Biol Blood Marrow Transplant 21 (2015) 799e808

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Musculoskeletal, Neurologic, and Cardiopulmonary Aspects of Physical Rehabilitation in Patients with Chronic Graft-versus-Host Disease Sean Robinson Smith 1, *, Andrew J. Haig 2, Daniel R. Couriel 3 1 2 3

Cancer Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan Adult Blood and Marrow Transplantation Program, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan

Article history: Received 9 August 2014 Accepted 20 October 2014 Key Words: Cancer rehabilitation Chronic graft-versus-host disease Physiatry Rehabilitation of chronic graftversus-host disease Graft-versus-host disease Bone marrow transplantation rehabilitation

a b s t r a c t Chronic graft-versus-host disease (cGVHD) has the potential to cause significant morbidity and mortality in people who undergo allogeneic hematopoietic stem cell transplantation. Management of complications due to cGVHD can be challenging because of multiorgan involvement and variable presentation of the disease. This paper outlines the diagnosis and management of musculoskeletal, neurologic, and cardiopulmonary manifestations of cGVHD that have the potential to cause profound functional impairment and that may significantly impact quality of life and lifespan. Expert evaluation by a physical medicine and rehabilitation physician and multidisciplinary team may be beneficial in the treatment of the disease sequelae, and examples of specific rehabilitation interventions are described. Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (HSCT) and it affects about 50% of patients [1]. Its pathophysiology is largely unknown and unlike acute GVHD, it can affect almost any organ system. The treatment for cGVHD, which almost invariably involves long-term administration of corticosteroids, causes additional toxicity and contributes to the complexity of this syndrome. Thus, cGVHD can significantly increase nonrelapse mortality and morbidity, with a profound impact on quality of life in patients who are otherwise in remission of their malignancy. Little research has been performed on the treatment of the physical impact of cGVHD and the resulting functional impairment in these otherwise cancer-free transplantation survivors. A Medline search of the terms disability or rehabilitation combined with the term graft-versus-host disease

Financial disclosure: See Acknowledgments on page 806. * Correspondence and reprint requests: Sean Robinson Smith, MD, Department of Physical Medicine and Rehabilitation, University of Michigan Medical School, 325 E. Eisenhower Parkway, Suite 100, Ann Arbor, MI 48108. E-mail address: [email protected] (S.R. Smith).

http://dx.doi.org/10.1016/j.bbmt.2014.10.019 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

returned 45 items as of the writing of this article, of which less than one-half related primarily to the topic. The 2005 National Institutes of Health Consensus statement for clinical trials in cGVHD was the first effort to bring attention to this problem, outlining the degree of impairment and evidencebased ancillary and supportive care [2]. Given the dearth of research in this area and lack of literature describing collaboration between bone marrow transplantation (BMT) oncologists and physiatrists, it is likely that physical medicine and rehabilitation (PM&R) physicians are underutilized in the comanagement of patients with cGVHD. Possible reasons for the lack of research focus in this area are outlined in Table 1. The impact of cGVHD on physical function can be profound and it may be difficult to distinguish from other transplantation-related long-term complications. When these effects are measured as performance status, they intimately correlate with survival. Unfortunately, the exact impact of physical rehabilitation on nonrelapse mortality, quality of life, and systemic therapy in cGVHD is largely unexplored. The positive effects of physical activity in both health and disease, as demonstrated in numerous other disorders, warrants a close interaction with the rehabilitation team. Although there are no specific trials in cGVHD, there is overwhelming evidence for the benefit of team

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rehabilitation in less complicated diseases [3-5]. Classically, team rehabilitation is led by a physiatrist and involves specialized nursing, physical and occupational therapy, psychosocial support, and other allied health professionals as needed. This can be performed ad hoc on an outpatient basis or in an acute inpatient rehabilitation unit for patients unable to be discharged home because of physical limitations. Postacute facilities (eg, subacute rehabilitation and/or skilled nursing facilities) provide less intense therapy for these debilitated and sick patients, and evidence is growing that morbidity and mortality are increased in patients with similar diagnoses managed in a postacute facility instead of an acute inpatient rehabilitation facility [6,7]. This manuscript focuses on the complications from cGVHD or its therapy, which can result in loss of physical functionality, and medical rehabilitation as a treatment. Other forms of supportive care and systemic therapy are beyond the scope of this review. Manifestations of cGVHD and their rehabilitation-based treatment are divided by organ system (see Table 2).

There are 2 typical manifestations of dermal cGVHD: lichenoid and sclerodermatous. Lichenoid manifestations include a maculopapular rash resembling lichen planus and have the potential to affect the oral cavity and vaginal mucosa. Sclerodermoid cGVHD, on the other hand, mimics systemic sclerosis and can manifest as skin tightening, atrophy, blistering, ulceration, loss of sweat glands, and joint contracture. The presentation can range from mild to significant involvement and the severity of cGVHD is based on the extent to which the skin and fascia are involved [10]. When the involvement of the skin and/or fascia surrounds joints, it can cause decreased range of motion, significantly restricting a patient’s ability to perform activities of daily living [9] and contributing to prolonged periods of immobility. Painful joint contractures may also result, further impairing function. Edema is often the first finding on physical exam of fascial involvement in GVHD [2]. Common joints affected are the wrists, shoulders, ankles, and hips, with the distal joints often affected first. Involvement is typically symmetric and can be progressive, involving more areas of the skin and joints over time. cGVHD is an independent risk factor for joint destruction and associated pain and dysfunction [11]. A patient affected by cutaneous cGVHD is already at risk for decubitus ulcers due to immobility from the disease and/ or its treatment, and thinning of the skin facilitates this problem. Ulcerations of the skin, either as a direct result of inflammatory destruction of the skin due to cGVHD or as a result of shear forces or pressure, cause pain and put the patient at a significant risk for cellulitis and osteomyelitis in this immunosuppressed patient population. Edema can result from inflammatory sweat gland destruction, also contributing to skin thinning and ulceration in addition to worsening functional impairment by adding weight in the extremities. Gastrointestinal GVHD, with loose, frequent stools, coupled with the inability of a patient to physically get to a toilet or commode, further complicates this picture and creates an environment where infection can rapidly spread. Treating both the GVHD and the weakness from muscle deterioration is essential. The “Muscle” section below further discusses this issue.

