¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Division of Dermatology, BC Children’s Hospital, Vancouver, BC, Canada

Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory skin disease that significantly impacts the quality of life of patients.¹ HS is more common in adults and adolescents, although true incidence rates may be underestimated due to a lack of earlier recognition of HS in children.² Pediatric HS is a challenging clinical entity to diagnose and manage. Although considered uncommon, treatment of pediatric HS can drastically improve psychosocial well-being and should be considered in children presenting with recurring painful skin nodules, abscesses, scarring and sinus tracts. Multiple comorbidities are associated with pediatric HS, including depression, anxiety, inflammatory bowel disease, metabolic syndrome, and obesity.³ Medical management of pediatric HS poses a unique challenge given the paucity of literature surrounding efficacy and long-term treatment outcomes in pediatric patients. The purpose of this article is to discuss the epidemiology, pathogenesis, comorbidities, and management of pediatric HS.

Keywords: childhood hidradenitis, early onset hidradenitis suppurativa, hidradenitis suppurativa in children, inflammatory disorders, pediatric dermatology

Introduction

Hidradenitis suppurativa (HS) is a chronic disease involving the follicular unit that typically presents with inflammatory intertriginous lesions.⁴ Depending on severity, cutaneous involvement can manifest as painful nodules, abscesses, sinus tracts, and/or hypertrophic scarring.⁵ HS usually presents in adolescents and adults, and is considered uncommon in children, with an estimated prevalence of less than 2% in prepubescent children.⁶ A recent cross-sectional analysis reported 96.8% of pediatric patients with HS were ≥10 years old, with the highest prevalence reported in patients aged 15-17 years old.⁷ Some have noted that delays in care for pediatric patients may reflect an under-recognition of pediatric HS.⁴ In the adult population, women are more commonly affected by HS in comparison to men. Similarly, pediatric HS is more commonly reported in girls, although the exact prevalence is unknown.⁸ Unfortunately, most literature on pediatric HS is limited to small case series, case studies, or extrapolation from adult studies.⁹ More pediatric focused research is needed to better understand disease burden, prevalence, and treatment.

Pathogenesis

The pathogenesis of HS specific to pediatric patients is not well understood and primarily relies on extrapolation from basic sciences and adults with HS. HS pathophysiology is complex and involves environmental, immunologic, and genetic factors. HS is considered a disorder of follicular occlusion, in which hair follicle dysregulation and inflammation play key roles.¹⁰ As affected hair follicles become occluded and eventually rupture, bacteria and keratin enter the surrounding dermis, promoting an inflammatory state and subsequent lesion formation. Many patients with HS have a positive family history, which has prompted genetic studies.¹¹ Gene mutations that alter antimicrobial peptides and cytokines have been demonstrated in patients with HS.¹² Heterozygous mutations in gamma‐secretase (γ‐S), a protease involved in follicular keratinization regulation have been identified in autosomal dominant forms, supporting a genetic link.^12,13 Gamma-secretase deficiencies have also been associated with impaired sebaceous gland formation and follicle disintegration in mice studies.¹⁴ Some research suggests that patients with early-onset HS appear more likely to have a positive family history.¹⁵ From an immunologic standpoint, both the innate and adaptive immune system play important roles. Decreased expression of antimicrobial peptides may facilitate superficial colonization by bacteria and promote ongoing inflammation through pro-inflammatory cytokines.¹⁶ Pro-inflammatory cytokines involved in HS include but are not limited to interleukin (IL)-1, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor (TNF)-alpha.^9,16 Other factors that can promote HS pathogenesis and impact disease severity include microbial dysbiosis, microbial colonization, mechanical friction, and hormones.¹⁷ In addition, sinus tracts develop a psoriasiform lining, which tries to recapitulate the epidermis, shedding keratin and causing further inflammation. Hence, persistent lesions still exist despite systemic therapy and deroofing is often curative and essential to include in full-spectrum care.

