Joseph P. Lynch, III, M.D.; 1 Yan Ling Ma, M.D.; 2 Michael N. Koss, M.D.; 2 Eric S. White, M.D.3

Disclosures

Semin Respir Crit Care Med. 2007;28(1):53-74. 

In This Article

Specific Complications of Intrathoracic Sarcoidosis

Clinically significant pulmonary vascular involvement is uncommon in sarcoidosis. However, sarcoid granulomatous lesions follow pulmonary vessels, and incidental histological involvement of vessels was noted in 42 to 89% of open-lung biopsies from patients with pulmonary sarcoidosis.[74,190] Pulmonary arterial hypertension (PAH) was reported in 1 to 5% of patients with sarcoidosis[191,192,193,194,195] but the incidence is much higher among patients with advanced fibrocystic sarcoidosis.[196,197,198,199,200] The United Network for Organ Sharing (UNOS) database identified 363 patients with sarcoidosis listed for lung transplantation (LT) in the United States between January 1995 and December 2002 who had undergone right heart catheterization (RHC).[200] This represented 73% of all listed sarcoid patients. PAH, defined as mean pulmonary arterial pressure (mPAP) > 25 mm Hg, was present in 74%; 36% had severe PAH, defined as mPAP > 40 mm Hg. Importantly, PFTs did not differ between those with or without PAH. However, patients with severe PAH were seven times more likely to require supplemental oxygen. Two previous studies found that PAH was an independent predictor of mortality among patients with sarcoidosis listed for LT.[197,199]

Mechanism(s) responsible for PAH in sarcoidosis include hypoxic vasoconstriction[192] infiltration or obliteration of pulmonary vessels by the granulomatous, fibrotic response;[201,202,203] and extrinsic compression of major pulmonary arteries by enlarged lymph nodes.[191,202] A retrospective study of 22 patients with sarcoidosis and PAH found that mPAP correlated inversely with carbon monoxide transfer factor (TCO) but not with spirometry (e.g., FVC, FEV1).[202] In that study, five lung explants from sarcoid patients with PAH undergoing LT were examined. Granulomas were predominantly located within the veins, associated with occlusive venopathy and chronic hemosiderosis; arterial lesions were minor.[202]

The diagnosis of PAH may be difficult. Noninvasive techniques include chest CT[204] and Doppler echocardiography (DE).[197] Chest CT may be useful to predict PAH in patients with parenchymal lung disease.[204] CT features that suggest PAH include main pulmonary artery (PA) diameter > 29 mm; segmental artery to bronchus ratio > 1:1 in three of four lobes;[204] ratio of the diameter of the main PA and of the ascending aorta > 1.[205] Doppler echocardiography is superior to CT in estimating PAH but is less accurate than RHC.[197] In a cohort of 374 patients with end-stage lung disease who were being evaluated for LT, estimates of systolic PAP (sPAP) could be made by DE in 166 (44%).[197] However, sPAP estimates were inaccurate (> 10 mm Hg difference) compared with RHC measurements. In addition, 48% of patients were misclassified as having PAH by DE. Sensitivity, specificity, and positive and negative predictive values of sPAP estimation for PAH were 85%, 55%, 52%, and 87%, respectively. DE was less accurate in patients with interstitial lung disease (ILD) compared with obstructive lung disease (OLD). The negative predictive value (NPV) of sPAP for DE was 96% among patients with OLD but only 44% for ILD. When right ventricular (RV) findings (e.g., RV dilatation, hypertrophy, or systolic dysfunction) were considered, NPV of DE was 96% for OLD and 74% for ILD. Thus a normal DE does not exclude PAH in patients with ILD. Further, an abnormal DE is not a reliable marker of PAH. When PAH is suspected in patients with sarcoidosis, a confirmatory RHC should be performed to assess the extent of PAP and responsiveness to vasodilators.

The presence of PAH in sarcoidosis markedly worsens survival. In one recent study of sarcoid patients with PAH, 2 and 5 year survival rates were 74% and 59%, respectively.[202] In sharp contrast, 5 year survival among sarcoid controls without PAH was 96.4%. Data regarding treatment of PAH complicating sarcoidosis are limited. Anecdotal successes were noted with corticosteroids in some patients. In a retrospective review, three of five sarcoid patients with PAH and no evidence for pulmonary fibrosis responded favorably to high-dose corticosteroids.[202] In contrast, none of five with radiographic evidence for pulmonary fibrosis improved.[202] The role of vasodilators[206] in sarcoid-associated PAH has not been elucidated, but short-and long-term responses were noted in case reports[192] or small series.[201,207] In the series of 22 patients with sarcoidosis and PAH reported by Nunes et al, none received long-term vasodilator therapy.[202] The authors urged caution in using vasodilator therapy because of the potential for precipitating pulmonary edema in patients with venooclusive disease.[202]

