Reduced G protein signaling despite impaired internalization and ß-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome.

WHIM syndrome is an inherited immune disorder caused by an autosomal dominant heterozygous mutation in CXCR4. The disease is characterized by neutropenia/leukopenia (secondary to retention of mature neutrophils in bone marrow), recurrent bacterial infections, treatment-refractory warts, and hypogammaglobulinemia. All mutations reported in WHIM patients lead to the truncations in the C-terminal domain of CXCR4, R334X being the most frequent. This defect prevents receptor internalization and enhances both calcium mobilization and ERK phosphorylation, resulting in increased chemotaxis in response to the unique ligand CXCL12. Here, we describe 3 patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying what we believe to be a novel Leu317fsX3 mutation in CXCR4, leading to a complete truncation of its intracellular tail. The analysis of the L317fsX3 mutation in cells derived from patients and in vitro cellular models reveals unique signaling features in comparison with R334X mutation. The L317fsX3 mutation impairs CXCR4 downregulation and ß-arrestin recruitment in response to CXCL12 and reduces other signaling events - including ERK1/2 phosphorylation, calcium mobilization, and chemotaxis - all processes that are typically enhanced in cells carrying the R334X mutation. Our findings suggest that, overall, the L317fsX3 mutation may be causative of a form of WHIM syndrome not associated with an augmented CXCR4 response to CXCL12.

Comparative Study of Intralesional Vitamin D3 Injection and Candida Albicans Antigen in Treating Plantar Warts.

BACKGROUND: Warts, or verrucae, are mucosal human papilloma virus (HPV) infections that are very challenging to treat. OBJECTIVE: To compare the safety and efficacy of intralesional injection of vitamin D3 versus intralesional injection of candida albicans antigen for plantar warts. METHODS: Forty patients were included in the study and were divided into two groups (A&B) with 20 patients each. Group A received intralesional vitamin D3 while Group B received intralesional Candida antigen. Injection was done every 3 weeks until clearance of warts or a maximum of three treatments. RESULTS: Nine patients showed complete clearance in group A (45%), while 6 patients (30%) showed partial response and no response in 5 patients (25%) of group (A). As for group (B), complete clearance of the treated warts was observed in 8 patients (40%), partial response in 6 patients (30%) while no response was observed in 6 patients (30%). No superiority of one treatment to the other was observed nor was any statistical significance in both groups’ responses noted. CONCLUSION: Treatment of multiple warts by intralesional injection of candida antigen or vitamin D3 is safe and effective, with good cure rates, has an excellent safety profile, with minimal recurrences and statistically equivalent. J Drugs Dermatol. 2021;20(5):546-549. doi:10.36849/JDD.5264.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.

Management of Difficult-to-Treat Warts: Traditional and New Approaches.

Warts are regularly treated by dermatologists, and while many respond readily to first-line treatments, others may represent a therapeutic challenge. Large, deep, numerous, and extensive warts; treatment-resistant lesions with higher risk for side effects, such as hypopigmentation; or patients unable to tolerate or comply with our treatment regimen, may need alternative treatment options. In this work we review the characteristics of select modalities that should be considered for difficult-to-treat warts. We discuss efficacy and tolerability data as well as practical features that can guide us to select the best treatment for every scenario. Novel approaches, still in an investigational phase, are also discussed to illustrate potential future directions of wart treatment.

CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent.

AMD3100 (plerixafor), a CXCR4 antagonist, has opened a variety of avenues for potential therapeutic approaches in different refractory diseases. The CXCL12/CXCR4 axis and its signaling pathways are involved in diverse disorders including HIV-1 infection, tumor development, non-Hodgkin lymphoma, multiple myeloma, WHIM Syndrome, and so on. The mechanisms of action of AMD3100 may relate to mobilizing hematopoietic stem cells, blocking infection of X4 HIV-1, increasing circulating neutrophils, lymphocytes and monocytes, reducing myeloid-derived suppressor cells, and enhancing cytotoxic T-cell infiltration in tumors. Here, we first revisit the pharmacological discovery of AMD3100. We then review monotherapy of AMD3100 and combination use of AMD3100 with other agents in various diseases. Among those, we highlight the perspective of AMD3100 as an immunomodulator to regulate immune responses particularly in the tumor microenvironment and synergize with other therapeutics. All the pre-clinical studies support the clinical testing of the monotherapy and combination therapies with AMD3100 and further development for use in humans.

