Sarcoidosis

Overview

Definition

Sarcoidosis is a multisystem inflammatory disease characterized by the formation of noncaseating granulomas Noncaseating granulomas Crohn’s Disease 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 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: Anatomy (90% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship)
• Thoracic lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy (hilar and mediastinal)

Extrapulmonary sarcoidosis is characterized by granuloma formation in:

• Eyes
• 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. Skin: Structure and Functions
• Joints
• Heart
• Kidney
• CNS and peripheral nervous system Peripheral nervous system The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. Nervous System: Anatomy, Structure, and Classification
• Exocrine glands Exocrine glands Glands of external secretion that release its secretions to the body’s cavities, organs, or surface, through a duct. Glandular Epithelium: Histology

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

Epidemiology

• Most common interstitial lung disease
• Estimated prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency:
  • 34 per 100,000 in African Americans
  • 10 per 100,000 in Caucasians 
• Age at onset:
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency peaks at 20–40 years of age.
  • Second peak in incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency for women between 45 and 65 
• Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria 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 Sporadic Selective IgA Deficiency, 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 tuberculosis Mycobacterium 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 Propionibacterium A genus of gram-positive, rod-shaped bacteria whose cells occur singly, in pairs or short chains, in V or y configurations, or in clumps resembling letters of the chinese alphabet. Its organisms are found in cheese and dairy products as well as on human skin and can occasionally cause soft tissue infections. Dog and Cat Bites) acnes

Genetic predispositions:

• Antigens of the major histocompatibility complex Major histocompatibility complex The genetic region which contains the loci of genes which determine the structure of the serologically defined (sd) and lymphocyte-defined (ld) transplantation antigens, genes which control the structure of the immune response-associated antigens, human; the immune response genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. Innate Immunity: Phagocytes and Antigen Presentation (MHC), especially the HLA-DR alleles:
  • HLA-DRB1*1101
  • HLA-DQB1*0201
• Possible association with ACE variants
• Ongoing studies looking at gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics networks

Pathophysiology

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

• Phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation of a new antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination by antigen-presenting cells Antigen-presenting cells A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors. Adaptive Immune Response (e.g., macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation and dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions)
• Activated macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation present the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination to helper T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions via the HLA-CD4 complex.
• Activated T cells Activated T cells Adaptive Cell-mediated Immunity and macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation release inflammatory mediators ( Th1 Th1 A subset of helper-inducer T-lymphocytes which synthesize and secrete interleukin-2; interferon-gamma; and interleukin-12. Due to their ability to kill antigen-presenting cells and their lymphokine-mediated effector activity, th1 cells are associated with vigorous delayed-type hypersensitivity reactions. T cells: Types and Functions response):
  • Interleukin 2 (IL-2)
  • Interferon gamma
  • Tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ( 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 Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response and chemokines Chemokines Class of pro-inflammatory cytokines that have the ability to attract and activate leukocytes. They can be divided into at least three structural branches: c; cc; and cxc; according to variations in a shared cysteine motif. Adaptive Cell-mediated Immunity
• Inflammatory mediators cause macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation to fuse into multinucleated giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis.
• Unable to destroy the antigens, the multinucleated giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis wall them off → noncaseating granuloma Noncaseating Granuloma Inflammation formation
• Fibroblasts are recruited and surround granulomas.
• Granulomas may progress to fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans; the mechanism is poorly understood.

Clinical Presentation

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

Löfgren syndrome

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

• Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion nodosum
• Hilar adenopathy
• Migratory polyarthralgia

Diagnosis

Diagnosing sarcoidosis typically requires: 

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

Imaging

• Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests:
  • 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 High-resolution CT Imaging of the Lungs and Pleura ( HRCT HRCT Pulmonary Function Tests):
  • Higher sensitivity than X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests
  • Indications:
    • Confirm findings from suspicious X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests
    • 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: Anatomy in patient with pulmonary symptoms but normal X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests
  • 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 Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans with lung distortion Distortion Defense Mechanisms 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 Bronchoscopy Endoscopic examination, therapy or surgery of the bronchi. Laryngomalacia and Tracheomalacia

• Bronchoalveolar lavage Bronchoalveolar lavage Washing out of the lungs with saline or mucolytic agents for diagnostic or therapeutic purposes. It is very useful in the diagnosis of diffuse pulmonary infiltrates in immunosuppressed patients. Pulmonary Fibrosis (BAL):
  • Obtained primarily to exclude alternative diagnosis (e.g., infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, malignancy Malignancy Hemothorax)
  • 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 Activated T cells Adaptive Cell-mediated Immunity, and IgG-secreting cells
    • ↑ CD4:CD8 ratio > 4:1
• Allows for less invasive pulmonary tissue sampling:
  • Endobronchial biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • Transbronchial lung biopsy Lung Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
  • Transbronchial needle aspiration Needle aspiration Using fine needles (finer than 22-gauge) to remove tissue or fluid specimens from the living body for examination in the pathology laboratory and for disease diagnosis. Peritonsillar Abscess

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

• Gold standard for diagnosis
• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 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. Skin: Structure and Functions lesions).
• Lung biopsies can be obtained via bronchoscopy Bronchoscopy Endoscopic examination, therapy or surgery of the bronchi. Laryngomalacia and Tracheomalacia or surgically (more invasive).
• Key finding: well-defined noncaseating granulomas Noncaseating granulomas Crohn’s Disease
  • Noncaseating: no central necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage
  • Multinucleated giant cells Giant cells Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In aids, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Giant Cell Arteritis
• Other histopathologic findings:
  • Asteroid bodies
  • Schaumann bodies

