Henoch-Schönlein purpura

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In medicine (rheumatology and pediatrics) Henoch-Schönlein purpura (HSP, also known as allergic purpura) is a systemic vasculitis (inflammation of blood vessels) characterized by deposition of immune complexes containing the antibody IgA, especially in the skin and kidney. It occurs mainly in children. Typical symptoms include palpable purpura (small hemorrhages in the skin), joint pains and abdominal pain. Most cases are self-limiting and require no treatment apart from symptom control, but the disease may relapse (in 33% of cases) and cause irreversible kidney damage (in 1%).^[1]

The disease was named Henoch-Schonlein purpura (HSP) after Johann Schonlein and Eduard Henoch due to their role in establishing the clinical manifestations of the disease

Henoch-Schönlein purpura (HSP) is an immune complex-mediated disease with circulating immune complexes and IgA rheumatoid factors usually follows upper respiratory tract infections, various viruses, and the bacteria have been implicated as triggers of the disease.

The common causes of Henoch-Schönlein purpura (HSP) are infections, medications, hypersesitivity, vaccinations, genetics etc.

Henoch-Schönlein purpura should be differentiated from other immune complex mediated small vessel vasculitis such as Anti-glomerular basement membrane disease, Cryoglobulinemic vasculitis, Hepatitis C virus-associated cryoglobulinemic vasculitis, Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis).

The incidence of HSP is approximately 6-20 cases per 100,000 individuals. The prevalence of HSP is more in children of 4-6 years age group. HSP usually affects Caucasians than any other ethnic groups. Males are more commonly affected by HSP than females. The Male to female ratio is approximately 1.5-2:1.

Henoch-Schönlein purpura (HSP) is associated with following risk factors it’s most common in children of 2 to 6 years, involves young boys more than girls, Asian and white race, spring, fall and winter months, Group A streptococci, Mycoplasma, Epstein-Barr virus infections, and environmental exposure of allergens, organophosphates, cold temperature.

There is insufficient evidence to recommend routine screening for HSP.

Henoch-Schönlein purpura is a self-limiting illness in the majority of patients but can rarely lead to complications such as proteinuria, End Stage Renal Disease, myocardial infarction, pulmonary hemorrhage, pleural effusion, intussusception, orchitis, GI bleeding, bowel infarction, seizures, neuropathies. The prognosis is usually good but rarely its worse in adults with renal involvement.

Henoch-Schönlein purpura is diagnosed using a biopsy of the skin and kidney.

The signs and symptoms of Henoch-Schönlein purpura (HSP) are skin lesions such as palpable purpura, abdominal pain, melena, bloody diarrhea, hematemesis, duodenal ulcers, arthralgia.

Physical examination of patients with HSP is usually remarkable for palpable purpura.

There is no specific diagnostic test available for HSP. Platelet count, coagulation studies such as PT, aPTT, and BT are done to rule out other diseases like coagulopathies. They are usually normal. Urinalysis is done to check for any blood in the urine or proteinuria for renal involvement. Serum IgA levels are elevated in the majority of patients with HSP, and in patients with renal involvement higher IgA levels are detected.

There are no ECG findings associated with Henoch-Schönlein purpura.

There are no x-ray findings associated with Henoch-Schönlein purpura (HSP).

Surgical intervention is not recommended for the management of Henoch-Schönlein purpura.

Henoch-Schönlein Purpura (HSP) is usually treated with supportive management by adequate hydration, balancing fluid and electrolyte, and controlling hypertension. Symptoms such as arthritis, edema, fever are treated with acetaminophen, leg elevation, and adequate hydration. Pharmacological management includes use of analgesics, NSAIDs, corticosteriods and various other immuno-suppressants. Plasmapheresis may be effective in delaying the progression of kidney disease and is usually done in addition to steroids.

There are no established measures for the primary prevention of Henoch-Schönlein purpura.

There are no established measures for the secondary prevention of Henoch-Schönlein purpura.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The disease was named Henoch-Schonlein purpura (HSP) after Johann Schonlein and Eduard Henoch due to their role in establishing the clinical manifestations of the disease.

