Irrelevance of Panton-Valentine leukocidin in hidradenitis suppurativa: results from a pilot, observational study

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic-relapsing, debilitating inflammatory disease of the hair follicle, which affects apocrine gland-bearing skin, most commonly the axillae, inguinal regions, anogenital area, and infra- and inter-mammary folds [1]. It is clinically characterized by recurrent, painful, deep-seated nodules commonly ending in abscesses and sinus tracts with persistent suppuration and hypertrophic, bridged scarring. HS usually presents after puberty and its estimated prevalence ranges from less than 0.1 to 4% [1, 2]. HS has a huge negative influence on patients’ lives due to its chronic course, pain and other disease-related symptoms, persistent malodor, peculiar anatomical localization, disfiguring sequelae, and lack of a definitive cure [3, 4].

The pathogenesis of HS is not fully recognized and appears to involve a number of interacting factors, including a susceptible genetic background, a dysregulated immune response to various heterogeneous stimuli, and follicular occlusion [1, 2, 5]. The role of bacterial infection in the initiation or propagation of HS remains under investigation [6, 7]. Most frequently bacteriological studies have shown a mixed growth of commensal microbes, which is more consistent with the view that HS is an immune-mediated condition rather than a disease of primary infectious etiology [7, 8]. Bacterial colonization of HS lesions may act synergistically with a dysfunctional immune response, involving both the innate and adaptive immune systems, which leads to a chronic, relapsing inflammatory scenario. On the other hand, HS may predispose to an increased risk of skin infections [9]. Panton-Valentine leukocidin (PVL) is a two-component pore-forming cytotoxin produced by Staphylococcus aureus inducing leukocyte destruction and tissue necrosis [10]. In addition, PVL is a polymorphonuclear neutrophils priming agent [11]. In keeping with this, it appears to be a highly relevant virulence factor which, among others, can exacerbate the pathogenicity of S. aureus infections [12]. In particular, it is related to deep-seated skin and soft tissue infections and causes furuncles, cutaneous abscesses, and severe necrotic skin infections [13, 14]. Moreover, PVL seems to be a marker for severity and recurrence [15]. Based on these assumptions, we were interested in assessing if S. aureus producing PVL could have some role in influencing clinical features and/or the course of HS, especially in the suppuration and recurrence of lesions.

Bacteria have long been considered in the pathogenesis of HS. It is generally acknowledged that bacteria do not play a direct role in the etiology of HS; however, they may be involved in the pathogenesis of HS via follicular dysbiosis and biofilm as well as eliciting an inflammatory response in a genetically predisposing background [7]. Interestingly, it had previously been shown that the microbiological population of HS changes considerably according to the clinical severity of the disease [17]. Our findings support the high prevalence of positive culturing samples from HS lesions [7], since bacteria specimens were isolated from almost all the study samples (29 of 30, 96.7%).

With special reference to S. aureus, this has often been described in association with HS and has even been proposed as a potential causative organism [18, 19]. However, the literature includes some controversial data [20] and its action in the pathogenesis of the disease remains unknown. Based on the recognized virulent role of PVL in S. aureus infections, especially in those by community-associated methicillin-resistant S. aureus (CA-MRSA), also at skin level [21, 22], we wanted to specifically seek its presence in HS lesions. In particular, we were interested in deepening a possible link between S. aureus producing PVL and degree of suppuration, skin involvement, disease chronicity, and recurrence. We focused on PVL because it exerts peculiar mechanisms of action that may be in some way compatible with HS. In fact, it induces the release of pro-inflammatory cytokines and nuclear factor kappa B (NF-κB) in neutrophils, leading to skin infections which tend to be invasive, necrotizing, and recurrent [22, 23]. Analyzing the findings obtained from the purulent skin disorders included as controls, these were fairly consistent with this pathogenic profile (Table 3). Prevalence of PVL-positive S. aureus was highly correlated with primary pyodermitis when compared with impetiginized lesions, primarily follicular inflammation and deep inflammatory processes.

The rate of S. aureus strains isolated from purulent material drained from abscesses and sinuses of HS patients was quite in line with previous reports, being about 17% [7, 19, 24]. The isolation of S. aureus did not correlate with patient or disease characteristics, including severity of HS in terms of Hurley’s score, number of sites affected, and frequency of recurrence, unlike what other researchers have found [25]. The most noteworthy finding of our study was that none of the strains of S. aureus isolated from HS purulent lesions expressed PVL. This finding strongly suggests an irrelevant role of PVL, not only in HS etiopathogenesis but also in its clinical features and course. Therefore, in speculating about the relevance of S. aureus in HS, our results seem to exclude the involvement of PVL. This can also be seen from a therapeutic perspective, since PVL does not seem to represent a potential target in the development of a treatment for HS.

The role of toxins, especially necrotizing toxins, in HS is uncertain and has been poorly investigated. Diphtheria by the toxigenic zoonotic pathogen Corynebacterium ulcerans is increasingly occurring in children, adolescents, and adults. In addition to diphtheria toxin (DT), the exotoxin phospholipase D (PLD) is considered an important virulence factor of C. ulcerans and C. pseudotuberculosis [26]. PLD has been found to induce dermonecrotic lesions, increased vascular permeability in vivo, and synergistic hemolysis of sheep blood cells.

Pseudomonas aeruginosa can cause severe human opportunistic infections, including many hospital-acquired infections. However, there is scarce evidence about its clinical relevance in patients with HS. Among its toxins, exotoxin A is the main virulence factor [27]. Similarly but less effectively than DT, exotoxin A interrupts protein synthesis in the host cell and has an immunosuppressive action. Pigments, such as pyocyanin, which catalyzes reactive oxygen species (ROS) production and attracts neutrophils, and pioverdin (siderophore), exert multiple detrimental effects on the host too. The blue-green phenazine, pyocyanin, is a key virulence factor that can kill competing organisms as well as host cells and can inactivate catalases to protect against ROS generated by host tissues [28]. Pyocyanin in particular can serve as a redox cycler similar to methyl viologen, resulting in superoxide radical production and oxidative stress [29]. The majority of these virulence factors are under the control of two regulatory systems: the two-component system and the sensing quorum, which allow the survival and multiplication of this microorganism in the host [30].

Despite the inherent potential to cause harmful effects in humans, little is known about the role of these toxins in HS and further investigation could be conducted. Furthermore, the methods used for their detection will still require time for their optimal development and application in this specific context.

This study has some limitations, especially the relatively small number of patients affected with HS included. However, it was designed as pilot in nature and with the possibility of an extension being planned in the event of positive results. The patients attended a tertiary clinic, specifically dedicated to HS, so the study population may be not representative of the entire population affected by this disease and a selection bias cannot be excluded. Other variables, such as comorbidities, body mass index, and lifestyle habits like smoking, potentially relevant for the study assessments, were not considered.