Hypersensitivity vasculitis in children

INTRODUCTION — The term "hypersensitivity vasculitis" has been used to refer to a vasculitis of small blood vessels of the skin that is secondary to an immune response or hypersensitivity reaction to an often unidentifiable exogenous substance. Names often used interchangeably with hypersensitivity vasculitis, but controversially, have included drug-induced vasculitis, cutaneous leukocytoclastic vasculitis, cutaneous small-vessel vasculitis, serum sickness, and allergic vasculitis [1]. The term "hypersensitivity vasculitis" was not included in the 2012 Chapel Hill Consensus Conference Nomenclature for systemic vasculitis [2] nor in its dermatologic addendum [3]. It is also not a named subtype of cutaneous vasculitis used in dermatology literature [4]. Hypersensitivity vasculitis, as traditionally classified [5], is best encompassed currently under the broad categories of either "single organ vasculitis" and named as cutaneous arteritis or cutaneous leukocytoclastic angiitis (eg, skin limited and without glomerulonephritis) [2] or alternatively under the category of "vasculitis associated with probable etiology" when there is an identifiable associated triggering agent or process (eg, infection, drug, or malignancy) [2,3]. (See "Vasculitis in children: Incidence and classification".)

Hypersensitivity vasculitis in children, including the clinical features, diagnosis, and treatment that are reviewed here, primarily encompasses what is now more commonly described as either cutaneous leukocytoclastic vasculitis or drug- and infection-triggered vasculitis (eg, minocycline-associated vasculitis or hepatitis B-associated vasculitis). Cutaneous vasculitis as a paraneoplastic presentation is rare in children [6], but there are reports of leukemia-associated vasculitis [7,8].

Serum sickness and serum sickness-like reactions share clinical and pathologic features with hypersensitivity vasculitis; however, many cases do not have actual vascular inflammation. Serum sickness and serum sickness-like disorders are presented separately. (See "Serum sickness and serum sickness-like reactions".)

Urticarial vasculitis and hypocomplementemic urticarial vasculitis, usually with systemic manifestation, are also discussed separately. (See "Urticarial vasculitis".)

DEFINITION — There are no pediatric-specific classification criteria for hypersensitivity vasculitis [9]. All available systems are based upon adult data. The most commonly used system is that of the American College of Rheumatology (ACR) [5] (see 'Drugs' below). Children were explicitly excluded when the ACR criteria were proposed in 1990 due to the lack of pediatric data. In the absence of clearly superior alternatives, the ACR criteria are nonetheless commonly used in children.

The ACR criteria for hypersensitivity vasculitis are as follows:

●Age >16 years

●Use of a possible offending drug in temporal relation to the symptoms

●Palpable purpura

●Maculopapular rash

●Biopsy of a skin lesion showing neutrophils around an arteriole or venule

The presence of three or more of these criteria has a sensitivity and specificity for the diagnosis of hypersensitivity vasculitis of 71 and 84 percent, respectively, among adults with known vasculitis [5]. These criteria do not distinguish hypersensitivity vasculitis from immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), with the latter characterized by palpable purpura and the deposition of IgA in the skin lesion [10]. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

ETIOLOGY — Hypersensitivity vasculitis was first reported after the administration of heterologous antisera and was initially called serum sickness. In the past, serum sickness was the most frequent form of vasculitis because of the use of therapeutic antisera.

Hypersensitivity vasculitis is thought to represent an immune response to agents reacting as haptens and resulting in immune complex deposition. In most cases, the inciting antigen is never identified, and the disease remains idiopathic. In others, it may be caused by a specific drug or occur in association with an infection, malignancy, or other systemic disease.

Drugs — Drugs are the most common identified cause of hypersensitivity vasculitis. Many medications can cause cutaneous vasculitis, but antibiotics (especially beta-lactams, sulfonamides), nonsteroidal antiinflammatory drugs, diuretics, anticonvulsants, and anti-tumor necrosis factor (TNF) biologic agents are often implicated as the inciting agents (table 1) [11-15]. (See "Overview of cutaneous small vessel vasculitis".)

