The host can be compromised in many different ways

Compromise can take a variety of forms, falling into two main groups:

These disorders of the immune system can be further subclassified as ‘primary’ or ‘secondary’ (Table 30.1):

Table 30.1 Factors that make a host compromised

Table 30.2 Infections that cause immunosuppression

Viral	Bacterial
Measles	Mycobacterium tuberculosis
Mumps	Mycobacterium leprae
Congenital rubella Epstein–Barr virus Cytomegalovirus HIV-1, HIV-2 HTLV-1	Brucella spp.

Primary defects of innate immunity include congenital defects in phagocytic cells or complement synthesis

Congenital defects in phagocytic cells confer susceptibility to infection, and of these perhaps the best known is chronic granulomatous disease (Fig. 30.1), in which an inherited failure to synthesize cytochrome b₂₄₅ leads to a failure to produce reactive oxygen intermediates during phagocytosis. As a result, the neutrophils cannot kill invading pathogens.

Figure 30.1 Bilateral draining lymph nodes in an 18-month-old boy with chronic granulomatous disease. Abscesses caused by Staphylococcus aureus had developed in both groins and had to be surgically drained.

(Courtesy of A.R. Hayward.)

The central role of complement in the innate defence mechanisms is undisputed, and inability to generate classical C3 convertase (see Ch. 10) through congenital defects in the synthesis of the early components, particularly C4 and C2, is associated with a high frequency of extracellular infections.

Secondary defects of innate defences include disruption of the body’s mechanical barriers

A variety of factors can disrupt the mechanical non-specific barriers to infection. For example, burns, traumatic injury and major surgery destroy the continuity of the skin and may leave poorly vascularized tissue near the body surface, providing a relatively defenceless site for microbes to colonize and invade. In health, the mucosal barriers of the respiratory and alimentary tract are vital to prevent infection. Damage sustained, for example, through endoscopy, surgery or radiotherapy, provides easy access for infecting organisms. Devices such as intravascular and urinary catheters, or procedures such as lumbar puncture or bone marrow aspiration, allow organisms to bypass the normal defences and enter normally sterile parts of the body. Foreign bodies such as prostheses, e.g. hip joints or heart valves, and cerebrospinal fluid (CSF) shunts alter the local non-specific host responses and provide surfaces that microbes can colonize more readily than the natural equivalents.

The adage ‘obstruction leads to infection’ is a valuable reminder that the defences of many body systems work partly through the clearance of undesirable materials, e.g. by urine flow, ciliary action in the respiratory tract, and peristalsis in the gut. Interference with these mechanisms as a result of pathologic obstruction, central nervous system dysfunction or surgical intervention tends to result in infection.

Primary adaptive immunodeficiency results from defects in the primary differentiation environment or in cell differentiation

The major congenital abnormalities arising in the adaptive immune system are depicted in Figure 30.2. A defect in the stromal microenvironment in which lymphocytes differentiate may lead to failure to produce B cells (Bruton-type agammaglobulinaemia) or T cells (DiGeorge syndrome).

Figure 30.2 The major primary cellular immunodeficiencies. The deficiency states (shown in purple boxes) derive either from defects in the primary differentiation environment (bone marrow or thymus) or during cell differentiation (shown as dashed arrows derived from the differentiation state indicated).

Differentiation pathways themselves may also be affected. For example, a non-functional recombinase enzyme will prevent the recombination of gene fragments that form the B-cell antibody or the T-cell receptor variable regions for antigen recognition, with a resulting severe combined immunodeficiency (SCID).

The most common form of congenital antibody deficiency – common variable immunodeficiency – is characterized by recurrent pyogenic infections and is probably heterogeneous. Although the number of immature B cells in the marrow tends to be normal, the peripheral B cells are either low in number or in some cases absent. Where present, they are unable to differentiate into plasma cells in some cases or to secrete antibody in others.

Transient hypogammaglobulinaemia of infancy, characterized by recurrent respiratory infections, is associated with a low serum IgG concentration, which often normalizes abruptly by 3–4    years of age (Fig. 30.3).

Figure 30.3 Serum immunoglobulin concentrations in a boy with transient hypogammaglobulinaemia compared with the range of normal controls. The patient developed mild paralytic polio when immunized at 4    months of age with live attenuated (Sabin) vaccine.

Immunoglobulin deficiency occurs naturally in human infants as the maternal serum IgG concentration decays. It is a serious problem in very premature babies as, depending on the gestational age, maternal IgG may not have crossed the placental barrier.

Causes of secondary adaptive immunodeficiency include malnutrition, infections, neoplasia, splenectomy and certain medical treatments

Worldwide, malnutrition is common and the most important cause of acquired immunodeficiency. The major form, protein–energy malnutrition (PEM) presents as a wide range of disorders, with kwashiorkor and marasmus at the two poles. It results in:

Infections themselves are often immunosuppressive (see Table 30.2), and none is more so than HIV infection, which gives rise to AIDS (see Ch. 21). Neoplasia of the lymphoid system frequently induces a state of reduced immunoreactivity, and splenectomy, for whatever reason, results in impaired humoral responses.

