The Shrinking Lungs Syndrome in Systemic Lupus Erythematosus

The Shrinking Lungs Syndrome in Systemic Lupus Erythematosus KENNETH

J. WARRINGTON, MD; KEVIN G. MODER, MD; AND W. MARK BRUTINEL, MD and improve pulmonary function in some patients with SLS, but other methods of treatment have occasionally been found to be helpful. Clinical presentation, method of diagnosis, pathogenesis, and treatment modalities are summarized in this review. An uncommon complication of systemic lupus erythematosus, SLS causes significant morbidity and, occasionally, mortality.

A comprehensive review of the literature on shrinking lungs syndrome (SLS) in systemic lupus erythematosus involved a MEDLINE search (1965-1997) of case reports and clinical series of patients with the diagnosis of SLS. A total of 49 well-documented cases of SLS were reviewed. Shrinking lungs syndrome is characterized by unexplained dyspnea, a restrictive pattern on pulmonary function test results, and an elevated hemldlaphragm. The cause of SLS remains controversial, with several authors attributing the disorder to diaphragmatic weakness and others suggesting that chest wall restriction accounts for the clinical syndrome. No definitive therapy exists. Corticosteroids have been reported to lessen symptoms

Mayo Clin Proc. 2000;75:467-472

=

SLE systemic lupus erythematosus; SLS syndrome

T

METHODS A comprehensive review of the literature on SLS in SLE involved a MEDLINE search (1965-1997) of case reports and clinical series of patients with the diagnosis of SLS. A total of 49 well-documented cases of SLS were reviewed.

he reported incidence of pulmonary disease in systemic lupus erythematosus (SLE) has been variable, with some authors suggesting that pleural or pulmonary involvement may occur in as many as 60% of patients with SLE.' Subclinical involvement occurs even more frequently, with autopsy series reporting a prevalence of up to 93%.2 The most common pleuropulmonary manifestation of SLE is pleuritis, with or without pleural effusion. Other pulmonary manifestations include acute lupus pneumonitis, chronic interstitial lung disease with fibrosis, alveolar hemorrhage, bronchiolitis obliterans, pulmonary vascular disease with pulmonary hypertension, and pulmonary embolism. I A less common entity is the shrinking lungs syndrome (SLS), characterized by unexplained dyspnea, small lung volume with restrictive physiology, and an elevated diaphragm.' The exact prevalence of this condition remains to be determined. An early report of 30 consecutive patients with SLE, not selected by respiratory symptoms, suggested that 23% of the patients had SLS.4 However, the small amount of published data on this condition and the fact that it is seldom seen in clinical practice seem disproportionate to this reported prevalence.

CLINICAL FEATURES The time to onset of SLS ranges from 4 months to 24 years after the diagnosis of SLE.5 Only 2 cases were reported in which SLS was the initial presenting feature of SLE.6 Patients with SLS presented with dyspnea on exertion, which progressed over several weeks to months, resulting in markedly decreased exercise tolerance and eventually dyspnea at rest. Pleuritic chest pain was a commonly recognized symptom. On clinical examination, patients were tachypneic, with rapid, shallow breathing and marked limitation of chest wall expansion.v'>" Use of accessory muscles of respiration was noted often, and paradoxical abdominal movement with the patient supine has been reported.' Auscultation of the lungs was generally unrevealing, but a few patients had bibasilar crackles, attributed to basal atelectasis.s-'?

Five patients had clinical or biochemical evidence of a myopathy at presentation, and 3 patients had a history of myositis. Two patients developed a generalized myopathy more than a year after their presentation with SLS, giving a total of 10 patients with myopathyY-6.1O.12.14.15 These 10 patients represent 27% of patients with SLS reported in the literature if 1 case series in which patients with myositis were specifically excluded is not counted" (Table 1).

