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Type III Hypersensitivity Reaction

Type III hypersensitivity, also known as immune complex-mediated hypersensitivity, occurs when antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions and antigens form immune complexes Immune complexes The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. C3 Deficiency (ICs) in circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment and deposit in susceptible tissues. The complement system Complement system Serum glycoproteins participating in the host defense mechanism of complement activation that creates the complement membrane attack complex. Included are glycoproteins in the various pathways of complement activation (classical complement pathway; alternative complement pathway; and lectin complement pathway). Innate Immunity: Barriers, Complement, and Cytokines triggers the immune response, leading to leukocyte recruitment Recruitment Skeletal Muscle Contraction and tissue injury. There is no single clinical syndrome for this hypersensitivity. Symptoms reflect the impairment of multiple organ systems based on sites of IC IC Inhaled Anesthetics deposition. Diagnostic workup depends largely on the history and includes laboratory tests, imaging, and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of the affected organ. Treatment consists of removal or avoidance of offending agents and, in severe conditions, 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 or immunosuppressive therapy.

Last updated: Nov 7, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

  • Hypersensitivity reaction
    • A “hyper” or exaggerated response to what should be considered harmless environmental antigens
    • Types I, II, and III are immediate reactions occurring within 24 hours.
    • Type IV reaction develops over several days.
  • Type III hypersensitivity reaction
    • Immune complex ( IC IC Inhaled Anesthetics)-mediated hypersensitivity: triggered by antigen-antibody (Ag-Ab) complexes deposited in tissues
    • Ag AG Metabolic Acidosis: intrinsic (part of the host) or extrinsic (exogenous source such as 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, virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology)
    • As with type II hypersensitivity, cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death is similar: Complement system Complement system Serum glycoproteins participating in the host defense mechanism of complement activation that creates the complement membrane attack complex. Included are glycoproteins in the various pathways of complement activation (classical complement pathway; alternative complement pathway; and lectin complement pathway). Innate Immunity: Barriers, Complement, and Cytokines leads to a reaction that produces cellular damage.
    • Unlike type II hypersensitivity, in type III reactions:
      • Antigens are not bound to cell surfaces. 
      • Ag-Ab complexes form in circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment.
      • Target of the immune response is not the tissue or cell. 
      • Target is the IC IC Inhaled Anesthetics deposited in the tissue.

Pathophysiology

Physiology

  • Immune complex formation normally results in antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination neutralization.
  • The complement system Complement system Serum glycoproteins participating in the host defense mechanism of complement activation that creates the complement membrane attack complex. Included are glycoproteins in the various pathways of complement activation (classical complement pathway; alternative complement pathway; and lectin complement pathway). Innate Immunity: Barriers, Complement, and Cytokines reduces pathologic IC IC Inhaled Anesthetics accumulation.
    • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (Ab) have 2 regions:
      • Fab Fab Univalent antigen-binding fragments composed of one entire immunoglobulin light chain and the amino terminal end of one of the immunoglobulin heavy chains from the hinge region, linked to each other by disulfide bonds. Fab contains the immunoglobulin variable regions, which are part of the antigen-binding site, and the first immunoglobulin constant regions. This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions region: attaches to antigens 
      • Fc Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions region: interacts with complement and Fc-bearing receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (FcR) cells
    • C1q: activates complement system Complement system Serum glycoproteins participating in the host defense mechanism of complement activation that creates the complement membrane attack complex. Included are glycoproteins in the various pathways of complement activation (classical complement pathway; alternative complement pathway; and lectin complement pathway). Innate Immunity: Barriers, Complement, and Cytokines and binds Ab Fc Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions region, mediating IC IC Inhaled Anesthetics clearance by FcR-bearing cells.
    • C3b: makes ICs soluble and tags them for 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 (opsonization).

