Five-year survival rates for childhood cancer now exceed 80% and with the significant progress made by the transplant community in developing less toxic conditioning regimens and in the treatment of posttransplant complications, allo-hematopoietic stem cell transplantation (HSCT) contributes significantly to that population of long-term survivors. In this context, the acute and long-term toxicities of chronic graft-versus-host disease (cGVHD) have an ever-increasing effect on organ function, quality of life, and survival; patients and families who initially felt great relief to be cured from the primary disease, now face the challenge of a chronic debilitating illness for which preventative and treatment strategies are suboptimal. Hence, the development of novel strategies that reduce and or control cGVHD, preserve graft-versus-tumor effects, facilitate engraftment and immune reconstitution, and enhance survival after allo-HSCT represents one of the most significant challenges facing physician-scientists and patients.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative approach for many pediatric diseases. According to the most recent analysis from the Center of International Blood and Marrow Transplant Research (CIBMTR) data, approximately 4500 allo-HSCTs are performed each year in children less than 20 years of age. Most children are transplanted for malignancy, however increasing numbers receive an allo-HSCT for nonmalignant diseases such as bone marrow failure, immunodeficiency, and certain metabolic syndromes/disorders. Concurrent with increasing indications for allo-HSCT, there has been a surge of interest in immune modulation to harness the graft-versus-tumor (GVT) effects when this procedure is used for hematologic malignancies. These factors along with improvements in the safety of allo-HSCT have led to an expanding population of long-term survivors, many of whom suffer from long-term toxicities, including chronic graft-versus-host disease (cGVHD).
cGVHD is the most significant nonrelapse cause of morbidity and mortality following allo-HSCT for malignant disease. Although the rates of cGVHD tend to be lower in children (20%–50%) than adults (60%–70%), the incidence of cGVHD in the pediatric population is substantial and has increased recently in association with the expanded use of peripheral blood stem cells (PBSCs) and unrelated donors. cGVHD has been characterized historically by autoimmune and alloimmune dysregulation occurring after the first 100 days of allo-HSCT. A newer set of diagnostic criteria have been developed and the definition of cGVHD has been refined to include the development of diagnostic features of immune dysfunction that may be present before day 100 and almost always occur within 3 years posttransplant. The median onset of cGVHD is approximately 6 months following allo-HSCT. As opposed to acute GVHD (aGVHD), which involves the skin, liver, and gastrointestinal (GI) tract, cGVHD can involve almost any organ of the body. cGVHD leads to significant morbidity, diminished quality of life, and decreased overall survival.
Incidence of cGVHD in pediatrics
The rates of cGVHD in the pediatric population depend on several variables and can range from as low as 6% in matched sibling cord blood transplants to as high as 65% in matched unrelated donor (MUD) PBSC transplants. In 2000, Eurocord and the International Bone Marrow Transplant Registry (IBMTR) compared 113 sibling cord blood HSCTs to 2052 HLA-matched sibling bone marrow transplants (BMTs). All of these patients were 15 years of age or younger and received a myeloablative preparative regimen, and most received cyclosporine (CSA)-based GVHD prophylaxis. The cord blood population had a 6% 3-year cumulative incidence of cGVHD versus 15% in the bone marrow recipients. In 2002, Zecca and colleagues published a retrospective analysis of 696 consecutive pediatric patients who underwent transplant in Italy between 1991 and 1999. The indication for transplant was malignancy in two-thirds, almost all patients received bone marrow (BM) as the stem cell source, and two-thirds had HLA-matched sibling donors. The overall incidence of cGVHD in this population was 25%, with a median time to diagnosis of 116 days after transplantation.
Pathophysiology
The scientific basis for the development of cGVHD is poorly understood and there are limited data specific to pediatrics. Historically, alloreactive donor T cells have been the primary factor implicated in the pathophysiology of cGVHD. However, a recent randomized trial failed to demonstrate that T-cell depletion reduced the incidence of cGVHD. Therefore, the role of direct T-cell–mediated allogeneic immune responses in cGVHD is not clear, and there is no strong correlation between the number of minor histocompatibility antigen–specific T cells and cGVHD.
