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Requests for reprints should be addressed to Brian A. Houston, MD, The Johns Hopkins Hospital, 600 N. Wolfe Street, Carnegie 568, Baltimore, MD, 21287.
When chest percussion revealed diminished lung volumes in a 52-year-old African American woman, her diagnostic possibilities expanded. The patient, hospitalized with fever, progressive dyspnea, and diffuse joint pain, felt well until 11 months earlier. At that time, she began a course of peginterferon alfa-2, ribavirin, and boceprevir for hepatitis C acquired from a blood transfusion.
Five months into this regimen, she experienced a paroxysm of nocturnal dyspnea and presented to an outside facility, where she was found to have a pulmonary embolism. She was treated with warfarin, and her condition improved over the next month. However, she then presented to another hospital with chest pain and was found to have diffuse ST-segment elevations on electrocardiogram (ECG), an erythrocyte sedimentation rate greater than 120 mm/hr, and a C-reactive protein level exceeding 20 mg/dL; findings were consistent with pericarditis. A 5-day course of prednisone substantially improved her symptoms. She then completed treatment for hepatitis C after she was found to have a sustained virologic response to this regimen.
One month prior to admission to the Johns Hopkins Hospital, she developed intermittent fevers, progressive dyspnea on exertion, and worsening pain in her shoulders, knees, wrists, and hands. This persisted until the night of evaluation, when she awoke with severe pleuritic chest pain and dyspnea that did not remit after 6 hours. She then presented to our facility for further evaluation.
Her medical history included depression, for which she was taking citalopram. She also was taking warfarin for her previously diagnosed pulmonary embolism. She had no prior history of arthritis, alopecia, serositis, oral ulcers, rashes, or pulmonary symptoms. A retired computer analyst, she lived at home with her husband and children. Her family history was notable for a mother with bilateral pulmonary emboli and a sister with lupus nephritis.
Assessment
In the emergency department, the patient appeared to be in mild respiratory distress, and she was unable to shake hands with the admitting house officer due to the severity of her arthritis. She had a temperature of 100.9° F (38.3° C), pulse of 112 beats/minute, blood pressure of 121/73 mm Hg, and respiratory rate of 18 breaths/minute with normal oxygen saturation on ambient air. A pulmonary examination revealed faint breath sounds, increased dullness in the inferior fields, and reduced bilateral diaphragmatic excursion by percussion. Her jugular venous pulse was not elevated above the level of the clavicle at 30 degrees inclination. She had scattered areas of mild alopecia with no rashes. Synovitis was evident in the carpal, metacarpophalangeal, and proximal interphalangeal joints, bilaterally, and at the knees and shoulders (Figure 1). She was hospitalized.
Figure 1Carpal, metacarpophalangeal, and proximal interphalangeal synovitis demonstrated Jaccoud arthropathy.
The patient's admission serum chemistry and hematology panels are provided in Table 1. Urinalysis was notable for 1+ proteinuria with a spot urine protein-to-creatinine ratio of 0.89. A cryoglobulin screen was negative, and hepatitis C polymerase chain reaction testing confirmed sustained virologic response. Results from an ECG, urine toxicology screen, and cultures of blood, sputum, and urine were unremarkable. Arterial blood gas revealed a mild respiratory alkalosis with normal oxygenation. Chest radiography disclosed elevated hemidiaphragms. Chest computed tomography with contrast provided confirmation, showing bibasilar atelectasis with very low lung volumes but no parenchymal abnormalities or pulmonary emboli (Figure 2).
Figure 2Chest x-ray and computed tomography with contrast of the chest, coronary view, showed bibasilar atelectasis with low lung volumes but no other parenchymal abnormalities or pulmonary emboli.
Additional studies showed a positive antinuclear antibody level at a titer of 1:640 with a homogenous pattern, a positive anti-ribonucleoprotein, and a positive test, with a titer of 1:640 or higher, for anti-double stranded DNA antibodies. Further laboratory studies were remarkable for mildly elevated anticardiolipin IgM antibody at 27 units, decreased complement component 3 at 62 mg/dL, normal complement component 4 at 18 mg/dL, and a negative result on anti-Smith antibody testing. Pulmonary function testing demonstrated a severe restrictive ventilatory pattern with respiratory muscle weakness (Table 2). Nerve conduction studies of the phrenic nerve and electromyogram of the diaphragm produced unremarkable results.
