Pulmonary Sarcoidosis Diagnosis And Treatment

Introduction

Defining pulmonary sarcoidosis

Pulmonary sarcoidosis is a medical condition that is symptomised by granulomatous growths (granulomas) that most commonly occur in the lungs and lymph nodes (or lymph glands). It is a rare disease that affects between 2 and 160 people per 100,000 globally. The prevalence stands at 20 in 100,000 people in the UK.^1,2 In most cases, symptoms of pulmonary sarcoidosis are non-severe and may self resolve without any medical interventions within a few months or years. However, in some instances the disease may be chronic resulting in serious health challenges. 

This article delves into the pathology of pulmonary sarcoidosis, detailing how the disease can affect your body. Taking into consideration the implications of the disease’s pathology, the importance of timely diagnosis and treatment will also be discussed.

Causes of pulmonary sarcoidosis 

The aetiology (cause or origin of disease) of pulmonary sarcoidosis remains a mystery, but it is thought to be due to the immune system’s overreaction to foreign substances such as allergens and pathogens. The pathology (study of a disease) of sarcoidosis may also be due to an autoimmune response to the body’s own tissues. Studies have presented evidence suggesting the disease may be caused by the immune system as samples collected from the bronchoalveolar lavage fluid of patients contained high amounts of immune system components. Studies have also described instances of microbial components being present in the tissues of sarcoidosis patients. Some studies have even identified components of the immune system that are usually present when the body is fighting certain microbial infections.^1,2 

Though the exact immune pathways leading to pulmonary sarcoidosis are unknown, the macrophages and T helper cells of the immune system have been implicated. It is thought that an unknown stimuli leads to the activation of macrophages, which are white blood cells (lymphocytes) of the immune system. The macrophages in turn release signalling molecules (cytokines) that lead to the activation of different f lymphocytes, T helper (Th) cells. The Th cells involved in the formation of the granulomas are T helper cells 1 and 17 (Th1 and Th17).^2,3 but as disease progresses, the development of fibrosis is thought to be caused by immune activity switching from Th1 and Th17 to a T helper cell 2 (Th2) dependent response.²

Risk factors

Genetics and environmental exposure are both potential risk factors; for example, there is an elevated risk of developing sarcoidosis amongst siblings. The chances are even higher for twins, especially identical twins.⁴ There is also a variation in the chances of developing sarcoidosis amongst people of different ethnicities. Environmental exposure studies have shown that some workers are more likely to develop sarcoidosis;  this includes people who work in the shipping, automotive and landscaping industries. Patients undergoing interferon therapy (taking interferon alpha) are also potentially at risk of developing pulmonary sarcoidosis. The prevalence of sarcoidosis is reportedly  greater in women.²

Pathophysiology and clinical symptoms 

Pathology and symptoms

The vast majority of pulmonary sarcoidosis patients, more than 90%, present with symptoms in the lungs and intrathoracic lymph nodes. A minority of patients, about 20-40% also exhibit symptoms in the skin, eyes and extrathoracic lymph nodes. In very few cases, less than 10%, the heart, spleen, bones, livers and kidneys have also be affected.^2,5 Intrathoracic refers to the lymph nodes occurring in the chest area whilst extrathoracic refers to the lymph nodes in other parts of the body.

Notably,  the granulomas observed in pulmonary sarcoidosis are typically described as being non-necrotising and non caseating.⁶ Non-necrotising granulomas do not contain any dead cells, whilst non-caseating simply means that the granulomas are a result of inflammation. Chronic and progressive sarcoidosis in the lungs may lead to fibrosis whereby the native tissues inside the lungs are replaced by connective tissues.

The general symptoms of pulmonary sarcoidosis are a persistent dry cough, shortness of breath (dyspnea), wheezing and chest discomfort. In the chest area, lymph nodes (hilar and mediastinal) are typically swollen whilst those under the skin may also be observed to be firm, rubbery and nontender.^7,8  Hilar refers to the lymph nodes occurring in the airways (bronchi) whilst the mediastinal lymph nodes occur within the region of trachea, heart and oesophagus.

Since the pathology of the disease may go beyond the lungs, there are several organ-specific symptoms.^5,9 

• In the eyes, sarcoidosis symptoms include itching and redness, blurred vision, pain and photophobia 
• On the skin, a reddish-purple and bumpy rash may appear, particularly on the shins (erythema nodosum) 
• If the heart is affected, arrhythmia, palpitations, edema and fainting may set in 

Pulmonary sarcoidosis is also signalled by the presence of Lӧfgren’s syndrome and the Heerfordt-Waldenstrӧm’s syndrome. Lӧfgren’s syndrome is characterised by three symptoms, bilateral hilar lymphadenopathy, erythema nodosum and ankle inflammation that may be accompanied by a fever. Heerfordt-Waldenstrӧm’s syndrome is symptomised by facial palsy, fever, swelling of the parotid gland and uveitis.

Diagnosis

Importance of early diagnosis

Early diagnosis of pulmonary sarcoidosis is key in alleviating chronicity and irreversible damage. At the onset, the disease is said to be acute or subacute whereby it may self resolve.⁹ However, in some patients the disease becomes chronic which may lead to irreversible health complications. Severe complication is extensive and can result in permanent lung dysfunction to such extent that patients may require a lung transplant.² 

Another complication is precapillary pulmonary hypertension, an acute medical condition whereby lifespan is significantly shortened because of dysfunction in the right side of the heart.² Early diagnosis is essential but the asymptomatic nature of early pulmonary sarcoidosis makes it difficult to detect the disease at the onset.

