Diffuse lymphadenopathy and fever without a rash: an atypical presentation of secondary syphilis

Background

Syphilis is caused by the spirochete bacteria Treponema pallidum. The disease occurs in multiple stages (primary, secondary and tertiary) with broad variation in clinical presentation. Symptoms can affect several organ systems as well as mimic other diseases including solid tumours, bone metastases, autoimmune conditions and lymphomas, both with and without extranodal involvement.1 2 While the hallmarks of secondary syphilis include a skin rash and/or mucous membrane lesions, these can be difficult to identify due to the often-missed locations and heterogeneity of appearances of the rash.1–4 Other symptoms less commonly associated with secondary syphilis include fever, headache, lymphadenopathy, weight loss and myalgias.1 2 The symptoms of secondary syphilis can resolve without treatment, though the disease itself continues into the latent, or possibly tertiary, stage.2 4 This transient nature and self-resolution of symptoms make diagnosis in the second stage challenging.

The incidence of syphilis in the USA has waned since its initial peak in the 1940s with the introduction of penicillin leading to a steep decline in cases.3 With regard to primary and secondary syphilis, in the 1980s–1990s, there was a peak incidence of 20.3 cases per 100 000 persons, which then fell in 2000 with near-eradication.5 Primary and secondary syphilis cases began to rise again in the early 2000s, and the incidence has since increased from 8724 cases in 2005 to 35 063 in 2018, with a rate of 10.8 cases per 100 000 persons.5

Evolution of this case highlights the importance of continually developing a broad differential diagnosis, especially for patients presenting with vague or systemic symptoms. Admission to the hospital allows opportunities to continuously re-evaluate patient presentations and incorporate new information rapidly. While fever and generalised lymphadenopathy are not a novel presentation of secondary syphilis,5 the patient’s low rapid plasma reagin (RPR) titre and low-risk sexual history placed this lower on the differential diagnosis. The patient also had an emergency department (ED) visit 2 months prior to her admission for a presumed hidradenitis suppurativa flare which confounded her presentation of axillary lymphadenopathy.

We hope our presentation and discussion lead to a broader initial differential diagnosis for lymphadenopathy and contribute to the growing literature of the variety of presentations of secondary syphilis.

Case presentation

A woman in her 30s with a history of asthma and hidradenitis suppurativa presented with 4 days of fevers, headache and back pain. She reported no sick contacts, no recent travel, no history of similar symptoms and no new sexual partners. She had presented to a different ED 1 day prior, and urinalysis (UA) showed turbid urine with 3+ ketones, 1+ blood, 1+ leucocyte esterase, 55 white blood cells, negative nitrite, >50 bacteria and 19 squamous cells, while chest X-ray was unremarkable. She left without being seen due to the wait time and re-presented to another ED the following day.

On re-presentation, the patient was febrile to 39.1°C with heart rate of 123 but with otherwise normal vital signs. Initial examination in the ED noted bilateral costovertebral angle tenderness but no other abnormalities. Examiners on admission noted anterior and posterior cervical and submandibular lymphadenopathy. Otherwise, the remainder of a complete exam (excluding genitourinary exam) was unremarkable. She was unable to tolerate oral intake due to nausea, and her pain could not be controlled with oral medications. She was admitted for intravenous antibiotics for initial diagnosis of presumed pyelonephritis.

Investigations

Workup in the ED was geared towards a presumed diagnosis of pyelonephritis and was remarkable for leucocytosis to 12.7×10⁹/L with neutrophilic predominance, UA with small leucocyte esterase without nitrites and moderate blood, and renal ultrasound without hydronephrosis. Otherwise, COVID-19 PCR testing and rapid streptococcal testing were negative. She had normal electrolytes, renal function and hepatic function. Similarly, lipase, lactate and urine pregnancy tests were negative. Blood cultures were drawn prior to administration of antibiotics.

On admission, additional lab work was unchanged; C reactive protein was elevated at 317 mg/L and erythrocyte sedimentation rate was elevated at 128 mm/hour. CT of the abdomen/pelvis obtained the day after admission showed multiple prominent pelvic and inguinal lymph nodes. Lumbar MRI, obtained due to persistent back pain and complaint of weakness, was unremarkable.

