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Cryoglobulinemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Synonyms and keywords: Cryoglobulinaemia

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Ayesha A. Khan, MD[3]

Overview

Cryoglobulinemia is the presence of high amount of heavy globulins (e.g. IgM) in the bloodstream which thicken or gel on exposure to cold. Cryoglobulins are circulating immunoglobulins or proteins that become insoluble at less than 4 degrees Celsius. The reaction is reversible; redissolution occurs at 37 degrees Celsius. Such proteins are called cryoglobulins. Cryoglobulinemia can lead to a medium-sized vessel vasculitis due to vascular deposition of circulating immune complexes. This leads to the triad of palpable purpura, arthralgias and peripheral neuropathy. The relationship of cryoglobulins and hepatitis C infection as well as B cell neoplasia provides an interesting link between infection, autoimmune disease and lymphoproliferative disorders.

Classification

Pathophysiology

Causes

Differentiating cryoglobulinemia from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

X Ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Findings

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

References


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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

In 1966, Meltzer and Franklin were the first ones to describe Meltzer triad which includes following clinical manifestations, purpura, arthralgia, and weakness.

Historical Perspective

The historical perspective of cryoglobulinemia is as follows:[1][2]

  • In 1966, Meltzer and Franklin were the first ones to describe Meltzer triad which includes following clinical manifestations, purpura, arthralgia, and weakness.
  • This triad of clinical manifestations was seen in the patients having essential mixed cryoglobulinemia.

References

  1. ↑ Meltzer M, Franklin EC, Elias K, McCluskey RT, Cooper N (1966). “Cryoglobulinemia–a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity”. Am J Med. 40 (6): 837–56. PMID 4956871.
  2. ↑ Monti G, Galli M, Invernizzi F, Pioltelli P, Saccardo F, Monteverde A; et al. (1995). “Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias”. QJM. 88 (2): 115–26. PMID 7704562.


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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Cryoglobulinemia is classically grouped into three types according to the Brouet classification. These are type 1, type 2 and type 3.

Classification

Cryoglobulinemia is classically grouped into three types according to the Brouet classification.[1]

Types of cryoglobulinemia
Associated diseases Type 1 Type 2 Type 3
  • Lymphoproliferative or plasma proliferative disorders(LPD)
  • Monoclonal gammopathy of undetermined significance (MGUS)
  • Hepatitis C virus
  • Connective tissue disease
  • Idiopathic
  • LPD
  • Hepatitis C virus
  • Connective tissue disease
  • Idiopathic
  • Other infections

Type I

  • It can lead to a glomerulopathy that is distinct from light chain disease in amyloidosis.

Type II

  • Type II is essential mixed cryoglobulinemia and the cryoglobulins are a polyclonal IgG and a momoclonal IgM rheumatoid factor directed against IgG.
  • Epstein-Barr Virus (EBV), HIV and Hepatitis B have been implicated but the majority is due to Hepatitis C (HCV).

Type III

  • Type III is also a mixed cryoglobulinemia (MC) where both the IgG and IgM are polyclonal.
  • It is seen in various autoimmune disorders and lymphoreticular disease as well as hepatitis C in almost 50%.

References

  1. ↑ Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974). “Biologic and clinical significance of cryoglobulins. A report of 86 cases”. Am. J. Med. 57 (5): 775–88. PMID 4216269.
  2. ↑ Ferri C, Zignego AL, Pileri SA (2002). “Cryoglobulins”. J. Clin. Pathol. 55 (1): 4–13. PMID 11825916.


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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]Feham Tariq, MD [3]

Overview

Cryoglobulins are proteins (single or mixed immunoglobulins) that precipitate from serum and plasma when cooled. They are produced due to chronic immune system activation and lymphoproliferation. Cryoglobulins have a tendency to redissolve on rewarming.

Pathophysiology

  • Cryoglobulins are proteins (single or mixed immunoglobulins) that precipitate from serum and plasma when cooled.
  • They are produced due to chronic immune system activation and lymphoproliferation.
  • Cryoglobulins have a tendency to redissolve on rewarming.
  • The pathogenesis of cryoglobulinemia differs slightly based on the type of disorder and disease associations.
  • The following are the major mechanisms involved in the pathogenesis of cryoglobulinemia:

Type I cryoglobulinemia (Monoclonal immunoglobulin)

Key background associations

  • Type I cryoglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as:
    • Multiple myelomas (MM)
    • Monoclonal gammopathy of undetermined significance (MGUS)
    • Waldenstrom’s macroglobulinemia
    • Chronic lymphocytic leukemia (CLL)

Mechanisms leading to precipitation of immunoglobulins (Ig)

The solubility of proteins depends upon concentration, hydrophobicity, size and surface charge, as well as the solution temperature, pH and ionic strength. The following mechanisms have been proposed to be implicated in the precipitation of immunoglobulins in patients suffering from type I cryoglobulinemia:

(a) Chronic immune stimulation

  • The lymphoproliferative and hematological disorders listed above lead to chronic activation of the immune system and production of higher concentrations of monoclonal immunoglobulins (usually IgG or IgM) at temperatures below 37 degrees celcius.

(b) Aggregation of immunoglobulins

  • Self aggregation through Fc fragment of immunoglobulins is the proposed mechanism of production of cryoglobulins in type I cryoglobulinemia

(i) Modification of Ig heavy (H) and light (L) chains

  • An abnormal glycosylation event in the heavy chain hypervariable region apparently leads to precipitation of immunoglobulins in type I cryoglobulinemia.[1]

(ii) Reduced concentration of sialic acid

  • Increased content of hydrophobic amino acids, decreased tyrosine and sialic acid residues has been known to lead to decreased solubility of immunoglobulins (Ig).[2]

(iii) Deficiency of galactose in the Fc portion of the Ig

  • Decreased galactose concentration in the Fc portion of immunoglobulins leads to decreased plasma solubility of immunoglobulins.[3]
  • The terminal sialylation of these proteins is dependent on the presence of galactose residues, hence decreased galactose leads to decreased sialylation, which in turn promotes precipitation of immunoglobulins.[4]
  • The decreased glycosylation has also been linked to the increased nephrophilic nature of cryoglobulins.

