The care pathway for children with urticaria, angioedema, mastocytosis

Abstract

Cutaneous involvement characterized by urticarial lesions with or without angioedema and itch is commonly observed in routine medical practice. The clinical approach may still remain complex in real life, because several diseases may display similar cutaneous manifestations. Urticaria is a common disease, characterized by the sudden appearance of wheals, with/without angioedema. The term Chronic Urticaria (CU) encompasses a group of conditions with different underlying causes and different mechanisms, but sharing the clinical picture of recurring wheals and/or angioedema for at least 6 weeks. Hereditary Angioedema (HAE) is a rare disorder characterized by recurrent episodes of non-pruritic, non-pitting, subcutaneous or submucosal edema affecting the extremities, face, throat, trunk, genitalia, or bowel, that are referred as "attacks". HAE is an autosomal dominant disease caused by a deficiency of functional C1 inhibitor, due to a mutation in C1-INH gene (serping 1 gene) characterized by the clonal proliferation of mast cells, leading to their accumulation, and possibly mediator release, in one or more organs. In childhood there are two main forms of mastocytosis, the Systemic and the Cutaneous. The clinical features of skin lesions in urticaria, angioedema and mastocytosis may differ depending on the aetiologic factors, and the underlying pathophysiological mechanisms. The diagnostic process, as stepwise approach in routine clinical practice, is here reviewed for CU, HAE and mastocytosis, resulting in an integrated method for improved management of these cutaneous diseases. Taking into account that usually these conditions have also a relevant impact on the quality of life of children, affecting social activities and behavior, the availability of care pathways could be helpful in disentangle the diagnostic issue achieving the most cost-effective ratio.

Keywords: Angioedema; Children; Clinical practice; Diagnosis; Epidemiology; Itch; Management; Mastocytosis; Skin; Urticaria.

Figure 1

The diagnostic pathway of Urticaria. Although allergy is a rare cause of CSU an allergy screening test should be considered in CSU patients with intermittent symptoms and a suggestive history. Chronic persistent bacterial, viral parasitic and fungal infections that may trigger urticarial symptoms in patients with CSU should be considered, only according to the patient’s history [7]. Total immunoglobulin count, antinuclear factor and skin biopsy should be considered in patients with single hives that lasts >24 hours, to rule out vasculitis or Schnitzler syndrome [8]. In Physical Urticaria the routine diagnosis is mainly aimed at the identification of the subtype of the urticaria through the appropriate physical stimulation tests and to the determination of trigger thresholds [7]. Since CU in children may be associated with autoimmune diseases, like celiac or thyroid disease, some Authors suggest to screen for them [9]. 30-50% of patients with CSU produce an immunoglobulin IgG type autoantibody against either the high affinity receptor FcERIα or IgE. However, the utility of the Autologous Serum Skin Test (ASST) remains unclear in identifying a distinct subgroup of patients with CU and in predicting natural history and response to treatment. So, current evidence does not support routine performance of this test in patients with CU [26]. Some other conditions should be considered in the diagnostic process mainly when an immunocomplex-induced disease is suspected. These include serum sickness or autoimmune diseases. When isolated angioedema is present, the assessment of C4 and C1 esterase inhibitor levels should be performed [8].

Figure 2

The diagnostic pathway of Hereditary Angioedema (HAE). According to the 2010 International Consensus algorithm for diagnosis, therapy and management of HAE, the diagnosis should be confirmed by measuring serum complement factor 4 (C4) and serum C1-inhibitor protein and its functional levels [27].

Figure 3

The diagnostic pathway of Mastocytosis. Mastocytosis is essentially suspected on clinical ground. Because mastocytosis is due to a clonal proliferation of MCs, the diagnosis is established by detection of MCs with abnormal morphologic features and immunophenotypes in the bone marrow or other extracutaneous organs and investigating specific mutations in its growth factor (c-KIT) receptor [21]. The SCORMA Index provides a standardized information on the severity of CM, with no burden for patients, which is particularly important in children. The simultaneous assessment of SCORMA Index and tryptase level is essential in all cases of pediatric mastocytosis [23].