Other rare vascular complications of sarcoidosis (limited to a few case reports) include pulmonary arterial stenoses from granulomatous involvement of the vessels,[203,208] extrinsic compression of pulmonary arteries by enlarged hilar lymph nodes or fibrosing mediastinitis,[209,210] and pulmonary veno-occlusive disease (resulting from obstruction of interlobular septa veins by granulomata or perivascular fibrosis).[211,212] Extensive fibrosis of mediastinal or vascular structures may result in narrowing or obstruction of innominate veins[213] or superior vena cava (SVC).[208,214,215,216,217,218,219,220]

Necrotizing sarcoid angiitis and granulomatosis (NSG), initially described by Liebow in 1973,[221] is a rare disorder characterized by pulmonary vasculitis, granulomas, and pulmonary nodules on chest radiographs.[222,223,224,225,226,227] Hilar adenopathy has been cited in 10% to 60% of patients.[224,225,226,227] Lung biopsies in NSG demonstrate a granulomatous vasculitis involving arteries and veins, confluent nonnecrotizing granulomata involving bronchi, bronchioles, and lung, and foci of parenchymal necrosis.[222,225] Vascular involvement (angiitis) typically consists of intramural granulomata or lymphocytic and plasma cell infiltrates confined to vessels walls.[227] Systemic vasculitis does not occur. Since the original description, seven series of NSG,[222,223,225,226,227,228,229] as well as case reports[224,230,231,232,233,234] have been published, for a total of x100 cases. In a recent review of 14 cases of NSG, 12 had extrapulmonary symptoms; pulmonary function was normal in 13, but DLCO was decreased in eight of 11 patients tested.[227] Chest radiographs demonstrated alveolar infiltrates in seven; nodules in seven; cavitation in two.[227] Clinical and radiographic features of NSG are similar to "nodular sarcoid" or "nummular sarcoidosis"[235,236,237,238]. Nodular sarcoidosis demonstrates focal nodules composed of masses of granulomas and hyalinized connective tissue.[235] We believe that NSG and nodular sarcoid are simply variants of sarcoidosis. Prognosis of these entities is usually excellent. The disease resolves in most patients (either spontaneously or in response to therapy). In one recent series, favorable responses to corticosteroids were noted in five of five treated patients with NSG.[227]

Stenosis or compression of bronchi may result from granulomatous inflammation of the bronchial wall, extrinsic compression from enlarged hilar nodes, or distortion of major bronchi caused by parenchymal fibrosis.[72,73,239,240,241] Proximal endobronchial stenosis is typically associated with dyspnea, cough, wheezing, and extrapulmonary manifestations.[72,73] Atelectasis of involved lobes or segments may result.[239,240,242,243,244] The right middle lobe is most often affected because of the small orifice, sharp angulation from the bronchus intermedius, and large number of local lymph nodes.[34] The incidence of bronchostenosis (by bronchoscopic assessment) in patients with sarcoidosis ranged from 2 to 26% in two studies,[72,241] but severe bronchostenosis is rare. In a retrospective study of 2500 patients with sarcoidosis, French investigators identified 18 patients with > 50% stenosis of proximal bronchi.[73] Bronchoscopic patterns included single focal stenosis, multiple focal stenoses, and diffuse narrowing of the bronchial tree.[73] Edema and inflammation of the mucosa at sites of stenosis were a universal finding. Endobronchial biopsies revealed non-necrotizing granulomata in 77% of patients.[73] Wheezing, high-pitched inspiratory "squeaks," or stridor may be evident on chest auscultation in patients with symptomatic bronchostenosis.[72] Helical CT scans are useful to determine the extent and nature of stenotic lesions in the lower respiratory tract,[78] but CT overestimates the degree of stenosis.[78,245] Early initiation of corticosteroid therapy may be efficacious.[73] Conversely, delay in therapy may result in acquired fixed stenoses and persistent ventilatory defects.[73] Dilatation of endobronchial stenoses should be considered for patients refractory to medical therapy.[246]