SKIN AND JOINTS Clinical Manifestations Cutaneous involvement is the most common manifestation of cGVHD, affecting about 90% to 100% of patients, and can lead to a great deal of functional impairment [8]. Cutaneous cGVHD can be classified into 2 distinct anatomic subcategories, dermal and fascial, though there is often coinvolvement of both [9].

Treatment Management options in cutaneous cGVHD are limited and of variable efficacy, particularly in advanced cases with marked sclerosis and limitation in the range of motion. The exact role of rehabilitation at different stages of the disease remains unknown. Although no randomized control trial for stretching and splinting has been conducted or shown to be efficacious in preventing skin and joint contractures, there are case reports and limited studies that show mild benefit of

Table 1 Challenges and Shortcomings of Research on Rehabilitation for cGVHD Challenges in Studying Rehabilitation Issues in cGVHD Chronic GVHD has not traditionally been a focus of PM&R (compared with stroke, spinal cord injury, amputation, etc) Polymorphic clinical presentation, so outcome measurements and standardization of trials is difficult Patient populations are essentially limited to tertiary care centers with a BMT program PM&R research has traditionally focused primarily on orthopedic, post-traumatic, and neurologic diagnoses BMT physicians may not be familiar with PM&R physician skill sets, may not collaborate frequently Examples of Topics in cGVHD Rehabilitation Needing More Research Effects of aerobic exercise on reversing cGVHD Bracing and/or splinting trials for sclerotic cGVHD Inpatient rehabilitation and the benefits of multidisciplinary assessment Prevalence of steroid myopathy and its impact on patient function and health Correlation between loss of physical function and hospital readmission

Table 2 Common Rehabilitation Issues in cGVHD Organ

Problem

Intervention

Skin/fascia

Sclerodermatous contractures

Muscle

Myopathy

Bone Peripheral nervous system

Osteoporosis Peripheral neuropathy

Cardiopulmonary

Physical deconditioning

OT for ROM and strengthening, splinting, iontophoresis. Surgery likely ineffective and may have negative outcomes. PT for fall prevention and strengthening. Bracing for weak muscles. Adaptive equipment (canes, walkers) as indicated. Core stabilization, bracing for pain or stability Bracing for motor weakness, nerve stabilizing agents for pain, wound prevention (proper footwear, frequent skin checks) Exercise program (possibly through PT), consider pulmonary or cardiac rehab for specific issues in these organ systems

OT indicates occupational therapy; ROM, range of motion; PT, physical therapy.

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Table 3 Examples of Orthoses Used in the Treatment of cGVHD Name

Picture

Pros

Cons

Resting hand splint

Figure 1

Dynamic hand splint Ankle foot orthosis

Figure 2 Figure 3

Holds fingers and hand in extension, easy to put on and take off Provides a stretch in addition to limiting flexion Holds ankle in dorsiflexion, prevents foot drop/drag

Multipodus (L’nard) boot

Figure 4

Does not provide an active stretch, unclear if prevents contractures More difficult to put on and fabricate, unclear efficacy Not effective at night, patient may need gait training in physical therapy Unclear efficacy, typically not used during ambulation

Provides dorsiflexion stretch at night, may prevent plantarflexion contracture

a rehabilitation program consisting of splinting and occupational therapy [12]. One descriptive study of 14 pediatric patients with cGVHD-related joint contractures showed that physical therapy and proper use of orthotics improved range of motion and function to near baseline [13]. This same study also showed that surgical release of contracted joints was unsuccessful in improving functional status, and, furthermore, that surgery made the involved joints refractory to conservative treatment, such as splinting. Splinting can take many forms, including supportive splints that prevent bad positioning, splints that create pressure to stretch, and serial casting or dial-lock splints changed weekly to aggressively treat severe contractures. One case report describes successful surgical release of multiple contracted joints in using Y-V plasties, a technique in which incisions are cut and reattached in a manner to reduce tension on the resultant scar. Benefits were apparently seen in improved range of motion in the patient 9 months after the operation [14]. Of importance, this case report describes the muscles and actual joints of the patient as not being obviously involved in any inflammatory process, though the skin showed chronic inflammatory changes. This suggests that other surgical interventions may have failed secondary to myofascial and joint inflammation and scarring from the autoimmune process. Because there is no convincing evidence that surgical correction of contracted joints in cGVHD is a viable option, conservative management with range-ofmotion exercises, splinting, and strengthening to improve gross- and fine-motor functioning should be a mainstay of treatment. More research is needed in this area to assess for improvement in function with these interventions. In general, thermal physical modalities are often used to treat contractures due to other conditions, including scleroderma. Theoretically, ice applied for 20 to 30 minutes over an area will decrease pain and might decrease inflammation. Other modalities may have beneficial effects: superficial heat can loosen bonds within collagen, paraffin baths can heat tissues as deep as 1 cm in the hands and feet, and ultrasound causes friction, allowing heating and collagen softening even deeper. Each of these heating modalities must be done with simultaneous stretching and, theoretically, the heat would increase rather than decrease inflammation. It is important to note that caution must be taken in patients with friable skin so as to avoid burns. Clinical trials of thermal modalities to treat cGVHD seem warranted. Paraffin bathing has been shown to be beneficial for patients with rheumatoid arthritis in reducing pain and improving range of motion [15]. In scleroderma, multiple studies show a benefit to using paraffin baths and physical therapy over physical therapy alone to improve range of motion and reduce pain, even with sustained results [16-18]. No similar studies exist in the cGVHD population.

