Introduction

Pulmonary fibrosis (PF) exists as a complication in both paediatric and adult populations, however there are significant differences in causative disease processes, incidence and prevalence, and histopathological changes. This article will aim to review the evolution of treatment principles of PF in both populations and how paediatric management can be guided by adult therapeutic developments.

In paediatric populations, PF is seen as a rare complication of specific forms of childhood interstitial lung diseases (chILD) . chILD itself is a seldomly seen classification with very few available studies of large patient groups, and the prevalence of paediatric PF amongst these cases is even rarer. The incidence of chILD is estimated at roughly 0.13–16.2 cases per 100,000 children per year . The group of chILD disorders is largely heterogenous and comprised of over 200 pulmonary disorders, making analysis and comparisons even more difficult . Amongst the chILD population, there is a suggested PF prevalence of 1–7 %, however these statistics are limited by the extreme sparsity of studies analysing lung biopsies in this patient group . In contrast, the incidence of fibrosing interstitial lung diseases amongst adult populations is almost tenfold higher , ranging from 1 to 51.56 per 100,000 person-years . Of these, idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease with an estimated incidence of 0.9–13.0 per 100,000 person-years .

The inherent rarity of PF in paediatric populations, in addition to the wide heterogeneity of chILD disorders, has made both defining the disease and creating management guidelines exceedingly difficult. Treatment of PF in adults has been more thoroughly studied in comparison given their larger patient population. The differences between the two populations means we cannot directly apply adult data to children, however there are still valuable lessons to be learned from adult research developments.

Differences in pulmonary fibrosis between children and adults

Given the heterogeneity of underlying disease processes, PF can appear differently when examined both radiographically and histologically.

In adult populations, IPF is the most common cause of pulmonary fibrosis, and its hallmark indicator is the presence of a usual interstitial pneumonia (UIP) pattern on imaging . On high-resolution computed tomography (HRCT), UIP is typically characterised by honeycombing with traction bronchiectasis/bronchiolectasis . Histologically, UIP is characterised by fibroblastic foci that drive heterogenous interstitial fibrosis, as well as honeycombing changes which result in massive architectural distortion . In adults, non-IPF interstitial lung diseases (ILDs) can present in many ways, however more commonly manifest as non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), alveolar fibrosis and elastosis (AFE) .

It is important to highlight that in paediatric populations, UIP is exceedingly rare . The most commonly seen pattern of interstitial pneumonia in children is NSIP . Radiologically, NSIP presents as ground glass opacities and reticulations , whilst on biopsy, NSIP is characterised by homogenous and mild interstitial fibrosis and does not have the significant architectural disturbance that is present in UIP .

From a radiological, histological, and causative disease point of view, there is more overlap between chILD/paediatric PF and non-IPF ILDs/progressive pulmonary fibrosis (PPF) in adults (see Table 1 ). PPF itself is a relatively new classification of non-IPF ILDs with pulmonary fibrosis amongst adults .

The emergence of anti-fibrotic agents in adult populations

There have been advancements in globally accepted guidelines for PPF and IPF amongst adult populations, largely due to the emergence of new anti-fibrotic agents pirfenidone and nintedanib. Pirfenidone is a non-peptide synthetic molecule that acts by decreasing TGF-β1, TNF-α, platelet derived growth factor (PDGF) and COL1A1 expression . In doing so, pirfenidone prevents the deposition of scar tissue and removes collagen depositions. Although nintedanib is also an anti-fibrotic agent, it has a different mechanism of action compared to pirfenidone. Nintedanib is a tyrosine-kinase inhibitor that targets various receptors including the fibroblast growth factor receptor, the vascular endothelial growth factor receptor, and the platelet-derived growth factor receptor . Inhibiting these receptors limits the processes of fibroblast proliferation and fibrosis progression.

The evolution of joint guidelines from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Latin American Thoracic Association (ATS/ERS/JRS/ALAT) neatly demonstrate the impact of these new anti-fibrotic drugs. In their 2011 guidelines, it was recommended that majority of IPF patients should not be treated with pirfenidone, whilst nintedanib was not mentioned at all . Following the publication of the 2011 guidelines, multiple large scale randomised controlled trials for both pirfenidone (CAPACITY trial , ASCEND trial ) and nintedanib (TOMORROW , INPULSIS-1 and INPULSIS-2 ) identified improved mortality and reduced forced vital capacity (FVC) decline following treatment with these agents. The following 2015 ATS/ERS/JRS/ALAT guidelines were subsequently updated to advocate for the use of both anti-fibrotic agents in IPF treatment and this recommendation has continued into the latest 2022 guidelines . These guidelines are similarly reflected in the 2017 guidelines by the Thoracic Society of Australia and New Zealand (TSANZ), advising for the use of pirfenidone or nintedanib as first-line monotherapy in IPF .

