\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Pulmonary Coccidioidomycosis Mimicking Malignancy Associated with
Sweet's Syndrome (Acute Febrile Neutrophilic Dermatosis)}



\author[1]{Nattanicha Chaisrimaneepan}%
\author[1]{Austin Guadarrama}%
\author[1]{Pitchaporn  Yingchoncharoen}%
\author[1]{Maria Batchinsky}%
\affil[1]{Texas Tech University Health Sciences Center}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Introduction}

Coccidioidomycosis, known as Valley Fever, is the disease caused by the
inhalation of arthroconidia from the soil-dwelling dimorphic
fungi,\emph{Coccidioides immitis} and \emph{Coccidioides posadasii}
{[}1{]}. In the United States, coccidioidomycosis is endemic to the
southwestern part of the country, with most cases located in the San
Joaquin Valley of California and Southern Arizona. The incidence of
coccidioidomycosis is approximately 10,000 cases reported annually
{[}1,2{]}. Coccidioidomycosis may affect any demographic, but primarily
affects those aged 40-60 years old and has a slight male predominance.
Clinical manifestations range from asymptomatic to disseminated
infection depending on the patient's immune status.

Cutaneous manifestations in coccidioidomycosis can be classified as
reactive or organism-containing lesions in secondary or primary
cutaneous infection {[}3{]}. Sweet syndrome, or acute febrile
neutrophilic dermatosis, is an inflammatory, non-infectious skin
reaction rarely observed as one of the reactive skin manifestations of
coccidioidomycosis. Patients with Sweet syndrome clinically present with
fever, leukocytosis with neutrophilia, and painful erythematous papules,
plaques, pustules, and nodules commonly appearing on the upper limbs,
trunk, head, and neck {[}4{]}. Here, we present a case of
coccidioidomycosis associated with Sweet's syndrome.

\textbf{Case description}

A 51-year-old man with a past medical history of 16 pack years of
smoking presented to the emergency department with new onset severe
bilateral ankle pain. He reported a 10-day history of fatigue, fever
with a maximum temperature of 102.5 F, night sweats, and the development
of erythematous, painful papular rashes that started on his knees and
continued to spread all over the body. The patient also noted an episode
of chest pain and dry coughs but denied shortness of breath and
hemoptysis. Additionally, the patient reported a 24-lb weight loss over
several weeks due to loss of appetite. He denied a history of oral or
genital ulcers.

Occupational history revealed he worked on a city farm and had
previously worked as an environmental specialist in a sewage plant. The
patient denied a history of exposure to animal droppings, hazardous
materials, recent travel outside the state, or sick contacts.

On physical examination, the patient was afebrile, and his respiratory
system was unremarkable. Posterior cervical lymphadenopathies and
multiple painful, well-circumscribed, erythematous, edematous plaques
involving 10-12 \% of his body surface area with sparing of the palms
and soles were noted (Fig 1.1-1.3). Mild swelling and pain with motion
of the bilateral ankles were observed.

\textbf{Methods}

Initial laboratory investigations showed mild leukocytosis at 10.82
K/uL(normal range: 4.23-9.07 K/uL), elevated ESR at 78 mm/hr., elevated
CRP at 19.2 mg/dl, and normal C3 and C4 levels. Hepatitis viral panel,
HIV, and syphilis were non-reactive. PCR for respiratory viral infection
and Neisseria and Chlamydia were all negative. A CT chest revealed a 1.5
cm spiculated nodule present in the posterior right lower lobe
surrounded by ground-glass attenuation with an enlarged right hilar
lymph node and a few sub-centimeter nodules in the right lower lobe (Fig
2.1). A CT-guided tissue biopsy of the peripheral lung nodule was
performed for definitive diagnosis. Additionally, skin biopsies of the
cutaneous manifestations were done. While anticipating the biopsy
results, the patient's rashes and painful swollen ankles gradually
resolved on their own.