Iontophoresis, a process by which topical medication is infiltrated into subcutaneous tissue via an electric gradient, or phonophoresis using ultrasound heating to administer subcutaneous medication, should also be considered, though again, no study has been conducted in this patient population. Cortisone may be transmitted deep to the epidermis, potentially penetrating fascial areas of inflammation and facilitating improved outcomes in patients with sclerotic cGVHD contractures. Alternatively, saline may be used in iontopohoresis to break up existing scar tissue. Most studies in the scleroderma population focus on vascular dilation for digital ischemia [19], though the concept of a local therapy remains intriguing in the cGVHD population to potentially limit systemic toxicity. Response to therapy can be subjective, and using in-clinic goniometry is the mainstay of joint range assessment. Obtaining an objective range of motion evaluation can be difficult and require specialized equipment, making this not tenable in everyday clinic visits and further complicating potential studies. The National Institutes of Health visual scale for assessing range of motion as recommended by the 2005 Consensus Statement [2] has been validated when assessing changes to the joint motion over time, though it is better at showing improvement than worsening of disease [20]. The Barthel Index of Activities of Daily Living is a validated and reproducible scale that helps to monitor of a patient’s ability to perform self care, which is especially important in patients where fine motor or repetitive activities may be impaired by dysfunction of the hands due to contracture [21]. Topical treatment for cGVHD involving the skin should be directed to discrete lesions or wounds, with the goal of preventing skin breakdown or treating existing lesions [10]. Preventive treatment should focus on treating the common manifestations of cutaneous cGVHD, including pruritus, sensitivity to ultraviolet rays, and rash. Topical corticosteroids and calcineurin inhibitors, and liberal application of a ultraviolet-blocking agent containing mexoryl, should be a mainstay of preventative care. In skin with breakdown, local wound dressings that maintain a moist environment promotes healing of the skin and phagocytosis of necrotic areas. A plastic surgery consultation is warranted in deep, stage III or IV wounds [22] or in wounds suspected to be infected. In summary, in patients with diffuse sclerodermatous cutaneous and articular involvement of cGVHD, targeted splinting and range of motion and strengthening exercises should be initiated. A PM&R consult may be helpful in coordinating these services and monitoring the patient’s response to therapy from a functional standpoint. Examples of orthotic splints that may be used are outlined in Table 3 and shown in Figures 1 through 4.

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Figure 1. Resting hand splint.

Figure 2. Dynamic hand splint.

MUSCLE Clinical Manifestations Muscle mass loss in cGVHD is multifactorial and is most frequently a result of disuse, deconditioning, or side effects of immunosuppressive treatment, particularly corticosteroids. Less frequently, GVHD itself can be the direct or indirect cause when fascia, peripheral nerves, or less frequently, muscles are involved [23]. In the more severe forms of cGVHD, patients may be confined to bed rest for prolonged periods of time, resulting in both strength and muscle mass decreases at a rate of about 1% per day [24]. The weightbearing lower extremities and low back extensor muscles are more affected than upper extremities, making it difficult to begin ambulating after prolonged periods of rest. Skeletal muscle repair is also hindered because of increased catabolism brought on by higher basal levels of glucocorticoids in the bloodstream during periods of immobility [25]. Furthermore, patients receiving long-term oral corticosteroids are at risk for developing steroid-induced myopathy. Steroid myopathy can be acute or chronic. Acute steroid myopathy typically occurs within 1 week of high-dose oral corticosteroid use and can be associated with rhabdomyolysis and pain. The chronic form occurs weeks to months into prolonged, high-dose steroid administration and is generally painless. Both forms cause proximal muscle weakness in the upper and lower extremities and the neck. Patients may report difficulty rising from a seated position or lifting up utensils to eat. The diagnosis is typically made clinically, though a muscle biopsy showing selective type II muscle fiber atrophy can be confirmatory [26], and magnetic resonance imaging may show fatty changes in proximal muscles. Notably, unlike other myopathies, steroid myopathy is not well detected on electromyography (EMG). Urine studies

may be diagnostic and may show elevated creatinine in chronic steroid myopathy and myoglobinuria in acute steroid myopathy. In addition to steroid myopathy, muscle mass and strength may be compromised because of an inflammatory myositis, mimicking polymyositis or dermatomyositis, that is a direct, immune-mediated result of cGVHD [27]. When this has been described in the literature, it is associated with tapering of immunosuppressant medications and is associated with the same genetic markers seen in patients with this autoimmune disease who have not undergone HSCT [23]. Typically, this presents with painful, symmetric proximal weakness with increased aldolase and creatine phospokinase seen on blood work. EMG is profoundly abnormal in the proximal limbs and paraspinal muscles in these disorders. A muscle biopsy is diagnostic [2,28]. Calcineurin inhibitors, such as cyclosporine, have been shown to be effective in the treatment of myositis [28], though specific studies in the GVHD population have not been conducted. In rare instances, myasthenia gravis may develop when tapering immunosuppressive medication because of preexisting autoantibodies against postsynaptic acetylcholine receptors [29]. This is most commonly seen in patients who received the HSCT for aplastic anemia [29]. Symptoms typically are progressive weakness with exertion, with recovery of strength after rest. Ptosis is a common first symptom and its presence along with generalized weakness may warrant further workup, such as an EMG that includes repetitive stimulation studies and blood tests to detect antibodies to acetylcholine receptors. Finally, as poor nutritional status is linked to a decline in muscle strength and mass, decreased energy level, poorer cognitive performance, and increased risk of complications

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Figure 3. Ankle foot orthosis.

Figure 4. Multipodus (L’nard) boot.

such as pressure ulcers or infection [30], careful attention must be paid to the nutritional level of patients with cGVHD. One study found that 40% of patients with GVHD have malnourishment [31]. The reasons for malnutrition are multifactorial and may include decreased appetite, poor absorption of nutrients because of gastrointestinal involvement of the disease or infection, increased catabolism due to immobility and immunosuppressive treatment, dysphagia, odynophagia due to oral lesions, depression, and more. Adequately treating the cause(s) of malnutrition are essential components to a strengthening program.

