Henoch-Schönlein Purpura

Henoch-Schönlein purpura (HSP), also known as immunoglobulin A vasculitis, is an autoimmune small-vessel vasculitis that typically presents as a tetrad of abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, arthralgia, hematuria, and purpuric rash. The pathophysiology involves the deposition of IgA immune complexes in multiple vessels following a trigger (infection/environmental), and the symptoms depend on the tissues that are involved. The diagnosis is established clinically, but can be supported with laboratory studies and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin or kidney biopsy. Management is mostly supportive, but may involve steroids and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants in more severe cases. Prognosis is usually excellent, but some patients may develop end-stage renal failure.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Henoch-Schönlein purpura (HSP) is an immunoglobulin A (IgA)-mediated small-vessel vasculitis.

Epidemiology

  • Most common vasculitis in children
  • 90% of cases occur in children 3–15 years of age.
  • 20/100,000 in children versus 5/100,000 in adults
  • More prevalent in whites
  • Men > women (1.2–1.8:1)
  • Rare in the summer months

Etiology

  • Multifactorial: genetic susceptibility and environmental triggers
  • Autoimmune/antigenic secondary to preceding infection (respiratory or GI) in 75% of the cases:
    • Most common identifiable preceding infection: group A 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)
    • Other infections: mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis, hepatitis, Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma and Campylobacter Campylobacter Campylobacter ("curved bacteria") is a genus of thermophilic, S-shaped, gram-negative bacilli. There are many species of Campylobacter, with C. jejuni and C. coli most commonly implicated in human disease. Campylobacter infections, viral upper respiratory infections (URIs)
    • Possible association with preceding MMR vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination
  • Can be preceded by insect bites
  • Possibly associated with IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy (Berger’s disease)
  • Associated with Familial Mediterranean 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
  • Drug induced: 
    • Ampicillin/penicillin
    • Erythromycin
    • Quinidine/quinine
    • Losartan

Pathophysiology

  • A disease of immune-complex deposition
  • Deposition of IgA, C3, and fibrin in small vessels results in vasculitis.
  • Neutrophils and monocytes predominate within the inflammatory infiltrate.
  • Multiple antigenic targets have been proposed, but inconsistently identified.
  • Affects tissues supplied by small vessels: 
    • Skin
    • 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
    • GI tract
    • Joints
    • CNS
  • Skin biopsy reveals leukocytoclastic vasculitis in the postcapillary venules.
  • Renal biopsy reveals immune-complex deposition in the mesangium.

Clinical Presentation

  • Classic tetrad:
    • Purpuric rash
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Arthralgia
    • Renal disease/hematuria
  • Skin (95%–100%):
    • 1st presenting sign in about ¾ of patients
    • Usually begins with an erythematous macular rash
    • Progresses to non-painful palpable purpura (hallmark clinical sign)
    • Symmetrically distributed in gravity-dependent areas (legs, buttocks)
    • The rash may resolve and then reoccur.
  • GI (35%–85%):
    • Nausea, vomiting
    • Colicky abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
    • Bloody or non-bloody diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Complications: intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception (ileo-ileal > ileocecal)
    • Most common GI complication in children, rare in adults
  • Arthralgia/arthritis (60%–85%):
    • Transient
    • Migratory
    • Swollen and tender joints
    • May affect 1–2 joints, mainly knee and ankle
    • Nonchronic, non-deforming
  • Renal (20%–54%):
    • Hematuria (ranging from microscopic to gross) is the most common finding.
    • Proteinuria (ranging from mild to nephrotic range):
      • Severe proteinuria is uncommon.
      • Signifies development of progressive disease
    • 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
    • Possible progression to chronic renal disease, especially in adults
  • Others:
    • Scrotal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/ 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 (2%–38%)
    • Subcutaneous 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
    • Encephalopathy
    • Keratitis/ uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea

Diagnosis

History and physical exam

  • Usually sufficient to establish diagnosis
  • URI/strep A prodrome followed by tetrad:
    • Rash
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Arthralgia
    • Renal disease

Laboratory workup

Laboratory workup is used to rule out differentials and evaluate complications.

  • CBC: 
    • Normal RBC count or normocytic 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 (due to GI bleeding)
    • Normal platelet count or thrombocytosis
  • Chemistry:
    • Elevated BUN and creatinine
    • Electrolyte disturbance
  • Prothrombin/partial thromboplastin time:
    • Should be normal in HSP
    • Abnormalities should raise the suspicion of alternative diagnoses
  • Acute-phase reactants:
    • Elevated CRP
    • Elevated erythrocyte sedimentation rate (ESR)
  • IgA: increased (50%)
  • C3/C4: reduced
  • Factor XIII: reduced (50%)
  • Urine Analysis (UA): 
    • Hematuria (ranges from microscopic to gross)
    • Proteinuria (ranges from mild to nephrotic range)

Biopsy

  • Reserved for unusual/severe presentations
  • More commonly needed in adult patients
  • Skin: leukocytoclastic vasculitis in postcapillary venules
  • Renal biopsy reveals immune-complex deposition in the mesangium
Hsp renal biopsy showing immunostaining for iga

Renal biopsy in Henoch-Schönlein purpura showing immunostaining for IgA

Image: “Henoch-Schönlein nephritis IgA immunostaining” by Lazarus Karamadoukis, Linmarie Ludeman, and Anthony J Williams. License: CC BY 2.0

Imaging

Imaging is used for complicated presentations.

