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Infective and Reactive Arthritis
SECTION 2 Syndromes by Body System: Bone and Joints
43
Infective and Reactive Arthritis ARJUN GUPTA | ELIE F. BERBARI | JAMES M. STECKELBERG | DOUGLAS R. OSMON
KEY CONCEPTS • The incidence of infective arthritis, especially iatrogenic cases is increasing. • Underlying joint disease is the most important risk factor. • Staphylococcus aureus is the most common identified organism in infective arthritis. • Synovial fluid analysis for cell count and cultures establish the diagnosis of infective arthritis. • The presence of crystals in the synovial fluid does not exclude concomitant bacterial arthritis, as crystal arthropathy and infection may co-occur in the same joint. • Patients with culture-negative infective arthritis for whom there exists a high degree of suspicion for bacterial arthritis should be treated for bacterial arthritis. • 16S rRNA gene polymerase chain reaction (PCR) has emerged as a useful tool for identification of bacterial pathogens in culture-negative arthritis, particularly in patients pretreated with antibiotics. • Management consists of prompt drainage of the joint and prolonged antimicrobial therapy.
incidence rate of 2.8 per 100 000 person years, although incidence has decreased in recent decades.5
Risk Factors Rheumatoid arthritis, diabetes mellitus, malignancy, old age, use of systemic steroids, HIV infection, hemodialysis and prior joint surgery are risk factors for bacterial arthritis.6,7 Abnormal joint architecture is the most important risk. Biological agents that target tumor necrosis factor for the treatment of rheumatoid arthritis are associated with a doubling of the risk of septic arthritis over traditional diseasemodifying antirheumatic drugs (DMARDs) and can also cause severe polyarticular infections.8 Behaviors that increase the risk of bacteremia, such as injection drug use, also predispose the joint to infection. Iatrogenic infection is an increasing problem1 with a recent report of a multistate outbreak of fungal arthritis caused by intra-articular injections of contaminated methylprednisolone9 and several cases of infective arthritis due to Clostridium spp. arthritis reported after tissue allograft reconstruction surgery due to aseptic processing of donor tissue.10 Disseminated gonococcal infection is more common among sexually active, menstruating women.5 The male : female ratio is approximately 1 : 4. Often the microbiologic etiology of infective arthritis can be predicted based on the specific risk factor predisposing to infection (Table 43-1).11
Pathogenesis Introduction Infective arthritis is an inflammation of the joint space caused by microbial invasion. Hematogenous seeding of the joint is the most common mechanism of infection in native joints. The incidence of infective arthritis in adults caused by bacteria other than Neisseria gonorrhoeae is relatively low, but these infections can cause major morbidity as a result of pain, immobility and loss of joint function. Successful treatment requires prompt drainage of the joint and prolonged antimicrobial therapy. This chapter discusses infective arthritis in adults, with the major emphasis on bacterial infective arthritis. Viral and reactive arthritis are discussed briefly. Infective arthritis caused by Borrelia burgdorferi is discussed in Chapter 46, and mycobacterial arthritis in Chapters 31 and 32.
Bacterial Arthritis Epidemiology The incidence of bacterial arthritis is rising due in part to an aging, immunocompromised population and an increased use of invasive procedures.1 In 2005, according to the Centers for Disease Control and Prevention (CDC), there were an estimated 24 000 cases of pyogenic arthritis that required hospitalization in the USA, of which 33% were 65 years of age or older.2 The CDC estimates that the incidence of septic arthritis is 6 per 100 000 individuals per year.1 These data are in agreement with other published incidence rates of bacterial arthritis in the general population.3,4 Disseminated gonococcal infection with associated gonococcal infective arthritis is the leading cause of hospital admission due to infective arthritis in the USA, with an estimated
382
Nongonococcal bacterial arthritis most often results from hematogenous seeding of the joint space. Synovial tissue has a rich vascular supply but no basement membrane – factors that favor ingress of blood-borne organisms.12 The bacteremia can be primary, or secondary to an infectious focus elsewhere in the body (e.g. pneumonia, cellulitis). A focus of infection is identified in approximately 50% of cases. Direct inoculation of micro-organisms into the joint space due to trauma, arthrotomy, arthroscopy or diagnostic and therapeutic arthrocentesis is another mechanism of infection. The risk of septic arthritis after arthrocentesis has been reported to be 0.002–0.007%; after arthroscopy it is reported to be 0.04–0.4%.13 Infection of the joint space as a result of contiguous soft tissue infection or periarticular osteomyelitis is much less common. Bacterial adhesins play a crucial role in the establishment of infection, and differential expression of adhesins correlates with septic arthritis rates in murine models.14 Once bacteria enter the joint space, macrophage activation occurs in response to the release of bacterial products.14 Release of enzymes (e.g. gelatinases) results in hydrolysis of proteoglycans and collagen.15 Pressure necrosis of the cartilage can occur from joint effusion. If left untreated, destruction of the articular cartilage eventually occurs, leading to irreversible joint damage. Staphylococcus aureus is the most common etiologic agent of infective arthritis in adults (Table 43-2).12,16 Methicillin-resistant Staph. aureus (MRSA) has been identified as an increasing cause of septic arthritis in some communities.17 In young sexually active persons, N. gonorrhoeae is the predominant pathogen. Common skin organisms, such as coagulase-negative staphylococci, may cause infection following arthroscopy and intra-articular injections. Infective arthritis due to gram-negative bacilli is more common in the elderly patients with
Chapter 43 Infective and Reactive Arthritis
TABLE 43-1
383
Epidemiologic and Clinical Features Associated With Specific Etiologic Agents of Infective Arthritis
Likely Etiologic Agent
Clinical or Epidemiologic Setting
BACTERIA Staphylococcus aureus
Rheumatoid arthritis, injection drug use, arthroscopy, arthrotomy, polyarticular arthritis
Coagulase-negative staphylococci
Arthroscopy, arthrotomy, foreign material
Neisseria gonorrhoeae
Young, sexually active, history of sexually transmitted disease or unprotected sex, menstruation, pregnancy, multiple skin lesions
Pseudomonas aeruginosa and other aerobic gram-negative bacteria
Injection drug use, elderly
Anaerobes
Human and animal bites, orthopedic allograft infection with allograft without sporicidal sterilization, anaerobic infection elsewhere in body
Usual oral flora
Human and animal bites
Eikenella corrodens
Human bite
Pasteurella multocida
Cat or dog bite
Streptobacillus moniliformis
Rat bite
Neisseria meningitidis
Multiple purpuric lesions
OTHER Mycoplasma spp.
Common variable hypogammaglobulinemia, urogenital procedures
Borrelia burgdorferi
Resident in endemic area, known or suspected tick exposure, history of erythema chronicum migrans
Tropheryma whipplei
Other manifestations of Whipple’s disease
MYCOBACTERIA Mycobacterium tuberculosis
Positive tuberculin skin test, resident in country where disease is endemic, known exposure history
Mycobacterium marinum
Exposure to aquatic environment
Mycobacterium avium intracellulare
HIV, T-cell suppression
Mycobacterium leprae
Resident in country where disease is endemic
FUNGI Sporothrix schenckii
History of trauma with exposure to colonized soil (e.g. sphagnum moss)
Candida
Prior known or suspected candidemia or culture-negative central infection, neutropenia
Aspergillus
Prior known or suspected invasive Aspergillus infection, prolonged neutropenia
Blastomyces dermatitidis
Resident in area where disease is endemic, exposure to beaver dams
Coccidioides immitis
Resident in area where disease is endemic 11
Data from Smith & Piercy.
TABLE 43-2
co-morbid illnesses.18 Alcoholism may predispose to pneumococcal septic arthritis.19
Etiologic Agents of Nongonococcal Bacterial Arthritis in Adults
Micro-organisms
Cases (%)
Staphylococcus aureus
68
Streptococci (including β-hemolytic streptococci, viridans group streptococci and Streptococcus pneumoniae)
20
Haemophilus influenzae Aerobic gram-negative bacilli Polymicrobial and miscellaneous Unknown Data from Roberts & Mock.17
1 10 1 <1
Prevention Examples of efforts to decrease the incidence of infective arthritis include public health measures to prevent the acquisition of N. gonorrhoeae, prophylactic foot care in patients with diabetes mellitus and eradication of injection drug use. Vaccination campaigns against Haemophilus influenzae and Streptococcus pneumoniae have resulted in a decline in invasive infections caused by these pathogens.20 Eradication of the Staph. aureus carrier state with the use of topical mupirocin and chlorhexidine body washes might play a role in reducing the risk of infection prior to joint surgery.21 Rapid screening for Staph. aureus, and decolonization with mupirocin has been shown to be a cost effective and effective method to prevent Staph. aureus nosocomial infections after surgery, as long as the prevalence of mupirocin resistance is low.