Pathogenesis

Immune complex formation: IC IC Inhaled Anesthetics formed by the binding of Ag AG Metabolic Acidosis and Ab

Immune complex deposition

Immune complex deposition depends on:

  • Physical properties of the IC IC Inhaled Anesthetics
  • Antigen-to-antibody ratio: 
    • Low antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions or excess antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions → decreased effector activation
  • Tissue-specific hemodynamics Hemodynamics The movement and the forces involved in the movement of the blood through the cardiovascular system. Vascular Resistance, Flow, and Mean Arterial Pressure
    • ICs first localize within blood vessels → vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
    • Common areas affected are “permeability”-susceptible tissues:
      • Glomeruli (nephritis)
      • Joints/synovium ( arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis)

Immune complex inflammatory reaction

  • IC IC Inhaled Anesthetics deposits activate the complement cascade Complement cascade The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. C3 Deficiency.
  • C3a initiates mast cell Mast cell Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Angioedema degranulation:
    • Histamine increases vascular permeability in the involved tissue. 
    • ICs enter tissue → normal tissue with IC IC Inhaled Anesthetics becomes a target for inflammatory response
  • C5a (chemoattractant) recruits neutrophils Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. Innate Immunity: Phagocytes and Antigen Presentation → release lysozymes and inflammatory mediators → cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death and tissue injury
  • C3b opsonizes the tissue → 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 and membrane attack complex Membrane attack complex A product of complement activation cascade, regardless of the pathways, that forms transmembrane channels causing disruption of the target cell membrane and cell lysis. It is formed by the sequential assembly of terminal complement components (complement C5b; complement C6; complement C7; complement C8; and complement C9) into the target membrane. The resultant C5b-8-poly-c9 is the ‘membrane attack complex’ or MAC. Type II Hypersensitivity Reaction (MAC)-mediated cell lysis
  • 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, natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology → release lytic mediators and injure tissue cells
  • Platelet aggregation Platelet aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Hemostasis can occur → micro thrombus formation
Immune complex mediated pathways underlying type iii hypersensitivity.

Immune complex–mediated pathways underlying type III hypersensitivity.

Image by Lecturio.

Clinical Presentation

Manifestations are affected by the route of entry, site(s) of IC IC Inhaled Anesthetics deposition, and persistence of antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination(s).

Arthus phenomenon/Arthus reaction

  • A locally injected antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (e.g., immunization like Tdap) causes a localized reaction.
  • Due to antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination excess and IC IC Inhaled Anesthetics deposition on vascular walls
  • Necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of affected tissues:  pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, redness Redness Inflammation, induration Induration Dermatologic Examination, and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema at the site of injection
  • Self-limited

Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus)

  • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions directed against parts of the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles: antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (ANA), a universal finding in SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
  • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions to other parts of the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles
    • Histone (anti-histone Ab)
    • DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure (anti-dsDNA Ab)
    • Ribonucleoprotein (anti-RNP Ab) 
    • Extractable nuclear antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination/Smith antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (Anti-Smith Ab)
  • Other: Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against phospholipids Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Lipid Metabolism in cells (antiphospholipid Ab)
    • Present in 30%–40% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
    • Increased risk of thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Ag-Ab complexes deposit in multiple areas:
    • 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/mucocutaneous ( malar rash Malar Rash Systemic Lupus Erythematosus, photosensitivity Photosensitivity Tetracyclines, oral ulcers Oral ulcers A loss of mucous substance of the mouth showing local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue. It is the result of a variety of causes, e.g., denture irritation, aphthous stomatitis; necrotizing gingivitis, toothbrushing, and various irritants. Chédiak-Higashi Syndrome)
    • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy (glomerulonephritis)
    • Joints ( arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis)
    • Blood vessels ( vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus, Raynaud’s phenomenon, blood clots)
    • Pleura Pleura The pleura is a serous membrane that lines the walls of the thoracic cavity and the surface of the lungs. This structure of mesodermal origin covers both lungs, the mediastinum, the thoracic surface of the diaphragm, and the inner part of the thoracic cage. The pleura is divided into a visceral pleura and parietal pleura. Pleura: Anatomy (effusion)
    • Pericardium Pericardium A conical fibroserous sac surrounding the heart and the roots of the great vessels (aorta; venae cavae; pulmonary artery). Pericardium consists of two sacs: the outer fibrous pericardium and the inner serous pericardium. The latter consists of an outer parietal layer facing the fibrous pericardium, and an inner visceral layer (epicardium) resting next to the heart, and a pericardial cavity between these two layers. Heart: Anatomy ( pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis)
    • Blood cells ( 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, leukopenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia)
    • Central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification (strokes, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures)

