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\begin{document}

\title{Secondary Syphilis Presenting as Fever of Unknown Origin}



\author[1]{Hannah Wilding}%
\author[1]{Amy Hays}%
\affil[1]{Penn State College of Medicine}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\textbf{Title:} Secondary Syphilis Presenting as Fever of Unknown Origin

\textbf{Authors:} Hannah Eloise Wilding, BS\textsuperscript{1}; Amy
Hays, MD\textsuperscript{2}

\textbf{Affiliations:}

\textsuperscript{1}Penn State College of Medicine, Hershey, PA, 17033

\textsuperscript{2}Penn State College of Medicine, Department of Family
and Community Medicine, Hershey, PA, 17033

\textbf{Corresponding Author:}

Hannah Wilding, BS

Penn State Milton S. Hershey Medical Center, 500 University Dr., Hershey
PA 17033.

Corresponding Author's Email: hwilding@pennstatehealth.psu.edu, Phone:
412-926-4501

\textbf{Other Contact Info:}

Amy Hays, MD, Assistant Professor of Family and Community Medicine

Penn State College of Medicine, 303 Benner Pike, Suite 1, State College,
PA 16801.

Email: ahays1@pennstatehealth.psu.edu, Phone: 814-272-5660

\textbf{Key Words:} Fever of Unknown Origin, Syphilis, Communicable
Diseases, Treponema pallidum

\textbf{Financial Support:} The authors have nothing to disclose.

\textbf{Conflicts of Interest:} The authors have no conflicts of
interest to disclose.

\textbf{Patient Consent Statement:} The authors have obtained a written
patient consent form related to use of clinical information. The patient
understands that anonymity cannot be guaranteed, but his name will not
be reported.

\textbf{Manuscript Counts:}

Abstract: 86 words

Text: 1137 words

Tables/Figures: 3

Supplementary Tables: 1

References: 10

\emph{}

\emph{Abstract}

A thirty-eight year-old male presented with a seven-week history of
persistent fever accompanied by recurrent night sweats, chills,
arthralgias, headache, and chest tightness. Initial laboratory testing
showed non-specific elevation of inflammatory markers, but was otherwise
unremarkable. A palmar rash developed one week later, prompting testing
for syphilis. Fluorescent treponemal antibody absorption (FTA-ABS) and
rapid plasma reagin (RPR) tests were both positive. Penicillin G was
administered and the patient recovered uneventfully. Our case emphasizes
the need for increased syphilis screening to ensure proper diagnosis and
prompt treatment.

\emph{Introduction}

Fever of unknown origin (FUO) is a challenging diagnostic dilemma.
Defined as a fever of 100.9\textsuperscript{o}F
(38.3\textsuperscript{o}C) or higher lasting at least three weeks with
an unrevealing diagnostic work up\textsuperscript{1}, FUO's in adults
typically represent unusual presentations of common illnesses. Most
often, the condition resolves without a specific diagnosis being
made\textsuperscript{2}.

The differential diagnosis for FUO is extensive. A helpful approach is
to consider infectious, inflammatory, and malignant diseases, as well as
miscellaneous conditions such as thyroiditis, thromboembolic disease,
and factitious fever. A comprehensive history emphasizing social and
travel components should precede a complete physical examination, with
laboratory tests and imaging guided by pertinent findings on history and
exam.

\emph{Key Clinical Message}

A case of secondary syphilis presenting as FUO reinforces the importance
of screening for this treatable infectious disease that is resurging
across the globe.

\emph{Case Report}

A thirty-eight year-old male presented to the outpatient primary care
clinic with a seven-week history of fever unresponsive to oral
antipyretics. The patient also noted recurrent chills, night sweats,
myalgias, headaches, and chest tightness. Three days before
presentation, he developed a cough with clear sputum. A complete review
of systems was otherwise negative. A careful history emphasizing
surgical, social, and travel components revealed that the patient had
undergone arthroscopic ACL reconstruction seven weeks prior to
presentation, after which his fever began. He tested negative for
COVID-19 pre-operatively. On surgical follow-up, his orthopedist found
no surgical or thromboembolic complications or other iatrogenic cause
for fever. Approximately one week after initial presentation, the
patient developed an erythematous maculopapular rash on the palmar
surfaces of both hands (\textbf{Figure 1} ). Arthralgias, myalgias, and
morning stiffness worsened, and the rash spread over his torso.

