Invasive Ureaplasma Infection in Patients Receiving Rituximab and Other Humoral Immunodeficiencies-A Case Report and Review of the Literature.

Ureaplasma species are small, fastidious bacteria that frequently colonize the lower reproductive tract of asymptomatic hosts. These organisms have been well described to cause chorioamnionitis, neonatal infection, and urethritis, and to a lesser degree surgical site infection and infection in transplant recipients. Outside of these settings, invasive Ureaplasma infections are rare. We describe the case of a young woman receiving rituximab for multiple sclerosis who presented with fever and bilateral renal abscesses due to Ureaplasma spp., which was successfully treated with oral doxycycline. We searched the literature for cases of invasive Ureaplasma infection and found a patient population that predominates with humoral immunodeficiency, either congenital or iatrogenic. Diagnostic and therapeutic interventions are discussed.

CASE REPORT

A 27-year-old female with multiple sclerosis on rituximab with neurogenic bladder and frequent urinary tract infections (UTIs) presented to a community hospital with fevers, chills, and vomiting and a positive urinalysis. Despite empiric treatment with vancomycin and piperacillin-tazobactam, her fevers persisted. A computed tomography (CT) scan of the abdomen and pelvis revealed bilateral, small renal abscesses that were up to 2.1 cm in dimension.

Her therapy was broadened to vancomycin and meropenem, but a repeat CT scan 5 days after admission revealed enlarging abscesses. The bilateral collections were aspirated 7 days after admission, but all cultures including aerobic, anaerobic, fungal, and acid-fast cultures failed to isolate a pathogen. She had persistent intermittent fevers above 102°F, but remaining vital signs were stable.

She was transferred to our facility 8 days after admission. Vancomycin was transitioned to linezolid and levofloxacin was added, but her fevers persisted. She had repeat aspiration of the left renal abscess; however, no pathogen was isolated.

From a catheterized specimen, specialized urine culture techniques isolated Ureaplasma spp. (Ureaplasma culture, Quest Diagnostics, no further speciation). There was insufficient abscess aspirate remaining to be tested for the presence of Ureaplasma spp. Doxycycline was orally administered, and all fevers abated within 24 hours. She remained normothermic as the remainder of antibiotics were discontinued.

She was treated with doxycycline for 6 weeks total, as serial CT scans showed slow resolution of her abscesses. Her urinary symptoms improved quickly after initiation of doxycycline, and she remained asymptomatic at follow-up in clinic.

LITERATURE REVIEW

We searched PubMed and Embase for the last 30 years for patients with Ureaplasma infections outside of urethritis, neonatal, and pregnancy (Appendix). From this search, we excluded patients with transplant (solid organ or bone marrow), surgical site infection, peritoneal dialysis catheters, and children (<18 years old). We subsequently excluded 1 patient ultimately diagnosed with reactive arthritis that improved on immunosuppression [1]. Table 1 summarizes the remaining 24 cases.

Table 1.

Reported Cases of Invasive Ureaplasma spp. Infection, Outside of Chorioamnionitis, Urethritis, Surgical Site Infections, and Transplant Recipients, 1989–2019

