| Infection and
Arthritis AN Chandrasekhar |
Infection is one of the important causes
for the inflammation of the joint (arthritis). Microorganisms which include
bacteria, viruses, fungi and parasites can cause arthritis, which can
be acute or chronic. Acute arthritis is generally caused by pyogenic bacteria
and termed as septic arthritis. Chronic arthritis is generally caused
by mycobacteria and fungi. In reactive arthritis and other forms of spondyloarthropathies,
arthritis can be secondary to infection elsewhere in the body. Infection
can be a triggering factor in some chronic inflammatory conditions, which
affect joints e.g. rheumatoid arthritis. On the basis of bacterial infection,
arthritides have been classified into infective, reactive and inflammatory
arthritis. Some microbes can cause infective as well as reactive arthritis.
The type of arthritis is determined by microbial factors as well as host
factors. |
Microbial Factors |
Virulence of the microbes, production
of toxic substances, degradability of microbial components and tissue
tropism are some important microbial factors. Staph. aureus and Neisseria gonorrhea appear to have a predilection for joint cavity and target a joint during bacteraemic phase. They have an enhanced ability to adhere to synovial tissue or produce toxins that facilitate colonisation during bacteraemic phase.1,2 Strains of N. gonorrhoea associated with disseminated disease (DGI) differ biologically from those associated with symptomatic localised disease. They are more resistant to killing by factors present in the serum and express specific cell surface proteins. The strains which cause asymptomatic localised infection do not provoke local inflammation and thus are not limited to mucosa and seed into the blood stream.3 Dissemination from local mucosal site also represents a failure of local inflammatory response to eradicate the bacteria due to production of IgA protease by some strains of gonococci.4 |
Certain strains of Group A streptococci
are particularly rheumatogenic.5 Virulence of streptococci has been linked
to the presence of M protein as well as large hyaluronic acid capsule. Organisms which cause reactive arthritis related to gastro-intestinal or genito-urinary tract infection, share some similarities. They are either facultative or obligate intracellular pathogens. They have lipopolysaccharide and are capable of establishing stable infection of host mucosa. These organisms and Group A streptococci can also cause damage to the joint because of antigenic similarities between the bacteria and self (HLA molecule or other articular structures. |
Consultant Rheumatologist, 28, Lady Madhavan
Nair Road, Mahalinga Puram, Nungam Bakkam, Chennai. |
Host Factors |
Age, sex, genetic susceptibility, immune
status of the individual as well as the diseased status of the joints
are some of the important host factors which determine the establishment
of infection and clinical manifestation of arthritis. Age of the patient and the underlying medical condition provide important clue to the probable infectious agent. Staphylococci are the most common bacterial cause of septic arthritis particularly in adults whereas in neonates Group B streptococci and Gram-negative organisms are generally associated. Haemophilus influenzae are most commonly found in children under 2 years of age, but account for only about 2% of cases in adults.6,7,8 There is greater incidence of gonococcal arthritis in women who are particularly susceptible to gonococcal bacteraemia during pregnancy, post-partum and during the first week of menstrual cycle. Rubella arthritis occurs primarily in post-pubertal women. Mumps arthritis occurs in post-pubertal men.9 |
The clinical manifestation of different
forms of spondylo- arthropathies and chronic inflammatory arthritis such
as rheumatoid arthritis appear to be determined by specific genes mostly
represented in the major histocompatibility complex. Some genes are necessary
for disease susceptibility and others act as modifiers responsible for
severity of disease. HLA B 27 (HLA class I antigen) positive individuals
are more prone to develop ankylosing spondylitis or any other form of
spondyloarthropathy. Severe forms of rheumatoid arthritis are associated
