Chronic GVHD
cGVHD pathogenesis in children is not fully understood but no major differences from adults have emerged from the few pediatric‐specific studies [27]. Children experience lower rates of cGVHD than adults [28–31] that vary widely with stem‐cell source, graft manipulations (ATGs, naïve or other forms of T‐cell depletion), and posttransplant cyclophosphamide. The NIH consensus reclassification also lowered cGVHD incidence by only considering classic cGVHD ± overlap subtype, effectively excluding isolated late acute GVHD (> day 100) from the definition. One prospective study that examined NIH cGVHD in children found an overall 21% and a 24.7% incidence of late acute GVHD. NIH global severity at onset was >80% moderate‐to‐severe [31]. Major risk factors for cGVHD in children are past acute GVHD, peripheral blood grafts, age ≥12 years, while only the first of these two factors are risks for late acute GVHD. While the frequency of organ involvement appears to parallel that seen in adults, the intersection of normal childhood development with morbid forms of cGVHD can contribute to failure‐to‐thrive, linear growth delay, skeletal deformities, as well as increased risk for late deaths due to infections even after IST has been discontinued [32].
Sclerotic forms of GVHD occur in 7% of children but it is unclear if this is truly lower than in adults given shorter follow‐up in the pediatric study [31], as well as heterogeneities in the incidence of peripheral blood grafts and TBI >450 cGy between adult and pediatric studies [30,31,33] given that these were the two major risk factors for sclerosis established from an earlier study [33]. Because this form of cGVHD is difficult to treat when advanced, irreversible manifestations have developed, early detection of joint limitation may be screened using the validated, easy to administer, Photographic Range of Motion (P‐ROM) scale [34]. P‐ROM is very sensitive to change in either direction and can also be used to follow therapeutic responses [35]. Chronic lung GVHD can be difficult to diagnose in children (see Pulmonary section).
Infection and immunity
Many patients without GVHD and off all IST after allogeneic HCT respond to vaccines and pathogens but a large registry study found infection to be a primary or contributing factor for almost 30% of late deaths [32]. At 12‐years post‐HCT, the CI of late fatal infections (LFI) was 6.4% in adults and 1.8% in children. Older adults and those with cGVHD on IST at 2‐years post‐HCT had highest risk for LFI. However, in children, cGVHD at 2 years carried a 9.5‐fold risk if on IST at 2 years but also a 2.7‐fold risk even if off IST [32] These data emphasize the importance of LTFU infection‐directed supportive care. Patients with active cGVHD are considered functionally asplenic. Numeric and functional immunity is delayed in patients when cGVHD is present or when HCT results in mixed T‐ and B‐cell lineage chimerism, especially if the underlying diagnosis was a primary immunodeficiency disease (PID). In general, antimicrobial prophylaxis directed against shingles, pneumocystis jirovecii pneumonia, encapsulated organisms, and often molds, is administered during cGVHD therapy [36]. In patients without cGVHD (often those with PID), if CD4 counts remain <200 per microliter or PHA proliferation is <50% lower limit of normal, PJP prophylaxis continues. Routine posttransplant vaccinations per “national guidelines” [37] or Carpenter and Englund is advised [38]. Judicious use of immunoglobulin replacement therapy for allogeneic HCT recipients per ASTCT “Choosing Wisely” unless profoundly low IgG (often with immeasurable IgA) [39]. By contrast, children transplanted for PID have variable B‐cell immune reconstitution and continue immunoglobulin replacement therapy until functional B‐cell reconstitution is documented.
Ocular
Cataracts and cGVHD‐associated keratoconjunctivitis sicca are common ocular late effects. Other eye exposure‐based complications for which formal ophthalmologic evaluations might be indicated include ischemic microvascular retinopathy (TBI, CNI, carmustine, busulfan), central retinal vein occlusion (metabolic syndrome or hypercoagulability) and ocular infections (late CMV disease, HSV, VZV, bacterial, fungal and toxoplasmosis). Thus, history should ask about impaired vision, dry or gritty eyes, diplopia, halos and history of opportunistic infections.
Twenty‐five percent to 50% of pediatric survivors will develop lens cataracts; mostly, these are not visually significant. Relevant exposures are TBI or prior cranial irradiation followed, less frequently, by busulfan and glucocorticoids. Using NIH consensus criteria, 30% of children with cGVHD developed dry eyes (9% with keratoconjunctivitis sicca) [31]; prior cranial/eye radiation can increase this risk [40]. Ophthalmologic examinations are advised at 1‐year post‐HCT, then yearly if abnormal or symptomatic. The NIH cGVHD eye score is helpful for symptom screening and treatment response [41].
Oral/dental
Xerostomia and subsequent neoplasms are the main LTFU risk. Unique pediatric risks, especially below age 6 years, include hypodontia, microdontia, enamel hypoplasia and root malformation. Xerostomia is related to cGVHD, TBI or other local radiation, medications, and can result in dental decay, infections, periodontal disease, difficulties with chewing, swallowing and speaking. A baseline panorex is advised to evaluate root development before dental procedures [13]. LTFU recommendations include regular dental examinations and cleanings, antimicrobial endocarditis prophylaxis per AHA guidelines, education about routine dental hygiene, avoidance of oral tobacco exposure, HPV vaccination to help prevent oral cancers, combined with annual oral examinations for subsequent neoplasms [36]. The latter are even more essential for patients with oral cGVHD, TBI exposure or underlying FA or dyskeratosis congenita (DC) [15,17,36].
Pulmonary
The major PFT impairments after HCT are airflow obstruction (AFO), restrictive lung disease (RLD), diffusion abnormality (DLCO) or combinations of all three, occurring months to years after HCT. Bronchiolitis obliterans syndrome (BOS) is a cGVHD manifestation with irreversible AFO, and may present insidiously as non‐productive cough, wheeze and dyspnea; patients may be asymptomatic for long periods despite moderate to severe AFO on PFTs. In children aged <6 years, PFT data is often unreliable and NIH consensus criteria for diagnosing BOS may be difficult to satisfy and so parametric response mapping from high‐resolution inspiration/expiration CT scans has been investigated to secure this diagnosis [42].
Restrictive pattern PFTs may be seen with dose‐related pulmonary fibrosis due to pre‐HCT or conditioning exposures to bleomycin, busulfan, carmustine, and lomustine. Other etiologies include cryptogenic organizing pneumonia (COP), or chest wall restriction due to TBI, chest wall irradiation, or cGVHD‐sclerosis. COP may generally be diagnosed after autologous or allogeneic HCT when a child who may have fever, also has solitary or multifocal pulmonary infiltrates on chest CT, and BAL testing has ruled out bacterial, viral, fungal and other opportunistic pathogens. Children transplanted for DC require close follow‐up for pulmonary fibrosis and are also at risk for pulmonary arteriovenous malformations and should be referred to pulmonologists if PFTs or focused radiologic findings are abnormal.
Late idiopathic pneumonia syndrome (IPS) is rare, presents acutely with florid dyspnea and widespread bilateral pulmonary infiltrates. Broad, empiric antimicrobial therapy is often administered while attempts to rule out infection are made, often in an already critically ill patient. IPS is treated with high‐dose steroids, often plus etanercept, but mortality is high.
Because development of BOS after allogeneic HCT can be insidious with a median onset of 1 year,