The evolution of IPF treatment highlights the landmark developments of pirfenidone and nintedanib. However, when analysing from a paediatric perspective the lessons gleaned from management of IPF are arguably less useful given its scarcity amongst children and the differences in radiological and histological presentations. The classification and management of PPF seems instead to be more useful for paediatric populations given the greater overlap. The ATS/ERS/JRS/ALAT 2022 guidelines reference systematic reviews and meta-analyses for both pirfenidone and nintedanib use in PPF. With regards to pirfenidone, they analysed two randomised controlled trials (2020 study by Maher et al. , 2021 RELIEF trial ). Ultimately, they found that use of pirfenidone in adult patients with PPF was associated with a statistically significant decrease in disease progression, seen via a mean change in FVC% predicted of 2.3 % . Whilst overall sentiment amongst committee members were in favour of pirfenidone use, concern remained over the low quality of evidence for measured outcomes, resulting in recommendation for further research into its safety and efficacy. The review of nintedanib examined a multi-national randomised control trial of 663 patients (INBUILD trial ) and a post hoc analysis of the same study population . Like pirfenidone, they found that nintedanib demonstrated a decrease in disease progression and made a conditional recommendation for use in PPF, however acknowledged the need for further research . Whilst benefit was demonstrated in the subgroups of patients with UIP, fibrotic NSIP and connective tissue disease related ILD, it was not replicated in other subgroups of including unclassified ILD, hypersensitivity pneumonitis and sarcoidosis.

A more recent 2023 Italian systematic review again examined the use of pirfenidone and nintedanib in adults with non-IPF ILD . In addition to the trials examined in the previous review, the review of nintedanib included the SENSCIS trial whilst the pirfenidone review had six further studies. The study agrees that despite only having two studies, both nintedanib trials are of high quality and suggest that nintedanib may have benefit in disease progression. Conversely, the quality of evidence for pirfenidone ranges from very low to low, but overall suggest some benefit to lung function. A level of caution is required for both drugs given the limitations in available evidence and the significant heterogeneity amongst ILDs, however recent evidence supports the use of nintedanib as a part of PPF management.

Management of paediatric pulmonary fibrosis

Given the rarity of PF and chILD, there is very limited available evidence to help develop treatment guidelines. Treatment data on paediatric PF has historically been limited to case reports, case series or small retrospective studies. Current treatment options for chILD are aimed at suppressing inflammation to prevent progression to fibrosis . The most common pharmacological options include corticosteroids, hydroxychloroquine (HCQ) and azithromycin . In cases of autoinflammatory diseases or where these initial options prove ineffective, use of immunosuppressive, immunomodulatory, or cytotoxic drugs such as azathioprine, cyclophosphamide, cyclosporine, or methotrexate are sometimes considered .

The American Thoracic Society released guidelines on chILD evaluation and management in 2013 , followed by the 2015 European guidelines on behalf of the chILD-EU collaboration . Both guidelines present recommendations based on clinician consensus given the limited available scientific evidence. However, whilst the European protocols propose specific pharmacologic therapies with suggested dosing, the American guidelines only briefly mention medications.

The 2013 American Thoracic Guidelines acknowledge the lack of any controlled trials aimed at therapeutic interventions for chILD. They discuss the reported usefulness of immunosuppressive pharmacotherapy (e.g., systemic corticosteroids, HCQ), but advise caution and a case-by-case approach given the well-known side effects of immunosuppressive therapy and limited evidence demonstrating significant beneficial effect. Aside from pharmacotherapy, the guidelines make strong recommendations for referral to a paediatric lung transplantation centre, as well as suggestions for supportive and preventive care (e.g., supplemental oxygen, vaccinations/palivizumab, social work assistance) .

The European protocols released two years later in 2015 and offered suggested treatment protocols created via a Delphi method, surveying over one hundred clinicians globally. Corticosteroids were the first line recommended treatment, delivered via oral prednisolone 1–2 mg/kg/day and/or monthly pulsed intravenous methylprednisolone 10–30 mg/kg/day delivered for three consecutive days. Following corticosteroids, HCQ is proposed as an alternative treatment, dosed at 10 mg/kg/day (with some centres reducing dosage to 6.5 mg/kg/day in children under the age of six). Azithromycin is also recommended as a second line drug equal to HCQ, with a dosage of 10 mg/kg three days a week .