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SECTION 2 Syndromes by Body System: Bone and Joints
Clinical Features NONGONOCOCCAL INFECTIVE ARTHRITIS Nongonococcal infective arthritis is typically monoarticular and has an acute presentation with symptoms usually present for less than 2 weeks. Patients complain of pain and limitation of motion in over 90% of cases.11 Fever is an inconsistent finding.7 Physical examination usually reveals a large effusion and a marked decrease in active and passive range of motion of the joint. These findings may be minimal or absent in those patients with rheumatoid arthritis, and they may be difficult to discern in hip or shoulder infections. The knee is the most commonly involved native joint in adults. Axial joint infection is more common among injection drug users. Polyarticular infection occurs in approximately 15% of patients, and is often due to Staph. aureus.22 It is more common among patients with rheumatoid arthritis and sepsis. The case fatality rate for patients with nongonococcal bacterial arthritis is estimated to be between 10% and 15%, and up to half of patients will have some degree of permanent loss of joint function.16,23 Morbidity and mortality are dependent on a number of factors, including age, rheumatoid arthritis, hip or shoulder infection, delay in therapy, polyarticular infection, persistently positive joint fluid cultures, bacteremia and the virulence of the infecting organism.3,24
GONOCOCCAL ARTHRITIS Initial gonococcal infection is often asymptomatic.25 Patients with disseminated gonococcal infection (DGI) commonly present early after dissemination with bacteremia, fever, polyarthralgia, tenosynovitis (typically of the hands and fingers) and multiple painless maculopapular, pustular, vesicular or necrotic skin lesions. Asymmetric joint involvement is common. The knee, elbow, wrist, metacarpophalangeal and ankle joints are the most commonly involved. This presentation has been described as the dermatitis–arthritis syndrome. If left untreated, the patient will present later with monoarticular arthritis, usually without tenosynovitis or skin lesions. The outcome of DGI is almost always satisfactory if adequate antimicrobial management is provided.25 In adults, the differential diagnosis of gonococcal arthritis includes gout, pseudogout, rheumatic fever, reactive arthritis and rheumatic illnesses such as rheumatoid arthritis. Gout and pseudogout are the most common noninfectious inflammatory arthritides that need to be differentiated.12 They should be suspected when there is a history of previous episodes, tophi and chondrocalcinosis on plain film. Synovial fluid analysis using polarized light microscopy is the most useful diagnostic test. Bacterial arthritis may coexist with crystal associated arthritis, and the presence of crystals does not rule out bacterial arthritis.26 The articular manifestations of rheumatic fever last for several weeks but do not cause permanent joint damage. Typically there is development of a migratory polyarthritis involving the knees, elbows, ankles and wrists that occurs within 1–5 weeks of the antecedent streptococcal pharyngitis. The diagnosis of rheumatic fever is dependent on satisfying the updated Jones criteria.27 Fungal and mycobacterial infection is usually monoarticular, but the presentation is usually over weeks to months. Diseases that must be distinguished from DGI include viral and reactive arthritis, rheumatic fever and secondary syphilis.
Diagnosis Although the history and physical examination can lead to a high index of suspicion for infection, a synovial fluid culture that yields a causative micro-organism is the only definitive method for diagnosing bacterial arthritis, although 16S rRNA gene PCR has emerged as a useful tool for identification of bacterial pathogens in culture-negative arthritis, particularly in patients pretreated with antibiotics. Molecular methods have been shown to have 100% specificity and positive predictive value (PPV) in diagnosing culture-negative bacterial infections.
Fever and rigors in the setting of an inflammatory arthritis have a low PPV for bacterial arthritis and have also been reported in crystalinduced arthropathy. The erythrocyte sedimentation rate (ESR), C-reactive protein and leukocyte counts are elevated in the majority of cases, although again the PPV of these tests in the setting of a monoarticular inflammatory arthritis is low. A rise in the ESR may help in the differential diagnosis of new joint pain and effusion in those patients who have rheumatoid arthritis.11 The role of serum and synovial procalcitonin levels in the diagnosis of bacterial arthritis remains undefined.28 Blood cultures are positive in up to 70% of all patients, and more often in patients who have polyarticular involvement.22 In DGI the majority of patients have an elevated ESR, and only 50% will have an abnormal leukocyte count.25 Neisseria gonorrhoeae can be detected in samples from the cervix, urethra, rectum, pharynx or urine in 80% of patients with DGI using culture or nucleic acid amplification tests (NAATs).29 The sensitivity of NAATs for the detection of N. gonorrhoeae in genital and nongenital anatomic sites is superior to culture.30 The diagnostic procedure of choice for bacterial arthritis is an arthrocentesis. This should be done immediately once the diagnosis of joint infection is suspected so as not to delay therapy. If synovial fluid cannot be obtained by blind needle aspiration, then aspiration should be done with the help of a radiologist. If necessary, an open arthrotomy should be performed. Synovial fluid is often cloudy or purulent in appearance. The synovial fluid should be routinely examined for uric acid and calcium pyrophosphate crystals, and a leukocyte count and differential should be obtained. The leukocyte count is usually greater than 50×109/L and often greater than 100×109/L, with more than 75% polymorphonuclear leukocytes. However, these findings can also be seen in patients who have inflammatory arthritis and crystal deposition arthritis. With increasing synovial fluid leukocyte count from >25–50–100×109/L, the likelihood ratio (LR) for bacterial arthritis increased from 2.9 to 7.7 to 28.7 Synovial fluid glucose and protein levels are less informative. The synovial fluid lactic acid and lactate dehydrogenase levels are often elevated, but this can be seen in other inflammatory joint disorders as well. The Gram stain is an important test, as it can provide an early guide to therapy. It is positive in 50–75% patients with nongonococcal bacterial arthritis.31 Synovial fluid should be cultured for both aerobes and anaerobes and other organisms, depending on the clinical circumstances. A study performed at the Mayo Clinic showed superior performance of the BACTEC Peds Plus/F bottle over the conventional agar plate method for the detection of clinically significant micro-organisms from synovial fluid specimens.32 The synovial fluid culture will be positive in 90% of cases of nongonococcal arthritis, assuming antibiotic therapy has not been started before sample collection.24 In patients with DGI, the synovial fluid cultures are positive in 25–30% of all patients and 50% of patients who present with monoarticular arthritis. If sufficient synovial fluid is obtained, an aliquot can be processed in an aerobic blood culture bottle similarly to routine blood cultures.33 This does not obviate Gram stain and solid agar culture of synovial fluid specimens. The role of nucleic acid amplification assays, including PCR, in detecting bacterial pathogens in patients who have infective arthritis is not yet well defined, although the technique seems to be a promising tool for the detection of infectious arthritis due to N. gonorrhoeae, Borrelia burgdorferi and Tropheryma whipplei. A recent study demonstrated rapid and accurate perioperative detection of Staphylococcus spp. in osteoarticular infections using real time PCR.34 No additional benefit of using PCR over culture in the diagnosis of joint infections has been established. The role of PCR in the diagnosis of bacterial arthritis is currently limited to identification of fastidious and slow growing organisms. Synovial tissue cultures are indicated only for chronic infective arthritis when mycobacterial or fungal arthritis is
Chapter 43 Infective and Reactive Arthritis
385
Figure 43-1 MRI scan of right knee of a patient who has Staphylococcus aureus septic arthritis. Note the soft tissue inflammation and a joint effusion.
suspected or when synovial fluid cultures cannot be obtained by less invasive techniques.
Radiology Plain radiographs are not usually helpful in making an initial diagnosis but are useful to identify concurrent osteomyelitis. Periarticular soft tissue swelling is the most common abnormality seen on plain radio graphy. Notably, the radiologic appearance of periarticular erosions and joint space narrowing typically takes weeks. It is often difficult to distinguish infection from inflammatory arthritis using radiographic methods in the setting of rheumatoid arthritis, but the development of a rapid destructive arthritis in one or two joints suggests infection. CT scans and MRI are more useful than plain radiographs for identifying concomitant periarticular osteomyelitis, soft tissue abscesses and joint effusions, but they are expensive and most often are not necessary (Figure 43-1).35
Management The keys to the management of infective arthritis are: • drainage of the purulent synovial fluid; • debridement of any concomitant periarticular osteomyelitis; and • administration of appropriate parenteral antimicrobial therapy. Patients with suspected bacterial arthritis in whom culture remains negative should be treated similarly to patients with bacterial arthritis. In one study, no significant difference in laboratory markers or clinical outcome was found between culture positive and culture-negative arthritis.36 Experimental models of septic arthritis suggest that early drainage and antimicrobial therapy prevent cartilage destruction. Local antimicrobial therapy may cause a chemical synovitis and is not advised.12 Joint immobilization and elevation is useful for symptomatic relief, but early active range of motion exercises are beneficial for ultimate functional outcome.