(iv) Somatic Ig mutations

  • Somatic hypermutation in the variable regions of the heavy (VH) and light chains (VL)  may also contribute to the insolubility of immunoglobulins.
  • Increased intraclonal VH and/or VL gene diversity has been shown to be present in various patients suffering from hepatitis C associated mixed cryoglobulinemia.[5]

(v) Non-specific Fc–Fc interactions

It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG:

  1. Hyperviscosity is typically associated with CG due to hematological malignancies and monoclonal immunoglobulins.
  2. “Meltzer’s triad” of palpable purpura, arthralgia and myalgia is generally seen with polyclonal CGs seen in essential-, viral-, or connective tissue disease-associated CG.
  • MC is closely associated with hepatitis C infection and is thought to activate B lymphocytes by binding to CD81.
  • 80-95% of patients with MC have circulating anti-HCV antibodies or circulating HCV RNA in the serum or within the cryoprecipitate.
  • Polyclonal IgG anti-HCV have been noted in the cryoprecipitate as well.
  • Approximately 50% of patients with chronic hepatitis C and 15% with hepatitis B will have circulating MC (1/2 Type II, 2/3 Type III).
  • It is unclear what the antigen trigger is for production of the MC, but it is though that the hepatitis C viral RNA itself may be the factor since it is found in high quantities in the cryoprecipitate.

References

  1. ↑ “Atypical glycosylation of an IgG monoclonal cryoimmunoglobulin”.
  2. ↑ Tomana M, Schrohenloher RE, Koopman WJ, Alarcón GS, Paul WA (March 1988). “Abnormal glycosylation of serum IgG from patients with chronic inflammatory diseases”. Arthritis Rheum. 31 (3): 333–8. PMID 3358797.
  3. ↑ Trendelenburg M, Schifferli JA (August 2003). “Cryoglobulins in chronic hepatitis C virus infection”. Clin. Exp. Immunol. 133 (2): 153–5. PMC 1808770. PMID 12869018.
  4. ↑ Otani M, Kuroki A, Kikuchi S, Kihara M, Nakata J, Ito K, Furukawa J, Shinohara Y, Izui S (November 2012). “Sialylation determines the nephritogenicity of IgG3 cryoglobulins”. J. Am. Soc. Nephrol. 23 (11): 1869–78. doi:10.1681/ASN.2012050477. PMC 3482736. PMID 23024299.
  5. ↑ “www.bloodjournal.org” (PDF).


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Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Common causes of cryoglobulinemia are primarily hematologic, oncologic, and rheumatic. Less commonly, cryoglobulinemia can be caused by infections such as HIV or Hepatitis C.

Causes

Common Causes

The common causes of cryoglobulinemia are as follows:[1][2][3][4]

Causes by Organ System

Cardiovascular Hypersensitivity vasculitis, Raynaud’s phenomenon
Chemical/Poisoning No underlying causes
Dental No underlying causes
Dermatologic Purpura
Drug Side Effect No underlying causes
Ear Nose Throat Sjögren’s syndrome
Endocrine No underlying causes
Environmental No underlying causes
Gastroenterologic No underlying causes
Genetic Sjögren’s syndrome
Hematologic B-cell hyperactivation  , B-cell hyperproliferation, Leukemia, Multiple myeloma, Myeloma, Primary macroglobulinemia, Purpura, Raynaud’s phenomenon
Iatrogenic No underlying causes
Infectious Disease Hepatitis c, Hiv, Mycoplasma pneumonia
Musculoskeletal/Orthopedic No underlying causes
Neurologic No underlying causes
Nutritional/Metabolic No underlying causes
Obstetric/Gynecologic No underlying causes
Oncologic Leukemia, Multiple myeloma, Myeloma, Primary macroglobulinemia, Waldenström macroglobulinaemia
Ophthalmologic No underlying causes
Overdose/Toxicity No underlying causes
Psychiatric No underlying causes
Pulmonary Mycoplasma pneumonia
Renal/Electrolyte Glomerulonephritis
Rheumatology/Immunology/Allergy Arthropathy, Rheumatoid arthritis, Rheumatoid disease, Systemic lupus erythematosus
Sexual Hiv
Trauma No underlying causes
Urologic No underlying causes
Miscellaneous No underlying causes

Causes in Alphabetical Order

References

  1. ↑ Scotto G, Cibelli DC, Saracino A, Prato R, Palumbo E, Fazio V; et al. (2006). “Cryoglobulinemia in subjects with HCV infection alone, HIV infection and HCV/HIV coinfection”. J Infect. 52 (4): 294–9. doi:10.1016/j.jinf.2005.05.025. PMID 16026843.
  2. ↑ Suszek D, Majdan M (2018). “[Cryoglobulins and cryoglobulinemic vasculitis]”. Wiad Lek. 71 (1 pt 1): 59–63. PMID 29558353.
  3. ↑ Blank N, Lorenz HM (2016). “[Cryoglobulinemic vasculitis]”. Z Rheumatol. 75 (3): 303–15. doi:10.1007/s00393-016-0076-4. PMID 27034078.
  4. ↑ Ramos-Casals M, Trejo O, García-Carrasco M, Cervera R, Font J (2000). “Mixed cryoglobulinemia: new concepts”. Lupus. 9 (2): 83–91. doi:10.1191/096120300678828127. PMID 10787003.


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Differentiating Cryoglobulinemia from other Diseases

Differentiating Cryoglobulinemia from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Cryoglobulinemia should be differentiated from hemolytic uremic syndrome, antiphospholipid syndrome, churg-strauss syndrome, polyarteritis nodosa, microscopic polyangitis and temporal arteritis.

