Abstract
Bacteria, viruses, fungi, and parasites can all cause arthritis of either acute or chronic nature, which can be divided into infective/septic, reactive, or inflammatory. Considerable advances have occurred in diagnostic techniques in the recent decades resulting in better treatment outcomes in patients with infective arthritis. Detection of emerging arthritogenic viruses has changed the epidemiology of infection-related arthritis. The role of viruses in the pathogenesis of chronic inflammatory arthritides such as rheumatoid arthritis is increasingly being recognized. We discuss the various causative agents of infective arthritis and emphasize on the approach to each type of arthritis, highlighting the diagnostic tests, along with their statistical accuracy. Various investigations including newer methods such as nucleic acid amplification using polymerase chain reaction are discussed along with the pitfalls in interpreting the tests.
Introduction
The colonization of the human body by an enormous load of microbes has been the focus of several research initiatives over the past decade, with a steady influx of new insights into their association with autoimmunity . The possible role of external microorganisms – viruses, bacteria, fungi, and parasites – both in causation and in the triggering of inflammatory arthritis is complex, but it has been appreciated since the time of Hippocrates . The World Health Organization, in association with the Arthritis and Rheumatism Research Council, analyzed the connection between joints and infection critically in 1974, and they classified the relationship into the following four groups :
Group I : This group includes septic or infectious arthritis with the causative organism being identified in joints secondary to an infection elsewhere in the body.
Group II : This group comprises post-infectious arthritis with bacterial antigens being detected in the joint.
Group III : This group includes reactive arthritis (ReA) with the infection originating in the urogenital or gastrointestinal system causing inflammatory joint disease, but the microbe not being detected in the joint.
Group IV : This group consists of inflammatory arthritis triggered by microbes, where neither the organism nor its product or antigen is established in the joint.
The type of arthritis is generally determined by both microbial and host factors alike. Age, genetic susceptibility, gender of the individual, presence of comorbidities, and status of the joints are some of the critical host factors. Important microbial factors include virulence of the organism, ability of the organism to produce toxic substances, degradability of microbial products, and tissue tropism . Pyogenic bacteria and viruses are generally the perpetrators of acute infectious arthritis, while chronic arthritis is usually caused by mycobacteria and fungus. With new viruses emerging as etiologic agents in acute inflammatory arthritis, swiftly changing its epidemiology, and with advances in the field of molecular biology, genetics (whole exome sequencing), and immunological investigations, it is important to understand the relationship between microorganisms and joints.
This review focuses on the role of various etiological agents causing primary infective arthritis, their myriad clinical presentations, laboratory tests aiding in diagnosis, and the common pitfalls to be considered while interpreting the tests.
Determinants and mechanism of infection-related arthritis
Microbial factors
Staphylococcus aureus and Neisseria gonorrhoeae are bacteria with a strong predilection for joint cavities, adhering to the synovial tissue and producing toxins which promote colonization during the bacteremia phase . S. aureus has multiple receptors, termed as microbial surface components recognizing adhesive matrix molecules, which aid in adherence to joint extracellular matrix or implanted devices . Certain strains of S. aureus that are positive for cytotoxin virulence (Panton–Valentine leukocidin, PVL) survive in neutrophils, and they are associated with fulminant joint infections in healthy individuals . N. gonorrhoeae strains possess many cell surface structures that are responsible for their virulence. They express specific cell surface and extracellular proteins, which make them resistant to killing by factors in the serum . Microbes responsible for causing ReA are generally facultative or obligate intracellular pathogens in the gastrointestinal or genitourinary tract, capable of infecting stable mucosa.
