Warts and verrucae are a common clinical problem. For patients with persistent lesions at what point do we consider them recalcitrant? This is a difficult question to answer as there are many factors to consider. In a paper published in 2011, Leung (1) suggests that this label should be used for lesions which have failed five treatments and not resolved in 6 months. On this basis, with clinical experience, this potentially could encapsulate a significant number of verrucae that we see ending up as being labelled “recalcitrant”! Although this may seem like just a case of semantics, it raises another issue – at what point should we consider referring patients for investigations to identify any underlying, undiagnosed immunosuppression?
Warts are an infection of the skin (and mucosal) surface caused by the human papilloma virus which cleverly has many mechanisms to evade the natural immune response meaning lesions typically can persist for some years, research suggesting adults can expect to have them for five years or more. The research uncovering how warts evade the immune system has been slow, but much has been learned from patients with known immunodeficiencies. These can have categorised into acquired and inherited disorders (2, 3).
[adapted from references (2, 3)] To understand recalcitrance, it is necessary to look at the interaction between the HPV virus and the skin. Essentially, the HPV infection, when entering the cell is able to utilise the cells natural processes to replicate itself. Entry into the basal layer cell is induced by a protein expressed on the capsid of the virus. Following cell entry, the virus travels to the nucleus and can only enter when the nuclear membrane is dissolved during prometaphase. As this occurs primarily in the basal layer of the skin, this is the only place infection can occur in the skin. Once inside, the HPV infection is able to override normal cell physiology and replicate. As the infected cells move up into the stratum spinosum and granulosum, this leads to continued cell proliferation, new blood vessel growth and the lack of major histocompatibility complex expression (cell surface “flags” denoting its status to the immune system). Ultimately, these changes are observed as the typical clinical characteristics as a wart.
Infection and survival of the wart is maintained by:
Blocking immune-related gene expression
Blocking immune pathways
Suppressing antigen presentation cells (Langerhans cells)
In order to clear an infection a cell mediated immune response is required utilising CD4 T cells and T helper (Th 1) cells. In HIV infection for example, there is a reduction in CD4+ helper cells. In rheumatoid arthritis and systemic lupus erythematosus similar changes occur leading to increased HPV prevalence compared to the general population (4, 5). Leiding and colleagues (3) in their paper have reviewed a range of immunodeficiencies which may manifest as wart persistence. The full paper details are located in the references, but a few examples are as follows: Epidermodysplasia Verruciformis (EV) is a rare, inherited skin disorder that renders an affected individual open to persistent HPV skin infection, often multiple types of HPV virus in one person. In some cases, some strains can lead to the development of malignant lesions. The problem arises as a result of a mutation in the EVER1 & 2 genes which encode for a membrane-based zinc transporter expressed on many immune cells important for HPV clearance. Consequently, this defect permits continued and persistent HPV gene expression and wart development.
Warts, Hypogammaglobinaemia, Infections and myelokathesis (WHIM syndrome) is a rare autosomal dominant condition. Patients often have a history of recurrent childhood bacterial and viral infections including cutaneous warts. In this condition is a faulty CXCR4 receptor which affects the signalling ability in the immune system and may manifest as a lack of neutrophils (neutropaenia).
Netherton Syndrome (SPINK5 Deficiency) is another rare autosomal (recessive) condition chararcterised by erythroderma, hair abnormalities, atopy including asthma and food allergies. Patients are particularly prone to the Herpes Simplex and Human Papilloma Virus. Spotting potential Immunodeficiency So how can we spot patients with potential immune deficiencies? A recent paper from Zempar et al., looking at wart persistence (3) has reviewed this issue and suggests an algorithm (figure 1). In the paper they suggest the term definition “recalcitrant” be used if the wart(s) have persisted for more than 18 months despite 2 or more treatments. Also, recurrence is defined as patients who show wart returning within 3-6 months of clearance of prior wart infections on two previous occasions. A history of any recurrent skin infection (bacterial, fungal or viral), especially those involving unusual organisms or demonstrating unusual severity or persistence are a red flag. If the patient meets these criteria, they suggest a refer to an immunologist.
Despite popular belief, there is no specific test an immunologist can undertake to detect immunodeficiency to HPV infection itself. However, a range of tests can be conducted such as full blood count, a metabolic panel, HIV, anti-nuclear antibody and immunoglobulin assessments to test for acquired causes. From here if required, genetic testing can be undertaken to look for a potential diagnosis such as those in table 1.
Figure 1: Zampella et al's proposed algorithm (3)
In clinical practice, this algorithm is certainly useful. Many of our patients, particularly adults, will present with warts that they have had for many years, and some will continue to be stubborn despite our best efforts. This in itself, according to this algorithm, warrants referral but this needs to be taken in the context of plantar warts which are known to be particularly stubborn. Consequently, other factors need to be considered particularly recurrence. For most of our patients, once their warts regress, they don’t often return (the warts and the patients), suggesting that an appropriate immune response has finally occurred and immune memory has been achieved. If, in rare cases, recurrence occurs within 3 - 6 months on two or more occasions, immunosuppression should be considered. In addition, those with large numbers of warts, or multiple large-sized recurring lesions should be considered for referral.
References
1. Leung L. Recalcitrant nongenital warts. Aust Fam Physician. 2011;40(1-2):40-2.
2. Leiding JW, Holland SM. Warts and all: human papillomavirus in primary immunodeficiencies. J Allergy Clin Immunol. 2012;130(5):1030-48.
3. Zampella J, Cohen B. Consideration of underlying immunodeficiency in refractory or recalcitrant warts: A review of the literature. Skin Health and Disease. 2022;early view
4. Johansson E, Pyrhönen S, Rostila T. Warts and wart virus antibodies in patients with systemic lupus erythematosus. Br Med J. 1977;1(6053):74-6.
5. Korkmaz C, Urer SM. Cutaneous warts in patients with lupus erythematosus. Rheumatol Int. 2004;24(3):137-40.