WEEK 2: Microbiology of joint disease

Question 1

What is septic arthritis?

Answer 1

inflammation of the joint secondary to an infection i.e. Bacterial, fungal, mycobacterial, viral or other pathogens infection.

Question 2

Question: Why is acute septic arthritis considered a serious orthopaedic emergency?

Question: What is the typical involvement of joints in acute septic arthritis, and what percentage of cases may present as poly-articular?

Question: Despite advances in treatment, what is a devastating complication associated with acute septic arthritis, and what is the prognosis for patients with this condition?

Question: What percentage of patients may experience permanent joint destruction if treatment for acute septic arthritis is not started quickly?

Question: What is the primary concern associated with acute septic arthritis, and why is it crucial to initiate treatment rapidly?

Answer 2

Acute septic arthritis rare BUT rapidly progressive & a serious orthopedic emergency.

Mostly a mono-articular i.e. involving one joint but may be poly-articular as well (~22% of cases).

Despite advances in treatment, prognosis is poor & permanent joint dysfunction is a devastating complication.
If treatment isn’t started quickly ~50% of patients incur permanent joint destruction

Question 3

Question: How does joint dysfunction contribute to the prognosis of acute septic arthritis, and why is it considered a severe complication?

Question: What is the difference in joint involvement between mono-articular and poly-articular presentations of acute septic arthritis?

Answer 3

Answer: Joint dysfunction contributes significantly to the prognosis of acute septic arthritis by potentially leading to permanent impairment of joint function. It is considered a severe complication because it can result in long-term disability and reduced quality of life for affected individuals.

Answer: The difference in joint involvement between mono-articular and poly-articular presentations of acute septic arthritis lies in the number of joints affected.

While mono-articular involvement means that only one joint is affected, poly-articular presentation indicates involvement of multiple joints, occurring in approximately 22% of cases.

Question 4

Septic arthritis has low Incidence in general population.

What is the average incidence rate?

The incidence rate is ~10x higher in which patients?

Also, rates vary with age and gender.
Describe the trend.

Answer 4

Incidence low in general pop.

~6–10cases/100 000 /yr.

BUT ~10x higher in patients with underlying joint disease e.g. rheumatoid arthritis

Also, rates vary with age i.e. higher in children & gender i.e. males more likely to be affected than females.

Question 5

State the risk factors for septic arthritis.

Answer 5

Rheumatoid arthritis, diabetes, prosthetic joint surgery, concurrent skin infection, intravenous drug use

Question 6

Aetiology of Septic arthritis

What is the predominant pathogen of septic arthritis?

How many % of S. aureus isolates from septic arthritic cases are MRSA.

State other causes of septic arthritis.

Microbiological associations may also exist with concomitant disease states:

Septic arthritis following infectious diarrhea may be caused by _____________

____________ was a leading causative pathogen of septic arthritis. But decrease in gonorrhea cases (In USA by 72% between 1975 to 1997) has had correlating reduction in gonococcal septic arthritis.

_________ occur as opportunistic pathogens in septic arthritis.

Answer 6

Staphylococcus aureus predominant pathogen of septic arthritis.

~6% - 22% of S. aureus isolates from septic arthritic cases are MRSA.

Others: Streptococcus pyogenes, Streptococcus pneumoniae (varying by patient age)

Microbiological associations may also exist with concomitant disease states:

Septic arthritis following infectious diarrhoea may be caused by Shigella species, Salmonella species, Campylobacter species or Yersinia species

Neisseria gonorrhoeae was a leading causative pathogen of septic arthritis.

But decrease in gonorrhea cases (In USA by 72% between 1975 to 1997) has had correlating reduction in gonococcal septic arthritis.

Fungi occur as opportunistic pathogens in septic arthritis.

Question 7

Etiology of septic arthritis by age-group.
(leading causes)
Neonates
1-4
4-16
16-40
>40

Answer 7

Neonates-Group B streptococcus
1-4-S aureus
4-16- S.aureus
16-40- Neisseria gonorrhea
>40- S aureus

Question 8

State Viral causes of Arthritis.