with HLA DR B1 alleles. Complement deficiency especially of the terminal components such as C5-C8 appears to be a risk factor for the development of neisserial infection.10 Exposure to infectious agents when the immune system is developing may be a cause for poly arthritis. Recent evidences suggest that an influenza A2 epidemic caused an intra uterine infection that predisposed children to the development of a subtype of juvenile chronic arthritis.11 |
Local factors and systemic factors predispose
to the development of arthritis. Staph aureus is the primary pathogen
recovered from primary septic arthritis as well as septic arthritis following
trauma, intra articular injection, under lying debilitating illness like
diabetes mellitus, rheumatoid arthritis and SLE. Staph epidermidis is the most common bacterial species associated with infection complicating articular prosthesis.12 Salmonella arthritis is a rare complication of salmonellosis. But patients with sickle cell anaemia and SLE are at an increased risk for salmonella arthritis because chronic salmonella carrier status is more common in these conditions due to impaired clearance by reticulo endothelial system.13,14 |
Joint infection is a relatively common
complication of immuno deficiency status particularly primary hypoglobulinaemia
(X-linked agamma-globulinaemia and common variable immunodeficiency) and
in majority of cases it has been shown to be due to mycoplasma infection.15,16 Gram negative enteric organisms, coagulase negative Staph species, methicillin resistant S. aureus and fungi must be considered in chronically hospitalised patients. |
Mode of spread of microbes to
the joint |
l. Haematogenous seeding is the most common route
for the entry of microbes into the joint. The primary focus of bacteraemia
could be an infected wound of the skin, abscess, tooth infection, or
respiratory infection. The organism may be transported within immune
complex (Yersinia triggered reactive arthritis) macrophage (enterobacteria),
polymorphonuclear leucocytes (elementary bodies of chlamydia) or the
microbial structures such as lipopolysaccharide alone may be transported
to the joints. But most bacteraemic episodes do not result in septic
arthritis and some bacteria that are frequent causes of bacteraemia
are rare causes of joint infection. Certain factors appear to predispose
such seeding of bacteria to the joints 2. Spread from an adjacent focus of infection e.g.,
from osteomyelitis in adults due to an anastomosis between the metaphysis
and synovial vascular bed, allowing direct entry of bacteria.17 |
Mechanism of Tissue Damage |
Damage to the articular tissue
can be mediated by different mechanisms. I. Products of infection mediated inflammation can directly cause damage. The initial site of infection in septic arthritis is the synovium. Once the infection is established, bacteria multiply and spread throughout the synovium and eventually into synovial fluid. The organisms are phagocytosed by polymorphs resulting in the release of chemotactic factors, activation of complement and recruitment of additional phagocytic cells, thus setting up classic inflammation. Prolonged inflammation damages joint capsule, articular cartilage, bone and tendon consequent to a) synovial ischaemia from markedly increased intra synovial fluid pressure and compression of blood vessels, b) phlogistic products of invading organisms and c) host defense mechanisms. |
In animal models, the proteoglycan content
of the cartilage is reduced by 40% within 48 hours of induction of joint
infection. Within 2-3 weeks significant loss of cartilage develops. This
underscores the need for prompt diagnosis and treatment of septic arthritis.18
Bacterial superantigens (Staph enterotoxin) cause toxic shock syndrome
and septic arthritis as a result of production of large quantities of
inflammatory cytokines.19 |
II. Immune response
mediated inflammation: Immune response, directed against a pathogen or
fragments of organism cause inflammation and much of the tissue injury
is caused by immune complexes. In gonococcal infection, after an acute
arthritis, synovitis may persist in response to the constituents of gonococcal
cell wall such as LPS and manifest as sterile chronic synovitis. This
has been proved in animal models. Both killed gonococci as well as purified
LPS can induce a purulent synovitis after an intra-articular injection.20
Effusion may be caused and maintained by host immunological mechanism.
Immune complex have been demonstrated in blood as well as in SF of patients
with DGI.21 |
Lyme disease caused by Borrelia burgdorferi manifests as acute arthritis.