Special considerations for resistance training must be made for patients with thrombocytopenia, as having a platelet count below 20,000 platelets/mL is associated with possible increased bleeding risk. Increased intracranial pressure, such as with the use of the Valsalva maneuver when weight training, has been shown to be associated with subarachnoid hemorrhage [32] and retinopathy [33], and has the potential to contribute to bleeding in various other sites in the body. Lifting restrictions, such as a 10-lb or 4.5-kg limit, should be initiated in thrombocytopenic patients to

Treatment Muscular disuse atrophy and steroid-induced myopathy are often seen in combination and management is difficult because patients often remain on corticosteroids for prolonged periods of time. Usually there is no clinical rationale for prolonged bed rest without any exercise. In the sickest patients, tilt table use, sitting at bedside, and upper limb exercises in bed can help modulate the deconditioning syndrome. A portable tilt table may be used on the BMT unit if the patient is not in an acute inpatient rehabilitation facility. Passive stretching also preserves muscle mass in addition to preventing contractures. There should be a low threshold for early intervention with a rehabilitation program to prevent muscular disuse atrophy. Resistance exercises should be introduced into a patient’s exercise regimen, as strength can be preserved in the setting of steroid myopathy, though improvement of strength to baseline is unlikely without discontinuation of corticosteroid therapy [1]. Examples of physical and occupational therapy prescriptions for common diagnoses in cGVHD are noted in Table 4.

Table 4 Examples of Therapy Prescriptions for Manifestations of cGVHD Steroid myopathy/proximal muscle weakness: PT 2-3 times a week for 4-6 weeks, then re-evaluate. Therapy should focus on light resistance training, including isometric strengthening of quadriceps, hamstrings, hip extensors, and hip abductors. Gait training (with or without an assistive device) should be performed. Core should be strengthened for spine stabilization. Home exercise program should be provided and the patient adequately educated as to how to perform the routine. Gait instability/fall risk: PT 2-3 times a week for 4-6 weeks, then re-evaluate. Include balance and gait training, focusing on ankle proprioceptive feedback and ambulating with a walker or cane as indicated. Strengthen hip abductors and quadriceps. Home exercise program. Sclerotic hand contractures: OT 1-3 times a week for 4-6 weeks, then re-evaluate. Work on hand and finger strengthening and dexterity utilizing modalities such as clay putty and resistance training. Stretch and strengthen surrounding musculature. Paraffin baths as indicated to improve stretch. Saline iontophoresis over wrist extensors. Home exercise program. Note that these prescriptions are only examples and need to be individualized for each patient.

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prevent these complications. Monitoring by a trained physical therapist for signs of bleeding during exercise is important, and having a PM&R physician concurrently monitoring a thrombocytopenic patient’s medical condition and response to therapy may be beneficial. One paper describes better platelet counts and fewer adverse events when therapy is conducted in the afternoon, though no comprehensive study has shown this to be the case [34]. Another showed that while on an acute inpatient rehabilitation unit, 10 of 18 thrombocytopenic patients (less than 100,000 platelets/mL in this study) had bleeding events, though no specific exercise was implicated in causing bleeding [35]. Barriers to adequate nutrition must also be assessed when optimizing a patient’s strength and conditioning. In addition to nutritional supplements, dexamethasone rinses can combat painful oral lesions that inhibit eating, and a referral to a speech and language pathologist for a swallowing evaluation is important in diagnosing and treating dysphagia. Medications such as megestrol, 400 to 800 mg daily, can improve cancer-associated cachexia and provide modest weight gain [36]. Dronabinol is also often used to stimulate appetite in cachexia; however, studies have shown that despite an initial increase in caloric intake, weight gain was found to be in the form of water or fat instead of lean body mass [37]. Given the synergistic effects of both exercise and optimal nutritional intake, it is important that any rehabilitation plan include attention to both of these factors. PERIPHERAL NERVES Clinical Manifestations cGVHD is associated with several possible neurologic sequelae, including mononeuropathies, generalized peripheral neuropathy, and inflammatory neuropathy. A combination of multiple neuropathies may also result, complicating diagnosis and treatment. Peripheral neuropathies in general can be autoimmune mediated, though there is not conclusive evidence that cGVHD directly causes neuropathy. Nevertheless, neuropathy in cGVHD and the absence of other known etiologies is typically characterized by a symmetric and painful presentation. Given chronic glucocorticoid use in this population, peripheral neuropathy from diabetes may develop. cGVHD has also been shown to cause a neuropathic process that resembles acute inflammatory demyelinating polyneuropathy (AIDP), and is thought to be a result of direct infiltration of peripheral nerves by donor T cells [38]. An EMG can be diagnostic and can show demyelination, axon loss, or both [39]. The first electromyographic sign of AIDP is an absent F-response, with subsequent findings of conduction block and denervation. Chemotherapy used before transplantation and immunosuppressive medications used to treat cGVHD are the most common causes of neuropathy. Tacrolimus has also been associated with a demyelinating peripheral neuropathy that can cause significant pain [40]. EMG can be diagnostic for peripheral neuropathy but it will not necessarily discern the cause. Neuropathies caused by chemotherapy are typically purely sensory or mixed motor and sensory, and about a one third of patients receiving these medications will develop some degree of disability [41]. Patients are also at risk of mononeuropathies caused by nerve entrapment, either by mechanical compression or fascial inflammation. As the inflamed fascia and/or skin surrounding peripheral nerves become fibrosed, the nerve may become entrapped and damaged. Nerves at high risk for entrapment are those with little surrounding tissue, such as