Answer 8

Hepatitis B virus
Herpes viruses
Coxsackievirus
Adenovirus
Arboviruses
Human parvovirus
Mumps virus
Rubella virus

Question 9

The microbial infection & the host’s inflammatory response collectively contribute to the resultant articular destruction.

The synovial membrane is vascularized, which facilitates hematogenous entry of bacteria (or phagocytes carrying bacteria) into the synovium.

Outline different ways microorganisms may gain access into the joint space.

Within the synovial space, bacteria e.g. S. aureus express adherence factors i.e. “Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), enabling them to bind to the hosts:
-Synovial cells
-Extracellular matrix proteins e.g. elastin, collagen, fibrinogen, fibrin, collagen, hyaluronic acid

State the MSCRAMMS of S. aureus and their function.

Answer 9

Microorganisms may gain access into the joint space via:
Direct seeding e.g. due to recent arthroplasty surgery i.e. prosthetic implantation or fracture fixation or joint aspiration or intra-articular steroid injection

Haematogenous route

Spread of a bone infection

Extension of a contiguous infection i.e. from a soft tissue infection

Recall for S. aureus these incl. ClfA, ClfB, FnBPA, FnBPB, Bone sialoprotein binding protein (Bbp), Elastin binding protein (Ebp) , Cna, Protein A, MHC Class II analog protein.

As bacteria multiply, some can produce biofilms e.g. S. aureus.

Question 10

State virulence factors that can be produced by S. aureus.

Answer 10

S. aureus can also exist as ‘small colony variants’ (SCVs) a phenotype with minimal growth & metabolism, enabling intracellular persistence in osteoblasts, fibroblasts.

Biofilms & SCVs have a higher resistance to antibiotics.

S. aureus can also secrete virulence factors such as:
-Protein A, capsular polysaccharide that aids in evasion of opsonization

-Toxic shock syndrome toxin (TSST-1) that acts as superantigen for non-specific activation of high nos. of T-cells

-α-hemolysin which causes blood coagulation

-Panton-Valentine toxin which enables survival within neutrophils and collectively the virulence factors lead to a fulminant joint infection which can recur over years

Question 11

The seeding & growth of bacteria in the synovium results in the host’s inflammatory response, characterized by__________.

However, the exacerbated inflammatory processes attempting to clear the bacterial infection may become chronic, causing persistent & irreversible damage to the cartilage.

Within the joint the triggered inflammatory cascade is characterised by:

Answer 11

Infiltration of leukocytes which produce reactive oxygen species

Production host matrix metalloproteinases

Production of lysosomal enzymes

2. An influx of immune cells i.e. neutrophils

-Activation of macrophages & release of inflammatory cytokines i.e. IL-1β, IL-6, TNF-α, MIP-2, GM-CSF

-Toll-like receptors (TLR’s) are key in recognizing microbial Pathogen associated molecular patterns (PAMPs) & activation of NF-kB which promotes further secretion of pro-inflammatory cytokines & neutrophil recruitment

-Activation of the C-reactive protein in the liver activates complementary pathways

-Phagocytosis by macrophages, PMNL’s releasing more lysosomal enzymes & ROS, all lead to the redness, swelling, pain experienced at the site of infection

T-cells are subsequently recruited to the joint cavity & activated upon antigen presentation by host antigen-presenting cells

High influx of T-cells, B-cells, macrophages causes thickening of the synovial membrane

Also the high levels of cytokines trigger the release of host matrix metalloproteinases which aggravate joint degradation

Initially degradation of the host proteoglycans, followed by collagen damage

Containment of the inflammatory process within the joint, results in increasing pressure, which hampers blood, oxygen & nutrient supply to the joint

Exacerbating destruction of cartilage & the synovium

Question 12

Describe the pathogenesis of septic arthritis.