Differential Diagnosis

Differential diagnosis included COVID-19, influenza A and B, Hepatitis
C, HIV, tickborne illnesses, post-operative wound infection,
thromboembolic disease, and infectious endocarditis. Tickborne
illnesses, particularly Lyme disease and Anaplasmosis common in the
geographical area where the patient lives, were excluded by serology.
Post-operative wound infection and thromboembolic disease were not
evident clinically. The lack of objective synovitis on exam made
rheumatological disease less likely. Malignancy was considered in light
of the complaint of night sweats, but there was no lymphadenopathy or
weight loss.

Diagnostic Testing

The patient was asked to record daily body temperatures for three weeks
(\textbf{Figure 2} ). Complete blood count, comprehensive metabolic
panel, liver function tests, thyroid stimulating hormone, erythrocyte
sedimentation rate, C-reactive protein, chest X-ray, urinalysis,
COVID-19 test, and influenza A and B tests were performed. Additionally,
titers for Lyme disease, Anaplasmosis, Hepatitis C, and HIV were
obtained. All were normal or negative, with the following exceptions:
lymphocyte count was low at 780 per mL, monocyte count was elevated at
1302 per mL, inflammatory markers were increased, and 2+ ketones and
trace protein were found on urinalysis. Elevation of inflammatory
markers was perceived to be a non-specific finding. Abnormal lab results
are listed in \textbf{Table 1} , while normal lab results are listed
in\textbf{Supplemental Table 1} .

At the time of development of palmar rash, antinuclear antibody titer
(ANA) was ordered. Three sets of blood cultures (obtained on different
days) and transthoracic echocardiogram were also performed to exclude
infectious endocarditis. The ANA titer was positive, but all other
studies were normal. As the rash spread, fluorescent treponemal antibody
absorption test (FTA-ABS) and rapid plasma reagin (RPR) test were
ordered, both returning positive. Accordingly, secondary syphilis was
diagnosed.

Treatment

The patient was treated with Penicillin G benzathine 2.4 million units
IM as an outpatient. Post-injection, the patient experienced a transient
flare of his rash, consistent with Jarisch-Herxheimer reaction. The rash
was self-limited and resolved after approximately 72 hours.

Outcome

Following treatment, the patient defervesced and all skin lesions
resolved within about one week. Despite his clinical improvement, the
patient noted depressive symptoms and attributed these to conflict with
his partner that resulted from the diagnosis of syphilis. Ten months
later, follow up RPR and HIV were negative, and the symptoms of
depression had resolved.

\emph{Discussion}

Syphilis is caused by the motile Gram-negative spirochete Treponema
pallidum. It has been described as the ``great imitator,'' due to its
invasive and immunoevasive nature\textsuperscript{3}. It is transmitted
sexually or vertically during pregnancy. In the 1990's, syphilis made a
resurgence worldwide, most prominently in men who have sex with men
(MSM). In 2015, the United States case rate for primary and secondary
syphilis in MSM was 221 times the rate for women and 106 times the rate
for heterosexual males\textsuperscript{3}. The World Health Organization
(WHO) estimated that 17.7 million people between ages 15-49 had syphilis
in 2012, with 5.6 million new cases yearly\textsuperscript{3}.

Treponema pallidum is an obligate human pathogen, which enters the body
through areas of microtrauma. Primary syphilis occurs approximately 2-3
weeks after initial infection, and is evidenced by the development of
the chancre. This phase of illness may pass unnoticed, thereby enabling
progression of infection\textsuperscript{4}. Approximately 4-8 weeks
after the primary stage, secondary syphilis presents as bacteremia
associated with a widespread maculopapular rash which may involve the
scalp, palms, and soles of the feet. Condyloma lata and systemic
symptoms may also be present. Late latent syphilis, or tertiary
syphilis, occurs in approximately 35\% of untreated patients, though
this is seen most commonly in resource-poor nations\textsuperscript{4}.
Tertiary syphilis may manifest as cardiovascular syphilis,
neurosyphilis, or gummatous syphilis\textsuperscript{4}.

