Molecular mechanisms and pathogenesis of shoulder sepsis

Microanatomy and cell biology

The hyaline cartilage of the articular surface is essentially acellular and consists of horizontally arranged collagen fibers in proteoglycan macromolecules. The boundaries of the joint cavity are composed of a richly vascularized cellular synovial tissue. It has been suggested that collagen fibers and the glycoprotein matrix, rather than the synovium, are the target substrata for microbial adhesion and colonization. ^,

Some synovial cells are phagocytic and appear to combat infection as part of the inflammatory response. Microscopic examination of infected joints in a lupine animal model indicated predominant colonization of cartilaginous, rather than synovial, surfaces. Receptors for collagen have been identified on the cell surfaces of certain strains of Staphylococcus aureus . The infrequent occurrence of bacteria on synovial tissue might reflect the innate resistance of synovial cells to colonization, the lack of appropriate synovial ligands, or functional host defense mechanisms at a synovial level. The subintimal vascularized layer contains fibroadipose tissue, lymphatic vessels, and nerves. Ultrastructural studies of the synovial subintimal vessels have revealed that gaps between endothelial cells are bridged by a fine membrane. There is no epithelial tissue in the synovial lining and therefore no structural barrier (basement membrane) to prevent the spread of infection from synovial blood vessels to the joint. The synovial lining in the transition zone is rarely more than three or four cell layers thick, placing the synovial blood vessels in a superficial position. Intra-articular hemorrhage caused by trauma, combined with transient bacteremia, may be implicated as a factor in the pathogenesis of joint sepsis. Hematogenous seeding can allow bacterial penetration of synovial vessels, producing an effusion consisting primarily of neutrophils that release cartilage-destroying lysosomal enzymes.

Articular (hyaline) cartilage varies from 2 to 4 mm in thickness in the large joints of adults. This avascular, aneural tissue consists of a relatively small number of cells and chondrocytes with an abundant extracellular matrix. The extracellular matrix contains collagen, a ground substance composed of carbohydrate and noncollagenous protein that has high water content. The chondrocytes are responsible for the synthesis and degradation of matrix components and are therefore ultimately responsible for the biomechanical and biologic properties of articular cartilage. Collagen (type II) produced by the chondrocytes accounts for more than half of the dry weight of adult articular cartilage. Individual collagen fibers, with a characteristic periodicity of 640 Å, vary from 300 to 800 Å in diameter, depending on their distance from the articular surface.

The principal component of the ground substance produced by chondrocytes is a protein polysaccharide complex termed proteoglycan . The central organizing molecule of proteoglycan is hyaluronic acid, with numerous glycosaminoglycans (mainly chondroitin sulfate and keratan sulfate) covalently bound from this central strand. Glycosaminoglycans carry considerable negative charge. The highly ordered array of electronegativity on the proteoglycan molecules interacts with large numbers of water molecules (small electric dipole). As a result, approximately 75% of the wet weight of articular cartilage is water, the majority of which is structured by the electrostatic forces of the proteoglycan molecule.

The structure of articular cartilage varies relative to its distance from the free surface. For the purposes of description, the tissue can be subdivided into three zones that run parallel to the articular surface ( Fig. 47.1 ). Electron microscopy of the free surface reveals a dense network of collagen fibers (40 to 120 Å in diameter) that is arranged tangentially to the load-bearing surface and at approximately right angles to each other. This dense, mat-like arrangement, the lamina obscurans, is acellular.

Zone 1, the superficial layer, contains large bundles of collagen fibers that are approximately 340 Å thick and lie parallel to the joint surface and at right angles to each other. This zone, the lamina splendens , has little or no intervening ground substance and contains the highest density of collagen. Chondrocytes in zone 1 are ellipsoid and are oriented parallel to the articular surface. Electron microscopy reveals little evidence of metabolic activity.

In zone 2 the collagen consists of individual, randomly oriented fibers of varying diameters. The chondrocytes in zone 2 tend to be more spherical and larger than those in zone 1, with abundant mitochondria and extensive endoplasmic reticulum, suggesting greater metabolic activity. The proteoglycan/collagen ratio in zone 2 is much higher than that near the surface.

In zone 3 the collagen fibers are thicker, often approximately 1400 Å in diameter, and tend to form a more orderly meshwork that lies radial to the articular surface. The chondrocytes in zone 3 are larger and tend to be arranged in columns, often appearing in groups of two to eight cells. The cells have been noted to have enlarged Golgi complexes, many mitochondria, and an extensively developed endoplasmic reticulum, indicating a high degree of metabolic activity.

Bone is a composite structure incorporating calcium hydroxyapatite crystals in a collagen matrix grossly similar to synthetic composites or to partially crystalline polymers. Devitalized bone provides a passive substratum for bacterial colonization as well as the ultimate incorporation of its proteinaceous and mineral constituents as bacterial metabolites. S. aureus binds to bone sialoprotein, a glycoprotein found in joints, and it produces chondrocyte proteases that hydrolyze synovial tissue.