Differentiating Cryoglobulinemia from other Diseases

Cryoglobulinemia should be differentiated from hemolytic uremic syndrome, antiphospholipid syndrome, churg-strauss syndrome, polyarteritis nodosa, microscopic polyangitis and temporal arteritis.

Abbreviations: ABG= Arterial blood gas, ANA= Antinuclear antibody, ANP= Atrial natriuretic peptide, ASO= Antistreptolysin O antibody, BNP= Brain natriuretic peptide, CBC= Complete blood count, COPD= Chronic obstructive pulmonary disease, CRP= C-reactive protein, CT= Computed tomography, CXR= Chest X-ray, DVT= Deep vein thrombosis, ESR= Erythrocyte sedimentation rate, HRCT= High Resolution CT, IgE= Immunoglobulin E, LDH= Lactate dehydrogenase, PCWP= Pulmonary capillary wedge pressure, PCR= Polymerase chain reaction, PFT= Pulmonary function test.

Diseases Clinical manifestations Para-clinical findings Gold standard Additional findings
Symptoms Physical examination
Lab Findings Imaging Histopathology
Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other
Large-Vessel Vasculitis Takayasu arteritis[1] + +/- + – + + +/- +/- MMP-3 and MMP-9 Leukocytosis, Anemia ↑ ↑CRP Aneurysmal dilatation of the aorta Blood vessel stenosis Circumferential thickening of the arterial wall (Macaroni sign) PET-scan, Cardiac CT Granulomatous inflammation of arteries Arteriography Coronary aneurysm
Giant cell arteritis[2] + – + +/- – – – +/- Pentraxin 3 (PTX3) Normal ↑ ↑CRP Stenosis, Occlusion, Dilatation Aneurysm – Mural inflammation in MRA Granulomatous inflammation of arteries Biopsy  Jaw pain and claudication
Neurological disease Cerebral aneurysm[3] + – – – – – +/- + – Normal Normal – Well-defined round, slightly hyperattenuating lesion Bulging out of the main lumen – Heterogeneous signal intensity in MRA Layers of smooth muscle cells, Intact endothelium Digital subtraction angiography (DSA) Nausea, Vomiting
Neurofibromatosis type 1[4] +/- – +/- – – – + + NF1 mutated gene Normal Normal Neurofibromin gene Bone abnormalities  Optical coherence tomography angiography (OCTA) – Optic nerve gliomas in MRI Elongated spindle-shaped cells in neurofibromas NIH diagnostic criteria Cafe au Lait spot
Neurofibromatosis type 2[5] +/- – +/- – +/- – – + NF2 mutated gene Normal Normal Schwannomin Meningioma, Schwannoma, Ependymoma Fluorescein angiography showed retinal hamartoma Localized schwannomas in nerve ultrasound Schwannoma in MRI Encapsulated biphasic nerve sheath tumor NIH diagnostic criteria Hearing loss, Vision loss
Systemic disease Fibromuscular dysplasia[6] + – +/- + + + + +/- Transforming growth factor β (TGF-β) Normal ↑ ↑ Cr or BUN Alternating stenosis and dilatations in CT angiography Stenosis in the renal arteries Luminal narrowing alternating with dilatation (Beads sign) Focal concentric, long-segment tubular stenosis or outpouching in MRA Fibrodysplastic changes, Collagen deposition Digital subtraction angiography (DSA)  Spontaneous coronary artery dissection (SCAD)
Ehlers-Danlos syndrome[7] – – – + +/- +/- – +/- TGF-β Normal Normal Cultured skin fibroblasts Multiple vascular segments with aneurysms and dissections Dissection of the posterolateral branch of the left circumflex coronary artery (LCx) Visceral arteries abnormality Vascular abnormalities in MRA Thin and rare collagen bundles in the dermis History and physical examination Bleeding, Bruisability, Heart murmur
Polymyalgia rheumatica (PMR)[8] + – +/- + – – – – Plasma fibrinogen Normocytic, normochromic anemia ↑ CRP Periodontoid localization of calcification Vessel wall thickening, Increased mural contrast enhancement Subacromial or subdeltoid bursitis High F-FDG accumulation around the joints in FDG PET-CT Small angular fibers, Pyknotic nuclear clumps, or target-targetoid fibers – Joint stiffness, Fatigue
Amyloidosis[9] +/- – – +/- +/- – + + Immunoglobulin light chain(Amyloid) Anemia Normal ↑ Cr or BUN,

↑ ALT or AST

Diffusely hypoattenuating and enlarged liver Amyloid deposition in the media and adventitia of small arteries  Solid organs increased echogenicity Tc-DPD for cardiac amyloid deposits Extracellular deposition of fibrillar proteins Biopsy Cardiomegaly, Dyspnea
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Medium-Vessel Vasculitis Polyarteritis nodosa[10] + + + + + + +/- +/- LAMP-2 protein autoantibodies Leukocytosis, Normochromic anemia, Thrombocytosis ↑ ↑ Cr or BUN,

