ARTHRITIS, INFECTIOUS, GRANULOMATOUS

ARTHRITIS, INFECTIOUS, GRANULOMATOUS - Bruce M. Rothschild, MD
BASICS
DESCRIPTION
• Invasion of joints by live microorganisms or their fragments. One of the few curable causes of arthritis. May allow early recognition of systemic infection/disease.
• System(s) Affected: Musculoskeletal
• Synonym(s): Fungal arthritis
GENERAL PREVENTION
Prophylaxis in presence of predisposing joint condition
EPIDEMIOLOGY
• Occurs in 1-3% of patients with tuberculosis infections
• Predominant age: Diffuse
• Predominant sex
- Male > Female (Brucella and mycobacterial)
- Female > male (fungal)
Prevalence
• 1 in 3,000,000
• Infrequent in pediatric population
RISK FACTORS
• Concurrent acquired immunodeficiency disease
• Concurrent extra-articular infection
• Prior arthritis in infected joint
• Trauma
• Rheumatoid arthritis
• Joint puncture or surgery
• Prosthetic joint
• Prior antibiotic, corticosteroid, or immunosuppressive therapy
• Serious chronic illness (e.g., diabetes, liver disease, malignancy, primary immunodeficiency)
• Defective phagocytic mechanisms (e.g., chronic granulomatous disease)
• Intravenous drug abuse
• Exposure history (e.g., unpasteurized milk)
• Farmers, butchers, veterinarians
• Travel/habitat history
• Gardening, especially for sporotrichosis
ETIOLOGY
• Hematogenous invasion by microorganisms (80-90%)
• Contiguous spread (10-15%)
• Direct penetration of microorganisms secondary to trauma
ASSOCIATED CONDITIONS
• Systemic infection
• Infection elsewhere
• Immunodeficiency (e.g., from medications)
• Immunosuppression
ALERT
Geriatric Considerations
• Grave in elderly
• Tuberculosis much more likely to occur


DIAGNOSIS
SIGNS AND SYMPTOMS
• Predominantly monoarticular (90%). Fungal may present as a migratory polyarthritis. (1,2)
• Joint tenderness
• Limited joint use/motion; especially in children
• Joint effusion
• Joint warmth; present in less than 50%
• Joint redness; present in less than 50%
• Loss of joint motion
• Tenosynovitis
• Sudden flare of single joint in patient with underlying joint disease
• Fever; in 50% at some time during course of infection
• Chills
• Malaise
• Cutaneous lesions
• Peripheral neuropathy
• Back pain; especially in tuberculosis and brucellosis
• Hypertrophic osteoarthropathy
• Fretfulness; especially in children
• Doughy swelling, with minimal tenderness
• Dactylitis
• Diaphoresis
• Headache
• Hepatosplenomegaly
• Lymphadenopathy
• Erythema nodosum
• Iritis (with mycobacterial arthritis)
TESTS
Lab
• Arthrocentesis (3, 4)[A], (5), (6)[A]
- Bacterial: For Gram stain, silver, and acid-fast stain and culture, cell count and differential, glucose
- Mycobacterial: Acid fast (positive in 20%), culture (positive in 80%)
- Must be done in all patients when possibility of infectious arthritis considered
- Synovial fluid usually cloudy with >20,000 WBC/HPF, but may have fewer white blood cells present or over 100,000 (Caveat: Cell count must be performed within 1 hour of obtaining specimen to be valid.)
- Synovial-fluid white count can be recognized as elevated (in presence of trauma) if the RBC/WBC ratio is significantly less than 700.
- Polymorphonuclear leukocytes usually predominate in synovial fluid (although granulomatous and viral arthritis may have a mononuclear cell predominance).
- Synovial-fluid glucose often more than 40 mg/dL (2.22 mmol/L) less than in simultaneously obtained serum glucose value (in fasting patient). However, arthrocentesis should not be delayed simply to obtain fasting synovial fluid glucose level.