• The historical perspective of Henoch-Schönlein purpura:^[1]
• The first case of Henoch-Schönlein purpura was described by Herberden in the year 1801.
• He described a young boy with a skin rash, abdominal pain, hematuria, and subcutaneous edema.
• The disease was named Henoch-Schonlein purpura (HSP) after Johann Schonlein and Eduard Henoch due to their role in establishing the clinical manifestations of the disease.
• Johann Schonlein identified purpura and joint pain as symptoms of HSP, which at the time he referred to as purpura rheumatica.
• Eduard Henoch described the associated gastrointestinal and renal complications of the HSP.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There is no established system for the classification of Henoch-Schönlein purpura.

There is no established system for the classification of Henoch-Schönlein purpura.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Henoch-Schönlein purpura (HSP) is an immune complex-mediated disease with circulating immune complexes and IgA rheumatoid factors usually follows upper respiratory tract infections, various viruses, and the bacteria have been implicated as triggers of the disease.

The pathophysiology of HSP:^[1][2][3]

• HSP is a small vessel leukocytoclastic vasculitis, but its pathophysiology is not completely understood.
• In patients with HSP the serum IgA levels are elevated, HSP is an immune complex-mediated disease with circulating immune complexes and IgA rheumatoid factors usually follows upper respiratory tract infections, various viruses, and the bacteria have been implicated as triggers of the disease.
• Patients with HSP have circulating IgA immune-complexes, patients with HSPN have an additional large molecular mass IgA1–IgG-containing circulating immune complexes.
• The IgA1 molecule has a hinge region containing up to six O-linked glycan chains consisting of N-acetylgalactosamine, usually with an attached β1,3-linked galactose.
• It has been reported that in patients with HSP, the activity of β1,3-galactosyltransferase in peripheral B cells is reduced, leading to a lack of terminal β1,3-galactosyl residues in the hinge region of IgA1.
• The primary defect leading to the production of such abnormally glycosylated IgA1 is probably heritable.
• These aberrantly glycosylated IgA1 molecules have been shown to form immune complexes with IgG antibodies specific for galactose-deficient IgA1, thereby inhibiting the binding of the IgA molecules to hepatic receptors and avoiding their internalization and degradation by hepatic cells.
• This formation results in an increased amount of IgA immune complexes in circulation.
• The complexes may then deposit in renal mesangial areas and activate the complement system by the alternative or lectin pathways, which play a major role in the pathophysiology of this disease.
• Further, after depositing in the mesangium, the galactose-deficient IgA1 immune complexes activate mesangial cells.
• This results in the proliferation of cells such as macrophages and lymphocytes and the production of inflammatory and profibrogenic cytokines and chemokines, which play a pivotal role in mesangial cell proliferation, matrix expansion, and inflammatory cell recruitment.
• Other mechanisms for developing HSP
  • Nephritis-associated plasmin receptor, a group A streptococcal antigen, has been reported in some cases of HSP.
  • Activation of the eosinophils and expression of the alpha-smooth muscle actin in the kidney also play a vital role in the pathogenesis of Henoch-Schönlein purpura.

Biopsy: ^[4][5][6]

• Indications
  • No rash
  • Abnormal renal function tests

Skin biopsy

• Light Microscopy
  • IgA deposition in postcapillary venules with IgA deposition and leukocytoclastic vasculitis in is a pathognomonic microscopic feature of Henoch-Schönlein Purpura.
  • Skin lesions less than 24 hrs are preferred as the chronic lesion lack the immunoglobulin isotypes essential for the diagnosis of HSP.
  • A biopsy from a different skin site is taken for the immunofluorescent studies to confirm the diagnosis.

Renal biopsy

• IgA deposition in the mesangium on immunofluorescence microscopy should be differentiated from the IgA nephropathy.
• Light microscopic features range from isolated mesangial proliferation to severe crescentic glomerulonephritis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The common causes of Henoch-Schönlein purpura (HSP) are infections, medications, hypersensitivity, vaccinations, genetics etc.

• The causes of the HSP is as follows:^{[1][2][3][4][5][6]}
• The exact cause of HSP is not clear.