Complement component 3c and tumor necrosis factor-α systemic assessment after Candida antigen immunotherapy in cutaneous warts.

BACKGROUND: Cutaneous warts are the commonest benign lesion produced by human papillomavirus. Lesions often regress spontaneously yet have a high rate of recurrence. They impair patients' quality of life and carry the potential risk of cancer. Nowadays, Candida antigen immunotherapy has become an encouraging therapeutic modality for warts. We tried to assess the role of the complement pathway and T helper 1 immune response in clinical response to Candida antigen immunotherapy via complement component 3c (C3c) and tumor necrosis factor (TNF)-α, respectively. METHODS: A total of 44 patients with cutaneous warts were enrolled in the study. Patients were injected with Candida antigen at 2-week interval until complete clearance of the lesion or for a maximum of 5 sessions. Blood samples were collected before initiation and after completion of immunotherapy. C3 and C4 were measured using an automated turbidimetric method. Mannose-binding lectin (MBL), C3c, and TNF-α were measured using enzyme-linked immune sorbent assay. RESULTS: A total of 56.4%, 17.9%, and 25.7% of the patients showed complete, partial, and no response to immunotherapy, respectively. Lesions on the dorsum of the foot and sole showed significant clearance (p value = 0.037). All patients had no deficient C3, C4, and MBL serum levels. C3c and TNF-α serum levels were significantly higher in non-responder group (p value < 0.001 and < 0.001, respectively). C3c and TNF-α serum levels were strongly correlated in all the studied patients (r = 0.8, p value < 0.001). CONCLUSIONS: Candida antigen immunotherapy is an effective therapeutic modality for cutaneous warts. C3c and TNF-α serum levels were higher in patients who failed to respond to immunotherapy. CLINICAL TRIAL REGISTRY NUMBER: NCT04399577 , May 2020 "retrospectively registered".

Intralesional immunotherapy with purified protein derivative (PPD) for cryotherapy-resistant warts.

BACKGROUND: Cryotherapy and immunotherapeutic modalities elicit nonspecific immune response against the human papillomavirus. There is a paucity of literature on the effects of a sequential shift to immunotherapy in cryotherapy-resistant warts. AIM: To study the efficacy of intralesional purified protein derivative (PPD) immunotherapy in cryotherapy-resistant warts. METHODS: Patients with cryotherapy-recalcitrant cutaneous warts were given intralesional injections of PPD into the index warts (oldest or largest) at 2-week intervals until complete clearance or up to a maximum of six injections. The response in the treated index and distant warts was defined as complete, partial, and no response (<25%). Complete responders were followed up for another 3 months to check for recurrence. RESULTS: Twenty-eight patients completed the study protocol. Of the eight patients with single warts, four (50%), one (12.5%), and three (37.5%) patients had complete, partial, and no response, respectively. Of the 20 patients with multiple warts, nine (45%) had complete clearance of all warts, two (10%) each had complete and partial response in the index wart, respectively, with no response of the distant warts, and seven (35%) had no response in all warts. Complete response was seen in an average of 3.1 injections (range 1-5). There was no recurrence at the follow-up visit. CONCLUSION: Immunotherapy with PPD has potential in producing regional and remote wart regression even in cryotherapy-resistant warts. It is a safe and economical modality in children, multiple warts, and difficult-to-treat warts.

Expressionof langerhans cell and plasmacytoid dendritic cell markers, and toll-like receptor 7/9 signaling pathway proteins in verruca vulgaris lesions.