But in some susceptible individuals, joint inflammation may persist
even after the by PCR (DNA) genetically has become negative.22 The development
of serological immune response against outer surface proteins has been
linked to the development of chronic arthritis.23 In rubella arthritis,
onset of rash and arthritis coincides with the antibody production,
suggesting a role for either antibody or immune complex in synovium.24
In hepatitis B infection, arthritis and urticaria may precede jaundice
due to the formation of immune complex containing hepatitis B antigen
and specific antibodies.25 Arthritis due to parasitic infestation is rare but can occur with Dracunculus medinensis (Guinea worm) in an endemic area like Tamilnadu. It can manifest as a result of localisation of parasite in the joint or as a reaction to the presence of parasite in neighbouring tissue. Septic arthritis can very rarely occur secondary to bacterial infection of the parasite in the subcutaneous lesions.26,27,28 |
III. A third mechanism
which involves autoimmune-mediated damage in addition to infection-mediated
inflammation and immune response mediated inflammation may also be involved.
A classic example is seen in rheumatic fever which causes damage to the
heart and may cause migratory polyarthritis as sequelae to an infection
in the throat. The immune response mounted against Group A b haemolytic
streptococci is directed against self due to antigenic similarity between
some streptococcal antigens and cardiac and/or articular tissue. Similar
mechanism of molecular mimicry has been implicated in the pathogenesis
of rheumatoid arthritis because of sharing of same aminoacid sequences
in specific portions of certain HLA DR molecules (HLA DR B1*04) and Epstein
Barr virus. |
A strong association between HLA B 27
and several forms of spondyloarthropathies particularly ankylosing spondylitis
has been reported from almost all ethnic populations.29,30,31 Apart from
molecular mimicry that is reported to exist between Klebsiella pneumoniae
and HLA B 27, other mechanisms have also been proposed for the pathogenesis.
Some studies suggest that HLA B 27 enhances the intracellular survival
of the microbes and make them more arthritogenic or alter the immune response
to produce more proinflammatory chemokines.32,33 |
Since HLA molecules determine the nature
of peptides to be presented to the T lymphocytes, the strong association
between HLA molecules and certain immunoinflammatory diseases can be very
well understood. |
Several viruses have been associated
with arthritis. Rubella, hepatitis B and C viruses, mumps and a parvovirus
B19 are most commonly associated and may cause arthritis through a combination
of mechanisms. Viruses may directly infect the synovial cell and cause
death of the cell by classic necrosis or programmed cell death. Death
may be mediated by cytotoxic T cells when they recognise the virally encoded
antigens on the cell surface. Immunoinflammatory damage can be mediated
through cytokines by transactivation of host gene by viral products. Humoral
immune response may generate antibodies that deposit immune complex either
locally or systemically with deposition of immune complexes in the synovium.
Molecular mimicry between host and viral antigens may break immune tolerance
and autoimmune mediated tissue injury follows.34 |
Additional mechanisms may be involved
in Human Immunodeficiency virus mediated spondyloarthropathies. Progressive
depletion of CD4 T cells may allow establishment of persistent infection
and/or greater invasiveness of gut microbes by diminishing help for B
cell dependent bacterial clearance mechanisms.35,36 |
Clinical Features |
Septic arthritis is a medical emergency.