Post-streptococcal glomerulonephritis ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis)

  • Reaction to nephritogenic antigens of group A beta-hemolytic streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus (GAS)
  • Can be from streptococcal throat Throat 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: Anatomy infection or 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 infection
  • Presentation: hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, and elevated creatinine

Serum sickness

  • Reaction to foreign antisera (e.g., antivenom)
  • Higher doses of administered agent more likely to result in a reaction
  • 1–2 weeks after exposure: 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, rash Rash Rocky Mountain Spotted Fever, arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis; proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children occurs with renal involvement

Hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis

  • Extrinsic allergic alveolitis Extrinsic allergic alveolitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis
  • Antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination: a microbe, protein, or chemical
  • IC IC Inhaled Anesthetics deposition in alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS), interstitium, bronchioli, and lung parenchyma
  • Farmer’s lung: Ag AG Metabolic Acidosis from thermophilic Thermophilic Campylobacter molds on crops
  • Bird fancier’s disease: Ag AG Metabolic Acidosis from intestinal mucin in droppings or feathers
  • Note: can also be T-lymphocyte–mediated (type IV reaction)

Polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides (PAN)

  • Etiology mostly idiopathic Idiopathic Dermatomyositis but can be a reaction to hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology surface Ag AG Metabolic Acidosis
  • Medium-sized arterial 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 → ↓ blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure, ↑ thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus; spares the veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins: Histology
  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy: most commonly involved organ
  • Presentation: 
    • Tender erythematous nodules Erythematous Nodules Hidradenitis Suppurativa, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, renal insufficiency, and neuropathy Neuropathy Leprosy
    • Some have abdominal symptoms (mesenteric arteritis)

Diagnosis and Management

Diagnosis

  • Clinical history and findings (Arthus reaction, serum sickness often diagnosed clinically)
  • Laboratory tests: 
    • CBC 
      • 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, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, leukopenia: SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
      • Eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome: serum sickness, hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis
    • Metabolic panel 
      • Creatinine is abnormal in reactions involving the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy
    • Serologies and culture
      • Hepatitis panel for polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides
      • Culture: streptococcal infection (only 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will have positive results because PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis occurs weeks after the infection)
    • Complement levels 
      • Generally found in low levels in associated conditions
    • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
      • ANA, anti-dsDNA Ab, antiSmith Ab, anti-RNP Ab, antiphospholipid Ab: SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus 
      • PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis: antistreptolysin Antistreptolysin Antibodies specific to streptolysins which indicate streptococcal infections. Postinfectious Glomerulonephritis O (ASO), streptozyme test
    • 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 
      • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children: SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus, PAN, serum sickness
      • PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis: hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Inflammatory markers 
      • Generally elevated C-reactive protein (CRP), erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess) during active 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
    • Imaging
      • High-resolution computed tomography (CT) (lung): hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis
      • Arteriography or CT/ magnetic resonance angiography Magnetic resonance angiography Non-invasive method of vascular imaging and determination of internal anatomy without injection of contrast media or radiation exposure. The technique is used especially in cerebral angiography as well as for studies of other vascular structures. Imaging of the Urinary System ( MRA MRA Imaging of the Heart and Great Vessels): for polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides
      • 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: joint involvement
    • Surgical procedures 
Hypersensitivity pneumonitis

A 27-year-old female patient with a history of exposure to mold Mold Mycology. High-resolution CT High-resolution CT Imaging of the Lungs and Pleura scans of the chest ( lung window Lung Window Computed Tomography (CT)) at the level of the lower lobes show extensive ground-glass opacities (asterisks), with overlapping foci of lobular air trapping (arrows).

