14 - 135 Infectious Arthritis

135 Infectious Arthritis

■ ■FURTHER READING Aronoff DM, Marrazzo JM: Infections caused by Clostridium per­ fringens and Paeniclostridium sordellii after unsafe abortion. Lancet Infect Dis 23:e48, 2023. Bruun T et al: Risk factors and predictors of mortality in streptococcal necrotizing soft-tissue infections: A multicenter prospective study. Clin Infect Dis 72:293, 2021. Bryant AE et al: Emerging erythromycin and clindamycin resistance in group A Streptococcus: Efficacy of linezolid and tedizolid in experi­ mental necrotizing infection. J Glob Antimicrob Resist 22:601, 2020. Daum RS et al: A placebo-controlled trial of antibiotics for smaller skin abscesses. N Engl J Med 376:2545, 2017. Davies MR et al: Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance. Nat Genet 47:84, 2015. Gessain A et al: Monkeypox. N Engl J Med 387:1783, 2022. Linner A et al: Clinical efficacy of polyspecific intravenous immuno­ globulin therapy in patients with streptococcal toxic shock syndrome: A comparative observational study. Clin Infect Dis 59:851, 2014. Rafei R et al: A global snapshot on the prevalent macrolide-resistant emm types of group A Streptococcus worldwide, their phenotypes and their resistance marker genotypes during the last two decades: A systematic review. Infect Genet Evol 99:105258, 2022. Stevens DL et al: Necrotizing soft tissue infections. Infect Dis Clin North Am 35:135, 2021. Talan DA et al: Bacteriologic analysis of infected dog and cat bites. Emergency Medicine Animal Bite Infection Study Group. N Engl J Med 340:85, 1999. Nongnooch Poowanawittayakom,

Lawrence C. Madoff

Infectious Arthritis Although Staphylococcus aureus, streptococci, and Neisseria gonorrhoeae are the most common causes of infectious arthritis, various mycobac­ teria, spirochetes, fungi, and viruses also infect joints (Table 135-1). Since acute bacterial infection can destroy articular cartilage rapidly, all inflamed joints must be evaluated without delay to exclude non­ infectious processes and determine appropriate antimicrobial therapy and drainage procedures. For more detailed information on infectious arthritis caused by specific organisms, the reader is referred to the chapters on those organisms. Acute bacterial infection typically involves a single joint or a few joints. Subacute or chronic monoarthritis or oligoarthritis suggests mycobacterial or fungal infection; episodic inflammation is seen in syphilis, Lyme disease, and the reactive arthritis that follows enteric infections and chlamydial urethritis. Acute polyarticular inflammation occurs as an immunologic reaction during the course of endocarditis, rheumatic fever, disseminated neisserial infection, and acute viral hepatitis. Viruses often infect multiple joints; however, bacterial infec­ tions generally cause mono- or oligoarthritis except in persons with underlying diseases such as rheumatoid arthritis. APPROACH TO THE PATIENT Infectious Arthritis Aspiration of synovial fluid or arthrocentesis—an essential element in the evaluation of potentially infected joints—can be performed without difficulty in most cases by the insertion of a large-bore

TABLE 135-1  Differential Diagnosis of Arthritis Syndromes CHRONIC MONARTICULAR ARTHRITIS ACUTE MONARTICULAR ARTHRITIS POLYARTICULAR ARTHRITIS Staphylococcus aureus Streptococcus pneumoniae β-Hemolytic streptococci Gram-negative bacilli Neisseria gonorrhoeae Candida spp. Crystal-induced arthritis Fracture Hemarthrosis Foreign body Osteoarthritis Ischemic necrosis Monoarticular rheumatoid arthritis Mycobacterium tuberculosis Nontuberculous mycobacteria Borrelia burgdorferi Treponema pallidum Candida spp. Sporothrix schenckii Coccidioides immitis Blastomyces dermatitidis Aspergillus spp. Cryptococcus neoformans Nocardia spp. Brucella spp. Legg-Calvé-Perthes disease Osteoarthritis Neisseria meningitidis N. gonorrhoeae Nongonococcal bacterial arthritis Bacterial endocarditis Candida spp. Poncet’s disease (tuberculous rheumatism) Hepatitis B virus Parvovirus B19 HIV Human T-lymphotropic virus type 1 Rubella virus Arthropod-borne viruses Sickle cell disease flare Reactive arthritis Serum sickness Acute rheumatic fever Inflammatory bowel disease Systemic lupus erythematosus Rheumatoid arthritis/ Still’s disease Other vasculitides Sarcoidosis CHAPTER 135 Infectious Arthritis needle into the site of maximal fluctuance or tenderness or by the route of easiest access. Ultrasonography or computed tomography (CT) may be used to guide aspiration of difficult-to-localize effu­ sions of the hip and, occasionally, the shoulder and other joints. Normal synovial fluid contains <180 cells (predominantly mononu­ clear cells) per microliter. Synovial cell counts averaging 100,000/μL (range, 25,000–250,000/μL), with >90% neutrophils, are character­ istic of acute bacterial infections. Crystal-induced, rheumatoid, and other noninfectious inflammatory arthritides usually are associated with <30,000–50,000 cells/μL; cell counts of 10,000–30,000/μL, with 50–70% neutrophils and the remainder lymphocytes, are common in mycobacterial and fungal infections. Definitive diagnosis of an infectious process relies on identification of the pathogen in stained smears of synovial fluid, isolation of the pathogen from cultures of synovial fluid and blood, or detection of microbial nucleic acids and proteins by nucleic acid amplification tests (NAATs) and immuno­ logic techniques. Gram stain is positive in about 30−50% of cases, and synovial fluid culture is positive in >60% of nongonococcal bacte­ rial arthritis cases. Matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF) mass spectrometry is helpful in patients who have negative culture and high suspicion of infectious arthritis. Sonication of explanted prosthetic joints (placement of the material into liquid and then immersion in an ultrasound bath) increases the yield of organism detection, especially in the case of prior antibiotic use within 14 days. ACUTE BACTERIAL ARTHRITIS ■ ■PATHOGENESIS Bacteria enter the joint from the bloodstream; from a contiguous site of infection in bone or soft tissue; or by direct inoculation during surgery, injection, animal or human bite, or trauma. In hematogenous infection, bacteria escape from synovial capillaries, which have no limiting base­ ment membrane, and within hours provoke neutrophilic infiltration