	Author (Year)	Case Presentation	Microorganism/Method of Diagnosis	Antimicrobial Treatment	Outcome	Risk Factors
1	Rouard (2019) [2]	88M prosthetic hip infection	U. urealyticum/16S rRNA PCR and culture	None	Died of multiple comorbidities	No known immunocompromising conditions
2	Gassiep (2017) [3]	51F hip septic arthritis, necrotizing soft tissue infection	U. urealyticum/16S rRNA PCR	Moxifloxacin	Improved	Mantle cell lymphoma; rituximab + hyper-CVAD, hypogammaglobulinemia
3	Korytny (2017) [4]	56M shoulder septic arthritis, orchitis, endocarditis	U. parvum/16S rRNA PCR (on joint fluid and on aortic valve)	Doxycycline	Improved	CNS lymphoma with chemotherapy (regimen not reported)
4	Roerdink (2016) [5]	69F bilateral prosthetic knee infection	U. urealyticum/16S rRNA PCR	Moxifloxacin + doxycycline	Improved	Hodgkin's lymphoma/R-CHOP
5	George (2015) [6]	21F native knee and prosthetic hip infection	Ureaplasma spp./16S rRNA PCR	Azithromycin	Improved	JIA on rituximab
6	Balsat (2014) [7]	18F polyarthritis	U. urealyticum/ PCR/ESI-MS	Levofloxacin + doxycycline	Improved	ALL on vincristine, steroids, daunorubicin, L-asparaginase, 1 dose tocilizumab
7	Farrell (2014) [8]	75M prosthetic knee infection	U. parvum/PCR/ESI-MS	Doxycycline	Improved	No known immunocompromising conditions, colon adenocarcinoma, nephrolithiasis
8	Deetjen (2014) [9]	20 (gender not specified) brain abscess	U. urealyticum/16S rRNA PCR	Doxycycline + clarithromycin	Improved	Burkitt's lymphoma, rituximab
9	Yazdani (2012) [10]	68F pyelonephritis, perinephric abscess, psoas abscess	U. urealyticum/PCR (further tests not specified)	Vancomycin + levofloxacin	Improved	Mantle cell lymphoma, rituximab
10	Goulenok (2011) [11]	24M shoulder septic arthritis	U. urealyticum/culture	Doxycycline	Improved	SLE, rituximab
11	Sköldenberg (2010) [12]	74F prosthetic hip infection	U. urealyticum/culture	Doxycycline	Improved	No known immunocompromising conditions
12	MacKenzie (2010) [13]	54M polyarthritis, prosthetic hip infection	U. parvum and Mycoplasma hominis/16S rRNA	Moxifloxacin	Died (septic shock; other nosocomial infection suspected)	NHL, rituximab, hypogammaglobulinemia
13	Tarrant (2009) [14]	100F spontaneous pericarditis, tamponade	Ureaplasma spp./culture	Doxycycline	Improved	No known immunocompromising conditions except age
14	Fenollar (2003) [15]	57F prosthetic valve endocarditis	U. parvum/16S rRNA PCR	None	Died (heart failure)	No known immunocompromising conditions
15	Heilmann (2001) [16]	25M polyarthritis	U. urealyticum/culture	Doxycycline + ciprofloxacin + valneumulin (not available in US)	Died (pneumonia)	CVID, hypogammaglobulinemia
16	Heilmann (2001) [16]	34F prosthetic knee septic arthritis	U. urealyticum/culture	Doxycycline + valneumulin	Improved	CVID, hypogammaglobulinemia
17	Lapusan (2001) [17]	38M septic arthritis, pneumonia, empyema	U. urealyticum/culture	Erythromycin → doxycycline	Died (disseminated disease)	Hypogammaglobulinemia
18	Frangogiannis (1998) [18]	31M ankle septic arthritis, endocarditis of unknown etiology	U. urealyticum/culture	Doxycycline and clarithromycin	Improved	CVID, hypogammaglobulinemia
19	Asmar (1998) [19]	18M knee septic arthritis, bacteremia	U. urealyticum/culture	Erythromycin, doxycycline, chloramphenicol → ofloxacin	Improved	Agammaglobulinemia
20	Puéchal (1995) [20]	30F septic polyarthritis	U. urealyticum/PCR	Doxycycline, IVIG	Improved	CVID
21	Forgacs (1993) [21]	53M wrist septic arthritis	U. urealyticum, Mycoplasma hominis, Mycoplasma salvarium/culture	Doxycycline	Improved	CVID
22	Lee (1992) [22]	27M septic polyarthritis	Ureaplasma spp./PCR	Doxycycline	Improved	Hypogammaglobulinemia
23	Lehmer (1991) [23]	38M wrist septic arthritis	U. urealyticum culture	Tetracycline, rosaramicin (macrolide)	Improved	CVID, hypogammaglobulinemia
24	Mohiuddin (1991) [24]	22M hip septic arthritis	U. urealyticum culture	Tetracycline	Improved	CVID, hypogammaglobulinemia

Abbreviations: ALL, acute lymphoblastic leukemia; CVID, common variable immune deficiency; ESI-MS, electrospray ionization–mass spectrometry; F, female; hyper-CVAD, cyclophosphamide, doxorubicin, vincristine, dexamethasone; JIA, juvenile idiopathic arthritis; M, male; NHL, non-Hodgkin's lymphoma; PCR, polymerase chain reaction; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; SLE, systemic lupus erythematosus.

