The Immunocompromised Patient

Physical Barriers

Physical barriers, the first line of defense against microorganisms, consist of intact skin, mucosa, cilia, biofilm, gastric acid, antimicrobial peptides and proteins on skin and mucous membranes, and resident microflora. Smoking and pulmonary disease impair physical barriers in the respiratory tract whereas mechanical ventilation or tracheostomy introduces large numbers of microbes that often overwhelm natural clearance. Gastric acid and pancreatic enzymes have antibacterial properties that prevent overgrowth in the upper gastrointestinal tract. Normal peristalsis and mucosal shedding help maintain normal gut flora. Alterations in these factors, such as broad-spectrum antibiotics, alter normal flora and permit overgrowth of pathogens such as Candida , multidrug-resistant organisms, and Clostridium difficile.

Initial Inflammatory Response and Innate Immunity

The initial inflammatory response to microbial invasion promotes phagocytosis and microbial killing while activating the immune system. This innate immune response is not dependent on prior exposure to the pathogen. The initial inflammatory response factors, mainly produced in the liver, activate many cell types to synthesize and release cytokines, chemokines, and “trigger molecules” that kill the invading organism. This response delivers humoral and cellular immune components to sites of inflammation and initiates antibody production. Cytokines, platelet-activating factor, and hormone-like proteins are secreted from various immune cells and play essential roles in mediation of this response. Cytokines cause migration and adhesion of polymorphonuclear leukocytes and monocytes to sites of bacterial invasion. These cells release granules of substances that mediate vasodilation and increased vascular permeability, leading to edema, warmth, and redness, and allow both phagocytic cells and humoral components to be concentrated at the site of infection.

Reticuloendothelial System

The reticuloendothelial system, composed of tissue macrophages and their blood-borne counterparts, monocytes, removes particulate matter, including microbes, from the lymph and blood. The tissue component is concentrated in the lymph nodes, spleen, liver, marrow, and lung and has particular affinity for encapsulated bacteria, such as pneumococci, meningococci, and Haemophilus influenzae . The overwhelming sepsis from encapsulated organisms that can occur in patients with asplenia demonstrates the vital importance of this non–microbe-specific system.

Humoral Immunity

Cell-Mediated Immunity

Cell-mediated immunity (CMI) includes immune responses mediated by T lymphocytes, natural killer (NK) cells, and mononuclear phagocytes. CMI is crucial in controlling infections caused by microbes that survive and replicate intracellularly, including most viruses and some bacterial (obligate and facultative intracellular types), fungal, and protozoan pathogens.

Only 5% of lymphocytes are in circulating blood. Most mature and are active in the marrow, thymus, spleen, and lymph nodes. The last two sites expose T cells to circulating antigens from invading microbes. Specialized antigen-presenting cells in the lymphoid system sequester antigen and antigen-antibody complexes and present them to T cells via a cell surface molecule called the major histocompatibility complex (MHC). Only with this specific presentation can a T lymphocyte become activated against a particular antigen.

Two major types of T lymphocytes are CD4 (helper cell) and CD8 (suppressor cell). CD4 lymphocytes provide help for other cells in the immune system, including enhanced B-cell antibody production and the production of cytokines. CD8 lymphocytes are generally cytotoxic and mediate the eradication of virally infected target cells and certain tumors. A decline in the number of CD4 cells, with predominance of CD8 cells, is responsible for the increased susceptibility to infection in patients with human immunodeficiency virus (HIV). Despite the cytotoxicity of CD8 cells, immunity is reduced without adequate numbers of CD4 cells.

Patients with defects in CMI are at increased risk for disseminated infection with intracellular bacteria, such as Mycobacterium tuberculosis, Listeria monocytogenes, and Salmonella species. The DNA viral infections, such as cytomegalovirus, herpes simplex, and varicella-zoster, also affect these patients more severely, as do fungal infections with Candida, Cryptococcus, Mucor, Aspergillus, and Pneumocystis . Finally, some protozoa are pathogenic in patients without intact CMI, such as Toxoplasma gondii . Some infections are seen only below a certain CD4 cell count. Pneumocystis pneumonia, for example, is seen almost exclusively in patients with CD4 counts below 200 cells/mL, whereas almost all patients with toxoplasmosis or cryptococcal meningitis have counts below 100 cells/mL. In settings where the CD4 count is not readily available, such as the ED, an absolute lymphocyte count of less than 1000 cells/mL is suggestive of a CD4 count of less than 200 cells/mL.

NK cells, closely related to lymphocytes, are important in the innate immune response and are found in high concentrations in blood and spleen. NK cells recognize infected cells and directly kill these cells while secreting cytokines that activate macrophages to destroy phagocytosed microbes. NK cells are important in defense against intracellular microbes, particularly viruses and intracellular bacteria such as L. monocytogenes .

Granulocytic Phagocytes

Granulocytic phagocytes are the cellular effectors of microbe killing, engulfing them and enzymatically lysing their cell membranes or walls. Two major types are polymorphonuclear leukocytes (neutrophils) and macrophages (the tissue version of circulating monocytes). Macrophages have surface receptors that recognize nonvertebrate carbohydrates, such as mannose, to identify and attack “invaders” rather than “self.”

Two other types of granulocytes, eosinophils and basophils, are less involved in the ingestion of organisms. Eosinophils attack certain parasitic helminths through the release of toxic proteins. This cell type can increase from 3% to 20% during times of high parasite load. Basophils (rare in circulation) and their tissue counterparts, mast cells, have a high affinity for IgE. On exposure to bound IgE, they release granules with histamine, prostaglandins, leukotrienes, and endogenous heparin to promote blood flow and inflammatory response in combating arthropod ectoparasites or helminth endoparasites. Activation of basophils by IgE bound to pollen and other allergens may affect the allergic-inflammatory response with increased vascular permeability, bronchospasm, and vasodilation.

Half of all neutrophils that leave the bone marrow circulate in the plasma. The other half become marginated, adhering to endothelium, primarily in the lungs, liver, and spleen. During periods of stress or with endogenous or exogenous catecholamines or corticosteroids, these neutrophils demarginate and enter the circulation. If the patient is not neutropenic, demargination causes an increased peripheral neutrophil count composed of mature cells. With bacterial infection, an increased proportion of immature (band) forms is more typically seen.

Neutrophils (and tissue macrophages) bind to and ingest bacteria through phagocytosis. This process is enhanced by proteins called opsonins that bind to bacterial surfaces, particularly important in defense against infection with S. pneumoniae, Streptococcus pyogenes, H. influenzae , and Staphylococcus aureus . C-reactive protein, one of the initial inflammatory response proteins, fulfills this function for certain bacteria, including S. pneumoniae . IgG and complement protein C3b also opsonize bacteria, again illustrating the interdependence of the immune system. Actual killing takes place within granulocytes when cytoplasmic granules enzymatically produce potent oxidants. Granulocytes further control bacterial proliferation at the site of infection by elaborating lactoferrin, which locally binds free iron necessary for bacterial replication.

In addition to phagocytosis, macrophages (located in the spleen, alveoli, liver, and lymph nodes) modulate the immune response by presenting antigens to lymphocytes and releasing cytokines and complement components. Activation of macrophages to ingest bacteria depends on interaction with interferon-γ, a cytokine manufactured by T cells, again bridging different components of the immune system.