the ulnar nerve at the cubital tunnel and peroneal nerve at the fibular head. A patient with poor muscle mass or fat reserve, which may be related to the disease course, is further at risk of peripheral nerve damage by pressure due to a lack of protective layers around the nerve. The median nerve at the carpal tunnel can also be damaged due to wrist flexion contractures. If a peripheral mononeuropathy is suspected, an EMG may be diagnostic for damage and ultrasound may confirm entrapment. Finally, as patients with cGVHD are often immunocompromised, varicella-zoster virus reactivation may also occur, resulting in painful neuralgias often in the distribution of a single nerve. Treatment Treatment for peripheral neuropathy associated with GVHD is supportive. Pain should be managed with gabamodifying medications such as gabapentin or pregabalin, with adjuvant therapy consisting of tricyclic antidepressants and duloxetine if needed [42]. Pain secondary to postherpetic neuralgia specifically was shown to be relieved with gabapentin in a randomized placebo-controlled trial [42]. Because medications rarely relieve pain completely in polyneuropathy, it is important to balance patient expectations against medication side effects as one proceeds with multidrug therapy, and to discontinue medications that do not show clear long-term benefit. If starting gabapentin or pregabalin, it is important to watch for lower extremity edema, a known and relatively common side effect, as it may compromise skin integrity. Treatment must also address restoring function with physical therapy and bracing, as the patient will be at risks for falls and injury. Sensory neuropathies can impair proprioception and motor neuropathies cause weakness; both are risk factors for falls. Specifically, increasing hip abduction strength and improving ankle proprioception, as can be accomplished in physical therapy, have a negative correlation with falls [43,44]. Furthermore, patient education about avoiding falls, as well as home/environmental modifications ranging from night lights to removal of slippery carpeting can decrease falls and minimize their consequences. This is typically the expertise of occupational therapy, and a referral to this service for a home safety evaluation may be indicated. Patients with decreased or absent sensation in their lower extremities due to neuropathy are also at risk for developing wounds. The wounds may have difficulty healing and can become infected, leading to osteomyelitis. Trauma can occur by bumping feet on walls or objects, or from shearing and repetitive trauma from footwear. Wide-toe diabetic shoes should be prescribed and fit by a certified orthotist, and the patient and/or caregivers should frequently inspect their feet for wounds. Discrete, painful areas of the feet should be offloaded with custom-fabricated orthotic shoe inserts to normalize gait. Peripheral mononeuropathies due to compression can be treated with physical therapy and proper positioning, though in the setting of inflammatory fasciitis, surgical release of scar tissue or local corticosteroid injection may be necessary. Nerve gliding, a stretching technique used in physical therapy to mobilize peripheral nerves entrapped by scar tissue, has shown some benefit [45], though this technique has not been studied specifically in patients with cGVHD. Pain can be controlled with similar medications used in generalized peripheral neuropathies. When splinting and protection fail, and if medical factors preclude decompressive surgery, corticosteroid injections into the area of compression may be

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appropriate. Such injections have been shown to relieve pain in non-cGVHD patients with carpal tunnel syndrome and other focal compression neuropathies [46]. If AIDP is confirmed diagnostically with EMG, intravenous immunoglobulin treatment should be initiated, as well as supportive therapy, including ventilator assistance for patients with respiratory compromise. A PM&R consultation can be helpful in both diagnosis and management of the disease. It is important to note that intravenous immunoglobulin has not been shown to be effective in treating cGVHD, and it should be administered only to patients who have a comorbidity, such as AIDP, that warrants the treatment and who are greater than 90 days out of HSCT [47]. BONE Clinical Manifestations As many as 50% of patients who undergo HSCT develop osteopenia or osteoporosis, and cGVHD is associated with an even higher incidence [48]. This is often the result of chronic glucocorticoid use, a major risk factor for osteopenia and osteoporosis because of increased bone turnover [49]. Other risk factors that these patients face that contribute to bone density loss are calcineurin inhibitor use, chemo- and radiation therapy, gonadal dysfunction, renal dysfunction, increased marrow turnover due to hematogenous malignancy, and decreased weight-bearing activity [48]. Although bone density is reduced, it typically decreases to levels seen in osteopenia and not osteoporosis. Bone density loss in cGVHD is typically seen more in the femoral heads than the vertebrae, a distinction when compared with menopausal osteoporosis [49,50]. This should be noted when evaluating dual-energy x-ray absorptiometric scan results. The HSCT itself causes a fundamental alteration of bone mineral metabolism, with loss seen in the first 6 to 12 months, followed by ensuing recovery [51]. Prolonged immobility and nutrient deficiency, in concert with paraspinal muscle atrophy, can contribute to debilitating back pain [52]. Decreased bone density puts patients at risk for compression fractures, which would limit their ability to bear weight and ambulate, as well as cause significant pain. In patients with axial back pain or known vertebral compression fractures, flexion/extension x-rays should be taken to assess for spinal stability. Potential components of spinal instability include fractures affecting central or bilateral vertebral elements, subluxation, involved vertebrae located at transitional levels (ie, C7 to T1, T11 to L2, L5 to S1), loss of > 50% vertebral body height, and pain [53]. Finally, patients with cGVHD are also at risk of developing avascular necrosis (AVN) of joints, most commonly the femoral heads. This is seen in 4% to 19% of HCT survivors [54,55] and is associated with many risk factors, including exposure to glucocorticoids and calcineurin inhibitors, the disease process itself, older age, and female gender [54]. Higher doses of glucocorticoids are associated with a greater risk of AVN [55]. Symptoms are typically pain with weight bearing or movement of the affected joint, and radiographs may show evidence of edema and bony destruction around the joints, sometimes with flattening of articular surfaces. The femoral head is the most common site for developing AVN, though the humeral head, knees, and ankles are often affected [51]. Treatment In addition to medical therapy consisting of vitamin D, calcium, and possibly bisphosphonate use [56], weight-

