Sarcoidosis

Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, heart, and eyes, most commonly. Acutely, sarcoidosis presents with lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, malaise, joint pains, a panniculitis on the shins known as erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum, and occasionally cough and shortness of breath. Chronic pulmonary sarcoidosis presents with an insidious onset of dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, cough, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, and a variety of other symptoms depending on the organ systems involved. Diagnosis often requires a biopsy of the granulomas. Management includes observation, NSAIDs, glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, and potentially one of several steroid-sparing agents. Acute sarcoidosis is usually self-limiting with an excellent prognosis, but chronic sarcoidosis can lead to severe pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis.

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Overview

Definition

Sarcoidosis is a multisystem inflammatory disease characterized by the formation of noncaseating granulomas that are most likely caused by a cell-mediated immune reaction of unknown etiology.

Pulmonary sarcoidosis is a restrictive interstitial lung disease with granuloma formation in the:

  • Lungs (90% of patients)
  • Thoracic lymph nodes (hilar and mediastinal)

Extrapulmonary sarcoidosis is characterized by granuloma formation in:

  • Eyes
  • Skin
  • Joints
  • Heart
  • Kidney
  • CNS and peripheral nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System
  • Exocrine glands

Sarcoidosis may be acute or chronic:

  • Löfgren syndrome: an acute presentation of sarcoidosis lasting weeks to months:
    • Usually resolves spontaneously without treatment
    • Typically in younger adults
  • Chronic disease: insidious onset, often progressive, may wax and wane
Ild classification

Categorization of interstitial lung diseases Interstitial Lung Diseases Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases
ILD ILD Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases: interstitial lung disease

Image by Lecturio.

Epidemiology

  • Most common interstitial lung disease
  • Estimated prevalence: 
    • 34 per 100,000 in African Americans
    • 10 per 100,000 in Caucasians 
  • Age at onset: 
    • Incidence peaks at 20–40 years of age.
    • Second peak in incidence for women between 45 and 65 
  • Sex bias Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases: women > men
  • Racial/ethnic bias Bias Epidemiological studies are designed to evaluate a hypothesized relationship between an exposure and an outcome; however, the existence and/or magnitude of these relationships may be erroneously affected by the design and execution of the study itself or by conscious or unconscious errors perpetrated by the investigators or the subjects. These systematic errors are called biases. Types of Biases: African American > other races
  • Most cases are sporadic, but about 5% are familial.

Etiology

Etiology is undetermined but is most likely multifactorial.

Theory: An infectious or environmental agent triggers a cell-mediated inflammatory immune response in a genetically susceptible host, leading to granuloma formation.

Potential triggering exposures:

  • Inhalation of talc, aluminum, beryllium, or zirconium
  • Exposure to dust and debris at the collapsed World Trade Center after 9/11
  • Infectious agents: 
    • Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Cutibacterium (previously Propionibacterium) acnes

Genetic predispositions:

  • Antigens of the major histocompatibility complex (MHC), especially the HLA-DR alleles:
    • HLA-DRB1*1101
    • HLA-DQB1*0201
  • Possible association with ACE variants
  • Ongoing studies looking at gene networks

Pathophysiology

Sarcoidosis is the result of a cell-mediated immune reaction. 

  • Phagocytosis of a new antigen by antigen-presenting cells (e.g., macrophages and dendritic cells)
  • Activated macrophages present the antigen to helper T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells via the HLA-CD4 complex.
  • Activated T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and macrophages release inflammatory mediators (Th1 response):
    • Interleukin 2 (IL-2)
    • Interferon gamma
    • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))
    • Other cytokines and chemokines
  • Inflammatory mediators cause macrophages to fuse into multinucleated giant cells.
  • Unable to destroy the antigens, the multinucleated giant cells wall them off → noncaseating granuloma formation
  • Fibroblasts are recruited and surround granulomas.
  • Granulomas may progress to fibrosis; the mechanism is poorly understood.
Granuloma

Noncaseating granuloma

Image: “Granuloma 20x” by Mutleysmith. License: Public Domain

Clinical Presentation

Sarcoidosis usually progresses slowly, with few symptoms initially. Symptoms appear as an increasing number of granulomas begin to affect organ function.