of the synovium. Neutrophils and bacteria enter the joint space; later, bacteria adhere to articular cartilage. Degradation of cartilage begins within 48 h as a result of increased intraarticular pressure, release of proteases and cytokines from chondrocytes and synovial macrophages, and invasion of the cartilage by bacteria and inflammatory cells. Histologic studies reveal bacteria lining the synovium and cartilage as well as abscesses extending into the synovium, cartilage, and—in severe cases—subchondral bone. Synovial proliferation results in the formation of a pannus over the cartilage, and thrombosis of inflamed synovial vessels develops. Bacterial factors that appear important in the pathogenesis of infective arthritis include various surface-associated adhesins in S. aureus that permit adherence to cartilage and endotoxins that promote chondrocyte-mediated breakdown of cartilage.

■ ■MICROBIOLOGY The hematogenous route of infection is the most common route in all age groups, and nearly every bacterial pathogen is capable of causing septic arthritis. In infants, group B streptococci, gram-negative enteric bacilli, and S. aureus are the most common pathogens. Since the advent of the Haemophilus influenzae vaccine, the predominant causes among children <5 years of age have been S. aureus, Streptococcus pyogenes (group A Streptococcus), and (in some centers) Kingella kingae. Among young adults and adolescents, N. gonorrhoeae is the most commonly implicated organism. S. aureus (including methicillin-resistant S. aureus [MRSA]) accounts for most nongonococcal isolates in adults of all ages; gram-negative bacilli, pneumococci, and β-hemolytic streptococci—

particularly groups A and B but also groups C, G, and F—are involved in up to one-third of cases in older adults, especially those with under­ lying comorbid illnesses. Gram-negative bacilli such as Pseudomonas may occur in immunocompromised patients or intravenous drug users. PART 5 Infectious Diseases Infections after surgical procedures or penetrating injuries are due most often to S. aureus and occasionally to other gram-positive bacte­ ria or gram-negative bacilli. Infections with coagulase-negative staphy­ lococci are unusual except after the implantation of prosthetic joints or arthroscopy. Anaerobic organisms, often in association with aerobic or facultative bacteria, are found after human bites and when decu­ bitus ulcers or intraabdominal abscesses spread into adjacent joints. Polymicrobial infections complicate traumatic injuries with extensive contamination. Bites and scratches from cats and other animals may introduce Pasteurella multocida or Bartonella henselae into joints either directly or hematogenously, and bites from humans may introduce Eikenella corrodens or other components of the oral flora. Penetration of a sharp object through a shoe is associated with Pseudomonas aeruginosa arthritis in the foot. ■ ■NONGONOCOCCAL BACTERIAL ARTHRITIS Epidemiology  Although hematogenous infections with virulent organisms such as S. aureus, H. influenzae, and pyogenic streptococci occur in healthy persons, there is an underlying host predisposition in many cases of septic arthritis. Patients with rheumatoid arthritis have the highest incidence of infective arthritis (most often secondary to S. aureus) because of chronically inflamed joints; glucocorticoid therapy; and frequent breakdown of rheumatoid nodules, vasculitic ulcers, and skin overlying deformed joints. Diabetes mellitus, glucocor­ ticoid therapy, hemodialysis, intravenous drug use, and malignancy all carry an increased risk of infection with S. aureus and gram-negative bacilli. Tumor necrosis factor inhibitors (e.g., etanercept, infliximab), which increasingly are used for the treatment of rheumatoid arthritis, predispose to mycobacterial infections and possibly to other pyogenic bacterial infections and could be associated with septic arthritis in this population. Pneumococcal infections complicate alcoholism, deficien­ cies of humoral immunity, and hemoglobinopathies. Pneumococci, Salmonella species, and H. influenzae cause septic arthritis in persons infected with HIV. Persons with primary immunoglobulin deficiency are at risk for mycoplasmal arthritis, which, while rare, results in per­ manent joint damage if tetracycline and replacement therapy with IV immunoglobulin are not administered promptly. IV drug users acquire staphylococcal and streptococcal infections from their own flora and

