Pulmonary surveillance in pediatric hematopoietic stem cell transplant: A multinational multidisciplinary survey

Abstract Background Hematopoietic Stem Cell Transplant (HSCT) is an established treatment for malignant and non‐malignant conditions and pulmonary disease is a leading cause of late term morbidity and mortality. Accurate and early detection of pulmonary complications is a critical step in improving long term outcomes. Existing guidelines for surveillance of pulmonary complications post‐HSCT contain conflicting recommendations. Aim To determine the breadth of current practice in monitoring for pulmonary complications of pediatric HSCT. Methods An institutional review board approved, online, anonymous multiple‐choice survey was distributed to HSCT and pulmonary physicians from the United States of America and Australasia using the REDcap platform. The survey was developed by members of the American Thoracic Society Working Group on Complications of Childhood Cancer, and was designed to assess patient management and service design. Results A total of 40 (34.8%) responses were received. The majority (62.5%) were pulmonologists, and 82.5% were from the United States of America. In all, 67.5% reported having a protocol for monitoring pulmonary complications and 50.0% reported adhering “well” or “very well” to protocols. Pulmonary function tests (PFTs) most commonly involved spirometry and diffusion capacity for carbon monoxide. The frequency of PFTs varied depending on time post‐HSCT and presence of complications. In all, 55.0% reported a set threshold for a clinically significant change in PFT. Conclusions These results illustrate current variation in surveillance for pulmonary complications of pediatric HSCT. The results of this survey will inform development of future guidelines for monitoring of pulmonary complications after pediatric HSCT.

Childhood Cancer, and was designed to assess patient management and service design.
Results: A total of 40 (34.8%) responses were received. The majority (62.5%) were pulmonologists, and 82.5% were from the United States of America. In all, 67.5% reported having a protocol for monitoring pulmonary complications and 50.0% reported adhering "well" or "very well" to protocols. Pulmonary function tests (PFTs) most commonly involved spirometry and diffusion capacity for carbon monoxide. The frequency of PFTs varied depending on time post-HSCT and presence of complications. In all, 55.0% reported a set threshold for a clinically significant change in PFT.
Conclusions: These results illustrate current variation in surveillance for pulmonary complications of pediatric HSCT. The results of this survey will inform development of future guidelines for monitoring of pulmonary complications after pediatric HSCT.  1,2 The rates of HSCT are increasing, and currently more than 50 000 3 are performed annually worldwide including approximately 1600 HSCTs in the pediatric age group. 4 Survival following HSCT has improved, with reduced relapse-and non-relapse-related mortality over time, [5][6][7] and survival expected well into adulthood. The combination of increased HSCT and improved survival means there are increasing numbers of HSCT survivors who need surveillance for late effects of HSCT. 2,7 A recent study found that adults who underwent HSCT in childhood had a 14.4-fold increased risk for death compared with the general population. 7 Pulmonary complications comprise a leading cause of nonrelapse morbidity and mortality after HSCT. 7,8 Among children, there are multiple late pulmonary complications of HSCT, including infection, graft vs. host disease (GVHD), pulmonary vascular disease, interstitial fibrosis and others. [9][10][11] Two categories of chronic lung disease, defined based on pulmonary function testing (PFT), are observed in the months and years following allogeneic HSCT: obstructive and restrictive lung disease. 10,[12][13][14][15] Obstructive lung disease, most commonly manifests as bronchiolitis obliterans syndrome (BOS) which is the most recognized form of chronic lung disease after HSCT. BOS is characterized by progressive, narrowing and destruction of small airways along with fixed airflow obstruction and is associated with increased morbidity and mortality. 8 The incidence of BOS after HSCT is 4.8%-6.5% [16][17][18] with a median time to development of 12.2 months. 19 Restrictive lung disease occurs in a smaller proportion of patients with a median time to diagnosis of 11 months post-HSCT. 20,21 This pattern is less specific for a single diagnosis, and is often multifactorial, including individuals with previous chest wall/thoracic surgery, radiation therapy, and deconditioning with neuromuscular weakness, as well as patients who develop acute lung injury (e.g. idiopathic pneumonia syndrome) and interstitial lung disease.
The clinical presentation of pulmonary complications of HSCT is often non-specific, and investigations such as PFTs, chest imaging, bronchoscopy with bronchoalveolar lavage, and lung biopsy are employed to elucidate the exact cause. Pulmonary complications can often be detected non-invasively, without ionizing radiation, and at relatively low cost by PFTs prior to the onset of clinical symptoms. This is important because early treatment has been shown to have profound implications for long term pulmonary health. [22][23][24] Two pediatric cohorts have examined the efficacy of monitoring pulmonary function testing longitudinally and revealed that compared to clinical signs and symptoms, screening PFTs led to earlier identification of pulmonary complications. 25,26 Screening for post-HSCT pulmonary complications with PFTs to facilitate early detection and treatment is generally considered standard of care.
Despite consensus that screening for post-HSCT pulmonary complications should occur, existing guidelines include conflicting recommendations regarding which tests should be performed, the frequency of testing and omit recommendations for patients unable to complete PFTs. 1,2,27 For example the Children's Oncology Group 2 recommend annual screening with spirometry and diffusion capacity for carbon monoxide (D L CO) only, whereas a multi-society guideline 27 does not specify which tests to use and recommends screening at 6 months post HSCT, 12 months, and then annually with increased frequency in those with graft vs host disease (GVHD). A guideline 1 aimed at patients who underwent HSCT for hemoglobinopathy recommends screening at 3, 6, and 12 months post HSCT and then annually for a further 2 years, with screening involving spirometry, plethysmography and D L CO. In addition, current guidelines do not include tests such as multiple breath washout (MBW) or impulse oscillometry, which may be more sensitive measures of peripheral airway function (where BOS occurs) and are feasible in young children. 28,29 There is also little guidance for how other investigations, such as CT, bronchoscopy and bronchoalveolar lavage and biopsy should be used. Furthermore, many of these modalities, as well as access to pediatric pulmonology expertise, are not routinely available at all centers worldwide. 30 Considering that early childhood is a critical period for lung development with long-lasting effects into adulthood, 31 optimizing pulmonary health in children post-HSCT is crucial. An opportunity therefore exists to improve screening for pulmonary complications of childhood HSCT at the international level. This was one of the key messages from a recent National Institutes of Health workshop regarding pulmonary complications of HSCT. 32 The workshop specifically called for standardization of lung function testing in this population, including the use of novel methods in the preschool age group.
The current project was established to better understand current multinational clinical practice. It was hypothesized that given the conflicting recommendations in guidelines, that there would be variation in practice between HSCT centers. In addition to intercenter variation, it was also suspected that HSCT physicians and pediatric pulmonologists would differ in their approach to post HSCT patients. As such, the aim was to survey both HSCT physicians and pediatric pulmonologists regarding their current practice of screening for and diagnosing pulmonary complications of HSCT.
Some of the results of this study has been previously reported in the form of an abstract. 33 2 | METHODS