Clinical Features and Diagnosis

Pediatric HS is a clinical diagnosis based on its typical morphology of deep nodules, cysts, sinus tracts, and fibrotic scars in intertriginous areas. A cross-sectional study assessing the clinical features of children <18 years old (mean age of 15.3 years) with HS reported a similar presenting clinical spectrum to adult-onset disease.¹⁸ Typical sites include those abundant with apocrine glands, such as the axillae, inframammary area, groin, and perianal region. Drainage from involved sites is a commonly reported symptom.¹⁹ There are currently no guidelines regarding investigations for HS in pediatric patients or adults. Laboratory investigations or skin biopsy are unnecessary for diagnosis, but imaging may be considered for operative planning when assessing sinus tracts.¹⁸ Ultimately, given the lack of research and consensus, there are currently no screening guidelines for investigating potential comorbidities in pediatric patients with HS. The Hurley staging system is often used to categorize patients into three disease groups based on their level of severity.²⁰ Stage I includes abscess formation (single or multiple), without sinus tract(s) or scarring, Stage II includes those with recurrent abscesses with sinus tracts and scarring present, and Stage III encompasses diffuse involvement, with multiple abscesses and interconnected sinus tracts.²⁰ The Sartorius scoring system is typically reserved for clinical trials and is not commonly used in clinical practice.8 Another useful scoring system is the International Hidradenitis Suppurativa Severity Score System (IHS4) which is a validated, dynamic assessment of HS severity that encompasses counting nodules, abscesses, and draining sinus tracts/fistulas.²¹ The Hidradenitis Suppurativa Quality Of Life (HiSQOL) scoring system may also be useful for capturing impactful areas of HS such as pain, odor, and drainage, which are not measured by the Dermatology Life Quality Index (DLQI) and should be considered by treatment providers.

Associated Comorbidities

Multiple comorbidities have been associated with pediatric HS, including more hormonal imbalances in comparison to adult populations, with manifestations including acne, premature adrenarche, adrenal hyperplasia, metabolic syndrome, and obesity.⁶ Although the overall association between early-onset HS and premature adrenarche and hormonal imbalance remains unclear, assessing for precocious puberty in children presenting with HS may be an important consideration depending on the clinical presentation. From a database of 870 pediatric patients, an elevated body mass index (BMI) and obesity were higher in comparison to reference population standards, as was the prevalence of smoking.¹⁸ Aside from metabolic syndrome, inflammatory bowel disease (IBD) and spondyloarthropathy have also been shown to be associated with HS.⁹ Patients with Down syndrome have been shown in multiple studies to have an earlier onset of HS although the mechanism behind this remains unknown.⁹ A detailed history, including inquiring about a family history of HS and associated comorbid symptoms and a physical examination should be completed. From a psychosocial perspective, HS can drastically impact quality of life and is associated with significant psychological distress.⁸ Painful, inflammatory lesions can limit children’s ability to play, exercise, or attend school which can contribute to obesity and further worsening of disease.⁶ Furthermore, social stigma surrounding HS can negatively affect psychosocial well-being, especially during the adolescent period. Overall, higher rates of anxiety and depression have been reported in pediatric-aged HS patients compared to those without HS.⁹ A cross-sectional study recently examined the quality of life impacts of HS in 25 pediatric patients aged 12-17 years of age.²² They found that 32% of patients had positive screening results for depression on the Patient Health Questionnaire-2, a depression screening tool.²² The Skindex-Teen questionnaire, an adolescent quality of life questionnaire for skin disease was also used, which demonstrated a higher average score in patients with more moderate-severe HS.²² Overall, clinicians should have a high level of suspicion for psychological comorbidities when treating pediatric patients with HS.

Treatment

Management of HS in the pediatric population is limited given the lack of information surrounding long-term outcomes. Determining the appropriate treatment involves weighing the biopsychosocial impact on the child, disease severity, and side effects of medications or procedures. In general, treatment of HS includes topical or systemic medications and surgical modalities depending on the severity. Lifestyle modifications are typically encouraged for all patients and include smoking cessation, weight management, and avoidance of triggers. Patient and family education should emphasize that HS is a chronic disease without a cure, with treatment focusing on disease and symptom management.