acquire pseudomonal and other gram-negative infections from drugs and injection paraphernalia. Clinical Manifestations  Patients with acute septic arthritis usu­ ally present with joint pain often with limitation of passive and active joint movement, joint swelling, and/or erythema. Approximately 90% of patients present with involvement of a single joint—most com­ monly the knee; less frequently the hip; and still less often the shoulder, wrist, or elbow. Small joints of the hands and feet are more likely to be affected after direct inoculation or a bite. Among IV drug users, infections of the spine, sacroiliac joints, and sternoclavicular joints (Fig. 135-1) are more common than infections of the appendicular skeleton. Poly­ articular infection is most common among patients with rheumatoid arthritis and may resemble a flare of the underlying disease. The usual presentation consists of moderate to severe pain that is uniform around the joint, effusion, muscle spasm, and decreased range of motion. Fever in the range of 38.3–38.9°C (101–102°F) and some­ times higher is common but may not be present, especially in persons with rheumatoid arthritis, renal or hepatic insufficiency, or conditions requiring immunosuppressive therapy. The inflamed, swollen joint is usually evident on examination except in the case of a deeply situated joint such as the hip, shoulder, or sacroiliac joint. Cellulitis, bursitis, and acute osteomyelitis, which may produce a similar clinical picture, should be distinguished from septic arthritis by preservation of pas­ sive range of motion and less-than-circumferential swelling. A focus of extraarticular infection, such as a boil, pneumonia, or endocarditis, should be sought. Peripheral-blood leukocytosis with a left shift and elevation of the erythrocyte sedimentation rate or C-reactive protein level are common. Plain radiographs show evidence of soft tissue swelling, joint space widening, and displacement of tissue planes by the distended capsule. Narrowing of the joint space and bony erosions indicate advanced infection and a poor prognosis. Ultrasound is useful for detecting effusions in the hip, and CT or MRI can demonstrate infections of the sacroiliac joint, the sternoclavicular joint, and the spine very well. Laboratory Findings  Specimens of peripheral blood and synovial fluid should be obtained before antibiotics are administered. Blood cultures are positive in up to 50–70% of S. aureus infections but are less frequently positive in infections due to other organisms. The synovial fluid is turbid, serosanguineous, or frankly purulent. Gram-stained smears confirm the presence of large numbers of neutrophils. Levels of total protein and lactate dehydrogenase in synovial fluid are elevated, FIGURE 135-1  Acute septic arthritis of the sternoclavicular joint. A man in his forties with a history of cirrhosis presented with a new onset of fever and lower neck pain. He had no history of IV drug use or previous catheter placement. Jaundice and a painful swollen area over his left sternoclavicular joint were evident on physical examination. Cultures of blood drawn at admission grew group B Streptococcus. The patient recovered after treatment with IV penicillin. (Courtesy of the late Francisco M. Marty, MD, Brigham and Women’s Hospital, Boston; with permission.)

and the glucose level is depressed; however, these findings are not specific for infection, and measurement of these levels is not neces­ sary for diagnosis. The synovial fluid should be examined for crystals because gout and pseudogout can resemble septic arthritis clinically, and infection and crystal-induced disease occasionally occur together. Organisms are seen on synovial fluid smears in nearly three-quarters of infections with S. aureus and streptococci and in 30–50% of infec­ tions due to gram-negative and other bacteria. Cultures of synovial fluid are positive in >90% of cases. Inoculation of synovial fluid into bottles containing liquid media for blood cultures increases the yield of a culture, especially if the pathogen is a fastidious organism or the patient is taking an antibiotic, but should be interpreted in the context of the Gram’s stain result. Pathogen nucleic acid amplification based assays (NAAT) or MALDI-TOF mass spectrometry, when available, can be useful for the diagnosis of partially treated or culture-negative arthritis. Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein tend to be elevated in septic arthritis but are nonspecific. Serum procalcitonin elevation is only ~50% sensitive and should not be used to rule out infectious arthritis. Synovial fluid procalcitonin might be useful, although data are limited. TREATMENT Nongonococcal Bacterial Arthritis Prompt administration of systemic antibiotics and drainage of the involved joint can prevent destruction of cartilage, postinfectious degenerative arthritis, joint instability, or deformity. Once samples of blood and synovial fluid have been obtained for culture, empiri­ cal antibiotics should be directed against the bacteria visualized on smears or the pathogens that are likely in light of the patient’s age and risk factors. Initial therapy should consist of IV-admin­ istered bactericidal agents; direct instillation of antibiotics into the joint is not necessary to achieve adequate levels in synovial fluid and tissue. If there are gram-positive cocci on the smear, IV vancomycin (15−20 mg/kg/dose) every 8–12 h should be started empirically. If methicillin-resistant S. aureus is an unlikely patho­ gen (e.g., when it is not widespread in the community), cefazolin (2 g every 8 h), oxacillin (2 g every 4 h), or nafcillin (2 g every 4 h) should be given. If initial Gram’s stain shows gram-negative bacilli, the risk for P. aeruginosa infection should be evaluated. If the patient does not have risk factors for P. aeruginosa infection, an IV third-generation cephalosporin such as cefotaxime (2 g every 8 h) or ceftriaxone (2 g every 24 h) provides adequate empirical coverage for most community-acquired infections. In addition, if the patient has a higher risk for P. aeruginosa infection, then anti-pseudomonal coverage such as cefepime (2 g every 8−12 h) or ceftazidime (2 g every 8 h) should be given. Double coverage of Pseudomonas with cephalosporin and ciprofloxacin or aminoglycoside can be consid­ ered empirically in severely ill patients or in the setting of highly resistant Pseudomonas infection incidence. Definitive therapy is based on the identity and antibiotic sus­ ceptibility of the bacteria isolated in culture. Infections due to staphylococci are treated with cefazolin, oxacillin, nafcillin, or van­ comycin for 4 weeks. In patients without evidence of endocarditis, IV antibiotics can be used for 7–14 days of treatment followed by oral antibiotics to complete the treatment course. Pneumococcal and streptococcal infections due to penicillin-susceptible organisms respond to 2 weeks of therapy with penicillin G (2 million units IV every 4 h); infections caused by H. influenzae and by strains of Streptococcus pneumoniae that are resistant to penicillin are treated with cefotaxime or ceftriaxone for 2 weeks. Most enteric gramnegative infections can be cured in 3–4 weeks by a second- or thirdgeneration cephalosporin given IV or by a fluoroquinolone such as levofloxacin (500 mg IV or PO every 24 h). P. aeruginosa infec­ tion should be treated for at least 2 weeks with antipseudomonal cephalosporin such as ceftazidime (2 g IV every 8 h), cefepime (2 g every 8–12 h). If tolerated, this regimen is continued for an additional

