HOW TO TREAT 29 sarcoidosis , allowing minimally invasively biopsy of mediastinal and hilar lymph nodes for confirmation of diagnosis and exclusion of other conditions . The ultrasound appearance of sarcoidosis is often characteristic with prominent septations ( see figure 6 ). When compared with traditional ‘ blind ’ transbronchial needle aspiration ( TBNA ), EBUS – TBNA has a vastly greater diagnostic yield : 54 % and 83 % respectively . 15 In addition , EBUS – TBNA provides higher diagnostic yield in earlier-stage disease than traditional biopsy methods ( 85 % in stage I disease ). Transbronchial forceps biopsy plays a role in diagnosis if EBUS – TBNA is non-diagnostic or when parenchymal disease predominates , but the procedure-related risks of bleeding and pneumothorax are much higher than with EBUS – TBNA . 16 , 17 Bronchoalveolar lavage may be performed at the time of bronchoscopy and shows a predominantly T-cell lymphocytic return despite peripheral blood lymphopenia . Elevated CD4 +: CD8 + ratios of greater than 3.5:1 ( normal 2:1 ) may suggest T helper 1 cell – mediated inflammation and increase suspicion of sarcoidosis .
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HOW TO TREAT 29 sarcoidosis , allowing minimally invasively biopsy of mediastinal and hilar lymph nodes for confirmation of diagnosis and exclusion of other conditions . The ultrasound appearance of sarcoidosis is often characteristic with prominent septations ( see figure 6 ). When compared with traditional ‘ blind ’ transbronchial needle aspiration ( TBNA ), EBUS – TBNA has a vastly greater diagnostic yield : 54 % and 83 % respectively . 15 In addition , EBUS – TBNA provides higher diagnostic yield in earlier-stage disease than traditional biopsy methods ( 85 % in stage I disease ). Transbronchial forceps biopsy plays a role in diagnosis if EBUS – TBNA is non-diagnostic or when parenchymal disease predominates , but the procedure-related risks of bleeding and pneumothorax are much higher than with EBUS – TBNA . 16 , 17 Bronchoalveolar lavage may be performed at the time of bronchoscopy and shows a predominantly T-cell lymphocytic return despite peripheral blood lymphopenia . Elevated CD4 +: CD8 + ratios of greater than 3.5:1 ( normal 2:1 ) may suggest T helper 1 cell – mediated inflammation and increase suspicion of sarcoidosis .
Serum ACE
There are few serum biomarkers for sarcoidosis , and all are of limited diagnostic utility as they lack sensitivity and specificity . Serum ACE is commonly used in evaluating sarcoidosis . However , because of the presence of elevated serum ACE levels in other conditions , its positive predictive value is low , and it plays no role in the diagnosis . Serum ACE is elevated in 30-80 % of individuals with sarcoidosis and , when elevated at baseline , can be monitored to evaluate response to therapy . 18 Serum ACE levels may be affected by ACEIs and misleading in patients taking these .
In summary , the authors would not recommend reliance upon ACE measurement for inclusion or exclusion of sarcoidosis , but rather , it should be used to moderate pre-test probability when considering the differential of sarcoidosis .
MANAGEMENT
Non-pharmacotherapy
THERE is limited scope for non-pharmacotherapy in disease regression or suppression ; however , basic principles can be put into place for patients to enhance outcomes . Cardiorespiratory exercise facilitates improved cardiorespiratory reserve and may alleviate symptom burden , such as dyspnoea ; it may also assist with weight loss , as weight gain may be a potential side effect of a sedentary lifestyle or corticosteroid therapy .
Vaccination for COVID-19 , influenza and pneumococcus is recommended , particularly for those on immunosuppressing agents . It is not clear if sarcoidosis patients without severe pulmonary disease who contract COVID-19 have worse outcomes . 19 Smoking avoidance or cessation should be encouraged , and while the evidence around vaping is unclear , the authors ’ recommendation is for all patients with underlying lung disease to avoid it .
