Clinical Meetings at RH Year 2004

2004 - A Young Lady with Progressive Dyspnoea

Drs W Chen, Wilson KS Yee, Department of Medicine, Kwong Wah Hospital

Case history
A 20-year-old lady has history of systemic lupus erythematosus (SLE) since 1998. Her presenting clinical features included fever, malar facial rash and arthritis. Immunology tests showed positive ANF, anti-DNA and anti-ENA antibodies. She responded well with oral prednisolone and hydroxychloroquine. She had 2 episodes of flare-up of SLE disease activities from 1998 to 200I and both responded to increased dose of prednisolone and non-steroidal anti-inflammatory drugs. Azathioprine was added for control of the disease and its steroid-sparing effect.

In June 2001, she presented to us with fever, multiple joint pain and left pleuritic chest pain for few weeks. Physical examination revealed left pleural rub. Chest radiography and ultrasound of thorax showed presence of mild left pleural effusion (Fig. I). Echocardiogram confirmed mild pericardial effusion, without evidence of any valvular dysfunction and pulmonary hypertension. Laboratory results revealed anaemia with positive direct anti-globulin test and increased SLE disease activity markers. The clinical picture was compatible with disease flare-up with serositis and haemolytic anaemia. She demonstrated both clinical improvement and radiological resolution of left pleural effusion after treatment with prednisolone 40 mg daily.



In November 2001, the lady was admitted for investigation of shortness of breath and impaired exercise tolerance. She reported a two-month history of dyspnoea especially on exertion. She also had pleuritic chest pain aggravated by coughing. On examination, she was in mild respiratory distress with RR 20/min. The chest was clear but expansion was symmetrically reduced over both lower zones. Other systemic review was unremarkable.

Investigation results were as follows:

CBP: WCC =3.1 X 109fL, Hb = 1O.5g/dL,PIt= 221 x 109fL
LRFf: normal
Autoimmune marker: ANF 1: 1280, Anti-DNA antibody 1: 1280
ABG (room air):
pH =7.36, PC02 =4.0mmHg, paz =9.1mmHg
ESR =60 mrn/hr, CRP =9 mg/L
C3 / C4: 0.49/0.14 gfL
CPK / LDH: normal

ECG - Sinus tachycardia 105/min, no acute ischaemic change, no SIQ3 T3.
Echocardiogram showed satisfactory LV function without pericardial effusion and pulmonary hypertension.
All CXR performed in July, September & November 2001 were compared (Fig. 2). Serial films showed progressive loss of lung volume with elevated diaphragms.


Fluoroscopy screening confirmed sluggish bilateral diaphragmatic movement. No ventilation perfusion mismatch was identified on VQ scan. CT thorax films showed no evidence of interstitial lung disease or significant pleural disease. Only mild sub- segmental basal atelectasis was observed over right lower lobe.

Lung function test on 17/11/2001 showed restrictive lung pattern with decreased FEVI / FVC / TLC / DLCO. KCO was preserved(Table 1). Respiratorymuscle strength was impaired as reflected by the low maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). The FVC was reduced by 34% when changing the body position from erect to supine, which indicated an underlying diaphragmatic muscle weakness.


Her clinical features were most compatible with the diagnosis of "Shrinking Lung Syndrome". She was treated with prednisolone 45 mg daily and azathioprine 75 mg daily. Indocid was prescribed for relief of pleuritic chest pain. Symptomatic improvement with decreased dyspnoea and pleuritic chest pain was resulted. The patient was then discharged home and the dose of prednisolone was gradually tailed down. Azathioprinewasmaintained.

CXR and lung function test were repeated 6 weeks later. The CXR showed re- expansion of lung volume. The FEVI/ FVC / TLC / DLCO improved by 20%. The MIP and MEP improved by 30% and 20 % respectively.

12 months later, she demonstrated further improvement of the lung function variables and respiratory muscle strength (MIP and MEP) back to baseline levels. CXR showed fully expanded lungs (Fig. 3).


Discussion
In systemic lupus erythematosus (SLE), pleuropulmonary involvement may occur in up to 60 - 80% of patients. The most common respiratory manifestation is pleuritis. "Shrinking Lung Syndrome" is a less commonly encountered entity.

The term Shrinking Lung Syndrome (SLS) first originated from Hoffbrand & Beck in 1965, when they described a group of patients with clinical features of unexplained progressive dyspnoea and pleuritic chest pain.) The chest radiography showed small but clear lung fields with diaphragmatic elevation. Lung function test showed restrictive pattern.

The exact prevalence of SLS is unknown. A MEDLINE search of case series and case reports with the diagnosis of SLS was performed (1965-2002) and only 56 documented cases were found. Female was the predominant sex involved. The mean age of disease presentation was 38. Half of patients had history of pleuritis and 20% patients had clinical or biochemical evidence of myopathy. The time to onset of SLS after the diagnosis of SLE was from 4 months to 24 years. They usually presented with progressive dyspnoea on exertion. Pleuritic chest pain was a commonly recognized symptom. CXR typically showed small and clear lung fields with elevated hemi-diaphragms. Other radiological features included pleural thickening and small pleural effusion. CT thorax was usually unremarkable, except for presence of pleural thickening, small pleural effusion and minor atelectasis. There was no evidence of interstitial pulmonary disease.

