|Year : 2021 | Volume
| Issue : 5 | Page : 47-57
Deepak Talwar1, Dhruv Talwar2, Hariharan Iyer1
1 Metro Centre for Respiratory Diseases, Noida, India
2 Department of Internal Medicine, JNMC, Wardha, Maharashtra, India
|Date of Submission||16-Apr-2021|
|Date of Acceptance||18-Aug-2021|
|Date of Web Publication||21-Dec-2021|
Dr. Deepak Talwar
Senior Consultant and Chairman, Metro Centre for Respiratory Diseases, Metro Hospitals and Heart Institute, Sector-11, Noida, UP
Source of Support: None, Conflict of Interest: None
Pulmonary sarcoidosis is an enigma due to its similarities with many other diseases in terms of presentation and hence the disease may require repeated reconsideration and revision of diagnosis. It is largely a diagnosis of exclusion. In India, exclusion of tuberculosis (TB) in every new suspected case of pulmonary sarcoidosis is a colossal task due to overlapping features and the high burden of TB. However, pulmonary sarcoidosis may be associated with extrapulmonary organ involvement, and in such cases, diagnosis can be made with greater certainty. Once diagnosed, whether to treat or not, and with what agent, and for how long are questions unsettled despite 150 years of the disease being known to mankind. This is due to a lack of randomized controlled trials as well as a dissimilar natural course of the disease among patients with a similar clinicoradiological presentations. This makes a generalization about treatment impossible and hence, individualized decisions need to be made utilizing predictors of future worsening by multidisciplinary experts. Oral steroids form the core of treatment but longterm side effects of oral steroids ultimately dictate the use of steroidsparing agents and discontinuation of steroids once the disease stabilizes and the goals of treatment are achieved. Some patients with a benign course of sarcoidosis may not require any treatment. There remains a gap in our knowledge of sarcoidosis, especially in the context of India, as it features as a common cause of interstitial lung disease and a close differential of TB. We need to intervene before the condition worsens, as this may reduce the survival significantly. However, this is not always possible and more research including longitudinal studies are needed to define and understand the course of the disease.
Keywords: Granuloma, non-casseating, pulmonary, sarcoidosis, steroid, tuberculosis
|How to cite this article:|
Talwar D, Talwar D, Iyer H. Pulmonary sarcoidosis. Indian J Rheumatol 2021;16, Suppl S1:47-57
| Introduction|| |
Sarcoidosis is an intriguing disease that fascinates physicians but can throw up surprises during the course. In India, a definite diagnosis of sarcoidosis is challenging due to overlapping features with tuberculosis (TB). Although sarcoidosis is a multisystem disease, pulmonary involvement is the most common cause of morbidity and mortality. The relationship between sarcoidosis and TB remains contentious with difficulty in distinguishing the two entities and was also stated in the earliest description of it by J Hutchinson in 1887 who thought it to be an unusual type of lupus. Despite the decades of research, the role of Mycobacterium TB in the etiopathogenesis of sarcoidosis remains unclear. Sarcoidosis was first reported in India by S K Gupta in 1982 but was considered rare till Jindal et al. elaborated on the difficulties in diagnosis and management, and since then, it is increasingly being diagnosed and reported. Corticosteroids are the first-line agents in the treatment of sarcoidosis and this may prove disastrous if TB is missed. Sarcoidosis blissfully does not have a progressive and fatal course in the majority and this review will focus on pulmonary sarcoidosis with emphasis on distinguishing it from TB and when and how to treat it especially in our country with a high burden of TB.
| Epidemiology|| |
The data on the prevalence of sarcoidosis varies across the world and is influenced by the high diagnostic dilemma and nonuniform reporting. The US reported a lesser prevalence in white people by 4–17 times, but the prevalence varies across continents from 1 to 160 cases per 100,000 people per year with the highest reported from Sweden and lowest from Japan., In blacks extrapulmonary sarcoidosis with multi-organ involvement is more common, leading to early death as compared to whites. Sarcoidosis has heterogeneous presentations across the world, varying with race, ethnicity, gender, age, etc., thus it appears that it has multi-factorial causation that includes genetic, environmental, and microbiological factors. Environmental insult in genetically predisposed with HLA allele, DQB1*0602 leads to progressive pulmonary sarcoidosis but more genes are likely to be linked to presentation and mortality in sarcoidosis.