From the Division of Rheumatology and Internal Medicine (K.J.W., K.G.M.) and Division of Pulmonary and Critical Care Medicine and Internal Medicine (W.M.B.), Mayo Clinic Rochester, Rochester, Minn. Address reprint requests and correspondence to Kevin G. Moder, MD, Division of Rheumatology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2000;75:467-472

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Table 1. Clinical Characteristics of Patients With Shrinking Lungs Syndrome*

Reference Hoffbrand & Beck,3 1965 Gibsonet aI,4 1977 Martenset aI,5 1983 J acobelli et al,15 1985 Wilcoxet al," 1988 Larocheet al," 1989 Stevenset al," 1990 Soubrieret aI,II 1995 Singlecase reports,t 1985-1997 Total

No. of cases

Mean age (y)

8 7 7 2 2 12 2 3

44

29 47 38

7 7 6 2

0 1 0

33 61 32

9 0 3

2 0

6 49

35 40

5 39

7

No. of females

No. of males I

3

No. (%) with pleurisy 4 (50) 7 (100) 1 (50) 9 (75)

No. (%) with evidence of myositis 1 (13) 2 (29) 2 (29) 1 (50)

I (33)

1 (50) None

None 22 (45)

3 (50) 10 (20)

*Ellipses indicatedata are not available. tSex of patient not specifiedin I case report. Twenty-two patients (45%) had a history of pleurisy, often recurrent, and 4 patients (8%) had a history of pericarditis. 1.10,1 1.15 .

DIAGNOSIS Positive findings in SLS include chest radiographic abnormalities, characteristically showing elevated hemidiaphragms (Figure 1).1,4'15 Other chest radiographic findings include pleural thickening in 7 patients (14%)5,6,8.16 and small pleural effusions in 4 patients (8%).5,16 Screening of the diaphragm, when performed, revealed "sluggish" movement of 1 or both hemidiaphragms,I,7,11 and 1 patient

Figure I. Posteroanterior chest radiograph of a patient with the shrinking lungs syndrome shows elevation of the right hemidiaphragm.

with severe respiratory compromise was noted to have no movement of the diaphragm at alL14 Laboratory examination revealed normal blood cell count and electrolyte, creatinine, and liver enzyme levels, whereas the erythrocyte sedimentation rate and serum levels of antinuclear antibodies were invariably increased. Creatine kinase levels were within normal limits in patients without a generalized myopathy.s"-" Five patients (10%) with myopathy at presentation with SLS had increased muscle enzyme values . In 1 study, no correlation was found between severity of respiratory dysfunction and clinical activity of SLE, mean prednisone dosages, disease duration, antinuclear antibodies, antinuclear DNA antibodies, or C3 levels.' Results of pulmonary function testing were abnormal in all patients described in the literature, characteristically showing a restrictive defect with decreased lung volumes (Table 2). Vital capacity ranged from 18% to 90% of predicted, with an overall mean value of 52%. Patients with evidence of myositis had lower lung volumes, with a mean vital capacity of 40%. The diffusing capacity for carbon monoxide was decreased, but the diffusion constant (KeD) that corrects for lung volume was normal or only slightly decreased (range, 77%-104%; mean, 95%). Maximal inspiratory and expiratory pressures at the mouth, performed to assess global respiratory muscle function, were decreased in several studies. 4.6,1O.13-16 These measurements, however, may underestimate respiratory muscle strength in some patients because of incomplete activation of the muscles during the maneuver." For this reason, Laroche et al" also assessed maximal respiratory pressures during a sniff maneuver, which has been shown to produce more reliable activation of the inspiratory muscles. Only 1 of their 12 patients had a decreased maxi-

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Table 2. Pulmonary Function Findings in Patients With Shrinking Lungs Syndrome* Reference Hoffbrand & Beck,3 1965 Gibson et al," 1977 Martens et aI,5 1983 Jacobelli et al," 1985 Wilcox et al," 1988 Laroche et al," 1989 Stevens et al," 1990 Soubrier et al,II 1995 Single case reports,

1985-1997

No. of cases

Predicted (%) meanVC

8 7 7 2 2 12 2 3

61 55 47 37 69 55 50 50

6

29

Predicted (%) mean TLC

Predicted (%) mean Dr.co

Cases (%) with low MIP

63 66

88 89

62 59 74 63

104 90

100 100 8 100

43

100

100

*DLCO =diffusion coefficient; MIP = maximal inspiratory pressure; Pdi = transdiaphragmatic pressure; TLC vital capacity. Ellipses indicate data are not available.

