The intimate dance of Staphylococcus aureus and cutaneous T-cell lymphoma

By Warren R. Heymann, MD, FAAD
July 19, 2023
Vol. 5, No. 29

I was aghast when I opened the PUVA unit when Joe told me that his mycosis fungoides (MF) was worsening — I understood why Alibert first described the disorder as resembling mushrooms in 1806. (1) His lesions had mushroomed and were impetiginized. I called his referring physician expressing my concern about a potential anaplastic transformation. I placed Joe on sulfamethoxazole-trimethoprim — within days his lesions improved dramatically, and the tumors shrank. I had always known that patients with cutaneous T-cell lymphoma (CTCL) are at risk from infection from Staphylococcus aureus (SA), often as a cause of their demise, and that SA could be a driving force worsening CTCL, but Joe’s case crystallized that tenet. This commentary will explore the intricate and intimate relationship of SA with CTCL.

CTCL is a group of skin-homing malignancies accounting for approximately 10% of non-Hodgkin lymphomas. (2) MF and Sezary syndrome (SS) are the most common forms of CTCL. (3) It has been proposed that MF and SS develop from different T-cell subsets, with MF deriving from skin-resident effector memory T cells (which remain in the skin) and SS developing from central memory T cells (long-lived, apoptosis-resistant cells found in blood, lymph nodes, and skin). (4) The etiology of CTCL is unknown but has focused on the following hypotheses (individually or in combination): 1) Genetic and epigenetic abnormalities, including deletions and translocations involving several different chromosomes or chromosomal segments; 2) Environmental and occupational exposure to solvents and chemicals; 3) An infectious etiology such as human T-lymphotropic virus Type 1 (currently lacking conclusive evidence), and 4) contributions from cytokines such as IL-2 and IL-4, among many others. (5)

Conceptually, secondary infection of CTCL with SA is straightforward. SA colonizes 31%–76% of patients with CTCL causing illnesses ranging from simple skin infections to sepsis. There are two key factors at play. Patients with CTCL have impaired barrier function, akin to patients with atopic dermatitis, with decreased expression of filaggrin and loricrin resulting in increased transepidermal water loss. Secondly, CTCL lesions demonstrate impaired expression of antimicrobial peptides (AMPs), such as beta-defensins and LL37, caused by Th2-mediated skewed Th17-cell activity. (4) CTCL patients are at risk for methicillin-resistant SA (MRSA) infection. In a study of 50 documented SA colonization or infection events in 26 erythrodermic CTCL patients, 17 (34%) were due to MRSA. (6) Treatment of infections with appropriate antibiotics (such as doxycycline or sulfamethoxazole-trimethoprim) is warranted — prophylactic courses of antibiotics are not advocated because of the potential creation of multidrug-resistant microbes. Despite the lack of evidence for efficacy, preventive measures include proper hygiene and decolonization methods (such as intranasal mupirocin and/or daily washes with chlorhexidine gluconate or bleach). (7) According to Lindahl et al: “there is an urgent need for novel non-antibiotic and highly selective anti-SA treatment modalities in order to gain life-long control of SA colonization of susceptible skin lesions in patients with malignant and benign chronic inflammatory skin diseases.” (8)

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What is most intriguing is how SA fuels CTCL progression. According to Fujii, SA produces toxins categorized in three groups: 1) superantigens (including staphylococcal enterotoxin (SE) and toxic shock syndrome toxin-1 (TSST-1)); 2) pore-forming toxins, and; 3) exfoliative toxins (ExT). Bacterial superantigens can stimulate CTCL cells directly or indirectly via the production of cytokines in non-malignant T cells, functioning as growth factors for CTCL cells. SEs cause bidirectional crosstalk between non-malignant T cells and malignant CTCL cells, promoting malignant cell growth. SA isolates from CTCL lesions express SEs that indirectly induce Janus kinase (JAK) 3/STAT3-mediated IL-10 production by malignant T cells; they may also be involved in the high expression of oncogenic microRNA miR-155 in CTCL cells. (4) Additionally, SA alpha-toxin may favor the persistence of malignant CTCL cells in vivo by inhibiting CD8+ T-cell cytotoxicity. (9)

Willerslev-Olsen et al demonstrated that SEs and SA isolates from lesions of CTCL patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Their preliminary data demonstrated that aggressive antibiotics yielded decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with SS, thereby supporting the concept that bacteria can fuel disease progression of CTCL. (10) In a prospective study of 8 patients with advanced CTCL, all experienced a significant diminution of clinical symptoms following aggressive, transient antibiotic therapy (IV carbepenem), lasting > 8 months in 2 patients, suggesting a lasting change in the tumor and its microenvironment. (11)

In conclusion, SA and CTCL are tangled in a tango, where each may seduce the other. Aside from the immediate need for antibiotics in infected lesions, it is hoped that the increased basic knowledge of this bidirectional interplay will lead to non-antibiotic strategies to improve the prognosis of advanced CTCL.