In our country, thoracic involvement is the most common presentation, followed by skin and eye involvement while cardiac and neurological involvement has been reported infrequently. The data about mortality in sarcoidosis from the US and other countries indicates variable yet high risk for early death. Pulmonary involvement remains the most common cause for mortality in the world except in Japan where cardiac sarcoidosis is the most frequent cause of death. Long-term studies have revealed a higher risk of malignancies after 10 years of diagnosis of sarcoidosis and various malignancies have been reported, commonly lymphomas. Concurrent diagnosis of malignancy and sarcoidosis also needs to be considered.
| Etiopathogenesis|| |
Granulomatous inflammation plays a central role in the pathogenesis of sarcoidosis and a variety of antigenic stimuli are believed to be responsible. [Figure 1] depicts the pathogenesis of granuloma formation in sarcoidosis. Previous immune memory leads to a heightened response during relapses. Many clinical conditions caused by a variety of organic and inorganic antigens are characterized by similar granulomatous inflammation and hence one needs to rule out these causes. Though initiation of inflammation in sarcoidosis had been linked to the presence of a poorly degradable antigen, it did not stand the rigors of further research. Mycobacterium TB protein (mKatG protein) has been found in bronchoalveolar lavage (BAL) obtained from patients with sarcoidosis but “one disease, one cause” is yet elusive in sarcoidosis. Hence, sarcoidosis remains a diagnosis of exclusion. Surprisingly, it has been noted that ethnic populations with a higher incidence of TB also have a higher incidence of sarcoidosis and over a while, the prevalence of both the diseases is parallel.
| Clinicoradiological Presentation|| |
Sarcoidosis can affect any organ and even multiple organs at any point in time, sequentially or consecutively. Pulmonary disease is reported in almost all cases at some point in time. It may present with constitutional symptoms such as malaise, fatigue, anorexia, fever, and joint pains. Organ-specific presentations, for example, dry cough, breathlessness, or chest pain are reported in 30–50% and when present may be indicative of parenchymal or endobronchial involvement. Since, these symptoms are nonspecific, a diagnostic delay of over 3 months has been reported in the majority vis-a-vis extrathoracic presentations of sarcoidosis. Hemoptysis is rare and should lead to the consideration of an alternative diagnosis. Physical examination is usually inconspicuous even when radiologically lungs are affected significantly. Clubbing should also raise the possibility of an alternative diagnosis. Few clinical features are distinctive of sarcoidosis but none is specific for its diagnosis. Sarcoidosis in children is uncommon, but clinical presentations and outcomes are similar to adults.
A chest radiograph is usually the first investigation. It is abnormal in 90% with over two-third cases showing lymphadenopathy. However, the most important clue is the symmetrical involvement of hilar lymph nodes [Figure 2]a. Although asymmetric or bulging lymphadenopathy can be seen, conditions such as TB and malignancy should be considered strongly where they are seen. At presentation, mid and upper zone pulmonary opacities (i.e., nodules and reticulation) are seen in 20–50% of patients [Figure 2]b. The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidations [Figure 2]c. In late presentations, there may be only lung changes without lymphadenopathy, and here the diagnosis is more perplexing [Figure 2]d. However, asymptomatic patients with chest radiological abnormality with or without extrapulmonary sarcoidosis are the common scenario in practice. Bilaterally symmetrical hilar lymphadenopathy with or without pulmonary infiltrates has differentials of TB, lymphoma or fungal infections, and diagnosis is often expedited with the use of transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS) in our country.
|Figure 2: Radiographic stages of sarcoidosis (a) Stage 1, (b) Stage 2, (c) Stage 3, and (d) Stage 4|
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Scadding's staging system originally had Stages 1, 2, and 3 but has now been modified to add stage 0: No adenopathy or infiltrates and Stage 4: Pulmonary fibrosis [Figure 2]d, which provides prognostic information. Resolution of radiological findings is 90% in Stage 1 and 33% in Stage 3 at 2 years' follow-up, and treatment of sarcoidosis is effective only in patients with lung parenchymal involvement.