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bearing activity should be initiated to improve bone density. Short, 20- to 30-minute bursts of walking followed by periods of rest are effective in improving bone density [57]. Resistance training, such as bicep curls and leg extension exercises, should also be undertaken to improve bone density in the long bones of the limbs. Nordic trekking poles can be useful in promoting an upright posture while simultaneously reducing stress on the spine and knees [58]. A patient with difficulty walking and/or lower extremity weakness should be referred to physical therapy to focus on improving balance and preventing falls (please see the “Treatment” subsection under “Peripheral Nerves” for more detail on the prevention of falls, and Table 4 for an example of a physical therapy prescription for a patient at risk for falls). Of note, many patients with osteoporosis develop hip flexor contractures due to sustained forward-flexed posture, so this should be examined and treated in physical therapy, if indicated. A tight iliopsoas muscle may lead to worsening lumbar lordosis, increasing pain, and adding force being applied to vertebrae already prone to fracture. For patients with compression fractures and/or axial back pain, treatment should be divided into acute and chronic. Acute compression fractures warrant flexion/extension xrays, as outlined above. In the setting of significant spinal instability, a cruciform anterior stabilization hyperextension (CASH) brace or Jewett brace should be considered. Both the CASH and the Jewett brace limit flexion, and thus do not load the oft-fractured anterior column of the spine, permitting healing. Proper fitting of these braces by a certified orthotist prevents unwanted vertebral movement and optimizes healing. Most compression fractures, however, are not unstable, so bracing is usually used more for comfort and to prevent progression of the kyphotic deformity. A soft corset brace can provide proprioceptive feedback to prevent spinal flexion and reduce pain. In deconditioned cGVHD patients, braces may not be helpful, as they can be restrictive and contribute to disuse muscle atrophy. Persons at risk for compression fractures and those who have had compression fractures should be involved in extension-based truncal exercises and not perform any flexion exercises. Flexion exercises, even combined with extension, are contraindicated as they increase deformity and risk of fracture [59]. Lifestyle modifications should be implemented to eliminate the need to lift or carry heavy objects. For patients in acute pain, opioid analgesics should be provided as the clinical picture warrants, and patients should lay supine for 15-mintue intervals multiple times a day. Activity should be gradually introduced as the patient’s pain level tolerates and with proper restrictions and/or bracing if instability is present. In healthy patients, kyphoplasty and vertebroplasty may decrease pain earlier than conservative treatment, but they are of not clearly superior to conservative treatment in the long term [60,61]. These procedures are only indicated in patients with an acute, unhealed compression fracture causing pain at the level of fracture that is not controlled by other measures [62]. A surgical referral may be warranted in patients who appear unstable or have neurological symptoms or an abnormal neurological exam. Ensuring that chronic pain from osteopenia/osteoporosis is properly treated is important, as chronic pain itself is associated with bone density loss [63]. AVN of joints can be treated operatively or nonoperatively. Joint replacement is definitive treatment for AVN, though considerations must be made for whether or not the patient is healthy enough to tolerate both surgery and

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the postoperative rehabilitation course. Other surgical options include joint-sparing surgery, and the surgical intervention will ultimately depend on the degree of AVN and the patient’s functional status [51]. The most important nonoperative treatment for AVN of weight-bearing joints is multidisciplinary rehabilitation, including assistive and mobility devices, physical therapy to strengthen the surrounding musculature of the affected joint(s), environmental modifications, and general strengthening and cardiovascular conditioning. Relative rest and icing painful joints are also appropriate. A corticosteroid injection, though seemingly counter-intuitive given the risk of corticosteroids inducing AVN, can also be beneficial in reducing inflammation around the joint, and, thus, pain. Ultrasound guidance is recommended to ensure that the corticosteroid is injected into the bursa surrounding the joint, which is often inflamed. Oral corticosteroids may not satisfactorily penetrate the bursa, thereby necessitating an injection to reduce local inflammation. Injections should be considered if the femoral or humeral heads are not flattened, as at the point of flattening the joint anatomy is so fundamentally altered that the main generator of pain is not the inflamed bursa, but rather the abnormal head of the bone grinding in the acetabulum or glenoid fossa. CARDIAC AND PULMONARY Clinical Manifestations Most cardiopulmonary issues related to cGVHD and HSCT are related to decreased aerobic capacity and performance status from a lack of physical activity [2,64]. As mentioned earlier, inactivity can cause profound muscle atrophy, as well as a decline in cardiac performance, with increased resting heart rate, decreased stroke volume, and decreased maximum oxygen consumption (VO2 max) [65]. Fatigue can also occur, in part due to anemia and associated decreased tissue oxygenation [66]. Furthermore, patients may have lower extremity edema from hepatic GVHD causing congestion, demanding more energy for ambulation [34] and potentially increasing cardiac afterload. Persons with cGVHD may have impaired function of respiratory muscles, with the muscles of expiration more affected than those of inspiration [67]. This is sometimes associated with known cGVHD complications, such as polymyositis and myasthenia gravis, but also occurs independent of other comorbidities. As pulmonary decline hinders patients’ ability to participate in physical and occupational therapy, addressing these impairments is essential to prevent the patient from further physical decompensation. Pulmonary complications of GVHD and HSCT can of course be a direct result of the disease, affecting up to 60% of patients, and potentially leading to bronchiolitis obliterans (BO) [68]. Pulmonary function tests are abnormal and indicate an obstructive process in patients with pulmonary cGVHD [2,10]. Treatment As outlined above in the “Muscle” section, mobilization of the hospitalized patient can prevent muscle mass loss and boost performance. For inpatients with cGVHD and pulmonary compromise, good pulmonary hygiene, including suctioning and mucous clearance, and pulmonary physical therapy consisting of vibration and pulmonary hygiene (suction, incentive spirometry, manual percussion), have been shown to be effective in preventing infection and improving symptom burden in patients with BO [69].