Evidence suggests that B cells also play a role in disease development. B lymphocytes have at least two important functions: production of antibodies and presentation of antigens to T cells, both of which may contribute to cGVHD. A coordinated B-T response to minor histocompatibility alloantigens (mHA) is well described, as is significant high-titer antibody responses to mHA that correlate with cGVHD in patients. Increased levels of nonspecific auto-(vs allo-) antibodies have repeatedly been described in association with cGVHD and include antinuclear antibody (ANA) ; anti-dsDNA antibody ; antimitochondrial antibody ; anticardiolipin antibody ; antismooth muscle antibody (ASMA); platelet antibodies; and antineutrophil antibodies. In addition, antiplatelet-derived growth factor receptor (PDGFR) antibodies have been associated with sclerotic cGVHD and are implicated in the fibrosis in idiopathic scleroderma, which shares many clinical features with classic cGVHD. Probably the best documented alloantibody association with cGVHD involves the H-Y antigen. Male patients who have received allo-HSCT from female donors are at higher risk for aGVHD and cGVHD. The Miklos group showed that the H-Y antibodies develop 4 to 12 months after BMT in approximately 50% of male patients receiving allo-HSCT from female donors. The cumulative incidence of cGVHD in the presence of H-Y antibodies was found to be 89% at 5 years post BMT versus 31% in the absence of H-Y antibodies ( P <.0001). Moreover, responses to the anti-B cell therapy, rituximab (anti-CD20 monoclonal antibody) in steroid-refractory cGVHD strongly suggest that B cells play a significant role in this disease.
Soluble factors may also play a role in the pathogenesis of cGVHD. On activation during cGVHD, dendritic cells (DCs) and B lymphocytes secrete inflammatory cytokines after recognition of their cognate antigen. DCs and macrophages produce monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, transforming growth factor-beta (TGF-β) and interferon-gamma (IFN-γ) which has been implicated in autoimmune disease and GVHD. Soluble IL2 receptor alpha (sIL2Rα), as a marker of activated T cells, correlates with the severity of aGVHD and cGVHD and with other autoimmune diseases. Specifically, cutaneous cGVHD has been associated with an increase in PDGF, cGVHD-associated sclerosis with high levels of TGF-β, fatigue and wasting with high levels of TNF-α, and immunodeficiency with high levels of IL10 and TGF-β. Cytokine polymorphisms of donor and recipient IL1 and IL6 genes, donor TNF receptor type II 169RR-homozygous genotype, recipient IL10 GG-homozygosity, and recipient IL1Rα polymorphisms may also play a role.
The Children’s Oncology Group (COG) recently published an analysis of peripheral blood biomarkers found in 52 children newly diagnosed with extensive cGVHD. Peripheral blood samples were evaluated for 13 known or suspected biomarkers and were compared with 28 time-matched controls with no evidence of cGVHD. Four plasma biomarkers (soluble B-cell–activating factor (sBAFF,) sCD13, anti-dsDNA, and sIL2R α) and 1 cellular biomarker (Toll-like receptor 9 (TLR9) high expressing cytosine-phosphate-guanosine (CpG) responsive B cells) correlated with the diagnosis of cGVHD and in combination, had high specificity (84%) and sensitivity (100%) for the diagnosis of cGVHD. sBAFF, anti-dsDNA antibody, soluble IL2 receptor α, and soluble CD13 were increased in early onset cGVHD compared with controls. Furthermore, sBAFF and anti-dsDNA were increased in late onset cGVHD. Levels of sBAFF and sCD13 were higher in patients with hepatic cGVHD, whereas anti-dsDNA levels were higher in patients with joint, sclerodermatous, and ocular involvement. Increased sBAFF was significantly associated with lichenoid skin rash and joint involvement, increased IL6 and MCP-1 with joint involvement, and increased anticardiolipin antibody with ocular involvement. All of these associations were statistically significant. None of the markers evaluated were associated with gastrointestinal, pulmonary, or musculoskeletal cGVHD. Biomarkers have the potential to predict the risk of developing cGVHD, improving classification, and directing cGVHD research and treatment, but require further investigation and large study validation.
Pathophysiology
The scientific basis for the development of cGVHD is poorly understood and there are limited data specific to pediatrics. Historically, alloreactive donor T cells have been the primary factor implicated in the pathophysiology of cGVHD. However, a recent randomized trial failed to demonstrate that T-cell depletion reduced the incidence of cGVHD. Therefore, the role of direct T-cell–mediated allogeneic immune responses in cGVHD is not clear, and there is no strong correlation between the number of minor histocompatibility antigen–specific T cells and cGVHD.