Answer 12

1. Entry into Joint Space:
   Microorganisms access the joint via direct seeding (e.g., arthroplasty surgery), hematogenous spread, extension from a bone infection, or contiguous infection.
   Within the synovial space, bacteria express adherence factors (MSCRAMMs) binding to synovial cells and extracellular matrix proteins.
2. Bacterial Characteristics:
   Some bacteria, like S. aureus, can form biofilms and exist as small colony variants (SCVs), enabling intracellular persistence in osteoblasts and fibroblasts.
   S. aureus secretes virulence factors (Protein A, TSST-1, α-hemolysin, Panton-Valentine toxin) contributing to pathogenicity.
3. Virulence Factors and Infection Progression:
   Virulence factors lead to a fulminant joint infection with the potential for recurrence over years.

Inflammatory response includes leukocyte infiltration, production of reactive oxygen species, matrix metalloproteinases, and lysosomal enzymes.
4. Chronic Inflammation:
Exacerbated inflammatory processes, attempting to clear the infection, may become chronic, causing persistent and irreversible damage to the cartilage.

Inflammatory cascade characterized by influx of immune cells, macrophage activation, release of inflammatory cytokines, and Toll-like receptors recognizing microbial patterns.

5. Immune Response and Joint Degradation:
   Activation of T-cells, B-cells, macrophages leads to synovial membrane thickening.
   High cytokine levels trigger host matrix metalloproteinases, resulting in degradation of proteoglycans and collagen.
   Increased pressure within the joint hampers blood, oxygen, and nutrient supply, exacerbating destruction of cartilage and synovium.

Question 13

Outline Clinical signs of septic arthritis.

Answer 13

Ranges from mild to severe
Main symptoms incl.: abrupt onset of high fever, chills, delirium, convulsions

In severe cases: sepsis or septic shock may occur

At the joint: heat, swelling redness, discomfort, dysfunction, restricted mobility.
BUT
in ‘deep joints’ e.g. the hip there may not be visible swelling and fever, but there may still be restricted movement at the joint due to pain.

Question 14

Discuss diagnosis of septic arthritis.

Answer 14

1. Arthrocentesis:
   Joint aspiration, a sterile needle & syringe used to drain fluid from a joint.
2. Specimens
   I. Synovial fluid/ Joint aspirate or blood culture
   Gross/ macroscopic examination
   White blood count & differential, glucose & protein determination
   Gram stain/ Acid fast stain
   Culture & antibiotic sensitivity tests

II. Blood test: leucocytes are markedly high, generally >109/L; detectable leucocyte esterase; ESR & CRP also significantly high, **elevated procalcitonin is also a significant inflammatory marker.

Nb. X-rays & CT are limited in diagnosing early septic arthritis. BUT helpful in the differential diagnosis of acute osteomyelitis.

Question 15

Discuss the Management of septic arthritis.

Answer 15

1. Adequate drainage of joint
   Needle aspiration
   Arthroscopic drainage
   Open drainage in difficult & deep joints
2. After thoroughly evaluating the patient’s medical history & clinical symptoms, early, appropriate administration of antibiotics (without waiting for bacteriological results) is essential & immobilization of the afflicted limb
3. Appropriate antimicrobials treatment: is long-term (at least 6-weeks) starting as intravenous & then oral administration
   Adjusted & being cognisant of the current antibiogram data & based on:
   Patient’s culture & sensitivity results
   NB. for babies <3mths, empiric therapy for septic arthritis should cover S. aureus, Streptococcus spp. & Gram-negative bacilli.
4. Doing concurrent lab tests to monitor synovial & blood leukocyte counts & microbial cultures
5. Physiotherapy

Question 16

Note the following ontreatment

Bacteria antibiotic susceptibility to antimicrobials may vary over time & from region to region, so it is important to be cognisant of the treatment guidelines & current antibiogram data

For example, currently:
S. aureus generally susceptible to vancomycin, teicoplanin, linezolid, rifampicin, amikacin, Gentamicin & ciprofloxacin. Has higher rates of resistance to penicillin

Klebsiella pneumoniae & Escherichia coli generally susceptible to carbapenems, 3rd gen. cephalosporins & ciprofloxacin

NOTE: rifampicin, amikacin, gentamicin, tetracycline & ciprofloxacin have side effects that make them unsuitable for children

Question 17

Discuss the following imaging exams in relkation to septic arthritis.
1. Xray and CT images
2. MRI
3. Surgery

Answer 17

1. X-ray & CT images:
   In the early phase of acute septic arthritis i.e. within one week of onset, the images of the articular structures will generally appear normal or show soft tissue swelling, joint space enlargement due to joint effusion.

