Acute Hemorrhagic Edema of Infancy (AHEI)
Also known as Finkelstein’s disease, Seidlmayer syndrome, infantile Henoch-Schönlein purpura, urticarial vasculitis of infancy, or benign cutaneous leukocytoclastic vasculitis of infancy (other nonthrombocytopenic purpura).
Are You Confident of the Diagnosis?
What you should be alert for in the history
The sudden onset of purpuric skin lesions, mild fever, and tender edema of the hands, feet, or face, with a history of a recent viral or bacterial infection, especially within the last 7-15 days, new medication usage, or vaccination in an otherwise healthy and well child suggests the diagnosis of acute hemorrhagic edema of infancy (AHEI).
Diagnostic criteria have been proposed that include:
Less than 2 years of age.
Purpuric or ecchymotic target-like skin lesions (Figure 1) with edema on the face, auricles, and extremities, with or without mucosal involvement.
Lack of systemic disease or visceral involvement.
Spontaneous recovery within a few days or weeks.
Characteristic findings on physical examination
Characteristic findings include purpura, approximately 1-6 cm in diameter, and petechiae. Skin lesions may erupt as erythematous macules, papules, or urticaria. They are sharp-edged and symmetric, and may be targetoid, annular, medallion-like, or cockade. Bullous lesions or necrosis may also be present.
Rash prominently affects the extremities and face, especially the ears, hands, and feet, and usually displays truncal and mucosal sparing; however truncal or mucosal involvement does not preclude the diagnosis. Nonpitting, tender edema of the distal extremities or more rarely the face, eyelids, earlobes, or scrotum may be present. The child otherwise appears well.
Expected results of diagnostic studies
Serologic studies may be performed to rule out more serious causes of acute purpuric lesions (such as septic vasculitis or disseminated intravascular coagulation), however, in classical cases, diagnostic tests are not needed. Blood tests usually reveal nonspecific findings including leukocytosis, thrombocytosis, an elevated erythrocyte sedimentation rate, or C-reactive protein. There will be normal coagulation studies, urinalysis, and complement and immunoglobulin levels. ASO titer, antinuclear antibodies, antideoxyribonucleic acid antibodies, and rheumatoid factor are negative.
If the diagnosis is in doubt, histopathology will illustrate leukocytoclastic vasculitis mediated by immune complexes. The vasculitis typically involves both capillaries and venules of the mid and upper dermis, with possible fibrinoid necrosis. The inflammatory infiltrate is predominately neutrophils with occasional eosinophils. Immunofluorescence studies may exhibit positivity for fibrinogen, C3, C1q, IgM, IgG, IgE, or even IgA, however, none are specific.
The presence of purpuric lesions and fever in a young child generates a broad differential that may include other causes for vasculitis, purpura, or petechiae. Henoch-Schönlein purpura (HSP), meningococcemia, Rocky Mountain spotted fever, cryoglobulinemic vasculitis, Kawasaki disease, erythema multiforme, thrombocytopenia, clotting disorders, and child abuse are all part of the initial differential.
The relatedness of AHEI and HSP is still debated; accordingly, HSP is strongly considered in the case of any child presenting with the rapid onset of purpuric lesions. HSP, however, affects older children (ages 2-6 years) and presents with abdominal or joint pain or renal involvement, features that are absent in AHEI. Moreover in HSP, the lesions usually do not affect the face and are more polymorphic, the duration of disease is much longer, and relapsing disease is common. Laboratory studies showing normal renal function with absence of abdominal or joint pain exclude the diagnosis.
Meningococcemia, Rocky Mountain spotted fever, or septicemia may present with a cutaneous hemorrhagic rash and tissue necrosis akin to purpura fulminans, but the child will appear toxic with hypotension and high fever. Cryoglobulinemic vasculitis may have skin lesions reminiscent of AHEI and may have a leukocytoclastic vasculitis on histology and an eosinophilic material within the vessels of the dermis may be seen.