Host factors
Systemic, local, and social host risk factors play a vital role in infectious arthritis. Normal joints, as compared with diseased or prosthetic joints, are resistant to infections. Certain factors in hosts increase the risk of bacteremia and weaken inherent defensive mechanisms. Age and gender of the patient are two important factors which determine the type of organism. Staphylococci are the most common agents of septic arthritis in adults . In children younger than 2 years, Haemophilus influenzae , S. aureus and group A streptococci are the common organisms . Of late, arthritis caused by Kingella kingae is on the rise in children . Women in their first week of menstrual cycle, pregnancy, puerperium and those with complement deficiencies (C5–C8) have a greater incidence of gonococcal arthritis . Genes, especially human leukocyte antigen (HLA) alleles, play a cardinal role in diseases such as spondyloarthritis and rheumatoid arthritis (RA). Intrauterine viral infections have been shown to predispose affected children to the development of juvenile idiopathic arthritis (JIA) . Local factors such as trauma, acupuncture procedures, intra-articular injections, joint surgeries, and arthroscopy are important factors for the development of infectious arthritis . Social factors that contribute to the risk include occupational exposure to animals (brucellosis), chronic alcoholism, intravenous drug abuse, and areas with increased risk of infections such as tuberculosis (TB) . Coexisting diseases such as diabetes, degenerative joint diseases, and RA also act as major host factors in causing septic arthritis . Table 1 summarizes the common host/risk factors for septic arthritis .
| Systemic factors | Degenerative joint disease Diabetes mellitus Rheumatoid arthritis Chronic renal failure Malignancies |
| Local factors | Direct joint trauma Recent joint surgery Open reduction of fractures Arthroscopy Prosthetic joint implants – knee or hip |
| Social factors | Occupational exposure to animals Low socioeconomic status Chronic alcohol abuse Intravenous drug abuse Promiscuous behavior related to STDs a |
| Other factors | Extremes of age Chronic hospitalization Use of biological agents Endemic areas for certain infections |
How do microbes reach the joint cavity?
Synovium is a highly vascular structure, containing no membrane barriers, providing a conducive environment for the seeding of bacteria. Hematogenous spread of bacteria from an infected wound over skin, an abscess, tooth infection, or disseminated systemic infection is the most common mode of entry into the joints . In the pediatric age group, spread of bacteria into the intracapsular region can occur following a break over the outer cortex of the bone . Capillaries running across the epiphyseal growth plate in infants aid in transmitting infection into the epiphysis and joint space. In adults, as the growth plate is resorbed, infection spreads laterally breaking through the cortex and lifting the periosteum, forming an abscess . Bacteremia from the gastrointestinal tract and the genitourinary tract gives rise to Gram-negative septic arthritis. Yersinia is transported within the immune complex, enterobacteria in macrophages, and Chlamydia bodies within polymorphonuclear leukocytes . Occasionally, microbial structures such as lipopolysaccharide are transported to the joints. Direct trauma including intra-articular injections, arthroscopies, and joint replacement surgeries can introduce microbes into the joints.
Etiological agents
Almost any organism can cause infection in the joints. Bacteria, viruses, parasites, and fungi can invade the joint cavity and result in various clinical presentations in different age groups. Viruses are known to trigger autoimmunity in genetically susceptible individuals leading to various connective tissue diseases such as RA, systemic lupus erythematosus (SLE), Sjögren’s syndrome, and antiphospholipid syndrome. Fungi, mycobacteria, parasites, and viruses cause chronic arthritis. Table 2 summarizes the common microbes causing arthritis in different patient groups, along with their sources .
