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, some centers recommend PFTs at 3 and 6 months, then annually for 5 years. Because more than one‐third of patients with cGVHD develop AFO, PFT testing is also advised when cGVHD is initially diagnosed, with repeat spirometry at least every three months times four, then full PFTs at least annually until systemic IST for cGVHD has ended. There is usually a rapid decline in FEV1 in the 6 months preceding a diagnosis of BOS, then stabilization, if a patient survives. Treatment of established BOS with systemic IST is often unsuccessful and worse survival is seen among those with FVC <67% at time of BOS diagnosis. Taking these facts together, early therapy is the goal before there has been extensive irreversible damage of small airways. To this end, a double‐blind randomized controlled study of inhaled corticosteroids (ICS) plus long acting beta agonist (LABA) showed that ICS/LABA can significantly improve FEV1 in moderate to severe BOS without changing IST [43].
Cardiovascular or metabolic
The three main LTFU categories of cardiovascular (CV) complications are heart failure (anthracycline but occasionally high‐dose cyclophosphamide‐related and augmented by radiation); radiation‐induced structural abnormalities in valves, coronary arteries or the conduction system; and development of metabolic syndrome (MS) components (dyslipidemia, hypertension, glucose intolerance). MS increase the risk for type 2 diabetes and atherosclerotic CV disease (CVD, myocardial infarction, vascular disease and stroke) [44–46].
Risk for CV toxicities is cumulative and includes genetics, pre‐HCT exposures plus side effects of cGVHD therapies (glucocorticoids, CNIs) since most patients take >2 years to discontinue all IST after an initial diagnosis of cGVHD; 10% require IST >5 years. Relative to siblings, allogeneic HCT survivors were 3–4 times more likely to report diabetes mellitus and twice as likely to report hypertension [47]. They were significantly more likely to develop hypertension than autologous recipients. TBI exposure was associated with an increased risk of diabetes mellitus (OR= 3.42, 95% CI: 1.55–7.52). Compared with a well‐matched general population, pediatric HCT survivors (>70% allogeneic recipients) had significantly higher rates of cardiomyopathy, stroke, dyslipidemia and diabetes [48], in an analysis that adjusted for sex, race, age, BMI, current smoking, daily fruit/vegetable intake, and recreational physical activity time. An analysis of potential risk reduction for serious CV outcomes (ischemic heart disease, cardiomyopathy, stroke) found that controlling dyslipidemia was most helpful, followed by control of hypertension, diabetes and smoking. Obesity was a risk factor for post‐HCT hypertension, dyslipidemia, and diabetes. Lower fruit/vegetable intake was associated with greater risk of dyslipidemia and diabetes, and lower physical activity level was associated with greater risk of hypertension and diabetes. Healthier survivor lifestyle characteristics attenuated the risk for all CV conditions assessed.
Pediatric survivorship recommendations usually begin by conducting an annual history and physical (dyspnea, chest pain, palpitations, exertional intolerance, edema), calculating anthracycline and radiation exposures, and requesting 2D‐echocardiography every 1–5 years depending on age plus exposures [12]. Variables used for COG’s risk algorithm require doxorubicin‐equivalent dose conversions, recognizing that total cumulative lifetime doses of anthracycline need to be multiplied by 4.0 (mitoxantrone), 5.0 (idarubicin), or by only 0.5 (daunorubicin) or 0.67 (epirubicin), due to potency differences. The Childhood Cancer Survivorship Study Cardiovascular Risk Calculator [49] uses information about exposures (anthracycline, alkylator, platinums, and radiation) but also demographics (gender, current age, age at HCT, use of medications to treat diabetes, dyslipidemia or hypertension) to predict incidence of heart failure, ischemic heart disease and stroke among survivors. Based on CCSG findings prevention of obesity and avoidance of smoking is important. Because improved survival and other benefits are observed in solid organ transplantation when dyslipidemia, hypertension and diabetes are addressed [13,50–53]. It is also reasonable to use medications to lower blood pressure and use statins to target lower LDL‐C after HCT when therapeutic lifestyle modifications are ineffective or not feasible. The lowest dose possible is used to minimize the potential for adverse drug interactions. Pleiotropic effects of statins may extend to improvement in renal function, hypertension, BMD, reduced incidence of AVN, and even improved control of GVHD [54–61].
Gastrointestinal or hepatic
HCT survivors have a >5‐fold burden of significant gastrointestinal (GI) complications compared to other cancer survivors which may include strictures of the esophagus and lower GI tract [62]. Strictures are most frequently due to cGVHD, prior candida esophagitis, GERD, or radiation >30 Gy; symptoms may include dysphagia and heartburn. Focal nodular hyperplasia is an often incidental benign finding, best diagnosed on gadolinium‐enhanced MRI and usually just needs to be monitored to avoid unnecessary invasive procedures [63,64]. Liver dysfunction due to GVHD, sequela of prior sinusoidal obstruction syndrome, hepatotropic viruses and iron overload may present with LFT abnormalities or hepatic synthetic defects. Chronic hepatitis B and C can lead to cirrhosis, portal hypertension and hepatocellular carcinoma. Unless GVHD is present at other sites, a liver biopsy might be indicated to confirm a liver GVHD diagnosis. Iron overload may exacerbate any LFT abnormality and so persistent elevation of serum ferritin might warrant checking transferrin saturation and possibly T2*MRI imaging to quantitate liver iron. Patients with significant LFT abnormalities should limit alcohol intake and avoid other hepatotoxins.
Renal or genitourinary
Chronic kidney disease (CKD), defined by structural damage or GFR <60 mL/min/1.73m2 for >3 months, is a common (18–42%) late effect in children and kidney damage can be associated with acute kidney injury (AKI), thrombotic microangiopathy (TMA), hemorrhagic cystitis, proteinuria, and hypertension [65–69]. Relevant exposures include chemotherapy (alkylators, fludarabine), radiation, CNIs, nephrotoxic antimicrobials, BK viremia or adenoviremia. There was a 4‐fold higher rate of CKD at 1 year among those with albuminuria and 6‐fold higher rate of non‐relapse mortality if overt proteinuria was present at day 100. Annual urinalysis for proteinuria (microalbuminuria), serum BUN, creatinine, electrolytes is standard, with reflexive nephrology consultation when abnormalities are found. Survivors should be screened for hypertension defined as average SBP and/or diastolic BP (DBP) that is ≥95th percentile for gender, age, and height on ≥3 occasions [67,68]. Major risk factors for idiopathic CKD are GVHD, acute renal failure, and after nonmyeloablative regimens, additional risk factors include long‐term use of calcineurin inhibitors and previous autologous HCT. Though hypertension after HCT has most commonly been treated with a long‐acting calcium channel blocker, blockade of the renin‐angiotensin