Since these guidelines were released, there have been two major randomised controlled trials targeted at therapies for chILD/paediatric PF populations. The first was a 2022 randomised controlled phase 2 trial assessing the efficacy of HCQ in chILD . The design recruited 35 patients with chronic diffuse parenchymal lung disease that were either eligible to commence (26 placed in the START arm) or cease (9 placed in the STOP arm) HCQ. Of the START arm, 9 were immediately initiated on HCQ whilst 17 received placebo for the first 4 weeks, then all subjects received a further 4 weeks of HCQ. Treatment duration was based off the HCQ clinical response monitoring period as per the 2015 European protocols . In the STOP arm, 4 out of 9 patients continued their dose of HCQ for 12 weeks whilst the other 5 were given placebos, followed up by a further 12 weeks of all patients not taking medication. The primary endpoint was change in oxygenation, evaluated via oxygen saturation (change of 5 % or more), respiratory rate or change in respiratory support. Secondary endpoints included health related quality of life, a 3 % change in oxygen saturation and 6-minute walk test distance. Ultimately, the study found no difference between placebo and HCQ groups for either primary or secondary endpoints. This outcome ran opposite to their pre-study hypothesis based off a previous literature review by the same authors that suggested a 41 % response rate . Whilst the study authors acknowledge the possibility of a false null hypothesis, they assert the need for revision of previous optimistic appraisals of HCQ use in chILD.

The second study was the 2023 InPedILD trial, a phase 3 randomised controlled trial aimed at assessing the safety profile and dose-exposure of nintedanib in paediatric patients with a fibrosing ILD . Thirty-nine patients between the ages of 6 and 17 with fibrosing ILD on HRCT were enrolled and randomised 2:1 between nintedanib and placebo. The double-blind period ran for 24 weeks at which point all patients were then treated with open label nintedanib. During the double-blind period adverse effects were reported in 84.6 % of both treatment groups. As seen in adult populations on nintedanib, the most frequent adverse event was diarrhoea, reported in 38.5 % of cases . The study also assessed the potential effect of nintedanib on epiphyseal growth plates and tooth development. Animal model data suggested that nintedanib’s inhibition of vascular endothelial growth factor receptor could have a reversible effect on bone growth and development . Epiphyseal growth plate imaging and dental examinations were performed on majority of patients from both groups at 24 weeks. No cases of premature closure of the physes were seen, and although there were 6 cases of presumed stunted dental root growth, re-review by paediatric dental experts suggested otherwise and treatment was resumed. Overall, the study suggests that nintedanib has an acceptable safety profile in paediatric populations and a weight-based dosing regimen that achieved comparable exposure to that of adults. The trial also found the mean change in FVC%-predicted for the nintedanib group was 0.3 % compared to −0.9 % in the placebo group. Whilst this reduction is like that seen in adult groups, the study advises caution given the short trial duration and limited data on lung function progression in chILD.

Outside of these two studies, data for other available PF therapies remains scarce. A case series covering 4 instances of pirfenidone use in paediatric PF suggested it was generally well tolerated with gastrointestinal side effects being the most common, again comparable to adult populations . Patient outcomes were mixed and overall conclusions on efficacy are not possible due to significant confounding factors. Another case report discussed improvements in lung function post pirfenidone treatment in a patient with systemic lupus erythematosus with HRCT proven NSIP, however they were also commenced on other therapies during treatment, muddling analysis of pirfenidone efficacy .

Lessons from adults

Given the exceeding rarity of paediatric patients with PF, a subsection of the already limited pool of chILD patients, there is significant paucity of available literature to guide management protocols. Therefore, despite the inherent differences, it is useful to examine the research developments for adult PF and draw parallels, if only to guide future targets for paediatric research. Although there is no clearly defined definition for paediatric PF, the trend of histological and radiological presentations tends to align more with those seen in PPF, as opposed to IPF . Recent studies within the last half decade have demonstrated the efficacy of nintedanib in the PPF population whilst more research is required for pirfenidone. The landmark InPedILD paediatric nintedanib study demonstrates comparable dose-exposure and side effect profile to that seen in adults and shows promise for future developments of paediatric PF management. Further research into paediatric PF is sorely needed but is currently limited by the inherent difficulties in approaching clinical trials in this population.

Conclusion

Management of PF in children is a severely under-researched area due to its rarity and heterogeneity. There have been some promising advancements in recent years, but there is still insufficient evidence to guide treatment protocols. The addition of antifibrotic medications (nintedanib and pirfenidone) has transformed management of adult PF and the latest study data is promising for future nintedanib integration into paediatric management, but again further studies are needed to prove its efficacy. Currently available guidelines are only focused on chILD with no dedicated PF protocols, but even these are severely limited by lack of research data. Whilst there are useful parallels to be drawn from research in adult populations, dedicated paediatric studies are ultimately needed for the progression of paediatric PF management.

Future directions for research

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  Further assessments of the safety and efficacy of anti-fibrotic agents in paediatric PF populations.

  
  
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  More higher-level evidence aimed at assessing the efficacy of current management guidelines for chILD.

  
  
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  Establishment of an internationally consistent, evidence-based guideline on management of paediatric PF.

  
  
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  Increased understanding of paediatric PF progression and development of a universally agreed definition and criteria.