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Bone Marrow Transplantation (2000) 26, 1117–1120
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Case report
Chronic graft-versus-host disease-related polymyositis as a cause of
respiratory failure following allogeneic bone marrow transplant
AM Leano1, K Miller2 and AC White1
Divisions of 1Pulmonary and Critical Care and 2Hematology-Oncology, Department of Medicine, New England Medical Center,
Tufts University School of Medicine, Tupper Research Institute, Boston, MA, USA
Summary:
An unusual case of respiratory failure and dropped
head syndrome as a complication of severe chronic
graft-versus-host disease (GVHD)-related polymyositis
is described. The patient required tracheostomy and
mechanical ventilation but recovered following treatment with aggressive immunosuppression and intensive
rehabilitation. The differential diagnoses of muscle
weakness in the bone marrow transplant (BMT) patient
and the dropped head syndrome are both discussed. To
our knowledge, this is the first reported case of respiratory failure requiring mechanical ventilation occurring
as a complication of GVHD-related polymyositis. Bone
Marrow Transplantation (2000) 26, 1117–1120.
Keywords: polymyositis; GVHD; respiratory failure;
BMT; dropped head syndrome
Respiratory failure in the setting of bone marrow transplantation (BMT) is usually acute in onset and occurs due to a
number of well described but poorly understood clinical
syndromes that occur in this patient population. The clinical
syndromes include diffuse alveolar hemorrhage,1 the idiopathic pneumonia syndrome,2 septic shock,3 pneumonia due
to conventional and opportunistic organisms4 or bronchiolitis obliterans.5 Chronic respiratory failure as a complication of muscle weakness in this patient population is not
well described and appears to be very uncommon. Polymyositis is a recognized but unusual complication of
chronic graft-versus-host disease (GVHD) due to BMT.6
We report a patient who developed GVHD-related polymyositis that resulted in profound weakness of both the
extensor muscles of the neck and muscles of respiration.
The patient gradually developed respiratory failure and ultimately required a tracheostomy and mechanical ventilation.
To our knowledge, GVHD as a cause of chronic respiratory
failure has not been previously described. The differential
diagnoses of respiratory muscle weakness in the BMT
Correspondence: Dr AC White, New England Medical Center, Pulmonary
and Critical Care Division, 750 Washington St, NEMC #257, Boston, MA
02111, USA
Received 8 May 2000; accepted 20 August 2000
patient and the ‘dropped head syndrome’ are both
discussed.
Case report
A 37-year-old female who had undergone a matched unrelated allogeneic BMT 2 years prior to admission presented
with a several month history of progressive weakness of
the muscles of both shoulders, neck and thighs. She had
difficulty performing simple tasks such as combing her hair
and brushing her teeth. In addition, she had diffuse myalgias and dysphagia for both liquids and solids. Ten years
previously she had been diagnosed with acute myeloid leukemia (M2) (AML) that responded to chemotherapy. The
disease relapsed 7 years later and she was treated with
induction chemotherapy, two cycles of consolidation followed by a matched (6/6) unrelated allogeneic BMT from
an ABO incompatible donor. She received a standard conditioning regimen comprising cyclophosphamide and total
body irradiation. Routine pulmonary function tests performed prior to BMT were all normal. Her course following
BMT was complicated by grade 1 acute and then extensive
chronic GVHD, involving primarily the oral mucosa and
skin. This was treated with corticosteroids (prednisone 10–
20 mg per day) and cyclosporine. Her medications at the
time of presentation included cyclosporine 50 mg daily,
nifedipine extended release 30 mg daily, prednisone 20 mg
daily and trimethoprim/sulfamethoxazole double strength
three times a week for P. carinii prophylaxis.
Positive findings on physical examination included a
Cushingoid appearance, focal areas of alopecia on the scalp
and scleroderma-like changes with skin thickening, patchy
areas of hyperpigmentation consistent with chronic GVHD
over her neck, trunk and arms. Neurological examination
revealed a mild, symmetric reduction in proximal motor
strength (4/5) in all extremities. There was profound weakness of the neck extensor muscles (2/5) with an inability
to keep her head elevated in a normal position. Neck flexion
was normal. Laboratory testing revealed an elevated total
creatinine phosphokinase (CPK) at 1445 U/l (normal range
20–165 U/l) and an elevated adolase of 24 U/l (normal
range 1.7–4.9 U/l). Skin biopsy revealed an interface dermatitis and folliculitis consistent with evolving chronic
GVHD. The following laboratory tests were normal: anti-
Respiratory failure post BMT
AM Leano et al
1118
nuclear antibody, rheumatoid factor, complement levels,
anti-Jo antibody, anti-SSA, anti-SCL-70 and toxoplasma
IgG titers. An electromyogram (EMG) performed on the
muscles of the left arm and leg revealed small, hypercomplex and short duration motor unit action potentials and
evidence of early recruitment in a patchy pattern. Fibrillation potentials and positive sharp waves were also found
in the same muscles. Sensory and motor conduction was
normal. These findings were consistent with a primary
myopathy. Pulmonary function tests showed a moderate to
severe restrictive pattern with a severe reduction in maximal inspiratory and expiratory pressures (Table 1). Chest
radiograph revealed a left lower lobe pneumonia. Arterial
blood gas analysis revealed pH 7.33, pCO2 52, pO2 49 on
oxygen (4 l/min) via nasal cannulae. The combination of
restrictive physiology, reduced respiratory muscle strength
and hypercarbia was considered diagnostic of respiratory
muscle weakness. The widened A-a gradient was due to a
left lower lobe pneumonia.
