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Thursday, November 1, 2012

A wart compendium: HPV infections in immunodeficiency diseases

November’s issue features an article from two NIAID researchers, Jennifer Leiding, MD and Steven Holland, MD, who present an inventory of HPV infections associated with primary immunodeficiencies (J Allergy Clin Immunol 2012;130:1030-1048). A short review of HPV immunopathology and epidemiology opens the authors’ discussions of the associated diseases and syndromes.

Beginning with those illnesses with which HPV infection is a predominant clinical presentation, Leiding and Holland present concise information on the symptomatic features, immunogenetic context and treatment approaches of the most common HPV-susceptible immunodeficiencies:

·      EV (epidermodysplasia verruciformis) is characterized by increased susceptibility to cutaneous HPV infection and associated with recurrent, pathological infection and malignant conversion. Autosomal recessive mutations in the genes EVER1 & 2, which code for transmembrane proteins thought to restrict HPV intracellular ingress, result in deficiency that raises HPV susceptibility across many immune cell types. HPV infection in EV is highly resistant to therapies.
·      WHIM (warts, hypogammaglobulinemia, infection and myelokathexis) syndrome, an autosomal dominant immunodeficiency, presents with pulmonary, gastrointestinal, and cutaneous infections and neutropenia. Dysplastic and malignant warts are the characteristic features. A gain-of-function mutation of the chemokine receptor CXCR4 results in impaired myeloid and dendritic cell signaling that permits greater HPV infection. Patients have good response to IVIg and bone marrow growth factors.
·      DOCK8 (dedicator of cytokinesis 8) deficiency is one of the combined immunodeficiencies in which infection by HPV and herpetic viruses are chronic and comorbid. Presentation is similar to STAT3-associated hyper-IgE syndrome.

Leiding and Holland also cover rare immunodeficiencies, such as idiopathic CD4 lymphopenia, severe combined immunodeficiency disease, GATA2 deficiency, Wiskott-Aldrich syndrome and Netherton syndrome, with which there have been a few reports of HPV infection. The authors provide an excellent table summarizing the immunodeficiency diseases that have associated HPV infection. Leiding and Holland wrap up noting that physicians should suspect immunodeficiency in their patients with recurrent, pervasive, and/or treatment refractory HPV infections.

Says first author Jennifer Leiding, from the National Institute of Allergy and Infectious Diseases: “Investigation of patients with susceptibility to HPV will lead to further understanding of host defense toward viruses as well as cutaneous and systemic immunity.”

Modeling asthma-related utilization

In the current socioeconomic climate, evaluating healthcare utilization in the context of chronic disease outcomes and intervention is vital. Think Framingham. Wu et al. in this month’s issue (J Allergy Clin Immunol 2012;130:1065-1070) step up to this challenge for asthma, designing and testing a prediction model that draws on data from the Childhood Asthma Management Program (CAMP). The authors use data on changes in prebronchodilator FEV1 % predicted in subjects treated with ICS to simulate prediction of hospitalization, ED visits, and oral CS therapy associated with exacerbations. The simulated results are then compared with the actual data from CAMP to assess the model’s reliability.

Wu et al. report remarkable consistency between the simulation predictions and the CAMP data. As one example, their model predicted a 48% decrease in hospitalizations with ICS therapy compared to placebo. The observed decrease in the CAMP data was 49%. The authors comment that further testing with data not involved in developing the model is required and they invite other asthma investigators to collaborate.