Graft-versus-host disease (GVHD) occurs when transplanted immunocompetent cells, which are introduced into an immunocompromised host, cause an immunologic insult to the host. A complex interaction occurs between the donor’s and recipient’s humoral and adaptive immunities, resulting in signs and symptoms similar to those seen in autoimmune diseases. Morbidity and mortality vary depending on the extent of involvement and the host’s response to treatment. Hematopoietic stem cell transplant or nonirradiated blood products administered to an immunocompromised patient are common associations with GVHD. Despite preventive and protective measures before, during and after the transplant, GVHD remains a significant cause of morbidity and mortality in transplant patients.

Historically, GVHD has been classified as acute or chronic, with 100 days being the cutoff time between the two. Given changes in transplant medicine and subsequent patient outcomes, the National Institutes of Health Consensus Development Project on the Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease has adapted the GVHD classification to the following: Acute GVHD includes (1) classic acute disease occurring within 100 days after transplantation and (2) persistent, recurrent, late-onset acute GVHD with an appearance of acute GVHD occurring beyond 100 days after transplantation (often seen with tapering or withdrawal of immunosuppressive therapy). Chronic GVHD includes a (1) classic chronic GVHD subtype and (2) an overlap syndrome with features of chronic and acute GVHD [42].

Early in the course of GVHD, findings may be subtle. Some patients may feel fatigue, lethargy, and mild pruritus, or develop slight erythema, all of which appear similar to a viral illness. Non-transplant physicians may help identify drug reactions, infections (especially viral exanthems in children), recurring malignancy or other skin conditions, which must be excluded prior to diagnosing GVHD.

Acute GVHD may present with pruritus, edema, erythema, and dysesthesia. As the process continues, skin involvement may range from erythematous macules to papules, vesicles, bullae, or ulceration (Figs. 24.3 and 24.4). Acute GVHD with generalized erythroderma or resembling Stevens-Johnson syndrome heralds a more severe reaction. Extracutaneous features often include cholestasis, nausea, vomiting, anorexia, diarrhea, or ileus [42]. The severity of the acute reaction is based on the skin findings, bilirubin levels, and gastrointestinal involvement.

Chronic GVHD can affect any organ system, although the skin may be the only organ involved (see Table 24.2).

Because of the potential severity of GVHD and often sub-optimal results with treatment, the main focus is on prevention. Pretreatment of transplant tissue via elimination of immunoreactive T cells and the use of immunosuppressive medications during the first 100–180 days post-transplant attempt to prevent GVHD. Prophylactic systemic medications that are most commonly used include tacrolimus, mycophenolate mofetil, methotrexate, cyclosporine, and steroids. Additionally, bowel rest, irradiation of blood products, and prophylaxis for fungal, viral, and bacterial infections also aim to prevent GVHD.

Acute GVHD is a risk factor for developing chronic GVHD, and chronic, progressive GVHD portends a poor prognosis. Therefore, treatment of any type of GVHD is important and depends on disease severity. Topical treatments for mild cutaneous symptoms are adequate [42]. When patients have more moderate to severe disease or multi-organ involvement, systemic immunosuppression is required. Additionally, contractures seen with sclerodermoid-type GVHD may need intervention by occupational and physical therapy [29]. A multidisciplinary approach, regardless of acuity, is prudent.

While the transplant team carefully manages patients, the non-transplant physician plays an important role in disease monitoring and patient education (see Table 24.3).

Topical steroids are the mainstay of treatment for localized cutaneous GVHD, although there are no well-designed studies in children or adults with GVHD [32]. Tacrolimus 0.03 % or pimecrolimus 1 % may similarly be considered instead of topical steroids. When topical medicaments fail to control mild disease, patients may benefit from prednisone, although results are often suboptimal [72].

Pediatric studies show that systemic tacrolimus in combination with mycophenolate mofetil is effective in reducing the incidence of acute GVHD [87]. A Cochrane review showed that mycophenolate mofetil and methotrexate are equally efficacious, although mycophenolate mofetil had a slightly better tolerability profile [63].

One pediatric study showed NB-UVB to benefit eight out of ten patients who failed first-line therapies. Other isolated pediatric case reports show good results with NB-UVB plus topical steroids for the treatment of eczematous-type GVHD [18, 124].

For both acute and chronic forms of GVHD, UVA1 as adjunctive treatment or first-line treatment may lead to complete or partial responses without concomitant steroids [144]. Bath PUVA may also be effective while avoiding the side effects of oral photosensitizers [15, 54, 144].

Etanercept, in addition to topical steroids, in grade I (skin-only) disease have reduced the incidence of development of grades II-IV GVHD when compared to topical steroids alone [44].

Imatinib may serve as a treatment for steroid-refractory chronic GVHD, possibly due to its anti-inflammatory effects as seen with several fibrotic diseases. An additional benefit is that patients do not require hospitalization or long-term venous access [85]. Extracorporeal photopheresis for chronic GVHD in adults and children may improve sclerotic changes in the skin for up to 12 years after the onset of GVHD [137].

Melkersson-Rosenthal syndrome (MRS) is a rare neuromucocutaneous disease characterized by infiltration of the skin and subcutaneous tissues with noncaseating granulomas. Patients predominately present as females in the third decade of life with an incomplete triad of fissured tongue (lingua plicata), relapsing facial paralysis, and recurrent or persistent facial edema [37] (Fig. 24.5). Children tend to present differently than adults, with unilateral facial nerve palsy as the inciting event. This can precede the edema by several months. Isolated eyelid edema as a solitary presenting sign of MRS has also been reported [100] (Fig. 24.6).