| Patient group | Etiological agent | Sources |
|---|---|---|
| Adults | Gonococci Nongonococcal bacteria Staphylococcus aureus Streptococci Haemophilus influenzae Pseudomonas aeruginosa Kingella kingae Moraxella osloensis Arcanobacterium haemolyticum Mycoplasma hominis Mycobacterium marinum Shigella sp. Salmonella sp. Ureaplasma urealyticum | Gonococci – cervical, urethral, or pharyngeal infection with dissemination Nongonococcal – bacteremia, direct inoculation |
| Neonates | Group B streptococci Escherichia coli Staphylococcus aureus | Maternal–fetal transmission |
| Children (<3 years) | Streptococcus pyogenes Streptococcus pneumoniae Staphylococcus aureus | Bacteremia – skin infections, otitis media, meningitis |
| Adolescents | Staphylococcus aureus Neisseria gonorrhoeae Pseudomonas aeruginosa Kingella kingae | Bacteremia or contiguous spread |
| All age groups | Viruses Parvovirus B19 Hepatitis B or C Rubella Togavirus Chikungunya virus Varicella Mumps virus Adenovirus Coxsackie – A9, B2, B3, B4 Retroviruses – HIV Epstein–Barr virus O’nyong nyong Ross River Barmah Forest virus Ockelbo agent | Viremia or immune complex deposition |
| Tick exposure | Borrelia burgdorferi | Bacteremia |
| Bite wounds – dog, cat, rat, humans | Human – Eikenella corrodens , Staphylococcus aureus , group B streptococci, oral anaerobes Dog or cat – Staphylococcus aureus , Pasteurella multocida , Pseudomonas sp., Moraxella sp., Haemophilus sp. Rat – Staphylococcus aureus, Streptobacillus moniliformis , Spirillum minus | Direct penetration into joints |
| Elderly | Streptococci | Bacteremia |
| Concomitant diseases | Enterobacter Pseudomonas aeruginosa Serratia marcescens Salmonella sp. | |
| Immunocompromised Intra-articular injections Arthroscopy HIV associated | Mycobacterium tuberculosis Mycobacterium kansasii Mycobacterium marinum Mycobacterium avium-intracellulare complex Mycobacterium fortuitum Mycobacterium haemophilum Mycobacterium terrae Mycobacterium chelonae Nocardia asteroides Fungi Sporothrix schenckii Coccidioides immitis Blastomyces dermatitidis Paracoccidioides brasiliensis Candida albicans Pseudallescheria boydii |
How do these microbes damage the articular tissue?
Acute infectious arthritis can cause a great deal of damage to the joint cavity within a short span of time. One or more of the following mechanisms may be used:
- (a)
Direct invasion by microbes : Once infection sets in following bacterial seeding, there is rapid proliferation of the microbes to involve the entire synovium and synovial fluid. Phagocytosis of the microbe by macrophages, synoviocytes, and polymorphs results in the release of chemotactic factors and activation of complements, resulting in inflammation. Synovial blood vessels become dilated, synovial tissue becomes edematous, and intra-articular pressure increases, eventually causing synovial ischemia . This, along with the impairment of the host defense mechanisms, plays a major role in damage to the joint cavity and articular cartilage.
- (b)
Immune mediated inflammation : Antigen–antibody complexes produced as a result of immune response against microbes or their fragments (e.g., lipopolysaccharide cell wall of gonococci) can cause inflammation . In Lyme disease, the development of an immune response against the outer surface protein leads to chronic arthritis . In places endemic for parasitic infestation with Dracunculus medinensis , arthritis occurs following localization of the worm in joints or as a reaction to its presence in the tissue nearby .
- (c)
Autoimmunity : Molecular mimicry in the pathogenesis of spondyloarthritis – ReA and RA – has been recognized . Earlier experiments have shown evidence of molecular mimicry between the HLA-B27 allele and many microbes . Many of the viruses causing arthritis bring about damage through cytokines produced by transactivation of the host gene by the viral products. Immune tolerance is breached by molecular mimicry between the host and viral antigens, thus leading to autoimmune-mediated tissue injury .
Determinants and mechanism of infection-related arthritis
Microbial factors
Staphylococcus aureus and Neisseria gonorrhoeae are bacteria with a strong predilection for joint cavities, adhering to the synovial tissue and producing toxins which promote colonization during the bacteremia phase . S. aureus has multiple receptors, termed as microbial surface components recognizing adhesive matrix molecules, which aid in adherence to joint extracellular matrix or implanted devices . Certain strains of S. aureus that are positive for cytotoxin virulence (Panton–Valentine leukocidin, PVL) survive in neutrophils, and they are associated with fulminant joint infections in healthy individuals . N. gonorrhoeae strains possess many cell surface structures that are responsible for their virulence. They express specific cell surface and extracellular proteins, which make them resistant to killing by factors in the serum . Microbes responsible for causing ReA are generally facultative or obligate intracellular pathogens in the gastrointestinal or genitourinary tract, capable of infecting stable mucosa.
