Overview
Septic arthritis due to Candida species can be due either to hematogenous dissemination or direct inoculation due to trauma, surgery, or intra-articular injections. Candida arthritis is for the most part a manifestation of disseminated or invasive candidiasis. The literature includes cases of patients with disregarded episodes of candidemia that later presented with Candida arthritis [207, 1600]. However, there are also cases of Candida arthritis that have presented after episodes of candidemia that were treated with appropriate dosages of amphotericin B [937].
Epidemiology
Available data regarding the incidence of this rare presentation of Candida infection are limited to case reports published in the English literature. Candida arthritis is an unusual manifestation of invasive candidiasis among adults. Bayer et al. reviewed the English literature up to 1978 and found only 17 cases related to hematogenous seeding [207]. In addition, none of the large series of invasive candidiasis report joint involvement [1082, 1376, 1602, 1724]. It should be kept in mind that joints are rarely examined in autopsy protocols, and most of these reports were based on autopsy findings. However, the overall rate of involvement appears low.
The situation in children is different. Due to the more extensive blood supply in growing bones and joints, hematogenous Candida arthritis is common in infants with invasive candidiasis [2108]. About one third of babies with Neonatal Candidiasis have joint and/or bone involvement [1128].
Candida arthritis following direct inoculation is described, but appears rare. Only 9 cases linked to intra-articular injection and 21 cases of inoculation by surgery had been reported up to 1992 [2108]. Seven additional cases with similar pathogenic mechanisms have been published since then [323, 440, 496, 631, 783, 2265, 2420].
Risk factors
Hematogenous-related Candida arthritis is associated with the usual risk factors for invasive candidiasis. Actually, Candida arthritis has been reported in all of the following patient groups with classic risk factors for candidemia:
- Infants. Of all groups at risk for Candida invasive disease, infants are the group that most frequently present with bone/joint involvement (see also Candida Osteomyelitis). The review by Silveira et al. found that 85% of cases reported in the literature were less than 6 months of age [2108, 2391].
- Neutropenic patients. [706, 1645].
- Organ transplant recipients. [170, 249, 496, 1351, 2135]
- Following abdominal surgery. [1319, 1658]
- Intravenous drug addicts of brown heroin. This group of patients presents with a unique picture of disseminated candidiasis that is usually associated with a special form of skeletal infection, which is the involvement of the costochondral joints [247, 250, 623, 719, 1281, 1368, 1813, 2467]
- Following Candidemia related to urinary tract manipulations that seed either previously healthy joints or joints with prostheses in place [1600, 1628].
- Following intra-articular injection and/or surgery for osteoarthritis, rheumatoid arthritis, gout, or osteoporosis
Candida species and Candida Arthritis
For hematogenous-related candidal arthritis, C. albicans is responsible for about 70% of cases, while the most frequent non-albicans species are C. tropicalis, C. parapsilosis, and C. krusei [1600, 1645]. For candidal arthritis related to direct inoculation, the species described, in order of approximate frequency, include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. zeylanoides [249, 1398, 2265, 2477]. C. parapsilosis is especially linked to arthritis in the setting of a prosthetic joint.
Clinical Manifestations
Candidal arthritis typically presents with pain or tenderness of the involved joint. In infants these symptoms are suggested by abnormal positioning of the affected limb. Fever is often absent, and the ability to observe joint warmth or swelling depends on the joint: more superficial joints (e.g., ankle or knee) will be warm and swollen.
Candidal arthritis usually affects large joints, most often the knees [980, 2108]. Hip, ankle and shoulder are the next most commonly affected [980]. Polyarticular involvement is seen in about one third of cases, and is more frequent among infants [349, 1600, 1649]. Arthritis may be the first clinical manifestation of neonatal candidiasis. While presentation may be delayed for some days or weeks following the episode of candidemia in adults, candidal arthritis in the neonate usually presents simultaneously with the acute phase of the disease [207, 1807].
Candida joint infection in infants usually presents with concomitant metaphyseal osteomyelitis [1807]. A free communication between the arterial supplies and venous channels of the metaphysis with the epiphyseal vessels explains the simultaneous seeding of bones and joints in cases of hematogenous dissemination.
When Candida arthritis occurs in patients with underlying chronic joint diseases, the diagnosis is commonly delayed because clinical findings are usually ascribed to the primary joint disease and the isolation of Candida is considered insignificant [207].