Classification

Intra-articular sepsis may be classified in order of pathogenesis and frequency as direct hematogenous; secondary to contiguous spread from osteomyelitis; or secondary to trauma, surgery, or intra-articular injection ( Fig. 47.2 and Box 47.1 ). Most joint infections are caused by hematogenous spread, although direct contamination is not uncommon with trauma. Inoculation of the joint with bacteria can occur in association with the intra-articular injection of steroid, local anesthetic, or synthetic joint fluid. Infection rates following arthroscopy are low, ranging from 0.4% to 3.4%. ^, Armstrong and Bolding reported that sepsis following arthroscopy could be associated with inadequate arthroscope disinfection and the use of intraoperative intra-articular corticosteroids. Tosh reported that inadequate sterilization caused an outbreak of Cutibacterium acnes (or C. acnes , formerly Propionibacterium acnes ) from retained tissue within the arthroscope.

BOX 47.1

Organisms Involved in Septic Arthritis and Osteomyelitis of the Shoulder

Bacteria

Staphylococcus aureus
Staphylococcus epidermidis , Streptococcus group B
Escherichia coli , Pseudomonas aeruginosa , Haemophilus influenzae type B, Neisseria gonorrhoeae , Mycobacterium tuberculosis , and Salmonella and Pneumococcus species
Yersinia enterocolitica

Fungi

Actinomyces species
Blastomyces species
Coccidioides species
Candida albicans
Sporothrix schenckii

Reported associations

Rheumatoid arthritis: Listeria monocytogenes
Renal transplant: Aspergillus fumigatus
Newborns and pregnant women: group B β-hemolytic Streptococcus agalactiae
Lymphedema: Pasteurella multocida
Septic arthritis in systemic lupus erythematosus: Mycobacterium xenopi
Chronic vesicoureteral reflux: E. coli
Sickle cell disease: Salmonella group G

Osteomyelitis of the humerus can spread into the joint, depending on the age of the patient, the type of infecting organism, and the severity of infection. Osteomyelitis of the clavicle or scapula is uncommon, although it can occur after surgery and internal fixation, from retained shrapnel fragments, or in heroin addicts. Brancos and colleagues reported that S. aureus and Pseudomonas aeruginosa were the etiologic agents in 75% and 11% of episodes, respectively, of septic arthritis in heroin addicts. The sternoclavicular joint was involved more commonly than the shoulder joint. Chaudhuri and colleagues have reported septic arthritis of the shoulder following mastectomy and radiotherapy for breast carcinoma. Lymphedema was present in all cases. The onset of infection was subacute in all cases, and delays in diagnosis led to destruction of the joint in all but one patient.

Hematogenous osteomyelitis, although common in children, is uncommon in adults until the sixth decade or later and is usually associated with a compromised immune system. Intravenous drug use is associated with the development of osteomyelitis in adults. Direct spread from wounds or foreign bodies, including total joint and internal fixation devices, is the most common etiology of shoulder sepsis in adults. Sepsis has been reported following shoulder arthrography, treatment for retroperitoneal abscess, and various gynecologic surgeries. In 1959, Gowans and Granieri reported the relationship between intra-articular injections of hydrocortisone acetate and the subsequent development of septic arthritis. Kelly and colleagues reported that two of their six patients had a history of multiple intra-articular injections of corticosteroid. Ward and Goldner reported that chronic disease was present in more than half of their 30 cases of glenohumeral pyarthrosis and that four cases were associated with ipsilateral forearm arteriovenous dialysis fistulas. Hiemstra reported limited data on subacromial bursal sepsis. However, of the 15 cases reporting subacromial bursal infections more recently, only 1 was preceded by a subacromial injection and 10 were in those with an immunocompromised condition. Soft tissue infection about the shoulder can also manifest in the form of pyomyositis, sometimes occurring as a result of hematogenous spread. Aglas and colleagues reported sternoclavicular joint arthritis as a complication of subclavian venous catheterization. Their two cases responded to antibiotic treatment. Glenohumeral pyarthrosis has been observed following acupuncture. Lossos and colleagues reported that associated medical conditions were present in the majority of their patients with septic arthritis of the shoulder.

Bacterial colonization

The pathogenesis of bone and joint infections is related, in part, to the preferential adhesive colonization of inert substrata, such as the articular surface of joints or damaged bone whose surfaces are not integrated with healthy tissue composed of living cells and intact extracellular polymers ( Fig. 47.3 ). ^, Almost all natural biologic surfaces are lined by a cellular epithelium or endothelium, with the exceptions being intra-articular cartilage and the surface of teeth. Mature enamel is the only human tissue that is totally acellular; it is primarily composed of inorganic hydroxyapatite crystals (96% by weight), with a small amount of water (3%) and an organic matrix (<1%). Cartilage and enamel are readily colonized by bacteria because they lack the protection by natural desquamation or by intact extracapsular polysaccharides that is provided by an active cellular layer. Their acellular surfaces are similar to many of those in nature for which bacteria have developed colonizing mechanisms. Certain strains of S. aureus adhere to specific sites on collagen fibrils, a process that is mediated by specific surface receptor proteins. Dissimilarities in surface structure are probably responsible for the specificity of bacteria species in colonizing these surfaces.