Clinically, hepatosplenomegaly, lymphadenopathy, or glomerulonephritis may be present. A history of lymphoma, leukemia, hepatitis C, or connective tissue disease is common in cryoglobulinemic vasculitis.
Kawasaki disease may mimic the rash, edema, and rare mucosal involvement of AHEI; it can be differentiated from AHEI by the presence of lymphadenopathy, conjunctivitis, and high fever. Erythema multiforme (EM) will generally present with more macules and papules that evolve into the classic targetoid lesions. Histopathology illustrates interface dermatitis with necrosis of keratinocytes, spongiosis, and exocytosis.
Thrombocytopenia, including idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP) can present with normal-high platelet counts in the former and normal-high platelet counts, normal hemoglobin/hematocrit, and normal renal function in the latter. Clotting disorders are characterized by more mucosal bleeding, and can be excluded by normal coagulation studies.
Child abuse should be considered as well, but can be distinguished by historical features and lack of other signs of abuse, including bulging fontanelles, unusual location of lesions, or physical deformity.
Who is at risk for Developing Acute Hemorrhagic Edema of Infancy?
The disease affects infants usually between 2 and 24 months of age with an average age of 13.75 months; however, there have been case reports of congenital cases and in children up to 4 years of age. There is a clear male preponderance, with a male to female ratio of 4.64:1. The disease occurs more frequently during the winter.
What is the Cause of Acute Hemorrhagic Edema of Infancy?
The exact mechanism of disease is currently unknown, but most reports suggest a temporal relation to infection, medication, or immunization. Implicated infections include mild upper respiratory infections, otitis media, or tonsillitis and more serious infections like deep neck abscess, bronchopneumonia, or tuberculosis.
Drugs reported as involved include anti-inflammatories including aspirin and acetaminophen, antibiotics including penicillins, macrolides, sulfonamides, and cephalosporins, and over-the-counter medications such as cough syrup. Many vaccines have been reported including diptheria-pertussis-tetanus, polio, Haemophilus influenzae conjugated, and measles.
Because AHEI shares many clinical and pathologic sequelae of HSP, many believe that AHEI and HSP are clinical manifestations of the same pathophysiologic continuum. Proponents argue that HSP and AHEI share a sudden onset of purpuric lesions usually following an antigenic insult, and the differences in patient age, rash distribution, and visceral involvement are hypothesized to be a function of the maturing immune system and variations in blood flow in younger children.
Specifically, IgA levels are negligible at birth, and remain minimal during infancy. This may explain why IgA immune complex deposition is seen in older children with HSP while typically absent in children with AHEI. The predilection for facial purpura in AHEI, versus HSP where skin lesions are mostly found on the lower extremity or buttocks, is speculated to be due to an infant’s proportionally large head and abundant blood flow there and gravity dependence in older children.
Other authors contend, however, that the differences in rash distribution (lack of facial involvement in HSP), morphology of skin lesions (increased pleomorphism in HSP), length of disease (4 weeks for HSP and 12 days for AHEI), presence of visceral complications (including gastrointestinal bleeding, arthritis, and nephritis in HSP), and immunofluorescence (presence of IgA deposits in HSP, rarely seen in AHEI) prove that they are two different disease processes.
AHEI is an acute cutaneous leukocytoclastic vasculitis likely initiated by an improper immune response to some foreign antigen, whether infectious or drug-related. The disease is characterized by circulating immune complexes and associated leukocytoclastic vasculitis. Perivascular IgM deposition is a common finding. IgA deposits, common histologic findings in HSP, are rarely seen in AHEI but may still be found.
Systemic Implications and Complications
Despite the sudden and dramatic appearance of skin lesions, AHEI is a benign and self-limited disease with no associated systemic complications. The skin lesions, when healed, may show areas of hyperpigmentation, atrophy, or scar. There have been reports of recurrence of AHEI, but this is atypical. If recurrence occurs, disease presentation, progression, and resolution is identical to the primary bout.
