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\begin{document}

\title{Angioinvasive Trichophyton rubrum associated necrotizing fasciitis in an
immunocompromised patient}



\author[1]{Michael Davis}%
\author[1]{Katelyn Rypka}%
\author[1]{Alexandra Perron}%
\author[1]{John Keilty}%
\author[1]{Benjamin Wils}%
\author[1]{Joshua Levine}%
\author[2]{Anthony Rezcallah}%
\author[2]{Robin Solomon}%
\author[2]{Noah Goldfarb}%
\author[2]{Anjum Kaka}%
\affil[1]{University of Minnesota Medical School Twin Cities Campus}%
\affil[2]{Minneapolis VA Health Care System}%


\vspace{-1em}



  
  \date{June 01, 2024}


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\textbf{Title:} Angioinvasive\emph{Trichophyton rubrum} associated
necrotizing fasciitis in an immunocompromised patient

\textbf{Authors:} Michael J. Davis, DO, MPH\textsuperscript{1-3*};
Katelyn J. Rypka, BS\textsuperscript{3-6*}; Alexandra K. Perron,
BA\textsuperscript{6}; John Keilty, BS\textsuperscript{6}; Benjamin
Wils, MS \textsuperscript{6}; Joshua Levine, BA \textsuperscript{6};
Anthony T. Rezcallah, MD\textsuperscript{7-8}; Robin Solomon,
MD\textsuperscript{9}; Noah Goldfarb, MD\textsuperscript{3-5+}; Anjum
Kaka, MD\textsuperscript{1, 3+}

Affiliations:

\textsuperscript{1}Department of Infectious Disease, Minneapolis VA
Health Care System, Minneapolis, MN

\textsuperscript{2}Department of Infectious Disease, University of
Minnesota, Minneapolis, MN

\textsuperscript{3}Department of Internal Medicine, Minneapolis VA
Health Care System, Minneapolis, MN

\textsuperscript{4}Department of Dermatology, Minneapolis VA Health Care
System, Minneapolis, MN

\textsuperscript{5}Department of Dermatology, University of Minnesota,
MN

\textsuperscript{6}University of Minnesota Medical School, Minneapolis,
MN

\textsuperscript{7}Department of Surgery, Minneapolis VA Health Care
System, Minneapolis, MN

\textsuperscript{8}Department of Surgery, University of Minnesota,
Minneapolis, MN

\textsuperscript{9}Department of Pathology, Minneapolis VA Health Care
System, Minneapolis, MN

*These authors contributed equally

+These authors contributed equally

\textbf{Key clinical message:}

Angioinvasive dermatophytosis with necrotizing fasciitis can be a rare
complication in immunocompromised patients with early surgical
debridement, 12 weeks of oral terbinafine, and reduction in
immunosuppression being a viable management strategy.

\textbf{Key words:} angioinvasive dermatophytosis, Trichophyton rubrum,
terbinafine, necrotizing fasciitis, hematologic malignancy,
immunosuppression

\textbf{Consent statement:} Written informed consent was obtained from
the patient to publish this report in accordance with the journal's
patient consent policy

\textbf{Introduction:}

Dermatophyte infections are characterized by local invasion of
superficial keratinized structures such as skin, hair, and nails by
members of the genera \emph{Trichophyton} , \emph{Microsporum} ,
and\emph{Epidermophyton} .\textsuperscript{1,2} Organisms from these
genera infect keratinocytes via arthrospores released from hyphae.
Following attachment to keratinocytes, these arthrospores germinate, and
establish infection in the stratum corneum of the
skin.\textsuperscript{2} These infections clinically manifest as annular
plaques with a collarette of scale. In humans, these infections are
limited to the superficial layers of the skin due to the keratinophilic
nature of the organism as well as intact cell mediated immunity limiting
spread of the infection to deeper tissues.\textsuperscript{1,3,4}
Uncommonly, when cell mediated immunity is impaired, these organisms can
invade down the hair follicle resulting in Majocchi granuloma. Rarely
deeper invasion may extend into the dermis and subcutaneous
tissue.\textsuperscript{5,6} With an increasingly large variety of
immunosuppressive medications on the market to treat patients with
autoimmune conditions, malignancies, and solid organ transplants, there
is an increasing population of immunosuppressed patients who may be at
risk for invasive dermatophyte infections. This case presents a patient
with recurrent tinea corporis who developed angioinvasive
dermatophytosis in the setting of ongoing immunosuppressive treatment
for chronic lymphocytic leukemia (CLL) and immune thrombocytopenia
purpura (ITP).