mal inspiratory pressure by this technique, whereas other studies reported abnormalities in 94% of patients with SLS. Arterial blood gas measurements with the patient at rest were either normal or showed mild arterial hypoxemia that worsened with exertion.t-" Further investigations, described subsequently, were performed to exclude other pathologic conditions that could account for the lung restriction and dyspnea. Findings on ventilation-perfusion scans were invariably normal. Bronchoscopy and bronchoalveolar lavage were unrevealing.Y':" Computed tomography of the chest was remarkable for small pleural effusions in 2 cases.v" pleural thickening in 2,8 and minor lower lobe opacities thought to represent areas of atelectasis in 3.8 However, there was no evidence to suggest interstitial pulmonary disease or severe pleural disease in any of the patients studied. Lung biopsy, open or transbronchial, demonstrated normal lung tissue, and an open pleural biopsy, performed to investigate an area of pleural thickening on chest radiography, showed fatty tissue." In 1 study, 15 no correlation was found between severity of respiratory dysfunction and clinical activity of SLE, mean prednisone dosages, disease duration, antinuclear antibody, antinuclear DNA antibodies, or C3 levels. PATHOGENESIS The etiology of SLS remains unclear. In 1954, 3 different groups of investigators recognized a subgroup of SLE patients with small lung fields and elevated diaphragms, not accounted for by associated pulmonary or pleural involvement."?" In 1965, Hoffbrand and Beck' noted that these patients with raised "sluggish" diaphragms had a restrictive pattern on pulmonary function testing and a progressive loss of lung volume. They thus coined the term shrinking lungs and postulated that excessive surface tension secondary to surfactant failure resulted in dif-

83

Cases (%) with low Pdi

100 100 100 100 25

100

=total lung capacity; VC =

fuse alveolar atelectasis, which was not radiologically detectable. In a 1977 study of 7 patients who had SLE with SLS, Gibson et al" found abnormalities in transdiaphragmatic pressures (using esophageal and gastric balloons) consistent with diaphragm dysfunction. They suggested that this was due to either severe diaphragm weakness or immobility of the diaphragm after extensive pleural adhesions and fibrosis. Martens et al' demonstrated decreased maximal transdiaphragmatic pressures, which further supported a hypothesis of diaphragm dysfunction. They reported that patients with SLS also had decreased maximal expiratory esophageal and gastric pressures, concluding that inspiratory and expiratory muscles were affected. The muscle weakness was attributed to the underlying SLE and not to malnutrition or to the use of corticosteroids.' Other smaller studies and case reports have described abnormal transdiaphragmatic pressures, suggesting diaphragmatic weakness in patients with SLS.7,13,IS.16 Specifically, gastric pressures were persistently negative in 1 report.' Phrenic nerve electromyographic studies excluded the presence of a demyelinating neuropathy and provided strong evidence against axonal degeneration as the cause of diaphragm weakness in these patients." Consistent with this hypothesis, the only clinicopathologic study of a patient with SLS in the literature reported that at autopsy both hemidiaphragms were markedly thinned, with diffuse fibrosis and muscle atrophy but no active inflammatory process. The lungs had minimal interstitial fibrosis, and there were no extensive pleural adhesions, providing further evidence that SLS was not secondary to an intrapulmonary abnormality and making diaphragm tethering secondary to fibrous pleural adhesions unlikely." This was in agreement with clinical findings of essentially normal computed tomography of the chest and pres-

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Table 3. Documented Treatment and Response of 19 Patients With Shrinking Lungs Syndrome* Reference Hoffbrand & Beck,' 1965

No. of cases

Jacobelli et al," 1985 Stevens et al,? 1990

I 6 1 2

Soubrier et ai, II 1995

3

Rubin & Urowitz," 1983 Pines et al,? 1985 Walz-Leblanc et al,'? 1992 Thomp son et al,? 1985 Munoz-Rodriguez et al,' 1997 Van Veen et al, " 1993

Treatment

Outcome Immediate symptomatic response Good symptomatic response

Steroids Steroids Steroids Prednisone, 30 mg/d Prednisone, 30 mg/d Prednisone, 0.5 mg/kg Prednisone, 60 mg/d Prednisone, 30 mg/d High-dose steroids Prednisone, 40 mg/d Prednisone, 40 mg/d Albuterol (neb), 5 mg/6 h