Host factors
Systemic, local, and social host risk factors play a vital role in infectious arthritis. Normal joints, as compared with diseased or prosthetic joints, are resistant to infections. Certain factors in hosts increase the risk of bacteremia and weaken inherent defensive mechanisms. Age and gender of the patient are two important factors which determine the type of organism. Staphylococci are the most common agents of septic arthritis in adults . In children younger than 2 years, Haemophilus influenzae , S. aureus and group A streptococci are the common organisms . Of late, arthritis caused by Kingella kingae is on the rise in children . Women in their first week of menstrual cycle, pregnancy, puerperium and those with complement deficiencies (C5–C8) have a greater incidence of gonococcal arthritis . Genes, especially human leukocyte antigen (HLA) alleles, play a cardinal role in diseases such as spondyloarthritis and rheumatoid arthritis (RA). Intrauterine viral infections have been shown to predispose affected children to the development of juvenile idiopathic arthritis (JIA) . Local factors such as trauma, acupuncture procedures, intra-articular injections, joint surgeries, and arthroscopy are important factors for the development of infectious arthritis . Social factors that contribute to the risk include occupational exposure to animals (brucellosis), chronic alcoholism, intravenous drug abuse, and areas with increased risk of infections such as tuberculosis (TB) . Coexisting diseases such as diabetes, degenerative joint diseases, and RA also act as major host factors in causing septic arthritis . Table 1 summarizes the common host/risk factors for septic arthritis .
| Systemic factors | Degenerative joint disease Diabetes mellitus Rheumatoid arthritis Chronic renal failure Malignancies |
| Local factors | Direct joint trauma Recent joint surgery Open reduction of fractures Arthroscopy Prosthetic joint implants – knee or hip |
| Social factors | Occupational exposure to animals Low socioeconomic status Chronic alcohol abuse Intravenous drug abuse Promiscuous behavior related to STDs a |
| Other factors | Extremes of age Chronic hospitalization Use of biological agents Endemic areas for certain infections |
How do microbes reach the joint cavity?
Synovium is a highly vascular structure, containing no membrane barriers, providing a conducive environment for the seeding of bacteria. Hematogenous spread of bacteria from an infected wound over skin, an abscess, tooth infection, or disseminated systemic infection is the most common mode of entry into the joints . In the pediatric age group, spread of bacteria into the intracapsular region can occur following a break over the outer cortex of the bone . Capillaries running across the epiphyseal growth plate in infants aid in transmitting infection into the epiphysis and joint space. In adults, as the growth plate is resorbed, infection spreads laterally breaking through the cortex and lifting the periosteum, forming an abscess . Bacteremia from the gastrointestinal tract and the genitourinary tract gives rise to Gram-negative septic arthritis. Yersinia is transported within the immune complex, enterobacteria in macrophages, and Chlamydia bodies within polymorphonuclear leukocytes . Occasionally, microbial structures such as lipopolysaccharide are transported to the joints. Direct trauma including intra-articular injections, arthroscopies, and joint replacement surgeries can introduce microbes into the joints.
Etiological agents
Almost any organism can cause infection in the joints. Bacteria, viruses, parasites, and fungi can invade the joint cavity and result in various clinical presentations in different age groups. Viruses are known to trigger autoimmunity in genetically susceptible individuals leading to various connective tissue diseases such as RA, systemic lupus erythematosus (SLE), Sjögren’s syndrome, and antiphospholipid syndrome. Fungi, mycobacteria, parasites, and viruses cause chronic arthritis. Table 2 summarizes the common microbes causing arthritis in different patient groups, along with their sources .