\textbf{Case presentation:}

A 69-year-old male with a history CLL, ITP, and recurrent tinea corporis
presented to the hospital with an ulcerating lesion at the site of a
previously diagnosed tinea corporis infection of his right medial ankle.

One month prior to presentation, the patient was started on high-dose
steroids for treatment of refractory ITP. After 2-3 weeks of
experiencing a limited response to steroid treatment, he was started on
rituximab and ultimately hospitalized for refractory ITP. During this
hospitalization, the patient's ITP was thought to be triggered by CLL
prompting the initiation of ibrutinib for treatment. Following the
initiation of ibrutinib, he was seen by dermatology for a new pruritic,
painful skin lesion on his right medial ankle. This skin lesion was
painful to the touch and noted to be a well-demarcated bright red plaque
with scattered hemorrhagic, dusky, purple papules within the plaque.
There was a collarette of scale overlying the edge of the lesion. A skin
scraping with potassium hydroxide preparation demonstrated numerous
branching hyphae. A biopsy of the lesion was deferred due to
thrombocytopenia (11,000/cmm). He was started on topical terbinafine 1\%
cream twice daily for presumed superficial tinea corporis infection. He
was discharged once his thrombocytopenia stabilized. Less than one week
from discharge, the patient's distal right lower extremity became
progressively more edematous with new ulceration and serosanguinous
drainage (Figure 1). He presented to the hospital again and admitted for
a second time (Table 1). He was evaluated with a computed tomography
scan of the right lower extremity which demonstrated diffuse
subcutaneous edema with pooling of fluid along the superficial fascia.
There were no signs of focal fluid collection or subcutaneous emphysema.
Due to clinical concern for necrotizing fasciitis, the patient was
urgently taken to the operating room by general surgery where he
underwent four-compartment fasciotomy of the right lower extremity as
well as excisional debridement of the involved area at the right ankle
until healthy appearing and bleeding tissue was reached.

Intraoperatively, there was extensive necrosis involving the dermis,
subcutaneous adipose tissue, and superficial fascial layers which were
debrided. The underlying muscle layers, tendons, and deep fascia
appeared alive and healthy. Tissue was sent for culture and pathology.
At the fasciotomy sites in the leg, there was a positive finger sign
between the adipose and the fascia as well as between the fascia and the
muscle, without frankly necrotic tissue in this part of the leg. While
the fascia and muscle appeared healthy, this clinical finding of easy
separation between the two tissue planes was thought to be
representative of early-stage infection in which necrosis of the
epimysium occurred without progression to widespread tissue necrosis.
Therefore, no further sharp debridement was performed. Pulse lavage
irrigation and debridement with nine liters of normal saline was then
performed at the surgical sites.

Operating room cultures grew \emph{Trichophyton rubrum} , as well as
methicillin-susceptible \emph{Staphylococcus aureu} s
and\emph{Enterococcus faecalis.} Pathology exam demonstrated numerous
branching, septated fungal hyphae within purulent inflammation in
subcutaneous tissue, fascia, and also intravascularly within a
thrombosed blood vessel (Figure 2). On post-operative day three, the
patient developed elevated temperatures and was noted to have skin
findings on his left lower extremity similar to the early stages of his
right lower extremity infection. On post-operative day four, he
underwent excisional debridement of his new left lower extremity lesion
at bedside. Deep tissue specimens of his left lower extremity lesion
grew \emph{Trichophyton rubrum} and pathological exam demonstrated
purulent inflammation with necrosis and branching septated fungal
hyphae. On post-operative day six, his right lower extremity wounds
showed stability (Figure 3).

Ultimately, this patient received daily wound care with multiple
dressing changes which allowed for his surgical wounds to granulate and
fill in appropriately. He was treated with a three-week course of
antibacterials for methicillin susceptible \emph{Staphylococcus
aureus}and \emph{Enterococcus faecalis} cultured from the right lower
extremity, and oral terbinafine 250mg daily for 12 weeks for his
invasive dermatophyte infection of both extremities. Given the extensive
debridement, his right lower extremity wounds were covered with split
thickness skin grafts six weeks post-operatively. At a clinic visit two
weeks after completing terbinafine treatment, the patient had well
healed skin grafts with no signs of recurrent infection.

