A previously healthy 8-month-old Hispanic boy presented with a 5-day history of an erythematous, non-pruritic papular eruption on both legs. The eruption was initially diagnosed as impetigo by his primary care practitioner but progressed despite trimethoprim / sulfamethoxazole therapy, with extension to the face, trunk, and all extremities. When the patient subsequently developed a fever of 100.8° F, emesis, diarrhea, and upper respiratory symptoms, he was referred to the pediatric dermatology clinic for evaluation. Further questioning revealed a 3-day febrile illness 6 weeks prior to presentation that was treated with ceftriaxone. Review of systems failed to identify any hematuria, blood in stool, or abdominal pain, but the parents did report swelling of the extremities and face, as well as decreased oral intake.
On examination, the infant was in no apparent distress, afebrile, and had mild rhinorrhea. His mucous membranes were unaffected, and no lymphadenopathy or hepatosplenomegaly was noted. Cutaneous exam revealed numerous edematous erythematous to violaceous plaques on the cheeks, arms, buttocks, and legs with minimal involvement of the trunk. Several lesions on the arms had a distinct cockade (rosette or iris-like) pattern (Figures 1–4). There were no vesicles, bullae, or necrosis. Edema of the bilateral lower extremities was noted. Laboratory work up revealed a normal complete blood count (CBC), comprehensive metabolic panel, creatinine, and urinalysis. Platelets were borderline elevated at 439 TH/μL (140–440 TH/μL), and erythrocyte sedimentation rate and C-reactive protein (CRP) were minimally elevated at 22 mm (0–15 mm) and 3.1 mg/dL (0.0–0.99 mg/dL), respectively.
On the basis of the non-toxic nature of the rash, along with its characteristic pattern and associated symptoms, the child was diagnosed with acute hemorrhagic edema of infancy (AHEI). AHEI is an acute, benign, and transient leukocytoclastic vasculitis occurring in early childhood.1 The diagnosis of AHEI is sometimes confirmed by biopsy, but experienced pediatricians and dermatologists often make the diagnosis based solely on clinical features.2 Some believe AHEI to be a variant of Henoch-Schonlein purpura (HSP), which occurs specifically in young children; as a result, the use of the term AHEI has been inconsistent throughout the literature.3–7
AHEI is a rare condition that occurs throughout the world with an unknown disease frequency. The majority of affected children are aged between 6 and 24 months of age, and boys are approximately two times more likely to be affected.8,9 Some authors also suggest there may be seasonal variation in the incidence of AHEI, with higher rates occurring in the colder months.1,3
The pathogenesis of acute hemorrhagic edema of infancy is poorly understood; however, it is thought to be an immune complex-mediated disease initiated by a prodromal illness. The literature suggests there may be many different prodromes, but the three most common, in descending order of frequency, are upper respiratory tract illness, diarrhea, and urinary tract infection. In addition, history of recent immunization or exposure to medications such as penicillin, cephalosporin, trimethoprim / sulfamethoxazole, and acetaminophen have been suggested to be triggers.2,3,5,8,10,11
The hallmark presentation of AHEI is the acute onset of a purpuric eruption and edema in a previously healthy infant. The rash can be quite severe in appearance, which often contrasts with the general well-being of the patient.12,13 The disease begins as macular or papular lesions that spread to include the face, ears, and extremities, with relative sparing of the trunk and mucous membranes. The lesions dramatically increase in size to between 1 and 5 cm in diameter and expand centrifugally, potentially giving a targetoid or cockade appearance.12 A tender, non-pitting edema develops that is typically isolated to the face and extremities. Children with AHEI also present with a low-grade fever in roughly 50% of cases.2 Additionally, Fiore et al3 have comprehensively documented several rarer associations with AHEI that include pruritus, bullae, oral petechiae, glomerulonephritis, abdominal pain, intussusception, arthralgia, and arthritis.