There are four stages of pulmonary sarcoidosis, dependent on the progression of the granulomas in the lungs. These stages are determined by means of medical imaging techniques such as X-rays.¹

• Granulomas occurring in the lymph nodes
• Granulomas are present in the lymph nodes and the lungs
• Granulomas are exclusively present in the lungs
• Pulmonary fibrosis or evidence of permanent lung scarring

Despite these markers which serve as signals of different stages of pulmonary sarcoidosis pathology, they overlap with the symptoms of other pulmonary diseases.⁶

Diagnosing pulmonary sarcoidosis

Challenges

The granulomas observed in pulmonary sarcoidosis are very similar to those that are caused by other diseases. These diseases range from bacterial infections such as Mycobacterium tuberculosis (TB), to fungal infections and some cancers. Therefore the ideal diagnostic criteria would include identifying the corresponding symptoms, identification of non-necrotising granulomas and measures to eliminate other diseases as being responsible for granuloma formation.^5,6 However, there are no standard procedures which have been established to ensure a definitive pulmonary sarcoidosis diagnosis. The differential diagnosis of pulmonary sarcoidosis is challenging when using both radioimaging techniques such as X-rays and histological specimens extracted from tissues of patients.

Techniques and strategies

Several diagnostic methods exist but have varying degrees of specificity,  diagnostic success and associated risk.²

• Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in case of swollen lymph nodes in lungs. The sensitivity, specificity and diagnosis rate is 83-93%, 100% and 77-84%, respectively
• Flexible fiberoptic bronchoscopy together with transbronchial lung biopsies for swollen lymph nodes in the lungs. The sensitivity, specificity and diagnosis rate is 37%, 100% and 50-75%, respectively
• Surgical mediastinoscopy for swollen lymph nodes in lungs. The sensitivity, specificity and diagnosis rate is 100%, 100% and 82-100%, respectively
• Percutaneous fine needle aspiration which comes with a risk of pneumothorax. Pneumothorax is the presence of air within the pleural cavity outside of the lungs

Differential diagnosis to eliminate other diseases that also cause granulomas

There are a plethora of diseases which share pathological patterns with sarcoidosis. Listed below are some of the diseases and how they can be differentiated from pulmonary sarcoidosis.²

• Bacterial and fungal infections can be eliminated by carrying out histopathology
• Lymphomas can be eliminated by carrying out histopathology and cytopathology
• Granulomatous-lymphocytic interstitial lung disease (GL-ILD) co-occurring with common variable immunodeficiency (CVID) can be eliminated by running serological tests
• Rheumatoid nodules can be eliminated by carrying out histopathological and running serological tests
• Langerhans cell histiocytosis can be eliminated by carrying out histopathological assessments

Treatment 

Most people with pulmonary sarcoidosis are devoid of any symptoms. There may need to be occasional interventions due to symptoms emerging from time to time. In most patients the symptoms are typically self resolving. Patients need to start treatment where disease progresses and may lead to risk of life. Treatment is administered as a means of reducing granulomas, restoring lung function and improving quality of life. There are three levels of treatment.^1,2

• As a first line of treatment corticosteroids, prednisone and prednisolone, are administered. These drugs are administered to improve lung function and administration should be terminated should there be a cessation of symptoms
• The second line of treatment entails the administration of cytotoxic or immunomodulatory drugs such as methotrexate. These drugs are used if patients cannot tolerate the corticosteroids. There is an ongoing debate around whether the second line drugs are more effective than the corticosteroids
• Tumour necrosis factor alpha (TNF-ɑ) inhibitors, which are essentially antibodies specific to  TNF-ɑ, are used as the third line of treatment. TNF-ɑ is an immune signalling molecule (cytokine) implicated in the formation of granulomas. As such, targeting this cytokine may improve treatment outcomes

Pulmonary sarcoidosis may advance to become fibrotic or affect organs other than the lungs so other treatment interventions are available; i.e., fibrotic patients may need oxygen therapy and pulmonary rehabilitation. In extra pulmonary patients such as those affected in the skin, treatment with antimalarial drugs such as hydroxychloroquine may be required.¹⁰

FAQs

How is pulmonary sarcoidosis diagnosed?

Pulmonary sarcoidosis is diagnosed by carrying out radioimaging of the test. Histopathological and serological analyses are also carried out.

How is pulmonary sarcoidosis treated?

Various classes of drugs are used to treat pulmonary sarcoidosis, the first line drugs being corticosteroids such as prednisone.

How does pulmonary sarcoidosis affect your lungs?

Pulmonary sarcoidosis may result in the formation of granulomas in the lungs. Though the disease is self limiting it may progress to result in severe lung damage.

Can lungs recover from pulmonary sarcoidosis?

The disease is asymptomatic or self resolving in most patients, but may progress to result in irreversible lung damage.

Summary

Pulmonary sarcoidosis is a disease that is signalled by the appearance of lumps known as granulomas inside the lungs accompanied by lymphadenopathy. The disease is typically asymptomatic and may go away without treatment. In some cases the disease may lead to fibrosis whereby lung function may be impaired severely. 

The disease is associated with lung impairment and swollen lymph nodes, other parts of the body can be affected. The causes of pulmonary sarcoidosis are unknown but overactive immune system response is a potential factor. Early diagnosis is imperative in pulmonary sarcoidosis because the progression of the disease may lead to serious complications that may reduce lifespan or quality of life. 

Diagnosis involves the radiological, serological and histopathological examination of lung tissues. Symptoms of sarcoidosis are similar to those of other diseases, so additional elimination steps need to be taken in order to ensure accurate diagnosis. 

Pharmacological treatment is split into three steps. The first line of treatment involves corticosteroids such as prednisone, whilst the second step involves immunomodulatory drugs such as methotrexate. The third step entails the use of TNF-ɑ inhibitors. In terms of sarcoidosis related complications and pathology in various organs, other than the lungs, other interventions may be required for disease treatment and management.