Septic arthritis in a previously healthy man with pan-negative infectious and rheumatologic work-up

Abstract

Neisseria gonorrhoeae is the causative organism in 0.6%–1.2% of septic arthritis cases in North America and Europe, and classically presents as migratory polyarthralgias and tenosynovitis, with later development of septic oligoarthritis. In men, urine gonorrhoea nucleic amplification testing (NAAT) is the preferred diagnostic test, as its sensitivity surpasses that of joint and blood culture in disseminated infections. We present a case of a previously healthy man who presented with septic arthritis of the wrist. He denied any sexual activity in the previous year. Urine gonorrhoea NAAT and cultures were negative. However, N. gonorrhoeae was later identified via 16s PCR of the patient’s synovial fluid, leading to a delayed diagnosis of gonococcal arthritis. In patients with septic arthritis, gonococcal infection should remain on the differential despite reported sexual history and negative urine NAAT. Clinicians should continue to follow cultures and provide antibiotic coverage until a causative organism is identified.

Background

Neisseria gonorrhoeae is the causative organism in 0.6%–1.2% of septic arthritis cases in North America and Europe.^{1 2} The classic presentation of gonococcal arthritis is asymmetric, migratory polyarthralgias for several days followed by fever and chills. Most infections are accompanied by tenosynovitis and discrete, small papulovescicular skin lesions.² Gonococcal infection should be suspected in the presence of risk factors for sexually transmitted diseases, such as new sexual partners or multiple partners, and in the absence of risk factors for non-gonococcal arthritis, including older age, recent surgery, indwelling catheters and soft tissue infections.³ Laboratory testing for suspected gonococcal arthritis includes blood cultures, synovial fluid cultures and cultures from mucosal sites. Because yield from blood cultures and synovial fluid cultures tend to be low, urine nucleic acid amplification testing (NAAT) is the preferred diagnostic test in heterosexual men due to its high sensitivity and specificity.⁴ We present an unusual case of gonococcal arthritis despite negative urine NAAT in a previously healthy male reporting no sexual activity in the past year.

Case presentation

In April 2019, a previously healthy 55-year-old man without significant medical history presented with fever and shaking chills following 4 days of swelling and pain in multiple joints. The joint pain started first in his left wrist 4 days prior, and the following day developed in his left knee and ankle, and later in the day in his right wrist. He denied any history of trauma and his only recent travel was to the Dominican Republic 1 month prior. His medical history was significant for a similar episode in 2006 of right elbow infectious bursitis, treated with antibiotics, following a trip to Costa Rica. The patient was born in France and currently resided in the southeastern USA. While in the Dominican Republic he went scuba diving; otherwise he remained in urban areas and did not recall any insect bites. He was married to a female partner but reported that he had not been sexually active for over a year. He denied any history of intravenous drug use and denied any joint pain prior to this episode, back pain, abdominal pain, diarrhoea or dysuria.

In the emergency room, the patient was tachycardic and febrile to 39.6°C (103.3°F). His left wrist was severely erythematous, swollen, tender and had limited range of motion. Moderate tenderness and swelling were noted in the other affected joints. In addition, an erythematous, blanching, macular rash was present on his anterior left lower leg. A small, 1 cm eschar was noted on the posterior distal left forearm. Labs were remarkable for white blood cells (WBC) 11.9×10⁹/L, erythrocyte sedimentation rate 41 mm/hour, and C-reactive protein 12.5 mg/dL. The patient was resuscitated with 2 L of saline. An arthrocentesis was performed on the left wrist that showed 110×10⁹/L WBCs, predominantly neutrophils, with no organisms on Gram stain and no crystals under polarised light. Due to concern for septic arthritis, the patient was started on intravenous vancomycin, piperacillin-tazobactam and ceftriaxone. He was taken urgently to the operating room for incision, drainage and irrigation of the left wrist. Purulent fluid was expressed from the radiocarpal joint space and an additional small dermal abscess filled with pus was found under the eschar in the left forearm and also drained. Intraoperative specimens again showed numerous leukocytes, but was negative for organisms or crystals. The fever, tachycardia and leukocytosis resolved by the next morning following antibiotics and surgical drainage of the left wrist and forearm.