For Hurley Stage I disease, conservative management with topical treatment, such as clindamycin 1% solution, azelaic acid 15%, resorcinol 15%, or combination treatment with clindamycin/ benzoyl peroxide is recommended.⁶ Of note, resorcinol is the only topical treatment with studies completed for HS in adults and is a medication that must be compounded. Topical antiseptics and clindamycin are considered safe for use but may be ineffective for more moderate or severe HS.²³ For non-prescription treatments, laser hair removal has been effective via the Hidradenitis Suppurativa Clinical Response (HiSCR) response in patients with mild-to-moderate disease.²⁴ Supplementation with 100 mg of oral zinc has also been shown to improve HS.²⁵ Concurrent supplementation with 4 mg of copper should be considered to prevent copper deficiency.²⁵ For those where topical treatments fail or children with Hurley Stage II disease, systemic medications can be explored. Systemic antibiotics such as doxycycline, clindamycin with rifampicin, metronidazole, and erythromycin are appropriate for use in children with more severe disease.⁶ Counselling regarding potential tooth discoloration and enamel hypoplasia should be done for patients under 8 years old receiving tetracycline antibiotics.²³ However, antibiotics are not a feasible long-term solution. If there is recurrence after treatment, adalimumab or secukinumab should be considered. Oral finasteride demonstrated improvement in resistant cases from a small pediatric case series, however potential side effects include transient sexual dysfunction in males, and pediatric safety data is lacking, particularly for prepubertal males.²⁶ Systemic retinoids used for the treatment of HS include acitretin and isotretinoin, although these have considerable risks and isotretinoin tends to be more effective in milder, folliculocentric subtypes. The long-lasting teratogenic effects of acitretin make it unsuitable for patients with childbearing potential and isotretinoin in children under 12 years of age has been reported to cause premature epiphyseal closure.²⁷ Importantly, all patients of childbearing potential should be counselled surrounding teratogenic effects where applicable.

In terms of biologics, adalimumab is currently the only approved choice in North America for pediatric patients older than 12 years of age who weigh at least 30 kg.²⁸ Safety data surrounding the use of adalimumab in pediatric patients for HS is limited, although adalimumab has been used effectively in pediatric patients for other inflammatory diseases including Crohn’s disease, psoriasis, and juvenile idiopathic arthritis.²⁹ Secukinumab, an IL-17 inhibitor, is both Health Canada and US FDA approved for treatment of adults with moderate-to-severe HS. Based on clinical studies in adults, it may be a therapeutic option for first- or second-line off-label treatment of pediatric HS patients.^30,31 Overall, dermatologists should have a low threshold to treat systemically and preventatively, as HS is typically a progressive disease that can become less responsive to biologic therapy as time passes and severity increases. Surgical modalities may be another option for older children. Depending on the extent of disease, wide excision and/or minimally invasive deroofing can be considered. A recent cross-sectional study found that surgical excision and deroofing were reported as useful for all 23 pediatric patients assessed, while those treated with simple excision had zero responders in 7 cases treated with simple excision.³² However, a surgical approach is more invasive and carries the risk of infection, scarring, and recurrence.⁹ A retrospective review of 11 patients under 18 years old with a total of 23 operative sites reported an overall complication rate of 87% and a 7% reoperation rate.³³ Remission after a single procedure was reported in 57% of included sites.³³ However, it is crucial to combine both medical preventative treatments with surgical therapy, as success rates are much higher with a combination approach.

Conclusion

Pediatric HS is an understudied and underrecognized disease with significant biopsychosocial impacts. Unfortunately, diagnosis is often delayed given the wide variety of presentations in early disease. Clinicians should consider associated comorbidities such as metabolic syndrome, inflammatory bowel disease, and anxiety and depression. Early recognition, diagnosis, and management are essential in improving quality of life and managing symptoms for children and adolescents with HS. Further research focused on long-term outcomes, associated comorbidities, and medical management is needed to improve our understanding and treatment of pediatric hidradenitis suppurativa.