| Patient group | Etiological agent | Sources |
|---|---|---|
| Adults | Gonococci Nongonococcal bacteria Staphylococcus aureus Streptococci Haemophilus influenzae Pseudomonas aeruginosa Kingella kingae Moraxella osloensis Arcanobacterium haemolyticum Mycoplasma hominis Mycobacterium marinum Shigella sp. Salmonella sp. Ureaplasma urealyticum | Gonococci – cervical, urethral, or pharyngeal infection with dissemination Nongonococcal – bacteremia, direct inoculation |
| Neonates | Group B streptococci Escherichia coli Staphylococcus aureus | Maternal–fetal transmission |
| Children (<3 years) | Streptococcus pyogenes Streptococcus pneumoniae Staphylococcus aureus | Bacteremia – skin infections, otitis media, meningitis |
| Adolescents | Staphylococcus aureus Neisseria gonorrhoeae Pseudomonas aeruginosa Kingella kingae | Bacteremia or contiguous spread |
| All age groups | Viruses Parvovirus B19 Hepatitis B or C Rubella Togavirus Chikungunya virus Varicella Mumps virus Adenovirus Coxsackie – A9, B2, B3, B4 Retroviruses – HIV Epstein–Barr virus O’nyong nyong Ross River Barmah Forest virus Ockelbo agent | Viremia or immune complex deposition |
| Tick exposure | Borrelia burgdorferi | Bacteremia |
| Bite wounds – dog, cat, rat, humans | Human – Eikenella corrodens , Staphylococcus aureus , group B streptococci, oral anaerobes Dog or cat – Staphylococcus aureus , Pasteurella multocida , Pseudomonas sp., Moraxella sp., Haemophilus sp. Rat – Staphylococcus aureus, Streptobacillus moniliformis , Spirillum minus | Direct penetration into joints |
| Elderly | Streptococci | Bacteremia |
| Concomitant diseases | Enterobacter Pseudomonas aeruginosa Serratia marcescens Salmonella sp. | |
| Immunocompromised Intra-articular injections Arthroscopy HIV associated | Mycobacterium tuberculosis Mycobacterium kansasii Mycobacterium marinum Mycobacterium avium-intracellulare complex Mycobacterium fortuitum Mycobacterium haemophilum Mycobacterium terrae Mycobacterium chelonae Nocardia asteroides Fungi Sporothrix schenckii Coccidioides immitis Blastomyces dermatitidis Paracoccidioides brasiliensis Candida albicans Pseudallescheria boydii |
How do these microbes damage the articular tissue?
Acute infectious arthritis can cause a great deal of damage to the joint cavity within a short span of time. One or more of the following mechanisms may be used:
- (a)
Direct invasion by microbes : Once infection sets in following bacterial seeding, there is rapid proliferation of the microbes to involve the entire synovium and synovial fluid. Phagocytosis of the microbe by macrophages, synoviocytes, and polymorphs results in the release of chemotactic factors and activation of complements, resulting in inflammation. Synovial blood vessels become dilated, synovial tissue becomes edematous, and intra-articular pressure increases, eventually causing synovial ischemia . This, along with the impairment of the host defense mechanisms, plays a major role in damage to the joint cavity and articular cartilage.
- (b)
Immune mediated inflammation : Antigen–antibody complexes produced as a result of immune response against microbes or their fragments (e.g., lipopolysaccharide cell wall of gonococci) can cause inflammation . In Lyme disease, the development of an immune response against the outer surface protein leads to chronic arthritis . In places endemic for parasitic infestation with Dracunculus medinensis , arthritis occurs following localization of the worm in joints or as a reaction to its presence in the tissue nearby .
- (c)
Autoimmunity : Molecular mimicry in the pathogenesis of spondyloarthritis – ReA and RA – has been recognized . Earlier experiments have shown evidence of molecular mimicry between the HLA-B27 allele and many microbes . Many of the viruses causing arthritis bring about damage through cytokines produced by transactivation of the host gene by the viral products. Immune tolerance is breached by molecular mimicry between the host and viral antigens, thus leading to autoimmune-mediated tissue injury .
Septic or infectious arthritis
Epidemiology
Data on septic arthritis are mostly from retrospective cohorts, and most of the case definitions include only the bacteriologically proven ones. The modified Newman criteria, which are generally used to define cases, require one of the four points to be fulfilled: (a) isolation of pathogenic organism from an affected joint; (b) isolation of a pathogenic organism from another source – blood or body fluids, in the background of a joint suspicious of sepsis; (c) typical clinical features and turbid synovial fluid in the presence of previous antibiotic therapy; and (d) postmortem or pathological features suspicious of septic arthritis .