With ongoing undifferentiated illness and persistent fever despite antibiotics, additional imaging studies were obtained. MRI of the brain was notable for a focal cytotoxic lesion of the corpus callosum splenium (non-specific, but potentially related to seizure, metabolic disturbance, infection, drug or toxin). CT of the neck revealed diffuse multistation bilateral lymphadenopathy throughout the neck. CT of the chest was notable for patchy consolidative and ground-glass opacities and multicompartmental hilar and axillary lymphadenopathy. Workup was broadened to include aetiologies of diffuse lymphadenopathy and fever. Lumbar puncture was attempted multiple times without success. The patient declined repeat attempts, even with imaging guidance. Epstein-Barr virus, hepatitis C, Bartonella antibodies, Ehrlichia serologies, HIV, gonorrhoea, chlamydia and blood cultures were unremarkable or negative. Antinuclear antibody was positive at 1:80 and speckled, although extractable nuclear antigen, rheumatoid factor and antineutrophil cytoplasmic antibody were negative. RPR was positive at 1:16 and confirmatory T. pallidum particle agglutination (TPPA) test subsequently came back positive. Lymph node biopsy was attempted, but the tissue sample was not satisfactory for pathology.

Differential diagnosis

This patient’s presentation was initially concerning for pyelonephritis given her fever, nausea, back pain and UA findings at the outside ED (as well as repeat UA on second presentation also consistent with infection). However, both cultures grew mixed urogenital flora, and she had no findings consistent with pyelonephritis on imaging. After examination by the inpatient team the following morning, the patient’s presentation became more concerning for bacterial or viral meningitis due to worsening headache, neck pain, cervical lymphadenopathy and continued fevers with a maximum temperature of 39.8°C. She also endorsed photophobia and blurry vision that started at the same time as her other presenting symptoms that had not been elicited in the ED.

Other sources of infection considered included pelvic inflammatory disease, intra-abdominal psoas or retroperitoneal abscess given back and flank pain; or skin and soft tissue infection due to patient’s hidradenitis. All of these were felt to be less likely as the patient remained febrile despite broad-spectrum antibiotic coverage, had negative gonorrhoea and chlamydia testing, and no signs of skin or soft tissue infection on imaging or exam.

The combination of fever and diffuse lymphadenopathy raised concern for malignancy including lymphoma or viral-associated lymphoproliferative disease (human herpesvirus-8 or Epstein-Barr virus). However, after positive RPR with confirmatory testing and gradual resolution of palpable lymphadenopathy with appropriate antibiotic regimen (penicillin), these were felt to be less likely. Other infectious aetiologies such as HIV, cytomegalovirus, Bartonella and Ehrlichiosis were also considered but serologies all resulted negative. Autoimmune considerations included systemic lupus erythematosus, Sjogren’s disease, mixed connective tissue disease and vasculitis. Other rare disorders considered included Castleman’s disease and Kikuchi’s disease, but these were thought to be less likely based on improvement with penicillin treatment.

Treatment

The patient initially received intravenous cefepime in the ED which was narrowed to intravenous ceftriaxone. As symptoms progressed and with concern for meningitis, treatment was broadened to intravenous vancomycin, ceftriaxone and acyclovir. At the recommendation of infectious disease (ID), intravenous vancomycin and acyclovir were discontinued, and she was continued on intravenous ceftriaxone. Doxycycline was added to cover tick-borne illness. Intravenous ceftriaxone was then discontinued as fevers resolved. Doxycycline was continued to complete a 10-day course, as Ehrlichia serologies were pending at the time of discharge. At the time of discharge, confirmatory TPPA testing had not yet resulted. Once confirmatory TPPA resulted positive, she began treatment with intramuscular penicillin at outpatient follow-up appointments.

Outcome and follow-up

The patient was discharged from the hospital after she defervesced and tolerated oral intake. TPPA confirmatory testing resulted positive shortly after, and she was seen in the ID clinic where she was treated with intramuscular penicillin. The diagnosis was reported to the health department of the patient’s county of residence, and her current sexual partner was also notified of the diagnosis. It is unknown if he followed-up for treatment. Fevers, palpable lymphadenopathy and back pain resolved following her treatment.

She continued to follow with ID for treatment given her atypical presentation. Unfortunately, she continued to experience persistent headaches. Although she had no symptoms of meningismus and neurological exam was normal during outpatient visits, her headache and abnormal MRI on presentation raised concern for neurosyphilis. At the time of publishing this case report, treatment plan is ongoing with lumbar puncture and neuroimaging studies pending to guide necessity for treatment of potential neurosyphilis.