↑ ALT or AST, Proteinuria

Focal regions of infarction or hemorrhage Multiple microaneurysms, Hemorrhage due to focal rupture, Occlusion Aneurysms and renal arteriovenous fistula in color Doppler sonography – Necrotizing inflammatory lesions Angiography Sudden weight loss, Abdominal pain
Hepatitis B virus-associated polyarteritis nodosa[11] +/- +/- + + +/- +/- + – HBsAg Leukocytosis, Normochromic anemia, Thrombocytosis ↑ ↑ ALT or AST Focal regions of infarction or hemorrhage Microaneurysms in mesenteric artery Aneurysms and renal arteriovenous fistula in color Doppler sonography – Necrotizing inflammatory lesions Angiography Peripheral neuropathy, Livedo reticularis
Kawasaki disease[12] – + +/- + + – +/- – NT-proBNP, Meprin A, Filamin C Normochromic anemia, ↑WBC with a left shift, Thrombocytosis  ↑ Acute-phase reactants, ↓Cholesterol, ↓HDL, ↓ApolipoA Coronary artery calcifications Coronary artery aneurysms, stenosis or occlusion Coronary artery anomaly in echocardiography Electron beam CT (EBCT) Acute destruction of the media by neutrophils, with loss of elastic fibers History and physical examination Diarrhea, Vomiting
Infectious disease Parvovirus B19 infection[13] + + + + – – – +/- B19 DNA, ↓Reticulocyte count Anemia ↑ anti–parvovirus B19 IgM – – Hydrops in fetal ultrasonography – – B19 DNA Purpuric rash, Erythema multiforme
Scarlet fever[14] + + +/- + – – – – Antistreptolysin-O (ASO) titers Leukocytosis ↑ ↑CRP Thickened pulmonary markings if pneumonia – – – Sparse neutrophilic perivascular infiltrate History and physical examination Sand-paper rashes, Sore throat
Toxic shock syndrome[15] + + + + – – – +/- Procalcitonin Leukocytosis with left shift ↑ Myoglobinuria, Sterile pyuria Acute respiratory distress syndrome – – – Necrolysis of keratinocytes in epidermis, Perivascular lymphocytic infiltrate Clinical criteria Peeling or rashes, Organ dysfunction
Mononucleosis[16] + + + + – – – – EBV DNA Atypical lymphocyte ↑ Heterophile antibodies CNS involvement – Splenomegaly Encephalitis in MRI Lymphoproliferative response in oropharynx, Lymphocytic infiltration in spleen Heterophile antibody test Splenomegaly, Palatal petechiae
Leptospirosis[17] + + + + +/- – – – IL-6, IL-8 and IL-10 Anemia – ↑Cr or BUN,

↑ALT or AST, Proteinuria

 Diffuse alveolar hemorrhage – – – Toxin-mediated break down of endothelial cell membranes of capillaries Culture and the microscopic agglutination test Red eyes, Skin rash
Lyme Disease[18] +/- + +/- + +/- – – – CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) Leukopenia, Thrombocytopenia – Microscopic hematuria, Proteinuria, ↑ALT or AST Punctate lesions in periventricular white matter in brain SPECT – – – Acrodermatitis chronica atrophicans Serologic tests Erythema migrans
Measles[19] +/- + +/- + – – – – Measles IgM Leukopenia, Lymphocytosis, Thrombocytopenia – ↑ALT or AST Pneumonia – – CXR Spongiosis and vesiculation in the epidermis with scattered dyskeratotic keratinocytes PCR Generalized rash, Cough, Coryza, or Conjunctivitis
Rocky Mountain Spotted Fever[20] + + + + – – – – R rickettsii serology Thrombocytopenia, Anemia  – ↑ALT or AST, Hyponatremia Infarction, edema, and meningeal enhancement – Myocardial or conduction abnormalities in echocardiography – Immunofluorescent or immunoperoxidase staining of R rickettsii Clinical criteria and tick exposure Rash on the palms and soles
Staphylococcal Scalded Skin Syndrome[21] + + + + – – +/- +/- Anti exfoliatin and anti alpha-toxin antibodies Leukocytosis with left shift ↑ Blood culture Pneumonia – – – Intraepidermal blister, dense superficial perivascular lymphohistiocytic infiltrate  Blood culture and clinical findings Widespread skin erythema, fluid-filled blisters
Toxic Epidermal Necrolysis[22] – + + – – – – +/- MicroRNA-124 Normochromic normocytic anemia, Eosinophilia ↑ Fluid loss and electrolyte abnormalities Tracheobronchial inflammation – – – Necrotic keratinocytes with full-thickness epithelial necrosis Histopathology and clinical findings Erythematous macular rash with purpuric centers
Cardiovascular disease Atrial Myxoma[23] – – +/- – – – – +/- Calretinin Mild anemia, Leukocytosis ↑ ↑IL-6 Atrial filling defect larger than a thrombus – Tumor location, size, attachment, and mobility in echocardiography Size, shape, and surface characteristics in MRI Lipidic cells embedded in a vascular myxoid stroma Echocardiography Dyspnea on exertion, Syncope
Cholesterol Embolism[24] +/- +/- – – + – – + IL-5 Eosinophilia, Leukocytosis   ↑ Eosinophiluria Thoracic and abdominal aortic sources of embolism Atheroembolism in abdominal aorta and the lower extremity arteries Excluding an intracardiac source of embolism with echocardiography  – Birefringent crystals or biconvex needle-shaped ghostly clefts within the arterial lumen Angiography  Livedo reticularis,

Ischemic patches

Segmental arterial mediolysis[25] + – – – + + + +/- – Leukocytosis – – Visceral artery aneurysm in CT angiography Alternating aneurysms and stenoses (beading) Retroperitoneal hematoma – Disruption of the smooth muscle in the media Angiography  Hematuria, Ischemic colitis
Systemic disease Antiphospholipid Syndrome[26] + + – – – – – +/- Antiphospholipid antibodies Thrombocytopenia, Hemolytic anemia – Lupus anticoagulant (LA) Stroke,

