Pulmonary/Thoracic Sarcoidosis by Dr. Malik Umer Farooq What is pulmonary sarcoidosis? Sarcoidosis is a rare disease caused by inflammation. It usually occurs in the lungs and lymph nodes, but it can occur in almost any organ. Sarcoidosis in the lungs is called pulmonary sarcoidosis. It causes small lumps of inflammatory cells in the lungs.

1. Pulmonary Sarcoidosis
Dr Malik Umer Farooq
(Pakistan)

2. Definition 1
A chronic, progressive, generalised, granulomatous reticulosis involving
almost any organ or tissue, characterized by hard tubercles. (Dorland’s
Pocket Medical Dictionary 29th Edition)
Reticulosis: Abnormal overgrowth, usually malignant, of any of the cells
of the lymphatic glands or the immune system.

3. Definition 2
• A multi-system disorder of unknown cause, likely resulting from the
the interplay of environmental and genetic factors
• Characterized by non- caseating granulomata and CD4+ Th-biased T Cell
response in affected organs
• Commonly involves the respiratory system but can affect nearly
all organs
• 50– 60% of people have spontaneous remissions; others may develop
chronic, and sometimes progressive, disease.
(Ref: Oxford Handbook of Respiratory Medicine 4th Edition)

4. Aetiology
It is a result of an abnormal immunological response to a benign
environmental trigger(s) or antigen(s).
The environmental trigger is likely a poorly degradable antigen but
not a specific antigen or infectious agent.
 This abnormal immunology occurs in a genetically predisposed host.

5. Genetics
ACCESS (A large multicentre study) was done which showed
evidence of Human Leukocyte Antigen association.
It showed HLA-DRB1*1101 is associated with susceptibility
to disease in blacks and whites; HLA-DRB1*0301 has been
associated with acute and remitting disease.
Genome-wide association studies have identified
polymorphisms in BTNL2, ANXA11, and FAM178A as
susceptibility genes in both familial and sporadic cases.

6. Immunopathology
Unknown antigen triggers CD4 (helper) T- cell activation and expansion → This
response is exaggerated and Th1- biased, with resultant interferon γ and IL2
production from these T- cells → Activated T- cells proliferate and release
mediators, attracting additional inflammatory cells with concomitant macrophage
activation and aggregation → Immune granuloma formation (enhanced by
interferon γ)
Granulomata cause increased local fibroblast stimulation and hence → eventual
fibrosis
The metabolic activity of macrophages causes raised angiotensin-converting
enzyme (ACE levels in serum, lung tissue, and bronchoalveolar fluid).
An increase in T- cell activity causes B- lymphocyte stimulation, which can
cause raised serum immunoglobulins and immune complexes
In most patients, these immune responses resolve over 2– 5 y.

7. Granuloma on a Lung Biopsy and other Areas

8. Description
a. Lung biopsy with 3 granulomas (arrows). b. Lung biopsy with central
necrosis (*), macrophages (**), and smaller, non-necrotizing
granulomas (***). c. Lung biopsy with suppurative (neutrophilic)
central necrosis. d. Cecal biopsy under low power (arrow indicates
poorly formed granuloma). e. Cecal sections with acute cryptitis with
crypt abscess. f. Cecal sections under high power with poorly formed
granuloma. Arrow, macrophages. * Eosinophils.

9. Differential Diagnoses of Granuloma on Lung
Biopsy
Sarcoidosis
Tuberculosis
EGPA (Eosinophilic granulomatosis with Polyangiitis)
Hypersensitivity Pneumonitis
NTM Infection (Non-tuberculous mycobacteria Infection)
Drug Reactions (cocaine, cromolyn (a mast cell stabilizer used in bronchial asthma and
allergic eye conditions), fluoxetine, methotrexate, nitrofurantoin, pentazocine (an opiate
analgesic), and procarbazine (chemotherapeutic agent used for the treatment of
Hodgkin’s Lymphoma and brain cancer))
Fungal Infections (Aspergillosis, Coccidioidomycosis, and Cryptococcosis)
Aspiration of Foreign Material
Primary Biliary Cholangitis (Bile ducts in the liver are slowly destroyed)
Sarcoid-like reaction to Malignancy (Lymphoma, Cervical Cancer, Liver Cancer, Lung
Cancer, Testicular Carcinoma, Uterine Carcinoma)