Langerhans cells (LCs) and plasmacytoid dendritic cells (pDCs) play an important role in the cutaneous immune response to viral infection. Verruca vulgaris (VV) is a chronic benign disease caused by human papillomavirus (HPV) infection.To investigate the possible roles of LCs, pDCs and toll-like receptor (TLR)7/9 signaling pathways in the pathogenesis of VV, we detected the expression of CD1a, CD2AP, CD123, TLR7/9, IFN regulatory factor 7 (IRF7), and interleukin-1 receptor-associated kinase 1 (IRAK1) in VV lesions.The expression of CD1a, CD2AP, CD123, TLR7/9, IRF7, and IRAK1 in 20 VV lesions was tested by immunohistochemistry. The density and number of stained cells were compared between VV lesions and the perilesional normal skin.The density and number of CD1a-, CD2AP-, CD123-, TLR9-, and IRAK1-positive cells in the papillary layer of VV lesions were significantly higher than those in the perilesional normal skin (P < .05). There were no significant differences in the density and positive rate of CD1a+ cells in the epidermis and of TLR7 and IRF7 cells in the dermis between VV lesions and the perilesional normal skin at the edge (P > .05).In VV, the number of LCs increases only in the dermis, indicating that LC's antigen-presenting function might not be inhibited. The increased number of pDCs in VV lesions suggests that HPV infection may recruit the pDCs to the virus-infected epithelium. We speculate that the TLR7/9 downstream signaling pathway is not fully activated in VV, leading to difficulty of HPV removal and the relapse of HPV-infected lesions.

Efficacy of Intralesional Cryosurgery in the Treatment of Multiple Extragenital Cutaneous Warts: A Randomized Controlled Study.

BACKGROUND: The efficacy of intralesional (IL) cryosurgery in the treatment of cutaneous warts has not been previously studied. OBJECTIVE: To compare the efficacy and safety of IL cryosurgery versus electrosurgery in multiple extragenital warts and investigate their effect on serum interleukin (IL)-12 and interferon-gamma (IFN-γ). MATERIALS AND METHODS: Thirty-one patients were included; 18 received IL cryosurgery, and 13 had electrosurgery. Treatment was performed for the largest or few (2-3) small warts (target) until cleared, leaving the remaining (distant) warts untreated. Clinical response of the target and distant warts and adverse effects were evaluated. Serum IL-12 and IFN-γ levels were assessed before and after treatment. RESULTS: All patients had complete clearing of the treated wart in both groups. IL cryosurgery was well tolerated; infection, ulceration, and recurrence occurred only with electrosurgery. Complete/near-complete resolution of the distant untreated warts was seen in 33.3% versus none of patients in the IL cryosurgery and electrosurgery groups, respectively (p = .003). Furthermore, IL-12 and IFN-γ levels showed a tendency to increase after IL cryosurgery, and their increase correlated with distant wart response. CONCLUSION: Intralesional cryosurgery is effective not only in clearing treated warts but also resolving untreated warts and possibly enhances human papillomavirus-directed immune response.

Evaluation of serum interleukin 17 and zinc levels in recalcitrant viral wart.

BACKGROUND: Warts are benign epithelial proliferations of the skin and mucosa caused by infection with HPV. Low IL-17 levels may contribute in occurrence, maintenance, severity, and recurrence of different types of cutaneous wart that depend mainly on the cell-mediated immunity defect. In a majority of the patients, zinc deficiency was associated with persistent, progressive, or recurrent viral warts. A careful dose of oral zinc sulfate may be helpful in the management of such patients. Zn deficiency negatively affects the Th17 cells. IL 6 induced STAT3 activation during chronic inflammation and Th17 development suppressed by Zn via attenuating this activation critically controls Th17-cell development. OBJECTIVES: To evaluate the role of interleukin 17 and zinc in recalcitrant warts. PATENTS AND METHODS: All studied patients were subjected to history taking and dermatological examination. The evaluation of serum IL-17 level was done by ELISA in 25 recalcitrant wart patients and 25 wart patients. The measurement of serum zinc level was determined by colorimetric methods, using Au 480 Beckman coulter chemistry analyzer. RESULTS: The results revealed a significant decrease in serum IL-17 and zinc levels in recalcitrant wart patients. CONCLUSION: Both IL-17 and zinc deficiency have a role in the pathogenesis of recalcitrant warts through the imbalance of immune system and deficiency of immune cells. There is no significant correlation between serum levels of IL-17 and zinc, suggesting that they have different mechanisms in affecting the immune system.

Combined bivalent human papillomavirus vaccine and Candida antigen versus Candida antigen alone in the treatment of recalcitrant warts.