Evidence suggests that B cells also play a role in disease development. B lymphocytes have at least two important functions: production of antibodies and presentation of antigens to T cells, both of which may contribute to cGVHD. A coordinated B-T response to minor histocompatibility alloantigens (mHA) is well described, as is significant high-titer antibody responses to mHA that correlate with cGVHD in patients. Increased levels of nonspecific auto-(vs allo-) antibodies have repeatedly been described in association with cGVHD and include antinuclear antibody (ANA) ; anti-dsDNA antibody ; antimitochondrial antibody ; anticardiolipin antibody ; antismooth muscle antibody (ASMA); platelet antibodies; and antineutrophil antibodies. In addition, antiplatelet-derived growth factor receptor (PDGFR) antibodies have been associated with sclerotic cGVHD and are implicated in the fibrosis in idiopathic scleroderma, which shares many clinical features with classic cGVHD. Probably the best documented alloantibody association with cGVHD involves the H-Y antigen. Male patients who have received allo-HSCT from female donors are at higher risk for aGVHD and cGVHD. The Miklos group showed that the H-Y antibodies develop 4 to 12 months after BMT in approximately 50% of male patients receiving allo-HSCT from female donors. The cumulative incidence of cGVHD in the presence of H-Y antibodies was found to be 89% at 5 years post BMT versus 31% in the absence of H-Y antibodies ( P <.0001). Moreover, responses to the anti-B cell therapy, rituximab (anti-CD20 monoclonal antibody) in steroid-refractory cGVHD strongly suggest that B cells play a significant role in this disease.
Soluble factors may also play a role in the pathogenesis of cGVHD. On activation during cGVHD, dendritic cells (DCs) and B lymphocytes secrete inflammatory cytokines after recognition of their cognate antigen. DCs and macrophages produce monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, transforming growth factor-beta (TGF-β) and interferon-gamma (IFN-γ) which has been implicated in autoimmune disease and GVHD. Soluble IL2 receptor alpha (sIL2Rα), as a marker of activated T cells, correlates with the severity of aGVHD and cGVHD and with other autoimmune diseases. Specifically, cutaneous cGVHD has been associated with an increase in PDGF, cGVHD-associated sclerosis with high levels of TGF-β, fatigue and wasting with high levels of TNF-α, and immunodeficiency with high levels of IL10 and TGF-β. Cytokine polymorphisms of donor and recipient IL1 and IL6 genes, donor TNF receptor type II 169RR-homozygous genotype, recipient IL10 GG-homozygosity, and recipient IL1Rα polymorphisms may also play a role.
The Children’s Oncology Group (COG) recently published an analysis of peripheral blood biomarkers found in 52 children newly diagnosed with extensive cGVHD. Peripheral blood samples were evaluated for 13 known or suspected biomarkers and were compared with 28 time-matched controls with no evidence of cGVHD. Four plasma biomarkers (soluble B-cell–activating factor (sBAFF,) sCD13, anti-dsDNA, and sIL2R α) and 1 cellular biomarker (Toll-like receptor 9 (TLR9) high expressing cytosine-phosphate-guanosine (CpG) responsive B cells) correlated with the diagnosis of cGVHD and in combination, had high specificity (84%) and sensitivity (100%) for the diagnosis of cGVHD. sBAFF, anti-dsDNA antibody, soluble IL2 receptor α, and soluble CD13 were increased in early onset cGVHD compared with controls. Furthermore, sBAFF and anti-dsDNA were increased in late onset cGVHD. Levels of sBAFF and sCD13 were higher in patients with hepatic cGVHD, whereas anti-dsDNA levels were higher in patients with joint, sclerodermatous, and ocular involvement. Increased sBAFF was significantly associated with lichenoid skin rash and joint involvement, increased IL6 and MCP-1 with joint involvement, and increased anticardiolipin antibody with ocular involvement. All of these associations were statistically significant. None of the markers evaluated were associated with gastrointestinal, pulmonary, or musculoskeletal cGVHD. Biomarkers have the potential to predict the risk of developing cGVHD, improving classification, and directing cGVHD research and treatment, but require further investigation and large study validation.
Risk factors
Known risk factors that have been repeatedly associated with higher risks of cGVHD include precedent aGVHD, unrelated donor, mismatched donor, PBSCs as donor source, older recipient or donor age, female donor into a male recipient, the use of total body irradiation (TBI), and malignant disease ( Table 1 ). By far the strongest predictor for the development of cGVHD seems to be the severity of aGVHD. Conversely, factors that have been found to be associated with lower rates of cGVHD include the use of cord blood stem cells and the use of methotrexate (MTX) with CSA for GVHD prophylaxis. Lower donor or recipient age also reduces the incidence of cGVHD, which has been hypothesized to be due in part to a lower exposure of young donors and recipients to infections. The following factors have little or no effect on the risk of developing cGVHD: T-cell depletion of the stem cell graft, CD34+ cell dose in the graft, or the use of prolonged immunosuppression.