Septic arthritis is reckoned to be one of the few emergencies in rheumatology. The incidence of septic arthritis in Europe has been described to be between four and 10 per 100,000 person-years in the general population and up to 30–100 per 100,000 person-years among patients with RA, those with prosthetic joints, the elderly, and immunocompromised individuals . Increasing antimicrobial resistance, aging population, use of invasive procedures, and immunosuppressed patients are major reasons for a rise in the incidence of septic arthritis in recent years . Hematogenous spread into the joint cavity following bacteremia is the most common mode of spread in septic arthritis. In adults, septic arthritis is broadly divided into gonococcal arthritis and nongonococcal arthritis.
Involvement of joints is generally monoarticular in close to 75% of patients . However, polyarticular involvement is not very uncommon and the prevalence has been rising in recent years, specifically in the presence of the risk factors discussed earlier . Recent-onset fever with local pain, warmth, swelling, and decreased range of movement in a large joint, in the presence of a risk factor, should sharply raise the suspicion level of septic arthritis. Disseminated gonococcal infection typically presents as migratory, asymmetric arthralgia predominantly affecting the wrists, knees, and ankles; moderate fever with chills; dermatitis; and asymmetric tenosynovitis affecting the wrists, ankles, and small joints leading to dactylitis, with a female preponderance . Gonococcal arthritis can also present as an asymmetric polyarticular or monoarticular disease . Table 3 summarizes the salient differences between gonococcal and nongonococcal arthritis. The Kocher criteria (difficulty in tolerating body weight, fever over 38.5 °C, erythrocyte sedimentation rate (ESR) > 40 mm/h, and leukocytosis > 12,000/cu mm) were used to differentiate septic arthritis from other causes of synovitis .
| Characteristics | Gonococcal | Nongonococcal |
|---|---|---|
| Patients | Predominantly women Sexually active adults | Newborns Elderly adults Adults with concomitant medical conditions – diabetes, rheumatoid arthritis, osteoarthritis |
| Presentation | Migratory polyarthritis Monoarthritis (rare) Asymmetric tenosynovitis Dermatitis | Monoarthritis |
| Culture positivity | Less than 50% | Nearly 90% |
| Prognosis | Good | Bad |
Anaerobes can also be etiological agents in 5–7% of septic arthritis. The usual organisms in this group include Bacteroides , Propionibacterium acnes , and anaerobic Gram-positive cocci. This is frequently found in patients with wound infections, those with joint arthroplasties, and in immunosuppressed hosts .
Investigations in the diagnosis of septic arthritis
A combination of clinical, laboratory, and imaging studies increases the specificity of the diagnosis of septic arthritis. Visualizing the causative organism on a Gram-stain smear or by culturing the microbe from the synovial fluid remains the gold standard of diagnosis.
Nongonococcal arthritis
Laboratory investigations: blood
Peripheral leukocyte counts may be elevated in adult patients. Li et al. have reported a sensitivity of 75% and a specificity of 55% for leukocytosis over 11,000/cu mm in the diagnosis of septic arthritis . Acute inflammatory markers – and C-reactive protein (CRP) – are generally elevated. CRP has been shown to be more useful than ESR in septic arthritis . However, no cutoff of inflammatory markers significantly changes the posttest probability of septic arthritis . Recent studies have shown increased sensitivity of serum procalcitonin in diagnosing acute bacterial arthritis, when used in the correct clinical setting . Blood cultures have low sensitivity, and they are positive only in 50% of cases . The neutrophil marker CD64 has been shown to be very useful in differentiating septic arthritis in patients with RA, with a sensitivity of 76% and a specificity of 94.4% . Highly sensitive molecular techniques such as mass spectroscopy and multiplex polymerase chain reaction can aid in faster diagnosis of septic arthritis .