SYNOVIAL FLUID DRAINAGE The optimal method of drainage of an infected joint remains controversial, in part because no well-controlled randomized trials exist to guide therapy.37 Therapy of each patient should be individualized. Many adults with septic arthritis have been managed with repeated joint aspirations instead of surgical debridement.24 Patients with DGI rarely require repeat joint aspirations, arthroscopy or arthrotomy.25 The use of arthroscopy has expanded in recent years because of the improved ability to adequately visualize and drain purulent material.
DEBRIDEMENT Recommended indications for surgical debridement have included effusions that fail to resolve with 7 days of conservative therapy and
Figure 43-2 Intraoperative photograph of right knee of a patient who has Staphylococcus aureus septic arthritis. Note the damaged joint and dark brown, boggy and hyperemic synovium.
inability to adequately drain the infected joint by aspiration or arthroscopy, either because of location or loculations of pus (Figure 43-2).11,38
ANTIMICROBIAL THERAPY Antimicrobial therapy should be administered as soon as the diagnosis is suspected and synovial fluid cultures obtained. Any delay in the administration of antimicrobial therapy may result in significant cartilage loss. To date there are no randomized studies to help guide the clinician in the antimicrobial therapy of septic arthritis. Initial antimicrobial therapy should be based on the results of the Gram stain and the specific clinical and epidemiologic setting. If no micro-organisms are seen on the Gram stain, empiric therapy for Staph. aureus (including MRSA), streptococci and gonococci (in young sexually active adults) should be given. Vancomycin should be administered if the initial Gram stain shows gram-positive cocci or empirically if no organisms are seen on the Gram stain, in patients at high risk for MRSA infection and when methicillin resistance rates are high in the community. Most experts administer 2–4 weeks of intravenous antimicrobial therapy for the treatment of nongonococcal septic arthritis.39 In most cases this can be administered on an outpatient basis after an initial period of hospitalization. Suggested antimicrobials for specific pathogens causing infective arthritis are shown in Table 43-3. Oral antimicrobial therapy with an effective agent with excellent bioavailability, such as ciprofloxacin or linezolid, is also acceptable, particularly if compliance with oral therapy can be assured and risk of fluoroquinolone resistance in suspected pathogens, particularly N. gonorrhoeae, is considered low. The initial drug of choice for gonococcal septic arthritis is parenteral ceftriaxone (see Table 43-3).40,41
Viral Arthritis Arthritis is a common complication of infections with hepatitis B virus, erythrovirus B19 (formerly paravovirus B19), rubella and alphaviruses, and is relatively rare with mumps virus, enteroviruses, adenoviruses and herpesviruses.42 The mechanisms by which viruses cause arthritis include joint invasion during viremia, immune complex deposition, insertion of the viral genome into the host DNA promoting autoimmunity through an ‘altered self ’, and immune dysregulation.43-45 Typically, viral arthritis occurs during the prodromal stage of viral infection and is associated with a rash. Symmetric polyarticular involvement, including the small joints of the hands, is typical. No specific pattern of joint involvement is unique to a specific viral
386 TABLE 43-3
SECTION 2 Syndromes by Body System: Bone and Joints
Antibiotic Therapy of Infective Arthritis in Adults for Selected Bacterial Micro-organisms Micro-organisms
Antibiotic Therapy
Alternative Therapy
Methicillin-sensitive strains
Nafcillin or oxacillin 1.5–2.0 g iv q4h or Cefazolin (or other first-generation cephalosporins in equivalent dosages) 1–2 g iv q8h
Vancomycin 15 mg/kg iv q12h
Methicillin-resistant strains
Vancomycin 15 mg/kg iv q12h
Consult a specialist in infectious diseases Linezolid 600 mg iv/po q12h
Penicillin-sensitive streptococci or pneumococci
Aqueous crystalline penicillin G 20 × 106 U iv q24h either continuously or in six equally divided doses or Ceftriaxone 2 g iv or im q24h or Cefazolin 1 g iv q8h
Vancomycin 15 mg/kg iv q12h, not to exceed 2 g in 24h unless serum levels are monitored
Enterococci or streptococci with an MIC ≥0.5 µg/mL or nutritionally variant streptococci (all enterococci causing infection must be tested for antimicrobial susceptibility in order to select optimal therapy)
Aqueous crystalline penicillin G 20 × 106 U iv q24h either continuously or in six equally divided doses, plus gentamicin sulfate 1 mg/kg iv or im q8h or Ampicillin sodium 12 g iv q24h either continuously or in six equally divided doses
Vancomycin 15 mg/kg iv q12h, not to exceed 2 g in 24h unless serum levels are monitored
Neisseria gonorrhoeae
Ceftriaxone 1 g im or iv q24h for 24–48 h after clinical improvement followed by Cefixime 400 mg po q12h for 1 week or Ciprofloxacin 500 mg po q12h for 1 week or Ofloxacin 400 mg po q12h for 1 week
Ciprofloxacin 400 mg iv q12h for 24–48 h after clinical improvement or Ofloxacin 400 mg iv q12h for 24–48h after clinical improvement or Spectinomycin 2 g im q12h for 24–48 h after clinical improvement followed by Ciprofloxacin 500 mg po q12h for 1 week or Ofloxacin 400 mg po q12h for 1 week
Enterobacteriaceae
Ceftriaxone 2 g iv q24h or Cefepime 2 g iv q12 h or other β-lactam (based on in vitro susceptibility)
Levofloxacin 500 mg po q24h
Staphylococcus aureus
Pseudomonas aeruginosa, Enterobacter spp.
Recommendations are for patients with normal renal function, who are not allergic to the medication and are modified based on results of in vitro sensitivities.
etiology. Diagnosis is based on historic and clinical clues (Table 43-4) and diagnostic testing is specific for each individual virus, the details of which are discussed in the relevant chapters. There has been a re-emergence of arthritogenic arboviruses (Chikungunya virus, Ross River virus) in different parts of the world.46 Viral arthritis is usually self-limiting but may progress to a chronic arthropathy especially in Chikungunya where less than 40% of patients had full recovery of symptoms after 1 year follow-up.47 Treatment is directed at symptom relief with analgesics and is discussed in the chapters devoted to specific viruses. Prevention of viral arthritis is dependent on vaccination against the specific pathogen.
Reactive Arthritis (Reiter’s Syndrome) Reactive arthritis describes the acute onset of an inflammatory arthritis soon after an infection elsewhere in the body in which micro-organisms cannot be cultured from the synovial fluid. In some instances, organisms in an aberrant persistent state (for example, Chlamydia trachomatis) and enteric bacterial genetic material have been detected in the affected joints. Patients with reactive arthritis can develop extraarticular manifestations such as the classic triad of arthritis, urethritis and conjunctivitis. Many affected persons are HLA-B27-positive. Micro-organisms associated with reactive arthritis are detailed in Box 43-1.48 A study evaluating the risk of reactive arthritis following a large outbreak of E. coli O157:H7 and Campylobacter species found an incidence of arthritis of 17.6% and 21.7%, respectively, in patients who developed moderate or severe gastroenteritis symptoms.49
BOX 43-1 MICRO-ORGANISMS ASSOCIATED WITH REACTIVE ARTHRITIS Definite association • • • • • • •
Chlamydia trachomatis Shigella flexneri Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni.
Data from Hughes & Keat.48
Typically, reactive arthritis begins several weeks after an antecedent infection. The initial clinical presentation is usually asymmetric oligoarticular arthritis without prominent constitutional symptoms. The syndrome also occurs without any identifiable symptoms of infection, particularly in cases that follow sexually acquired acquisition of typical pathogens. Laboratory abnormalities are nonspecific and include mild elevations in the leukocyte count, ESR and C-reactive protein. Stool tests, urogenital swabs and serology can sometimes identify a preceding or concomitant infection with one of the pathogens that classically induce reactive arthritis. Arthrocentesis should be performed for diagnostic purposes to rule out bacterial arthritis. Reactive arthritis is normally a self-limited disease, but chronic arthritis and sacroiliitis can occur in up to 15–30% of patients.