| Patient | Donor/Graft | Transplant | |
|---|---|---|---|
| Increased cGVHD risk | Older ageMalignancy | Female donor to male patient MismatchedUnrelatedPeripheral blood stem cellsDonor lymphocyte infusionsOlder age | Acute GVHDTotal irradiation in preparative regimen |
| Possible increased cGVHD risk | CMV positiveCMV reactivation | CD 34+ cell dose | |
| Decreased cGVHD risk | Younger age | Cord blood | Anti-thyroglobulin in preparative regimenCampath-1H in preparative regimen |
| Possible decreased cGVHD risk | Methotrexate and cyclosporine prophylaxis |
Although ex vivo strategies to deplete donor T cells have not significantly influenced the rates of cGVHD, the addition of antithymocyte globulin (ATG) or Campath-1H to the conditioning regimen does seem to affect the development of cGVHD. ATG is widely used before allo-HSCT, particularly with HLA-matched unrelated donors or mismatched relatives, to prevent graft rejection and GVHD. The addition of ATG has resulted in low rates of GVHD after pediatric mismatched cord blood transplant similar to those found in matched unrelated BM transplants. Many umbilical cord blood (UCB) transplant regimens incorporate ATG suggesting a possible contribution of this agent to the low rates of GVHD. Despite encouraging results, ATG may adversely affect posttransplant immune reconstitution. The reasons why in vivo T cell depletion is more effective in preventing GVHD than ex vivo depletion are incompletely understood. However, agents such as Campath and ATG have a long half-life in the recipient, affecting not only donor T cells but also antigen presenting cells (APCs), natural killer (NK) cells, regulatory T cells, and B cells in the graft and the recipient. The subsequent effects on posttransplant proliferation, cell trafficking and signaling likely promote a more tolerogenic environment.
Allo-HSCT using unrelated volunteer donors remains a significant risk factor for the development of cGVHD. Fifty percent of allo-HSCT performed in patients less than 20 years of age are from unrelated donors. Earlier studies of unrelated donor BMT in the pediatric population during the 1980s and early 1990s report high incidences of cGVHD (50%–69%) compared with more recent studies showing rates less than 50% (39%–47%). Recent improvements and increasing utilization of high-resolution typing of HLA class I and class II loci has further decreased the rates of cGVHD in the unrelated population to 30%, rates comparable to those seen in children transplanted from HLA-identical siblings.
Recently, the impact of hematopoietic stem cell source on the incidence of cGVHD has been investigated. Mobilized PBSCs are now the primary stem cell source in the adult population. However, despite this dramatic increase in adults, BM remains the predominant stem cell source used in pediatric transplantation. CIBMTR data from 2003 to 2006 show that the distribution of stem cell sources for allo-HSCT in children is approximately 42% BM, 37% cord blood, and 21% PBSC. Although still modest, use of PBSCs mobilized by granulocyte colony-stimulating factor (G-CSF) is increasing in pediatrics and is likely to continue to escalate. Adult studies have demonstrated higher incidences of cGVHD or refractory cGVHD when using PBSC versus BM. Despite increased incidence of cGVHD in adults, the use of PBSC has been associated with decreased treatment-related mortality (TRM) and decreased relapse rates in leukemia patients. The data on children are less clear. One recent study showed no significant differences in TRM, aGVHD, cGVHD, OS, or relapse-free survival in pediatric PBSC recipients (n = 38) compared with marrow (n = 23). This is in contrast to previous studies that consistently show increased rates of cGVHD. One study of 90 children undergoing PBSC transplants in Spain showed that patients with cGVHD had improved disease-free survival with lower relapse rates and similar TRM. However, a retrospective IBMTR analysis of pediatric PBSC recipients reported poorer survival with PBSC transplants in comparison with BM despite similar rates of relapse. Patients in this study had similar rates of aGVHD, but rates of cGVHD were higher with a relative risk of 1.85 in the PBSC group. Thus, despite the lack of randomized studies in children, it seems that the risk of cGVHD with PBSC is higher than BM, although the overall effects on TRM and relapse-free survival are unclear.
Because of the relatively limited stem cell doses in UCB units, this source has been most frequently used in pediatric patients. Most cord blood units are from unrelated donors with only a small fraction coming from a suitably matched sibling. Initially, UCB transplants were associated with poor engraftment and high TRM, however more recent results are promising with high engraftment rates (>80%) and low incidence of acute and chronic GVHD (6%–28%), allowing for a greater degree of HLA mismatch. The degree of mismatch does not seem to affect the development of cGVHD in cord blood transplants. There is also a suggestion that cGVHD in unrelated UCB transplants is more responsive to therapy than in recipients of unrelated BMT.