Figure 30.4 Thymic histology in normal children and children with protein–energy malnutrition (PEM). (A) Normal thymus showing a cortex and medullary zones. (B) Acute involution in PEM characterized by lobular atrophy, loss of distinction between cortex and medulla, depletion of lymphocytes and enlarged Hassall’s corpuscles. C, cortex; CT, connective tissue; H, Hassall’s corpuscle; L, lobule; M, medulla.

(Courtesy of R.K. Chandra.)

Figure 30.5 The proportion of T cells is decreased in malnourished patients compared with healthy controls. B-cell counts are usually unaltered, and lymphocytes lacking T- and B-cell markers are increased.

Treatment of disease can also cause immunosuppression. For example:

It is important to recognize immunodeficiencies and to understand which procedures are likely to compromise the natural defences of a patient. Due to improvements in medical technology, many immune defects, particularly immunosuppression resulting from radiotherapy or cytotoxic drugs, are transient, and patients who survive the period of immunosuppression have a good chance of a complete recovery.

Burns damage the body’s mechanical barriers, neutrophil function and immune responses

Burn wounds are sterile immediately after the burn is inflicted, but inevitably become colonized within hours with a mixed bacterial flora. Burn injuries cause direct damage to the mechanical barriers of the body and abnormalities in neutrophil function and immune responses. In addition, there is a major physiologic derangement with loss of fluids and electrolytes. The burn provides a highly nutritious surface for organisms to colonize, and the incidence of serious infection varies with the size and depth of the burn and the age of the patient. Topical antimicrobial therapy should prevent infection of burns of    <       30% of the total body area, but larger burns are always colonized. Non-invasive infection is confined to the eschar, which is the non-viable skin debris on the surface of deep burns. It is characterized by rapid separation of the eschar from the underlying tissue and a heavy exudate of purulent material from the burn wound. The systemic symptoms are usually relatively mild. However, organisms can invade from heavily colonized burn eschars into viable tissue beneath and rapidly destroy the tissue, converting partial-thickness burns into full skin-thickness destruction. From here, it is a small step to invasion of the lymphatics and thence to the bloodstream or direct invasion of blood vessels, and to septicaemia. Septicaemia in patients with burns is often polymicrobial.

The major pathogens in burns are aerobic and facultatively anaerobic bacteria and fungi

The most important pathogens in burn wounds are:

P. aeruginosa is a devastating Gram-negative pathogen of burned patients

P. aeruginosa is an opportunist Gram-negative rod that has a long and infamous association with burn infections. It grows well in the moist environment of a burn wound, producing a foul, green-pigmented discharge and necrosis. Invasion is common, and the characteristic skin lesions (ecthyma gangrenosum) that are pathognomonic of P. aeruginosa septicaemia may appear on non-burned areas (see Fig. 30.6). Host factors predisposing to infection include:

It is virtually impossible to prevent colonization. Prevention of infection depends largely on inhibiting the multiplication of organisms colonizing the burn by applying topical agents such as silver nitrate.

Staph. aureus is the foremost pathogen of burn wounds

The most important predisposing factor to Staph. aureus infection in burns patients appears to be an abnormality of the antibacterial function of neutrophils. Infections follow a more insidious course than streptococcal infections (see below), and it may be several days before the full-blown infection is apparent. The organism is capable of destroying granulation tissue, invading and causing septicaemia. Staph. aureus infections of skin are discussed in detail in Chapter 26. Treatment with antistaphylococcal agents such as cloxacillin or nafcillin (or a glycopeptide if methicillin-resistant Staph. aureus is isolated) should be administered if there is evidence of invasive infection. Every effort should be made to prevent the spread of staphylococci from patient to patient. Although transmissible by both air-borne and contact routes, the contact route is by far the more important.

The high transmissibility of Strep. pyogenes makes it the scourge of burns wards

Strep. pyogenes (group A strep) infections of skin and soft tissue are discussed in some detail in Chapter 23. Strep. pyogenes was the most common cause of burn wound infection in the pre-antibiotic era and is still to be feared in burns wards. The infection usually occurs within the first few days of injury and is characterized by a rapid deterioration in the state of the burn wound and invasion of neighbouring healthy tissue. The patient may become severely toxic and will die within hours unless treated appropriately. Strep. pyogenes rarely infects healthy granulation tissue, but freshly grafted wounds may become infected, resulting in destruction of the graft. Every effort should be made to prevent spread. Penicillin is the drug of choice for treatment, and erythromycin or vancomycin can be used for penicillin-allergic patients.

Beta-haemolytic streptococci of other Lancefield groups (notably groups C and G) and enterococci are also important pathogens of burn wounds.

Staph. aureus is the most important cause of surgical wound infection

Staph. aureus surgical wound infection (see Ch. 36) may be acquired during surgery or postoperatively and may originate from the patient or from another patient or staff member. The wound is less well defended than normal tissue; it may have a damaged blood supply and there may be foreign bodies such as sutures. Classic studies of wound infections have shown that far fewer staphylococci are needed to initiate infection around a suture than in normal healthy skin. Wound infections can be severe and the organisms can invade the bloodstream, with consequent seeding of other sites such as the heart valves, causing endocarditis (see Ch. 29) or bones, causing osteomyelitis (see Ch. 26), thereby further compromising the patient.