The pathological report of the lung biopsy demonstrated granulomatous
inflammation with multinucleated giant cells and was negative for
malignancy, raising suspicion for inflammatory processes which included
fungal infection, tuberculosis, and sarcoidosis (Fig 3.1-3.2). The
immunohistochemistry stains for CD68 highlighted histiocytes, and CK7
showed lung parenchyma around granulomas. GMS was negative for fungal
infection and AFB was negative for mycobacteria (Fig 4). The skin
biopsies showed significant papillary dermal edema with a mixed
inflammatory infiltrate composed of lymphocytes and neutrophils, and
direct immunofluorescence studies were all negative, consistent with
Sweet's syndrome.

Additional laboratory investigations including QuantiFERON TB,
Aspergillus, Histoplasma, Blastomyces, Thermoactinomyces \emph{spp.} ,
Saccharoplyspora rectivir, and Saccharomonospora viridis later returned
negative. Coccidioides Ab Complement Fixation (CF) was positive with a
titer of 1:16, yeast phase Ab titer of 1:32, and mycelial phase Ab
\textless{}1:8. Antibody to TP antigen IgM, and antibody to F antigen
IgG were also positive. The patient was diagnosed with pulmonary
coccidioidomycosis associated with Sweet's syndrome. Due to borderline
Coccidioides CF (titer 1:16) and yeast phase Ab (titer 1:32), the
infectious disease team recommended treating the infection as
disseminated coccidioidomycosis with fluconazole 800 mg daily for at
least 3 months even though there was no clinical evidence apart from
yeast phase Ab titer of 1:32.

\textbf{Results (outcome and follow-up)}

At the outpatient follow-up, a CT chest was repeated one week after
treatment initiation and demonstrated a decrease in size of both the
pulmonary nodule at the right posterior lung base and right hilar
adenopathy. Additionally, there were no new nodule formations or
infiltrating lesions (Fig 2.2). Coccidioides CF titer has decreased to
1:2 after two months of fluconazole treatment and the patient has had
complete resolution of symptoms.

\textbf{Discussion}

Coccidioidomycosis manifests a heterogeneous clinical spectrum depending
on the immune status of the host. The true number of cases is 6 to 14
times greater than the number reported since only 40\% of
coccidioidomycosis infections are symptomatic; among them, some do not
seek medical care, others are misdiagnosed, and some identified cases
are not reported {[}4{]}. Males are reported to have a greater risk for
dissemination, suggesting a hormonal or genetic component. However, dust
exposure within endemic regions due to occupation is considered the
primary risk factor for infection {[}3{]}.

Primary pulmonary coccidioidal infection is the most common disease
presentation in immunocompetent patients, with symptoms manifesting 7-21
days after exposure. Pulmonary symptoms are typically associated with
systemic complaints such as fever, headache, night sweats, weight loss,
and fatigue {[}1,2{]}. Patients with primary pulmonary disease may also
develop symmetric arthralgia and cutaneous manifestations. Radiographic
findings in primary pulmonary disease include dense pulmonary
infiltration, hilar adenopathy, and pulmonary nodules or cavities.
Conversely, disseminated coccidioidomycosis infection often involves the
skin, bones, joints, and central nervous system. Progression to
disseminated disease through hematogenous or lymphatic spread occurs in
less than 0.2\% of coccidioidal infections, with immunocompromised
patients being at the highest risk {[}1,2{]}.

Skin involvement is one of the most common extrapulmonary manifestations
of coccidioidal infection. It can be categorized as reactive lesions and
organism-specific lesions. Reactive manifestations that do not contain
visible microorganisms include erythema nodosum, erythema multiforme,
acute generalized exanthema, and Sweet's syndrome. These manifestations
occur during acute primary pulmonary infection in up to 50\% of cases
due to host immunological response {[}3{]}. Organism-specific
manifestations contain microorganisms within lesions and can be
classified as primary cutaneous disease from direct inoculation or
secondary cutaneous disease from hematogenous spreading {[}3{]}.