High-resolution computed tomography (HRCT) chest plays a key role in the diagnosis; being more sensitive and helps in the prognostication of a patient with pulmonary sarcoidosis. The classic pattern on HRCT is widespread, well-defined nodules with smooth or irregular margins measuring 2–5 mm in diameter, present in 80–100% of cases, even in patients with atypical radiological presentations. These nodules crowd around bronchovascular bundles, interlobular septa, interlobar fissures, and subpleural regions in line with the pathogenesis of sarcoid granulomas along the lymphatics [Figure 3]a and [Figure 3]b. Ground-glass opacities are uncommon and when present indicates fine fibrosis or very tiny nodules rather than alveolitis. Pulmonary fibrosis is seen in 20–25% of pulmonary sarcoidosis, has upper lobe predilection, with distortion of lobar architecture and volume loss with or without honeycombing [Figure 3]c and [Figure 3]d.
|Figure 3: High-resolution computed tomography findings in sarcoidosis: (a) small nodules, (b) peri-lymphatic distribution, (c) upper lobe fibrosis with bullous changes, and (d) upper lobe honeycombing|
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Large airways may show diffuse thickening due to submucosal disease but narrowing should be viewed with suspicion as lymph nodes are generally pliable. Small airways may be involved and seen as air trapping but it is not a predominant finding. Although atypical, mosaic attenuation, miliary nodules, macronodules (galaxy sign), consolidation, organizing pneumonia, cavitation, honeycombing, nonfissural distribution of the nodules, basal or peripheral predominance of the disease, and atypical lymphadenopathies are also seen in pulmonary sarcoidosis [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d.
|Figure 4: Uncommon findings in sarcoidosis: (a) miliary nodules with GGOs, (b) galaxy sign, (c) consolidation, and (d) organizing pneumonia|
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Lymph nodes in sarcoidosis are usually discrete, smooth, bilateral, symmetrical, and usually not associated with central hypodensity, whereas central necrosis and asymmetric conglomerate lymph nodes are classically described in TB, but such classical findings are not universal. A combination of more characteristic findings on imaging can be diagnostic of sarcoidosis, for example, peri-lymphatic micronodules with upper lobe distribution with bilateral symmetrical hilar and subcarinal lymphadenopathy [Figure 5]a, [Figure 5]b, [Figure 5]c, [Figure 5]d. Pleural effusions are rare but exudative, lymphocyte-predominant, similar to that seen in TB have been described in sarcoidosis as well.
|Figure 5: Atypical sarcoidosis (a) cavity, (b) mosaic attenuation, (c) cannon balls, and (d) pleural effusion|
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Presence of any of the following three clinical situations is fairly characteristic and a presumptive diagnosis can be made in these cases: (1) Asymptomatic young male with bilateral symmetrical hilar lymphadenopathy, (2) Lofgren syndrome, and (3) Heerfordt syndrome. However, to be more certain, a standard protocol of obtaining tissue diagnosis in appropriate clinicoradiological settings is warranted in all.
| Fluorodeoxyglucose positron emission tomography and gallium scan|| |
Positron emission tomography (PET) scan displays fluorodeoxyglucose (FDG) avid positivity in active granulomatous inflammation from sarcoidosis and is useful not only in determining active versus inactive disease and extent of extrathoracic involvement but also appropriate site to biopsy for tissue diagnosis. However, PET avidity is also seen in malignancy or TB. Hence, PET scans may not be of use in many cases except for guiding biopsies and are not routinely performed for the diagnosis of sarcoidosis. However, a PET scan can be useful in making therapeutic decisions and monitoring the disease, especially when biologic drugs are being used to demonstrate and target active disease [Figure 6]a, [Figure 6]b, [Figure 6]c, [Figure 6]d, [Figure 6]e.