Image: “ Hypersensitivity Pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis” by Torres PP, Moreira MA, Silva DG, da Gama RR RR Relative risk (RR) is the risk of a disease or condition occurring in a group or population with a particular exposure relative to a control (unexposed) group. Measures of Risk, Sugita DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, Moreira MA. License: CC BY 4.0

Management

  • Remove or avoid offending agent
  • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines, nonsteroidal anti-inflammatory drugs ( NSAIDs NSAIDS Primary vs Secondary Headaches) for symptom relief ( rash Rash Rocky Mountain Spotted Fever, itching, joint pains)
  • In reactions due to infection ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis), antibiotic therapy if infection is still present
  • Control of complications such as hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis, PAN), edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis, SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus), airway Airway ABCDE Assessment symptoms ( hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis)
  • 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 used in severe cases to suppress 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
  • Therapeutic options for specific conditions:
    • Hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis: immunosuppressive therapy ( mycophenolate Mycophenolate Immunosuppressants, 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)
    • SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus:
      • Antimalarials ( 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, chloroquine Chloroquine The prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. Antimalarial Drugs
      • Immunosuppressive therapy: mycophenolate Mycophenolate Immunosuppressants, 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, cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants, rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
      • Long-term anticoagulation Anticoagulation Pulmonary Hypertension Drugs if with thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus: warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants, low-molecular-weight heparin
    • PAN:
      • 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, a disease-modifying anti-rheumatic drug ( DMARD DMARD Disease-modifying antirheumatic drugs are antiinflammatory medications used to manage rheumatoid arthritis. The medications slow, but do not cure, the progression of the disease. The medications are classified as either synthetic or biologic agents and each has unique mechanisms of action and side effects. Disease-Modifying Antirheumatic Drugs (DMARDs))
      • Immunosuppressive therapy ( cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants, 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)
  • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis for end-stage renal disease from SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
  • Organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation:
    • Lung transplantation Lung transplantation The transference of either one or both of the lungs from one human or animal to another. Organ Transplantation for advanced lung disease in hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis (HP), previously called extrinsic allergic alveolitis, is an immunologically induced inflammatory disease affecting the alveoli, bronchioles, and lung parenchyma. It is caused by repeated inhalation of an inciting agent in a susceptible host that triggers first a type III (complement-mediated) hypersensitivity reaction in the acute phase and then a type IV (delayed) reaction in the subacute and chronic phases. Hypersensitivity Pneumonitis
    • Renal transplantation for end-stage renal disease in SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus

References

  1. King, T., Flaherty, K. & Hollingsworth, H. (Eds.). (2019). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis. UpToDate. Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-treatment-prognosis-and-prevention
  2. King, T., Flaherty, K. & Hollingsworth, H. (Eds.). (2020). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. UpToDate.  Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-treatment-prognosis-and-prevention
  3. Lu, L., Suscovich, T., Fortune, S., Galit, A. (2017). Beyond Binding: antibody effector functions in infectious diseases. Nature Reviews Immunology, 18, 46–61. https://doi.org/10.1038/nri.2017.106
  4. Mak, T., Saunders, M., Jett, B. (2007). Primer to the Immune response. Elsevier, 2nd ed.
  5. Mayadas, T., Tsokos, G., Tsuboi, N. (2009). Mechanisms of Immune Complex-mediated Neutrophil Recruitment and Tissue Injury : official publication of the Circulation, 120(20), 2012–2014. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.108.771170
  6. Merkel, P., Hunder, G. & Ramirez Curtis, M. (Eds.) (2019). Clinical manifestations and diagnosis of polyarteritis arteritis nodosa in adults. UpToDate.  Retrieved 17 Aug 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults
  7. Wallace, D., Gladman, D., Pisetsky, D.,Shur, P & Ramirez Curtis, M. (Eds.) (2019). Overview of the management and prognosis of systemic lupus erythematosus in adults. UpToDate. Retrieved  17 Aug 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-lupus-erythematosus-in-adults
  8. Wallace, D., Pisetsky, D., Shur, P & Ramirez Curtis, M. (Eds.) (2020,). Overview of the management and prognosis of systemic lupus erythematosus in adults. UpToDate. Retrieved  17 Aug 2020, from https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-systemic-lupus-erythematosus-in-adults

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