2 weeks; alternatively, a fluoroquinolone such as ciprofloxacin (750 mg PO twice daily) may be given.

Timely drainage of pus and necrotic debris from the infected joint is required for a favorable outcome. Needle aspiration of read­ ily accessible joints such as the knee may be adequate if loculations or particulate matter in the joint does not prevent its thorough decompression. Arthroscopic drainage and lavage may be employed initially or within several days if repeated needle aspiration fails to relieve symptoms, decrease the volume of the effusion and the synovial white cell count, and clear bacteria from smears and cul­ tures. In some cases, arthrotomy is necessary to remove loculations and debride infected synovium, cartilage, or bone. Septic arthritis of the hip is best managed with arthrotomy, particularly in young children, in whom infection threatens the viability of the femoral head. Septic joints do not require immobilization except for pain control before symptoms are alleviated by treatment. Weight bear­ ing should be avoided until signs of inflammation have subsided, but frequent passive motion of the joint is indicated to maintain full mobility. Although some clinical studies suggest that adjunctive use of glucocorticoids showed some benefit in children with septic arthritis, they are not widely used in clinical practice. ■ ■GONOCOCCAL ARTHRITIS Epidemiology  In the past, gonococcal arthritis (Chap. 161) accounted for up to 70% of episodes of infectious arthritis in persons <40 years of age in the United States. As the rates of mucosal gonor­ rhea have fallen in the United States, it is likely that the proportion of septic arthritis caused by N. gonorrhoeae also has fallen considerably. Arthritis due to N. gonorrhoeae is a consequence of bacteremia arising from gonococcal infection or, more frequently, from asymptomatic gonococcal mucosal colonization of the urethra, cervix, or pharynx. Women are at greatest risk during menses and during pregnancy and overall are two to three times more likely than men to develop disseminated gonococcal infection (DGI) and arthritis. Persons with complement deficiencies, especially of the terminal components, are prone to recurrent episodes of gonococcemia. Eculizumab, which is a long-acting monoclonal antibody targeting the C5 complement com­ ponent and used mainly for the treatment of paroxysmal nocturnal hemoglobinuria, also has been reported to be associated with dissemi­ nated gonococcal infection. CHAPTER 135 Infectious Arthritis Clinical Manifestations and Laboratory Findings  The most common manifestation of DGI is a syndrome of arthritis-dermatitis. Patients present with fever, chills, rash, tenosynovitis, and articular symptoms. Small numbers of papules that progress to hemorrhagic pustules develop on the trunk and the extensor surfaces of the distal extremities. Migratory arthritis and tenosynovitis of the knees, hands, wrists, feet, and ankles are prominent. The cutaneous lesions and articular findings are believed to be the consequence of an immune reaction to circulating gonococci and immune-complex deposition in tissues. Thus, cultures of synovial fluid are consistently negative, and blood cultures are positive in <45% of patients. Synovial fluid may be difficult to obtain from inflamed joints and usually contains only 10,000–20,000 leukocytes/μL. True gonococcal septic arthritis is less common than the DGI syn­ drome and always follows DGI, which is unrecognized in one-third of patients. A single joint such as the hip, knee, ankle, or wrist is usually involved. Synovial fluid, which contains >50,000 leukocytes/μL, can be obtained with ease; the gonococcus is evident only occasionally in Gram-stained smears, and cultures of synovial fluid are positive in <40% of cases. Blood cultures are almost always negative. Because it is difficult to isolate gonococci from synovial fluid and blood, specimens for culture should be obtained from potentially infected mucosal sites. NAAT-based urine tests also may be positive. Culture requires endocervical (in female patients) or urethral (in male patients) swab specimens. Culture is available for detection of rectal, oropharyngeal, and conjunctival gonococcal infection. Cultures and Gram-stained smears of skin lesions are occasionally positive.