Spirometry Spirometry Measurement of volume of air inhaled or exhaled by the lung. Pulmonary Function Tests

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 Vital capacity The volume of air that is exhaled by a maximal expiration following a maximal inspiration. Ventilation: Mechanics of Breathing (FVC; total forced exhaled volume)
  • ↓ Total lung capacity Total lung capacity The volume of air contained in the lungs at the end of a maximal inspiration. It is the equivalent to each of the following sums: vital capacity plus residual volume; inspiratory capacity plus functional residual capacity; tidal volume plus inspiratory reserve volume plus functional residual capacity; or tidal volume plus inspiratory reserve volume plus expiratory reserve volume plus residual volume. Ventilation: Mechanics of Breathing (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: Anatomy at the end of a maximal inspiration Inspiration Ventilation: Mechanics of Breathing)
  • ↓ Compliance Compliance Distensibility measure of a chamber such as the lungs (lung compliance) or bladder. Compliance is expressed as a change in volume per unit change in pressure. Veins: Histology ( 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: Anatomy 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 Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans)
• Impaired gas diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis across the alveolar membrane: ↓ diffusing capacity of the lung for carbon monoxide Carbon monoxide Carbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death. Carbon Monoxide Poisoning ( DLCO DLCO Pulmonary Function Tests)

Other testing

• Electrocardiography Electrocardiography Recording of the moment-to-moment electromotive forces of the heart as projected onto various sites on the body’s surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a cathode ray tube display. Electrocardiogram (ECG): to assess for cardiac involvement
• Ophthalmologic examination: to assess for eye involvement
• Tuberculin Tuberculin A protein extracted from boiled culture of tubercle bacilli (Mycobacterium tuberculosis). It is used in the tuberculin skin test (tuberculin test) for the diagnosis of tuberculosis infection in asymptomatic persons. Type IV Hypersensitivity Reaction 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. Skin: Structure and Functions 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 and Types (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 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: Anatomy involvement
  • ↑ BUN and creatinine if renal involvement
• Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children:
  • Hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis
• Inflammatory markers:
  • ↑ ESR ESR Soft Tissue Abscess
  • ↑ CRP
• Others:
  • ↑ ACE
  • ↑ IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis

Management

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

• Observation: 
  • Indicated in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with high rates of spontaneous resolution:
    • Acute sarcoidosis 
    • Stage 1 Stage 1 Trypanosoma brucei/African trypanosomiasis chronic sarcoidosis
  • NSAIDs NSAIDS Primary vs Secondary Headaches for treatment of pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways if needed
• Corticosteroids Corticosteroids Chorioretinitis: 1st-line therapy in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with:
  • ≥ Stage 2 disease with simultaneously restricted pulmonary function
  • Renal insufficiency ( 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 and hyperuricemia Hyperuricemia Excessive uric acid or urate in blood as defined by its solubility in plasma at 37 degrees c; greater than 0. 42 mmol per liter (7. 0 mg/dl) in men or 0. 36 mmol per liter (6. 0 mg/dl) in women. Gout) 
  • Extrapulmonary involvement
  • Severe systemic symptoms
  • Severe arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis (Löfgren syndrome)
  • Localized symptoms including 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 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. Skin: Structure and Functions lesions → administered locally
• Steroid-sparing agents: 2nd-line therapy:
  • Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
  • Mycophenolate Mycophenolate Immunosuppressants
  • Hydroxychloroquine Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. Immunosuppressants
  • Leflunomide Leflunomide An isoxazole derivative that inhibits dihydroorotate dehydrogenase, the fourth enzyme in the pyrimidine biosynthetic pathway. It is used an immunosuppressive agent in the treatment of rheumatoid arthritis. Disease-Modifying Antirheumatic Drugs (DMARDs)
  • Infliximab Infliximab A chimeric monoclonal antibody to tnf-alpha that is used in the treatment of rheumatoid arthritis; ankylosing spondylitis; psoriatic arthritis and Crohn’s disease. Disease-Modifying Antirheumatic Drugs (DMARDs) (anti-TNF agent)
• Lung transplantation Lung transplantation The transference of either one or both of the lungs from one human or animal to another. Organ Transplantation: in cases of advanced pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

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 capsulatum Histoplasma capsulatum Histoplasma/Histoplasmosis: 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 Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus, cough, and chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways that develop 2–4 weeks after exposure. In immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis individuals, the infection may be fatal. Both sarcoidosis and 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 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 Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion 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 Noncaseating granulomas Crohn’s Disease. Treatment involves antifungal Antifungal Azoles medications.
• 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: disease caused by Mycobacterium tuberculosis Mycobacterium 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 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: Anatomy, but it can also damage other parts of the body. 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 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 Tuberculin A protein extracted from boiled culture of tubercle bacilli (Mycobacterium tuberculosis). It is used in the tuberculin skin test (tuberculin test) for the diagnosis of tuberculosis infection in asymptomatic persons. Type IV Hypersensitivity Reaction 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. Skin: Structure and Functions test, sputum cultures, and lung imaging. Biopsies show caseating granulomas (central necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage), whereas sarcoid granulomas are noncaseating. Management is with antimycobacterial drugs. 
• Idiopathic Idiopathic Dermatomyositis pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans: interstitial lung disease, characterized by irreversible pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans and impaired pulmonary function: Idiopathic Idiopathic Dermatomyositis pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans 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 Dry Cough Strongyloidiasis, and fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia. Diagnosis is by chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests or CT, along with pulmonary function tests. Management is supportive, along with therapy targeting the underlying cause. 
• Lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum: cancers originating from lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology, including B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions, 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 Chemotherapy Osteosarcoma.