Based on these data a diagnosis of polymyositis secondary to chronic GVHD was made and she was started on
intravenous methylprednisolone 80 mg daily in addition to
antibiotics for the pneumonia. Despite an initial clinical
improvement with resolution of the pneumonia, the muscle
weakness slowly progressed with severe weakness in neck
extension to the point she was unable to maintain her head
in a normal position without the support of an external neck
brace. A MRI of the neck with gadolinium was performed
and revealed atrophy of the cervical and masticator muscles
with intense enhancement seen in the tongue, platysma, paraspinus, sternocleidomastoid and trapezius muscles (Figure
1). These findings were consistent with an active myositis.
As a result of progressive weakness of her neck muscles
and accessory muscles of respiration she gradually
developed more difficulty in keeping her upper airway patent (despite a splint), in maintaining normal ventilation and
in effectively clearing her secretions. She had numerous
episodes of mucus plugging and atelectasis and ultimately
underwent tracheostomy for both airway protection and
mechanical ventilation. She was treated with an intensive
regimen of immunosuppression for 6 months comprising
monthly intravenous cyclophosphamide (1 g), methylprednisolone starting at 100 mg daily, mycophenylate mofetil
Table 1
Figure 1 MRI of the head and neck region demonstrating intense
enhancement of the following muscles (each arrowed): masseter (a), lateral pterygoid (b), paraspinal (c) and sternocleidomastoid (d).
Results of pulmonary function tests
FEV1
FVC
FEV1/FVC
TLC
Dlco/VA
MIP
MEP
Observed
% Predicted
1.16 l
1.19 l
97%
2.11 l
5.78 l/min/mm Hg
31
33
44
40
49
102
36
22
FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity;
TLC = total lung capacity; Dlco/VA = diffusing capacity corrected for
alveolar volume; MIP = maximal inspiratory pressure; MEP = maximal
expiratory pressure.
Bone Marrow Transplantation
500 mg twice a day, monthly intravenous immunoglobulin
(0.5 g per kg) and photopheresis for 2 days a month for
the first 3 months. Over the 6 month period the dose of
methylprednisolone was slowly tapered by 10 mg every 2
weeks provided the CPK continued to fall. The muscle
weakness gradually improved on this regimen, the muscle
enzymes normalized, the chronic GVHD regressed and she
was successfully weaned from mechanical ventilation and
eventually decannulated. Unfortunately, 1 year after her
recovery she developed bacterial sepsis while on vacation
and died.
Respiratory failure post BMT
AM Leano et al
Discussion
This patient with chronic GVHD experienced a myopathic
syndrome with clinical, laboratory and radiological features
of polymyositis. We believe this is the first reported case
of a patient developing respiratory failure requiring mechanical ventilation as a complication of GVHD-related polymyositis. Polymyositis is a rare complication of chronic
GVHD occurring in approximately 3% of the BMT population.6,7 The mean time from allogeneic BMT to onset of
myositis ranges from 100 days to 54 months.6,8 As demonstrated in the case we describe, patients with GVHD-related
polymyositis usually have other manifestations of acute or
chronic GVHD. Polymyositis has been reported as the sole
manifestation of chronic GVHD.9 Presenting symptoms of
GVHD-related polymyositis include moderate to severe
proximal muscle weakness, myalgias and arthralgias.6
Rarely, patients may present with muscle pain in the
absence of any demonstrable weakness.6 Supporting laboratory evidence includes an elevated total CPK (up to 40
times normal) and an elevated adolase. An elevated antinuclear antibody or rheumatoid factor level has been reported
in GVHD-related polymyositis,6 making it difficult to
distinguish serologically between this disease and the
polymyositis seen with connective tissue diseases.