Pulmonary embolism, Budd-Chiari syndrome

Thrombus in major vessels Valve thickening, vegetations, or insufficiency in echocardiography – Noninflammatory bland thrombosis without perivascular inflammation Hx of thrombosis and antiphospholipid antibodies Miscarriage, Pulmonary hypertension
Juvenile Idiopathic Arthritis[27] – – – + +/- – – – Rheumatoid factor (RF), S100A12 Lymphocytosis, Thrombocytopenia ↑ Myeloid-related proteins 8/14 (MRP8/14) Synovial hypertrophy, Joint effusions Cerebral vasculitis Inflamed synovium Bone scanning Vascular congestion, RBC extravasation, Venular lumen occlusion Conventional radiography Evanescent rash, Dactylitis 
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Small-Vessel Vasculitis ANCA-associated vasculitis Microscopic polyangiitis[28] + – – +/- – – – + Anti-PR3 antibody (C-ANCA) (40%), Anti-MPO antibody (P-ANCA) (60%) Leukocytosis, Normocytic anemia ↑ Proteinuria, Erythrocyte casts Suspected pancreatitis Mesenteric angiography for differentiating from polyarteritis nodosa – Bilateral nodular, and patchy opacities in CXR Glomerulonephritis with focal necrosis, crescent formation, and lack or paucity of immunoglobulin deposits Histological confirmation Rash, Hemoptysis 
Granulomatosis with polyangiitis (Wegener’s)[29] + +/- +/- – – – – + Anti-PR3 antibody (C-ANCA) (90%), Anti-MPO antibody (P-ANCA) (10%) Leukocytosis, Normochromic normocytic anemia ↑ ↑Cr or BUN, Hypoalbuminemia Consolidation, Patchy or diffuse ground-glass opacities Occlusion or stenosis of LAD and RCA in coronary angiography – Single or multiple nodules and masses with cavitation in CXR Parenchymal necrosis, Granulomatous inflammation Histological confirmation Conjunctivitis,

Episcleritis,

Uveitis,

Optic nerve vasculitis

Eosinophilic granulomatosis with polyangiitis

(Churg-Strauss)[30]

+/- – – + – – – + Anti-MPO antibody (P-ANCA) (40%), Eotaxin-3 Eosinophilia, Anemia ↑ ↑Cr or BUN, Proteinuria, Erythrocyte casts, ↑IgE levels Significant enlargement of peripheral pulmonary arteries Myocardial ischemia and infarction in coronary angiography Congestive heart failure (CHF) in echocardiography Extensive air-space opacities in CXR Small necrotizing granulomas with eosinophilic core surrounded by macrophages and epithelioid giant cells Histological confirmation Allergic rhinitis, Asthma, Urticarial rash
Hydralazine-associated ANCA-associated vasculitis[31] – – – + – – – +/- Anti-MPO antibody (P-ANCA), Anti-histone antibodies Anemia – ↑Cr or BUN, Hypoalbuminemia Bilateral pulmonary infiltrates Aneurysms or occlusions of the visceral arteries – – Pauci-immune necrotizing and crescentic glomerulonephritis Histological confirmation Sinusitis, Hemoptysis
Immune complex small-vessel vasculitis Anti-glomerular basement membrane disease[32] + +/- – – – – + – Anti-GBM antibodies Hypochromic microcytic anemia, Thrombocytopenia – ↓C3 level Pulmonary hemorrhage – Normal kidneys Alveolar infiltrates spreading from the hilum in CXR Cellular crescents in the glomeruli, Intra-alveolar hemorrhages Anti-GBM antibodies Hemoptysis, Hematuria
Cryoglobulinemic vasculitis[33] +/- +/- – + +/- – – – C4 component Leukocytosis, Anemia ↑ ANA, hypocomplementemia R/O underlying malignancy Stenosis or occlusions of the visceral arteries Bacterial endocarditis in echocardiography Interstitial involvement or pleural effusions in CXR HCV-associated proteins in vasculitic skin, Intraluminal cryoglobulin deposits  Histological confirmation Acrocyanosis, Retinal hemorrhage, Purpura
Hepatitis C virus-associated cryoglobulinemic vasculitis[34] +/- +/- + + – – + +/- HCV RNA, Cryoglobulins Leukocytosis, Anemia ↑ ↓Serum C4, Positive RF Increased hepatic echogenicity – Hepatomegaly, Splenomegaly Increased hepatic echogenicity in MRI Vasculitic skin, Antigen infilteration in lesions HCV RNA, Histological confirmation Palpable purpura, Microscopic hematuria
IgA vasculitis (Henoch-Schönlein purpura)[35] – – + + – – – – IgA Normochromic anemia, Leukocytosis  ↑ Stool OB, ↓C3, ↓C4 – – Increased bowel wall thickness, hematomas, peritoneal fluid, and intussusception Dilated loops of bowel consistent in abdominal X-ray Leukocytoclastic vasculitis in postcapillary venules with IgA deposition History and physical examination Hematuria, Palpable purpura
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)[36] – – +/- + – – – – C1q Mild anemia ↑ ANA, ↓C1q, ↓C3, ↓C4 – – Hepatomegaly, Splenomegaly – Deposits of immunoglobulins, complement, or fibrin around blood vessels Urticaria,

