes dif - cult, so SFTPC mutations should be considered in any young patient with what appears to be combined pulmonary brosis and emphysema [84]. At later stages of disease, honeycombing can predominate.

Histologically, the most frequently related pattern in adults is UIP, but NSIP, organizing pneumonia, or desquamative interstitial pneumonia have also been reported. Moderate infammation and centrilobular brosis can be observed [76].

Treatment

In children, treatments that have been reported to be successful in case reports or short series include methylprednisolone, hydroxychloroquine, and azithromycin [81, 85–87]. No treatment appears to reduce disease in a patient with prominent honeycombing. The effectiveness of anti - brotic drugs, such as pirfenidone or nintedanib, is unknown. The disease does not appear to recur after pulmonary transplantation [85].

Because lung brosis may alter spine growth during childhood, acquired scoliosis and pectus excavatum are frequent and may require corrective surgery (Fig. 24.5).

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