Drug-induced vasculitis is a poorly defined disorder since proving causality is difficult. As a result, characterization of all suspected cases of drug-induced vasculitis should include [11]:

●Precipitating agent

●Involved organs (eg, isolated to the skin, gastrointestinal tract, etc)

●Pathologic description

Food — There are rare reports of foods and food additives as potential triggers of hypersensitivity vasculitis in children [16]. As an example, in two reported cases, symptoms resolved after elimination of the suspected food antigen and recurred with reintroduction of the specific food (rechallenge) [16]. In one child, the offending agent was cow's milk and, in the other, chocolate and other cocoa-containing products.

Infection — Several infectious agents have been associated with hypersensitivity vasculitis, including hepatitis B or C, streptococcal agents, Mycobacterium tuberculosis, and human immunodeficiency virus (HIV) [10,12,17]. Hypersensitivity vasculitis has also been reported in patients with endocarditis and infected shunts [10].

PATHOGENESIS — Hypersensitivity vasculitis begins with deposition of soluble immune complexes that, together with immune reactants, are histologically identifiable in vessels early in the disease [18]. Immune complexes activate the classic and alternative complement pathways. The consequent mast cell degranulation, activation of neutrophils, release of cytokines and enzymes, and other processes in the cascade lead to tissue destruction and ultimately neutrophil phagocytosis (leukocytoclastic vasculitis) and removal of the immune complexes within 24 hours [18,19]. (See "Complement pathways".)

CLINICAL MANIFESTATIONS — The hallmark of hypersensitivity vasculitis is the skin finding of palpable purpura and/or petechiae (picture 1A-B). Lesions most commonly occur in areas of decreased or slowed blood flow, particularly the lower extremities and other dependent areas, or under tight-fitting clothing. Edema may accompany some lesions. Other cutaneous manifestations of the vasculitis seen in some cases include macules, papules, ulcers, subcutaneous nodules, and urticaria.

In most patients, symptoms begin 7 to 10 days after antigen exposure, the time required to produce a sufficient quantity of primary antibody to form antigen-antibody complexes [11]. Symptoms may be delayed for two weeks or more in the case of longer-acting drugs, such as benzathine penicillin, while the latent period may be as short as two to seven days with a secondary exposure [20]. Manifestations usually appear abruptly. Skin lesions generally are at the same stage of development and typically resolve after a period of days to weeks. Postinflammatory pigmentation is common. Ulcerative or necrotic lesions may persist longer and leave residual scarring.

Additional findings may include [10-12,19]:

●Fever

●Malaise

●Myalgias/arthralgias

●Arthritis

●Abdominal pain

●Lymphadenopathy

Despite the fact that skin lesions predominate, other organ systems may be involved to varying degrees. However, it is difficult to ascertain the frequency of noncutaneous organ involvement because of the lack of detailed description of internal organ involvement in most cases and a bias for reporting isolated cases with serious end-organ damage. In adult series, glomerulonephritis, interstitial nephritis, kidney impairment and varying degrees of hepatocellular injury have all been described [12,15]. Lung, heart, and central nervous system involvement are less commonly reported. (See "Overview of cutaneous small vessel vasculitis".)

Although hypersensitivity vasculitis is usually acute and abates once the antigen has been cleared, prolonged disease may occur in conditions associated with chronic antigen exposure, such as persistent hepatitis B or C virus infection. Occasionally, chronic vasculitis may occur without an identifiable trigger. (See "Extrahepatic manifestations of hepatitis C virus infection".)