Resurgence of Syphilis

The incidence of syphilis in the United States has gradually increased
over the last 20 years. The Centers for Disease Control and Prevention
(CDC) reported an increase in primary and secondary cases, from 5,973 in
2000 to 30,644 in 2017\textsuperscript{5}. This resurgence may result
from unprotected sexual intercourse, multiple sexual partners, MSM, the
popularity of online dating apps, intravenous drug use, and HIV
co-infection\textsuperscript{5}. Accordingly, the CDC recommends
universal screening for syphilis in pregnancy. Testing protocols for
high-risk patients, including incarcerated populations, sex workers,
MSM, patients with HIV, and transgender/gender-diverse people have also
been developed\textsuperscript{6,7}.

FUO and Syphilis

In summary, syphilis is an uncommon etiology for fever of unknown
origin. Evidence-based clinical resources, including UpToDate and
American Family Physician, do not thoroughly discuss syphilis in the
differential diagnosis of FUO\textsuperscript{1,2,8}. Extensive
literature search reveals minimal and largely outdated case reports for
this duo\textsuperscript{9,10}. In such case reports, syphilis was
similarly not discovered as the FUO etiology until multiple weeks of
clinical workup.

Given this increasing incidence of syphilis, physicians need to remain
vigilant. In addition, the stigma associated with this diagnosis may
make patients reticent to provide relevant historical data. When
considering the risk factors for syphilis, many patients belonging to
these stigmatized populations are also medically underserved. Physicians
bear the responsibility of investigating this diagnosis, while obtaining
a history in a patient-sensitive manner. Treatment for this condition is
simple and effective, whereas the sequelae of untreated syphilis may be
catastrophic.

\emph{Acknowledgements}

The authors would like to acknowledge Dr. Mark Stephens, MD, MS for his
writing assistance and technical editing.

\textbf{Patient Consent Statement:} The authors have obtained a written
patient consent form related to use of clinical information. The patient
understands that anonymity cannot be guaranteed, but his name will not
be reported.

\textbf{Author contributions:} Conceptualization, AH, HW; Writing --
Original Draft Preparation, HW; Writing -- Review \& Editing, HW, AH;
Supervision, AH. All authors approve the manuscript as submitted.

\emph{References}

1. Bor D. Approach to the adult with fever of unknown
origin.\emph{UpToDate} . Wolters Kluwer; 2022.

2. David A, Quinlan JD. Fever of Unknown Origin in Adults. \emph{Am Fam
Physician} . Feb 1 2022;105(2):137-143.

3. Peeling RW, Mabey D, Kamb ML, Chen XS, Radolf JD, Benzaken AS.
Syphilis. \emph{Nat Rev Dis Primers} . Oct 12 2017;3:17073.
doi:10.1038/nrdp.2017.73

4. French P. Syphilis. \emph{Bmj} . Jan 20 2007;334(7585):143-7.
doi:10.1136/bmj.39085.518148.BE

5. Schmidt R, Carson PJ, Jansen RJ. Resurgence of Syphilis in the United
States: An Assessment of Contributing Factors. \emph{Infect Dis (Auckl)}
. 2019;12:1178633719883282. doi:10.1177/1178633719883282

6. Screening Recommendations and Considerations Referenced in Treatment
Guidelines and Original Sources. U.S. Department of Health and Human
Services. Accessed March 3, 2023.
https://www.cdc.gov/std/treatment-guidelines/screening-recommendations.htm

7. Bach S, Heavey E. Resurgence of syphilis in the US. \emph{Nurse
Pract} . Oct 1 2021;46(10):28-35. doi:10.1097/01.npr.0000790496.90015.74

8. Roth AR, Basello GM. Approach to the adult patient with fever of
unknown origin. \emph{Am Fam Physician} . Dec 1 2003;68(11):2223-8.

9. Chung WM, Pien FD, Grekin JL. Syphilis: a cause of fever of unknown
origin. \emph{Cutis} . May 1983;31(5):537-40.

10. Mahapatra R, Clarke G, Lobo Z, Psevdos G. Cervical syphilitic
lymphadenitis causing fever of unknown origin followed by rash of
secondary syphilis. \emph{Indian J Pathol Microbiol} . Apr-Jun
2019;62(2):339-340. doi:10.4103/ijpm.ijpm\_188\_18

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