For outpatients, aerobic activity should still be emphasized to reduce the risk of mortality from cardiovascular disease and improve function. This can be done through a structured physical therapy or patient-directed program. The compliance rate of patients after HSCT and on glucocorticoid therapy undergoing a structured physical therapy program was found to be 54%, with hospital readmission being the most common reason for noncompliance [70]. Despite the potential benefits of a structured exercise program, little data exist specific to patients with cGVHD. There are, however, data to suggest that even self-directed exercise immediately after BMT reduces symptom burden [71,72]. One study looked at an exercise program intervention for patients undergoing HSCT both while in the hospital and after discharge, and it noted improved muscle strength, aerobic capacity, and functional performance (stair climbing), with reduced severity of diarrhea and days on parental nutrition. The outcomes, however, were statistically significant on the day of discharge from the hospital, and the implications of exercise on patients with cGVHD are not clarified by this study [71]. Another study evaluated mice models and showed that an 11-week exercise program resulted in less physical deterioration than in the control, nonexercise group [73]. Cardiac rehabilitation referral should be considered in patients with congestive heart failure or who are at risk of developing dangerous arrhythmias. The benefits of cardiac rehabilitation in the general population has been shown to reduce mortality, boost exercise capacity, reduce symptoms, reduce stress, boost self-worth, and improve safety [65]. Effects are typically observed within 6 to 10 weeks but may be seen as early as 10 days of initiating a program [74]. This has not been studied specifically in patients with cGVHD. Outpatient pulmonary rehabilitation should be considered in patients with BO and/or who have maximum O2 consumption of 75% or less during exercise, a forced expiratory volume at 1 second of less than 2000 mL, or an forced expiratory volume at 1 second to forced vital capacity ratio of less than 60% [52]. One trial studied 11 GVHD patients with BO who underwent a standard outpatient pulmonary rehabilitation program and found statistically significant improvement in 6-minute walk test distance and patientreported physical functioning, including dyspnea [69]. CONCLUSION Despite the numerous potential complications of cGVHD, relatively little is known about patient medical rehabilitation. There is a dearth of cGVHD rehabilitation knowledge including diagnosis, treatment, and monitoring of progress. More research is needed in these areas to ensure optimal patient care and potentially develop protocols. Enhancing patient function and quality-of-life through an adequate rehabilitation program has the potential to spare other systemic therapies like corticosteroids, which may cause considerable toxicity. Thus, given the known health benefits of patient mobilization and exercise, it is entirely possible that a comprehensive, customized medical rehabilitation plan after allogeneic transplantation may prevent the consequences of advanced cGVHD and improve patient outcomes. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.

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REFERENCES 1. Gillis TA, Donovan ES. Rehabilitation following bone marrow transplantation. Cancer. 2001;92:998-1007. 2. Filipovich AH, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-956. 3. Guzmán J, et al. Multidisciplinary rehabilitation for chronic low back pain: systematic review. BMJ. 2001;322:1511-1516. 4. Khan F, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database Syst Rev. 2007;CD006036. 5. Semlyen JK, Summers SJ, Barnes MP. Traumatic brain injury: efficacy of multidisciplinary rehabilitation. Arch Phys Med Rehabil. 1998;79:678-683. 6. Belagaje SR, Zander K, Thackeray L, Gupta R. Disposition to home or acute rehabilitation is associated with a favorable clinical outcome in the SENTIS trial. J Neurointerv Surg. 2014. http://dx.doi.org/10.1136/ neurintsurg-2014-011132. [Epub ahead of print]. 7. Walsh MB, Herbold J. Outcome after rehabilitation for total joint replacement at IRF and SNF: a case-controlled comparison. Am J Phys Med Rehabil. 2006;85:1-5. 8. Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad Dermatol. 1998;38:369-392. 9. Janin A, et al. Fasciitis in chronic graft-versus-host disease: a clinicopathologic study of 14 cases. Ann Intern Med. 1994;120:993-998. 10. Couriel D, et al. Ancillary therapy and supportive care of chronic graftversus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006;12:375-396. 11. Rennie JA, Auchterlonie IA. Rheumatological manifestations of the leukaemias and graft versus host disease. Baillière’s Clinical Rheumatol. 1991;5:231-251. 12. Choi IS, et al. Therapeutic experience on multiple contractures in sclerodermoid chronic graft versus host disease. Support Care Cancer. 2009;17:851-855. 13. Beredjiklian PK, et al. Orthopaedic manifestations of chronic graftversus-host disease. J Pediatr Orthop. 1998;18:572-575. 14. Kim JB, Liakopoulou E, Watson JS. Successful treatment of refractory joint contractures caused by sclerodermatous graft versus host disease. J Plast Reconstr Aesthet Surg. 2008;61:1235-1238. 15. Welch V, Brosseau L, Casimiro L, et al. Thermotherapy for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2002. Issue 2. Art. No.: CD002826. DOI: 10.1002/14651858.CD002826. 16. Sandqvist G, Åkesson A, Eklund M. Evaluation of paraffin bath treatment in patients with systemic sclerosis. Disabil Rehabil. 2004;26:981-987. 17. Pils K, Graninger W, Sadil F. Paraffin hand bath for scleroderma. Phys Med Rehabil. 1991;1:19-21. 18. Askew LJ, et al. Objective evaluation of hand function in scleroderma patients to assess effectiveness of physical therapy. Rheumatology. 1983;22:224-232. 19. Roustit M, Blaise S, Cracowski JL. Trials and tribulations of skin iontophoresis in therapeutics. Br J Clin Pharmacol. 2014;77:63-71. 20. Inamoto Y, et al. Assessment of joint and fascia manifestations in chronic graft-versus-host disease. Arthritis Rheumatol. 2014;66:1044-1052. 21. Collin C, et al. The Barthel ADL Index: a reliability study. Disabil Rehabil. 1988;10:61-63. 22. Black J, et al. National Pressure Ulcer Advisory Panel’s updated pressure ulcer staging system. Adv Skin Wound Care. 2007;20:269-274. 23. Couriel DR, et al. Chronic graft-versus-host disease manifesting as polymyositis: an uncommon presentation. Bone Marrow Transplant. 2002;30:543-546. 24. Deitrick JE, Whedon GD, Shorr E. Effects of immobilization upon various metabolic and physiologic functions of normal men. Am J Med. 1948;4:3-36. 25. Ferrando AA, et al. Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J Clin Endocrinol Metab. 1999;84:3515-3521. 26. Gupta A, Gupta Y. Glucocorticoid-induced myopathy: pathophysiology, diagnosis, and treatment. Indian J Endocrinol Metab. 2013;17:913. 27. Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology. 2003;42:34-39. 28. Mimura T, Kanda H, Kubo K. Treatment of steroid-resistant polymyositis and dermatomyositis [Article in Japanese]. Nihon Rinsho. 2001;59: 2062-2070. 29. Lefvert AK, Björkholm M. Antibodies against the acetylcholine receptor in hematologic disorders: implications for the development of myasthenia gravis after bone marrow grafting. N Eng J Med. 1987;317:170. 30. Grover Z, Ee LC. Protein energy malnutrition. Pediatr Clin North Am. 2009;56:1055-1068. 31. Jacobsohn DA, et al. Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2002;29: 231-236. 32. Matsuda M, et al. Circumstances, activities, and events precipitating aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2007; 16:25-29.