LABORATORY FINDINGS — Although no specific laboratory test is diagnostic of hypersensitivity vasculitis, the following nonspecific findings are often seen in affected patients [12,13]:

●Mild leukocytosis

●Low serum complement levels, particularly C3 and C4, although there is no specific pattern of complement findings suggestive of the diagnosis

●Elevated inflammatory markers, such as erythrocyte sedimentation and C-reactive protein

●Positive culture or serology (eg, hepatitis C virus) of an infectious agent associated with hypersensitivity vasculitis (see 'Infection' above and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis")

●Hematuria, proteinuria, and cellular casts in patients with kidney involvement

HISTOPATHOLOGY — Histopathology of palpable petechiae or purpura of the skin biopsied early in disease reveals prominent inflammation of the small blood vessels. Vessel walls and perivascular areas are infiltrated by neutrophils with resulting fibrinoid necrosis. This pattern is typically described as "leukocytoclastic vasculitis" (image 1A-B), referring to the residual nuclear debris caused by the infiltrating neutrophils. In general, postcapillary venules are the most prominently involved vessels, with less frequent capillary and arteriole involvement. Drug-induced small vessel vasculitis is associated with a greater degree of tissue eosinophilia than non-drug-induced vasculitis [21].

The histologic pattern is highly sensitive to the age of the lesion. Lesions that are less than 24 hours old are most likely to demonstrate predominantly polymorphonuclear infiltration and other classic pathologic findings. Older lesions, on the other hand, show an increasing predominance of mononuclear cells as tissue repair supervenes.

In patients with kidney involvement, kidney biopsy, if performed, typically reveals a proliferative glomerulonephritis with immunoglobulin (primarily immunoglobulin G [IgG]) and complement deposition along the glomerular capillary wall.

DIAGNOSIS — The diagnosis of hypersensitivity vasculitis is based upon clinical findings of palpable purpura and/or petechiae (picture 1A-B); a history of an offending agent, such as a drug or infection; a biopsied skin lesion that is characterized by a leukocytoclastic vasculitis (image 1A-B) [5]; and exclusion of other systemic conditions that may present with similar disease manifestations. (See 'Differential diagnosis' below.)

In children, additional clinical criteria may be necessary to distinguish hypersensitivity vasculitis from the more commonly seen immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), such as IgA deposition that is seen in patients with IgAV (HSP), but not in those with hypersensitivity vasculitis.

DIFFERENTIAL DIAGNOSIS — Hypersensitivity vasculitis may be difficult to distinguish from other forms of vasculitis, particularly when findings are confined to the skin.

IgA vasculitis (Henoch-Schönlein purpura) — Immunoglobulin A vasculitis (IgAV) is the most common disorder in the differential diagnosis of hypersensitivity vasculitis in children [10,22]. In both disorders, patients have leukocytoclastic vasculitis of small vessels. Palpable purpura and arthralgia are prominent features of IgAV. Additional features associated with IgAV include bowel angina, gastrointestinal bleeding, and/or hematuria. In contrast to patients with hypersensitivity vasculitis, patients with IgAV usually have normal complement levels and evidence of IgA-containing immune complexes on skin or kidney biopsy. An absence of recent use of medications that have the potential to cause vasculitis is also suggestive of the diagnosis of IgAV rather than hypersensitivity vasculitis. In practice, however, it may be difficult to distinguish between IgAV and hypersensitivity vasculitis, especially in the absence of these differentiating factors. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

Malignancy-associated vasculitis — Malignancy-associated vasculitis is uncommon in children, but it has been reported [7,8,23]. Thus, patients who develop palpable purpura should be examined carefully for other signs or symptoms of a malignancy.

Systemic vasculitides — Systemic vasculitides (eg, granulomatosis with polyangiitis, polyarteritis nodosa, and microscopic polyarteritis), although uncommon in children, may occasionally present with predominantly cutaneous involvement, such as palpable purpura. The presence of systemic signs and symptoms, evidence of major organ involvement, and antineutrophil cytoplasmic antibody (ANCA) positivity are helpful in identifying these syndromes and distinguishing them from hypersensitivity vasculitis [2,9,12]. Biopsy tissue showing pathologic lesions typical of these conditions, rather than immune complexes seen in hypersensitivity vasculitis, will usually confirm the diagnosis. (See "Vasculitis in children: Incidence and classification".)