All specimens for culture should be plated onto Thayer-Martin agar directly or in special transport media at the bedside and transferred promptly to the microbiology laboratory in an atmosphere of 5% CO2. NAAT assays are extremely sensitive in detecting gonococcal DNA in synovial fluid, but they are not FDA approved for this purpose. A dramatic alleviation of symptoms within 12–24 h after the initiation of appropriate antibiotic therapy supports a clinical diagnosis of the DGI syndrome if cultures are negative.

TREATMENT Gonococcal Arthritis Initial treatment consists of ceftriaxone (1 g IV or IM every 24 h) to cover possible penicillin-resistant organisms. Once local and sys­ temic signs are clearly resolving, a 7-day course of antibiotics may be completed with daily IM ceftriaxone given at 500 mg daily (or 1g for those weighing over 150 kg). An oral fluoroquinolone such as ciprofloxacin (500 mg twice daily) may be used if the organism is known to be susceptible. If penicillin-susceptible organisms are isolated, amoxicillin (500 mg four times daily) may be used. Sup­ purative arthritis usually responds to needle aspiration of involved joints and 7–14 days of antibiotic treatment. Arthroscopic lavage or arthrotomy is rarely required. The Centers for Disease Control rec­ ommends that when chlamydial infection has not been excluded, treatment with PO doxycycline 100 mg twice daily for 7 days should be given. Sexual partners should be offered testing and presumptive treatment for gonorrhea and chlamydial infection. It is notewor­ thy that arthritis symptoms similar to those seen in DGI occur in meningococcemia. A dermatitis–arthritis syndrome, purulent monoarthritis, and reactive polyarthritis have been described. All respond to treatment with appropriate antibiotics. PART 5 Infectious Diseases SPIROCHETAL ARTHRITIS ■ ■LYME DISEASE Lyme disease (Chap. 191) due to infection with the spirochete Borrelia burgdorferi causes arthritis in up to 60% of persons who are not treated. Intermittent arthralgias and myalgias—but not arthritis—occur within days or weeks of inoculation of the spirochete by the Ixodes tick. Later, there are three patterns of joint disease: (1) Fifty percent of untreated persons experience intermittent episodes of monoarthritis or oligoar­ thritis involving the knee and/or other large joints. The symptoms wax and wane without treatment over months, and each year, 10–20% of patients report loss of joint symptoms. (2) Twenty percent of untreated persons develop a pattern of waxing and waning arthralgias. (3) Ten percent of untreated patients develop chronic inflammatory synovitis that results in erosive lesions and destruction of the joint. Serologic tests for IgG antibodies to B. burgdorferi are positive in >90% of per­ sons with Lyme arthritis, and a NAAT detects Borrelia DNA in synovial fluid in 85% of patients. TREATMENT Lyme Arthritis Lyme arthritis generally responds well to therapy. A regimen of oral doxycycline (100 mg twice daily for 28 days), oral amoxicillin (500 mg three times daily for 28 days), or parenteral ceftriax­ one (2 g/d for 2–4 weeks) is recommended. Patients who do not respond to a total of 2 months of oral therapy or 1 month of par­ enteral therapy are unlikely to benefit from additional antibiotic therapy and are treated with anti-inflammatory agents or synovec­ tomy. Failure of therapy is associated with host features such as the human leukocyte antigen DR4 (HLA-DR4) genotype, persistent reactivity to OspA (outer-surface protein A), and the presence of hLFA-1 (human leukocyte function–associated antigen 1), which cross-reacts with OspA.