Laboratory investigations: synovial fluid
Gross examination of the synovial fluid by a rheumatologist has been shown to have 94% sensitivity and 58% specificity for differentiating between inflammatory and noninflammatory conditions causing acute arthritis . Table 4 summarizes the sensitivity, specificity, and positive and negative likelihood ratios (LRs) of the various synovial fluid analyses. Analysis of the protein, glucose, and lactate dehydrogenase levels in synovial fluid is not very useful. Cytokine assays including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-1β have been experimentally performed to differentiate septic arthritis from other inflammatory arthritis, with high sensitivity but low specificity . However, these tests are not readily available to clinicians; hence, they cannot be recommended for routine practice. Polymerase chain reaction (PCR) pathogen-specific probes and Gram stains have been attempted in synovial fluid analysis. Yang et al. used a pathogen-specific probe for this purpose with a positive LR 31.7 (95% confidence interval (CI) 14.3–45.3) and a negative LR 0.05 (95% CI 0.009–0.189) . Yusuf et al. have proposed microcalorimetry of synovial fluid as a potential test, which detects organisms by their heat production and can be used to differentiate septic arthritis from other causes of arthritis .
| Tests | Source | Sensitivity | Specificity | Positive LR (95% CI) | Negative LR (95% CI) |
|---|---|---|---|---|---|
| Leucocytes > 50,000/cu mm | Shmerling et al. (1990) | 63 | 97 | 19.0 (6.0–62.0) | 0.38 (0.23–0.63) |
| Soderquist et al. (1998) | 58 | 74 | 2.2 (1.1–4.4) | 0.57 (0.36–0.90) | |
| Li et al. (2007) | 50 | 88 | 4.0 | 0.57 | |
| Leucocytes > 100,000/cu mm | Shmerling et al. | 19 | 100 | 37.0 (2.0–687.0) | 0.81 (0.68–0.97) |
| Soderquist et al. (1998) | 30 | 93 | 4.7 (1.1–20.0) | 0.75 (0.59–0.96) | |
| Li et al. (2004) | 31 | N/A | N/A | N/A | |
| Low glucose | Shmerling et al. (1990) | 44 | 85 | 2.9 (1.5–5.6) | 0.66 (0.46–0.94) |
| Soderquist et al. (1998) | 64 | 85 | 4.2 (1.4–13.0) | 0.43 (0.24–0.78) | |
| Protein > 3 g/dL | Shmerling et al. (1990) | 48 | 46 | 0.89 (0.55–1.40) | 1.10 (0.68–1.80) |
| LDH > 250 U/L | Shmerling et al. (1990) | 100 | 50 | 1.9 (1.5–2.5) | 0.09 (0.01–1.40) |
| Polymorphonuclear cells ≥ 90% | Shmerling et al. (1990) | 57 | 68 | 1.8 (1.0–3.0) | 0.63 (0.39–1.00) |
| Soderquist et al. (1998) | 92 | 78 | 4.2 (3.3–5.3) | 0.10 (0.04–0.26) |
Synovial fluid white blood cell (WBC) analysis is an easily reproducible and reliable test, which can be recommended in routine practice, to augment the clinical assessment. A meta-analysis by Carpenter et al. has summarized a positive LR of 4.7 (95% CI, 2.5–8.5) and 13.2 (95% CI, 3.6–51.1) for a synovial WBC count of >50,000/cu mm or >100,000/cu mm, respectively . The posttest probability of septic arthritis increases to 64% and 83% from a pretest probability of 27%, if the synovial fluid WBC count is >50,000/cu mm, but <100,000/cu mm and >100,000/cu mm, respectively .