10. Thoracic/Pulmonary Sarcoidosis
Clinical Features:
More than 90% of people with Sarcoidosis have thoracic involvement
with an abnormal Chest Radiograph.
• Pulmonary sarcoidosis can be an incidental CXR finding in ~30% of
patients.
• There is spontaneous remission in two-thirds, and 10– 30% have a
chronic course.

11. Scadding Radiological Classification of Thoracic Sarcoidosis

12. Scadding
Radiological
Classification of
Thoracic
Sarcoidosis
Cont.

13. Clinical Pearls
 Stage I: 85% resolve spontaneously over 2 y; 15% develop lung
infiltrates.
 The average time for bilateral hilar lymphadenopathy resolution is
8 months.

14. Interstitial Lung Involvement
May be asymptomatic or cause morbidity and mortality, with
dyspnoea, cough, chest ache, or frank pain, malaise, fatigue, and
impaired quality of life (QoL). Rarely have crackles or clubbing on
examination.
Pulmonary infiltrates on CXR:
Can return to normal over time or progress to fibrosis and respiratory
failure. Lung function tests may be normal or may show a restrictive
defect with a reduced transfer factor.
Differential diagnosis
• Other interstitial lung disease (ILD), malignancy, infection.

15. Clinical Courses
1. Löfgren’s syndrome
2. Persistent or progressive infiltrative lung disease
 Löfgren’s syndrome:
An acute, usually self-limiting disease characterized by fever, bilateral
hilar lymphadenopathy, arthralgia, and erythema nodosum.
Occurs particularly in Caucasians. Has a good prognosis and resolves
completely and spontaneously in 80% within 1-2 years. A minority may
develop lung disease.

16. Erythema Nodosum

17. Erythema
Nodosum
Mnemonic

18. Erythema Nodosum Definition
 Erythema nodosum (EN) is a common acute nodular septal
panniculitis, characterized by the sudden onset of erythematous,
firm, solid, deep nodules or plaques that are painful on palpation and
mainly localized on extensor surfaces of the legs.
Panniculitis: Panniculitis (inflammation of the subcutaneous fat) is a
relatively uncommon condition that usually presents with
inflammatory nodules or plaques. A wide variety of subtypes of
panniculitis exist, including panniculitides related to infection, external
insults, malignancy, and inflammatory diseases

19. Hilar/Mediastinal Lymphadenopathy
Usually bilateral and symmetrical; rarely unilateral and asymmetrical.
(If so, then other differentials such as primary tuberculosis, oat cell
carcinoma, pulmonary arterial aneurysm/stenosis etc)
There may be associated malaise and arthralgia which can be
managed with NSAIDs.
May Need CT and/or lymph node aspiration/biopsy.
Doesn’t require systemic steroid treatment

20. Differential Diagnoses of B/L Hilar
Lymphadenopathy on CXR:
• Sarcoidosis
• Tuberculosis
• Lymphoma
• Lung cancer, especially small cell lung cancer (SCLC)
• Coccidioidomycosis and histoplasmosis
• Berylliosis
• Mycoplasma
• Hypersensitivity pneumonitis