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¹University of Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract:
Cutaneous leishmaniasis (CL) is an infection caused by the Leishmania protozoa, which are primarily transmitted through bites of infected female sandflies. This article provides a comprehensive overview of the clinical management of CL, including an in-depth analysis of its epidemiology, prevention and control measures, diagnostic modalities – particularly molecular and serological, differential diagnosis with other lesions, and treatment options. Also discussed are recent concerns regarding the endemicity of CL, with a focus on the significant rise in travel-related cases as well as locally acquired cases, providing insight into the changing epidemiological landscape.

Keywords: cutaneous leishmaniasis, neglected tropical diseases, zoonotic diseases, clinical management, differential diagnosis

Introduction

Cutaneous leishmaniasis (CL) is a form of leishmaniasis, a protozoal infection that affects the skin or internal organs. Other forms of leishmanisis are more severe but rarer. CL remains a significant public health challenge due to its widespread prevalence and potential to cause severe disfigurement and morbidity.^1,2 The prevention, diagnosis, and treatment of CL require a multifaceted approach. According to the World Health Organization (WHO), there were over 200,000 reported cases of CL in 2022, and the number of cases continues to rise, making CL one of the most common skin diseases globally.³ The WHO has classified CL and its other forms as neglected tropical diseases (NTDs), reflecting their significant impact in endemic regions.³ The impact of CL is also increasing in non-endemic areas due to factors such as international travel, migration, and the influence of climate change.^4,5 Therefore, managing CL and other NTDs has become a critical issue.

Epidemiology

The global distribution of CL encompasses tropical and subtropical regions, with endemic areas in the Central and South Americas, Mediterranean basin, Middle East, and parts of Asia and Africa.³ According to the WHO, CL affects approximately 0.7 to 1.2 million people annually.^1,3 The disease burden is particularly high in countries like Brazil, Iran, Afghanistan, and Syria.^6,7

In North America, CL is not commonly found, but there have been cases reported among travelers and military personnel returning from regions where the disease is prevalent.⁸ It is important to note that there have been cases of CL originating in Texas and Oklahoma, indicating the potential for local transmission.^2,8,9 In 2023 alone, the Texas Department of State Health Services has reported at least 9 new cases of CL (also the average number of new cases in the past decade), and new cases are recommended to be reported within a week.^10,11 These locally acquired cases are believed to be a result of climate change, which has expanded the habitable range of sandfly vectors.¹² The increasing number of reported cases in non-endemic regions emphasizes the need for heightened surveillance and awareness among healthcare providers in these areas.¹³

Prevention and Control

It is essential to implement effective prevention and control strategies to reduce the incidence of CL. One of the primary methods of prevention is vector control, which involves measures such as the use of insecticide-treated bed nets and indoor residual spraying.⁴ Personal protective measures, including wearing long-sleeved clothing and using insect repellents, are also recommended.¹⁴ It is also advisable to avoid outdoor activities during dusk and dawn when sandflies are most active.¹⁵ These comprehensive strategies collectively contribute to reducing the risk of contracting CL.

Environmental management strategies focus on reducing sandfly breeding sites by improving sanitation and housing conditions.^1,3,12 Such approaches include the removal of organic waste and rubble, which serve as breeding sites for sandflies, and improving housing structures to prevent sandfly entry.^7,16 Public health education campaigns are also essential in raising awareness about preventive measures and encouraging community participation.^17-19 These campaigns target both endemic regions and non-endemic areas at risk of CL introduction, emphasizing the importance of early diagnosis and treatment.^20,21 Additionally, the development and distribution of a vaccine for CL is an area of active research, though no effective vaccine is currently available.^8,22

Diagnosis

An accurate diagnosis of CL is crucial for effective treatment, as most species present a unique manifestation (Table 1). Clinically, CL is characterized by ulcerative skin lesions, often located on exposed areas such as the face, arms, and legs.^2,14,17-19 The lesions may vary in appearance and can be single or multiple, with a chronic course if left untreated.^4,23

Laboratory confirmation of CL is achieved through several methods:

Microscopy

A direct visualization of Leishmania amastigotes in stained tissue smears is a common diagnostic method. However, its sensitivity varies depending on the parasite load and the skill of the technician.^1,15 Giemsa-stained smears of lesion material can be examined under a microscope; this method remains widely used due to its simplicity and low cost.²⁴

Culture

Culturing Leishmania parasites from lesion aspirates or biopsies in specialized media can provide a definitive diagnosis, but it is time-consuming and requires laboratory facilities.⁴ Media such as Novy-MacNeal-Nicolle (NNN) or Schneider’s Drosophila medium are commonly used for parasite cultures.^25,26

Molecular Techniques

Polymerase chain reaction (PCR) has become increasingly popular due to its high sensitivity and specificity. It can detect and identify Leishmania species, which is essential for guiding treatment decisions.^2,4 Real-time and loop-mediated isothermal amplification (LAMP) are advanced molecular techniques that can also provide rapid and accurate diagnosis.^27,28

Serological Tests

These are generally less useful for CL due to variable antibody responses but may have a role in epidemiological studies.²⁹ However, specific serological tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescent antibody test (IFAT) can aid in diagnosis under certain conditions.^8,30,31

Other recent advancements include the development of rapid diagnostic tests (RDTs) that offer point-of-care diagnosis with minimal laboratory infrastructure.^1,30 These tests are particularly useful in resource-limited settings and for large-scale epidemiological surveys.³⁰ The combination of RDTs and clinical presentations, along with anecdotal histories, provides the best diagnosis of CL and can improve the subsequent quality of care.

Differential Diagnosis

Differentiating CL from other skin conditions is critical to avoid misdiagnosis and inappropriate treatment (Figure 1).^17-20,32 The differential diagnosis includes:

Fungal Infections

Sporotrichosis and chromoblastomycosis present with chronic skin lesions resembling CL. Sporotrichosis, caused by Sporothrix schenckii, typically presents with nodular lesions that can ulcerate, resembling CL.³⁴

Parasitic Infections

Cutaneous larva migrans (CLM) and myiasis should be considered, particularly in endemic regions. CLM, caused by hookworm larvae, presents with serpiginous tracks on the skin, which can be distinguished from CL lesions.³⁵

Non-Infectious Conditions

Skin cancers, eczema, psoriasis, and autoimmune diseases such as lupus erythematosus can present with lesions that resemble CL.² Basal cell carcinoma and squamous cell carcinoma may present as ulcerative lesions similar to CL but typically have different clinical and histopathological features.⁹

Therefore, a combination of thorough clinical evaluations and appropriate laboratory tests is necessary to establish the correct diagnosis.¹⁵ Biopsy and histopathological examination can aid in differentiating CL from other conditions, especially when combined with molecular techniques.¹⁸

Pharmaceutical Treatments

One of the difficulties in the management of CL is that its treatment varies based on the species of Leishmania, geographical region, and patient factors.^17,19 The mainstay of treatment includes antimonial compounds, amphotericin B, pentamidine, and miltefosine.^{4,7,14,15,20,24} Most of these pharmacologic agents can be effective against multiple species, but the conditions presented by each case should guide the treatment decision and may limit the choice of therapy (Table 2). Recent studies have even considered the use of multiple treatments to synergize therapeutic effects.^1,3

Pentavalent Antimonial Compounds

Meglumine antimoniate and sodium stibogluconate (SSG) have been the first-line treatments for decades. They are effective but associated with significant side effects such as cardiotoxicity and hepatotoxicity.¹⁵ These drugs require intramuscular or intravenous administration, and treatment courses typically last 20 to 28 days.²⁴

Amphotericin B

This antifungal agent is effective against various Leishmania species. Liposomal formulations have improved the safety profile but remain expensive.² Liposomal amphotericin B (AmBisome®) is administered intravenously and is preferred for its lower toxicity and shorter treatment duration compared to conventional formulations.³⁶

Pentamidine

Used primarily for L. guyanensis infections, pentamidine is an alternative when antimonies are contraindicated or ineffective.³⁷ It is administered intramuscularly or intravenously, and common side effects include nephrotoxicity, hypotension, and hyperglycemia.²⁰