Chapter 43 Infective and Reactive Arthritis
TABLE 43-4
387
Clinical or Epidemiologic Features of Infective Arthritis Caused by Selected Viruses
Viral Agent
Epidemiologic Features
Clinical Characteristics
Outcome
Rubella (including rubella vaccine)
No prior vaccination; 51–61% of rubella cases; 0–14% of patients receiving vaccination. Less common with new vaccine. Ratio of women : men – 9 : 1
Symmetric arthritis of the metacarpal and proximal phalangeal joints, wrist, elbow, ankle, knee; onset variable in relationship to rash. May mimic rheumatoid arthritis. Post vaccination disease less symptomatic
Spontaneous resolution in days to weeks but may be chronic or recur
Erythrovirus B19
60% of adult cases, females > males. Childcare providers or school teachers; unusual in children
Sudden severe polyarticular arthritis in small joints. May mimic rheumatoid arthritis
Spontaneous resolution most common. Chronic arthritis can occur
Hepatitis A
10–14% of cases of hepatitis A; typical risk factors for acquisition of hepatitis A
Often associated with rash
Resolves spontaneously
Hepatitis B
10–25% of cases of hepatitis B; typical risk factors for acquisition of hepatitis B
Severe arthritis of sudden onset, symmetric, polyarthritis involving hand and knee; morning stiffness is considerable; skin rash may be present including urticaria
May last 1–3 weeks. Typically resolves during the preicteric phase. Chronic arthritis may occur with chronic hepatitis B infection
Hepatitis C
Typical risk factors for acquisition of hepatitis C
Can occur with acute or chronic infection. Sudden onset; joint pain in hands, wrists and shoulders often greater than physical findings. May mimic rheumatoid arthritis. Distinct from cryoglobulinemia with hepatitis C
May resolve spontaneously. Has been reported to persist for months and recur
HIV
Typical HIV-associated risk factors. Approximately 8% of HIV infected patients affected
Most cases are monoarticular but monoarticular and polyarticular presentations occur. Distinct from Reiter’s syndrome or psoriatic arthritis which also occur in HIV-infected individuals. Occurs in multiple stages of HIV infection
Usually resolves in several weeks. May persist for months
May occur in epidemics. May be associated with rash. Constitutional symptoms may be present
Spontaneous resolution is typical. Chronic arthritis is unusual except with Chikungunya and Sindbis virus
Arthropod-borne Chikungunya
O’nyong-nyong Sindbis virus Ross River agent Barmah Forest virus
East Africa, India, South East Asia, Philippines East Africa Sweden, Finland, Russia Australia, New Zealand, New Guinea Australia
Data from Smith & Piercy,11 Siegel & Gall42 and Naides.43
Treatment is with anti-inflammatory agents. The role of antibacterial therapy is controversial. Randomized trials evaluating the efficacy of antimicrobials in patients with reactive arthritis have been limited by small numbers of patients. Recently a double blind placebo controlled trial showed that Chlamydia spp. (C. trachomatis and C. pneumoniae) PCR-positive patients given combination antibiotics for 6 months
fared much better than those given placebo.50 Prevention of infection is reliant on effective prevention and treatment of precipitating antecedent infections. References available online at expertconsult.com.
KEY REFERENCES Baron E.J., Miller J.M., Weinstein M.P., et al.: A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM) (a). Clin Infect Dis 2013; 57(4):485-488. Carter J.D., Espinoza L.R., Inman R.D., et al.: Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum 2010; 62(5):12981307. Centers for Disease Control and Prevention: CDC Grand Rounds: the growing threat of multidrug-resistant gonorrhea. MMWR Morb Mortal Wkly Rep 2013; 62(6): 103-106. Centers for Disease Control and Prevention: Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae – 2014. Recommendations and reports. MMWR Morb Mortal Wkly Rep 2014; 63(RR-02):1-19.
Coakley G., Mathews C., Field M., et al.: BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults. Rheumatology (Oxford) 2006; 45(8):1039-1041. Dubouix-Bourandy A., de Ladoucette A., Pietri V., et al.: Direct detection of Staphylococcus osteoarticular infections by use of Xpert MRSA/SA SSTI real-time PCR. J Clin Microbiol 2011; 49(12):4225-4230. Frazee B.W., Fee C., Lambert L.: How common is MRSA in adult septic arthritis? Ann Emerg Med 2009; 54(5): 695-700. Geirsson A.J., Statkevicius S., Vikingsson A.: Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008; 67(5):638-643. Gupta M.N., Sturrock R.D., Field M.: A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology (Oxford) 2001; 40(1):24-30. Margaretten M.E., Kohlwes J., Moore D., et al.: Does this adult patient have septic arthritis? JAMA 2007; 297(13): 1478-1488.
Phillips P.E.: Viral arthritis. Curr Opin Rheumatol 1997; 9(4):337-344. Smith J.W., Piercy E.A.: Infectious arthritis. Clin Infect Dis 1995; 20(2):225-230, quiz 31. Smith R.M., Schaefer M.K., Kainer M.A., et al.: Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med 2013; 369(17):15981609. Shmerling R.H., Delbanco T.L., Tosteson A.N., et al.: Synovial fluid tests. What should be ordered? JAMA 1990; 264(8):1009-1014. Uckay I., Tovmirzaeva L., Garbino J., et al.: Short parenteral antibiotic treatment for adult septic arthritis after successful drainage. Int J Infect Dis 2013; 17(3):e199-e205.
Chapter 43 Infective and Reactive Arthritis 387.e1
REFERENCES 1. Geirsson A.J., Statkevicius S., Vikingsson A.: Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008; 67(5):638-643. 2. DeFrances C.J., Cullen K.A., Kozak L.J.: National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat 13 2007; 165:1-209. 3. Cooper C., Cawley M.I.: Bacterial arthritis in an English health district: a 10 year review. Ann Rheum Dis 1986; 45(6):458-463. 4. Kaandorp C.J., Dinant H.J., van de Laar M.A., et al.: Incidence and sources of native and prosthetic joint infection: a community based prospective survey. Ann Rheum Dis 1997; 56(8):470-475. 5. Bleich A.T., Sheffield J.S., Wendel G.D. Jr, et al.: Disseminated gonococcal infection in women. Obstet Gynecol 2012; 119(3):597-602. 6. Kaandorp C.J., Van Schaardenburg D., Krijnen P., et al.: Risk factors for septic arthritis in patients with joint disease. A prospective study. Arthritis Rheum 1995; 38(12):1819-1825. 7. Margaretten M.E., Kohlwes J., Moore D., et al.: Does this adult patient have septic arthritis? JAMA 2007; 297(13):1478-1488. 8. Galloway J.B., Hyrich K.L., Mercer L.K., et al.: Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011; 70(10):1810-1814. 9. Smith R.M., Schaefer M.K., Kainer M.A., et al.: Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med 2013; 369(17):15981609. 10. From the Centers for Disease Control and Prevention: Update: allograft-associated bacterial infections–United States, 2002. JAMA 2002; 287(13):1642-1644. 11. Smith J.W., Piercy E.A.: Infectious arthritis. Clin Infect Dis 1995; 20(2):225-230, quiz 31. 12. Goldenberg D.L.: Septic arthritis. Lancet 1998; 351(9097):197-202. 13. Armstrong R.W., Bolding F., Joseph R.: Septic arthritis following arthroscopy: clinical syndromes and analysis of risk factors. Arthroscopy 1992; 8(2):213-223. 14. Shirtliff M.E., Mader J.T.: Acute septic arthritis. Clin Microbiol Rev 2002; 15(4):527-544. 15. Chu S.C., Yang S.F., Lue K.H., et al.: Clinical significance of gelatinases in septic arthritis of native and replaced knees. Clin Orthop Relat Res 2004; 427:179-183. 16. Morgan D.S., Fisher D., Merianos A., et al.: An 18 year clinical review of septic arthritis from tropical Australia. Epidemiol Infect 1996; 117(3):423-428. 17. Roberts N.J., Mock D.J.: Joint Infections. In: Reese R.E. BRF, ed. Joint infections: a practical approach to infectious diseases. Boston: Little, Brown; 1996. 18. Frazee B.W., Fee C., Lambert L.: How common is MRSA in adult septic arthritis? Ann Emerg Med 2009; 54(5):695-700.