Staging and grading
Signs and symptoms of cGVHD typically present 6 to 18 months after allo-HSCT and the onset can be progressive (aGVHD progressing directly to cGVHD), quiescent (precedent aGVHD resolved), or de novo (no history of aGVHD). Grading of cGVHD severity was historically defined as limited or extensive. Although there was prognostic significance to this categorization, investigators have tried to refine prognostic grading scales using survival as the primary endpoint. The two principal grading scales set forth by Akpek (2001) and Lee (2002) show that thrombocytopenia, progressive onset, extensive skin involvement, GI involvement, and low Karnofsky performance status at diagnosis of cGVHD are clearly associated with decreased survival. A newly proposed cGVHD diagnosis and scoring system offers an updated definition of cGVHD in which the diagnosis is based on the specificity of signs and histopathology rather than the traditional criterion of time of onset since transplantation (more or <100 days). The National Institutes of Health consensus criteria further refine the grading system based on multiple clinical parameters into mild, moderate, and severe categories. The prognostic and clinical significance of this grading system has yet to be validated.
Clinical manifestations
cGVHD most commonly involves the skin, eyes, oral cavity, GI tract, liver, and lungs ( Table 2 ). Other organ systems such as the kidneys or heart can also be affected, although far less frequently. Manifestations of cGVHD can include more inflammatory and acute-type features such as erythematous rash, mucositis, diarrhea, transaminitis, and pulmonary infiltrates, or can be more fibrotic and chronic in nature such as sclerotic or lichen planus-type skin changes, fasciitis, sicca syndrome, esophageal strictures, and bronchiolitis obliterans (BO). Age-based, multidisciplinary, ancillary supportive care is essential to the optimal management of cGVHD in the pediatric patient.
| Organ | Signs | Symptoms |
|---|---|---|
| Skin, nails, hair | Sclerosis, lichen sclerosus-like, lichen planus-like features Sweat impairment Ichthyosis Keratosis pilaris Hypo-, hyper -, depigmentation Erythema, poikiloderma Maculopapular rash Nail dystrophy Pterygium unguis Alopecia Scaling, papulosquamous lesions of scalp Hair depigmentation | Pruritus Dryness Longitudinal ridging, splitting of nail Nail loss Thinning of hair Premature graying |
| Vulvovaginal | Lichen planus-like features Vaginal scarring or stenosis Erosions, fissures, ulcers | Dyspareunia Vaginal dryness |
| Muscles, fascia, joints | Fasciitis Sclerosis Myositis or polymyositis Edema | Joint stiffness or contractures Muscle cramps or pain Arthralgia or arthritis Weakness |
| Eyes | Cicatricial conjunctivitis Keratoconjunctivitis sicca Punctate keratopathy Blepharitis | Dry, gritty, or painful eyes Photophobia |
| Mouth | Erythema Lichen-type features Hyperkeratotic plaques Xerostomia Mucocele Mucosal atrophy Pseudomembrane formation Ulcers Gingivitis, mucositis | Dry mouth Pain Difficulty swallowing Oral sensitivity Change in taste Increased dental caries |
| GI tract | Esophageal web or strictures Exocrine pancreatic insufficiency Vomiting Diarrhea | Anorexia Nausea Weight loss, failure to thrive Abdominal cramping |
| Liver | Hyperbilirubinemia Tranaminitis | Jaundice |
| Lung | Bronchiolitis obliterans BOOP | Dyspnea on exertion |
| Hematopoeitic/immune | Anemia, thrombocytopenia, Eosinophilia Hypo- or hyper-gammaglobulinemia Autoantibodies (AIHA, ITP) | |
| Other | Effusions Peripheral neuropathy Nephrotic syndrome Myasthenia gravis Cardiac conduction abnormality Cardiomyopathy Coronary artery fibrotic changes | Varied |
Cutaneous
The skin is the most commonly involved organ of cGVHD. Changes in the skin can be superficial, epidermal (hypo-, hyper-, or depigmentation) or deep into the subcutis and fascial layers. Features commonly seen that may overlap with aGVHD include erythema, maculopapular rash, and pruritis. Diagnostic features of cGVHD include sclerotic, lichen planus-like, morphea-like or lichen sclerosus-like changes and poikiloderma (the combination of atrophy, telangiectasia, and pigmentary changes to the skin). The most severe and difficult-to-treat skin manifestation is sclerotic GVHD. Extensive sclerotic skin changes with superficial or deep subcutaneous or fascial involvement develops in approximately 3% to 4% of patients with cGVHD and can be life threatening. The process is characterized by fibrosis of the skin or subcutaneous tissues and may result in joint contractures, severe wasting, and chest wall restriction. The mean onset of sclerotic skin changes following transplant is late (529 days in 1 study ). Other manifestations of disease include ichthyosis, keratosis pilaris, and sweat gland impairment. The skin appendages may also be involved as manifested by nail loss or dystrophia, scalp changes and alopecia, or premature graying. Skin care should include topical moisturizers, antipruritic agents, strict photoprotection, and close surveillance for cutaneous malignancy.