|Figure 6: F-18 fluorodeoxyglucose positron emission tomography images in sarcoidosis (a) bilateral hilar and subcarinal lymphadenopathy with liver and spleen involvement (b) Mediastinal lymphadenopathy with peripheral lymph nodes in inguinal and neck region as well as parotid and liver involvement (c) hilar mediastinal lymphadenopathy with uptake in left ventricle (d) uptake in lungs “Lungs on fire” and (e) mediastinal uptake as “Burning mediastinum” signs|
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Gallium 67 scans show the classical “lambda sign” (right paratracheal and bi-hilar lymphadenopathy) in 72% and “panda sign” (parotid and lacrimal gland uptake) in 79% of selected patients and both have been reported in 62% of patients with sarcoidosis. However, they are neither specific as they may be seen in HIV, Sjogren's syndrome, SLE, lymphoma, and after radiation in head-and-neck malignancies and nor sensitive.
| Biomarkers|| |
Serum angiotensin-converting enzyme (ACE) is a membrane-bound glycoprotein expressed by epithelial cells of many tissues but most abundant on the luminal surface of vascular endothelium, pulmonary epithelium, epithelioid cells of sarcoid granulomas, alveolar macrophages, and converts angiotensin I to angiotensin II. Polymorphisms of the ACE gene with insertion or deletion in its gene may lead to the changes in the serum ACE levels in both normal beings and patients with sarcoidosis. Less than 50% of sarcoid patients (60% in acute and 10% in chronic cases) have raised serum ACE levels and it is also elevated in TB, lymphoma or atypical mycobacterial infections mimicking sarcoidosis. Normal serum ACE levels do not exclude sarcoidosis, while raised levels can only be of supportive value when clinicoradiological findings are highly suggestive of sarcoidosis. Hence, it is of little value in distinguishing sarcoidosis from other diseases. Differences between available commercial kits with variable reference limits and their quality makes the test less reliable. No absolute cutoff value has high sensitivity and specificity for the diagnosis of sarcoidosis. Serum ACE levels do not correlate with disease activity or predictably change with corticosteroids; hence, it is not recommended for monitoring.
| Mantoux and Interferon Gamma Assays|| |
Sarcoidosis patients exhibit depressed delayed hypersensitivity manifesting as cutaneous anergy to tubercular antigen. This is demonstrated even in countries with a high prevalence of TB. This tuberculin anergy is commonly utilized as a diagnostic tool and is seen in active sarcoidosis which disappears with disease inactivity and a positive test may suggest an alternative diagnosis. A negative test at a cutoff of 10 mm reaction to 5TU purified protein derivative (PPD) has high sensitivity (90%) for sarcoidosis in appropriate settings. However, a negative tuberculin test does not exclude TB, as it may be negative in immunocompromised cases. Although Mantoux test (MT) is negative in 90% of cases of sarcoidosis, it is also negative in 6–35% of cases of TB. Similarly, positive MT is seen in up to 40% of cases of sarcoidosis due to coexistent TB or in a patient with sarcoidosis with a history of TB.
Interferon-gamma release assays (IGRAs) have a higher sensitivity and specificity for detecting MTB infection than the conventional tuberculin skin test (TST), as they utilize antigens specific for the MTB complex. A positive IGRA, just like a positive PPD response, does not mean active TB infection and indicates exposure to tuberculous bacteria. IGRA continues to remain positive in patients with active sarcoidosis as only cutaneous anergy is reported in them. Hence, IGRA is better than TST in detecting latent TB infection in patients with sarcoidosis and has been reported in 29% of sarcoidosis patients.
| Xpert Mycobacterium tuberculosis|| |
Molecular genetic studies involving real-time polymerase chain reaction (PCR) methodology have been tested to distinguish between sarcoidosis and TB on tissue samples obtained on biopsy of involved organs for DNA of MTB. However, its simple presence does not distinguish between active and latent TB and hence is not helpful in the diagnosis in countries with a high prevalence of TB. However, quantitative real-time PCR assays by the same authors have been shown to distinguish between TB where multiple copies are demonstrable in TB versus a low number of copies in sarcoidosis. Although it is recommended to do Gene X-pert on all aspirated or biopsied material, it was reported to have similar sensitivity, specificity, positive and negative predicted value in comparison with the tuberculin test.