19. McGuire N.M., Kauffman C.A.: Septic arthritis in the elderly. J Am Geriatr Soc 1985; 33(3):170-174. 20. Ross J.J., Saltzman C.L., Carling P., et al.: Pneumococcal septic arthritis: review of 190 cases. Clin Infect Dis 2003; 36(3):319-327. 21. Peltola H., Kallio M.J., Unkila-Kallio L.: Reduced incidence of septic arthritis in children by Haemophilus influenzae type-b vaccination. Implications for treatment. J Bone Joint Surg Br 1998; 80(3):471-473. 22. Larkin S.A., Murphy B.S.: Preoperative decolonization of methicillin-resistant Staphylococcus aureus. Orthopedics 2008; 31(1):37-41. 23. Dubost J.J., Fis I., Denis P., et al.: Polyarticular septic arthritis. Medicine (Baltimore) 1993; 72(5):296310. 24. Gupta M.N., Sturrock R.D., Field M.: A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology (Oxford) 2001; 40(1):24-30. 25. Goldenberg D.L., Reed J.I.: Bacterial arthritis. N Engl J Med 1985; 312(12):764-771. 26. Cucurull E., Espinoza L.R.: Gonococcal arthritis. Rheum Dis Clin North Am 1998; 24(2):305-322. 27. Papanicolas L.E., Hakendorf P., Gordon D.L.: Concomitant septic arthritis in crystal monoarthritis. J Rheumatol 2012; 39(1):157-160. 28. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA 1992; 268(15):2069-2073. 29. Shen C.J., Wu M.S., Lin K.H., et al.: The use of procalcitonin in the diagnosis of bone and joint infection: a systemic review and meta-analysis. Eur J Clin Microbiol Infect Dis 2013; 32(6):807-814. 30. O’Brien J.P., Goldenberg D.L., Rice P.A.: Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine (Baltimore) 1983; 62(6):395406. 31. Centers for Disease Control and Prevention: Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae – 2014. Recommendations and reports. MMWR Morb Mortal Wkly Rep 2014; 63(RR-02):1-19. 32. Shmerling R.H., Delbanco T.L., Tosteson A.N., et al.: Synovial fluid tests. What should be ordered? JAMA 1990; 264(8):1009-1014. 33. Hughes J.G., Vetter E.A., Patel R., et al.: Culture with BACTEC Peds Plus/F bottle compared with conventional methods for detection of bacteria in synovial fluid. J Clin Microbiol 2001; 39(12):4468-4471. 34. Baron E.J., Miller J.M., Weinstein M.P., et al.: A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM) (a). Clin Infect Dis 2013; 57(4):485-488.
35. Dubouix-Bourandy A., de Ladoucette A., Pietri V., et al.: Direct detection of Staphylococcus osteoarticular infections by use of Xpert MRSA/SA SSTI real-time PCR. J Clin Microbiol 2011; 49(12):4225-4230. 36. Coakley G., Mathews C., Field M., et al.: BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults. Rheumatology (Oxford) 2006; 45(8):1039-1041. 37. Gupta M.N., Sturrock R.D., Field M.: Prospective comparative study of patients with culture proven and high suspicion of adult onset septic arthritis. Ann Rheum Dis 2003; 62(4):327-331. 38. Mathews C.J., Kingsley G., Field M., et al.: Management of septic arthritis: a systematic review. Ann Rheum Dis 2007; 66(4):440-445. 39. Abdel M.P., Perry K.I., Morrey M.E., et al.: Arthroscopic management of native shoulder septic arthritis. J Shoulder Elbow Surg 2013; 22(3):418-421. 40. Uckay I., Tovmirzaeva L., Garbino J., et al.: Short parenteral antibiotic treatment for adult septic arthritis after successful drainage. Int J Infect Dis 2013; 17(3):e199-e205. 41. Centers for Disease Control and Prevention: CDC Grand Rounds: the growing threat of multidrugresistant gonorrhea. MMWR Morb Mortal Wkly Rep 2013; 62(6):103-106. 42. Siegel L.B., Gall E.P.: Viral infection as a cause of arthritis. Am Fam Physician 1996; 54(6):2009-2015. 43. Naides S.J.: Viral arthritis including HIV. Curr Opin Rheumatol 1995; 7(4):337-342. 44. Phillips P.E.: Viral arthritis. Curr Opin Rheumatol 1997; 9(4):337-344. 45. Schnitzer T.J., Penmetcha M.: Viral arthritis. Curr Opin Rheumatol 1996; 8(4):341-345. 46. Suhrbier A., Jaffar-Bandjee M.C., Gasque P.: Arthritogenic alphaviruses – an overview. Nat Rev Rheumatol 2012; 8(7):420-429. 47. Couturier E., Guillemin F., Mura M., et al.: Impaired quality of life after chikungunya virus infection: a 2-year follow-up study. Rheumatology (Oxford) 2012; 51(7):1315-1322. 48. Hughes R.A., Keat A.C.: Reiter’s syndrome and reactive arthritis: a current view. Semin Arthritis Rheum 1994; 24(3):190-210. 49. Garg A.X., Pope J.E., Thiessen-Philbrook H., et al.: Arthritis risk after acute bacterial gastroenteritis. Rheumatology (Oxford) 2008; 47(2):200-204. 50. Carter J.D., Espinoza L.R., Inman R.D., et al.: Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum 2010; 62(5):1298-1307.
43
Infective and Reactive Arthritis ARJUN GUPTA | ELIE F. BERBARI | JAMES M. STECKELBERG | DOUGLAS R. OSMON
KEY CONCEPTS • The incidence of infective arthritis, especially iatrogenic cases is increasing. • Underlying joint disease is the most important risk factor. • Staphylococcus aureus is the most common identified organism in infective arthritis. • Synovial fluid analysis for cell count and cultures establish the diagnosis of infective arthritis. • The presence of crystals in the synovial fluid does not exclude concomitant bacterial arthritis, as crystal arthropathy and infection may co-occur in the same joint. • Patients with culture-negative infective arthritis for whom there exists a high degree of suspicion for bacterial arthritis should be treated for bacterial arthritis. • 16S rRNA gene polymerase chain reaction (PCR) has emerged as a useful tool for identification of bacterial pathogens in culture-negative arthritis, particularly in patients pretreated with antibiotics. • Management consists of prompt drainage of the joint and prolonged antimicrobial therapy.
incidence rate of 2.8 per 100 000 person years, although incidence has decreased in recent decades.5
Risk Factors Rheumatoid arthritis, diabetes mellitus, malignancy, old age, use of systemic steroids, HIV infection, hemodialysis and prior joint surgery are risk factors for bacterial arthritis.6,7 Abnormal joint architecture is the most important risk. Biological agents that target tumor necrosis factor for the treatment of rheumatoid arthritis are associated with a doubling of the risk of septic arthritis over traditional diseasemodifying antirheumatic drugs (DMARDs) and can also cause severe polyarticular infections.8 Behaviors that increase the risk of bacteremia, such as injection drug use, also predispose the joint to infection. Iatrogenic infection is an increasing problem1 with a recent report of a multistate outbreak of fungal arthritis caused by intra-articular injections of contaminated methylprednisolone9 and several cases of infective arthritis due to Clostridium spp. arthritis reported after tissue allograft reconstruction surgery due to aseptic processing of donor tissue.10 Disseminated gonococcal infection is more common among sexually active, menstruating women.5 The male : female ratio is approximately 1 : 4. Often the microbiologic etiology of infective arthritis can be predicted based on the specific risk factor predisposing to infection (Table 43-1).11
Pathogenesis Introduction Infective arthritis is an inflammation of the joint space caused by microbial invasion. Hematogenous seeding of the joint is the most common mechanism of infection in native joints. The incidence of infective arthritis in adults caused by bacteria other than Neisseria gonorrhoeae is relatively low, but these infections can cause major morbidity as a result of pain, immobility and loss of joint function. Successful treatment requires prompt drainage of the joint and prolonged antimicrobial therapy. This chapter discusses infective arthritis in adults, with the major emphasis on bacterial infective arthritis. Viral and reactive arthritis are discussed briefly. Infective arthritis caused by Borrelia burgdorferi is discussed in Chapter 46, and mycobacterial arthritis in Chapters 31 and 32.
Bacterial Arthritis Epidemiology The incidence of bacterial arthritis is rising due in part to an aging, immunocompromised population and an increased use of invasive procedures.1 In 2005, according to the Centers for Disease Control and Prevention (CDC), there were an estimated 24 000 cases of pyogenic arthritis that required hospitalization in the USA, of which 33% were 65 years of age or older.2 The CDC estimates that the incidence of septic arthritis is 6 per 100 000 individuals per year.1 These data are in agreement with other published incidence rates of bacterial arthritis in the general population.3,4 Disseminated gonococcal infection with associated gonococcal infective arthritis is the leading cause of hospital admission due to infective arthritis in the USA, with an estimated
382
Nongonococcal bacterial arthritis most often results from hematogenous seeding of the joint space. Synovial tissue has a rich vascular supply but no basement membrane – factors that favor ingress of blood-borne organisms.12 The bacteremia can be primary, or secondary to an infectious focus elsewhere in the body (e.g. pneumonia, cellulitis). A focus of infection is identified in approximately 50% of cases. Direct inoculation of micro-organisms into the joint space due to trauma, arthrotomy, arthroscopy or diagnostic and therapeutic arthrocentesis is another mechanism of infection. The risk of septic arthritis after arthrocentesis has been reported to be 0.002–0.007%; after arthroscopy it is reported to be 0.04–0.4%.13 Infection of the joint space as a result of contiguous soft tissue infection or periarticular osteomyelitis is much less common. Bacterial adhesins play a crucial role in the establishment of infection, and differential expression of adhesins correlates with septic arthritis rates in murine models.14 Once bacteria enter the joint space, macrophage activation occurs in response to the release of bacterial products.14 Release of enzymes (e.g. gelatinases) results in hydrolysis of proteoglycans and collagen.15 Pressure necrosis of the cartilage can occur from joint effusion. If left untreated, destruction of the articular cartilage eventually occurs, leading to irreversible joint damage. Staphylococcus aureus is the most common etiologic agent of infective arthritis in adults (Table 43-2).12,16 Methicillin-resistant Staph. aureus (MRSA) has been identified as an increasing cause of septic arthritis in some communities.17 In young sexually active persons, N. gonorrhoeae is the predominant pathogen. Common skin organisms, such as coagulase-negative staphylococci, may cause infection following arthroscopy and intra-articular injections. Infective arthritis due to gram-negative bacilli is more common in the elderly patients with
Chapter 43 Infective and Reactive Arthritis
TABLE 43-1
383
Epidemiologic and Clinical Features Associated With Specific Etiologic Agents of Infective Arthritis
Likely Etiologic Agent
Clinical or Epidemiologic Setting
BACTERIA Staphylococcus aureus
Rheumatoid arthritis, injection drug use, arthroscopy, arthrotomy, polyarticular arthritis
Coagulase-negative staphylococci
Arthroscopy, arthrotomy, foreign material
Neisseria gonorrhoeae
Young, sexually active, history of sexually transmitted disease or unprotected sex, menstruation, pregnancy, multiple skin lesions
Pseudomonas aeruginosa and other aerobic gram-negative bacteria
Injection drug use, elderly
Anaerobes
Human and animal bites, orthopedic allograft infection with allograft without sporicidal sterilization, anaerobic infection elsewhere in body
Usual oral flora
Human and animal bites
Eikenella corrodens
Human bite
Pasteurella multocida
Cat or dog bite
Streptobacillus moniliformis
Rat bite
Neisseria meningitidis
Multiple purpuric lesions
OTHER Mycoplasma spp.