Generally, AHEI is a benign and self-limiting disease that spontaneously resolves without treatment after 1-3 weeks. The goal of therapy is to provide supportive care to the child and prevent scarring or secondary infection. There is no effective treatment for AHEI, but in a patient where infection has been ruled out, some case reports describe some clinical improvement with corticosteroids (prednisone 1.5-2mg/kg/day) or dapsone (one patient 25mg daily). Antihistamines (such as hydroxyzine 2mg/kg/day q6 to 8 hours) have also been suggested to hasten wound healing (Table I).
|Mild||Supportive care including NSAID only|
|Moderate||Supportive care +/- trial of antihistamine or systemic corticosteroid|
|Severe||Supportive care + trial of antihistamine or systemic corticosteroid|
|Concomitant Infection||Add broad-spectrum antibiotics, narrow antibiotic choice after culture results|
NSAID = Nonsteroidal antiinflammatory drug
Systemic corticosteroid = prednisone, prednisolone, methylprednisolone, or betamethasone have been used
Optimal Therapeutic Approach for Acute Hemorrhagic Edema of Infancy
The first-line therapy is to provide supportive care for the child and utilize nonsteroidal anti-inflammatory drugs (NSAIDs) for fever and pain control. NSAIDs are especially important if articular or cartilageal structures are involved. Acetosalicylic acid (aspirin) should be avoided because of potential risk of Reye’s syndrome. NSAIDs have generally not been associated with Reye’s syndrome.
If lesions are suspected to have secondary infection, addition of broad spectrum antibiotics is recommended pending culture and sensitivity reports.
If moderate or severe skin lesions develop or extensive scarring is feared, a trial of an antihistamine or systemic corticosteroid may be explored as an adjunctive therapy. However the utility of these agents for patients with AHEI is uncertain and many suggest that these medications have no effect in modifying the disease course.
Treatment of children presenting with purpuric lesions centers on first ruling out life-threatening causes of purpura. If the diagnosis is in doubt, an initial laboratory work-up should include a complete blood count, basic metabolic profile, coagulation studies, urinalysis, and either an erythrocyte sedimentation rate or C-reactive protein. This information coupled with history and physical examination should be sufficient to rule out all nondermatologic causes of purpura. Histopathologic analysis of a skin biopsy should be able to then identify AHEI as the diagnosis if uncertainty remains.
It is important to understand that despite the dramatic appearance of the skin lesions in AHEI, the disease is completely benign and will spontaneously resolve. There are no systemic complications and the disease does not require any long-term monitoring or follow-up. It is important to recognize these lesions as benign early, as to avoid any unnecessary testing or biopsies.
Supportive care is the only needed therapeutic intervention. Because short-term usage of either an antihistamines or a corticosteroid carries little risk to the patient, a trial of either may be attempted; however clinical improvement is not assured.
Unusual Clinical Scenarios to Consider in Patient Management
A case has been reported in a 21-year-old woman that completely resolved after 3 weeks without therapy. This suggests that perhaps this disease may be under-recognized in adults.
What is the Evidence?
Karremann, M, Jordan, AJ, Bell, N. “Acute hemorrhagic edema of infancy: Report of 4 cases and review of the current literature”. Clin Pediatr. vol. 48. 2009. pp. 323-6. (A detailed review of acute hemorrhagic edema of infancy which compares the clinical history of their four patients with the medical literature. Includes information on presentation, etiology, diagnosis, and treatment.)
Long, D, Helm, KF. “Acute hemorrhagic edema of infancy: Finkelstein’s disease”. Cutis. vol. 61. 1998. pp. 283-4. (A review of the clinical and historical features of AHEI, emphasizing the presentation and characteristic features of the skin lesions.)