■ ■SYPHILITIC ARTHRITIS Articular manifestations occur in different stages of syphilis (Chap. 187). In early congenital syphilis, periarticular swelling and immobilization of the involved limbs (Parrot’s pseudoparalysis) compli­ cate osteochondritis of long bones. Clutton’s joint, a late manifestation of congenital syphilis that typically develops between ages 8 and 15 years, is caused by chronic painless synovitis with effusions of large joints, particularly the knees and elbows. Secondary syphilis may be associated with arthralgias, with symmetric arthritis of the knees and ankles and occasionally of the shoulders and wrists, and with sacroi­ liitis. The arthritis follows a subacute to chronic course with a mixed mononuclear and neutrophilic synovial-fluid pleocytosis (typical cell counts, 5000–15,000/μL). Immunologic mechanisms may contribute to the arthritis, and symptoms usually improve rapidly with penicillin therapy. In tertiary syphilis, Charcot joint results from sensory loss due to tabes dorsalis. Penicillin is not helpful in this setting. MYCOBACTERIAL ARTHRITIS Tuberculous arthritis (Chap. 183) accounts for ~1% of all cases of tuberculosis and 10% of extrapulmonary cases. The most common presentation is chronic granulomatous monoarthritis. An unusual syndrome, Poncet’s disease, is a reactive symmetric form of polyar­ thritis that affects persons with visceral or disseminated tuberculosis. No mycobacteria are found in the joints, and symptoms resolve with antituberculous therapy. Unlike tuberculous osteomyelitis (Pott’s disease) (Chap. 136), which typically involves the thoracic and lumbar spine (50% of cases), tuber­ culous arthritis primarily involves the large weight-bearing joints, in particular the hips, knees, and ankles, and only occasionally involves smaller non-weight-bearing joints. Progressive monoarticular swelling and pain develop over months or years, and systemic symptoms are seen in only half of all cases. Tuberculous arthritis occurs as part of a disseminated primary infection or through late reactivation, often in persons with HIV infection or other immunocompromised hosts. Coexistent active pulmonary tuberculosis is unusual. Aspiration of the involved joint yields fluid with an average cell count of 20,000/μL, with ~50% neutrophils. Acid-fast staining of the fluid yields positive results in fewer than one-third of cases, and cul­ tures are positive in 80%. Culture of synovial tissue taken at biopsy is positive in ~90% of cases and shows granulomatous inflammation in most. NAAT can shorten the time to diagnosis to 1 or 2 days. Radio­ graphs reveal peripheral erosions at the points of synovial attachment, periarticular osteopenia, and eventually joint-space narrowing. Therapy for tuberculous arthritis is the same as that for tuberculous pulmonary dis­ ease, requiring the administration of multiple agents for 6–9 months. Therapy is more prolonged in immunosuppressed individuals, such as those infected with HIV. Various atypical mycobacteria (Chap. 185) found in water and soil may cause chronic indolent arthritis. Such disease results from trauma and direct inoculation associated with farming, gardening, or aquatic activities. Smaller joints, such as the digits, wrists, and knees, are usu­ ally involved. Involvement of tendon sheaths and bursae is typical. The mycobacterial species involved include Mycobacterium marinum, M. avium complex, M. terrae, M. kansasii, M. fortuitum, and M. chelonae. In persons who have HIV infection or are receiving immunosuppressive therapy, hematogenous spread to the joints has been reported for M. kansasii, M. avium complex, and M. haemophilum. Diagnosis usu­ ally requires biopsy and culture, and therapy is based on antimicrobial susceptibility patterns. FUNGAL ARTHRITIS Fungi are an unusual cause of chronic monoarticular arthritis. Granu­ lomatous articular infection with the endemic dimorphic fungi Coc­ cidioides immitis, Blastomyces dermatitidis, and (less commonly) Histoplasma capsulatum (Fig. 135-2) results from hematogenous seed­ ing or direct extension from bony lesions in persons with disseminated disease. Joint involvement is an unusual complication of sporotrichosis (infection with Sporothrix schenckii) among gardeners and other per­ sons who work with soil or sphagnum moss. Articular sporotrichosis

A B C FIGURE 135-2  Chronic arthritis caused by Histoplasma capsulatum in the left knee. A. A man in his sixties from El Salvador presented with a history of progressive knee pain and difficulty walking for several years. He had undergone arthroscopy for a meniscal tear 7 years before presentation (without relief) and had received several intraarticular glucocorticoid injections. The patient developed significant deformity of the knee over time, including a large effusion in the lateral aspect. B. An x-ray of the knee showed multiple abnormalities, including severe medial femorotibial joint-space narrowing, several large subchondral cysts within the tibia and the patellofemoral compartment, a large suprapatellar joint effusion, and a large soft tissue mass projecting laterally over the knee. C. MRI further defined these abnormalities and demonstrated the cystic nature of the lateral knee abnormality. Synovial biopsies demonstrated chronic inflammation with giant cells, and cultures grew H. capsulatum after 3 weeks of incubation. All clinical cystic lesions and the effusion resolved after 1 year of treatment with itraconazole. The patient underwent a left total-knee replacement for definitive treatment. (Courtesy of the late Francisco M. Marty, MD, Brigham and Women’s Hospital, Boston; with permission.) is six times more common among men than among women, and alco­ holics and other debilitated hosts are at risk for polyarticular infection. Candida infection involving a single joint—usually the knee, hip, or shoulder—results from surgical procedures, intraarticular injec­ tions, or (among critically ill patients with debilitating illnesses such as diabetes mellitus or hepatic or renal insufficiency and patients receiving immunosuppressive therapy) hematogenous spread. Candida infections in IV drug users typically involve the spine, sacroiliac joints, or other fibrocartilaginous joints. Unusual cases of arthritis due to Aspergillus species, Cryptococcus neoformans, Pseudallescheria boydii, and the dematiaceous fungi also have resulted from direct inoculation or disseminated hematogenous infection in immunocompromised persons. In the United States, a 2012 national outbreak of fungal arthri­ tis (and meningitis) caused by Exserohilum rostratum was linked to intraspinal and intraarticular injection of a contaminated preparation of methylprednisolone acetate. The synovial fluid in fungal arthritis usually contains 10,000–40,000 cells/μL, with ~70% neutrophils. Stained specimens and cultures of synovial tissue often confirm the diagnosis of fungal arthritis when studies of synovial fluid give negative results. Treatment consists of drainage and lavage of the joint and systemic administration of an anti­ fungal agent directed at a specific pathogen. The doses and duration of therapy are the same as for disseminated disease (see Part 5, Section 16). In fungal prosthetic joint infection, the removal of all prosthetic joint material is highly recommended. VIRAL ARTHRITIS Viruses produce arthritis by infecting synovial tissue during systemic infection or by provoking an immunologic reaction that involves joints. As many as 50% of women report persistent arthralgias and 10% report frank arthritis within 3 days of the rash that follows natural infection with rubella virus and within 2–6 weeks after receipt of live-virus vac­ cine. Episodes of symmetric inflammation of fingers, wrists, and knees uncommonly recur for >1 year, but a syndrome of chronic fatigue, low-grade fever, headaches, and myalgias can persist for months or years. IV immunoglobulin has been helpful in selected cases. Self-limited monoarticular or migratory polyarthritis may develop within 2 weeks of the parotitis of mumps; this sequela is more common among men than women. Approximately 10% of children and 60% of women develop polyarthritis or polyarthralgia in small joints after infection with parvovirus B19. In adults, arthropathy sometimes occurs without fever or rash. Pain and stiffness, with less prominent swelling (pri­ marily of the hands but also of the knees, wrists, and ankles), usually resolve within weeks, although a small proportion of patients develop chronic arthropathy.