Characteristic findings on muscle biopsy include multiple
foci of muscle cell necrosis, interstitial fibrosis and infiltration with lymphocytes.7 The majority of the infiltrating
lymphocytes are T cells with a CD4/CD8 ratio of ⬍1. The
CD8-positive cells lack the T cell suppressor-associated
antigen, Leu-15, indicating that they belong to the cytotoxic
subclass. Other cell types that have been noted on biopsy
included polyclonal B cells, lymphocytes expressing CD16
and CD57 (natural killer cells) and monocytic–histiocytic
cells expressing CD68.7 To our knowledge, analysis of
restriction fragment length polymorphisms has not been
performed on the infiltrating lymphocytes in GVHD-related
polymyositis and therefore it is not possible to determine
if the cells originate from donor or recipient. In polymyositis, the EMG shows a characteristic increase in small short
polyphasic action potentials, the presence of which help
exclude a steroid myopathy.7
GVHD-related polymyositis usually responds to corticosteroids but may relapse as the corticosteroids are tapered.8
In the case we report additional immunosuppressive therapy
was required to manage the severe GVHD-related polymyositis. Patients usually require treatment for 5–30
months and the overall prognosis appears to depend more
on the activity of the chronic GVHD rather than the severity
of the polymyositis.8
Although a muscle biopsy was not obtained, due to concerns about wound healing in the setting of extensive skin
GVHD and steroid use, we believe that there is sufficient
evidence to support a diagnosis of GVHD-related polymyositis in this case. The clinical features of polymyositis
with elevated muscle enzymes, along with evidence of
inflammation on MRI, all occurred in the setting of biopsy
proven chronic GVHD. The patient’s skin rash had the typical features of GVHD rather than dermatomyositis. The
most compelling evidence supporting a diagnosis of
GVHD-related polymyositis is the resolution of the poly-
myositis at the same time as the chronic GVHD regressed
with immunosuppressive therapy.
Possible causes of skeletal muscle weakness in the BMT
patient include corticosteroid-induced myopathy, disuse
atrophy, poor nutritional status, electrolyte disorders, druginduced muscle weakness and myasthenia gravis. Eleven
cases of myasthenia gravis secondary to chronic GVHD
have been reported in the literature.10 It is clinically indistinguishable from classic myasthenia gravis and presents
with ocular weakness, normal muscle enzymes and an
abnormal response to repetitive nerve stimulation. These
features serve to distinguish it from polymyositis.10 In the
BMT patient the disordered immune regulation of chronic
GVHD disease is thought to trigger the development of, or
release the inhibition of anti-acetylcholine receptor antibody B cell clones.8 As with classic myasthenia gravis,
patients with GVHD-related myasthenia gravis usually
respond favorably to cholinesterase inhibitors and immunosuppressants. Recently, both myasthenia gravis and polymyositis have been reported to occur in the same patient.11
An additional prominent feature of this patient’s clinical
presentation was weakness of the extensor muscles of the
cervical spine resulting in her inability to maintain her head
in the normal position. This clinical sign is known as the
‘dropped head syndrome’. The syndrome has been
described both as an isolated clinical entity and also as a
manifestation of a generalized neuromuscular disorder. The
differential diagnosis of the ‘dropped head syndrome’
includes myasthenia gravis, amyotrophic lateral sclerosis,
motor neuron disease, polymyositis/dermatomyositis,
nemaline myopathy13 and isolated neck extensor myopathy.12
Respiratory muscle weakness causing respiratory failure
and requiring mechanical ventilation has not been previously reported in the BMT population. In the case
described, the presence of both respiratory muscle weakness combined with impairment of control of the upper airway due to the ‘dropped head syndrome’ eventually precipitated respiratory failure. Conditions that may cause both
the ‘dropped head syndrome’ and respiratory muscle
weakness are listed in Table 2.
In summary, this case demonstrates that respiratory failure and the dropped head syndrome may occur as severe
manifestations of GVHD-related polymyositis. As the number of patients undergoing BMT increases and survival
improves, clinicians should be aware that chronic respiratory failure due to skeletal muscle weakness can occur in
patients with GVHD-related polymyositis.
1119
Table 2
Conditions that may cause weakness of both neck extensors
and respiratory muscles
Amyotrophic lateral sclerosis
Myasthenia gravis
Polymyositis/dermatomyositis
Acid maltase deficiency
Fascioscapulohumeral muscular dystrophy
Myotonic dystrophy
Nemaline myopathy
Graft-versus-host disease
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AM Leano et al
1120
Acknowledgements
We would like to thank Barbara Carter MD for her invaluable
help with labelling the MRI and Sonya Harris for secretarial
assistance.
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