Immunity, inflammation and infection

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Immunity, inflammation and infection

Immune responses

Innate immunity

The innate system produces a semi-specific response to newly encountered organisms. It is also essential to triggering adaptive responses via signalling cytokines. Macrophages and dendritic cells patrol the tissues for foreign proteins likely to indicate infection. Invaders bearing foreign proteins are engulfed and destroyed by antimicrobial molecules and the complement system is activated. Once engaged, the Toll-like receptors prompt the cells to unleash particular suites of cytokines which recruit additional macrophages, dendritic cells and other immune cells to contain and destroy the infecting organisms. Dendritic cells containing engulfed protein then transit to lymph nodes where they present fragments of the pathogen’s protein to an array of T cells and release more cytokines. Lipopolysaccharide (LPS) produced by Gram-negative bacteria is a particularly powerful immune stimulator. It prompts inflammatory cells to release tumour necrosis factor alpha (TNF-alpha), interferon and interleukin-1 (IL1). These cytokines are probably the most important in controlling the inflammatory response, and also, if unchecked, in causing autoimmune disorders, e.g. rheumatoid arthritis.

At least 10 human varieties of TLRs are known. They act in pairs and each pair binds to a different class of protein characteristic of a type or group of organisms, e.g. Gram-negative bacteria, single-stranded DNA viruses or flagellin. The released cytokines generate the typical symptoms of infection—fever and flu-like symptoms.

Overactivity of this innate system can lead to potentially fatal sepsis. TLRs may also be implicated in autoimmunity by responding inappropriately, for example to damaged cells. A range of drugs that activate particular TLRs are in advanced stages of testing, e.g. as vaccine adjuvants or antiviral agents. Inhibitors are also under development for treating sepsis, inflammatory bowel disease and autoimmune diseases, so far with limited success.

Inflammation

Acute inflammation

Introduction: Acute inflammation is the principal mechanism by which living tissues respond to injury. The purpose is to neutralise the injurious agent, to remove damaged or necrotic tissue and to restore the tissue to useful function. The central feature is formation of an inflammatory exudate with three principal components: serum, leucocytes (predominantly neutrophils) and fibrinogen.

Formation of inflammatory exudate involves local vascular changes collectively responsible for the four ‘cardinal signs of Celsus’—rubor (redness), tumor (swelling), calor (heat) and dolor (pain)—as well as loss of function. These vascular phenomena are described in Figure 3.1. The outcomes of acute inflammation are summarised in Figure 3.2.

Abscess formation (Fig. 3.3): An abscess is a collection of pus (dead and dying neutrophils plus proteinaceous exudate) walled off by a zone of acute inflammation. Acute abscess formation particularly occurs in response to certain pyogenic microorganisms that attract neutrophils but are resistant to phagocytosis and lysosomal destruction. Abscesses also form in response to localised tissue necrosis and to some organic foreign bodies (e.g. wood splinters, linen suture material). The main pyogenic organisms of surgical importance are Staphylococcus aureus, some streptococci (particularly Strep. pyogenes), Escherichia coli and related Gram-negative bacilli (‘coliforms’), and Bacteroides species (spp.).

Without treatment, abscesses eventually tend to ‘point’ to a nearby epithelial surface (e.g. skin, gut, bronchus), and then discharge their contents. If the injurious agent is thereby eliminated, spontaneous drainage leads to healing. If an abscess is remote from a surface (e.g. deep in the breast), it progressively enlarges causing much tissue destruction. Sometimes local defence mechanisms are overwhelmed, leading to runaway local infection (cellulitis) and sometimes systemic sepsis.

Even with small, well-localised abscesses, showers of bacteria may enter the general circulation (bacteraemia) but are mopped up by hepatic and splenic phagocytic cells before they can proliferate. This is responsible for the swinging pyrexia characteristic of an abscess. The abscess site may not be clinically evident if deep-seated (e.g. subphrenic or pelvic abscess) and the patient may be otherwise well. In the presence of an abscess, circulating neutrophils rise dramatically as they are released from the bone marrow; thus, a marked neutrophil leucocytosis (i.e. WBC greater than 15 × 109/L with more than 80% neutrophils) usually indicates a pyogenic infection. Severe infection causing excessive cytokine responses spilling over into the systemic circulation causes systemic sepsis and rapid clinical deterioration (see p. 51).

Wound healing

Healing by primary intention: The simplest example of organisation and repair is healing of an uncomplicated skin incision (see Fig. 3.4). There is no necrotic tissue and the wound margins are brought into apposition with sutures. An acute inflammatory response develops in the vicinity of the incision, and by the third day granulation tissue bridges the dermal defect. In the meantime, epithelium proliferating rapidly from the wound edges restores the epidermis. Fibroblasts invade the granulation tissue, laying down collagen so the repair is strong enough for suture removal after 5–10 days. The scar is still red but blood vessels gradually regress and it becomes a pale linear scar within a few months. This is known as healing by primary intention.