About 2 weeks before the onset of jaundice, up to 10% of persons with acute hepatitis B develop an immune complex–mediated, serum sickness–like reaction with maculopapular rash, urticaria, fever, and arthralgias. Less common developments include symmetric arthritis involving the hands, wrists, elbows, or ankles and morning stiffness that resembles a flare of rheumatoid arthritis. Symptoms resolve at the time jaundice develops. Many persons with chronic hepatitis C infec­ tion report persistent arthralgia or arthritis, both in the presence and in the absence of cryoglobulinemia. CHAPTER 135 Painful arthritis often accompanies the fever and rash of several arthropod-borne viral infections, including those caused by Zika, chikungunya, O’nyong-nyong, Ross River, Mayaro, and Barmah For­ est viruses (Chap. 215). Symmetric arthritis involving the hands and wrists may occur during the convalescent phase of infection with lym­ phocytic choriomeningitis virus. Patients infected with an enterovirus frequently report arthralgias, and echovirus has been isolated from patients with acute polyarthritis. Infectious Arthritis Several arthritis syndromes are associated with HIV infection. An incomplete form of reactive arthritis with painful lower-extremity oligoarthritis may follow an episode of urethritis in HIV-infected per­ sons. HIV-associated reactive arthritis appears to be extremely com­ mon among persons with the HLA-B27 haplotype, but sacroiliac joint disease is unusual and is seen mostly in the absence of HLA-B27. Up to one-third of HIV-infected persons with psoriasis develop psoriatic arthritis. Painless monoarthropathy and persistent symmetric polyar­ thropathy occasionally complicate HIV infection. Chronic persistent oligoarthritis of the shoulders, wrists, hands, and knees occurs in women infected with human T-lymphotropic virus type 1. Synovial thickening, destruction of articular cartilage, and leukemic-appearing atypical lymphocytes in synovial fluid are characteristic, but progression to T cell leukemia is unusual. PARASITIC ARTHRITIS Arthritis due to parasitic infection is rare. The guinea worm Dra­ cunculus medinensis may cause destructive joint lesions in the lower extremities as migrating gravid female worms invade joints or cause ulcers in adjacent soft tissues that become secondarily infected. Hydatid cysts infect bones in 1–2% of cases of infection with Echi­ nococcus granulosus. The expanding destructive cystic lesions may spread to and destroy adjacent joints, particularly the hip and pelvis. In rare cases, chronic synovitis has been associated with the presence of schistosomal eggs in synovial biopsies. Monoarticular arthritis in children with lymphatic filariasis appears to respond to therapy with diethylcarbamazine even in the absence of microfilariae in synovial fluid. Reactive arthritis has been attributed to hookworm,

Strongyloides, Cryptosporidium, and Giardia infection in case reports, but confirmation is required.