Common variable hypogammaglobulinemia, urogenital procedures
Borrelia burgdorferi
Resident in endemic area, known or suspected tick exposure, history of erythema chronicum migrans
Tropheryma whipplei
Other manifestations of Whipple’s disease
MYCOBACTERIA Mycobacterium tuberculosis
Positive tuberculin skin test, resident in country where disease is endemic, known exposure history
Mycobacterium marinum
Exposure to aquatic environment
Mycobacterium avium intracellulare
HIV, T-cell suppression
Mycobacterium leprae
Resident in country where disease is endemic
FUNGI Sporothrix schenckii
History of trauma with exposure to colonized soil (e.g. sphagnum moss)
Candida
Prior known or suspected candidemia or culture-negative central infection, neutropenia
Aspergillus
Prior known or suspected invasive Aspergillus infection, prolonged neutropenia
Blastomyces dermatitidis
Resident in area where disease is endemic, exposure to beaver dams
Coccidioides immitis
Resident in area where disease is endemic 11
Data from Smith & Piercy.
TABLE 43-2
co-morbid illnesses.18 Alcoholism may predispose to pneumococcal septic arthritis.19
Etiologic Agents of Nongonococcal Bacterial Arthritis in Adults
Micro-organisms
Cases (%)
Staphylococcus aureus
68
Streptococci (including β-hemolytic streptococci, viridans group streptococci and Streptococcus pneumoniae)
20
Haemophilus influenzae Aerobic gram-negative bacilli Polymicrobial and miscellaneous Unknown Data from Roberts & Mock.17
1 10 1 <1
Prevention Examples of efforts to decrease the incidence of infective arthritis include public health measures to prevent the acquisition of N. gonorrhoeae, prophylactic foot care in patients with diabetes mellitus and eradication of injection drug use. Vaccination campaigns against Haemophilus influenzae and Streptococcus pneumoniae have resulted in a decline in invasive infections caused by these pathogens.20 Eradication of the Staph. aureus carrier state with the use of topical mupirocin and chlorhexidine body washes might play a role in reducing the risk of infection prior to joint surgery.21 Rapid screening for Staph. aureus, and decolonization with mupirocin has been shown to be a cost effective and effective method to prevent Staph. aureus nosocomial infections after surgery, as long as the prevalence of mupirocin resistance is low.
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SECTION 2 Syndromes by Body System: Bone and Joints
Clinical Features NONGONOCOCCAL INFECTIVE ARTHRITIS Nongonococcal infective arthritis is typically monoarticular and has an acute presentation with symptoms usually present for less than 2 weeks. Patients complain of pain and limitation of motion in over 90% of cases.11 Fever is an inconsistent finding.7 Physical examination usually reveals a large effusion and a marked decrease in active and passive range of motion of the joint. These findings may be minimal or absent in those patients with rheumatoid arthritis, and they may be difficult to discern in hip or shoulder infections. The knee is the most commonly involved native joint in adults. Axial joint infection is more common among injection drug users. Polyarticular infection occurs in approximately 15% of patients, and is often due to Staph. aureus.22 It is more common among patients with rheumatoid arthritis and sepsis. The case fatality rate for patients with nongonococcal bacterial arthritis is estimated to be between 10% and 15%, and up to half of patients will have some degree of permanent loss of joint function.16,23 Morbidity and mortality are dependent on a number of factors, including age, rheumatoid arthritis, hip or shoulder infection, delay in therapy, polyarticular infection, persistently positive joint fluid cultures, bacteremia and the virulence of the infecting organism.3,24
GONOCOCCAL ARTHRITIS Initial gonococcal infection is often asymptomatic.25 Patients with disseminated gonococcal infection (DGI) commonly present early after dissemination with bacteremia, fever, polyarthralgia, tenosynovitis (typically of the hands and fingers) and multiple painless maculopapular, pustular, vesicular or necrotic skin lesions. Asymmetric joint involvement is common. The knee, elbow, wrist, metacarpophalangeal and ankle joints are the most commonly involved. This presentation has been described as the dermatitis–arthritis syndrome. If left untreated, the patient will present later with monoarticular arthritis, usually without tenosynovitis or skin lesions. The outcome of DGI is almost always satisfactory if adequate antimicrobial management is provided.25 In adults, the differential diagnosis of gonococcal arthritis includes gout, pseudogout, rheumatic fever, reactive arthritis and rheumatic illnesses such as rheumatoid arthritis. Gout and pseudogout are the most common noninfectious inflammatory arthritides that need to be differentiated.12 They should be suspected when there is a history of previous episodes, tophi and chondrocalcinosis on plain film. Synovial fluid analysis using polarized light microscopy is the most useful diagnostic test. Bacterial arthritis may coexist with crystal associated arthritis, and the presence of crystals does not rule out bacterial arthritis.26 The articular manifestations of rheumatic fever last for several weeks but do not cause permanent joint damage. Typically there is development of a migratory polyarthritis involving the knees, elbows, ankles and wrists that occurs within 1–5 weeks of the antecedent streptococcal pharyngitis. The diagnosis of rheumatic fever is dependent on satisfying the updated Jones criteria.27 Fungal and mycobacterial infection is usually monoarticular, but the presentation is usually over weeks to months. Diseases that must be distinguished from DGI include viral and reactive arthritis, rheumatic fever and secondary syphilis.
Diagnosis Although the history and physical examination can lead to a high index of suspicion for infection, a synovial fluid culture that yields a causative micro-organism is the only definitive method for diagnosing bacterial arthritis, although 16S rRNA gene PCR has emerged as a useful tool for identification of bacterial pathogens in culture-negative arthritis, particularly in patients pretreated with antibiotics. Molecular methods have been shown to have 100% specificity and positive predictive value (PPV) in diagnosing culture-negative bacterial infections.
