Invasive Ureaplasma urealyticum infection mimicking diffuse large B-cell lymphoma relapse: A case report

Abstract

Ureaplasma spp. are typically benign colonizers of the urogenital tract but may cause invasive disease in immunocompromised patients. In rare cases, such infections may mimic malignancy and lead to significant diagnostic delay. Diagnosis is challenging due to non-specific clinical manifestations, poor visibility on Gram stain, and limitations of standard culture methods. We report a rare case of invasive Ureaplasma urealyticum infection in a patient in complete remission after rituximab-based chemoimmunotherapy for diffuse large B-cell lymphoma transformed from follicular lymphoma. The infection manifested as a progressively destructive soft tissue lesion involving the scrotum and abdominal wall and was suspected to represent lymphoma progression. Conventional microbiologic investigations remained negative, and the diagnosis was ultimately established through microbiome analysis based on 16S rRNA gene amplicon sequencing. Antimicrobial susceptibility testing guided prolonged dual-agent therapy with doxycycline and moxifloxacin, resulting in complete resolution. Clinicians should consider invasive Ureaplasma infection in immunocompromised patients with persistent culture-negative infections or PET-positive lesions suggestive of malignancy, as early molecular diagnostics may prevent diagnostic delay and unnecessary invasive procedures.

Introduction

Ureaplasma spp. are typically benign colonizers of the genitourinary tract in healthy, asymptomatic adults. In immunocompromised individuals, however, they may act as opportunistic pathogens, causing invasive infections that present significant diagnostic and therapeutic challenges [1]. Although typically associated with urogenital disease, Ureaplasma can occasionally cause extragenital invasive infections—particularly in immunosuppressed patients—including septic arthritis, endocarditis, osteomyelitis, soft tissue infections, and peritonitis [2], [3], [4], [5], [6], [7]. Opportunistic infections have also been linked to B-cell depletion and hypogammaglobulinemia following rituximab therapy [1]. In addition, systemic Ureaplasma infections have been implicated in hyperammonemia syndrome, a potentially fatal encephalopathy described in patients undergoing solid organ or hematopoietic stem cell transplantation [8]. The organism’s fastidious growth requirements, absence of a cell wall, and intrinsic resistance to β-lactam antibiotics further complicate both diagnosis and treatment [9].

We present a rare case of invasive Ureaplasma urealyticum infection in a patient in complete remission following rituximab-based chemoimmunotherapy for diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL). While Ureaplasma infections have occasionally been reported in immunocompromised lymphoma patients, this case is particularly notable for its close clinical resemblance to lymphoma relapse, which led to a substantial diagnostic delay and complicated clinical course.

Case Summary

A 43-year-old man was initially diagnosed with FL, presenting with Ann Arbor stage IIIA disease characterized by widespread lymphadenopathy and massive splenomegaly. First-line therapy with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) resulted in a complete response, confirmed by end-of-treatment ¹⁸F-flouro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT). This was followed by maintenance rituximab administered every two months for two years. Seven years after diagnosis, the patient experienced histological transformation, with a localized relapse of DLBCL confined to the bladder (Ann Arbor stage I). He was scheduled for four additional cycles of R-CHOP. Following the third cycle of second-line R-CHOP therapy, the patient developed right-sided scrotal pain, swelling, and erythema. Scrotal ultrasound revealed an edematous epididymis with normal testicular morphology, consistent with epididymitis. Empiric treatment with oral ciprofloxacin 500 mg twice daily for 10 days provided only minimal relief. Due to persistent symptoms, therapy was switched to oral amoxicillin-clavulanate 500 mg/125 mg three times daily for 14 days, coinciding with initiation of the final R-CHOP cycle. A follow-up ultrasound showed continued signs of infection without abscess formation, prompting re-initiation of ciprofloxacin at an increased dose of 750 mg twice daily for 30 days. Importantly, all blood and urine cultures up to this point were negative. Despite the extended course, symptoms progressed with worsening pain and purulent scrotal discharge. These findings raised concern for underlying lymphoma as a perpetuating factor. Intravenous ciprofloxacin 400 mg twice daily was initiated, and PET/CT demonstrated uptake suggestive of tumor infiltration in the right epididymis and a new hypermetabolic lesion extending from the right part of the prostate to the right seminal vesicle and lower abdomen (Fig. 1).

Fig. 1.