  • Ultrasound: 
    • To evaluate scrotal 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
    • To evaluate for intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception (may show “target sign”)
  • Abdominal X-ray: to evaluate for intestinal obstruction
  • MRI/CT head: for neurological symptoms (small vessels)
Target sign typical of intussusception on abdominal ultrasound

Target sign typical of intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception on abdominal ultrasound

Image: “Pelvic plastron secondary to acute appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis in a child presented as appendiceal intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception. A case report” by Christianakis E, Sakelaropoulos A, Papantzimas C, Pitiakoudis M, Filippou G, Filippou D, Rizos S, Paschalidis N. License: CC BY 2.0

Management

Management

  • Supportive treatment (the only measure needed in mild cases):
    • Rest: bedrest with extremity elevation
    • Hydration
    • Analgesics:
      • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen
      • NSAIDs
  • Renal involvement:
    • Observation with UA, and measurement of BP weekly for 6 weeks and monthly for 6 months:
      • Observe for hematuria
      • Observe for proteinuria
    • Antihypertensives, if needed
    • Corticosteroids, if persistent nephritic syndrome Nephritic syndrome Nephritic syndrome is a broad category of glomerular diseases characterized by glomerular hematuria, variable loss of renal function, and hypertension. These features are in contrast to those of nephrotic syndrome, which includes glomerular diseases characterized by severe proteinuria, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephritic Syndrome
    • Immunosuppressants
    • Plasmapheresis (delays progression)
    • End-stage renal disease: kidney transplant
  • Abdominal:
    • Corticosteroids for severe abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Surgery for intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception/bowel ischemia
  • CNS: immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants/corticosteroids
  • Arthralgia: corticosteroids for severe joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Prognosis

  • Excellent prognosis if:
    • Mild renal symptoms
    • No CNS involvement
    • < 3 years of age
    • Duration < 6 weeks
  • Morbidity and mortality increase in the following cases:
    • Recurrent rash in 6 months
    • Severe renal symptoms
    • Adults
  • ⅔ of cases experience no recurrence.

Differential Diagnosis

  • Acute glomerulonephritis: an immune-mediated inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the glomeruli. Causes involve primary and secondary inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and often follow a streptococcal infection. Acute glomerulonephritis presents with generalized 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, hypertension, and dark urine. Diagnosis is based on UA, blood work, and positive streptococcal cultures/titers. Management is mostly supportive.
  • Berger’s disease ( IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy): the most common cause of primary glomerulonephritis worldwide, which presents with IgA deposition in the mesangial tissues. A differentiating factor from HSP is the lack of extra-renal manifestations. Definitive diagnosis is based on renal biopsy. Management includes steroids and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.
  • Idiopathic thrombocytopenic purpura: immune-mediated destruction of platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, which also presents with a purpuric rash. The differentiating factor is that HSP often results in thrombocytosis. Diagnosis is based on clinical presentation and low platelet counts. Management includes steroids and splenectomy in certain cases.
  • Meningitis in children Meningitis in Children Meningitis is inflammation of the meninges around the brain and spinal cord. The majority of cases occur during childhood and are predominantly viral or bacterial in etiology. Clinical presentation is influenced by the age of the child and the causative pathogen, but meningitis typically presents with signs of meningeal irritation, fever, and lethargy. Meningitis in Children: Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria meningiditis infections present with a similar rash that is non-blanching and associated with high-grade 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. Diagnosis is established with CSF Gram stain and culture, and the treatment is with antibiotics.
  • Infective endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the endocardium secondary to infection. Infective endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis is associated with a skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin rash similar to that seen in HSP. Diagnosis is established with blood cultures and echocardiogram. Antibiotics are the mainstay of treatment.

References

  1. Dedeoglu, F., Kim, S. (2019). IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis. Retrieved March 2, 2021, from https://www.uptodate.com/contents/iga-vasculitis-henoch-schonlein-purpura-clinical-manifestations-and-diagnosis
  2. Dedeoglu, F., Kim, S. (2021). IgA vasculitis (Henoch-Schönlein purpura): Management. Retrieved March 2, 2021, from https://www.uptodate.com/contents/iga-vasculitis-henoch-schonlein-purpura-management
  3. Bhimma, R. (2021). Henoch-Schönlein purpura (IgA vasculitis). Retrieved March 2, 2021, from https://emedicine.medscape.com/article/984105-overview
  4. Leung, A.K.C., Barankin, B., Leong, K.F. (2020). Henoch-Schönlein purpura in children: An updated review. Curr Pediatr Rev: 16(4),265–276. https://pubmed.ncbi.nlm.nih.gov/32384035/

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