Specific Diagnostic Strategies
The diagnosis of Candida arthritis is based primarily on isolation of Candida from the synovial fluid. Histopathologic confirmation is nice, but certainly not required. Histopathologic findings include thickened and hyperemic synovial linings, nonspecific acute and chronic inflammatory infiltrates and erosion of cartilage. Unlike other forms of fungal arthritis, granulomas are not seen in cases of Candida arthritis. Yeast forms are rarely found in these specimens [706, 1600].
Synovial fluid studies will show the classic changes of septic arthritis including elevated protein concentration, high white blood counts, and polymorphonuclear predominance. The glucose concentration is usually not depressed. Mononuclear effusions are occasionally found. An association between mononuclear effusion non-albicans species has been reported [706]. Gram stain of synovial fluid is negative in the majority of cases [207, 706].
Radiologic studies show the nonspecific findings consistent with arthritis (soft tissues swelling and effusion). As mentioned above, infants often also have an adjacent focus of osteomyelitis [1600]. Small areas of radiolucency in the cortex of the metaphyseal zone surrounded by a slight sclerotic reaction are thought to suggest osteomyelitis in this setting [15, 349, 1211, 1649].
Therapies
Management of Candida arthritis requires treatment of both local and systemic therapy. Systemic therapy along the lines of the therapy that would be appropriate for invasive candidiasis is combined with joint aspiration, synovectomy, and/or localized installation of amphotericin B.
Antifungal therapy
Long-term antifungal therapy is usually necessary [1600]. Intra-articular amphotericin B has been tried due to both the theoretical advantages of increased local therapeutic concentrations and reduction of systemic side effects. While clearly providing no systemic therapy for other sites of infection, a few authors have reported successful outcomes [1600, 1807, 1850]. However, these data are quite limited, and the availability of both less toxic forms of amphotericin B and of new antifungal agents has seemed to largely eliminate the need for this strategy.
Intravenous amphotericin B has long been the standard therapy for neonates and neutropenic patients with any form of deep organ Candida infection. Most published experiences in the treatment of Candida arthritis report successful results when using this agent alone or in combination with 5-fluorocytosine [980]. Synovial fluid levels of amphotericin B vary between 20 to 100% of serum concentration [1162]. Precise doses and length of therapy have not been studied, but we would recommend doses of 0.5-1 mg/kg/day for no less than 10 days, followed by an oral regimen with one azole for a period enough to eradicate Candida from the synovial fluid.
Ketoconazole at dosages of 400 to 800 mg/day given orally has been successfully used to treat the osteoarticular syndrome of heroin drug addicts and for cases of hematogeneous hip and knee Candida arthritis [2108]. Fluconazole has, however, largely supplanted the use of this agent. But, these reports do support the principle that azole antifungal agents can be used successfully for this disease.
Fluconazole levels in the synovial fluid have been documented to be between 90 to 100% of those in plasma [1667, 2391]. A number of cases have been successfully treated with this convenient antifungal agent, even among neonates [1521, 1667, 2265, 2391]. One case of failure when using this agent has also been reported [440]. Dosage of 200 to 400 mg/day for variable periods of 3-7 months have been used [1667, 2265, 2391].
Finally, cases not responding to standard therapy or related to unusual Candida species may benefit from the currently growing knowledge on susceptibility testing for antifungal agents and specially for azoles [1911]. For this reason, it is recommended to keep the isolate for certain time and if necessary request MIC testing from a laboratory familiar with the (A):NCCLS N/A(L):M27 procedure [1623].
Infections of prosthetic joints almost always require a combination of surgery to remove the infected prosthesis, antifungal therapy, and then placement of a new joint prosthesis once the local infection has resolved [2265]. Although success with just medical therapy (fluconazole for 17 months) was described in one patient [1523], this patient was only followed for 11 months after the end of treatment and other experience would predict a high risk of relapse without surgical therapy. However, this experience does suggest that one could try this approach in a patient for whom surgery presented significant problems.
Local procedures also have value. Repeated synovial aspiration, following the general principles for treatment of bacterial septic arthritis, is useful until the joint effusion resolves. Synovectomy may be of help when sequential aspirations and antifungal therapy fail to produce relief. Difficult cases for whom multiple synovectomies were required have been described [883].