21. Case courtesy of Mohammadtaghi Niknejad,
Radiopaedia.org, rID: 21198
CXR Showing B/L Hilar Lymphadenopathy

22. What to do when a person with possible
Sarcoidosis comes to your clinic?
 Make a diagnosis clinically, do HRCT and/or on histological grounds.
 Assess the presence/extent/severity of extrapulmonary involvement
by doing the following investigations: CBC, CXR, PFTs, ECG, slit-lamp
examination, RFTs, serum calcium, LFTs, Immunoglobulin assay, and
ACE. (Immunoglobulins and ACE can be raised in active sarcoidosis)
Determine if the condition is stable or progressive? Do CBC, CXR, PFT
(VC ± kCO), oximetry, ACE, and urea (if renal involvement)
Plan for treatment

23. Diagnosis & Monitoring
Diagnosis is based on a characteristic clinical picture, plus:
• Histological evidence of non-caseating granuloma in any tissue
• Characteristic picture on imaging (thoracic high-resolution computed
tomography (HRCT) scan or gallium scan)
• Lymphocytosis on bronchoalveolar lavage (BAL).
Other diseases capable of producing similar clinical and histological
picture, particularly TB and lymphoma should be excluded

24. Investigations for Sarcoidosis
 HRCT Chest:
• Micronodules in a subpleural and broncho-vascular distribution.
• Fissural nodularity and bronchial distortion. Irregular linear opacities, ground-glass shadowing related to
broncho-vascular bundles, and nodular or ill-defined shadows.
• Air trapping due to small airway granulomata is common.
• Endobronchial disease in 55%.
• Minority has a usual interstitial pneumonia (UIP) pattern, associated with a worse prognosis.
• Hilar and mediastinal lymphadenopathy.
• UIP pattern:
 honeycombing is the distinguishing feature of UIP and must be present. +/- traction bronchiectasis.
 reticular abnormalities.
 distribution: subpleural with a basal predominance.
 absence of features suggestive of an alternative diagnosis.

25. UIP vs NSIP Video

26. Investigations for Thoracic Sarcoidosis Cont.
 CT- guided biopsy of nodes yields a tissue diagnosis
 Bronchoscopy: TBB, TBNA (Transbronchial Needle Aspiration), Bronchial Biopsy,
EBUS Biopsy, or BAL may not be necessary if there is no diagnostic doubt.
However, it can help exclude infectious agents.
• Positive yield of endobronchial biopsy is 40– 60%. It is higher if there is visible abnormal mucosa.
• The positive yield of TBB is 40– 90% (yield still high even if lungs appear normal on HRCT). It is the initial
procedure of choice for suspected pulmonary sarcoidosis.
• TBNA of mediastinal lymph nodes yield a diagnosis in 60– 90% of cases.
• TBB and TBNA have a higher yield together than either alone. However, the presence of non-caseating
granulomas on TBB or bronchial biopsy is more significant than on lymph node sampling, as granuloma can
accompany tumour infiltration of lymph nodes.
• BAL in sarcoidosis shows a CD4:CD8 ratio of >3.5. A BAL lymphocytosis supports the diagnosis but is not
diagnostic (also seen in hypersensitivity pneumonitis (HP) and drug-induced alveolitis).

27. Investigations for Thoracic Sarcoidosis Cont.
Mediastinoscopy for central or paratracheal nodes or open lung
biopsy: 90% positive yield.
May be necessary to exclude lymphoma, or if the diagnosis is uncertain and no
result/non-accessible nodes for EBUS and TBNA.
Lymph node ± lung can be biopsied (usually via video-assisted thoracoscopic
surgery (VATS))
Biopsy other affected areas such as skin, liver, etc., if indicated, as these may be
easier to biopsy in order to make a diagnosis
 Mantoux/ Heaf test is typically grade 0 in sarcoidosis (peripheral cutaneous anergy to tuberculin due to
migration of T- cells to active sites of disease). Positive Mantoux or Heaf test make sarcoidosis a less likely
diagnosis although does not necessarily make TB more likely.
Heaf testing is not widely used now.