Rapid improvement in dyspnea Good symptomatic response Symptom free after 2 rno Symptom free after 3 mo Symptoms better after I rno No response Relief of dyspnea Dyspnea improved within 2 d Improved exercise tolerance

Salbutamol (inh), 800 flgl6 h Theophylline, 750 mgld

Clinical & functional improvement Dyspnea improved over weeks

Lung function with therap y 43% increase in TLC after I y Improved lung function 100% increase in VC after 2 mo 19% increase in VC after 10 d Lung function normal after I y Lung function norma l after 10 mo 22% improvement in TLC after 6 mo

85% increase in TLC after 7 mo 47% increase in TLC after 12 d 56% increase in TLC after 14 mo 31% increase in TLC after I wk

*inh = inhaled ; neb = nebulized; TLC = total lung capacity; VC = vital capacity. Ellipses indicate data are not available.

ervation of the diffusion coefficient, arguing against an intrapulmonary process accounting for the reduction in lung volurnes.v" However, in a study by Laroche et al," 9 of 12 patients had normal transdiaphragmatic pressures, as measured by the sniff maneuver. In 3 patients, maximal transdiaphragmatic pressure was moderately reduced, but phrenic nerve stimulation demonstrated that this was due to incomplete activation of the diaphragm rather than to a primary abnormality of the diaphragm. The authors concluded that SLS was not primarily due to an isolated weakness of the diaphragm. In this study, patients who had any previous evidence of polymyositis were specifically excluded, whereas in other reports several of the patients studied had evidence of a myopathy at some point in the course of their illness. It is still possible that SLS represents a myopathic process in which routine electromyographic studies may yield normal findings. One possibility is a steroid-related myopathy. However, several patients described in the literature presented with SLS before the initiation of corticosteroid therapy. Also, improvement in both lung volumes and measures of respiratory muscle strength has been noted with high-dose corticosteroid therapy.14 Laroche et al 8 suggested a restriction in chest wall expansion as the cause for small lung volumes in SLS, based on analysis of lung recoil pressures and dynamic compliance. All patients in their study had a shallow pattern of breathing during a maximal voluntary ventilation maneuver, which was not explained by respiratory muscle weakness. Intercostal muscle biopsy and pleural biopsy, however, when performed in patients with SLS, failed to show

any important abnormality. Intercostal muscle electromyography in 1 patient was reported as normal.v' Therefore, some patients may have diaphragmatic involvement by a myopathic process; in others, chest wall restriction seems to account for the clinical syndrome.

TREATMENT The treatment of SLS has been empirical because the cause remains controversial. Most cases reported in the literature have been managed by increasing the dose of corticosteroid used to treat the underlying SLE, presumably attempting to control a subclinical respiratory myositis in these patients . The dosages used were 30 to 60 mg of prednisone per day, with subsequent tapering according to symptoms (Table 3). Although earlier reports merely described symptomatic improvement in dyspnea and chest pain with corticosteroids, I others have shown a consistent increase in maximal inspiratory pressures and total lung capacity with treatment." 10,I 1,15 Of those patients receiving increased dosages of corticosteroids, 83% demonstrated symptomatic improvement and increase in lung volumes. Improvement in chest radiographic appearance with diaphragmatic descent after corticosteroid therapy also was described." However, there are no reports comparing transdiaphragmatic pressures before and after initiation of treatment. There was, in particular, no correlation between response to corticosteroids and a clinical history of myositis, although the number of patients was small.l.6.10.14.15 Symptomatic improvement has been noted within 2 days of starting corticosteroid therapy, 10 but most authors have observed clinical response over several weeks to