Pulmonary Function Test
Typical lung functions show restrictive ventilatory defect with a low diffusing capacity, but airflow obstruction has been more prevalent in some sarcoidosis groups and all radiological stages. More advanced sarcoidosis more commonly exhibits mixed ventilatory defects. An isolated reduction in DLCO is also a common abnormality seen on pulmonary function testing. Lung physiology moderately correlates with CT radiographic findings and DLCO has a predictive role in future worsening as well as progression.
| Diagnostic Approach|| |
At present, the diagnosis of sarcoidosis is made in the context of appropriate clinicoradiological findings, supported by histopathological evidence of noncaseating granuloma with alternative etiologies ruled out. Obtaining tissue for pathological confirmation in pulmonary sarcoidosis is invariable from intrathoracic lymph nodes or lung tissue obtained through bronchoscopy with its ancillaries. However, cervical lymph nodes, skin lesions or hepatic lesions if present, can be sampled and help in a more certain diagnosis. American Thoracic Society guidelines [Table 1] consider sarcoidosis as being highly probable versus probable based on clinical, radiological, or laboratory findings reliant on their relatively commonality and specificity in sarcoidosis, although multiple features at the presentation from this list secure the diagnosis of sarcoidosis with more certainty. Certain baseline evaluations as enlisted in [Table 2] are recommended even in asymptomatic pulmonary sarcoidosis patients.
|Table 1: Clinico-radiological findings with laboratory results which if present in newly suspected case of sarcoidosis, are indicative of either highly probable or probable to be associated with sarcoidosis|
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|Table 2: Extra pulmonary organ screening test recommended even if asymptomatic in newly diagnosed case of pulmonary sarcoidosis|
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|Table 3: Suggested treatment in various stages of pulmonary sarcoidosis as per available evidence from research|
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| Fiber-optic Bronchoscopy: Endobronchial, Conventional Blind Transbronchial Needle Aspiration, and Transbronchial Lung Biopsy|| |
This is a tool to sample endobronchial tissue, lung parenchyma, or mediastinal lymph nodes. It is the standard investigation in a suspected case of sarcoidosis. The choice of diagnostic procedure depends on the pretest level of confidence in making a diagnosis of sarcoidosis and the stage of sarcoidosis on CT scans. An endobronchial biopsy is the safest and easiest to perform with positivity in >70% in cobblestone appearing mucosa but ~30% in normal looking airways, hence should be taken in all cases irrespective of appearance of airways. In symptomatic cases with isolated intrathoracic lymphadenopathy, either of conventional (blind) or EBUS-guided biopsy has a success rate of ~80%, while the diagnostic yield of conventional transbronchial lung biopsy (TBLB) is around 70%., In patients with involvement of both lymph nodes and lung parenchyma (considering the spectrum of differential diagnoses), TBLB (preferably cryo-biopsy) and bronchoalveolar lavage might reveal unexpected findings leading to alternative diagnoses (hypersensitivity pneumonitis) and should be pursued.
| Real-time Endobronchial ultrasound (EBUS) and Transoesophageal Endoscopic ultrasound (EUS) guided aspiration|| |
Endobronchial ultrasound has revolutionized sampling of mediastinal and hilar lymph nodes in the present century and has become the main tool in the diagnosis of pulmonary sarcoidosis in Stages 1 and 2. Esophagal endoscopic real-time ultrasound-guided needle aspiration (can be done using the same EBUS bronchoscope. Individual studies and meta-analyses of heterogeneous groups of patients have shown overall diagnostic accuracy exceeding 80%. This is surprisingly less than expected and hence combining with TBLB and endobronchial biopsy irrespective of whether involved or not on imaging or visual inspection increases the diagnostic yield to above 86% as reported by Gupta et al.