Healing by secondary intention: If tissue loss prevents the wound edges from coming together, healing has to bridge the defect, which is initially filled with blood clot. This later becomes infiltrated by vascular granulation tissue from the healthy wound base. Inflammatory exudate solidifies, forming a protective scab. Fibroblasts invade and lay down collagen in the extracellular spaces; after about a week, some fibroblasts differentiate into myofibroblasts and contraction of their myofibrils eventually shrinks the wound defect by 40–80%, beginning about 2 weeks after the injury. Over the weeks and months, blood vessels regress and more collagen is formed, leaving a relatively avascular scar; gradual contraction of the mature collagen (cicatrisation), combined with wound contraction, ensures the final scar is much smaller than the original defect. The epidermal defect is gradually bridged by epithelial proliferation from the wound margins. Epithelial cells slide over each other beneath the edges of the scab on the granulation tissue surface and the scab is eventually shed. This whole process is known as healing by secondary intention (see Fig. 3.4).

Chronic inflammation

Sometimes an injurious agent persists over a long period causing continuing tissue destruction. The body attempts to deal with the original and the continuing damage by acute inflammation, organisation and repair, all at the same time. The damaged area may display several pathological processes at once, i.e. tissue necrosis, an inflammatory response, granulation tissue formation and fibrous scarring. This is known as chronic inflammation and is characterised histologically by a predominance of macrophages (sometimes forming giant cells), responsible for phagocytosis of necrotic debris. Lymphocytes and plasma cells are also present, indicating immunological involvement in chronic inflammation.

Chronic inflammation represents a tenuous balance between a persistent injurious agent and the body’s reparative responses. Healing only occurs if the injurious agent is removed and then proceeds in the usual manner but often with much more scarring.

A range of agents can lead to chronic inflammation. The clinical patterns can be grouped into three categories:

Chronic abscesses

A chronic abscess arises if the agent causing an acute abscess is not fully eliminated. Pus continues to be formed and the abscess either persists, discharges continuously via a sinus or else ‘points’ and discharges periodically with the sinus healing over between times. A chronic abscess wall consists of fibrous scar tissue lined with granulation tissue.

Causes of chronic abscesses include:

• Infected foreign bodies are probably the most common cause in modern surgical practice. Foreign bodies implanted deliberately may become infected (e.g. synthetic mesh for inguinal hernia repair, prosthetic hip joint); others become embedded during trauma (e.g. glass fragments)

• Dead (necrotic) tissue can act as a foreign body, forming a nidus for infection. For example, diabetes may be complicated by deep foot infections with necrosis of tendon and bone leading to chronic abscesses and ulcers. Hairs deeply implanted in the natal cleft skin may cause a pilonidal sinus or abscess. An infected dead tooth or root fragment may intermittently discharge via an associated ‘gum boil’ (see Fig. 3.6). Chronic osteomyelitis is associated with remnants of dead bone known as sequestra

• Deep abscesses. A chronic abscess can arise without a foreign body if the acute abscess is so deep as to prevent spontaneous drainage. The best example is a subphrenic abscess

Chronic ulcers

An ulcer is defined as a persistent defect in an epithelial or mucosal surface. Except for malignant ulcers, ulceration usually results from low-grade mechanical or chemical injury to epithelium and supporting tissue, together with an impaired reparative response. For example, elderly debilitated patients are susceptible to pressure sores (‘bed sores’) which develop over bony prominences such as the sacrum and heels. In these cases, immobility or diminished protective pain responses prevent the patient regularly shifting position to relieve the pressure of body weight. Tissue necrosis results and healing is impaired by the presence of necrotic tissue and continuing pressure ischaemia. Other contributing factors may include poor tissue perfusion (from cardiac or peripheral vascular disease) and malnutrition.

Another common ulcer is the longstanding leg ulcer in chronic venous insufficiency; this fails to heal because of local nutritional impairment induced by high venous pressure and oedema and is often exacerbated by secondary infection. Ischaemic leg ulcers fail to heal because of insufficient arterial blood flow.

In summary, a chronic ulcer represents an unresolved balance between persistent damaging factors and inadequate reparative responses. The principle of managing ulcers is to remove damaging factors and promote healing mechanisms.

Specific granulomatous infections and inflammations

Certain microorganisms excite a minimal acute inflammatory response whilst stimulating a chronic inflammatory response almost from the outset. These include Mycobacterium tuberculosis, Mycobacterium leprae and Treponema pallidum (causing tuberculosis, leprosy and syphilis, respectively). Lesions are characterised by accumulation of macrophages forming granulomas, and the diseases are known as granulomatous infections.