So X-rays & CT scans are limited in their capacity to diagnose early septic arthritis but they are helpful in differential diagnosis of acute osteomyelitis.

2. MRI: can be used to detect destruction of articular cartilage.

Surgery: in cases whereby septic arthritis diagnosis is characterized by joint discomfort, reduced mobility & inability to bear weight, then surgery or arthroscopy for irrigation & debridement to drain purulent fluid is essential
With arthroscopic irrigation & debridement, most patients would only need one surgical surgery to eliminate the infection

Irrigation:

Sterile fluid (usually saline) is introduced into the joint through one of the incisions. This fluid helps flush out debris, bacteria, and infected material from the joint space.
Debridement:

Using specialized instruments inserted through additional incisions, the surgeon performs debridement. This involves removing infected tissue, debris, and any necrotic material that may be present in the joint.

Question 18

What is arthritis?

Answer 18

“While the word arthritis is used by clinicians to specifically, it is used in public health to refer more generally to more than 100 rheumatic diseases and conditions that affect joints, the tissues that surround the joint, and other connective tissue

Question 19

What is Rheumatoid Arthritis (RA)?

Answer 19

A chronic systemic autoimmune inflammatory disease that causes aggressive inflammatory changes in the synovium which causes joint pain/stiffness/swelling and ultimately leads to joint damage and functional impairment.

Rheumatoid arthritis (RA) is an inflammatory systemic disease, with the hallmark of symmetric peripheral polyarthritis.

Question 20

What is the prevalence of rheumatoid arthritis globally?

Who is more likely to be affected?

Answer 20

PREVALENCE : Affects 0.5-1.0% of population globally

Women are two to three times as likely to be affected as men.

Question 21

Describe the following variants of rheumatoid arthritis.
-Juvenile rheumatoid arthritis (JRA):
-Still’s disease (systemic JRA):
-Felty’s syndrome:

Answer 21

Variants of RA:

-Juvenile rheumatoid arthritis (JRA): individuals younger than 16 years, large joints predominantly involved, rheumatoid factor often negative.

-Still’s disease (systemic JRA): fever, leukocytosis, enlargement of liver, spleen and lymph nodes

Felty’s syndrome: RA + splenomegaly + neutropenia

Question 22

Describe the pathogenesis of rheumatoid arthritis.

Answer 22

The pathogenesis of RA is not completely understood.

An external trigger (eg, cigarette smoking, infection, or trauma) that triggers an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals.

Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction.

Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, whereas B cells produce autoantibodies (ie, RFs). A

bnormal production of numerous cytokines, chemokines, and other inflammatory mediators (eg, tumor necrosis factor alpha [TNF-a], interleukin [IL]-1, IL-6, IL-8, transforming growth factor beta [TGF-ß], fibroblast growth factor [FGF], and platelet-derived growth factor [PDGF]) has been demonstrated in patients with RA.

Ultimately, inflammation and exuberant proliferation of the synovium (ie, pannus) leads to destruction of various tissues, including cartilage (see the image below), bone, tendons, ligaments, and blood vessels.

Although the articular structures are the primary sites involved by RA, other tissues are also affected.

Question 23

What is Systemic Lupus Erythromatosus (SLE)?

Answer 23

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that can affect various organs and tissues throughout the body. It is a type of lupus, an autoimmune disorder where the immune system mistakenly attacks healthy tissues. SLE is the most common and severe form of lupus.

Question 24

Outline the symptoms of SLE.

Answer 24

Non-specific:
-Fatigue
-Weight loss
-Malaise = generally feeling ill
-Fever
-Anorexia (over time)
-Arthritis
90% of patients experience arthritic symptoms.
Symmetrical
Appears in hands, wrists, and knees mainly

Question 25

Outline the skin manifestations of SLE.

