Case 2: Culture-Negative Elbow Arthritis in a 10-Year-Old Boy

A 10-year-old, fully vaccinated boy presents to the emergency department (ED) with 4 days of left elbow swelling, pain, and erythema. Review of systems is negative for fever, rashes, or other joint swelling or pain in the last 4 days. He had an upper respiratory infection 1 week prior and reports a remote history of Staphylococcus aureus skin infection and a recent minor trauma (fall on the floor 2 days prior). Past medical history is notable for 2 years of recurrent joint swelling with mild pain involving the left knee and/or left ankle, with no concurrent fever, rashes, or severe pain that limits activities. The episodes would ultimately resolve spontaneously but return later. Previous evaluation of recurrent joint swelling with knee arthrocentesis a year ago was reportedly unrevealing. He has 2 dogs, a cat, and a hamster at home, where he lives in a rural area near the woods in the Midwestern United States. He denies any travel or known tick bites. Family history is notable for rheumatoid arthritis, Crohn disease, and a thyroid disorder.In the ED, vital signs are within normal limits. Physical examination reveals a nontoxic child with a significantly swollen left elbow. There is limited range of motion with elbow extension without significant pain or warmth. Examination of all other joints showed no abnormalities. There is no lymphadenopathy. Laboratory findings are notable for a normal white blood cell (WBC) count with differential, mildly elevated erythrocyte sedimentation rate (29 mm/hour, reference range [RR] <13) and C-reactive protein (1.6 mg/dL, RR < 1.0). Additionally, x-ray and ultrasound show a moderate-sized effusion. A bedside arthrocentesis yields a cloudy fluid with 198 000/mm3 red blood cells (RBCs), 354 000/mm3 WBCs with 87% polymorphonuclear leukocytes (PMNs), and negative Gram stain. A blood culture is obtained, and a synovial fluid culture is submitted using aerobic and anaerobic blood culture bottles. The patient is admitted to the hospital due to concern for a septic elbow, where further workup reveals the diagnosis.A thorough history and examination can frequently distinguish between the broad categories of pediatric elbow joint swelling (Table 1). With a clear onset following an inciting event, particularly in the absence of constitutional symptoms and elevated RBCs on arthrocentesis, hemarthrosis due to a traumatic joint injury should be considered.In the context of exceedingly elevated WBCs/PMNs in synovial fluid, septic arthritis is high on the differential. Septic arthritis typically presents with concurrent fever affecting a single joint in the lower extremity (hip| > |knee| > |ankle),1 with rare involvement of the upper extremities.2,3 Joint examination elicits extreme pain with micromotion. Although neither sensitive nor specific, WBCs of >50 000/mm3 with PMNs >90% in synovial fluid may increase the likelihood of bacterial infection.4 Staphylococci and Streptococci are the most common causative organisms of bacterial septic arthritis in all age groups.4 To diagnose, Gram stain and cultures of synovial fluid should be obtained, ideally with the fluid placed in blood culture bottles for enhanced yield of organism isolation.5 Even then, culture-negative septic arthritis is reported in up to 43% to 69% of pediatric cases.6,7 This could be associated with antibiotic pretreatment or infection with fastidious or unculturable organisms. Therefore, alternative, non–culture-based diagnostics should be considered in certain cases. For instance, in children aged 6 to 48 months, Kingella kingae can be on the microbiologic differential,8,9 and nucleic acid amplification test (NAAT) on synovial fluid should be added if available because K. kingae detection rate of NAAT is 4-fold higher compared with cultures. In teenagers presenting with septic arthritis with no alternative etiology, gonococcal septic arthritis should be considered; given low yield of gonococcal isolation in synovial fluid (<50%), NAAT from mucosal sites (genitourinary sites and/or freshly voided urine and, if clinically indicated, rectal and oropharyngeal swabs) should be performed as supportive evidence.10 Lyme serology should be obtained in culture-negative septic arthritis especially in endemic areas. Lastly, viruses, including parvovirus B19 or rubella, may be associated with arthritis, but synovial fluid WBCs are typically <50 000/mm3 in these cases.11 Infectious etiologies of arthritis in children, with suggested diagnostic studies, are summarized in Table 2.Postinfectious or reactive arthritis should be on the differential if there is recent or concomitant upper respiratory (eg, poststreptococcal reactive arthritis), gastrointestinal (eg, Shigella, Salmonella, Yersinia, or Campylobacter), or genitourinary tract infection (eg, Chlamydia trachomatis). Synovial fluid WBCs are typically <50 000/mm3 in this case.11 Inflammatory causes, such as rheumatologic disease (eg, juvenile idiopathic arthritis [JIA], systemic lupus erythematosus, or systemic vasculitis), inflammatory bowel disease or celiac disease with extra-gastrointestinal manifestations, or serum sickness, should also be considered. Given a history of intermittent swelling on other joints (left knee/ankle) and strong family history of autoimmune conditions in the index case, JIA was considered; elbow arthritis may occur in up to 25% of JIA cases, but elbow monoarthritis itself is a rare presenting symptom.12,13 A thorough workup to rule out infectious and reactive arthritis should be performed before a definitive diagnosis of JIA is made.Finally, bone or soft-tissue tumors often grow in the bones around joints and cause chronic progressive localized pain around a palpable mass. Bony neoplasms rarely affect the upper extremity and typically involve the proximal humerus when they do, thus making this an unlikely diagnosis for