Histological confirmation

Urticaria, Hematuria
Gastrointestinal disease Acute mesenteric ischemia[37] – +/- – – – – – – I-FABP, Alpha-GST, Ischemia-modified albumin (IMA) Leukocytosis, ↑HCT –  ↑Amylase Bowel wall thickening, Intestinal pneumatosis, Portomesenteric thrombosis Mesenteric venous thrombosis  Arterial stenosis or occlusion of the celiac or superior mesenteric arteries in duplex ultrasound Ileus with distended loops of bowel, Bowel wall thickening in abdominal X-ray Superficial mucosal hemorrhage, edema and necrosis History and physical examination Abdominal pain, Distension, Absent bowel sounds
Cardiovascular disease Infective Endocarditis[38] + + + – – – – + NT-proBNP Normochromic-normocytic anemia ↑ Hyperglobulinemia, Cryoglobulinemia Metastatic infections, such as splenic infarct, renal infarcts, or psoas abscess – Vegetation, abscess, or new dehiscence of a prosthetic valvein echocardiography Vertebral osteomyelitis in MRI Vegetation or intracardiac abscess demonstrating active endocarditis Echocardiography (TTE) Janeway lesions, Osler nodes, Roth spots, Vertebral osteomyelitis
Leukocytoclastic Vasculitis[39] + – – + – – – + IgM, IgA, IgG Leukocytosis, Anemia ↑ Hypocomplementemia – Vascular stenosis and obstruction in visceral angiography – – Perivascular inflammatory infiltrate of neutrophils with leukocytoclasia (releasing nuclear debris) Histological confirmation Palpable purpura, Petechiae 
Pulmonary disease Langerhans Cell Histiocytosis[40] +/- – – + – – – – CD1a, CD207,BRAF-V600E Anemia ↑ Hypercalcemia Pulmonary cysts and nodules, Bone lytic lesions – Hepatomegaly, Splenomegaly Cerebellum and pons hyperintensity in MRI Birbeck granules by electron microscopy Histological confirmation Brown to purplish papules, Eczematous rash
Non-Small Cell Lung Cancer[41] – +/- + – – – – +/- EGFR, ROS1, EML4-ALK,  PD-L1 Leukocytosis, Anemia ↑ Hypercalcemia, Hyponatremia Pulmonary lesion or mass – Pulmonary marginal lesions Staging and response to treatment in PET-CT Adenocarcinoma, Squamous cell carcinoma High resolution CT-scan Cough, Hemoptysis
Small Cell Lung Cancer[42] – +/- + – – – – +/- p53, Thyroid transcription factor-1 (TTF1) Anemia ↑ Hyponatremia Large hilar mass with bulky mediastinal adenopathy – Endobronchial ultrasound (EBUS) Standard staging Spindled cells with dark nuclei, scant cytoplasm, and fine, granular nuclear chromatin High resolution CT-scan Cough, Hemoptysis
Pulmonary Infarction[43] +/- – – – – – + – D-dimer Mild leukocytosis, Mild anemia – Hypoxemia, Hypocarbia or Hypercarbia, Respiratory alkalosis Pulmonary embolism Low-density filling defect within the pulmonary artery Pericardial effusion in echocardiography Pulmonary infiltrates, atelectasis, and pleural effusions in CXR Infarct induced apoptosis Pulmonary artery angiography Cough, Hemoptysis
Renal disease Acute Poststreptococcal Glomerulonephritis[44] – – – + – – + +/- Antistreptolysin-O (ASO) titers Leukocytosis ↑ Hypocomplementemia – – Normal to slightly enlarged kidneys Central venous congestion in a hilar pattern in CXR Hypercellularity of endothelial and mesangial cells, Infiltration of the glomerular tuft with polymorphonuclear cells Histological confirmation Hematuria
Hematologic disease Hemolytic-Uremic Syndrome[45] + + – + – – + + C5b-9, ADAMTS13 Anemia, Thrombocytopenia, Reticulocytosis  ↑ ↑Lactate dehydrogenase (LDH), Hypercalcemia  Thalami, brainstem, or cerebellum abnormality Cerebral microangiopathy or hypertension Hypoechoic kidney  Abnormal hyperintensity in the brain cisterns in MRI Microthromboses include fibrin thrombi that may occlude the glomerular tuft Clinical findings coupled with laboratory abnormalities Hematuria, Proteinuria 
Chronic Lymphocytic Leukemia (CLL)[46] + + + + +/- – – +/- CD5, CD19, CD20, IgVH Absolute lymphocytosis, Smudge cells ↑ Flow cytometry Staging – – – Large atypical cells, cleaved cells, and prolymphocytes  Chromosomal and genetic testing Easy bruising
Multiple Myeloma[47] + – + + + + +/- +/- Ig light chain Anemia, Thrombocytopenia, Leukopenia ↑ Bone marrow aspiration and biopsy, ↑Cr Osseous involvement and lytic lesions Peripheral zone of increased vascularity in lesions – Punched-out lesion in skull X-ray Clonal proliferation of plasma cells Protein electrophoresis plus conventional X-rays Constipation
Hypereosinophilic Syndrome[48] +/- +/- – – – – – – IgE, CD117 with CD2 Eosinophilia – ↑Serum tryptase Lymphadenopathy and splenomegaly – Intracardiac thrombi in echocardiography – Reticulin stain for myelofibrosis and tryptase staining for mast cells Clinical findings coupled with laboratory abnormalities Splinter hemorrhages, Raynaud phenomenon
Non-Hodgkin Lymphoma[49] + + + + +/- +/- +/- +/- MYC, BCL2, BCL6, and TP53 Lymphocytosis, Anemia, Thrombocytopenia ↑ ↑Lactate dehydrogenase (LDH), Hypercalcemia  Enlarged lymph nodes, Hepatosplenomegaly, Filling defects in the liver and spleen – Hepatosplenomegaly Mediastinal lymphadenopathy Small cleaved or noncleaved, intermediate, or large cell with a follicular or diffuse pattern Surgically excised tissue biopsy Easy bruising, Testicular mass, Skin lesion
Serum Sickness[50] + + – +/- +/- – – +/- IL-1, IL-6, TNF Leukopenia  ↑ Polyclonal gammopathy, ↑Cr, Cryoglobulinemia – – – – Arteritic lesions are focal, necrotizing, and inflammatory involving all layers of the artery Clinical findings coupled with laboratory abnormalities Hematuria, Skin rash
Disseminated Intravascular Coagulation[51] +/- + – +/- – – + + Fibrin degradation product (FDP) Thrombocytopenia, Schistocytes ↑ ↑D-dimer, aPTT and PT Intracranial hemorrhage – – – Ischemia and necrosis due to fibrin deposition in small and medium-sized vessels Clinical findings coupled with laboratory abnormalities  Acral cyanosis, Hemorrhagic skin infarctions
Idiopathic Thrombocytopenic Purpura[52] + +/- – + – – – + FC gamma receptors (FCGR) IIb Anemia, Thrombocytopenia – HIV, ANA R/O other causes – R/O splenomegaly – Increased number of normal morphologic megakaryocytes Clinical findings coupled with thrombocytopenia Easy bruising, Purpura
Systemic disease Sarcoidosis[53] + + + + – – – +/-  IL-2 and IFN-γ Mild anemia ↑ ↑ACE, ↑1, 25-dihydroxyvitamin D Active alveolitis or fibrosis – Hepatosplenomegaly Bilateral hilar adenopathy Noncaseating granulomas (NCGs) Histological confirmation Heart block, Ocular lesion
Legionella Infection[54] + + + + – – – +/- Inflammatory cytokines Leukocytosis with left shift, Thrombocytosis ↑ ↑D-dimer, FDP, Hyponatremia Pleural effusion – – Nonspecific and indistinguishable CXR Intra-alveolar inflammation, Microabscesses in the parenchyma Sputum culture Cough, Diarrhea
Systemic lupus erythematosus[55] + + + + – – + + Anti dsDNA, ANA  Leukopenia, Lymphopenia, Anemia, Thrombocytopenia ↑ ↑Cr or BUN,