28. Mantoux and Heaf Testing (Heaf Testing no
Longer Done)

29. Monitoring of Disease
Clinical Assessment and serial measurement are keys to monitoring of disease
It includes the following tests:
• PFT→ Restrictive defect with decreased VC and TLC. TLCO provides the most sensitive
measure of change
• CXR→ may improve with time or treatment
• HRCT→ can help with the determination of active disease
• Serum Calcium→ May rise in active sarcoidosis or summer months. Hypercalcemia may
cause renal impairment so RFTs must be checked. Calcium and vitamin D
supplementation are not recommended if bone protection for osteoporosis prevention is
being considered. (Bisphosphonates are recommended)
• BAL→ Reduction in BAL Lymphocytosis suggests improvement.
• PET Scan→ May be positive in areas of disease activity except for the brain and heart.

30. Management of Pulmonary Sarcoidosis
Most patients with Pulmonary Sarcoidosis don’t require treatment.
Asymptomatic CXR infiltrates are usually just monitored.
The most recent BTS guidelines for Sarcoidosis were released in 2008

31. BTS Guidelines for Pulmonary Sarcoidosis
(2008)
 Because of the high rate of spontaneous remission, treatment is not indicated for asymptomatic stage I
disease
 Because of high rates of remission, treatment is not indicated in asymptomatic stage II or III diseases with
mildly abnormal lung function and stable disease
 Oral corticosteroids are the first line of therapy in patients with progressive disease determined by radiology
or lung function, significant symptoms, or extrapulmonary disease requiring treatment
 Treatment with prednisolone (or equivalent) 0.5 mg/kg/day for 4 weeks, then reduced to a maintenance
dose which will control symptoms and disease progression, should be used for a period of 6– 24 months
 Bisphosphonates should be used to minimize steroid-induced osteoporosis
 Inhaled corticosteroids, either as initial treatment or maintenance therapy, are not of significant benefit.
They may be considered for symptom control (cough) in a subgroup of patients
 Other immunosuppressive or anti-inflammatory treatments only have a limited role but should be
considered in patients when corticosteroids are not controlling the disease or side effects are intolerable. At
present, methotrexate is the treatment of choice

32. BTS Guidelines for Pulmonary Sarcoidosis
(2008) Cont.
Lung transplantation should be
considered in end- stage
pulmonary sarcoidosis.

33. Starting the Treatment
 When required, treatment is usually with steroids initially. Good evidence for short- to medium-term
improvement in symptoms, respiratory function, and radiology, but long-term benefits are less clear
 Give high doses, such as 30 mg prednisolone/ day, to control active disease. Rarely need >40 mg/ day.
Usually give this high dose for 2– 3 weeks, and then reduce if there has been a clinical response
 Maintenance dose of around 5– 20 mg to control symptoms and prevent progression of the disease. Leave
on this dose for a few months, then slowly reduce the steroid dose. Maintain a low dose of prednisolone (5–
7.5 mg/ day or alternate days) for prolonged periods of up to 12 months to consolidate resolution, before
considering complete withdrawal. Remember bone protection with a bisphosphonate (avoid routine calcium
and vitamin D supplementation)
 Some patients, e.g., with progressive pulmonary sarcoidosis, may require longer treatment (years) of low-
dose prednisolone to prevent relapse
 Inhaled steroids are of limited efficacy in sarcoidosis but may be useful if there is cough or bronchial
hyperreactivity
 Relapses often occur when treatment is stopped and may require the reintroduction of steroids or the
increase of steroid dose. Duration and dose of steroids is dictated by site and response to treatment

34. Treatment Cont.
 If steroid treatment fails or sarcoidosis is life-threatening, other immunosuppressive regimes may be
indicated e.g., pulsed high-dose intravenous (IV) methylprednisolone, especially for neurosarcoidosis
 In cases where prolonged immunosuppression is required, or if steroid side effects cannot be tolerated,
other immunosuppressive drugs should be considered. Possibilities include azathioprine and methotrexate.
There is limited data for their use in sarcoidosis
 Patients who have troublesome symptoms related to sarcoidosis, such as arthralgia, skin disease, fever,
sweats, ocular symptoms, and systemic symptoms such as fatigue, may require symptomatic steroid
treatment. Lower initial doses, such as 20 mg/day, are likely to be sufficient to gain symptomatic control, and
doses can then be reduced.