| Transbronchial Cryo-Lung Biopsy|| |
This is an innovative technique being used in the diagnostic workup of interstitial lung diseases (ILD) and has been used in the diagnosis of pulmonary sarcoidosis with a diagnostic sensitivity of 67%, similar to that by EBUS alone but by combining both procedures it is reported to be ~100%. As expected, transbronchial lung cryobiopsy scores over EBUS (67% vs. 11%) in nonsarcoidosis patients with parenchymal abnormalities on CT scans.
| Histopathological Diagnosis|| |
Bronchoalveolar lavage shows CD4-positive T-helper 1 lymphocytic response though 10–15% have normal cell counts. Increased ratio of CD4+/CD8+ lymphocytes (>3·5:1) is seen in 50–60% of active sarcoidosis, but its specificity varies depending upon the radiographic stage of disease and hence has a disputed role in diagnostic work of pulmonary sarcoidosis.
Pathology shows characteristic compact, nonnecrotizing granulomas, composed of epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate and clustered along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles [Figure 2]a. Conventionally, giant cells contain intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates [Figure 7]a, [Figure 7]b, [Figure 7]c. The normal lung is seen in uninvolved areas. In chronic sarcoidosis, lymphocytes are sparse while increasingly fibrotic changes in the lung are observed. Granulomas enlarge and form hyaline nodules rich with dense eosinophilic collagen. Multiple bronchial, transbronchial biopsies or lung cryobiopsy, as well as serial sectioning of biopsies, might increase the diagnostic yield.
|Figure 7: Characteristic “Granuloma” in sarcoidosis (a) naked, compact perivascular, non-caseating granuloma on biopsy (b) loose nonnecrotizing granuloma from EBUS sample (c) granuloma with inclusion bodies and giant cells on tru-cut lung biopsy|
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Necrosis is the most contentious finding in granuloma which pushes pathologists' decision toward TB, especially in our country. However, central, pink fibrinoid necrosis is reported in 20% of sarcoidosis and nonnecrotizing granulomas are reported in 24% of TB. Besides mycobacterial diseases, necrosis is also seen in granulomas due to fungal infections, vasculitis, or chronic aspiration. Characteristic cytoplasmic inclusions being described with exotic names and descriptions in sarcoidosis too can be seen in reaction to exogenous material as well as aspiration or intravenous drug abuse. Mycobacterial and fungal workup by PCR test as well as conventional smear and cultures is recommended in all cases to rule out infective etiologies with similar pathology. Therefore, even when the clinical presentation is highly consistent with sarcoidosis and alternative diagnoses unlikely, one should investigate comprehensively and exclude other causes.
| Sarcoidosis Diagnostic Scoring|| |
Sarcoidosis diagnostic score (SDS) proposed by Bickett et al. defined SDS clinical as well as SDS biopsy prediction scores from the cohorts of biopsy-proven cases of sarcoidosis. SDS biopsy score of >6 had sensitivity and specificity of 99.3% and 100% respectively, although SDS clinical score showed much less sensitivity as well as specificity. To expand the use of SDS to countries with a high burden of TB, a multinational study was done and included India to evaluate SDS clinical and biopsy scores in differentiating sarcoidosis from other granulomatous diseases. It revealed poor sensitivity (72.3%) and high specificity (98.6%) for clinical score but very low specificity (28.9%) and high sensitivity (100%) for biopsy score at same cutoffs. More comprehensive scoring systems including radionuclide results have been reported with a good discriminative value between smear-negative TB and sarcoidosis. It is of special relevance for Asian countries but is complicated.
| Predicting Prognosis in Pulmonary Sarcoidosis|| |
Baseline HRCT is the main tool to predict future prognosis in pulmonary sarcoidosis. To identify patients at high risk of mortality, Walsh et al. corroborated composite physiological index (CPI) incorporating forced vital capacity, DLCO, FEV1 and HRCT variables (extent of pulmonary fibrosis and diameter of the main pulmonary artery) and reported cutoff of 40 units as a demarcation between good and bad prognosis. However, even in patients with relatively preserved spirometry (CPI <40), the ratio of the diameter of the main pulmonary artery to that of ascending aorta being >1, or the presence of extensive fibrosis on HRCT significantly increased the risk of mortality.
| Treatment|| |
Treating physicians need to keep in mind that most patients with pulmonary sarcoidosis do not require treatment as either they are asymptomatic or they will have a self-limited or non-progressive disease. Hence, the most important message is that “Diagnosis of Pulmonary sarcoidosis is not sufficient to initiate treatment.”