Corticosteroids
Glucocorticoids are the mainstay of sarcoidosis pharmacotherapy , but their use should always be considered after a risk – benefit analysis . In the Australian context , most patients with sarcoidosis do not require steroids or other immunosuppressive therapies . 6 Only consider glucocorticoids where there is evidence of significant end-organ damage or for those with symptoms where there could reasonably be a higher risk of mortality or permanent disability . 20
The authors do not advise the initiation of corticosteroids outside of specialist practice , and there is no evidence for short-course steroid therapy ; instead , an intermediate to high dose of steroid — for example , prednisone 25-50mg — with prolonged weaning doses are the mainstay of clinical practice . 20 Both short- and long-term steroid complications should be considered , and where prolonged glucocorticoid therapy is required , steroid-sparing agents may be needed to limit side effects . 21
One of the primary areas where GPs can facilitate management is the monitoring and management of glucocorticoid side effects , such as screening for steroid-induced diabetes , hypertension and osteoporosis ( see box 5 ). Typically , osteoporosis screening is indicated if doses of 5mg or more of prednisolone are used daily for more than three months ; hypertension and hyperglycaemia will usually present in days to weeks of steroid commencement .
Steroid-sparing agents
Evidence surrounding the use of second-line agents is limited , although both traditional and biologic therapies have been trialled . Steroid-sparing agents are considered in instances of disease progression despite glucocorticoid therapy or if glucocorticoid toxicity becomes unacceptable ( see table 3 ). Methotrexate is often favoured as the initial second-line agent of choice independent of the organ system affected . Anti-TNF-a agents , such as infliximab , are also used in the treatment of refractory sarcoidosis . 20 In local experience , this treatment decision is often facilitated through an interstitial lung disease multidisciplinary team .
Figure 7 offers a management algorithm for pulmonary sarcoidosis .
Lung transplantation
Lung transplantation may be a treatment option for those with advanced sarcoidosis and significant parenchymal lung disease . Lung transplantation in Australia has a 69 % five-year survival rate , which exceeds global averages . 22
A
Figure 3 . Chest CT .
A . High-resolution CT chest demonstrating predominantly left lung nodular changes .
B . The corresponding high-resolution CT demonstrating mediastinal and hilar lymphadenopathy .
Figure 2 . H & E stain of a non-necrotising ( non-caseating ) granuloma identified with intraoperative cytology via EBUS . Lymphocytes (<) and epithelioid histiocytes (*) can be seen forming the granuloma with surrounding erythrocytes (#) and cellular debris ( CD ).
Table 2 . Scadding criteria for the stages of sarcoidosis
Stage Radiological characteristics Spontaneous resolution rate (%)
0 Normal chest X-ray - I Hilar or mediastinal lymphadenopathy only 60-90 II Hilar or mediastinal lymphadenopathy with lung parenchymal changes 40-70
III Parenchymal disease without hilar or mediastinal lymphadenopathy 10-20 IV Pulmonary fibrosis 0
While granulomatous disease can recur in the transplanted lung , there is often minimal disease recurrence because of the level of immunosuppression required for transplant graft survival . Complications , such as pulmonary hypertension or cardiac amyloidosis , may complicate the ability for transplantation to be performed successfully . 23
CARDIAC SARCOIDOSIS
CARDIAC involvement of sarcoidosis is reported to occur in 5-10 % of systemic sarcoidosis , although this prevalence is likely underestimated based on post-mortem and advanced imaging studies . 24 Cardiac sarcoidosis is a serious manifestation of the disease and requires involvement of subspecialty cardiologists in both cardiac imaging and electrophysiology . It often presents as a disturbance of the intrinsic electrical pathways and can manifest as complete heart block or sudden cardiac death . A combination of electrophysiological support in the form of a implanted pacemaker with or without a defibrillator as well as medical therapy with glucocorticoids and steroid-sparing agents may be required . 20
Symptoms suggestive of cardiac dysrhythmia should not be taken lightly ; perform a screening
B
ECG in all patients with a diagnosis of sarcoidosis who present with these symptoms . 11 If there are concerns arising from the clinical assessment , promptly refer the patient for evaluation regarding the need for an implantable device . Some of the features associated with higher mortality and morbidity for cardiac sarcoidosis are seen in box 6 .
Figure 8 offers a management algorithm for cardiac sarcoidosis .
SARCOIDOSIS- ASSOCIATED FATIGUE
SARCOIDOSIS-associated fatigue is an often underappreciated