Sweet's syndrome has been observed as one of the reactive skin
manifestations of coccidioidomycosis. Few cases have been reported, with
most patients presenting with erythematous plaques commonly involving
the trunk, neck, and upper extremities {[}5,6{]}. Skin biopsy specimens
in Sweet's syndrome typically show a diffuse inflammatory infiltrate in
the dermis, with neutrophils and leukocytoclastic debris. The treatment
for Sweet's syndrome should focus on the underlying cause. When no
specific cause is evident, systemic corticosteroids are the mainstay of
therapy; however, they are not recommended in the setting of
coccidioidal infection.

Our patient did not have dominant respiratory symptoms associated with
primary coccidioidal infection, but instead presented with
extrapulmonary non-specific systemic symptoms such as fever, night
sweats, and weight loss. While these symptoms were suspicious of
malignancy, the patient's arthralgia and cutaneous manifestations were
suggestive of an underlying inflammatory process. The initial CT chest
showed a spiculated lung mass with hilar lymphadenopathy, also
suggestive of malignancy. Initial radiographic findings in primary
coccidioidal infection may resemble malignancy. Additionally, cutaneous
manifestations associated with Sweet's syndrome can be associated with
pregnancy, drugs, infection, and malignancy; As such, a biopsy of the
lung mass should be considered for definitive diagnosis. In this case,
the lung biopsy specimen showed granuloma formation with scattered
eosinophils and no malignant cells. An immunohistochemical marker CK7, a
marker for primary lung cancer, was also negative. These results,
correlated with clinical findings and positive coccidioidal serology
studies, allowed for the correct diagnosis of coccidioidomycosis to be
established.

Diagnosis of suspected primary coccidioidal infection is confirmed with
serology testing. Enzyme-linked immunoassay (EIA) is performed to detect
coccidioidal IgM and IgG antibodies. Immunodiffusion testing is
typically performed after an initial positive EIA test to quantify
coccidioidal antibody concentration and support the diagnosis.
Definitive diagnostic testing may be performed with histopathology of
biopsy specimens, revealing granulomatous inflammation and spherules of
endospores upon cytological staining {[}7,8{]}. Finally, fungal culture
from patient respiratory samples may be used for definitive diagnosis,
since \emph{Coccidioides spp.} are not part of the normal human
microbiota.

Treatment of coccidioidomycosis is based on the severity of pulmonary
infection, the presence or absence of dissemination, and host immunity
status. Asymptomatic or mild disease may not require antifungal therapy
because the disease is commonly self-limiting in normal hosts. However,
it is important to classify between primary pulmonary and disseminated
infection to decide on the duration of treatment {[}7{]}. Several
studies indicated that CF titers of 1:32 were considered a specific
indication of heightened activity and possible dissemination {[}7,8{]}.
Our patient showed no clinical evidence of disseminated infection, but
with a high yeast phase Ab titer (1:32), which is infectious, the
infectious disease consultant decided to pursue the treatment for
disseminated coccidioidomycosis with Fluconazole 800 mg for at least 3
months.

\textsuperscript{\textbf{Conclusion}}

\textsuperscript{This case illustrates the potential for immunologic
extrapulmonary manifestations during acute pulmonary coccidioidal
infection and the value of a complete history in patients residing
within endemic regions. The patient's occupational history led the
admitting team to include fungal infection in the differential diagnosis
despite initial pulmonary workup suggesting malignancy. Diagnosis of
coccidioidomycosis can be difficult, as signs and symptoms may be
relatively nonspecific and resemble other respiratory diseases or lung
malignancies. In our case, recognition of the cutaneous manifestations
and rheumatologic symptoms of this disease aided in making the correct
diagnosis. While radiographic imaging studies help make a diagnosis of
coccidioidomycosis, initial findings may be unremarkable or share
similarities with other diseases, such as malignancy in the case of our
patient. Therefore, histopathological studies from lung biopsy and
serology studies were used to make a definitive diagnosis of
coccidioidomycosis.}

\textsuperscript{}

\textbf{AUTHOR CONTRIBUTIONS}

Nattanicha Chaisrimaneepan:~Resources; writing -- original draft;
writing -- review and editing.

