Septic arthritis due to Mycoplasma orale in a young patient with hypogammaglobulinemia

Abstract

Mycoplasma orale is an obligate intracellular bacterium usually found as a commensal in the human oral cavity. Symptomatic infections with this organism are rare, but severe disease has been described in the setting of impaired humoral immunity. Here, we describe a case in which M. orale was identified from the joint fluid of a patient with septic arthritis, splenic lesions, and agammaglobulinemia. A 15-year-old boy was admitted to the hospital with fever, progressive left knee swelling, and pain. His medical history was significant for Burkitt’s lymphoma, the treatment of which had included rituximab 6 years earlier. M. orale was identified in the synovial fluid using 16S ribosomal RNA gene sequencing. He was also found to be hypogammaglobulinemic, and imaging revealed multiple splenic lesions. He was treated with doxycycline and intravenous immunoglobulin, which resulted in complete resolution of his arthritis and other symptoms. Mycoplasma species should be suspected in patients with humoral immunodeficiency and compatible findings.

Case Presentation

A 15-year-old boy from the Ukraine, who had been living in Canada for the previous 6 months on a study visa, was evaluated at BC Children’s Hospital with a chief complaint of progressive left knee swelling and pain. His symptoms had begun 6 weeks before presentation, along with fever, cough, night sweats, and a 5-kilogram weight loss. He denied significant trauma to the left knee, and a review of systems was otherwise negative. His medical history was significant for Burkitt’s lymphoma, which had been treated with chemotherapy and rituximab 6 years earlier in the Ukraine. There had been no significant infections or other health concerns since then.

On examination, the patient was unable to weight bear and had limited range of motion and a large effusion of the left knee. The remainder of the exam was normal. Laboratory investigations revealed a borderline microcytic anemia (hemoglobin of 103 g/L and mean corpuscular volume of 76 fL), C-reactive protein of 117 mg/L, erythrocyte sedimentation rate of 86 mm/h, and ferritin of 326 µg/L. No bacterial growth was obtained from blood and urine cultures, HIV serology was negative, and X-rays of the knee and chest were unremarkable. An MRI of the left knee demonstrated a large effusion, with enhancement of the synovium and bone marrow of the distal femur and proximal tibia, without evidence of soft tissue or bony injury.

Diagnosis

The affected knee was aspirated, and the synovial fluid was negative by bacterial culture and polymerase chain reaction (PCR) targeting Kingella kingae, Borrelia burgdorferi, Ureaplasma species, and Mycoplasma pneumoniae. A 16S ribosomal RNA (rRNA) PCR performed using standard methods was positive (1), and the sequence matched definitively to Mycoplasma orale.

An immunologic workup revealed a profoundly low immunoglobulin G (IgG) level of <0.3 g/L (normal range 4.9–14.6 g/L) and nearly absent CD19 lymphocyte (B cell) count of 0.03 × 10⁹/L (normal range 0.2–0.6 × 10⁹/L). Antibody titres to tetanus and diphtheria were absent despite a history of routine immunization. Multiple splenic lesions were seen on abdominal ultrasound and positron emission tomography–computerized tomography (Figure 1). A bone marrow biopsy was not suggestive of oncologic recurrence, and flow cytometry testing for SH2D1A and XIAP to investigate X-linked lymphoproliferative disease (XLP) was negative.

Figure 1:

Positron emission tomography–computerized tomography of the knee and viscera: (A) FDG avidity of the synovium of the left knee and (B) lesions in the spleen and possibly the liver

FDG = Fluorodeoxyglucose

The working diagnosis was septic arthritis and splenic infection due to M. orale, for which a 3-month course of doxycycline (100 mg by mouth twice daily) was prescribed. Monthly intravenous immunoglobulin (IVIG) infusions were also initiated at a dose of 600 mg/kg due to the presence of a severe and invasive infection in the context of undetectable IgG level and absent B lymphocytes. On follow-up at 6 months, the patient’s inflammatory markers had normalized, the B cell count was 0.2 × 10⁹/L, he had regained weight, and his arthritis and other symptoms had resolved, although his immunoglobulin M levels remained <0.3 g/L.

Discussion

The diagnosis in this case was made on the basis of the detection of M. orale DNA in the joint fluid. Specific culture methods were not performed for mycoplasma because the infection was not suspected a priori. The diagnosis is highly likely because of the plausibility of mycoplasmal arthritis and visceral infection in the setting of hypogammaglobulinemia. Members of the Mycoplasma genus have the smallest known self-replicating genomes among prokaryotes, and they lack a peptidoglycan cell wall (2,3). They are thought to have evolved to be obligate parasites, invading host cells to obtain their nutrients. Typically, M. orale exists as a commensal in the human oral cavity (4). Although several Mycoplasma species (e.g., M. pneumoniae and M. genitalum) are important causes of infection in healthy individuals, hypogammaglobulinemia is a recognized risk factor for severe and disseminated disease (2,3,5). M. orale is only rarely an opportunistic pathogen, but it has been reported to cause arthritis and disseminated infection in the context of impaired humoral immunity (2,6). It is likely that the arthritis was due to M. orale, given the unambiguous 16S PCR result, the absence of other pathogens, and the compatible clinical setting. The treatment of M. orale infection or mycoplasmal arthritis has not been well defined, and evidence is limited to case reports and small series that have typically described the use of tetracyclines or macrolides for between 3 months and 2 years, with varying results (2,5,6). The rapid and complete response to doxycycline, albeit in combination with IVIG, after weeks of progressive symptoms lends further support for M. orale as the cause of disease.

The most likely reason for humoral immunodeficiency in this case was rituximab-induced persistent hypogammaglobulinemia, a B lymphocyte–depleting monoclonal antibody against CD20. Although uncommon, rituximab can result in long-term B cell aplasia (7,8). The etiology of this patient’s agammaglobulinemia remains uncertain, however, because no immunologic studies obtained before administration of rituximab were available. Other primary immunodeficiencies such as X-linked agammaglobulinemia, autosomal recessive agammaglobulinemia, or transient hypogammaglobulinemia of infancy are less likely, given the patient’s age and absence of previous infections; common-variable immunodeficiency as a contributing factor cannot be excluded (9). The possibility of XLP was also considered given the history of Burkitt’s lymphoma but ruled out by SH2D1A and XIAP testing (10). At the time of this patient’s presentation, access to next-generation sequencing and genetic testing for underlying inborn errors of immunity was extremely limited, and the patient’s family indicated their intention to emigrate to another country and were subsequently lost to follow-up.

This case demonstrates the importance of entertaining a wide infectious differential diagnosis for unusual clinical presentations. Atypical pathogens should be considered, with appropriate molecular testing including PCR for opportunistic infections and 16S rRNA gene sequencing when appropriate (11). In this case, the use of molecular technology on aspirated synovial fluid revealed a match to M. orale, which was instrumental in determining the cause and treatment of the septic knee arthritis. Immunodeficiency due to either primary or secondary causes should be on the differential diagnosis for infections when the initial investigations return no conclusive microbiological cause or an unusual microorganism. Finally, children who receive rituximab should undergo follow-up to ensure reconstitution of humoral immunity (7,8).

Ethics Approval:

N/A

Informed Consent:

Informed patient consent has been secured from all patients whose personal information is included in the article or the parents or guardians of minors.

Funding:

No funding was received for this work.

Disclosures:

S Gantt reports grants and personal fees from Merck and personal fees from GSK, Moderna, and Curevo, outside the submitted work.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A