A tuberculous cold abscess, now rare in developed countries, is a pus-like accumulation of liquefied caseous material containing the occasional mycobacterium. In contrast to a pyogenic abscess, the lesion is cold to the touch since there is no acute inflammatory vascular response. Cervical lymph node tuberculosis (‘scrofula’) often produced a ‘collar-stud’ abscess, i.e. a superficial fluctuant abscess communicating with a deep (and often larger) lymph node abscess via a small fascial defect. Tuberculosis of the thoracolumbar spine causes local destruction and deformity and may track down beneath the inguinal ligament within the psoas sheath, presenting as a ‘psoas abscess’ in the groin. A tuberculous ulcer overlying tuberculous inguinal nodes is shown in Figure 3.7.

Certain extremely fine particulate materials such as talc and beryllium produce similar granulomatous reactions known as foreign body granulomas. Talc was traditionally used as a lubricant powder in surgical gloves and sometimes caused severe peritoneal granulomatous reactions. For this reason, when body cavities are opened, best practice is to use gloves without powder.

Infection

General principles

It is important to distinguish between colonisation, infection and sepsis:

Clinically significant infection arises when the size of an inoculum or the virulence of a microorganism is sufficient to overcome the innate and adaptive immune responses and lead to symptoms. The virulence of an organism depends on its qualities of adherence and invasiveness and its ability to produce toxins. Tissue invasion of microorganisms may be enhanced by their secretion of enzymes (e.g. hyaluronidase and streptokinase), by mechanisms to avoid phagocytosis (e.g. encapsulation or spore formation), by inherent resistance to lysosomal destruction or by their ability to kill phagocytes. Toxins may be secreted by the organism (exotoxins) or released upon the death of the organism (endotoxins). In either case the toxin may produce local tissue damage (e.g. gas gangrene), cause distant toxic effects (e.g. tetanus), or activate cytokine systems to cause systemic sepsis, sometimes including disseminated intravascular coagulopathy.

Infections may be community-acquired (e.g. pneumococcal lobar pneumonia in a fit young adult) or hospital-acquired. The latter are also known as nosocomial infections and are defined as infections not present or incubating at the time of admission. A third category is health care-associated infection (HCAI) in patients making frequent contacts with health care institutions or in long-term care. Nosocomial infection may be acquired by cross-infection from infected patients, from contaminated furnishings, or from ‘carriers’ among staff by inhalation, ingestion or through contamination of medical equipment and devices such as intravenous cannulae or urinary catheters. These infections are often caused by antibiotic-resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA). Risk of such infections can be drastically reduced by the simple measure of everyone in contact with patients cleansing their hands with alcohol-based gel between every patient contact. Known MRSA-infected patients or carriers should be isolated when in hospital. Patients having operations where infection carries very high risk should ideally be treated in areas separated from sick patients, especially emergency admissions from long-term care institutions. Particular risk is associated with eye surgery, joint replacements and prosthetic vascular grafts.

Postoperative patients are at particular risk of nosocomial infections (e.g. pneumonias, urinary tract infections) as host defences are impaired by the surgical assault, and physiological protective mechanisms are disrupted allowing infection to gain ascendancy. For example, neutropenia predisposes to infection, and smokers are more liable to develop bronchopneumonia following general anaesthesia. The surgical patient’s general resistance may be further impaired by malnutrition, malignancy, rheumatoid disease, corticosteroids or other immunosuppressive drugs.

In post-surgical (‘surgical site’) infections, organisms enter the tissues via an abnormal breach of epithelium. This may be surface damage (such as a surgical or traumatic wound or an injection) or result from a perforated viscus. The infecting organisms are often part of the patient’s normal skin, bowel or respiratory tract flora or are normally present in the external environment. For example, Staph. epidermidis is commonly present on skin but causes serious chronic infection of implanted arterial grafts.

Methods of control of nosocomial infection

Universal blood and body fluid precautions

Increasing awareness of blood-borne viral infections such as hepatitis B and C and the prevalence of HIV led to the concept of universal blood and body fluid precautions in combating cross-infection between patients and staff. Staff often try to be vigilant with high-risk patients but relax at other times. However, this extra care soon lapses. For this reason, every patient should be assumed to be a potential carrier of blood-borne infection and precautions employed whenever skin is likely to be breached and whenever instruments contaminated with blood or other body fluids are handled. Transmission of infection occurs in obvious situations such as needle-stick injury (see below) and with less obvious events such as splashes of infected material into the eye.

Disposable gloves should be worn for all medical procedures and physical examinations except for palpating skin with no obvious open lesion in patient or examiner. Staff with broken skin should apply occlusive dressings. Protective eyewear should be worn during invasive procedures to prevent conjunctival splashes.

Hepatitis B vaccination:

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