The patient's inflammatory arthritis, history of serositis, proteinuria, and serology results confirmed a diagnosis of systemic lupus erythematosus. This finding, combined with restrictive lung deficits with atelectasis and otherwise normal lung parenchyma, established the final diagnosis of shrinking lung syndrome. Hoffbrand and Beck first described the disorder in a 1965 case series of 24 patients with lupus, 8 of whom developed “unexplained breathlessness;” all had progressively lower lung volumes and restrictive ventilatory deficits.
The continuing disappearance of aerated lung on chest radiography led the authors to propose the term “shrinking lungs.”
Estimations of prevalence are difficult, since the syndrome is a rare manifestation of systemic lupus erythematosus. A 2008 systematic review counted only 77 cases in the literature.
Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation.
Although uniform diagnostic criteria have not been established, shrinking lung syndrome is suggested by several clinical features. The index case series described the hallmark pattern of elevated hemidiaphragms, normal lung parenchyma, and restrictive deficits on pulmonary function testing in a patient with systemic lupus. This sine qua non triad represents the only universally described components of shrinking lung syndrome.
Risk factors and pathophysiology remain unclear. The severity of restrictive deficit does not correlate with lupus clinical activity, prednisone dosage, disease duration, or with levels of antinuclear antibodies, anti-double-stranded DNA antibodies, or complement component 3.
Neither was evident in our patient. In the index case series, pleural disease was implicated, but other clinicopathologic series have found no such evidence among patients with shrinking lung syndrome.
Thus, given the heterogeneous and inconsistent physiologic lesions reported in association with shrinking lung syndrome, it may represent a common final pathway of multiple lupus-mediated pulmonary complications.
The rapid progression and preceding interferon exposure make our patient's case unique. Time to onset varies widely, but on average, shrinking lung syndrome occurs 4.3 years after diagnosis of lupus.
However, in our patient, the manifestations of shrinking lung syndrome arose nearly contemporaneously with those of systemic lupus erythematosus. Interferon-induced systemic lupus has been previously described, and the temporal association between interferon therapy and the onset of her symptoms implicate interferon as causal in the induction of lupus as opposed to a de novo case arising spontaneously.
We found no prior reported cases of shrinking lung syndrome in association with interferon as the culprit agent contributing to drug-induced lupus.
Management
Corticosteroid therapy has been the mainstay of treatment in nearly all described cases of lupus-related shrinking lung syndrome. Initiation of treatment with prednisone (dosage range, 20-60 mg daily) has been associated with both symptomatic improvement and objective recovery on pulmonary function testing in several case series, and these are usually seen within several weeks.
Our patient was initiated on prednisone and hydroxychloroquine therapy. By the ninth hospital day, she was ambulating freely for the first time in weeks and was without dyspnea. She has remained free of dyspnea and her arthritis is vastly improved with slow down-titration of her steroid dosage and maintenance on hydroxychloroquine therapy. However, systemic lupus erythematosus often does not resolve once the initiating agent—interferon, in this patient's case—is withdrawn.
There are scarce case reports of shrinking lung syndrome refractory to corticosteroid therapy. One patient developed effort-dependent respiratory failure and was unable to be weaned from the ventilator, accounting for the only published report of mortality from shrinking lung syndrome. Theophylline, azathioprine, cyclophosphamide, and rituximab have each been used successfully in a small number of patients with steroid-refractory disease.
Shrinking lung syndrome, though associated with profound morbidity, is under-recognized in clinical practice. Prompt diagnosis and treatment often results in substantial improvement, underscoring the importance of identifying this challenging entity.
References
Hoffbrand B.I.
Beck E.R.
“Unexplained” dyspnoea and shrinking lungs in systemic lupus erythematosus.
Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation.
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