Imaging studies
Imaging should always be used in conjunction with the overall clinical assessment. Soft-tissue involvement including distension of the joint capsule, “fat pad” sign, and widening of the joint space due to localized effusion may be seen in plain radiographs . Advanced imaging techniques aiding early detection and aggressive therapy from the beginning have shown better outcomes in inflammatory arthritides. Musculoskeletal ultrasound (MSUS) is a noninvasive, inexpensive, dynamic, operator-dependent tool that detects early joint effusions and tenosynovitis. Non-echo-free effusions are characteristic of septic arthritis. MSUS has already found a niche in routine clinical practice among rheumatologists. As compared with radiography and computed tomography (CT), magnetic resonance imaging (MRI) has greater resolution for soft-tissue abnormalities. Its spatial resolution helps in better visualization of joints, and it is being used to a great extent in the diagnosis of septic arthritis. The disadvantages of patient discomfort, high costs, and lack of universal availability are shrinking steadily with the introduction of office extremity MRIs with dedicated coils . Radionuclide scans are helpful in detecting localized areas of inflammation. The radiopharmaceuticals 67 Ga citrate and 111 In chloride can attach to serum proteins leaking from the blood stream into areas of inflammation. Although these scans are sensitive and specific in assessing active infection, the details of bone and joint are not well depicted. Three-phase 99m Tc methyldiphosphonate scans can differentiate the details of bone and joints to a good extent .
Gonococcal arthritis
Peripheral leukocytosis and elevated inflammatory markers are present in more than half of these patients. Culture for N. gonorrhoeae is often negative in skin lesions, less than one-third in blood cultures, and <50% in synovial fluid. Gram stains are even less sensitive . However, the organism can be easily cultured from the genitourinary tract, with high yield. Blood and synovial fluid samples for detecting the organism should be plated on preheated chocolate agar, and secretions from the genitourinary tract, pharynx and rectum should be cultured on prewarmed Thayer–Martin or modified New York medium with suitable antibiotic supplementation . In culture-negative cases of suspected gonococcal arthritis, Polymerase chain reaction (PCR) techniques can be useful in detecting gonococcal DNA in synovial fluid, with a specificity and sensitivity of 96.4% and 78.6%, respectively . Lack of standardization, poor availability, and lack of information regarding antibiotic sensitivity have been the major limitations for this technique not finding its place in routine clinical practice.
Pitfalls in the investigation of septic arthritis
All investigations in septic arthritis should be interpreted only in conjunction with the clinical assessment in each patient. It is important to have a good understanding of the pitfalls before interpreting the test reports.
Laboratory investigations: Blood
None of the studies investigating the sensitivity and specificity of leukocytosis have reported an overall diagnostic accuracy of peripheral WBC count in diagnosing septic arthritis, as peripheral WBC count can be affected by numerous factors.
Elevated inflammatory markers should be interpreted with caution. Many factors such as concomitant disease, increased globulin proteins, age, obesity, pregnancy, and heparinized blood can elevate the ESR, and increased plasma viscosity, abnormal red cell shape, and decreased plasma proteins can falsely lower the ESR levels . Pregnancy, trauma, obesity, and malignancies can falsely elevate CRP levels as well. The posttest probability of septic arthritis does not change significantly with any cutoff for ESR or CRP in the diagnosis of septic arthritis.
The sensitivity of blood cultures ranges from 23% to 36% in various studies . A negative culture needs to be followed up further by more sensitive tests in the background of a strong suspicion of septic arthritis.
Laboratory investigations: Synovial fluid
Artifacts such as glove powder and debris need to be considered during synovial fluid microscopy. Septic arthritis can also coexist with crystal arthropathy. Synovial glucose and protein levels do not significantly change the posttest probability of septic arthritis. The sensitivity of Gram staining of synovial fluid for the diagnosis of septic arthritis is low (50–69%), and it varies with the pathogenic organism. Gram-stain microscopy of the synovial fluid has been reported to have a false-negative rate of 25–50% . Prior use of antibiotics can give false-negative results. Freemont et al. estimated 30–80% of the synovial fluid cultures to be false negative . PCR techniques are highly sensitive and need to be interpreted carefully for false positives.
Imaging
Bone marrow edema in MRI, considered an early sign of infection, needs to be interpreted with caution, keeping in mind other causes such as trauma, inflammatory arthritis, and volume acquisition, which can also beget similar findings. Ultrasound, although highly sensitive, is an operator-dependent imaging modality.
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