- Synovial-fluid eosinophilia may occasionally be seen in the healing phase of infection, but parasitic (e.g., guinea-worm) infection must also be considered.
- Approach must avoid contaminated tissue (e.g., overlying cellulitis).
- Drug-sensitivity testing recommended
- The presence of crystals in the synovial fluid (e.g., urate or calcium pyrophosphate) does not exclude infectious arthritis.
- Depressed synovial fluid levels of complement
• Synovial membrane: Biopsy and culture
• Blood, urine, sputum cultures
- Fungal blood cultures
- Polymerase chain reaction for specific microorganisms
- All cultures should be held for 2 weeks; acid-fast cultures for 6 weeks
• Gastric lavage for acid fast: Increases yield 7%
• Serum testing
- Polymerase chain reaction DNA analysis for tuberculosis
- Westergren erythrocyte sedimentation: Often elevated, but normal in 20%
- Rheumatoid factor positive in 50% if endocarditis present
- Elevated peripheral white blood cell count
- Cryoglobulins
- Immune complexes
- Febrile agglutinins (to include Brucella- and rickettsial-related titers)
- Antistreptolysin-O titer usually normal
- Decreased serum complement levels
• Other
- Disorders that may alter lab results: Diabetes
- Drugs that may alter lab results: Insulin, antibiotics
Imaging
• X-ray (1,2),(4)[A],(5),(6-8)[A]
- X-ray changes usually a late phenomenon
- Soft-tissue swelling
- Osteoporosis
- Effacement of the obturator fat pad (with hip involvement) or psoas shadow
- Rarefaction of subchondral bone
- Joint-space loss
- Erosions
- Joint destruction with ankylosis
- Subchondral erosion with preservation of joint space strongly suggests granulomatous infection.
• Technetium joint scans: Reveal distribution of inflammation, not just infection
• Gallium scan, Ceretec or indium WBC scans: Reveal inflammation as well as infection
• Computerized tomography: To identify sequestration
• Magnetic resonance imaging: Perhaps early cartilage damage, osteomyelitis (1),(4)[A]
Pathological Findings
Synovial biopsy may reveal granulomas and possibly the causative organism.
DIFFERENTIAL DIAGNOSIS
• Gout
• Pseudogout (calcium pyrophosphate deposition disease)
• Spondyloarthropathy (Reiter syndrome, psoriatic arthritis, ankylosing spondylitis, arthritis of inflammatory bowel disease)
• Juvenile rheumatoid arthritis
• Type IIa hyperlipoproteinemia
• Foreign body synovitis
• Rheumatoid arthritis
• Rheumatic fever
• AIDS
• Cellulitis
• Palindromic rheumatism
• Neuropathic arthropathy
• Lyme arthritis
• Sarcoidosis
• Pyogenic arthritis
TREATMENT
GENERAL MEASURES
• Appropriate care
- Fungal: Initial hospitalization for parenteral therapy
- Mycobacterial: Outpatient, once diagnosed
- Brucella: Outpatient, once diagnosed
• Repeat arthrocentesis to drain joint as fluid reaccumulates.
• Avoid adding anti-inflammatory therapy to avoid compromising the assessment of the therapeutic response to the antibiotic.
• Infection associated with prosthetic joints may be difficult to eradicate without removal.
• For Brucella or fungal infections, continue treatment for 1-2 weeks after total resolution of all signs of inflammation, and 6-8 weeks if joint was previously diseased (e.g., arthritis).
• Antigranulomatous therapy requires a long program (see Tuberculosis).
• Intra-articular antibiotics are not indicated.
• Infectious-disease consultation may be helpful.
Diet
As tolerated
Activity
Limit/splint joint initially, while pursuing full passive range of motion Alternative approach: Continuous passive motion.
MEDICATION (DRUGS)
• Medications based on sensitivity of organisms
• Mycobacterial infection (4)[A], (5,7)[A], (8)
- Use combination of isoniazid, rifampin, and pyrazinamide/ethambutol.