• Common causes
  • Infections–
  • Medications
  • Hypersensitivity
  • Vaccinations– certain vaccines can cause HSP such as Typhoid, HBV, Measles, Yellow fever, and Cholera.
• Rare causes
  • Genetics– very rarely HSP can occur in twins and within the family
  • Other triggers Certain drugs, bacteria, insect bites, viral infections, food, cold weather, and trauma may also cause HSP.
• In HSP, the antibodies are directed against the blood vessels causing vasculitis, bleeding into the skin leading to a subsequent skin rash.
• Allergic reaction to foods may cause HSP.
• Very rarely HSP can occur in twins and within the family.
  

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Henoch-Schönlein purpura should be differentiated from other immune complex mediated small vessel vasculitis such as Anti-glomerular basement membrane disease, Cryoglobulinemic vasculitis, Hepatitis C virus-associated cryoglobulinemic vasculitis, Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis).

Henoch-Schönlein purpura should be differentiated from other immune complex mediated small vessel vasculitis such as Anti-glomerular basement membrane disease, Cryoglobulinemic vasculitis, Hepatitis C virus-associated cryoglobulinemic vasculitis, Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis).

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)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The incidence of HSP is approximately 6-20 cases per 100,000 individuals. The prevalence of HSP is more in children of 4-6 years age group. HSP usually affects Caucasians than any other ethnic groups. Males are more commonly affected by HSP than females. The Male to female ratio is approximately 1.5-2:1.

Epidemiology and demgraphics of HSP:^[1][2]

• The incidence of HSP is approximately 6-20 cases per 100,000 individuals.

• The prevalence of HSP is more in children of 4-6 years age group.

• HSP usually affects Caucasians than any other ethnic groups.

• Males are more commonly affected by HSP than females. The Male to female ratio is approximately 1.5-2:1.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Henoch-Schönlein purpura (HSP) is associated with following risk factors it’s most common in children of 2 to 6 years, involves young boys more than girls, Asian and white race, spring, fall and winter months, Group A streptococci, Mycoplasma, Epstein-Barr virus infections, and environmental exposure of allergens, organophosphates, cold temperature.

The risk factors of the Henoch-Schönlein purpura are as follows:^{[1][2][3][4][5]}

• Age– Most common in children of 2 to 6 years.
• Sex– Males more than females.
• Race– Asian and white.
• Season– Spring, fall and winter months.
• Infections– Group A streptococci, Mycoplasma, Epstein-Barr virus.
• Environmental – allergens, organophosphates, cold temperature.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Henoch-Schönlein purpura is a self-limiting illness in the majority of patients but can rarely lead to complications such as proteinuria, End Stage Renal Disease, myocardial infarction, pulmonary hemorrhage, pleural effusion, intussusception, orchitis, GI bleeding, bowel infarction, seizures, neuropathies. The prognosis is usually good but rarely its worse in adults with renal involvement.

• The natural history of HSP is as follows:^{[1][2][3][4][5][6][7]}
• Henoch-Schönlein purpura is a self-limiting illness in the majority of patients.
• The abdominal and joint pain may be debilitating, and steroids have been used with some success in relieving the abdominal pain.
• The vasculitis of the gastrointestinal tract causes significant blood loss and occasionally leading to bowel ischemia, which may necessitate bowel resection.
• There is no clear evidence that remedy alters the progression of the HSP, however, the significant long-term morbidity related to the renal disease that has led to trials of steroids and other immunosuppressive drugs.

The complications of the HSP are as follows:^{[1][2][3][4][5][6][7]}

• Renal involvement- Proteinuria, End Stage Renal Disease in 1% of patients.

• Other complications
  • Myocardial infarction
  • Pulmonary hemorrhage
  • Pleural effusion
  • Intussusception of both small and large intestines
  • Orchitis
  • GI bleeding
  • Bowel infarction
  • Seizures
  • Neuropathies.

• The prognosis of the HSP:^{[8][2][9][10][11][12]}
• Henoch-Schönlein purpura is an acute self-limited illness, can seldom cause complications.
• Initial attacks of HSP can last for several months. One in every four patients will have one or more recurrences.
• HSP is more benign, short course and less recurrent in children less than three years.
• CKD can progress more than 10 years after the initial HSP attack.
• The long-term prognosis of HSP depends on the extent of the kidney involvement.
• Renal involvement of more common and the prognosis is worst in adults with HSP than the children.

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