Serial 18F-FDG PET/CT imaging during the course of invasive Ureaplasma urealyticum infection. Top row: Fused contrast-enhanced CT and 18F-FDG PET (coronal view). Middle row: 18F-FDG PET maximum intensity projection. Bottom row: Fused 18F-FDG PET/CT (transaxial view). PET scale SUV 0–7. Columns from left to right: (1) August 2016 – Baseline scan showing widespread lymphadenopathy and splenomegaly at initial lymphoma diagnosis. (2) February 2023 – Localized relapse with focal uptake in the posterior bladder wall (arrow). (3) August 2023 – Uptake in the right seminal vesicle and epididymis with adjacent pelvic soft tissue involvement. (4) September 2023 – Progressive metabolically active soft tissue infiltration extending into the scrotum and abdominal wall (oval). (5) December 2023 – Persistent metabolic activity in the affected regions. (6) March 2024 – Resolution of metabolic activity following antimicrobial therapy.

The patient underwent incision and drainage of the abscess followed by right orchiectomy. Histopathology showed chronic inflammation without evidence of malignancy. Repeated cultures from abscess drainage and blood remained negative. After multiple surgical revisions and a 7-day course of intravenous ciprofloxacin, the infection was presumed resolved, and the patient was discharged. Two weeks later, he was readmitted with a recurrent abscess now extending into the abdominal wall (Fig. 2).

Fig. 2.

Clinical manifestations of invasive Ureaplasma urealyticum infection. (A) Scrotal swelling and erythema. (B) Extension of infection into the abdominal wall. (C) Scrotal abscess requiring surgical drainage.

Renewed surgical revision was performed, and empiric antibiotic therapy was initiated with intravenous piperacillin-tazobactam 4 g/0.5 g four times daily, supplemented by weight-adjusted gentamicin. Despite daily surgical drainage and irrigation, the patient remained febrile with persistently elevated C-reactive protein (CRP) (Fig. 3).

Fig. 3.

C-reactive protein (CRP) trajectory with timing of antimicrobial and surgical interventions.

Given the ongoing deterioration and lack of response to broad-spectrum antibiotics, concern persisted for an underlying lymphoma contributing to persistence of infection. A repeat PET/CT demonstrated continued hypermetabolic activity in the affected regions, findings suggestive of either unresolved infection or recurrent malignancy (Fig. 1). Further abscess drainage and biopsies were performed. Specimens were submitted for culture, testing for Mycobacterium tuberculosis and Actinomyces spp., and microbiome analysis using 16S rRNA gene amplicon sequencing, as previously described [10], [11]. The microbiome analysis initially identified a mono-infection with Ureaplasma spp. with > 12,000 reads, prompting empiric treatment with oral doxycycline 100 mg twice daily combined with ultrasound-guided abscess drainage, which led to marked clinical improvement and near normalization of CRP. Subsequently, both culture results and specific polymerase chain reaction (PCR) confirmed the pathogen as Ureaplasma urealyticum with high loads. Susceptibility testing demonstrated sensitivity to doxycycline and moxifloxacin, but resistance to clindamycin (as expected) and azithromycin. Antibiotic therapy was discontinued after two months, but symptoms rapidly recurred with new secretion from the surgical site. Microbiome analysis again revealed a mono-infection with Ureaplasma spp. with > 34,000 reads. Doxycycline was reinstated and supplemented with oral moxifloxacin 400 mg twice daily for a further two months. Follow-up demonstrated resolution of symptoms, progressive reduction of the abscess on PET/CT (Fig. 1), and normalization of CRP (Fig. 3). The patient remains asymptomatic nearly two years after completing therapy, with no clinical or biochemical evidence of recurrence.

Discussion

We report a case of Ureaplasma urealyticum infection clinically mimicking refractory lymphoma. The persistent hypermetabolic lesions on PET/CT in a patient with recent DLBCL transformation created a compelling radiologic impression of refractory lymphoma. The absence of microbiologic confirmation despite repeated cultures further reinforced this interpretation and delayed consideration of atypical pathogens. This case illustrates how invasive Ureaplasma infection can closely mimic malignancy both clinically and radiologically.