Laboratory findings are generally mild and may include leukocytosis, lymphocytosis, thrombocytosis, and eosinophilia.2,12 Erythrocyte sedimentation rates (ESR) and CRP may be normal or minimally elevated. Urinalysis results are generally within normal limits.2 Histopathological analysis reveals leukocytoclastic vasculitis, neutrophil and mononuclear cell infiltration, extravasation of red blood cells, and fibrinoid necrosis.3,14 Direct immunofluorescence may reveal deposits of C1q, C3, and fibrinogen, along with a variable expression of immunoglobulins. Approximately 80% of patients have vascular deposits of IgM, 30% of IgA, 30% of IgE, and 20% of IgG.9,12,14
The differential diagnosis for AHEI includes Henoch-Schonlein purpura, erythema multiforme (EM), meningococcemia, Kawasaki disease, urticaria with hemorrhagic elements, drug-induced lesions, and child abuse. Distinguishing between AHEI and HSP may be difficult, as they are both types of leukocytoclastic vasculitis, and indeed some authors believe they are essentially the same condition occurring at different ages. However, there are several distinctions that have led many to believe the two diseases are separate, albeit closely related, entities.2–4,12,15
First, the eruption seen in AHEI tends to have an ecchymotic cockade or targetoid pattern located on the face and extremities, whereas that in HSP tends to be papulo-petechial and located primarily on the lower extremities.1,3,12 Second, direct immunofluorescence of skin biopsy in HSP often reveals IgA deposits, but this is the case in only 25% to 30% of AHEI cases.14,16 Third, HSP is associated with renal disease, arthritis, and GI complications, whereas these are less commonly seen in AHEI. In particular, more than 40% of HSP children develop renal complications and 2% develop end-stage renal disease in the long term.16 In AHEI, microscopic hematuria and mild proteinuria are sometimes seen, but only in approximately 2% of cases, all of which are transient with no accounts of subsequent long-standing renal injury.3,17 In those HSP patients without renal symptoms, monitoring of blood pressure and urinalysis is indicated for up to 6 months since the renal manifestation of the disease may present after the onset of cutaneous symptoms.18 Follow-up monitoring of renal function is not currently recommended for AHEI. The differences between AHEI and HSP, along with those distinguishing EM, a mucocutaneous disease with similar symptoms, are summarized in Table 1.1,3,6,12,16,20–23
Important Differences Between Acute Hemorrhagic Edema of Infancy (AHEI), Henoch-Schonlein Purpura (HSP), and Erythema Multiforme (EM)1,3,6,12,16,20–23
The purpuric eruptions and edema seen in AHEI are self-limited and resolve without sequelae within 6 to 21 days in the majority of cases. Comprehensive metabolic panel, CBC, and biopsy may be considered to rule out other potential conditions. In addition, urinalysis and stool guaiac are recommended to rule out renal and GI involvement.19 Although there is no recommended treatment for AHEI, a few authors suggest prescribing systemic corticosteroids if the ears or joints are involved to reduce the chance of long-term complications; however there is no consensus regarding the need for this intervention, and one should rule out the possibility of HSP before instituting steroids, as long-term follow-up differs.14 Reassurance should be given to the family of the self-limited and benign nature of the disease.
In this case, the parents were reassured that the disease was a transient vasculitis perhaps secondary to an infectious agent. Skin biopsy was deferred. Of note, there is no current recommendation regarding the need for biopsy, and policy often varies between institutions.2 When the diagnosis is in question, biopsy should be performed, along with immunofluorescence evaluation for IgA.
One month later, the parents reported that their son’s purpuric lesions and edema had resolved and he was no longer febrile.
In summary, AHEI is a transient leukocytoclastic vasculitis primarily affecting infants between 6 and 24 months of age. A non-toxic, purpuric, cockade-type rash sparing the trunk, and the presence of edema of the lower extremity and face, characterizes the disease. Differentiation between AHEI and Henoch-Schonlein purpura is often difficult, but there are several common distinguishing factors, including differential distribution of the rash, and the absence of renal, gastrointestinal and joint findings in AHEI.