Alsufyani, MH. “Acute hemorrhagic edema of infancy: unusual scarring and review of the English language literature”. Int J Dermatol. vol. 48. 2009. pp. 617-22. (An exhaustive review that highlights the controversy between AHEI and HSP as separate entities and whether active treatment is preferred over conservative therapies. Also describes pathogenesis, clinical features, diagnostic studies, differential, management, and prognosis.)
Shetty, AK, Desselle, BC, Ey, JL. “Infantile Henoch-Schönlein Purpura”. Arch Fam Med. vol. 9. 2000. pp. 553-6. (A great and straightforward review that describes HSP and the relatedness to AHEI. Also carefully looks at the differential for a child with purpura and fever. Emphasizes the differences between classic HSP and the presentation in an infant.)
Shah, D, Goraya, JS, Poddar, B, Parmar, VR. “Acute infantile hemorrhagic edema and Henoch- Schönlein Purpura overlap in a child”. Pediatr Dermatol. vol. 19. 2002. pp. 92-3. (A case report and argument that AHEI is an infantile form of HSP. Describes the overlap of clinical features characteristic of HSP and AHEI in a child.)
Saraclar, Y, Tinaztepe, K, Adalioğlu, G, Tuncer, A. “Acute hemorrhagic edema of infancy (AHEI)–a variant of Henoch-Schönlein purpura or a distinct clinical entity”. J Allergy Clin Immunol. vol. 86. 1990. pp. 473-83. (An interesting study that looked at the clinical, serologic, immunohistologic characteristics of 12 infants with AHEI, found that the immunohistologic pattern in AHEI is quite different from HSP, and argues why they should be considered separate entities.)
Legrain, V, Lejean, S, Taïeb, A. “Infantile acute hemorrhagic edema of the skin: study of ten cases”. J Am Acad Dermatol. vol. 24. 1992. pp. 17-22. (A study looking at the features of AHEI seen in 10 cases. Reports that IgA deposits can be found, but are a rare finding, suggesting a difference between AHEI and HSP.)
Krause, I, Lazarov, A, Rachmel, A. “Acute haemorrhagic oedema of infancy, a benign variant of leucocytoclastic vascultits”. Acta Paediatr. vol. 85. 1996. pp. 114-7. (A report of five cases of AHEI with clinical and histologic descriptions. Suggests that AHEI is a unique disorder and proposes novel diagnostic criteria.)
da Silva Manzoni, AP, Viecili, JB, de Andrade, CB. “Acute hemorrhagic edema of infancy: a case report”. Int J Dermatol. vol. 43. 2004. pp. 48-51. (A case report of AHEI that showed remarkable response to corticosteroids and suggests treatment be started on a case to case basis.)
Gonggryp, LA, Todd, G. “Acute hemorrhagic edema of childhood (AHE)”. Pediatr Dermatol. vol. 15. 1998. pp. 91-6. (A report of four cases with classic AHEI. Very good description of the clinical history and presentation of each case, and how they responded to a variety of treatments including one case that responded quite well to dapsone. Also contains a very good differential with discussion of distinguishing features of each.)
Ilknur, T, Fetil, E, Lebe, B, Günes, AT. “Leukocytoclastic vasculitis presenting as acute hemorrhagic edema in a 21-year-old patient”. Int J Dermatol. vol. 50. 2011. pp. 860-2. (A case report of a 21 year old woman with acute hemorrhagic edema suggests that this disorder may occur in adults, and perhaps goes unretcognized by those not familar with the entity.)
Moura, Serra E, Garcia, C, Sokolova, A, Torre, ML, Amaro, C. “Acute Hemorrhagic Edema of Infancy”. Eur Ann Allergy Clin Immunol. vol. 48. 2016 Jan. pp. 22-6. (A case report and a good recent review.)
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- Are You Confident of the Diagnosis?
- Who is at risk for Developing Acute Hemorrhagic Edema of Infancy?
- What is the Cause of Acute Hemorrhagic Edema of Infancy?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for Acute Hemorrhagic Edema of Infancy
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management