POSTINFECTIOUS OR REACTIVE ARTHRITIS Reactive polyarthritis develops several weeks after ~1% of cases of non­ gonococcal urethritis and 2% of enteric infections, particularly those due to Yersinia enterocolitica, Shigella flexneri, Campylobacter jejuni, Clostridioides difficile, and Salmonella species. Only a minority of these patients have the other findings of classic reactive arthritis, including urethritis, conjunctivitis, uveitis, oral ulcers, and rash. Studies have identified microbial DNA or antigen in synovial fluid or blood, but the pathogenesis of this condition is poorly understood. The arthritis may occur several days or weeks after the infection and can be associ­ ated with dactylitis, enthesitis, or extraarticular involvement such as conjunctivitis. Reactive arthritis is most common among young men (except after Yersinia infection) and has been linked to the HLA-B27 locus as a potential genetic predisposing factor. Patients report painful, asym­ metric oligoarthritis that affects mainly the knees, ankles, and feet. Low back pain is common, and radiographic evidence of sacroiliitis is found in patients with long-standing disease. Most patients recover within 6 months, but prolonged recurrent disease is more common in cases that follow chlamydial urethritis. Anti-inflammatory agents help relieve symptoms, but the role of prolonged antibiotic therapy in elimi­ nating microbial antigen from the synovium is controversial. Migratory polyarthritis and fever constitute the usual presentation of acute rheumatic fever in adults (Chap. 371). This presentation is distinct from that of poststreptococcal reactive arthritis, which also follows infections with group A Streptococcus but is not migratory, lasts beyond the typical 3-week maximum of acute rheumatic fever, and responds poorly to aspirin. PART 5 Infectious Diseases INFECTIONS IN PROSTHETIC JOINTS Infection complicates 0.5–2% of total joint replacements. Prosthetic joint infection occurs more often in knee arthroplasty compared with hip arthroplasty. The majority of infections are acquired intraopera­ tively or immediately postoperatively as a result of wound breakdown or infection; less commonly, these joint infections develop later after joint replacement and are the result of hematogenous spread or direct inoculation. The presentation may be acute, with fever, pain, and local signs of inflammation, especially in infections due to S. aureus, pyogenic streptococci, and gram-negative bacilli. Alternatively, infec­ tion may persist for months or years without causing constitutional symptoms when less virulent organisms—such as coagulase-negative staphylococci, Cutibacterium (formerly Propionibacterium) species, enterococci, or diphtheroids—are involved. Such indolent infections usually are acquired during joint implantation and are discovered dur­ ing evaluation of chronic unexplained pain or after a radiograph shows loosening of the prosthesis; the erythrocyte sedimentation rate and C-reactive protein level are usually elevated in such cases. The diagnosis is best made by needle aspiration of the joint; acci­ dental introduction of organisms during aspiration must be avoided meticulously. Synovial fluid pleocytosis with a predominance of poly­ morphonuclear leukocytes is highly suggestive of infection, since other inflammatory processes uncommonly affect prosthetic joints. Culture and Gram’s stain usually yield the responsible pathogen. Sonication of explanted prosthetic material can improve the yield of culture, presum­ ably by breaking up bacterial biofilms on the surfaces of prostheses. Semiquantitative culture should be obtained since a low number of organisms can represent contaminants. Molecular diagnostic testing of synovial fluid, sonicate fluid, or periprosthetic tissue also may improve the yield when routine culture is negative; however, it is not always available in microbiology laboratories. Use of special media for unusual pathogens such as fungi, atypical mycobacteria, and Mycoplasma may be necessary if routine and anaerobic cultures are negative. Molecular diagnostic results should be interpreted cautiously since they may represent colonization rather than a true pathogen. Testing of synovial fluid for alpha-defensin, C-reactive protein, leukocyte esterase, and

calprotectin can be considered in challenging cases. These tests must be interpreted in the context of the synovial fluid leukocyte count and neutrophil percentage. TREATMENT Prosthetic Joint Infections Treatment includes surgery and high doses of parenteral antibiotics, which are given for 4–6 weeks because bone is usually involved. In most cases, the prosthesis must be removed and replaced to cure the infection. Implantation of a new prosthesis is best delayed for several weeks or months because relapses of infection occur most commonly within this time frame. In some cases, reimplantation is not possible, and the patient must manage without a joint, with a fused joint, or even with amputation. Cure of infection without removal of the prosthesis is occasionally possible in cases that are due to streptococci or pneumococci and that lack radiologic evidence of loosening of the prosthesis. In these cases, antibiotic therapy must be initiated within several days of the onset of infec­ tion, and the joint should be drained vigorously by open arthrotomy or arthroscopically, preferably with polyethylene liner exchange, to have a more successful outcome. In selected patients who prefer to avoid the high morbidity rate associated with joint removal and reimplantation, lifelong suppression of the infection with antibiot­ ics may be a reasonable goal. A high cure rate with retention of the prosthesis has been reported when the combination of oral rifampin and another antibiotic (e.g., a quinolone, an antistaphylococcal penicillin, or vancomycin) is given for 3–6 months to persons with staphylococcal prosthetic joint infection of short duration. This approach is based on the ability of rifampin to kill organisms adher­ ent to foreign material and in the stationary growth phase. ■ ■PREVENTION To avoid the disastrous consequences of infection, candidates for joint replacement should be selected with care. All modifiable risk factors should be identified and minimized preoperatively to improve the surgical outcome and prevent surgical site infection. Preoperative screening for S. aureus with decolonization should be considered. Rates of infection are particularly high among patients with rheumatoid arthritis, persons who have undergone previous surgery on the joint, and persons with medical conditions requiring immunosuppressive therapy. Perioperative antibiotic prophylaxis, usually with cefazolin, and measures to decrease intraoperative contamination, such as lami­ nar flow, have lowered the rates of perioperative infection to <1% in many centers. After implantation, measures should be taken to prevent or rapidly treat extraarticular infections that might give rise to hema­ togenous spread to the prosthesis. The effectiveness of prophylactic antibiotics for the prevention of hematogenous infection after dental procedures has not been demonstrated; in fact, viridans streptococci and other components of the oral flora are extremely unusual causes of prosthetic joint infection. Accordingly, the American Dental Associa­ tion and the American Academy of Orthopaedic Surgeons do not rec­ ommend antibiotic prophylaxis for most dental patients with total joint replacements and have stated that there is no convincing evidence to support its use. Similarly, guidelines issued by the American Urological Association and the American Academy of Orthopaedic Surgeons do not recommend the use of prophylactic antibiotics for most patients with prosthetic joints who are undergoing urologic procedures but state that prophylaxis should be considered in certain situations—e.g., for patients (especially immunocompromised patients) who are under­ going a procedure posing a relatively high risk of bacteremia (e.g., lithotripsy or surgery involving bowel segments). ■ ■FURTHER READING Bardin T: Gonococcal arthritis. Best Pract Res Clin Rheumatol 17:201, 2003. Beam E, Osmon D: Prosthetic joint infection update. Infect Dis Clin North Am 32:843, 2018.