Differential diagnosis

Given the patient’s septic clinical presentation with over 110×10⁹/L WBCs with neutrophil predominance in the joint aspirate, our clinical suspicion for a bacterial joint infection was high. Common organisms in septic arthritis include methicillin-sensitive and -resistant Staphylococcus aureus and Streptococcus pneumoniae; Gram-negative organisms such as Salmonella and Pseudomonas were considered possible, but less likely given the absence of medical comorbidities. Tuberculosis was unlikely in an immunocompetent patient with no history of potential exposure. Despite the absence of sexual history, the history of asymmetric polyarthritis with skin involvement led us to keep gonococcal infection in our differential diagnosis. Neisseria meningitidis can also cause oligoarticular septic arthritis, without the clinical syndrome typical of meningococcemia, in rare reported cases.^{5 6}

Viral joint infection can present with sudden onset polyarticular arthritis alongside a rash, like our patient experienced. Viral etiologies of polyarthritis include parvovirus, rubella, mumps, adenovirus and enteroviruses. Synovial fluid findings in viral arthritis can vary depending on the aetiology, and highly elevated WBC counts are possible, though usually lymphocytes predominate. Viral arthritis usually is preceded by a prodrome, which our patient denied. He did report travel to a region with Zika, dengue and chikungunya; however, our suspicion was low given the absence of prodromal symptoms or insect bites.

Inflammatory joint disease was also considered on our differential diagnosis, but initially thought to be less likely than infectious etiologies due to the patient’s presentation and joint aspirate cytology. Adult Still’s disease was considered a possibility given fever, rash and arthritis; however, the patient lacked the characteristic recurrent, quotidian pattern of fevers and other systemic symptoms. While inflammatory joint disease can be associated with highly elevated WBC counts, highly elevated WBC counts above 100 000 are more predictive of infectious arthritides.⁷ A full rheumatologic work-up for polyarthritis would include serum markers for rheumatoid arthritis, seronegative spondyloarthritides, systemic lupus erythematosus, vasculitides, and polymyositis.

Crystal arthritides are also common causes of arthritis, though an initial septic presentation would be unusual.

Investigations

Joint aspirate, intraoperative specimens and blood were sent to the laboratory for culture. Due to concern for gonococcal arthritis given the history of asymmetric polyarthritis despite the patient’s denial of any sexual contacts, we sent a urine gonorrhoea/chlamydia (G/C) NAAT that returned as negative for both organisms. HIV antigen/antibody test was also negative and HbA1C was 5.8. To rule out bacteremia with endocarditis, transthoracic echocardiography was performed, and showed no valvular abnormalities.

Clinical suspicion for viral infection and rheumatologic disease was low given the acute onset of symptoms and rapid improvement following antibiotics and source control. However, blood cultures and synovial fluid cultures remained negative for growth at 48 hours. At this time, the clinical team chose to send additional tests to rule out viral and rheumatologic etiologies. Adenovirus antibody, Lyme antibody and enterovirus RNA were negative. Parvovirus IgG was present, but IgM was not detectable. Anti-nuclear antibodies was mildly positive at 1:320 dilution with a speckled pattern. Reflex autoimmune disease panel (including anti-cardiolipin, complement C3 and C4, anti-dsDNA, anti-Smith, anti-Jo, anti-La, anti-RNP, anti-Scl) was pan-negative and p-ANCA and c-ANCA were not detected.

Outcome and follow-up

On hospital day 4, the patient was clinically stable and was ready to be discharged with 4 weeks ofintravenous vancomycin and ceftriaxone. Since no definitive diagnosis had yet been reached and the suspicion for an infectious aetiology was high, we requested the laboratory perform a multiplex 16s/18s PCR, a series of nucleic amplification tests for multiple bacteria and fungi, on the patient’s synovial fluid obtained during surgery. While NAAT of synovial fluid is not approved by the United States Food and Drug Administration (US FDA), our laboratory performs this test in cases where no microbes have been identified on culture or other diagnostic tests despite high clinical suspicion for infection. A disclaimer that the assay has not been approved the US FDA is included alongside all reported results.

The results of the multiplex 16s/18s PCR returned while preparations for discharge were being made. The laboratory reported that N. gonorrhoeae was identified in the synovial fluid. While the result came from an off-label diagnostic method, between the high pre-test clinical suspicion for gonococcal arthritis and literature demonstrating that PCR-based methods are highly specific, a final diagnosis of gonococcal arthritis was made.

The antibiotic regimen was changed to a 2-week course of ceftriaxone. The patient was informed that the organism identified was sexually transmitted, but continued to state that he had not been sexually active for years. The patient’s primary care physician was notified and the patient was discharged with outpatient follow-up. Synovial fluid culture eventually grew rare N. gonorrhoeae after 5 days, confirming our diagnosis.