Mycetomas (typically due to Aspergillus species) may develop in cystic spaces (typically in the upper lobes) in patients with advanced (stage III or IV) sarcoidosis.[39,40,247,248] Ipsilateral pleural thickening usually precedes the fungus ball or air-crescent sign.[249] Mycetomas are often asymptomatic, but fatal hemorrhage can occur due to invasion of vessel walls.[243,247,250] Prognosis of aspergilloma is poor (fatality rates > 50%); most fatalities reflect progression of the underlying disease rather than a direct complication of mycetoma.[39,40] Surgical resection is advised for localized lesions in patients able to tolerate surgery[39,40,247] but the risk of surgery may be prohibitive in patients with severe parenchymal disease or extensive pleural adhesions.[39,247] Anecdotal success has been cited with topical or intracavitary therapy, but experience is limited.[251,252] Systemic antifungal therapy is of unproven value. Bronchial embolization may control intractable bleeding.[40]

Clinically significant pleural manifestations (e.g., pneumothorax, pleural effusions, chylothorax) occur in 2 to 4% of patients with sarcoidosis.[253,254,255,256,257,258,259] Pleural thickening may be observed when sensitive techniques are applied but is usually not associated with clinical symptoms. Two studies using HRCT cited pleural thickening in 9%[32] and 11%[260] of sarcoid patients, respectively. The incidence is higher in patients with chronic fibrocystic sarcoidosis. A study of 61 patients with chronic sarcoidosis (> 2 years duration) cited pleural involvement on chest CT in 25 (41%); this included 20 cases of pleural thickening and five effusions.[261] Pleural thickening was more common among patients with parenchymal fibrosis (stage IV), restrictive PFTs, and low DLCO. Earlier reports noted that pleural involvement in sarcoidosis was typically associated with widespread parenchymal lung disease.[262,263] Subpleural or pleural nodules[264,265] may be observed by HRCT in 22 to 76% of sarcoidosis cases,[101,266,267] but rarely cause symptoms. Pleural effusions complicate sarcoidosis in < 3% of patients and, when present, are usually asymptomatic.[259] Kostina et al detected only three pleural effusions among 2775 patients with pulmonary sarcoidosis.[268] The incidence is more common when more sensitive tests are used. In a recent prospective study, thoracic ultrasonograms were performed in 181 consecutive outpatients with sarcoidosis.[257] Pleural effusions were detected in five (2.8%) but only three were attributed to sarcoidosis; two were a manifestation of congestive heart failure. Sarcoid pleural effusions may be either transudative or exudative; lymphocytosis occurs in two thirds of cases,[253,254,257,259] with predominance of CD4 lymphocytes.[259,269,270] A few cases of eosinophilic pleural effusions were described.[271,272] Although exceedingly rare, cases of massive pleural effusions have been described.[273,274,275,276,277] In one case, pleural sarcoidosis with "trapped lung" required decortication for relief of symptoms.[278] Pneumothorax may complicate sarcoidosis,[255,259,268,279,280,281,282] due to rupture of bullae or necrosis of subpleural granulomas.[259] Only a few cases of chylothorax complicating sarcoidosis have been reported.[283,284,285,286,287]

Sarcoid-like granulomatous response is a rare complication of infection due to human immunodeficiency virus (HIV).[288,289,290,291,292,293] Chest radiographic[288] and histological[292] findings are similar to sarcoidosis in non-HIV infected patients. Most cases occur after beginning highly active antiretroviral therapy (HAART),[288,291,292,293,294,295] but sarcoidosis can precede institution of HAART.[288,296] The sarcoid-like granulomas following HAART likely reflect immune reconstitution, with influx of naive and IL-2 receptor-positive CD4 cells.[292,297,298] However, CD8 alveolitis was noted in one case.[299] Administration of exogenous IL-2, which leads to a sustained increase in CD4 T cells,[300] may precipitate sarcoid-like lesions in HIV-infected patients. In one HIV-infected patient with undetectable viral load under HAART, sarcoidosis developed 2 months after initiation of IL-2 treatment.[293] Symptoms resolved following discontinuation of IL-2. Treatment of sarcoid-like reaction in HIV-infected patients is controversial, but favorable responses to corticosteroids have been noted.[290,298]

Type 1 interferons (e.g., IFN-α or IFN-β), used to treat viral hepatitis, multiple sclerosis, and diverse autoimmune and malignant disorders, may increase IFN-γ and IL-2 levels, evoking a Th1 lymphocyte bias and granulomatous inflammation.[301,302,303] Sarcoidosis is a rare complication of IFN-α or IFN-β, therapy.[301,302,304,305,306,307,308,309,310,311] In a review of 60 cases of sarcoidosis following recombinant IFN-α (rIFNa) therapy; 52 (87%) were receiving pegylated a-INF for hepatitis C virus (HCV) infection.[303] The remaining cases were associated with hepatitis B infection,[309] lymphoproliferative malignancies,[312,313] and other hematologic conditions. The incidence of sarcoidosis among patients with HCV infection treated with rIFN-α was < 0.5% in most studies[302,303,304] but one study cited an incidence of 5%.[314] Ramos-Casals et al reported 68 cases of sarcoidosis associated with chronic HCV infection; 76% had lung involvement; 30%, skin involvement.[304] Sarcoidosis developed within 6 months of antiviral therapy in two thirds of patients. HCV-positive patients with sarcoidosis had a lower incidence of lymphadenopathy (hilar or extrapulmonary) and a higher frequency of cutaneous and articular involvement compared with HCV-negative sarcoid patients.[304] Most cases of sarcoidosis resolve with withdrawal of rIFN-α or dose reduction[303,304] but corticosteroids are required in some patients.[302,315] However, corticosteroids or immunosuppressive agents may increase the viral load[304] and should be reserved for highly selected patients.