Fever and rigors in the setting of an inflammatory arthritis have a low PPV for bacterial arthritis and have also been reported in crystalinduced arthropathy. The erythrocyte sedimentation rate (ESR), C-reactive protein and leukocyte counts are elevated in the majority of cases, although again the PPV of these tests in the setting of a monoarticular inflammatory arthritis is low. A rise in the ESR may help in the differential diagnosis of new joint pain and effusion in those patients who have rheumatoid arthritis.11 The role of serum and synovial procalcitonin levels in the diagnosis of bacterial arthritis remains undefined.28 Blood cultures are positive in up to 70% of all patients, and more often in patients who have polyarticular involvement.22 In DGI the majority of patients have an elevated ESR, and only 50% will have an abnormal leukocyte count.25 Neisseria gonorrhoeae can be detected in samples from the cervix, urethra, rectum, pharynx or urine in 80% of patients with DGI using culture or nucleic acid amplification tests (NAATs).29 The sensitivity of NAATs for the detection of N. gonorrhoeae in genital and nongenital anatomic sites is superior to culture.30 The diagnostic procedure of choice for bacterial arthritis is an arthrocentesis. This should be done immediately once the diagnosis of joint infection is suspected so as not to delay therapy. If synovial fluid cannot be obtained by blind needle aspiration, then aspiration should be done with the help of a radiologist. If necessary, an open arthrotomy should be performed. Synovial fluid is often cloudy or purulent in appearance. The synovial fluid should be routinely examined for uric acid and calcium pyrophosphate crystals, and a leukocyte count and differential should be obtained. The leukocyte count is usually greater than 50×109/L and often greater than 100×109/L, with more than 75% polymorphonuclear leukocytes. However, these findings can also be seen in patients who have inflammatory arthritis and crystal deposition arthritis. With increasing synovial fluid leukocyte count from >25–50–100×109/L, the likelihood ratio (LR) for bacterial arthritis increased from 2.9 to 7.7 to 28.7 Synovial fluid glucose and protein levels are less informative. The synovial fluid lactic acid and lactate dehydrogenase levels are often elevated, but this can be seen in other inflammatory joint disorders as well. The Gram stain is an important test, as it can provide an early guide to therapy. It is positive in 50–75% patients with nongonococcal bacterial arthritis.31 Synovial fluid should be cultured for both aerobes and anaerobes and other organisms, depending on the clinical circumstances. A study performed at the Mayo Clinic showed superior performance of the BACTEC Peds Plus/F bottle over the conventional agar plate method for the detection of clinically significant micro-organisms from synovial fluid specimens.32 The synovial fluid culture will be positive in 90% of cases of nongonococcal arthritis, assuming antibiotic therapy has not been started before sample collection.24 In patients with DGI, the synovial fluid cultures are positive in 25–30% of all patients and 50% of patients who present with monoarticular arthritis. If sufficient synovial fluid is obtained, an aliquot can be processed in an aerobic blood culture bottle similarly to routine blood cultures.33 This does not obviate Gram stain and solid agar culture of synovial fluid specimens. The role of nucleic acid amplification assays, including PCR, in detecting bacterial pathogens in patients who have infective arthritis is not yet well defined, although the technique seems to be a promising tool for the detection of infectious arthritis due to N. gonorrhoeae, Borrelia burgdorferi and Tropheryma whipplei. A recent study demonstrated rapid and accurate perioperative detection of Staphylococcus spp. in osteoarticular infections using real time PCR.34 No additional benefit of using PCR over culture in the diagnosis of joint infections has been established. The role of PCR in the diagnosis of bacterial arthritis is currently limited to identification of fastidious and slow growing organisms. Synovial tissue cultures are indicated only for chronic infective arthritis when mycobacterial or fungal arthritis is
Chapter 43 Infective and Reactive Arthritis
385
Figure 43-1 MRI scan of right knee of a patient who has Staphylococcus aureus septic arthritis. Note the soft tissue inflammation and a joint effusion.
suspected or when synovial fluid cultures cannot be obtained by less invasive techniques.
Radiology Plain radiographs are not usually helpful in making an initial diagnosis but are useful to identify concurrent osteomyelitis. Periarticular soft tissue swelling is the most common abnormality seen on plain radio graphy. Notably, the radiologic appearance of periarticular erosions and joint space narrowing typically takes weeks. It is often difficult to distinguish infection from inflammatory arthritis using radiographic methods in the setting of rheumatoid arthritis, but the development of a rapid destructive arthritis in one or two joints suggests infection. CT scans and MRI are more useful than plain radiographs for identifying concomitant periarticular osteomyelitis, soft tissue abscesses and joint effusions, but they are expensive and most often are not necessary (Figure 43-1).35
Management The keys to the management of infective arthritis are: • drainage of the purulent synovial fluid; • debridement of any concomitant periarticular osteomyelitis; and • administration of appropriate parenteral antimicrobial therapy. Patients with suspected bacterial arthritis in whom culture remains negative should be treated similarly to patients with bacterial arthritis. In one study, no significant difference in laboratory markers or clinical outcome was found between culture positive and culture-negative arthritis.36 Experimental models of septic arthritis suggest that early drainage and antimicrobial therapy prevent cartilage destruction. Local antimicrobial therapy may cause a chemical synovitis and is not advised.12 Joint immobilization and elevation is useful for symptomatic relief, but early active range of motion exercises are beneficial for ultimate functional outcome.
SYNOVIAL FLUID DRAINAGE The optimal method of drainage of an infected joint remains controversial, in part because no well-controlled randomized trials exist to guide therapy.37 Therapy of each patient should be individualized. Many adults with septic arthritis have been managed with repeated joint aspirations instead of surgical debridement.24 Patients with DGI rarely require repeat joint aspirations, arthroscopy or arthrotomy.25 The use of arthroscopy has expanded in recent years because of the improved ability to adequately visualize and drain purulent material.
DEBRIDEMENT Recommended indications for surgical debridement have included effusions that fail to resolve with 7 days of conservative therapy and
Figure 43-2 Intraoperative photograph of right knee of a patient who has Staphylococcus aureus septic arthritis. Note the damaged joint and dark brown, boggy and hyperemic synovium.
inability to adequately drain the infected joint by aspiration or arthroscopy, either because of location or loculations of pus (Figure 43-2).11,38
ANTIMICROBIAL THERAPY Antimicrobial therapy should be administered as soon as the diagnosis is suspected and synovial fluid cultures obtained. Any delay in the administration of antimicrobial therapy may result in significant cartilage loss. To date there are no randomized studies to help guide the clinician in the antimicrobial therapy of septic arthritis. Initial antimicrobial therapy should be based on the results of the Gram stain and the specific clinical and epidemiologic setting. If no micro-organisms are seen on the Gram stain, empiric therapy for Staph. aureus (including MRSA), streptococci and gonococci (in young sexually active adults) should be given. Vancomycin should be administered if the initial Gram stain shows gram-positive cocci or empirically if no organisms are seen on the Gram stain, in patients at high risk for MRSA infection and when methicillin resistance rates are high in the community. Most experts administer 2–4 weeks of intravenous antimicrobial therapy for the treatment of nongonococcal septic arthritis.39 In most cases this can be administered on an outpatient basis after an initial period of hospitalization. Suggested antimicrobials for specific pathogens causing infective arthritis are shown in Table 43-3. Oral antimicrobial therapy with an effective agent with excellent bioavailability, such as ciprofloxacin or linezolid, is also acceptable, particularly if compliance with oral therapy can be assured and risk of fluoroquinolone resistance in suspected pathogens, particularly N. gonorrhoeae, is considered low. The initial drug of choice for gonococcal septic arthritis is parenteral ceftriaxone (see Table 43-3).40,41
Viral Arthritis Arthritis is a common complication of infections with hepatitis B virus, erythrovirus B19 (formerly paravovirus B19), rubella and alphaviruses, and is relatively rare with mumps virus, enteroviruses, adenoviruses and herpesviruses.42 The mechanisms by which viruses cause arthritis include joint invasion during viremia, immune complex deposition, insertion of the viral genome into the host DNA promoting autoimmunity through an ‘altered self ’, and immune dysregulation.43-45 Typically, viral arthritis occurs during the prodromal stage of viral infection and is associated with a rash. Symmetric polyarticular involvement, including the small joints of the hands, is typical. No specific pattern of joint involvement is unique to a specific viral
386 TABLE 43-3
SECTION 2 Syndromes by Body System: Bone and Joints
Antibiotic Therapy of Infective Arthritis in Adults for Selected Bacterial Micro-organisms Micro-organisms
Antibiotic Therapy
Alternative Therapy
Methicillin-sensitive strains
Nafcillin or oxacillin 1.5–2.0 g iv q4h or Cefazolin (or other first-generation cephalosporins in equivalent dosages) 1–2 g iv q8h
Vancomycin 15 mg/kg iv q12h
Methicillin-resistant strains
Vancomycin 15 mg/kg iv q12h
Consult a specialist in infectious diseases Linezolid 600 mg iv/po q12h
Penicillin-sensitive streptococci or pneumococci
Aqueous crystalline penicillin G 20 × 106 U iv q24h either continuously or in six equally divided doses or Ceftriaxone 2 g iv or im q24h or Cefazolin 1 g iv q8h
Vancomycin 15 mg/kg iv q12h, not to exceed 2 g in 24h unless serum levels are monitored
Enterococci or streptococci with an MIC ≥0.5 µg/mL or nutritionally variant streptococci (all enterococci causing infection must be tested for antimicrobial susceptibility in order to select optimal therapy)
Aqueous crystalline penicillin G 20 × 106 U iv q24h either continuously or in six equally divided doses, plus gentamicin sulfate 1 mg/kg iv or im q8h or Ampicillin sodium 12 g iv q24h either continuously or in six equally divided doses
Vancomycin 15 mg/kg iv q12h, not to exceed 2 g in 24h unless serum levels are monitored
Neisseria gonorrhoeae
Ceftriaxone 1 g im or iv q24h for 24–48 h after clinical improvement followed by Cefixime 400 mg po q12h for 1 week or Ciprofloxacin 500 mg po q12h for 1 week or Ofloxacin 400 mg po q12h for 1 week
Ciprofloxacin 400 mg iv q12h for 24–48 h after clinical improvement or Ofloxacin 400 mg iv q12h for 24–48h after clinical improvement or Spectinomycin 2 g im q12h for 24–48 h after clinical improvement followed by Ciprofloxacin 500 mg po q12h for 1 week or Ofloxacin 400 mg po q12h for 1 week
Enterobacteriaceae
Ceftriaxone 2 g iv q24h or Cefepime 2 g iv q12 h or other β-lactam (based on in vitro susceptibility)
Levofloxacin 500 mg po q24h
Staphylococcus aureus
Pseudomonas aeruginosa, Enterobacter spp.