Point to Remember: Patients with cutaneous T-cell lymphoma are at risk for Staphylococcal skin infection and sepsis. Staphylococcus aureus colonization and infection may also fuel CTCL progression. Judicious use of antibiotics and preventive measures are essential in treating these patients. Current research may yield novel non-antibiotic management strategies.

Our expert’s viewpoint

Ellen J. Kim, MD, FAAD
Professor of Dermatology at the Hospital of the University of Pennsylvania

As a CTCL clinician, I am ever on the lookout for skin impetiginization/infection with Staphylococcus aureus, particularly in our erythrodermic and ulcerated tumor CTCL patients. This can be overt (honey-colored drainage or crusting) or quite subtle (increased fissuring or erosions on exam, subjective reports of skin “stickiness”). We also counsel avoiding indwelling central catheters if at all possible in our CTCL patients given the high risk of line infection when skin is colonized by Staphylococcus. By these maneuvers we can hopefully avoid bacteremia/sepsis (historically the leading cause of mortality in advanced CTCL patients). Dilute bleach baths (followed by topical steroid and emollient soak and smear regimen immediately after) for 2 weeks are a key skin-directed regimen I recommend in the setting of any CTCL flare. As outlined so comprehensively by Dr. Heymann, judicious antimicrobial interventions can definitely improve CTCL skin activity in the short term without necessarily changing their current CTCL therapeutic regimen.

1. Bieber T. Jean-Louis Alibert. In Löser C, Plewig G, Burgdorf WHC (eds.) Pantheon of Dermatology. Springer. Berlin 2008, pp 19-21.

2. Licht P, Mailänder V. Transcriptional Heterogeneity and the Microbiome of Cutaneous T-Cell Lymphoma. Cells. 2022 Jan 19;11(3):328. doi: 10.3390/cells11030328. PMID: 35159138; PMCID: PMC8834405.

3. Vakiti A, Padala SA, Singh D. Sezary Syndrome. 2021 Aug 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29763049.

4. Fujii K. Pathogenesis of cutaneous T cell lymphoma: Involvement of Staphylococcus aureus. J Dermatol. 2022 Feb;49(2):202-209. doi: 10.1111/1346-8138.16288. Epub 2021 Dec 19. PMID: 34927279.

5. Vaidya T, Badri T. Mycosis Fungoides. 2021 Aug 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30137856.

6. Emge DA, Bassett RL, Duvic M, Huen AO. Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in erythrodermic cutaneous T-cell lymphoma (CTCL) patients. Arch Dermatol Res. 2020 May;312(4):283-288. doi: 10.1007/s00403-019-02015-7. Epub 2019 Nov 27. PMID: 31776647.

7. Adithya Sateesh B, Bhagat YV, Thomas SE, Sood A, Michael MB. Recurrent Bacterial Infections in Cutaneous T-cell Lymphoma. Cureus. 2022 Jan 3;14(1):e20912. doi: 10.7759/cureus.20912. PMID: 35154913; PMCID: PMC8815712.

8. Lindahl LM, Iversen L, Ødum N, Kilian M. Staphylococcus aureus and Antibiotics in Cutaneous T-Cell Lymphoma. Dermatology. 2021 Oct 7:1-3. doi: 10.1159/000517829. Epub ahead of print. PMID: 34619677.

9. Blümel E, Munir Ahmad S, Nastasi C, Willerslev-Olsen A, Gluud M, Fredholm S, Hu T, Surewaard BGJ, Lindahl LM, Fogh H, Koralov SB, Rahbek Gjerdrum LM, Clark RA, Iversen L, Krejsgaard T, Bonefeld CM, Geisler C, Becker JC, Woetmann A, Andersen MH, Buus TB, Ødum N. Staphylococcus aureus alpha-toxin inhibits CD8+ T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma. Oncoimmunology. 2020 Apr 17;9(1):1751561. doi: 10.1080/2162402X.2020.1751561. PMID: 32363124; PMCID: PMC7185203.

10. Willerslev-Olsen A, Gjerdrum LMR, Lindahl LM, Buus TB, Pallesen EMH, Gluud M, Bzorek M, Nielsen BS, Kamstrup MR, Rittig AH, Bonefeld CM, Krejsgaard T, Geisler C, Koralov SB, Litman T, Becker JC, Woetmann A, Iversen L, Odum N. Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2021 Oct;141(10):2449-2458. doi: 10.1016/j.jid.2021.01.038. Epub 2021 Apr 20. PMID: 33862068.

11. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, Nielsen PR, Blümel E, Rittig AH, Celis P, Herpers B, Becker JC, Stausbøl-Grøn B, Wasik MA, Gluud M, Fredholm S, Buus TB, Johansen C, Nastasi C, Peiffer L, Kubat L, Bzorek M, Eriksen JO, Krejsgaard T, Bonefeld CM, Geisler C,Mustelin T, Langhoff E, Givskov M, Woetmann A, Kilian M, Litman T, Iversen L, Odum N. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood. 2019 Sep 26;134(13):1072-1083. doi: 10.1182/blood.2018888107. Epub 2019 Jul 22. PMID: 31331920; PMCID: PMC6764271.

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