807

33. Gibran SK, et al. Changes in the retinal inner limiting membrane associated with Valsalva retinopathy. Br J Ophthalmol. 2007;91: 701-702. 34. James MC. Physical therapy for patients after bone marrow transplantation. Phys Ther. 1987;67:946-952. 35. Shahpar S, et al. Are there adverse effects to rehabilitation in cancer patients with thrombocytopenia? [Poster 23]. PM R. 2011;3:S183. 36. Berenstein EG, Ortiz Z. Megestrol acetate for the treatment of anorexiacachexia syndrome. Cochrane Database Syst Rev. 2005. 37. Wilner Z, Scott L, Arnold RM. Cannabinoids in the treatment of symptoms in cancer and AIDS. 2nd edition #93. J Palliat Med. 2011;14: 509-510. 38. Haruki H, et al. Neuropathy in chronic graft-versus-host disease caused by donor T cells. Muscle Nerve. 2012;46:610-611. 39. Sullivan KM, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57:267-276. 40. Wu G, Weng FL, Balaraman V. Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient. BMJ Case Rep. 2013. http://dx.doi.org/10.1136/bcr-2013-201099. 41. Hausheer FH, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33: 15-49. 42. Hurley RW, Adams M, Benzon HR. Neuropathic pain: treatment guidelines and updates. Curr Opin Anesthesiol. 2013;26:580-587. 43. Richardson JK, et al. Fibular motor nerve conduction studies and ankle sensorimotor capacities. Muscle Nerve. 2013;47:497-503. 44. Richardson JK, et al. Hip strength: ankle proprioceptive threshold ratio predicts falls and injury in diabetic neuropathy. Muscle Nerve. 2014;50: 437-442. 45. Akalin E, et al. Treatment of carpal tunnel syndrome with nerve and tendon gliding exercises. Am J Phys Med Rehabil. 2002;81:108-113. 46. Andreu JL, et al. Local injection versus surgery in carpal tunnel syndrome: Neurophysiologic outcomes of a randomized clinical trial. Clin Neurophysiol. 2014;125:1479-1484. 47. Winston DJ, et al. A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation. Bone Marrow Transplant. 2001;28:187-196. 48. McClune BL, et al. Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant. 2011;46:1-9. 49. Schimmer AD, et al. Decreased bone mineral density is common after autologous blood or marrow transplantation. Bone Marrow Transplant. 2001;28:387-391. 50. Stern JM, et al. Bone density loss during treatment of chronic GVHD. Bone Marrow Transplant. 1996;17:395-400. 51. McClune B, Majhail NS, Flowers ME. Bone loss and avascular necrosis of bone after hematopoietic cell transplantation. Semin Hematol. 2012;49: 59-65. 52. Cuccurullo S. Physical medicine and rehabilitation board review, 2nd ed. New York: Demos; 2010. 53. Fisher CG, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine. 2010;35:E1221-E1229. 54. Enright H, Haake R, Weisdorf D. Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation. Am J Med. 1990;89:733-738. 55. McAvoy S, et al. Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010;161231-161236. 56. Kilbanski A, et al. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785. 57. Asikainen TM, Kukkonen-Harjula K, Miilunpalo S. Exercise for health for early postmenopausal women. Sports Med. 2004;34:753-778. 58. Bohne M, Abendroth-Smith J. Effects of hiking downhill using trekking poles while carrying external loads. Med Sci Sports Exerc. 2007;39:177. 59. Sinaki M. Exercise for patients with osteoporosis: management of vertebral compression fractures and trunk strengthening for fall prevention. PM R. 2012;4:882-888. 60. Lee HM, et al. Comparative analysis of clinical outcomes in patients with osteoporotic vertebral compression fractures (OVCFs): conservative treatment versus balloon kyphoplasty. Spine J. 2012;12:998-1005. 61. Yi X, et al. Recompression in new levels after percutaneous vertebroplasty and kyphoplasty compared with conservative treatment. Arch Orthop Trauma Surg. 2014;134:21-30. 62. National Institute for Health and Care Excellence (NICE). Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for treating osteoporotic vertebral compression fractures. London, UK: National Institute for Health and Care Excellence (NICE); 2013 p. 55 (Technology appraisal guidance; no. 279). 63. Ringe JD. Too many osteoporosis patients are undertreated with analgesics. Chronic pain promotes bone loss [Article in German]. MMW Fortschritte der Medizin. 2003;145:43-45.

808

S.R. Smith et al. / Biol Blood Marrow Transplant 21 (2015) 799e808

64. Hogarty AN, et al. Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr. 2000;136:311-317. 65. Strax TE, et al. Physical modalities, therapeutic exercise, extended bedrest, and aging effects. Physical medicine and rehabilitation board review. In: Cuccurullo S, editor. Demos Medical Publishing; 2004. 66. Washington RL. Cardiopulmonary sequelae after bone marrow transplantation. J Pediatr. 2000;136:280-282. 67. White AC, et al. Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation. Chest. 2005; 128:145-152. 68. Krowka MJ, Rosenow EC, Hoagland HC. Pulmonary complications of bone marrow transplantation. Chest. 1985;87:237-246. 69. Epler GR. Bronchiolitis obliterans and airways obstruction associated with graft-versus-host disease. Clin Chest Med. 1988;9:551-556.

70. Morris GS, et al. Adherence of stem cell transplant recipients receiving glucocorticoid therapy to an exercise-based rehabilitation program. Support Care Cancer. 2012;20:2391-2398. 71. Jarden M, et al. A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT. Bone Marrow Transplant. 2009;43:725-737. 72. Wiskemann J, et al. Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation. Blood. 2011;117:2604-2613. 73. Fiuza-Luces C, et al. Effects of exercise interventions in graft-versushost disease models. Cell Transplant. 2013;22:2409-2420. 74. Whiteson JH. Cardiac Rehabilitation. Physical medicine and rehabilitation. In: Braddom RL, editor. Elsevier Health Sciences; 2007. p. 709-737.