Recommendations are for patients with normal renal function, who are not allergic to the medication and are modified based on results of in vitro sensitivities.
etiology. Diagnosis is based on historic and clinical clues (Table 43-4) and diagnostic testing is specific for each individual virus, the details of which are discussed in the relevant chapters. There has been a re-emergence of arthritogenic arboviruses (Chikungunya virus, Ross River virus) in different parts of the world.46 Viral arthritis is usually self-limiting but may progress to a chronic arthropathy especially in Chikungunya where less than 40% of patients had full recovery of symptoms after 1 year follow-up.47 Treatment is directed at symptom relief with analgesics and is discussed in the chapters devoted to specific viruses. Prevention of viral arthritis is dependent on vaccination against the specific pathogen.
Reactive Arthritis (Reiter’s Syndrome) Reactive arthritis describes the acute onset of an inflammatory arthritis soon after an infection elsewhere in the body in which micro-organisms cannot be cultured from the synovial fluid. In some instances, organisms in an aberrant persistent state (for example, Chlamydia trachomatis) and enteric bacterial genetic material have been detected in the affected joints. Patients with reactive arthritis can develop extraarticular manifestations such as the classic triad of arthritis, urethritis and conjunctivitis. Many affected persons are HLA-B27-positive. Micro-organisms associated with reactive arthritis are detailed in Box 43-1.48 A study evaluating the risk of reactive arthritis following a large outbreak of E. coli O157:H7 and Campylobacter species found an incidence of arthritis of 17.6% and 21.7%, respectively, in patients who developed moderate or severe gastroenteritis symptoms.49
BOX 43-1 MICRO-ORGANISMS ASSOCIATED WITH REACTIVE ARTHRITIS Definite association • • • • • • •
Chlamydia trachomatis Shigella flexneri Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni.
Data from Hughes & Keat.48
Typically, reactive arthritis begins several weeks after an antecedent infection. The initial clinical presentation is usually asymmetric oligoarticular arthritis without prominent constitutional symptoms. The syndrome also occurs without any identifiable symptoms of infection, particularly in cases that follow sexually acquired acquisition of typical pathogens. Laboratory abnormalities are nonspecific and include mild elevations in the leukocyte count, ESR and C-reactive protein. Stool tests, urogenital swabs and serology can sometimes identify a preceding or concomitant infection with one of the pathogens that classically induce reactive arthritis. Arthrocentesis should be performed for diagnostic purposes to rule out bacterial arthritis. Reactive arthritis is normally a self-limited disease, but chronic arthritis and sacroiliitis can occur in up to 15–30% of patients.
Chapter 43 Infective and Reactive Arthritis
TABLE 43-4
387
Clinical or Epidemiologic Features of Infective Arthritis Caused by Selected Viruses
Viral Agent
Epidemiologic Features
Clinical Characteristics
Outcome
Rubella (including rubella vaccine)
No prior vaccination; 51–61% of rubella cases; 0–14% of patients receiving vaccination. Less common with new vaccine. Ratio of women : men – 9 : 1
Symmetric arthritis of the metacarpal and proximal phalangeal joints, wrist, elbow, ankle, knee; onset variable in relationship to rash. May mimic rheumatoid arthritis. Post vaccination disease less symptomatic
Spontaneous resolution in days to weeks but may be chronic or recur
Erythrovirus B19
60% of adult cases, females > males. Childcare providers or school teachers; unusual in children
Sudden severe polyarticular arthritis in small joints. May mimic rheumatoid arthritis
Spontaneous resolution most common. Chronic arthritis can occur
Hepatitis A
10–14% of cases of hepatitis A; typical risk factors for acquisition of hepatitis A
Often associated with rash
Resolves spontaneously
Hepatitis B
10–25% of cases of hepatitis B; typical risk factors for acquisition of hepatitis B
Severe arthritis of sudden onset, symmetric, polyarthritis involving hand and knee; morning stiffness is considerable; skin rash may be present including urticaria
May last 1–3 weeks. Typically resolves during the preicteric phase. Chronic arthritis may occur with chronic hepatitis B infection
Hepatitis C
Typical risk factors for acquisition of hepatitis C
Can occur with acute or chronic infection. Sudden onset; joint pain in hands, wrists and shoulders often greater than physical findings. May mimic rheumatoid arthritis. Distinct from cryoglobulinemia with hepatitis C
May resolve spontaneously. Has been reported to persist for months and recur
HIV
Typical HIV-associated risk factors. Approximately 8% of HIV infected patients affected
Most cases are monoarticular but monoarticular and polyarticular presentations occur. Distinct from Reiter’s syndrome or psoriatic arthritis which also occur in HIV-infected individuals. Occurs in multiple stages of HIV infection
Usually resolves in several weeks. May persist for months
May occur in epidemics. May be associated with rash. Constitutional symptoms may be present
Spontaneous resolution is typical. Chronic arthritis is unusual except with Chikungunya and Sindbis virus
Arthropod-borne Chikungunya
O’nyong-nyong Sindbis virus Ross River agent Barmah Forest virus
East Africa, India, South East Asia, Philippines East Africa Sweden, Finland, Russia Australia, New Zealand, New Guinea Australia
Data from Smith & Piercy,11 Siegel & Gall42 and Naides.43
Treatment is with anti-inflammatory agents. The role of antibacterial therapy is controversial. Randomized trials evaluating the efficacy of antimicrobials in patients with reactive arthritis have been limited by small numbers of patients. Recently a double blind placebo controlled trial showed that Chlamydia spp. (C. trachomatis and C. pneumoniae) PCR-positive patients given combination antibiotics for 6 months
fared much better than those given placebo.50 Prevention of infection is reliant on effective prevention and treatment of precipitating antecedent infections. References available online at expertconsult.com.
KEY REFERENCES Baron E.J., Miller J.M., Weinstein M.P., et al.: A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM) (a). Clin Infect Dis 2013; 57(4):485-488. Carter J.D., Espinoza L.R., Inman R.D., et al.: Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum 2010; 62(5):12981307. Centers for Disease Control and Prevention: CDC Grand Rounds: the growing threat of multidrug-resistant gonorrhea. MMWR Morb Mortal Wkly Rep 2013; 62(6): 103-106. Centers for Disease Control and Prevention: Recommendations for the laboratory-based detection of Chlamydia trachomatis and Neisseria gonorrhoeae – 2014. Recommendations and reports. MMWR Morb Mortal Wkly Rep 2014; 63(RR-02):1-19.
Coakley G., Mathews C., Field M., et al.: BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults. Rheumatology (Oxford) 2006; 45(8):1039-1041. Dubouix-Bourandy A., de Ladoucette A., Pietri V., et al.: Direct detection of Staphylococcus osteoarticular infections by use of Xpert MRSA/SA SSTI real-time PCR. J Clin Microbiol 2011; 49(12):4225-4230. Frazee B.W., Fee C., Lambert L.: How common is MRSA in adult septic arthritis? Ann Emerg Med 2009; 54(5): 695-700. Geirsson A.J., Statkevicius S., Vikingsson A.: Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008; 67(5):638-643. Gupta M.N., Sturrock R.D., Field M.: A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology (Oxford) 2001; 40(1):24-30. Margaretten M.E., Kohlwes J., Moore D., et al.: Does this adult patient have septic arthritis? JAMA 2007; 297(13): 1478-1488.
Phillips P.E.: Viral arthritis. Curr Opin Rheumatol 1997; 9(4):337-344. Smith J.W., Piercy E.A.: Infectious arthritis. Clin Infect Dis 1995; 20(2):225-230, quiz 31. Smith R.M., Schaefer M.K., Kainer M.A., et al.: Fungal infections associated with contaminated methylprednisolone injections. N Engl J Med 2013; 369(17):15981609. Shmerling R.H., Delbanco T.L., Tosteson A.N., et al.: Synovial fluid tests. What should be ordered? JAMA 1990; 264(8):1009-1014. Uckay I., Tovmirzaeva L., Garbino J., et al.: Short parenteral antibiotic treatment for adult septic arthritis after successful drainage. Int J Infect Dis 2013; 17(3):e199-e205.
Chapter 43 Infective and Reactive Arthritis 387.e1
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