BACKGROUND: The burden of human papillomavirus (HPV) infection and HPV-associated diseases is consistently growing worldwide. Several combination therapies are being tested nowadays for the treatment of recalcitrant warts, with promising results. AIMS: To evaluate the potential therapeutic role of combined bivalent HPV vaccine (Cervarix) and Candida antigen versus candida antigen alone in the treatment of multiple recalcitrant warts. PATIENTS/METHODS: Forty patients with recalcitrant warts were enrolled into this study. They were divided into two groups (A and B), each including 20 patients. Patients in the group (A) received intralesional Candida antigen injection alone for five sessions at 2-week intervals. Patients in the group B received combined treatment of bivalent recombinant HPV vaccine and intralesional Candida antigen. Candida antigen was administered as in the group A, while Cervarix vaccine was given intramuscularly at 0, 1, and 6 months as scheduled. Follow-up was made monthly for 6 months to detect any possible recurrence. RESULTS: Eight patients (40%) in the group (A) showed complete clearance of warts after intralesional Candida antigen injection alone, while 14 patients (70%) in the group (B) showed complete regression of warts after the combined therapy. No significant side effects were reported in both groups, and no recurrence was detected. CONCLUSION: Bivalent human papillomavirus vaccine combined with Candida antigen is a promising, effective, and safe modality for the treatment of multiple recalcitrant warts.

Complete Multilineage CD4 Expression Defect Associated With Warts Due to an Inherited Homozygous CD4 Gene Mutation.

Idiopathic T-CD4 lymphocytopenia (ICL) is a rare and heterogeneous syndrome characterized by opportunistic infections due to reduced CD4 T-lymphocytes (<300 cells/µl or <20% T-cells) in the absence of HIV infection and other primary causes of lymphopenia. Molecular testing of ICL has revealed defects in genes not specific to CD4 T-cells, with pleiotropic effects on other cell types. Here we report for the first time an absolute CD4 lymphocytopenia (<0.01 CD4+ T-cells/µl) due to an autosomal recessive CD4 gene mutation that completely abrogates CD4 protein expression on the surface membrane of T-cells, monocytes, and dendritic cells. A 45-year-old female born to consanguineous parents consulted because of exuberant, relapsing, and treatment-refractory warts on her hands and feet since the age of 10 years, in the absence of other recurrent infections or symptoms. Serological studies were negative for severe infections, including HIV 1/2, HTLV-1, and syphilis, but positive for CMV and EBV. Blood analysis showed the absence of CD4+ T-cells (<0.01%) with repeatedly increased counts of B-cells, naïve CD8+ T-lymphocytes, and particularly, CD4/CD8 double-negative (DN) TCRαß+ TCRγδ- T-cells (30% of T-cells; 400 cells/µl). Flow cytometric staining of CD4 using monoclonal antibodies directed against five different epitopes, located in two different domains of the protein, confirmed no cell surface membrane or intracytoplasmic expression of CD4 on T-cells, monocytes, and dendritic cells but normal soluble CD4 plasma levels. DN T-cells showed a phenotypic and functional profile similar to normal CD4+ T-cells as regards expression of maturation markers, T-helper and T-regulatory chemokine receptors, TCRvß repertoire, and in vitro cytokine production against polyclonal and antigen-specific stimuli. Sequencing of the CD4 gene revealed a homozygous (splicing) mutation affecting the last bp on intron 7-8, leading to deletion of the juxtamembrane and intracellular domains of the protein and complete abrogation of CD4 expression on the cell membrane. These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling and point out the need for better understanding the role of CD4 on thymic selection and the immune response.

Comparative study of autoimplantation therapy and intralesional injection of MMR vaccine in warts treatment.

Autoimplantation is a simple technique and considered as a novel method of immunotherapy in treating warts. Intralesional immunotherapy by mumps, measles, and rubella (MMR) vaccine is also a promising treatment modality for multiple warts. To compare the efficacy and safety of both the methods in treating multiple warts, the study included 80 patients divided into two groups (Group A and Group B), each containing 40 patients. Informed consent was taken from each patient before enrollment into the study. Group A patients were treated by autoimplantation technique every 2 weeks for a maximum of four treatments. Similarly, Group B patients received MMR intralesional injection at a dose of 0.5 ml every 2 weeks for a maximum of four treatments. Complete clearance of the donor wart was observed in 60% patients in Group A, whereas complete clearance in the Group B injected by MMR was 72.5%. On the other hand, a significant difference (p < .05) was found in the therapeutic response among nonmanipulated warts in both groups, where complete clearance was observed in 47.5% of Group A patients versus 20% of Group B patients. Autoimplantation is a suitable approach for patients with multiple warts associated with distant lesions, while MMR injection is ideal for a single or fewer number of warts.