Musculoskeletal
Musculoskeletal involvement of cGVHD in children can result in myositis, fasciitis, muscle weakness, cramping, edema, and pain. Functional limitations from joint contractures, arthralgias and fatigue can be severe, and therefore close monitoring for decreased range of motion and early intervention with physical therapy, occupational therapy, and splinting is essential. Rarely, surgical joint capsular release may be indicated to help preserve range of motion in involved joints although such intervention has been associated with mixed and transient responses. Other commonly seen musculoskeletal complications include osteoporosis and avascular necrosis, complications that are the direct result of steroid therapy for cGVHD. Careful follow-up with bone density studies and use of vitamin D and calcium supplementation in conjunction with biphosphonates in select patients are therefore warranted.
Ocular
GVHD of the eyes affects up to 80% of patients with cGVHD. Patients typically present with dry or gritty eyes (sicca syndrome), photophobia, erythema, or edema. Patients can suffer from lacrimal gland dysfunction and conjunctival inflammation leading to cicatrical conjunctivitis, keratoconjunctivitis, punctate keratopathy, and blepharitis. Topical therapies, such as corticosteroid or cyclosporine drops, can be effective and optimization of these therapies is warranted. Patients may also benefit from local measures such as punctual plugs or scleral lenses, which provide significant symptomatic relief. It is important to follow these patients closely with serial Schirmer tests to assess the degree of wetting and to intervene early at the onset of ocular involvement even before the evolution of symptoms. A Schirmer test without anesthesia may be difficult to perform and is not recommended in younger children; an ophthalmologist’s input may be needed for objective scoring in these children. Ocular care consists of photoprotection along with regular evaluation for infection, cataract formation, and increased intraocular pressure. For children who are old enough to tolerate the procedure, routine Schirmer evaluation should be done to monitor tear production. Regional care may include artificial tears, ocular ointments, punctal occlusion, humidified environment, occlusive eye wear, moisture chamber eyeglasses, or gas-permeable scleral contact lens.
Oral
Oral cGVHD can involve the mucosa or the salivary glands. Symptoms include oral pain, dry mouth, taste changes, and food sensitivity. Examination may reveal mucosal erythema, lichen-type changes, xerostomia, mucosal atrophy, mucoceles, and ulcers. The largest single-center series of oral cGVHD in pediatric patients described the findings of 49 patients seen at a multidisciplinary pediatric HSCT clinic at the Dana-Farber Cancer Institute. Oral mucosal involvement was identified in 45% of patients, however only 8% of patients reported mouth pain and all patients reported being able to eat well. The most common manifestation was erythema (42%), followed by reticular (36%) and ulcerative (21%) forms. Forty-five percent of patients required specific therapy for their oral mucosal cGVHD despite being currently treated with at least 1 systemic immunomodulatory agent. Salivary gland and sclerotic diseases were rarely observed. Children with isolated oral cGVHD can often be treated with topical steroid rinses, although responses to topical therapy are varied and many patients require systemic treatment. Other treatment options include topical tacrolimus and agents that stimulate salivary gland function, but no strategy has been shown to have significant benefit over another and some may lead to increased rates of oral squamous cell carcinoma. Secondary infections with viruses (especially herpes simplex) and yeasts are common; therefore using a local antifungal preparation in combination with the steroid rinse is recommended. Patients should adhere to strict oral hygiene and have close regular follow-up with an experienced oral health care specialist.
Gastrointestinal (GI) Tract
Children with cGVHD may have varied GI complaints including nausea, anorexia, abdominal pain, weight loss, cramping, or diarrhea. Although these symptoms may be related to cGVHD, the only finding that is strictly diagnostic of cGVHD of the GI tracts is esophageal sclerosis in the form of an esophageal web or stricture. Many GI symptoms are attributable to other causes including late aGVHD, infection, dysmotility, lactose intolerance, pancreatic insufficiency, or drug-related side effects. As many of these problems can be remedied by other means, full evaluation of symptoms, including upper and lower endoscopy, is important before increasing or continuing immunosuppressive medication, as these may not treat the cause and may actually worsen the child’s symptoms.