Skin manifestations only appear in how many % of lupus patients?

Answer 25

-Malar or Butterfly Rash
-Discoid Rash – Stimulated by UV light

Skin manifestations only appear in 30-40% of lupus patients.

Question 26

Outline the Renal (Kidney) Manifestations of SLE.

How many % of all lupus patients experience renal manifestations?

Answer 26

50-70% of all lupus patients experience renal manifestations.

Most Dangerous:
Glomerulonephritis where at least 50% of the glomeruli have cellular proliferation.
Glomeruli – capillary beds in the kidney that filter the blood.
Renal Failure because of Glomerulonephritis is the leading cause of death among lupus patients.

Question 27

State other Manifestations of SLE.

Answer 27

Cardiac

Central Nervous System

Hematological

Question 28

Outline the causes of SLE.

Answer 28

1. Genetic Predisposition:
   There is a genetic component to SLE, and certain genetic factors are associated with an increased susceptibility to the disease. Individuals with a family history of autoimmune disorders may be at a higher risk.
2. Environmental Triggers:
   Environmental factors play a significant role in triggering the onset of SLE in genetically predisposed individuals. Common triggers include exposure to ultraviolet (UV) light, infections (especially Epstein-Barr virus), certain medications, and hormonal changes.
3. Loss of Immune Tolerance:
   In SLE, there is a breakdown of immune tolerance, leading to the immune system mistakenly recognizing and attacking the body’s own cells and tissues. The exact mechanisms behind this loss of tolerance are not fully understood.

Question 29

Describe the pathogenesis of SLE.

Answer 29

1. The plasma cells are producing antibodies that are specific for self-proteins.
2. Overactive B-cells
   -Estrogen is a stimulator of B-cell activity
   Lupus is much more prevalent in females of ages 15-45 Height of Estrogen production.

-IL-10, also a B-cell stimulator is in high concentration in lupus patient serum.
High concentration linked to cell damage caused by inflammation.

3. Suppressed regulatory function in T-cells.
4. Lack of T-cells
5. Activation of the Complement system

Question 30

What is osteoarthritis?

Answer 30

Osteoarthritis (OA) is a common degenerative joint disorder characterized by the gradual breakdown of cartilage in the joints.

It is one of the most prevalent forms of arthritis and typically affects weight-bearing joints and those involved in repetitive motion.

Question 31

Describe the pathophysiology of osteoarthritis.

Which joints are mainly affected?

Answer 31

Protective Cartilage at the end of bone is worn down over time.

Main areas of OA are the knees, hips, hands, and spine.

Question 32

Outline OA: Symptoms and Signs.

Answer 32

Pain is related to use
Pain gets worse during the day
Minimal morning stiffness (<20 min) and after inactivity
Range of motion decreases
Joint instability
Bony enlargement
Restricted movement
Variable swelling and/or instability

Question 33

State the risk factors of osteoarthritis.

Answer 33

Age: 75% of persons over age 70 have OA
Female sex
Obesity
Occupation (overuse)
Hereditary
Trauma
Neuromuscular dysfunction
Metabolic disorders

Question 34

Outline Underlying Disease Associations of OA and CPPD Disease (pseudogout).

Answer 34

Hemochromatosis
Hyperparathyroidism
Hypothyroidism
Hypophosphatasia
Hypomagnesemia
Neuropathic joints
Trauma
Aging, hereditary

Question 35

Compare rheumatoid arthritis and osteoarthritis.
Age of onset
Speed of onset
Distibution
Joints affected

Answer 35

Age of onset
*RA: Can happen at any age
*OA: Associated with aging

Speed of onset
*RA: Rapid, weeks to months
*OA: Slow, gradual takes years

Distibution
*Symmetrical
*Non-symmetrical

Joints affected
*RA: Hands and feet joints mostly affected
*OA: weight bearing joints: KNEES, HIP, HANDS, VERTERBRAL JOINTS

Question 36

What is Post-Traumatic Arthritis?