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months. Improvement in lung volumes often predates symptomatic relief by several weeks. Three patients (17 %) with SLS did not respond to corticosteroids.I":" One of these was successfully treated with theophylline, 750 mg/d, with a subsequent 31 % increase in total lung capacity after 1 week and symptomatic improvement occurring over several weeks." The authors felt that this observation supported the hypothesis of diaphragm weakness in SLS because theophylline has been shown to improve respiratory force by increasing the muscle strength of the diaphragm in animals and in healthy human subjects." Other isolated case reports suggest that the use of inhaled ~-adrenergic receptor agonists may be beneficial. One patient who progressed clinically despite 2 months of increased corticosteroid dosage demonstrated a 47% increase in total lung capacity and improved exercise tolerance after 12 days of nebulized albuterol therapy.' A second patient is reported to have had marked improvement in total lung capacity, but this was 14 months after initiation of l3-adrenergic receptor agonist therapy, making it difficult to conclude a cause-and-effect relationship.P These authors postulated that l3-adrenergic receptor agonists may improve respiratory muscle strength because intravenously administered terbutaline has been shown to have some positive inotropic effect on the fatigued diaphragm of dogs, as documented by increased transdiaphragmatic pressures after therapy." Still, this effect was modest and would not entirely explain the improvement in lung volumes in the 2 patients. These reports must be considered in light of observations that prolonged follow-up of patients with SLS demonstrated spontaneous improvement after several years, with no relationship to subsequent flares of their lupus." Potential therapies for SLS may include steroid-sparing immunosuppressants such as cyclophosphamide or azathioprine. In patients with a severe restrictive process, supplemental oxygen for resting or exertional hypoxemia may be necessary. These patients would potentially also benefit from noninvasive modes of mechanical ventilation, particularly at night. PROGNOSIS

The prognosis for patients who have SLS is reported to be good, with most patients demonstrating gradual improvement or stabilization of their pulmonary function. There is only 1 report of death occurring from SLS, in a patient who became ventilator dependent because of poor respiratory effort, despite therapy with high-dose corticosteroids." Martens et aP reported that 7 patients with SLS had stable lung function over 38.5 patient-years while receiving low-dose corticosteroid therapy, concurring with observations by other aurhors.v":"

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DISCUSSION

The prevalence of SLS is unknown. Reported data suggesting that 23% of SLE patients not selected by pulmonary symptoms had SLS are inconsistent with our clinical experience.' Also, only a few small studies have been published in the literature, with 49 cases reported since 1965. A review of Mayo Clinic records since 1966 revealed only 2 patients with SLE listed with this diagnosis. On review of these records, the diagnosis could not be confirmed in either. The pathogenesis of SLS remains controversial. Again, conflicting reports are based on the analysis of data from small numbers of patients. However, most authors have clearly documented weakness of the respiratory muscles, predominantly the diaphragm, in patients with SLS.7,I3,15.16 This has been attributed to a myopathic process, unrelated to corticosteroid use.' Severe abnormalities of the pulmonary parenchyma, pleura, or phrenic nerves have not been demonstrated despite extensive investigation. 6-8. 13,14.16 Other authors were unable to reproduce findings consistent with isolated diaphragmatic weakness, but their studies suggest that a restriction of chest wall expansion may be the major abnormality in patients with SLS.8 Thus, the same disease process that affects the diaphragm in some patients may affect mainly the intercostal muscles in others. However, most authors agree that the clinical entity of shrinking lungs is heterogeneous and may be related to multiple pathogenetic mechanisms.t':" The treatment of SLS has presumably been targeted to control the underlying autoimmune process; several authors have reported success with corticosteroid therapy.I,6.1O,14,15 Most patients had prompt symptomatic improvement, but objective evidence of increased lung volumes was usually demonstrable only after many weeks or months. This improvement continued until most patients eventually returned to their baseline pulmonary function, despite repeated flares in their lupus or a gradual tapering of their corticosteroid dosage. Unfortunately, only isolated anecdotal reports exist regarding other treatment modalities, and no reports exist regarding the use of immunosuppressants as steroid-sparing agents. Also, given the rarity of this syndrome, randomized clinical trials most likely will never be conducted. CONCLUSION

Shrinking lungs syndrome affects a small proportion of patients with SLE, causing disabling pulmonary symptoms and, infrequently, death. The underlying etiology remains obscure. Understanding which subset of SLE patients is predisposed to developing SLS, correlation of autoimmune markers with SLS, and controlled therapeutic trials for SLS are challenges for future research.

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