Weight loss and reduced body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) remain poorly understood, but they are critical issues in children with multi-organ cGVHD. Maintaining adequate nutrition is essential and careful evaluation of growth and head circumference in infants is required. In adults with cGVHD, low BMI is a predictor for mortality. A retrospective study of 18 children with extensive cGVHD found that patients with multi-organ involvement had a mean maximal decrease in BMI of 20.9% in contrast to patients with 1 organ system involved who had a mean maximal decrease in BMI of 5%. Weight loss often preceded overt signs and symptoms of cGVHD, suggesting an altered metabolic state and/or subclinical malabsorption in these patients. Thus, weight loss and malnutrition (as reflected by a decrease in BMI) are clinically significant issues in children with multisystem cGVHD and are likely systemic manifestations of the disease; they may contribute, to increased mortality in this group. Treatment of GI manifestations may include dietary modification, enzyme supplementation for malabsorption, gastroesophageal reflux management, and esophageal dilatation.
Hepatic
cGVHD of the liver can be one of the most difficult manifestations to diagnose, as many possible causes for liver inflammation and damage exist in this population: infection, drug toxicity, iron overload, focal nodular hyperplasia, and so forth. To confirm the diagnosis evaluation must include viral studies for hepatitis A, B, C, and Epstein-Barr virus, cytomegalovirus (CMV), varicella zoster virus, and adenovirus to exclude infection as a cofactor or cause of hepatic dysfunction. Liver biopsy is often required to confirm the diagnosis; this is particularly important for those patients with no other signs or symptoms of cGVHD. The typical appearance of hepatic cGVHD is that of fibrosis resulting in obstructive jaundice, with increases in alkaline phosphatase, γ-glutamyl transferase (GGT), and serum bilirubin levels. Liver biopsies can show portal fibrosis and bile duct dropout and can ultimately progress to cirrhosis and bridging necrosis. Ursodeoxycholic acid can be used for patients with hyperbilirubinemia. Although cholestasic hepatic cGVHD is the classic manifestation of liver involvement, hepatitic cGVHD is being identified more often, with some patients presenting with isolated increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. First described in adult patients, this hepatitic pattern has also been recognized in pediatric patients. The histologic pattern reveals bile duct epithelial damage, significant portal/periportal inflammation, and lobular necro-inflammation. The clinical and histologic patterns of hepatitic cGVHD described in this pediatric study are similar to that described in adults.
Pulmonary
Two forms of chronic pulmonary dysfunction are common in patients surviving greater than 100 days following allo-HSCT: obstructive lung disease (OLD) and restrictive lung disease (RLD). The incidence of lung toxicity ranges from 30% to 60%. Collagen deposition and the development of fibrosis either in the interstitial (RLD) or peribronchiolar (OLD) space are believed to contribute to lung dysfunction. Although RLD and OLD exist as late onset, noninfectious lung complications following allo-HSCT, they can be distinguished by several clinical parameters as described later ( Table 3 ).
| Clinical Factor | OLD | RLD |
|---|---|---|
| Diagnostic entity | BO | BOOP |
| Onset | Late (3–12 months) | Early (within 3 months) |
| Symptoms | Dyspnea, nonproductive cough | Dyspnea, nonproductive cough |
| Physical examination | Wheezing | Rales |
| Pulmonary function tests FEV 1 /FVC TLC DL CO | Obstructive physiology Decreased Normal Decreased | Restrictive physiology Normal Decreased Decreased |
| CT scan findings | Air trapping (expiration) Bronchial wall thickening Ground glass opacities Centrilobular nodules | Fluffy consolidations Ground glass opacities |
| Laboratory data | Nonspecific | Increased CRP Peripheral neutrophila |
| Chronic GVHD | Strong association | Variable, positive with BOOP |
The most common and recognizable form of OLD is BO. BO is a serious life-threatening manifestation of cGVHD that is characterized by an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive OLD. The presence of BO post transplant is diagnostic for cGVHD. There are no effective therapies for BO, and patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression. Mortality approaches 100% in some studies, with a mean fatality rate of 61% Patients with BO may be asymptomatic early in the time course of disease, but typically present with a cough, wheezing, or dyspnea on exertion. As suggested, pulmonary function tests (PFTs) show obstructive lung mechanics with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in 1 second (FEV 1 ) and associated decreases in the FEV 1 /FVC ratio with or without significant declines in the diffusing capacity of lung for carbon monoxide (DL CO ).
The most recognizable form of RLD after allo-HSCT is BO organizing pneumonia (BOOP). Clinical features include dry cough, shortness of breath, and fever, and radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in less than 10% of allo-HSCT recipients, the development of BOOP is strongly associated with prior acute and chronic GVHD. The term BOOP should not be used interchangeably with BO to describe a patient with chronic lung dysfunction after allo-HSCT, although such usage is unfortunately widespread. The two disorders differ with respect to histopathology, pulmonary function characteristics, and most importantly, response to therapy; BOOP after HSCT is quite responsive to corticosteroids, whereas BO is not (see Table 3 ).