Miltefosine

As the first oral drug approved for CL, miltefosine is effective against several species and has a more favorable safety profile, though it is teratogenic and requires monitoring for gastrointestinal side effects.³⁸ Treatment with miltefosine typically lasts 28 days and is even effective against visceral leishmaniasis.^24,39

Recent research has focused on combination therapies to improve efficacy and reduce the duration of treatment.⁴ Combination therapy using miltefosine with other drugs such as paromomycin or liposomal amphotericin B has shown promise in clinical trials.²⁴

Drug Resistance

The emergence of drug resistance in CL is influenced by various factors, including parasite genetics, host immune responses, and treatment regimens.⁴⁰ Studies have highlighted the role of genetic mutations in mediating resistance to antimonies, amphotericin B, and miltefosine.^39,41 For instance, mutations in genes encoding proteins involved in drug transport and metabolism, such as aquaglyceroporin 1 (AQP1) and multidrug resistance protein 1 (MRP1), have been associated with decreased drug susceptibility in Leishmania parasites.^42,43

AQP1 is a transmembrane channel protein that facilitates the passage of water, glycerol, and certain small solutes across the cell membrane of Leishmania parasites.^42,44 Importantly, the channel also serves as a conduit for the uptake of antimonial drugs like SSG. Therefore, mutations in the AQP1 gene can lead to structural alterations in the protein, resulting in reduced drug uptake and diminished susceptibility to antimonials.⁴⁵ Similarly, MRP1 belongs to the ATP-binding cassette (ABC) transporter family and is involved in the efflux of a broad range of substrates, including chemotherapeutic agents.⁴¹ Overexpression or mutations of MRP1 can confer resistance to multiple antileishmanial drugs by actively reducing their intracellular concentrations and, consequently, their therapeutic efficacy.⁴³ Therefore, an understanding of the molecular basis of drug resistance is essential for the development of effective therapeutic strategies and the identification of novel drug targets to combat CL.

Moreover, environmental factors, including drug pressure and host immune status, play a crucial role in shaping the dynamics of drug resistance in CL. Prolonged exposure to suboptimal drug concentrations can select for resistant parasite strains.^40,42 Additionally, immunocompromised individuals, such as those co-infected with human immunodeficiency virus (HIV), are more susceptible to treatment failure and the development of drug resistance due to impaired immune responses.³³

Non-Pharmaceutical Treatments

Non-pharmaceutical treatments are often used in conjunction with pharmaceutical therapies or when drug treatment is contraindicated.^2,46 These methods provide alternative patient options and can be tailored to individual needs and preferences. Current treatments include cryotherapy, photodynamic therapy, and surgical excision.^19,20,46

Cryotherapy

Cryotherarpy involves the application of liquid nitrogen to freeze and destroy the lesion. It is effective for localized lesions but may require multiple sessions.⁴⁷ Cryotherapy is a simple, low-cost option that can be performed in outpatient settings and is particularly useful for lesions in accessible areas.⁴⁸

Photodynamic Therapy

Photodynamic therapy utilizes light-activated compounds to selectively target and destroy Leishmania parasites. The application of a photosensitizing agent followed by exposure to a specific wavelength of light, leads to the generation of reactive oxygen species that kill the parasites.⁴⁹ For patients who cannot tolerate systemic treatments, photodynamic therapy is a promising solution.⁵⁰

Surgical Excision

Surgical excision can be considered for single, well-defined lesions that are resistant to other treatments.^23,51 It carries the risk of scarring and should be performed by experienced clinicians.^2,52

Conclusion

Managing CL involves a comprehensive approach that includes prevention, accurate diagnosis, and effective treatment. Recent advancements in diagnostic tools and treatment options have improved the management of CL. However, challenges remain, particularly in non-endemic regions like North America, where awareness and expertise may be limited.^4,8 Increased travel and climate change could lead to a rise in cases, highlighting the need for continued research and international collaboration to address these challenges and reduce the burden of CL globally.³

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Ustekinumab-kfce SC/IV use

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