Clinical manifestations of sarcoidosis by organ system
Organ system Clinical presentation of sarcoidosis
Systemic symptoms (typically in acute presentations)
  • Fever
  • Myalgias
  • Weight loss
  • Fatigue and exhaustion
Pulmonary
  • Chest pain
  • Dry cough
  • Dyspnea on exertion
  • Severe complications: pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension or cor pulmonale Cor Pulmonale Cor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom. Cor Pulmonale (as consequences of pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis)
Lymph
  • Intrathoracic lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Hilar and mediastinal
    • Bilateral involvement (differentiates sarcoidosis from tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis and malignancy)
  • Peripheral lymph node enlargement
Ocular
  • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea (most common)
  • Granulomas may involve:
    • Orbit Orbit The orbit is the cavity of the skull in which the eye and its appendages are situated. The orbit is composed of 7 bones and has a pyramidal shape, with its apex pointed posteromedially. The orbital contents comprise the eye, extraocular muscles, 5 cranial nerves, blood vessels, fat, the lacrimal apparatus, among others. The Orbit and Extraocular Muscles
    • Anterior and posterior segments of the eye
    • Conjunctiva
    • Lacrimal glands
    • Extraocular muscles
    • Eyelids
  • Symptoms include dry eye, blurred vision, photophobia, redness, and pain.
Cutaneous
  • Erythema nodosum:
    • A panniculitis ( inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the subcutaneous fat)
    • Painful inflammatory nodules, usually on the shins
  • Lupus pernio:
    • Violaceous or erythematous indurated papules, plaques, and nodules
    • Primarily on the face: nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, cheeks, chin, and ears
    • Accompanied by significant scar formation
Musculoskeletal
  • Polyarthritis (joint pain and swelling)
  • Granulomatous myositis
Cardiac
  • Cardiac arrhythmia with ↑ risk of sudden cardiac death
  • Conduction defects (heart block)
  • Heart failure
  • Restrictive cardiomyopathy Restrictive Cardiomyopathy Restrictive cardiomyopathy (RCM) is a fairly uncommon condition characterized by progressive stiffening of the cardiac muscle, which causes impaired relaxation and refilling of the heart during diastole, resulting in diastolic dysfunction and eventual heart failure. Restrictive Cardiomyopathy
Nervous system
  • Lymphocytic meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
  • Facial paralysis (cranial nerve palsy)
  • Hypothalamic–pituitary dysfunction:
    • Diabetes insipidus Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus
    • Hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism
    • Amenorrhea
  • Spinal cord involvement
  • Peripheral neuropathies
Other potential sites of involvement
  • Upper respiratory tract: larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx, pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx, nares, and sinuses
  • Kidney
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen
  • GI tract
  • Exocrine glands: parotid and salivary

Löfgren syndrome

An acute presentation of sarcoidosis with a classic triad of symptoms:

  • Erythema nodosum
  • Hilar adenopathy
  • Migratory polyarthralgia

Diagnosis

Diagnosing sarcoidosis typically requires: 

  1. Compatible clinical and radiologic manifestations
  2. Noncaseating granulomas on pathology
  3. Exclusion of other conditions

Imaging

  • Chest X-ray:
    • Best initial test
    • Findings:
      • Bilateral hilar lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy (classic finding)
      • Bilateral reticulonodular infiltrates (often upper lobes)
      • Honeycombing (end-stage disease)
  • High-resolution CT (HRCT):
    • Higher sensitivity than X-ray
    • Indications:
      • Confirm findings from suspicious X-ray
      • Further evaluate lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs in patient with pulmonary symptoms but normal X-ray
    • Findings:
      • Bilateral hilar and mediastinal lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
      • Small centrilobular parenchymal nodules
      • Mid–upper zone predominance of lung parenchymal changes
      • Fine nodularity
      • Ground-glass opacification
      • Fibrosis with lung distortion and traction bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis

Bronchoscopy

  • Bronchoalveolar lavage (BAL)
    • Obtained primarily to exclude alternative diagnosis (e.g., infections, malignancy)
    • Lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis ≥ 25% suggests a granulomatous process.
    • Findings consistent with pulmonary sarcoidosis:
      • ↓ CD8 cells
      • ↑ CD4 cells, activated T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, and IgG-secreting cells
      • ↑ CD4:CD8 ratio > 4:1
  • Allows for less invasive pulmonary tissue sampling:
    • Endobronchial biopsy
    • Transbronchial lung biopsy
    • Transbronchial needle aspiration

Biopsy

  • Gold standard for diagnosis
  • Biopsy the most accessible affected site (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions).
  • Lung biopsies can be obtained via bronchoscopy or surgically (more invasive).
  • Key finding: well-defined noncaseating granulomas 
    • Noncaseating: no central necrosis
    • Multinucleated giant cells
  • Other histopathologic findings: 
    • Asteroid bodies
    • Schaumann bodies

Spirometry

Obtained to assess severity of respiratory involvement and monitor disease; less helpful in actually establishing diagnosis

  • Sarcoid usually demonstrates a restrictive pattern:
    • ↓ Forced vital capacity (FVC; total forced exhaled volume)
    • ↓ Total lung capacity (TLC; total volume in lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs at the end of a maximal inspiration)
    • ↓ Compliance ( lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs have difficulty expanding)
  • Mixed restrictive/obstructive patterns are also possible in severe disease:
    • Mixed patterns have both restrictive and obstructive findings.
    • Obstructive findings:
      • ↓ Forced expiratory volume in 1 second (FEV1):FVC ratio
      • ↓ Airflow (airways are partially obstructed by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and fibrosis)
  • Impaired gas diffusion across the alveolar membrane: ↓ diffusing capacity of the lung for carbon monoxide (DLCO)

Other testing

  • Electrocardiography: to assess for cardiac involvement
  • Ophthalmologic examination: to assess for eye involvement
  • Tuberculin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin test: to rule out tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • Other testing guided by clinical presentation

Laboratory testing

These tests are important in assessing and monitoring the extent of disease rather than making the diagnosis. The following findings are often seen in sarcoidosis.

  • CBC:
    • Leukopenia
    • Lymphopenia
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview (uncommon)
  • CMP:
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
    • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests if liver involvement
    • ↑ BUN and creatinine if renal involvement
  • Urinalysis:
    • Hypercalciuria
  • Inflammatory markers:
    • ↑ ESR
    • ↑ CRP
  • Others:
    • ↑ ACE
    • ↑ IgG

Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis

Table: Staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis schema according to presence or absence of bilateral hilar lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy and by the presence or absence of lung infiltrates
Stage Chest X-ray Symptoms Frequency
0 Extrapulmonary disease only None 10%
1 BHL only None or mild cough 50%
2 BHL plus parenchymal infiltrates None, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, or cough 25%
3 Parenchymal infiltrates only Dyspnea 10%
4 Advanced pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis Dyspnea 5%
BHL: bilateral hilar lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy

Management

Management is based on stage and location of disease and includes:

  • Observation: 
    • Indicated in patients with high rates of spontaneous resolution:
      • Acute sarcoidosis 
      • Stage 1 chronic sarcoidosis
    • NSAIDs for treatment of pain if needed
  • Corticosteroids: 1st-line therapy in patients with:
    • ≥ Stage 2 disease with simultaneously restricted pulmonary function
    • Renal insufficiency (hypercalcemia and hyperuricemia) 
    • Extrapulmonary involvement
    • Severe systemic symptoms
    • Severe arthritis (Löfgren syndrome)
    • Localized symptoms including uveitis and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions → administered locally
  • Steroid-sparing agents: 2nd-line therapy:
    • Azathioprine
    • Methotrexate
    • Mycophenolate
    • Hydroxychloroquine
    • Leflunomide
    • Infliximab (anti- TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) agent)
  • Lung transplantation: in cases of advanced pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis

Prognosis

Table: Remission rates
Stage Remission rate
0
1 90%
2 70%
3 20%
4 < 5%

Differential Diagnosis

  • Pneumoconiosis Pneumoconiosis Pneumoconiosis is an occupational disease that results from the inhalation and deposition of mineral dusts and other inorganic particles in the lung. It can be categorized according to the type of causative particle involved or by the type of response provoked. Pneumoconiosis: occupational disease that consists of a group of restrictive interstitial lung diseases Interstitial Lung Diseases Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial Lung Diseases caused by inhalation of toxic dust, including silica, asbestos, beryllium, and others: Pneumoconiosis Pneumoconiosis Pneumoconiosis is an occupational disease that results from the inhalation and deposition of mineral dusts and other inorganic particles in the lung. It can be categorized according to the type of causative particle involved or by the type of response provoked. Pneumoconiosis presents with cough and progressive dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Diagnosis is by occupational history, imaging, and histology. Management is largely supportive.
  • Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis: infection caused by the fungus Histoplasma Histoplasma Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Histoplasma/Histoplasmosis capsulatum: Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis presents with symptoms of pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, including fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, myalgias, cough, and chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain that develop 2–4 weeks after exposure. In immunocompromised individuals, the infection may be fatal. Both sarcoidosis and histoplasmosis can cause pulmonary infiltrates, mediastinal lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, and erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum. Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis tends to form caseating granulomas, while sarcoidosis causes noncaseating granulomas. Treatment involves antifungal medications.
  • Tuberculosis: disease caused by Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis: The bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview usually attacks the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, but it can also damage other parts of the body. Tuberculosis presents with a chronic cough with hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis. The diagnosis is made with a tuberculin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin test, sputum cultures, and lung imaging. Biopsies show caseating granulomas (central necrosis), whereas sarcoid granulomas are noncaseating. Management is with antimycobacterial drugs. 
  • Idiopathic pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis: interstitial lung disease, characterized by irreversible pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis and impaired pulmonary function: Idiopathic pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis presents with exertional dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, persistent dry cough, and fatigue. Diagnosis is by chest X-ray or CT, along with pulmonary function tests. Management is supportive, along with therapy targeting the underlying cause. 
  • Lymphoma: cancers originating from lymphocytes, including B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, and natural killer (NK) cells: Lymphomas often present with constitutional signs and/or painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. Similar to sarcoidosis, imaging findings may include thoracic lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. Management is based on the specific stage and type of cancer and is usually chemotherapy.

References

  1. King T (2020). Clinical manifestations and diagnosis of pulmonary sarcoidosis. UpToDate. Retrieved March 2, 2021 from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-pulmonary-sarcoidosis
  2. Kamanger N (2020). Sarcoidosis. Emedicine. Retrieved March 2, 2021 from https://emedicine.medscape.com/article/301914-overview
  3. Jameson, J, Fauci A, Kasper S, Hauser D, Jameson J, Loscalzo J (2018). Harrison’s Principles of Internal Medicine (20th ed., vol. 2. chapter 390). 
  4. Fontenot A, King T (2020). Pathology and pathogenesis of sarcoidosis. In Hollingsworth H (Ed.). UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/pathology-and-pathogenesis-of-sarcoidosis
  5. King T (2020). Extrapulmonary manifestations of sarcoidosis. In Hollingsworth H (Ed.). UpToDate. Retrieved March 3, 2021, from https://www.uptodate.com/contents/extrapulmonary-manifestations-of-sarcoidosis
  6. King T (2020). Treatment of pulmonary sarcoidosis: Disease refractory to glucocorticoid therapy. In Hollingsworth H (Ed.). UpToDate. Retrieved March 5, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-sarcoidosis-disease-refractory-to-glucocorticoid-therapy

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