In addition, other clinical diagnoses (eg, pneumonias, chest wall fibrosis) can be associated with signs and symptoms of lung dysfunction, therefore an extensive workup of the affected individual is recommended. Testing should include a high-resolution, computer-assisted tomography (CT) scan of the chest, which may reveal an infectious process or air trapping, and when clinically possible, serial complete PFTs that include an assessment of lung volumes, spirometry, and DL CO . When evaluating lung function in this context, it is important to keep some key elements in mind. Specifically, pediatric allo-HSCT patients may not continue on the normal growth curves for height and weight. Recipients of total body or chest wall irradiation may not have proportional chest wall growth. Care must therefore be taken to not only follow percent-predicted values but also to evaluate actual lung volumes over time; because PFTs are scored as a percentage of the predicted norms, from healthy age-matched controls, a drop in the percent-predicted value may actually reflect poor lung growth rather than a physiologic drop in lung function. A broncho-alveolar lavage may be necessary to evaluate for possible concurrent infection and aggressive therapy for proven infection is essential. A biopsy may be needed for definitive diagnosis, however this is commonly avoided because of the risks of the procedure. When a definitive tissue diagnosis cannot be made, the term bronchiolitis obliterans syndrome is applied. Pneumothorax, pneumomediastinum, and subcutaneous emphysema are rare and often represent advanced disease. Ancillary support requires infection surveillance, pneumocystis prophylaxis, and treatment of gastroesophageal reflux. Initial therapy for pulmonary cGVHD should include a trial of enhanced systemic immunosuppression. Benefit may also be observed with inhaled corticosteroids, bronchodilators, supplementary oxygen, and pulmonary rehabilitation. As noted earlier, novel targeted therapies may also hold promise. Consideration of lung transplantation is given to the rare appropriate candidate with severe BO.
Hematopoietic System
Cytopenias are common following allo-HSCT. The mechanisms contributing to marrow dysfunction are not clearly defined and are likely to be multifactorial. Cytopenias may result from stromal damage, but antibody-mediated autoimmune neutropenia, anemia, and thrombocytopenia are also common. It is also important to eliminate drug toxicity, infection, graft failure, or disease relapse as the underlying cause. Thrombocytopenia is the most common hematopoeitic manifestation of cGVHD and occurs in approximately 35% of affected patients. Thrombocytopenia alone does not meet the diagnostic criteria for cGVHD, however several studies have shown that thrombocytopenia at the time of cGVHD diagnosis confers a poor prognosis, although thrombocytopenia may be a poor prognostic factor independent of GVHD. Eosinophilia is also frequently seen in children and can precede the development of overt cGVHD.
Immune System
Patients with cGVHD have associated immune dysregulation and delayed immune reconstitution as a direct consequence of GVHD and immunosuppressive therapy. In addition, patients with mucosal involvement (skin, oral, or GI) lack intact barriers thus increasing the risk of infections. Thus, opportunistic infections are common and remain the leading cause of death in patients with active cGVHD. Functional asplenia, shown by persistence of Howell-Jolly bodies and a higher incidence of pneumococcal sepsis, is also commonly seen and can remain for life despite resolution of cGVHD. Therefore, lifelong prophylaxis against encapsulated organisms is recommended. Patients should also receive prophylaxis against Pneumocystis jiroveci until complete resolution of cGVHD and for at least 6 months after discontinuation of immunosuppressive therapy. Supplemental intravenous immunoglobulin (IVIG) replacement is typically used when patients have the combination of severe hypogammaglobulinemia (IgG <400 mg/dL) and recurrent infections. Patients at risk for CMV should be monitored closely with CMV polymerase chain reaction or antigenemia. Patients receiving steroid rinses for oral GVHD are at high risk for local candida infections and topical antifungal prophylaxis (eg, nystatin swishes or clotrimazole troches) should be used. Patients on steroid doses equal to or greater than the equivalent of prednisone 0.8 mg/kg/d should also be given antifungal and antiviral prophylaxis. The decision to discontinue antifungal and antiviral therapy is dependent on each patient and the intensity of the therapy they are receiving. Up-to-date recommendations from the Centers for Disease Control (CDC) and Prevention for infection prophylaxis are available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm . Vaccinations are critical to enhance immunity against specific organisms but are typically delayed until 6 to 12 months after HSCT as per institutional guidelines or according to CDC recommendations ( http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4910a1.htm ). Live vaccines should be avoided in this patient population.
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