Treatment of sarcoidosis remains controversial. Corticosteroids (CSs) are the cornerstone of therapy for severe or progressive sarcoidosis (pulmonary or extrapulmonary), and often produce dramatic resolution of disease.[65,316,317] The long-term benefit of CS therapy has not been established because relapses may occur upon taper or cessation of therapy.[4,23,25] The decision to treat requires a careful assessment of acuity and severity of disease, likelihood of SR, and risks associated with therapy. Treatment should be circumscribed and focused. Treatment is rarely appropriate for stage I disease unless extrapulmonary symptoms are prominent. In symptomatic patients with stage II or III disease, a trial of CSs should be considered after an initial observation period (6 to 12 months). Immediate treatment, however, is appropriate for patients with severe symptoms or pulmonary dysfunction and presumed active alveolitis. Therapy is rarely efficacious, however, and may be associated with significant toxicities in patients with far-advanced fibrosis, honeycombing, or bullae (radiographic stage IV).

The appropriate dose and duration of CS therapy has not been evaluated in controlled, randomized trials. For most patients, initial daily dose of prednisone 40 mg/day (or equivalent) for 4 weeks, tapered to 40 mg alternate days by 3 months, is sufficient. Higher doses may be appropriate for patients with cardiac or central nervous system involvement, or selected patients with severe pulmonary sarcoidosis. Responses to CSs are usually evident within 4 to 8 weeks. Failure to respond to CSs may reflect inadequate dose or duration of therapy, presence of irreversible fibrotic or cystic disease, noncompliance, or intrinsic CS resistance. Among CS-responders, we continue prednisone, albeit in a tapering fashion. The rate of taper is individualized according to response and adverse effects. A minimum of 12 months of therapy (among responders) is recommended. In selected patients, long-term (often years) of low-dose, alternate-day prednisone may be required to prevent relapses.

Inhaled CSs suppress endobronchial or alveolar inflammation but have limited efficacy.[318,319,320,321,322,323] Inhaled CSs are expensive, and we do not employ these agents for patients with symptomatic pulmonary sarcoidosis. However, inhaled CSs may have an adjunctive role among patients manifesting bronchial hyperreactivity or cough.

Immunosuppressive, cytotoxic, and immunomodulatory agents have been used to treat patients failing or experiencing adverse effects from CSs.[324] The optimal agent(s) has not been determined because controlled studies comparing various agents are lacking. Favorable responses have been cited with methotrexate,[325,326,327] azathioprine,[328,329,330]; leflunamide,[331,332] cyclophosphamide,[333,334,335] chlorambucil,[336] cyclosporine A,[337] antimalarials (chloroquine or hydroxychloroquine),[338,339,340] pentoxyfylline,[341,342] thalidomide,[343,344,345] and TNF-α inhibitors[346] (particularly infliximab).[347,348,349] Because of potential serious toxicities (including oncogenesis) associated with cyclophosphamide and chlorambucil,[350] we do not use these agents to treat pulmonary sarcoidosis. We reserve the use of thalidomide and pentoxyfyline for research trials. For patients with progressive pulmonary sarcoidosis refractory to CSs, we initiate treatment with azathioprine (dose 100 to 150 mg/d PO) or methotrexate (dose 15-25 mg once weekly PO). These agents can be used in lieu of or in addition to CSs. Hydroxychloroquine (dose 200 mg twice daily) has minimal toxicity and may have modest benefit as adjunctive therapy in selected patients with pulmonary or extrapulmonary sarcoidosis. Infliximab is reserved for severe cases refractory to CSs and these alternative agents. Novel medical therapies for sarcoidosis are discussed in detail by Drs. Baughman and Lower in this issue.

LT (either single or bilateral) is a viable option for patients with end-stage pulmonary sarcoidosis refractory to medical therapy.[198,351] Dr. Shah discusses LT for sarcoidosis in depth elsewhere in this issue.

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