Enamel is mostly crystalline and inorganic, whereas cartilage is noncrystalline and organic. Enamel contains no collagen, whereas collagen is ubiquitous in cartilage and bone. S. aureus is the natural colonizer of cartilage but not of enamel, because it contains collagen receptors. The specificity of colonization is also modulated in part by lectins and the host-derived synovial fluid, blood, and serum; by conditioning films of protein; and by polysaccharide macromolecules. The colonization of teeth by Streptococcus mutans and other organisms is a natural polymicrobial process and may be symbiotic or slowly destructive; however, bacterial colonization of articular cartilage is unnatural and rapidly destructive.

The acellular cartilage matrix and inanimate biomaterial surfaces offer no resistance to colonization by S. aureus and Staphylococcus epidermidis , respectively. The observed invasion and gradual destruction of the cartilage over time supports clinical observations of the course of untreated septic arthritis ( Fig. 47.4 ). ^, The acellular cartilaginous surfaces of joints are particularly vulnerable to sepsis because they allow direct exposure to bacteria from open trauma, surgical procedures, or hematogenous spread. This mechanism parallels previous observations on the mechanism of osteomyelitis, which suggest that the adhesion of bacteria to surfaces not protected by living cells, such as dead bone or cartilage, via receptors and extracellular polysaccharides is a factor in pathogenesis. ^,

Intra-articular sepsis and osteomyelitis

The articular cavity is a potential dead space that can provide a favorable environment for bacterial growth. In this avascular and relatively acellular sequestered space, host defense mechanisms are at a disadvantage. Synovial cells are not actively antibacterial, although they are somewhat phagocytic. White blood cells must be delivered to the area and lack a surface for active locomotion. Under such conditions, phagocytic action is expected to be impaired, especially against encapsulated organisms.

Spontaneous intra-articular sepsis of the shoulder results from random hematogenous bacterial seeding. The synovial vasculature is abundant, and the vessels lack a limiting basement membrane. Bacteremia, especially caused by Neisseria gonorrhoeae , increases the risk of intra-articular spread. Nosocomial infections in neonatal intensive care units are usually related to the presence of intravascular devices. Contiguous spread from adjacent and intracapsular metaphyseal osteomyelitis also occurs. Surgery, arthroscopy, total joint replacement, aspirations, and steroid injections can also result in the direct inoculation of bacteria into the intra-articular space. The presence of foreign bodies from trauma or after surgery (stainless steel, chrome-cobalt alloys, ultrahigh-molecular-weight polyethylene, and methylmethacrylate) increases the possibility of infection by providing a foreign body nidus for colonization, allowing antibiotic-resistant colonization to occur. ^, The presence of a foreign body also decreases the size of the inoculant required for sepsis and perturbs the host’s defense mechanisms.

Septic arthritis of the shoulder most often involves the glenohumeral joint. The acromioclavicular and sternoclavicular joints are occasionally infected in specific patient groups or after steroid injections in arthritis. Direct contamination from open wounds is also possible. Sternoclavicular sepsis is more common in drug abusers and usually involves gram-negative organisms, specifically P. aeruginosa . The involvement of S. aureus , Escherichia coli , Brucella species, and N. gonorrhoeae has also been reported.

Septic arthritis of the shoulder has been reported to represent up to 14% of all septic arthritis cases. In earlier studies the incidence was 3.4%. Caksen and colleagues reported shoulder involvement in 2 of 49 joints involved in their series of pediatric patients with septic arthritis. A more elderly population, increased trauma, and the common use of articular and periarticular steroids may be the factors in this epidemiology. The primary causal organism of shoulder sepsis is S. aureus . Sepsis in immunocompromised patients may be polyarticular as well as polymicrobial. Ten percent of septic arthritis cases involve more than one joint, and it is likely to occur in children.

Hematogenous osteomyelitis accounts for most cases of osteomyelitis in children. Contiguous osteomyelitis is more common in adults, secondary to surgery and direct inoculation. In patients older than 50 years, contiguous osteomyelitis and diseases related to vascular insufficiency are predominant. Of the bones of the shoulder, the humerus is most commonly involved in osteomyelitis. In drug abusers the clavicle is occasionally involved due to hematogenous spread. The scapula is rarely involved; usually infection occurs by direct inoculation or contiguous spread ( Fig. 47.5 and Table 47.1 ).

TABLE 47.1

Frequency of Joint Involvement in Infectious Arthritis (%)

From Mandell L, Douglas KG Jr, Bennett JE, eds. Principles and Practice of Infectious Diseases . 2nd ed. New York: John Wiley; 1985:698.

	BACTERIAL (SUPPURATIVE)
Joint	Children ^a	Adults ^b	Mycobacterial ^c	Viral
Knee	41	48	24	60
Hip	23	24	20	4
Ankle	14	7	12	30
Elbow	12	11	8	20
Wrist	4	7	20	55
Shoulder	4	15	4	5
Interphalangeal and metacarpal	1.4	1	12	75
Sternoclavicular	0.4	8	0	0
Sacroiliac	0.4	2	0	0