RESULTS

Excluding patients with other known risk factors, humoral immunodeficiencies, either hypogammaglobulinemia or receipt of rituximab, are associated with the majority (17/24, 71%) of invasive Ureaplasma infections (Table 1). The remaining 7 patients (cases 1, 3, 6, 7, 11, 13, 14) were notable for 2 patients with lymphoma on unreported or other chemotherapy (3, 6), 1 centenarian (12), and 4 patients with a prosthetic implant infection: hip (1, 10), knee (6), and heart valve (13). Nineteen of 24 (79%) patients improved with therapy, and only 1 (4%) patient died of disseminated infection. Septic arthritis was the most common manifestation in this group (21/24, 88%).

DISCUSSION

Ureaplasma was discovered in 1954 and initially called T-mycoplasma, due to its similarities to Mycoplasma species, but notable for its small colony sizes (“T” to indicate “tiny”) [25]. Although our report depicts the rarity of invasive Ureaplasma infection, earlier cases may have been classified as Mycoplasma spp. [26], before the separation of these genera in 1974 [27]. Ureaplasma spp. are frequent colonizers in asymptomatic patients, but they have been implicated in chorioamnionitis, neonatal infection, urethritis [28, 29], surgical site infections [30], and post-transplant severe hyperammonemia [31, 32]. This case report and literature review identifies a subset of patients outside of these populations who are at risk for invasive disease:

1. Humoral immunodeficiency: Rituximab, a monoclonal antibody against CD20 found on B lymphocytes, was approved by the Food and Drug Administration in 1997 [33], and its use has significantly expanded in recent years to treat a variety of autoimmune and malignant processes. Rituximab has been associated with serious infections as a result of a variety of mechanisms including prolonged B-cell depletion and hypogammaglobulinemia [34]. Interestingly, most reported cases of invasive Ureaplasma disease since 2010 have been observed in patients receiving this therapy. Prior studies have shown that patients with hypogammaglobulinemia are more likely to be colonized with Ureaplasma and Mycoplasma [35]. Furthermore, although neutrophils can phagocytose Ureaplasma and Mycoplasma, the bacteria remain viable in the absence of antibody. It has been postulated that neutrophils with viable bacteria may facilitate dissemination, tracking to areas of inflammation; however, further studies are needed [36].

2. Prosthetic implant: We found 4 cases of prosthetic implant infection, 3 joints and 1 heart valve, in patients without known immunodeficiencies. Although rare, Ureaplasma may be considered in culture-negative implant infections failing standard therapy.

Ureaplasma does not grow on routine media or appear on gram stain; therefore, a specialized culture or 16S rRNA polymerase chain reaction (PCR) assay must be employed. Empiric therapy may be indicated in settings of severe infection, owing to these tests' long turnaround times. Tetracyclines, macrolides, and quinolones all have activity against Ureaplasma spp. Although susceptibility testing is not widely available, there has been concern for increasing resistance globally [37]. Consequently, despite treatment with levofloxacin, our patient only improved when doxycycline was administered. In patients with severe illness due to suspected or confirmed Ureaplasma spp. infection, agents from 2 different classes can be used to increase the likelihood of therapeutic success [38].

CONCLUSIONS

This case review should alert providers to consider Ureaplasma spp. in infected patients with negative standard cultures, who have humoral immunodeficiency, whether it be congenital (eg, hypogammaglobulinemia) or iatrogenic (eg, anti-CD20 therapy). Specialized culture or PCR is necessary for confirmation of diagnosis. Therapy involves selection of an agent from the tetracycline, macrolide, and/or quinolone classes.