The goal of treatment in sarcoidosis is to suppress, reduce or limit the burden of granulomatous inflammation. This principle is based on a caveat that persistent, uncontrolled inflammation may progress to cause irreversible fibrosis with resultant lung damage in cases with pulmonary sarcoidosis. Oral corticosteroids remain the backbone of therapy, although steroids do not cure sarcoidosis. Immunomodulatory and cytotoxic drugs are used in patients who either fail to respond or cannot tolerate steroids or as steroid-sparing agents in responsive patients who require long term treatment. Sarcoidosis is more common in nonsmokers and smoking has been reported to be protective in the development of sarcoidosis.
Intention to treat should take in to account the possibility of a spontaneous resolution reported in 20% of stage 2 and 3 diseases over six months weigh up watchful observation vis-a-vis the risk of therapy-induced side effects. Once corticosteroid therapy is started, it generally has to be continued for a long time to prevent relapses. Further complicating this issue is the fact that there is no evidence to suggest that therapy prevents progression or fibrosis in pulmonary sarcoidosis and there are no clear predictors to decide on long term therapy.
| Indications and Duration of Treatment|| |
Broadly, the main indications for the treatment of sarcoidosis are either life-threatening and organ-threatening disease or unacceptably impaired quality of life, both being contentious in pulmonary sarcoidosis due to the lack of robust evidence. Therefore, indications for treatment based on expert opinion are as follows:
- Worsening respiratory symptoms, principally dyspnea
- Severe or significant pulmonary function impairment (i.e., ≥10% reduction in forced vital capacity or ≥15% reduction in DLCO from baseline values) or
- Major radiological progression (i.e., development of cavities or honeycomb changes, or substantial worsening of interstitial abnormalities).
Once initiated, the duration is 9–12 months or longer as per disease behavior. Relapses dictate long-term treatment, but lack of clearly defined goals in every patient leads to prolonged treatment with serious side effects. Type of presentation may give clue to a more predictable duration of treatment, for example, in erythema nodosum, stage 1 disease, ocular involvement while more fibrotic changes in the lung may require close monitoring regarding risk versus benefit in continuing therapy beyond a certain period. Lung parenchymal involvement is the most frequent indication for prolonged treatment in sarcoidosis.
Often treatment is initiated due to the symptoms of cough, chest pain, weight loss, arthralgias, low fever, etc., interfering with the quality of life and here the aim is to make the patient feel better and thus treatment should be tapered off quickly in such cases. However, in the absence of a high burden of systemic disease, one should look for symptomatic treatment to make the patient feel better and evaluate the need on an individual case basis. Fatigue is multifactorial in origin, is difficult to tackle and neuro-stimulants may help.
| Steroids and Immunosuppressives|| |
Oral steroids are recommended in Stage 2–4 symptomatic pulmonary disease and second-line drugs are generally required for patients who experience progressive disease despite corticosteroid treatment or are not able to tolerate corticosteroids or as steroid-sparing agents in relapsing cases [Table 1]. In a retrospective cohort study those treated with corticosteroids had a significantly higher number of adverse effects, for example, diabetes, hypertension, weight gain, hyperlipidemia, eye, and bone effects than those who did not get steroids. The most common alternative strategies include antimetabolites and cytotoxic drugs (i.e., methotrexate, azathioprine, leflunomide, and mycophenolate mofetil) the monoclonal anti-tumor necrosis factor alpha (TNFα) antibody infliximab. These drugs are used as corticosteroid-sparing agents either alone or in combination with low-dose corticosteroids and may have other added benefits.