35. Indications for Immunosuppressive Treatment
 Increasing symptoms, deteriorating PFTs, and worsening CXR infiltrates
 Cardiac sarcoidosis
 Neurosarcoidosis
 Sight-threatening ocular sarcoidosis
 Hypercalcaemia
 Lupus pernio: Lupus pernio is a chronic raised indurated (hardened) lesion of the skin, often purplish in
colour. It is seen on the nose, ears, cheeks, lips, and forehead. It is the pathognomic of sarcoidosis.
 Splenic, hepatic, or renal sarcoidosis.

36. Cutaneous lesions of sarcoidosis (lupus pernio). Red-to-purple
indurated plaques and nodules affecting the nose and cheeks.

37. Treatment Cont.
Other drugs used in Sarcoidosis:
• Indicated If there is progressive pulmonary sarcoidosis refractory to
steroids
 Methotrexate Given once/week 10– 15 mg PO for 6- month trial. Use instead of, or in addition to, low-dose
prednisolone. Avoid if there is hepatic or renal failure. Side effects: gastrointestinal (GI) upset, stomatitis,
pneumonitis, myelosuppression. Teratogenic. Monitor FBC and mean corpuscular volume (MCV), aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) every 2 weeks for 3 months, then monthly.
• Do not use for >2 y without review. Useful for chronic sarcoidosis and cutaneous disease
 Azathioprine Used in neurosarcoidosis and stages II/ III pulmonary sarcoidosis with partial/no steroid response.
100– 150 mg/day. Use instead of, or in addition to, low-dose prednisolone.
• Side effects: myelosuppression, GI upset, stomatitis, idiosyncratic reaction— fever, rash. Low oncogenic potential.
No gonadal toxicity.
• Check FBC every 2 weeks for 3 months, then monthly.
• Thiopurine methyltransferase (TPMT) testing should be performed prior to the commencement

38. Other Drugs used in Sarcoidosis Cont.
 Anti-malarials Hydroxychloroquine 200 mg od/ bd. For skin and particularly hypercalcemia.
• Steroid-sparing. Can be given with steroids and another immunosuppressant in severe sarcoidosis.
Side effects: rarely ocular toxicity
 Others: Leflunomide (an immunosuppressive DMARd), ciclosporin (a calcineurin inhibitor, used as an
immunosuppressant medication ), thalidomide ( used as a first-line treatment for multiple myeloma in
combination with dexamethasone or with melphalan and prednisone to treat acute episodes of erythema
nodosum leprosum, as well as for maintenance therapy), TNF- α inhibitors (etanercept, infliximab,
adalimumab, golimumab), to be used in conjunction with specialist centres.

39. Prognosis
There are no prognostic markers in sarcoidosis, apart from:
 Good prognosis Lofgren’s syndrome has a complete resolution in 80% of people. (Associated with HLA-
DQB1*0201)
 Poorer prognosis with chronic disease Lupus pernio, nasal mucosa involvement, chronic uveitis, chronic
hypercalcaemia, nephrocalcinosis, neural involvement, age >40, and black race
 Prognosis according to CXR appearance:
• Stage II: 50% of cases recover spontaneously in 2 y; 30– 40% requires systemic steroids; 10– 15% require
long-term steroids
• Stage III: worse prognosis. Only 30% show significant improvement with steroids
 Gene expression from mRNA profiling has shown early promise in differentiating progressive from non-
progressive disease.

40. Lung Transplant
 Consider if the patient has end-stage lung disease, rapidly progressive disease despite treatment,
or if they are O2- dependent.
 Sarcoidosis is a rare indication for a lung transplant.
 Granulomata recur in the transplanted lung but do not cause higher rates of graft failure.