Answer 36

Post-traumatic arthritis (PTA) is a form of osteoarthritis that develops after an injury or trauma to a joint.

It occurs when the cartilage in a joint is damaged as a result of a previous injury, such as a fracture, dislocation, or severe sprain.

The initial injury disrupts the normal functioning of the joint and can lead to accelerated wear and tear on the joint surfaces, eventually causing arthritis.

May not appear until 10-15 years after the injury.

Symptoms include:
Joint Pain
Swelling
Fluid Accumulation
Bone Spurs
Most likely to involve the knees and hips

Question 37

What is GOUT?

Answer 37

Disorder of purine metabolism → hyperuricemia

Deposition of monosodium urate crystals into articular cartilage, synovial membrane and periarticular soft tissues (tophi, tophaceous gout)

Question 38

Describe the prevalence of Gout.

Answer 38

30 – 60 years, male preponderance.

Acute gouty arthritis: metatarsophalangeal joint of the big toe (70%), ankle, knee, wrist, elbow, the affected joint is red, hot, swollen, very painful and tender

Chronic gouty arthritis: follows recurrent episodes of acute gouty arthritis, progressive erosion of cartilage and bone – limited joint function

Question 39

Discuss the pathophysiology of Gout.

Answer 39

Metabolic disorder

Inflammation due to Monosodium Uric crystals being deposited in the synovial fluid

Associated with Hyperuricemia
Serum urate levels about 6.8 mg/dL

Initially produces acute, episodic flairs that progress to chronic arthritis.

The accumulation of urate crystals and the subsequent inflammatory response lead to acute gout attacks. These attacks are characterized by severe joint pain, swelling, and tenderness. The big toe is a common site of involvement, but gout can affect other joints as well.

If hyperuricemia persists or is not effectively managed, recurrent gout attacks can occur, leading to chronic gout. In chronic gout, urate crystals may accumulate to form tophi, which are chalky deposits of urate crystals. Tophi can develop in and around joints, tendons, and soft tissues.

Question 40

State the causes and risk factors of Gout.

Answer 40

Genetic Predisposition:

There is a genetic component to gout, and individuals with a family history of gout are at an increased risk. Certain genetic factors may influence how the body processes and excretes uric acid, contributing to hyperuricemia and gout development.
Dietary Choices (High-Purine Foods):

Purines are natural substances found in certain foods. When purines are broken down, uric acid is produced. Foods rich in purines include organ meats (liver, kidney), red meat, seafood (anchovies, sardines, mussels), and some types of beans. Excessive consumption of these high-purine foods can contribute to elevated uric acid levels.
Excessive Alcohol Intake:

Alcohol, particularly beer and spirits, has been linked to an increased risk of gout. Alcohol can interfere with the elimination of uric acid by the kidneys, leading to elevated levels in the bloodstream. Beer, in particular, contains purines and compounds that can contribute to gout development.
Obesity:

Obesity is a significant risk factor for gout. Excess body weight is associated with higher uric acid levels, and obesity can contribute to insulin resistance, which may further elevate uric acid levels.
Certain Medications:

Some medications can increase the risk of gout or exacerbate existing gout. Diuretics (used to treat hypertension), low-dose aspirin, and medications that suppress the immune system are examples of drugs that may affect uric acid levels.
Underlying Health Conditions:

Certain health conditions contribute to an increased risk of gout. Conditions such as kidney disease, metabolic syndrome, hypertension, and diabetes can impact the body’s ability to regulate uric acid levels, leading to hyperuricemia and gout.
Age and Gender:

Gout is more common in older adults, and the risk tends to increase with age. Men are more likely to develop gout than premenopausal women. However, the risk in women increases after menopause.
Dehydration:

Inadequate fluid intake or conditions that lead to dehydration can reduce the excretion of uric acid by the kidneys, contributing to its accumulation in the bloodstream.
Trauma or Surgery:

Physical trauma or surgery can sometimes trigger a gout attack. This may be due to the release of uric acid from damaged cells or changes in the body’s metabolism during the recovery process.