acute elbow swelling.14The patient underwent surgical washout due to the concern of septic arthritis. Significantly cloudy synovial fluid was encountered, which demonstrated 13 000/mm3 WBCs (90% PMNs), 259 000/mm3 RBCs, and negative Gram stain. He was placed on empirical clindamycin thereafter. Cultures of synovial fluid were ultimately negative as well as NAATs for Streptococcus pyogenes, S. aureus, and K. kingae. Lyme serology and anti-DNase B were added, and a rheumatology consult was obtained. The workup for noninfectious causes of arthritis guided by rheumatology, including tests for fecal calprotectin, HLA B27, tissue transglutaminase immunoglobulin A (IgA) antibody, antinuclear antibody, rheumatoid factor, and angiotensin-1–converting level was unremarkable. Anti-DNase B was only minimally elevated (405 U/mL, RR 0-310), and Lyme antibodies came back positive for IgG. Clindamycin was empirically switched to oral doxycycline for suspected Lyme arthritis, with Western immunoblot still pending at discharge. The final diagnosis was confirmed by positive Borrelia burgdorferi IgG immunoblots. The patient finished 28 days of doxycycline, and the swelling of the left elbow completely resolved after 28 days of therapy.Lyme arthritis is frequently mistaken for bacterial septic arthritis given similar clinical and laboratory features.15 Patients with Lyme arthritis present with mono- or oligoarthritis in large joints, particularly the knee (>90% of cases), with far less involvement of other joints, such as the elbow.15 In comparison to bacterial arthritis, Lyme arthritis usually lacks systemic symptoms and the exquisite joint pain with minimal movement.16 Although the mechanism of joint destruction is only partially understood, the milder joint pain appears to be due to the fact that unlike classic septic arthritis organisms such as S. aureus, B. burgdorferi does not produce proteases that cause rapid hyaline cartilage destruction.17 Most cases occur without a history of earlier stage of illness (including erythema migrans), with up to 80% of patients not experiencing or recalling a preceding tick bite or rash.18,19 The joint swelling may be episodic or last weeks at a time, then may resolve with later recurrence.18,19 If untreated during the earlier stage of Lyme disease, approximately 60% of patients can develop Lyme arthritis in a few months to 2 years. Synovial fluid analyses can show high WBCs (40 000–80 000/mm3)/PMNs (>75%), which prompts immediate surgical washouts for presumed septic arthritis.16,20,21The standard 2-tier serologic testing should be considered for patients with consistent symptoms/signs of Lyme arthritis and plausible geographic exposure, starting with an enzyme-linked immunosorbent assay (ELISA) or immunofluorescent antibody (IFA), and reflex to Western immunoblot if ELISA/IFA is positive or equivocal. Although ELISA and IFA alone are sensitive, they are unable to distinguish active vs past infection. Western immunoblot with IgM and IgG detection are more specific and better able to determine early vs late Lyme disease. Confirmed IgG seroreactivity with immunoblot is highly sensitive (95%–100%) and exhibits increased specificity for late Lyme disease.22,23 The limitations of using this current 2-tier testing are as follows: (1) serology for the diagnosis of early Lyme disease in patients with erythema migrans may yield false-negative results as antibodies take time (days to weeks) to develop, and (2) confirmatory second-tier testing can take time to yield results, leading to potential delays of up to a week in diagnosis. B. burgdorferi NAAT in synovial fluid/tissue may be considered in those for whom more definitive information is necessary.23Diagnosis of Lyme arthritis of the elbow is additionally challenging given its rarity 15,19 and difficulty in assessing disability as a non–weight-bearing joint. Common features of Lyme monoarthritis of the elbow include an absent history of tick bite or skin rash, absence of fevers, and the presence of a joint effusion on radiograph.24 Among the 4 published cases, there was an average delay of 4.75 days between presentation and positive serology result, but all patients recovered once starting appropriate antibiotics.24 Therefore, a high index of suspicion for Lyme arthritis of the elbow is essential to guide early diagnosis and targeted therapy in those with geographic exposure.The mainstay of treatment for Lyme arthritis is oral antibiotics for 28 days, usually with doxycycline.23 There is a growing consensus among recent national guidelines that doxycycline use for a duration of up to 14 days seems safe for all ages.23 However, limited safety data exist regarding prolonged doxycycline use (eg, >14 days of therapy) in children younger than 8 years of age, and the use of alternative agents, such as amoxicillin, is currently recommended for this age group.25 Intravenous ceftriaxone can be an alternative option in those with no or minimal response to an initial course of oral antibiotics.23The patient did well with no further recurrent joint swelling at 6 months’ follow-up in clinic.Lyme arthritis affects the knee joint in 90% of cases but should not be discounted in patients who present with swelling and pain of other joints.Up to 60% of patients with untreated early Lyme disease will experience Lyme arthritis; the majority do not recall a preceding tick bite or skin rash.22Lyme arthritis can mimic septic arthritis; however, patients typically have less severe symptoms and signs due to a slower, less destructive infectious process.17A high index of suspicion for Lyme arthritis should be maintained in patients with suspected septic arthritis with sterile synovial fluid.A 2-tier serum antibody testing is recommended for the diagnosis over NAAT or culture on synovial fluid or tissue.Oral antibiotic therapy with doxycycline or amoxicillin for 28 days is recommended for the treatment.