- Isoniazid 5 mg/kg, up to 300 mg PO every day
- Rifampin 10 mg/kg, up to 600 mg PO every day
- Pyrazinamide 15-30 mg/kg up to 2 g per day. After 2 months, replace with ethambutol 15 mg/kg
- Continue therapy for 9-24 months.
- Request infectious-disease consultation.
• Brucella (6)[A]
- Tetracycline plus streptomycin or trimethoprim-sulfamethoxazole or rifampin (for dosage, see manufacturer's literature)
• Fungal infection (5)
- Choice of medication depends on organism
- Amphotericin B
- Ketoconazole
- Flucytosine (5-fluorocytosine)
• Contraindications
- Tetracycline not for use in pregnancy or children 8 years
• Precautions
- Observe for allergic reactions/serum sickness
- Tetracycline may cause photosensitivity; sunscreen recommended
• Significant possible interactions
- Tetracycline: Avoid concurrent administration with antacids, dairy products, or iron
- Ketoconazole: Multiple drug interactions
• Alternative drugs: See Tuberculosis.
SURGERY
Arthrotomy indicated only if fluid accumulated is loculated and/or not amenable to needle drainage
FOLLOW-UP
PROGNOSIS
• Early initiation of treatment should allow cure.
• Delayed recognition/treatment complicated by increased morbidity and mortality
COMPLICATIONS
• Limited joint range of motion
• Flail or fused joint
• Carpal-tunnel syndrome
• Septic necrosis
• Sinus formation
• Ankylosis
• Joint dislocation
• Osteomyelitis
• Shortening of limb (in children)
PATIENT MONITORING
• Verify sterilization of joint and reversion of inflammatory signs to normal
• Treatment of mycobacterial arthritis requires monthly complete blood count, assessment of liver and kidney function, and urinalysis.
• Essential to follow up frequently after stopping antibiotics to detect relapse.
• As dictated by therapy protocols (e.g., amphotericin B)
REFERENCES
1. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders Co.; 2002:2375-2612.
2. Rothschild BM, Martin L. Skeletal Impact of Disease Pathology. Albuquerque, NM: New Mexico Museum of Natural History; 2006.
3. Fukushima M, Kakinuma K, Hayashi H, et al. Detection and identification of mycobacterial species isolated by DNA microarray. J Clin Microbiol. 2003;41:2605-2615.
4. Hus C-Y, Shih TT-F. Tuberculous infection of the wrists: MRI features. Am J Roentgenol. 2004;183:623-628.
5. Kelly WW, Harris ED Jr, Ruddy S, Sledge CB. Textbook of Rheumatology. Philadelphia, PA: WB Saunders Co.; 1997.
6. Yilmaz E, Parlak M, Akalin H, et al. Brucella spondylitis: Review of 25 cases. J Clin Rheumatol. 2004;10:300-307.
7. Papagelopoulos PJ, Papadopoulos EC, Mavrogenis AF, et al. Tuberculous sacroilitis. A case report and review of the literature. Eur Spine J. 2005;14:683-688.
8. Sawlani V, Chandra T, Mishra RN, Aggarwal A, Jain UK, Gujral RB. MRI features of tuberculosis of peripheral joints. Clin Radiol. 2003;58:755-762.
9. Gershwin ME, Robbins DL. Musculoskeletal Diseases of Children. New York, NY: Grune  Stratton; 1983.
10. Rothschild BM, Rothschild C. Recognition of hypertrophic osteoarthropathy in skeletal remains. J Rheum. 1998;25:2221-2228.
MISCELLANEOUS
• Other notes: Infectious arthritis may be caused by many other organisms including bacterial (particularly neisseria), rickettsial, parasitic, fungal, and viral agents. Much of the information contained in this profile applies to these other organisms as well as to granulomatous infections.
• See also: Brucellosis