↑ALT or AST, Proteinuria

Interstitial lung disease, Pneumonitis, Pulmonary emboli, Alveolar hemorrhage Aneurysms Pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis in echocardiography Central nervous system (CNS) lupus white-matter changes in MRI Staging lupus nephritis Anti-dsDNA antibody test Skin rashes or photosensitivity
Rheumatoid arthritis[56] – – + + + + – – RF, Anti-CCP antibody Anemia ↑ ↑Cr or BUN,

↑ALT or AST, ANA

Microfractures Aneurysms Effusions in joints Basilar invagination with cranial migration of an eroded odontoid peg in MRI Influx of inflammatory cells into the synovial membrane, with angiogenesis, proliferation of chronic inflammatory cells Clinical findings coupled anti-CCP antibody Rheumatoid nodules
Relapsing polychondritis[57] – +/- +/- + + – – – – Leukocytosis, Anemia – Cryoglobulins, ANA, C-ANCA Calcification of cartilaginous structures Aortic root dilatation Aortic root dilatation and degree of aortic regurgitation in echocardiography Tracheal stenosis in CXR Chondrolysis, Chondritis, Perichondritis Clinical findings coupled with imaging Ear pain and redness, Polyarthritis
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Variable-vessel vasculitis Behçet’s syndrome[58] – – – + – – +/- – CXCL1  Mild anemia, Neutrophilia ↑ Factor V Leiden Focal CNS lesions Aneurysm formation and thrombosis areas Valve vegetations and ventricular thrombi in echocardiography Meningoencephalitis  in MRI Lymphocytic and plasma cell invasion in the prickle cell layer of the epidermis Clinical criteria Genital ulcerations, Oral ulceration
Cogan’s syndrome[59] +/- – – +/- – – – +  Anti-Hsp70 antibodies Anemia, Thrombocytosis ↑ RF, ANA Thickening and enhancement of both posterior sclera  Stenosis, thrombosis or more lesions in aortic root Aortic insufficiency in echocardiography Early interstitial keratitis by slit lamp Muscle necrosis and atrophy resembling myositis – Red eye, Hearing loss, Vertigo
Gastrointestinal disease Inflammatory Bowel Disease[60] +/- + + + + – – – Anti-Saccharomyces cerevisiae antibody (ASCA), P-ANCA Leukocytosis, Anemia ↑  Iron or vitamin deficiency, Stool OB Mesenteric fat stranding, bowel wall enhancement, increased vascularity (comb sign) – Fistulas, Abscesses, Stenosis Grossly denuded mucosa with active bleeding in colonoscopy Crypt abscesses and mucosal ulceration, Granulomas  Endoscopy  GI bleeding
Whipple’s disease[61] + +/- + + + + + + CCR6, Gut-homing marker integrin β7-chain, T whippelii DNA Mild anemia, Neutrophilia ↑ 72-hour fecal fat determination Nonspecific malabsorption – Hepatosplenomegaly – Periodic acid-Schiff–positive macrophages infiltration in lamina propria of the small bowel Broad-spectrum PCR amplifications Cachexia,

Glossitis

Sjögren’s syndrome[62] – – +/- + – – – – Anti-Ro and Anti-La, Anti-alpha-fodrin antibody Anemia,

Leukopenia,

Eosinophilia

↑ Hypergammaglobulinemia, Low bicarbonate level, Hypokalemia  Salt and pepper or honeycomb appearance in parotid glands – Multicystic or reticular pattern in atrophic salivary gland R/O obstructions or strictures with Sialography  Focal aggregates of lymphocytes Schirmer test Keratoconjunctivitis, Gingival inflammation
Single-organ vasculitis Primary central nervous system vasculitis[63] + + + – + – + + von Willebrand factor antigen (vWF) Normal – CSF pleocytosis, predominantly lymphocytes Cerebral infarcts or hemorrhages with mass effect, or hydrocephalus Aneurysm in circle of Willis – Progression of the disease or response to therapy in MRI Chronic granulomatous inflammation and giant cells Histological confirmation Skin rash, Purpura
Infectious disease Aspergillosis[64] + + + – – – – + Aspergillus nucleic acid in blood, Galactomannan Eosinophilia ↑ ↑Serum IgE Aspergilloma mass within a cavity Mass effect stenosis – Aspergilloma mass within the brain in MRI Septate hyphae, branching at acute angles, and tissue necrosis with granulomata and blood vessel invasion Histological confirmation Hemoptysis, Aspergilloma
Histoplasmosis[65] + + + + + – – + – Mild anemia ↑ ↑ALP, ↑LDH Cerebral histoplasmosis  – Valvular involvement in echocardiography PFT Presence of yeast forms in tissue through hematoxylin and eosin staining Sputum cultures Pneumonia, Mediastinitis
Herpes Simplex Encephalitis[66] + + – – – – – + HSV DNA Mild lymphocytosis ↑ CSF pleocytosis Low-density lesions in the temporal and/or frontal lobe – – Hemorrhagic lesion in white matter Multinuclear giant cells PCR or brain biopsy Seizures,