All patients with SLS had abnormal lung function tests, characteristically showing a restrictive pattern with a decreased FEV1and PVc. The TLC and DLCO were also reduced. The KCO was either normal or slightly decreased. The respiratory muscle strength was impaired in most studies as reflected by the decrease in MIP (maximal inspiratory pressure) and MEP (maximal expiratory pressure) at the mouth. A low trans-diaphragmatic pressure was detected in some studies. Laboratory results are usually unremarkable except for raised erythrocyte sedimentation rate and anti- nuclear antibodies. Muscle enzyme was within normal range in patients without evidence of generalized myopathy. Other investigations like bronchoscopy, lung biopsy and ventilation perfusion scan were usually unrevealing.

No clinical correlation between severities of respiratory muscle dysfunction and clinical activities of SLE, disease duration and anti-DNA antibodies or C3 levels was found.5

Etiology
The pathogenesis of SLS remains controversial. Diaphragmatic dysfunction was first proposed as the cause for loss of lung volume in SLS by Gibson.2 He studied seven patients with history of SLE and SLS, and found severe abnormalities in trans- diaphragmatic pressures using the intra-oesophageal and gastric balloon. The finding was consistent with diaphragmatic dysfunction. The loss of lung volume in SLS patients was thought to be due either to severe diaphragmatic weakness or diaphragmatic immobility after extensive pleural adhesion and fibrosis. Gibson's work was also confirmed by other studies.4,16,17

The role of diaphragmatic myopathy in SLS was further supported by a clinical pathological study of a lupus lady who had SLS and died of bronchopneumonia. The postmortem findings demonstrated, that both hemi-diaphragms were markedly thinned, with diffuse fibrosis and muscle atrophy. Only minimal interstitial fibrosis in the lungs was found. Rubinet et al suggested that the progressive restrictive lung
defect was due to severe intrinsic diaphragmatic weakness secondary to diffuse diaphragmatic fibrosis.3

Phrenic nerve dysfunction has also been proposed as a cause for the diaphragmatic muscle weakness. Wilcox et al studied 9 lupus patients with diaphragmatic muscle weakness (↓ Pdi). All of them had normal electrophysiological studies including both phrenic nerve latencies and compound diaphragm action potential. These findings excluded the possibility of underlying demyelinating neuropathy and axonal degeneration. They concluded that diaphragmatic weakness in SLE was unlikely to be caused by phrenic nerve neuropathy.7

Steroid induced myopathy was considered as a potential contributing factor to the respiratory muscle weakness in SLS. However, indirect evidence suggested that it was not the predominant factor because some patients presented with SLS before receiving corticosteroid therapy. Moreover, improvement in lung volumes and respiratory muscle strength was noted in patients taking high dose steroid therapy3

Another possibility for the diaphragmatic muscle weakness was myasthenia-like syndrome. However, none of the SLS patients had overt clinical features of myasthenia. All of them demonstrated negative Tensilon test and undetectable anti- acetylcholine antibodies.

Laroche et al studied 12 lupus patients with SLS and found that only 3 of them had moderately reduced maximal trans-diaphragmatic pressures. Their phrenic nerve stimulation tests revealed incomplete diaphragmatic activation. They concluded that SLS was not primarily due to an isolated diaphragmatic muscle weakness. All patients showed a shallow breathing pattern during maximal voluntary ventilation maneuver which could not be properly explained by respiratory muscles weakness. They 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.s

So far, the pathogenesis of SLS remains obscure. It may be related to multiple underlying pathological processes. Some patients may have more than one active aetiological factor. In fact, SLS had also been reported in association with other autoimmune diseases, like Sjogren syndrome (Tavoni 1999), rheumatoid arthritis (Ahmend Shahbaz 2001), and systemic sclerosis (Carlo Alberto 2001).

Treatment
The treatment of SLS had been emr.irical. Earlier reports described symptomatic improvement with corticosteroids.I,,5.9,IZ.13,14. 15. Some have shown a consistent increase in maximal inspiratory pressures and total lung capacity. Improvement in chest radiographic appearance with diaphragmatic descent was also described.1.5.9.lz,15 The usual dose of prednisolone was 0.5 to Img/day with subsequent tapering of the dose according to the symptomatic response. Most observed clinical response was over several weeks to months but Walz-Leblanc reported a case of symptomatic improvement within 2 days of starting corticosteroid therapy.9 Martens et al reported that 7 patients with SLS had stable lung function test over 38.5 patient-years while receiving low-dose corticosteroid therapy.4

Some patients did not respond well to high dose corticosteroid. One patient was treated successfully with theophylline 750 mg daily, with a subsequent 31% increase in total lung capacity and symptomatic improvement. Theophylline had been shown to improve the respiratory force by increasing the diaphragmatic muscle strength in animals and healthy human.10

Other case reports suggested using inhaled betaz-adrenergic receptor agonist for the treatment of SLS in steroid non-responders. Two case reports demonstrated both symptomatic and lung function improvement after using inhaled albuterol and salbutamol.6.1I The authors proposed that inhaled betaz-adrenergic receptor may improve respiratory muscle strength because intravenous terbutaline had been shown to exert positive inotropic effects on the fatigued diaphragm of dogs. However, this effect was modest and could not explain the clinical outcome entirely.

Immunosuppressive drugs like azathioprine and cyclophosphamide were considered as other potential therapy for the treatment of SLS. However, their use should be based on patient's overall disease activities and presence of any underlying extra- thoracic involvement.

Conclusion
Shrinking lung syndrome is a rare disease, affecting a small subset of patients with systemic lupus erythematosus. Since the pathogenesis of SLS is controversial, the treatment strategy remains empirical and has been targeted to control the underlying autoimmune process. There is no universally accepted standard treatment protocol. Most patients demonstrated a gradual improvement or only a minor deterioration of the pulmonary function in the long term.

References

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