Use of Topical and Systemic Retinoids in Solid Organ Transplant Recipients: Update and Review of the Current Literature.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at an increased risk of epithelial malignancies, mainly squamous cell carcinoma, and its precursor lesions such as actinic keratoses, warts, and porokeratosis, which may respond to retinoid therapy. OBJECTIVE: To review the published evidence on the efficacy and safety of topical and systemic retinoids for the treatment and prophylaxis of malignant and premalignant conditions that mostly afflict SOTRs. MATERIALS AND METHODS: Systematic review of the literature to summarize the level of evidence and grade of recommendation for retinoid therapy with emphasis in the SOTR population. RESULTS: Acitretin has the highest strength of recommendation (Grade A) for prophylaxis of nonmelanoma skin cancer (NMSC) and treatment and prophylaxis of actinic keratoses in SOTR. In nonimmunosuppressed patients, acitretin and isotretinoin have a Grade B recommendation for treatment of recalcitrant warts. Topical retinoids have not shown efficacy in preventing NMSC in immunocompetent patients. CONCLUSION: Retinoids constitute a highly efficacious alternative for the management of the most common conditions that affect SOTRs. Acitretin has the most robust evidence for chemoprophylaxis in SOTRs. Knowledge about the specific indications and expected side effects of topical and systemic retinoids may help optimize their therapeutic potential.

Intralesional vitamin D3 versus intralesional purified protein derivative in treatment of multiple warts: A comparative clinical and immunological study.

Intralesional (IL) vitamin D3 is an emerging treatment for cutaneous warts. However, its effectiveness and exact mechanism is not fully evaluated. We aimed to compare the efficacy and safety of IL purified protein derivative (PPD) and IL vitamin D3 in multiple warts and to investigate their systemic effect clinically and immunologically. Forty-five patients with multiple extragenital warts were treated with IL-PPD (22 patients) or IL vitamin D3 injection (23 patients) for a maximum of three sessions at 3 week intervals. Decrease in size and number of warts and adverse effects were evaluated. Serum interleukin-12 (IL-12) and interferon-gamma (IFN-γ) levels were measured before and 3 weeks after the last session. Higher clearance rates for all warts were observed with IL-PPD compared to IL vitamin D (59.1% vs. 21.7% complete clearance, p < .001). Significant increase was found in both serum IL-12 and IFN-γ after PPD treatment (p = .034 and p = .04, respectively), but only IFN-γ after vitamin D3 treatment (p = 0.02). Both IL vitamin D3 and PPD showed positive results in treatment of multiple warts. However, PPD showed higher clinical efficacy and more increase in both IL-12 and IFN-γ levels.

New Insights into the Role of Human Papillomavirus in Anal Cancer and Anal Wart Development.

Human papillomavirus is associated with several anogenital and oropharyngeal lesions, including warts, premalignant lesions, and cancer. There are specific groups that were identified as high-risk groups for anal squamous cell carcinoma and anal human papillomavirus infection, namely HIV-positive patients, men who have sex with men, women with genital tract neoplasia, and solid organ transplant recipients. Condylomas have classically been considered to be a benign lesion, with an exception made for the Buschke-Loewenstein tumor, but several publications have shown that a high percentage of condylomas harbor high-grade lesions. Due to the similarities between anal and cervical carcinogenesis, anal cancer screening based on anal cytology and referral to high-resolution anoscopy, in case of abnormalities, have been advocated. Testing for anal human papillomavirus is not routinely done in anal cancer screening, because of the very high prevalence in high-risk populations. The large majority of anal cancers are squamous cell carcinomas (SCC), and around 90% are attributed to human papillomavirus. Human papillomavirus positivity in anal SCC seems to have a prognostic value, with better survival in those patients with positive tumors. Prophylactic vaccination has been shown to be important for prevention of anal human papillomavirus-related lesions.

Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies.

BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.