\textbf{Discussion:}

Given the keratinophilic nature of dermatophytes, invasion deeper than
the stratum corneum in the skin is rare.\textsuperscript{1} However,
this case demonstrates that increased immunosuppression in patients with
superficial dermatophyte infections may predispose to angioinvasive
disease involving deeper tissues. The most common predisposing factors
associated with invasive dermatophyte infections include: superficial
dermatophytosis, solid organ transplant, topical immunosuppressants,
gene mutations, diabetes, and trauma.\textsuperscript{6} The development
of our patient's angioinvasive dermatophyte infection was preceded by
increasing immunosuppression with high dose steroids, rituximab, and
ibrutinib in the setting of worsening CLL and ITP. It is known that
immunosuppressive agents used in hematologic malignancies such as bruton
tyrosine kinase inhibitors (ibrutinib) and anti-CD20 monoclonal
antibodies (rituximab) are associated with an increased risk of invasive
fungal infection.\textsuperscript{7-10} Classically, these fungal
infections include invasive yeast infections such as candidiasis, mold
infections including aspergillosis and fusariosis, endemic fungal
disease, and classic opportunistic infections such as cryptococcus and
pneumocystis jiroveci.\textsuperscript{8} Invasive dermatophyte
infections are rarely considered when increasing a patient's
immunosuppression. In the setting of superficial dermatophyte
infections, clinicians should be aware of the possibility of invasive
disease when increasing immunosuppression similar to the more classic
non-dermatophyte invasive fungal infections. When a superficial
dermatophyte infection presents with a dusky appearance and/or leads to
pain out of proportion to exam, there should be concern for invasive
disease, including necrotizing fasciitis, and early biopsy/surgical
intervention should be considered.

Antifungal treatment guidance for invasive dermatophyte infections is
scarce. When dermatophyte infections extend beyond the stratum corneum,
it is generally recommended to transition from topical to oral therapy.
There is not a consensus on the preferred oral antifungal. A recent
systematic review of invasive dermatophyte infections showed that the
most commonly used agents were terbinafine and
itraconazole.\textsuperscript{6} However, a number of patients were
treated with other antifungals including griseofulvin, fluconazole,
amphotericin B, and posaconazole.\textsuperscript{6} There was
additional variability in the duration of treatment for the cases
reviewed. We treated our patient with oral terbinafine 250 mg daily for
12 weeks. This drug, dose, and duration of therapy in combination with
surgical debridement and reduced immunosuppression resulted in clinical
clearance of infection.

\textbf{Conclusions:}

This case demonstrates a rare presentation of an angioinvasive
dermatophyte necrotizing soft tissue infection in the setting of
hematologic malignancy and increasing immunosuppression. In patients
with superficial dermatophyte infections, immunosuppression may
predispose to deeper infection and potentially angioinvasive disease. If
superficial dermatophyte lesions appear dusky with pain out of
proportion to exam, early biopsy should be pursued to assess for deeper
invasion. Early and aggressive surgical debridement with assessment and
washout of the fascial compartments can halt progression of necrotizing
soft tissue infections and result in limb salvage. This case
additionally adds to the paucity of literature on management strategies
of angioinvasive dermatophyte infections which included surgical
debridement, reduction of immunosuppression, and a 12-week course of
oral terbinafine 250 mg daily.

\textbf{Author Contributions:}

Michael J. Davis, DO, MPH: Primary author of manuscript contributing
infectious disease case perspective. Writing -- original draft, Writing
-- review \& editing, literature review.

Katelyn Rypka: Co-primary author of manuscript contributing dermatologic
case perspective. Writing -- original draft, Writing -- review \&
editing, literature review.

Alexandra K. Perron: Assisted with surgical perspective of case. Writing
-- review \& editing, literature review

John Keilty: Assisted with surgical perspective of case. Writing --
review \& editing, literature review.

Benjamin Wils: Assisted with surgical perspective of case. Writing --
review \& editing, literature review.

Joshua Levine: Assisted with surgical perspective of case. Writing --
review \& editing, literature review.

Anthony T. Rezcallah, MD: Staff surgeon providing surgical insight into
case. Writing -- review \& editing, supervision.

Robin Solomon, MD: Pathologist providing histopathologic images.

Noah Goldfarb, MD\textsuperscript{:} Staff dermatologist providing
dermatologic insight into case. Writing -- review \& editing,
supervision.

Anjum Kaka, MD: Staff infectious disease provider assisting with
infectious disease insight into case. Writing -- review \& editing,
supervision.