The etiology of MRS is unknown. It is theorized that granulomas lead to lymphatic and vascular congestion, which causes swelling of the lips, cheeks, and/or eyelids [37]. A genetic link is suspected, as up to 30 % of cases have a first- or second-degree relative with a history of “facial palsy [119].” Additionally, autoimmune diseases and infectious etiologies have been associated with MRS in some case reports.

Due to the rarity of the condition and paucity of reported cases of pediatric MRS, treatment relies upon anecdotal evidence in children and studies from the adult literature. Therapeutic management is determined by the severity of disease. In solitary lip swelling, topical and intralesional therapies should be attempted first. When patients have disfiguring or debilitating symptoms, or if conservative measures are ineffective, oral agents are the next appropriate step. Finally, surgical approaches may be employed if there is permanent aesthetic and functional deformity and all other therapies have failed.

Because of its variable presentation, MRS is a diagnosis of exclusion. It can present in a similar fashion to other disorders such as Bell’s palsy, angioedema, contact dermatitis, Crohn’s disease (CD) or infection. A skin biopsy can aid in diagnosis, but may only show edema in the early stages. Additional studies may help exclude diseases in the differential diagnosis.

Crohn’s disease (CD) is a chronic granulomatous inflammatory bowel disorder that can affect any part of the gastrointestinal (GI) system. Extraintestinal manifestations can affect the skin, joints, eyes, and liver. The etiology of CD is multifactorial and is due to an immune-mediated inflammatory process.

Pediatric patients with underlying CD most commonly present with growth failure. GI signs and symptoms may be subtle, such as mild indigestion after meals or intermittent constipation. More common manifestations of CD include diarrhea, weight loss, fever, and fatigue.

Cutaneous CD falls into one of two categories: “nonspecific” or “specific,” which are detailed in Table 24.10. About 20 % of patients with CD present with cutaneous lesions preceding the onset of GI disease by months or years. Of the children with cutaneous CD, up to two-thirds have genital involvement (Figs. 24.7 and 24.8), which may have the mistaken appearance of child abuse or sexually transmitted infections [31, 94, 98, 101]. In general, any pediatric patient with GI complaints and cutaneous lesions should be biopsied for evaluation and referred to gastroenterology. Furthermore, patients with isolated genital swelling and erythema should be evaluated for CD in the appropriate clinical setting.

The goal of treatment in pediatric CD is to optimize nourishment for growth and development. Additionally, management of the systemic disease by the gastroenterologist to induce remission and prevent relapse is critical. Localized lesions can be treated with topical steroids and/or intralesional steroids. If lesions are located on the face, low-potency steroids or calcineurin inhibitors should be used. Multiple lesions or complicated lesions such as fistulas or abscesses may require systemic medications [57, 96].

Finally, cutaneous or GI surgery is reserved for patients who do not respond to medications, or in patients with progressive, debilitating complications.

Sarcoidosis is a multisystem disorder characterized by noncaseating granuloma formation due to an unknown etiology. Although it most commonly affects adults, there are two observed pediatric forms, early-onset sarcoidosis (EOS) and a later-onset disease. The two groups vary in presentation and systemic involvement (Table 24.14).

EOS is caused by a sporadic mutation in the NOD2 gene, also known as CARD15. Blau syndrome, clinically identical to EOS, is also caused by a NOD2 mutation, but is due to an autosomal dominant inheritance [27]. The course of EOS is unpredictable, as some lesions can persist for many years while others can occur intermittently with sporadic resolution. Pediatric patients in the older population (ages >5 years) tend to have advanced disease demonstrating constitutional symptoms and pulmonary findings similar to adults [147]. The cutaneous findings of the two variants of pediatric sarcoidosis have overlapping features and a wide range of distinct primary lesions (Fig. 24.9 and Table 24.14).

The prognosis of pediatric sarcoidosis relies upon the degree of organ involvement, as neurosarcoidosis and extensive hilar involvement have shown increased morbidity and mortality [112]. Erythema nodosum portends a favorable prognosis, similar to that seen in adults [114]. Cutaneous sarcoidosis may herald future systemic involvement, which can lag behind the cutaneous presentation by several years. Thus, even with resolution of cutaneous sarcoidosis, patients should be monitored annually for development of extracutaneous involvement [83]. While the majority of pediatric cases resolve spontaneously within 6 years, some have persistent organ damage [79].

In general, treatment should reflect the activity and symptomology of disease and the type of organ involvement. If the disease is symptomatic, rapidly progressive, scarring, or otherwise affecting quality of life, the provider must address the risks and benefits of choosing a particular therapy. Limited cutaneous disease may only require topical therapy, whereas more aggressive disease often necessitates systemic therapy. Also, combinations of therapies may help control the inflammatory process.

Sarcoidosis is a diagnosis of exclusion. It is important to check inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein. Angiotensin converting enzyme levels are helpful in the older pediatric population due to the involvement of the lung as well as its utility in following disease activity and response to treatment. However, it must be noted that unaffected children can have angiotensin converting enzyme levels greater than two standard deviations of the adult range [103].