Ureaplasma urealyticum and Ureaplasma parvum are the two Ureaplasma spp. known to infect humans. Although generally regarded as transient colonizers of the urogenital tract, these organisms can occasionally cause invasive disease, particularly in B-cell immunocompromised hosts. Disseminated Ureaplasma spp. infections have been reported in patients with lymphoma, manifesting as multifocal abscesses, septic arthritis or endocarditis [12], [13]. More commonly, however, invasive infections are described in patients with humoral immunodeficiency, including hypogammaglobulinemia or those receiving B-cell-depleting therapies such as rituximab [1], [14]. Unlike many pathogens, Ureaplasma is not effectively controlled by neutrophil-mediated responses, and antibody-mediated immunity is the primary host defense mechanism.

To our knowledge, this is the first reported case of a localized, progressively expanding, and destructive soft tissue infection presenting as a mass lesion radiologically indistinguishable from lymphoma and Ureaplasma urealyticum identified as the most likely causative pathogen based on converging microbiological and clinical evidence. The patient’s immunosuppressive profile, including two rituximab-containing regimens with two years of maintenance therapy, likely predisposed him to this invasive infection. Notably, his treatment history was otherwise not associated with major infectious complications. Earlier recognition of the pathogen might have prevented repeated surgical interventions, including orchiectomy, and multiple hospital admissions. Moreover, delayed diagnosis of invasive Ureaplasma spp. infection in rituximab-treated individuals carries a risk of severe complications such as life-threatening hyperammonemia syndrome [15].

In B-cell immunocompromised patients with persistent infections unresponsive to standard regimens and with repeatedly negative cultures, Ureaplasma spp. and other mycoplasmas should be considered in the differential diagnosis. These organisms lack a cell wall, which means that they will be selected by the preferred use of beta-lactam antimicrobials; they do not retain Gram stain and require specialized diagnostic techniques [16]. Serology is unreliable given the absence of validated assays for Ureaplasma, and in B-cell deficiencies, the serological response to other species may be lacking. The growth of Ureaplasma spp. requires urea in the culture media, and growth on solid medium produces very small colonies requiring inspection in a microscope; therefore, standard culture methods fail to detect these organisms. Molecular methods are easier to use for diagnostic purposes. In our case, conventional cultures consistently failed to identify the pathogen, and diagnosis was ultimately established only through 16S rRNA gene sequencing and culture on specialized media after a diagnostic delay of several months.

Ureaplasma spp. can acquire resistance to multiple antibiotic classes [17]. Therefore, antimicrobial susceptibility testing should be considered, especially in refractory cases. Although these organisms are generally susceptible to tetracyclines, macrolides, and fluoroquinolones, resistance patterns are variable [18], [19]. Since no standardized treatment guidelines exist, therapy must be individualized according to disease severity and host immune status. In our case, susceptibility testing demonstrated sensitivity to doxycycline and moxifloxacin but resistance to azithromycin and clindamycin. The failure of ciprofloxacin despite prolonged high-dose therapy underscores the importance of selecting fluoroquinolones with enhanced activity against atypical organisms. Doxycycline monotherapy yielded only partial improvement, whereas combination therapy with doxycycline and moxifloxacin achieved complete resolution. Nearly four months of treatment were required for durable infection control. Our case further supports recommendations for dual-agent therapy in comparable clinical contexts [18], [20].

Conclusion

This case highlights the importance of considering Ureaplasma spp. in immunocompromised patients with culture-negative infections and PET-positive mass lesions suggestive of malignancy. In similar clinical scenarios, a structured diagnostic approach that includes early evaluation for atypical pathogens and timely use of molecular diagnostics may help reduce diagnostic delay and prevent unnecessary surgery or life-threatening complications.

Author agreement

All authors agree to be accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Appropriate informed consent has been obtained from the patient(s) for publication of this case report and any accompanying images, in accordance with the journal’s policies.

All authors declare that they have no conflicts of interest related to this work unless otherwise stated in the manuscript. Any sources of funding or support have been fully disclosed.

On behalf of all authors by the corresponding author.

CRediT authorship contribution statement

Julie Marie Grüner: Writing – review & editing, Methodology, Investigation. Lise Mette Rahbek Gjerdrum: Writing – review & editing, Methodology, Investigation. Lars Møller Pedersen: Writing – review & editing, Supervision, Methodology, Conceptualization. Simon Østergaard: Writing – review & editing, Writing – original draft, Methodology. Xiaohui Chen Nielsen: Writing – review & editing, Supervision, Methodology, Investigation, Conceptualization. Jørgen Skov Jensen: Writing – review & editing, Supervision, Methodology, Investigation, Conceptualization.

Informed consent

Written informed consent for publication of this case report and all accompanying images was obtained from the patient.

Funding

This research received no external funding.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.