\textbf{Conflicts of interest} :

Dr. Goldfarb has participated in clinical trials with Abbvie, Pfizer,
Chemocentrix and DeepX Health, and has served on advisory boards and
consulted for Novartis and Boehringer Ingelheim. The content of this
article is solely the responsibility of the authors and does not
necessarily represent the official views of any other companies or
organizations.

\textbf{References:}

1. Weitzman I, Summerbell RC: The dermatophytes. Clin Microbiol Rev.
1995, 8:240-259. 10.1128/CMR.8.2.240

2. Zurita J, Hay RJ: Adherence of dermatophyte microconidia and
arthroconidia to human keratinocytes in vitro. J Invest Dermatol. 1987,
89:529-534. 10.1111/1523-1747.ep12461067

3. Calderon RA: Immunoregulation of dermatophytosis. Crit Rev Microbiol.
1989, 16:339-368. 10.3109/10408418909104472

4. Tani K, Adachi M, Nakamura Y, et al.: The effect of dermatophytes on
cytokine production by human keratinocytes. Arch Dermatol Res. 2007,
299:381-387. 10.1007/s00403-007-0780-7

5. Lanternier F, Pathan S, Vincent QB, et al.: Deep dermatophytosis and
inherited CARD9 deficiency. N Engl J Med. 2013, 369:1704-1714.
10.1056/NEJMoa1208487

6. Wang R, Huang C, Zhang Y, Li R: Invasive dermatophyte infection: A
systematic review. Mycoses. 2021, 64:340-348. 10.1111/myc.13212

7. Fiorcari S, Maffei R, Vallerini D, et al.: BTK Inhibition Impairs the
Innate Response Against Fungal Infection in Patients With Chronic
Lymphocytic Leukemia. Front Immunol. 2020, 11:2158.
10.3389/fimmu.2020.02158

8. Little JS, Weiss ZF, Hammond SP: Invasive Fungal Infections and
Targeted Therapies in Hematological Malignancies. J Fungi (Basel). 2021,
7. 10.3390/jof7121058

9. Nasillo V, Lagreca I, Vallerini D, et al.: BTK Inhibitors Impair
Platelet-Mediated Antifungal Activity. Cells. 2022, 11.
10.3390/cells11061003

10. Ruchlemer R, Ben-Ami R, Bar-Meir M, et al.: Ibrutinib-associated
invasive fungal diseases in patients with chronic lymphocytic leukaemia
and non-Hodgkin lymphoma: An observational study. Mycoses. 2019,
62:1140-1147. 10.1111/myc.13001

\textbf{Figures/Tables:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
Day\strut
\end{minipage} & \begin{minipage}[b]{0.47\columnwidth}\raggedright\strut
Event\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Prednisone 50mg BID, 14-day course}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Dexamethasone 40mg daily, 4-day course}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Rituximab infusion}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Hospital admission for refractory thrombocytopenia}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
25\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{IVIG infusion} \textbf{Prednisone 50mg BID started}
\textbf{Ibrutinib 420mg daily started}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{IVIG infusion}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Rituximab infusion} \textbf{Right lower extremity lesion noted}
\textbf{Prednisone dose change from 50mg BID to 80mg daily}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
30\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Dermatology consulted} \textbf{KOH of skin scraping with
branching fungal hyphae} \textbf{Topical terbinafine 1\% cream BID
application}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
31\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Discharge from hospital}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Prednisone dose change from 80mg daily to 60mg daily}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
\textbf{Hospital admission for necrotizing fasciitis of right lower
extremity}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 1:} Events preceding hospital admission for dermatophyte
associated necrotizing fasciitis\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1:} Well-demarcated scaley annular plaque of the medial
right lower extremity with dusky hemorrhagic papules\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2A:} Fungal elements demonstrated within a blood vessel
from debrided right lower extremity tissue (Grocott's methenamine silver
stain, magnification 20x)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 2B:} Septated fungal elements demonstrated within
subcutaneous tissue (Grocott's methenamine silver stain, magnification
40x)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 2C:} Tissue demonstrating branching, septated fungal
elements (Grocott's methenamine silver stain, magnification 60x)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Figure 2D:} Excised tissue from right lower extremity fasciotomy
(Hematoxylin and Eosin stain, magnification 40x)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Figure 3:} Right lower extremity wound post-operative day 6
after four compartment fasciotomy and debridement.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2A/Figure-2A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2B/Figure-2B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2C/Figure-2C}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2D/Figure-2D}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
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