Other rheumatic diseases — Vasculitis secondary to an underlying rheumatologic condition, such as systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, juvenile dermatomyositis, or sarcoidosis, can rarely present with vasculitic skin rashes. In these conditions, there is not typically lower limb predominance. Once these diagnoses are considered, the child should be evaluated for distinguishing clinical features and laboratory findings of these conditions. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations" and "Clinical manifestations and diagnosis of sarcoidosis".)

TREATMENT — Treatment of patients with hypersensitivity vasculitis includes:

●Removal of the inciting agent – Removal of the suspected inciting antigen (eg, discontinuation of the implicated drug) should lead to resolution of the lesions within a period of days to a few weeks. This supports the diagnosis [13,15].

In patients with infection-associated hypersensitivity vasculitis, treatment should be aimed at the underlying infection.

●Symptomatic treatment – The disease often resolves spontaneously, without need for treatment when the vasculitis is mild and limited to the skin. Leg elevation, compression stockings, and simple analgesics may help with discomfort for lower limb disease, and antihistamines may help with associated itchiness. In patients with severe or persistent cutaneous disease, drugs such as colchicine, antihistamines, nonsteroidal antiinflammatory drugs, and/or dapsone may be helpful [13,15,17]. Immunosuppressive therapy with glucocorticoids or cytotoxic agents should be reserved for the infrequent patient with fulminant or progressive disease or with serious end-organ involvement [2]. (See "Vasculitis in children: Management overview".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Vasculitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Hypersensitivity vasculitis refers to inflammation of small blood vessels of the skin. The process is caused by an immune response or hypersensitivity reaction to an exogenous substance, although the trigger is frequently not identifiable. (See 'Introduction' above and 'Definition' above.)

●Etiology and pathogenesis – Hypersensitivity vasculitis is thought to be caused by agents that act as haptens and stimulate an immune response. In some cases, the inciting antigen is an identifiable drug, infection, or, rarely, a malignancy. (See 'Pathogenesis' above and 'Etiology' above and 'Differential diagnosis' above.)

●Clinical findings – The major clinical finding is cutaneous palpable purpura and/or petechiae (picture 1A-B). Biopsy of the lesions reveals prominent inflammation of the small blood vessels, typically with neutrophilic or mononuclear infiltration of the vessel wall and perivascular region, called leukocytoclastic vasculitis. Additional findings may include fever, malaise, myalgia, arthralgia/arthritis, lymphadenopathy, and kidney or liver disease. Rarely, vasculitis lesions may occur in the lung, heart, and central nervous system. (See 'Clinical manifestations' above and 'Histopathology' above.)

●Diagnosis – The diagnosis of hypersensitivity vasculitis is based upon clinical findings of palpable purpura and/or petechiae; the history of exposure to a potential inciting agent, such as a drug or infection; and a skin biopsy that demonstrates a leukocytoclastic vasculitis (image 1A-B). (See 'Diagnosis' above.)

●Differential diagnosis – In children, immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) is the most common disorder in the differential diagnosis of hypersensitivity vasculitis. Normal complement levels and IgA deposition help to distinguish IgAV from hypersensitivity vasculitis. (See 'Differential diagnosis' above and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)

●Treatment – The major intervention in the treatment of children with hypersensitivity vasculitis is removal of the inciting agent. Symptomatic therapy used in severe or persistent skin lesions includes colchicine, antihistamines, nonsteroidal antiinflammatory drugs, and dapsone. Immunosuppressive therapy with glucocorticoids or cytotoxic agents should be reserved for the infrequent patient with fulminant or progressive disease or other organ involvement. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Karyl S Barron, MD, who contributed to earlier versions of this topic review.