The patient completed his 2-week course of ceftriaxone and continued to recover function in affected joints. Three months after hospital discharge, he continued to do well.

Discussion

Gonococcal arthritis should be considered in the differential for patients presenting with septic arthritis accompanied by migratory polyarthralgias, tenosynovitis or skin findings.^{1 2} It is important to take a thorough sexual history in the absence of partners and family, as we attempted to do in this case. However, patients may not always be forthcoming, and sexually transmitted infections should remain on the differential even if patients do not seem to have any risk factors.

Disseminated gonococcal infection is usually accompanied by evidence of infection at the original mucosal site. In heterosexual men, the urine G/C NAAT is the preferred diagnostic test.⁴ However, in our case, we found that even if the initial urine NAAT is negative for gonorrhoea, a diagnosis of gonococcal arthritis should not be ruled out when clinical suspicion is high given the patient’s presentation. Cultures should continue to be followed and antibiotics with gonococcal coverage should be continued. In this case, the synovial fluid did not grow bacteria until 72 hours.

N. gonorrhoeae is known for its fragility and difficulty to culture. Blood and synovial fluid culture yields N. gonorrhoeae in approximately 50% of cases, and culture from mucosal swabs are positive in 80% of cases.⁴ NAAT of the synovial fluid is more sensitive than culture; although it is not validated for synovial fluid testing, NAAT can be performed on synovial fluid if the culture does not yield organisms.² Even if nucleic amplification methods are more sensitive than culture, acquiring cultures when possible is always recommended because in addition to definite diagnosis, cultures provide information about drug susceptibility.

The urine gonorrhoea NAAT test is approximately 99% sensitive and 99% specific in men, although the accuracy is somewhat lower in men who have sex with men (MSM) or when the urine sample is not the first void.^{8 9} Despite the overall strength of the urine gonorrhoea NAAT, there are instances when it fails. A previous case reported two HIV-positive, MSM men with septic arthritis with negative initial urine NAAT who later had joint cultures with N. gonorrhoeae.¹⁰ To the authors’ knowledge, our case report is the first to report of urine NAAT-negative, joint culture-positive gonococcal arthritis in an immunocompetent, presumably heterosexual male.

Lastly, when relying on PCR-based diagnostic methods, it is important to note that the bacterial genome is highly conserved among Neisseria species. N. gonorrhoeae and N. meningitidis share between 80% and 90% of genome sequence identity.¹¹ While uncommon, N. meningitidis has also been identified as the causative organism in multiple cases of septic arthritis.^{5 6} It is thought to seed the joint through the blood in individuals with asymptomatic nasopharyngeal colonisation.⁵ At the time of the patient’s hospitalisation, meningococcal arthritis was not considered in the differential diagnosis due to its rarity; no providers caring for this patient had previously encountered meningococcal arthritis. Only on later review was meningococcal arthritis taken into account, especially given the absence of sexual activity. At that time, the specimens had been discarded and it was no longer possible to perform molecular analyses to clarify the diagnosis.

In summary, we present a case of a gonococcal arthritis despite negative urine G/C NAAT. In patients with septic arthritis, N. gonorrhoeae infection should remain on the differential regardless of a patient’s reported sexual history, even if the initial urine G/C NAAT is negative. Clinicians should continue to follow blood, synovial, and mucosal cultures and provide antibiotic coverage for N. gonorrhoeae until a causative organism is identified, which can be up to 3–4 days following the collection of the specimen.

Learning points.

• Gonococcal arthritis should be considered in the differential for patients presenting with septic arthritis accompanied by migratory and asymmetric polyarthralgias, tenosynovitis or skin involvement.

• In patients with septic arthritis, Neisseria gonorrhoea infection should remain on the differential regardless of a patient’s reported sexual history, even if the initial urine G/C NAAT is negative.

• N. gonorrhoea is known for its fragility and difficulty to culture. Blood and synovial fluid culture yields N. gonorrhoea in approximately 50% of cases, and culture from mucosal swabs are positive in 80% of cases.

• Nucleic acid amplification tests (NAAT) of the synovial fluid are more sensitive than culture; although it is not validated for synovial fluid testing, NAAT can be performed on synovial fluid if the culture does not yield organisms.

• N. gonorrhoea and N. meningitidis share 80%–90% genome sequence identity. PCR-based detection methods may misidentify meningococcal infection as gonococcal infection. Therefore, in patients without risk factors for gonococcal disease, further analysis such as multilocus sequence typing, should be considered.