Comparing methotrexate and azathioprine as the second line therapy, a retrospective study showed more infections in the azathioprine group with similar efficacy. However, potential hepatic or pulmonary toxicity of methotrexate needs to be kept in mind and appropriate monitoring is recommended. Mycophenolate Mofetil use is limited to patients who either fail to respond to or experience adverse effects from methotrexate and azathioprine. Leflunomide can be used as a steroid-sparing agent where methotrexate, mycophenolate, or azathioprine cannot be used because of intolerance or contraindication.
| Biologicals|| |
TNFα antagonists are generally reserved for refractory sarcoidosis with patients showing persistent disease despite treatment with corticosteroids and at least one second-line immunosuppressant agent, especially when there is organ-threatening or life-threatening disease. In chronic pulmonary sarcoidosis, infliximab has been shown to statistically significantly improve lung functions versus placebo. There are data to advocate its use in active (and steroid-resistant) pulmonary disease assessed by 18F-FDG PET scans where a mean improvement of 6.6% in the percentage of predicted FVC was reported. Since FDG uptake correlated strongly with the improvement of lung functions after infliximab, it may be beneficial to identify likely responders on PET scans while taking a call to initiate anti-TNFα agents in refractory pulmonary sarcoidosis.
| Antifibrotics|| |
Pulmonary sarcoidosis in Stage 4 may show only fibrosis and it progresses despite treatment from an early stage with steroids and/or immunosuppressives. Antifibrotics (pirfenidone and nintedanib) may be considered in patients satisfying the criteria for progressively fibrosing ILD (clinical, radiological, functional worsening despite adequate therapy). Both antifibrotics drugs though approved in IPF have recently been shown to be effective in non-IPF fibrosing-ILDs which progress despite appropriate therapy. Sarcoidosis related ILDs were also included in the INBUILD trial. Pirfenidone is also expected to have similar benefits, but the evidence is awaited to date.
| Monitoring Response in Pulmonary Sarcoidosis|| |
The optimal tools and timing to assess response to treatment in patients with pulmonary sarcoidosis have not been established. According to expert opinion, however, assessing the response to therapy is a multidisciplinary exercise, requiring assessment of symptoms, physical examination, imaging, and pulmonary function tests. As such, a favorable response to treatment is generally defined by an improvement in symptoms, a reduction or clearing of radiographic abnormalities, and physiological improvement (e.g.: an increase in forced vital capacity ≥10% or an increase in DLCO ≥15% from baseline values). Physiological changes correlate more closely with HRCT findings than chest X-rays and discordant DLCO should raise the possibility of sarcoid associated pulmonary hypertension (SAPH). Large proportion of patients undergo spontaneous remission, and the apparent treatment effect might simply mirror the natural course of the disease.
| Complications of Pulmonary Sarcoidosis|| |
Advanced pulmonary sarcoidosis occurs in about 5% of cases but is responsible for the largest share of illness and death. Besides SAPH, infections (fungal, TB) are common. Acute worsening in advanced fibrosing sarcoidosis is a reality and infection, bronchospasm, heart failure, etc., have been reported. Such worsening in advanced fibrotic sarcoidosis has been reported 2 or more times/year in 73% of cases but mostly responds to antibiotics and steroids.
Aspergillus-related complications have been reported in Stage 4 sarcoidosis in 3–12% of cases and are identified by the characteristic findings on chest imaging with upper lobes being more affected by fibrosis in advanced pulmonary sarcoidosis. TB is always a threat in clearly diagnosed cases of sarcoidosis too in India and there is a proposed possibility of both diseases starting concurrently.
| Conclusion|| |
Pulmonary sarcoidosis has variable clinical as well as radiological presentations, but sarcoidosis related pulmonary fibrosis which progresses accounts for most of the morbidity and mortality. The spontaneous resolution makes it impossible to accurately predict the future course of disease in all, and complete and thorough evaluation with very careful observation, monitoring, and long-term follow-up is required in all cases. Every newly diagnosed case of pulmonary sarcoidosis is a challenge and needs individualised decision making for its management. A multidisciplinary team approach appears to be prudent for this disease. The use of immunomodulation and biologicals also requires a team of experts as these therapies may stabilize progressive fibrotic sarcoidosis, but also have the potential to predispose to life-threatening infections.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]