30 Infections in the compromised host

The human body has a complex system of protective mechanisms to prevent infection. This involves both the adaptive (cellular and humoral) immune system and the innate defence system (e.g. skin, mucous membranes). (These have been described in detail in Chapters 9 10 and 11.) So far, we have concentrated on the common and serious infections occurring in people whose protective mechanisms are largely intact. In these circumstances, the interactions between host and parasite are such that the parasite has to use all its guile to survive and invade the host, and the healthy host is able to combat such an invasion. The focus of this chapter involves the infections that arise when the host defences are compromised, resulting in the host–parasite equation being weighted heavily in favour of the parasite.

The compromised host

Compromised hosts are people with one or more defects in their body’s natural defences against microbial invaders. Consequently they are much more liable to suffer from severe and life-threatening infections. Modern medicine has effective methods for treating many types of cancers, is improving organ transplantation techniques and has developed technology that enables people with otherwise fatal diseases to lead prolonged and productive lives. A consequence of these achievements, however, is an increasing number of compromised people prone to infection. In addition, viral infections including HIV and HTLV result in a compromised immune system referred to as AIDS and adult T-cell leukaemia/lymphoma (ATLL), respectively.

The host can be compromised in many different ways

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

• defects, accidental or intentional, in the body’s innate defence mechanisms

• deficiencies in the adaptive immune response.

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

• Primary immunodeficiency is inherited or occurs by exposure in utero to environmental factors or by other unknown mechanisms. It is rare, and varies in severity depending upon the type of defect.

• Secondary or acquired immunodeficiency is due to an underlying disease state (Table 30.2) or occurs as a result of treatment for a disease.

Table 30.1 Factors that make a host compromised

Factors affecting innate systems
Primary	Complement deficiencies, phagocyte cell deficiencies
Secondary	Burns, trauma, major surgery, catheterization, foreign bodies (e.g. shunts, prostheses), obstruction
Factors affecting adaptive systems
Primary	T-cell defects, B-cell deficiencies, severe combined immunodeficiency
Secondary	Malnutrition, infectious diseases, neoplasia, irradiation, chemotherapy, splenectomy

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:

• drastic effects on the structure of the lymphoid organs (Fig. 30.4)

• gross reductions in the synthesis of complement components

• sluggish chemotactic responses of phagocytes

• lowered concentrations of secretory and mucosal IgA

• reduced affinity of IgG

• in particular, a serious deficit in circulating T-cell numbers (Fig. 30.5), leading to inadequate cell-mediated responses.

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:

• Cytotoxic agents such as cyclophosphamide and azathioprine cause leukopenia or deranged T- and B-cell function.

• Corticosteroids reduce the number of circulating lymphocytes, monocytes and eosinophils and suppress leukocyte accumulation at sites of inflammation.

• Radiotherapy adversely affects the proliferation of lymphoid cells.

Therefore a patient receiving treatment for neoplastic disease will be immunocompromised as a result of both the disease and the treatment.

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.

Microbes that infect the compromised host

Immunocompromised people can become infected with any pathogen able to infect immunocompetent individuals as well as those opportunist pathogens that do not cause disease in a healthy person. They may be lethal when the host defences are lowered. Different types of defect predispose to infection with different pathogens depending upon the critical mechanisms operating in the defence against each microorganism (Fig. 30.6). Here, we will concentrate mainly on the opportunist infections and refer to other chapters for information about other pathogens.

Figure 30.6 Ecthyma gangrenosum in a child with Pseudomonas septicaemia associated with immunodeficiency.

(Courtesy of H. Tubbs.)

Infections of the host with deficient innate immunity due to physical factors

Burn wound infections

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:

• Pseudomonas aeruginosa and other Gram-negative rods

• Staphylococcus aureus

• Streptococcus pyogenes

• other streptococci

• enterococci.

Candida spp. and Aspergillus together account for about 5% of infections. Anaerobes are rare in burn wound infections. Herpesvirus infections have been reported and are most likely due to reactivation at a damaged skin site.

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:

• abnormalities in the antibacterial activities of neutrophils

• deficiencies in serum opsonins.

Added to these are the virulence factors of the organism, which include the production of elastase, protease and exotoxin. This combination makes P. aeruginosa the most devastating Gram-negative pathogen of burned patients. Treatment is difficult because of the organism’s innate resistance to many antibacterial agents. A combination of aminoglycoside, usually gentamicin or tobramycin, with one of the beta-lactams such as azlocillin, ceftazidime or imipenem is usually favoured, but several units have reported strains resistant to these agents.

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.