| Study instrument
The survey instrument (see Appendix A) was developed by a core group of members of the American Thoracic Society Working Group

| Analysis
As data was non-normally distributed, correlations were tested using the Mann Whitney test, with p-values <.05 considered significant. All statistical analyses were performed using GraphPad Prism, version 6.01 (GraphPad Software Inc., La Jolla, California).

| RESULTS
The  (Table 1). year which is summarized in Figure 1.

| Standard follow up
The majority of respondents (27/

| Pulmonary function testing
The

| DISCUSSION
The survey illustrates variation in practices for monitoring pulmonary health of pediatric HSCT survivors. We suspect that this is due to a lack of standardized guidelines, which reflects a paucity of data about which approaches are optimal. It may also reflect differences in access to diagnostic resources. 30  A survey of North American HSCT center directors demonstrated that 71% of centers without a dedicated follow up clinic had an identified pulmonologist they referred patients to, and in centers with a dedicated clinic, a pulmonologist was involved in 84.4% of those clinics. 38 In the current survey, all respondents had access to pediatric pulmonologists, however only 52.5% reported there was an identified pulmonologist for referrals and 52.5% reported routine referral of patients to pediatric pulmonology. A potential explanation for the lower rates in this current survey is differences in practice between adult and pediatric HSCT centers. Follow-up of children who have undergone HSCT is complex and subspecialty expertise is needed.
The ideal scenario would involve at least one dedicated pulmonologist at each center working closely together with HSCT physicians to deliver patient care and develop screening programs and research projects to answer clinically relevant questions.
There are some limitations to the current project. Firstly, use of a survey approach relies on respondents' answers to questions rather than a direct assessment of practices. It would be expensive and impractical to perform in-person assessments of practice across centers on two continents. Our survey concluded just prior to the start of the SARS-CoV-2 pandemic, and thus our results reflect pre-pandemic practices.  ACKNOWLEDGMENT N/A.

CONFLICT OF INTEREST
The authors have no conflicts to disclose.

ETHICS STATEMENT
Institutional review board approval was obtained from the Royal Children's Hospital, Melbourne, Australia (HREC number 2019.230). Completion of the electronic survey was viewed as consent to participate.
In particular the start of electronic survey contained the following phrase: "By completing the survey we assume you give informed consent to use your anonymous responses in our analysis and publications."

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.