Austin Guadarrama: writing--original draft, resources

Pitchaporn Yingchoncharoen: Conceptualization; resources;
writing-original draft

Maria Batchinsky : Resources

\textbf{ACKNOWLEDGEMENT}

We would like to express our gratitude to Dr. Daniel Davis and Dr. Brian
Shroeder, our colleagues and attending, who were involved in the care of
the patient. We graciously appreciate Dr. Kenneth Nugent's opinion from
the pulmonology aspect to proceed with the lung biopsy.

\textbf{FUNDING INFORMATION}

The authors did not receive financial support for the research,
authorship, and/or publication of this article.

\textbf{CONFLICT OF INTEREST STATEMENT}

There are no conflicts of interest to declare.

\textbf{CONSENT}

Verbal and written consent was obtained from the patient to publish this
case.



\textbf{Reference}

1. Williams SL, Chiller T. Update on the epidemiology, diagnosis, and
treatment of coccidioidomycosis. \emph{Journal of Fungi} .
2022;8(7):666.

2. McCotter OZ, Benedict K, Engelthaler DM, et al. Update on the
Epidemiology of coccidioidomycosis in the United States. \emph{Medical
Mycology} . 2019;57(Supplement\_1):S30-S40. doi:10.1093/mmy/myy095

3. Garcia Garcia SC, Salas Alanis JC, Flores MG, Gonzalez Gonzalez SE,
Vera Cabrera L, Ocampo Candiani J. Coccidioidomycosis and the skin: a
comprehensive review. \emph{An Bras Dermatol} . Sep-Oct
2015;90(5):610-9. doi:10.1590/abd1806-4841.20153805

4. Cohen PR, Kurzrock R. Sweet's syndrome: a review of current treatment
options. \emph{Am J Clin Dermatol} . 2002;3(2):117-31.
doi:10.2165/00128071-200203020-00005

5. Jafri Z, Shedlofsky, L., Newman, A., Lam, T., \& Mengesha, Y. A Sweet
Presentation of a Bitter Disease: Acute Febrile Neutrophilic Dermatosis
Associated with Coccidioidomycoses. \emph{SKIN The Journal of Cutaneous
Medicine} . Mar 6, 2021 2021;5(2):174--177.
doi:\emph{https://doi.org/10.25251/skin.5.2.17}

6. DiCaudo DJ, Ortiz KJ, Mengden SJ, Lim KK. Sweet syndrome (acute
febrile neutrophilic dermatosis) associated with pulmonary
coccidioidomycosis. \emph{Arch Dermatol} . Jul 2005;141(7):881-4.
doi:10.1001/archderm.141.7.881

7. Pe\selectlanguage{ngerman}çanha-Pietrobom PM, Tirado-Sánchez A, Gonçalves SS, Bonifaz A,
Colombo AL. Diagnosis and Treatment of Pulmonary Coccidioidomycosis and
Paracoccidioidomycosis. \emph{Journal of Fungi} . 2023;9(2):218.

8. McHardy IH, Dinh BN, Waldman S, et al. Coccidioidomycosis Complement
Fixation Titer Trends in the Age of Antifungals. \emph{J Clin Microbiol}
. Dec 2018;56(12)doi:10.1128/jcm.01318-18\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 1.1-1.3: Multiple tender erythematous edematous plaques and
papules distributed on the trunk and extremities.

Figure 2.1: A computed tomography (CT) of the chest shows a 1.5 cm
spiculated right lower lobe lung nodule.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 2.2: Computed tomography (CT) of the chest shows a reduction in
the size of pulmonary nodule to 0.9 cm after one week of fluconazole
treatment.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

Figure 3.1: Histopathology with H\&E stain at 40x of the right lung
biopsy specimen shows granulomatous inflammation with infiltration of
multinucleated giant cells and scattered eosinophils.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

Figure 3.2: Histopathology with H\&E stain at 60x magnification shows
multinucleated giant cells.

Figure 4: Lung tissue histopathology with AFB stain at 40x which shows
negative result for mycobacteria.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