Vomiting

Systemic disease Eclampsia[67] + + – + – – + + VEGF, PlGF, Soluble FLT-1 Anemia, Thrombocytopenia, Schistocytes – ↑Bilirubin, ↓Haptoglobin, ↑LDH, ↑Cr Cortical hypodense areas in the occipital lobes, Diffuse cerebral edema – Poor fetal growth, Oligohydramnios, Abnormal umbilical artery  Increased signal at the gray-white matter junction in MRI – 24-hour urine study  Seizure, Edema
Fibromuscular dysplasia[6] + – +/- + + + + +/- Transforming growth factor β (TGF-β) Normal ↑ ↑ Cr or BUN Alternating stenosis and dilatations in CT angiography Stenosis in the renal arteries Luminal narrowing alternating with dilatation (Beads sign) Focal concentric, long-segment tubular stenosis or outpouching in MRA Fibrodysplastic changes, Collagen deposition Digital subtraction angiography (DSA)  Spontaneous coronary artery dissection (SCAD)


References

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  2. ↑ Calvo-Romero JM (2003). “Giant cell arteritis”. Postgrad Med J. 79 (935): 511–5. PMC 1742823. PMID 13679546.
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  29. ↑ Kubaisi B, Abu Samra K, Foster CS (2016). “Granulomatosis with polyangiitis (Wegener’s disease): An updated review of ocular disease manifestations”. Intractable Rare Dis Res. 5 (2): 61–9. doi:10.5582/irdr.2016.01014. PMC 4869584. PMID 27195187.
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  60. ↑ Wehkamp J, Götz M, Herrlinger K, Steurer W, Stange EF (2016). “Inflammatory Bowel Disease”. Dtsch Arztebl Int. 113 (5): 72–82. doi:10.3238/arztebl.2016.0072. PMC 4782273. PMID 26900160.
  61. ↑ Dutly F, Altwegg M (2001). “Whipple’s disease and “Tropheryma whippelii““. Clin Microbiol Rev. 14 (3): 561–83. doi:10.1128/CMR.14.3.561-583.2001. PMC 88990. PMID 11432814.
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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

The prevalence of cryoglobulinemia is approximately 1 per 100,000 individuals worldwide. The mean age reported is 42-52 years. It is more prevalent in females as compared to males, the ratio being 3:1.

Epidemiology and Demographics

Incidence

  • The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

Prevalence

  • The prevalence of cryoglobulinemia is approximately 1 per 100,000 individuals worldwide.[1]

Case Fatality Rate

Age

  • The mean age reported is 42-52 years.

Gender

  • Cryoglobulinemia is more prevalent in females as compared to males.[2]
  • The ratio is 3:1.

Region

  • The majority of cryoglobulinemia cases are reported in Mediterranean basin.


References

  1. ↑ Gorevic PD, Kassab HJ, Levo Y, Kohn R, Meltzer M, Prose P; et al. (1980). “Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients”. Am J Med. 69 (2): 287–308. PMID 6996482.
  2. ↑ Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974). “Biologic and clinical significance of cryoglobulins. A report of 86 cases”. Am J Med. 57 (5): 775–88. PMID 4216269.


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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Common risk factors of cryoglobulemia are certain malignancies, autoimmune diseases and infections. Among these, leukemia, multiple myeloma, rheumatoid arthritis, hepatitis B, cytomegalovirus are more commonly seen risk factors in patients having cryoglobulemia. Other risk factors that contribute to cryoglobulinemia are epstein-Barr virus, human parvovirus B19 and mycoplasma pneumonia.

Risk Factors

Type I cryoglobulinemia is most often related to hematologic malignancies.

Types II and III are most often found in people who have a chronic (long-lasting) inflammatory condition, such as an autoimmune disease or infections such as hepatitis C. Most patients with mixed cryoglobulinemia have a chronic hepatitis C infection.

Common risk factors

The common risk factors of cryoglobulemia are as follows:[1][2][3]

Malignancy:

Autoimmune disorders:

Infections:

References

  1. ↑ Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y (2009). “Infection and vasculitis”. Rheumatology (Oxford). 48 (5): 475–82. doi:10.1093/rheumatology/kep026. PMID 19258377.
  2. ↑ Rodríguez-Pla A, Stone JH (2006). “Vasculitis and systemic infections”. Curr Opin Rheumatol. 18 (1): 39–47. PMID 16344618.
  3. ↑ Fabris P, Tositti G, Giordani MT, Romanò L, Betterle C, Pignattari E; et al. (2003). “Prevalence and clinical significance of circulating cryoglobulins in HIV-positive patients with and without co-infection with hepatitis C virus”. J Med Virol. 69 (3): 339–43. doi:10.1002/jmv.10294. PMID 12526043.


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Screening

Screening

Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Natural History

Complications

The complications of cryoglobulinemia are as follows:

Prognosis

Patients having severe manifestations of the disease such as pulmonary vasculitis, end-stage renal disease, cardiac vasculitis and central nervous system vasculitis have generally poor prognosis of the disease. The prognosis of cryoglobulinemia depends on the organ system involved and varies accordingly.

Organ system involved Survival rate
Glomerulonephritis 79%
Pulmonary vasculitis 22%
Central nervous system vasculitis 66%
Gastrointestinal vasculitis 67%
Cardiac vasculitis 100%

References


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Diagnosis

Diagnosis

Diagnostic Study of Choice | History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | MRI | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Case Studies

Case Studies

Case #1

Acknowledgements

Acknowledgements

The content on this page was first contributed by: Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

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