The outcome is favourable if detected during first 2-3 days. A delay in
diagnosis particularly septic arthritis of hip in children often results
in joint destruction. |
The clinical presentation varies with
age. In neonatal period and upto 1 year of age, the symptoms are usually
systemic rather than local and are more of sepsis rather than local arthritis.37
In adults, the symptoms are localised and most commonly affect the lower
extremities.38 |
The joint capsule is distended, warm,
reddened and oedematous. But localisation of pain and tenderness may be
difficult and erythema, warmth and swelling are not detectable in deep
seated joints. Systemic signs and symptoms are common. The incidence of
fever in acute bacterial arthritis varies from 25%-90%.39-42 Therefore,
while the presence of fever in patients with acute arthritis should always
raise the suspicion of pyogenic infection, absence of fever does not exclude
the diagnosis. Typically, pyogenic arthritis is monoarticular and affect
knee (50%) followed by hip (20%). Approximately 20% bacteraemic episodes
can lead to polyarthritis.41-43 10% rheumatoid arthritis patients are
at risk for the development of pyogenic arthritis of the affected joint.41,42 |
Arthritis is the most common presenting
symptom of rheumatic fever and has been recorded in 45-65% of affected
children and teenagers.44,45 Arthritis is migratory and it is unusual
for acute rheumatic fever to involve one joint like knee or wrist joint
for a period longer than 1-2 weeks. In such cases, other possible causes
of arthritis such as juvenile chronic arthritis or septic arthritis should
seriously be considered.46 |
The general clinical characteristics
of Brucella arthritis are similar to that of infectious arthritis due
to other organisms. Large peripheral joints, sacroiliac joint and spine
are the usual joints involved.47 |
Disseminated gonococcal infection can
affect skin, joint and less commonly heart and meninges. Arthritic lesions
in disseminated gonococcal infection (DGI) has been classified according
to the presence or absence of purulent effusion.3,48,49 In group I, two-thirds
of the patients present with acute illness, migratory polyarthritis with
non purulent effusion and predilection for upper extremities. Though blood
culture may be positive, SF culture is negative. Group II patients present
with purulent mono arthritis affecting knee and SF culture will be positive.
Osteoarticular tuberculosis can manifest as spondylitis (Pott’s
disease) in 50%, peripheral arthritis in 20%, osteomyelitis, tenosynovitis
or Poncet’s disease which is an acute articular involvement without
bacteriological evidence for the joint involvement.26 Peripheral arthritis
more commonly occurs in joints of lower extremities. Usually single joint
is affected. Hip, knee, ankle, sacroiliac joint are affected in that order.50,51 |
Majority of viral arthritis are acute
and self-limited illnesses, usually accompanied by fever, distinct cutaneous
manifestation and other clinical features. The most common arthritogenic
viruses are rubella and hepatitis B and C viruses and also a variety of
mosquito borne viral infections causing epidemics. Chronic polyarthritis
mimicking RA especially in adults may occur with parvo virus B19 infection,52
hepatitis B and C infections. In rubella infection, joint complaints are
common in adults especially in women. Joint involvement is usually symmetrical
and may be migratory and occur 1 week before or after the onset of rash.
Arthritis normally resolves over a few days to 2 weeks. In some patients
it may persist for several months or years.53,54 |
Arthritis in Hepatitis B infection is
immune complex mediated and is usually sudden in onset and often severe.
Several joints are involved simultaneously and may be migratory or additive.
Arthritis and urticaria may precede jaundice by days to weeks and usually
subside soon after the onset of clinical jaundice.55 |
Acute onset poly arthritis in rheumatoid
like distribution may occur in HIV infection. In spite of gross immunodeficiency,
only a very low incidence of septic arthritis has been reported.56,57
The most frequently encountered condition in HIV infected individuals
is spondyloarthropathies. Reiter’s syndrome may occur in 11% of
HIV infected individuals.58,59 In contrast to HIV negative Reiter’s,
cutaneous manifestations are very conspicuous and sustained. Involvement
of the musculoskeletal system (spondyloarthropathies) and skin (psoriasiform
disease) are distinctive clinical markers for advanced HIV infection.60 |
|
References 12. Inman RD, Gallegos KV, Brause BD, Redecha PB and Christian CL.
Clinical and microbial features of prosthetic joint infection. American
Journal of Medicine 1984;77:47-53. 29. Chandrasekaran AN, Porkodi R, Achuthan K, Radha Madhavan, Parthiban
M. Spectrum of clinical and immunological features of systemic rheumatic
disorders in a referral hospital in South India: Primary Ankylosing
Spondylitis. JIRA 36. Rank RG, Ramsey KH and Hough AJ. Antibody mediated modulation of
arthritis induced by Chlamydia. American Journal of Pathology 1988;132:372-381. 43. Manshady RM, Thompson GR and Weiss JJ. Septic arthritis in a general
hospital 1966-1977. Journal of Rheumatology 1980;7:523-530. |