Chapter 7. Deficiencies of the Host Response

The nonspecific inflammatory response and the immune response act synergistically in defense against infection. Deficits in either process often result in increased susceptibility to attack by pathogenic microorganisms, manifested clinically as recurrent or intractable infection or as an opportunistic infection, ie, infection by a pathogen of low virulence that does not cause disease in a normal host.

Deficiency of the Vascular Response

Diabetes Mellitus

In diabetes mellitus, involvement of small arterioles characterized by thickening of the basement membrane increases susceptibility to infection. These abnormal vessels may fail to dilate and do not show the normal changes in permeability associated with the acute inflammatory response.

Vascular Disease (Ischemia)

Severe arterial narrowing limits the amount of blood entering an injured area during acute inflammation and contributes to the decreased resistance to infection observed in older patients, in whom severe arterial narrowing due to atherosclerosis is common.

Abnormal Neutrophil Function

Quantitative Disorders

Neutropenia (decreased numbers of neutrophils) due to any cause is associated with a defective cellular response in acute inflammation that leads to increased susceptibility to infection. A severe reduction in the peripheral blood neutrophil count (< 1000/μL) must occur before the risk of infection is significantly increased. The most common cause of neutropenia in clinical practice is cancer treatment utilizing cytotoxic drugs and radiation therapy (Chapter 26: Blood: III. the White Blood Cells).

Qualitative Disorders

Abnormal neutrophil function may be manifested as disorders of neutrophil motility. Intrinsic abnormalities that affect motility are rare and include lazy leukocyte syndrome, in which neutrophil emigration is abnormal, and Chédiak-Higashi syndrome, which is characterized by defective movement and degranulation of neutrophils associated with the presence of large cytoplasmic granular inclusions composed of greatly enlarged lysosomes. The condition is inherited as an autosomal recessive trait. Melanosomes also are abnormal, leading to partial albinism.

Neutrophil motility may also be impaired by lack of the CD11/CD18 cell adhesion complex, deficiency of complement components, or the presence of antineutrophil antibodies in rheumatoid arthritis.

Disorders of Phagocytosis

Abnormalities of phagocytosis may result from deficiency of opsonins, as occurs in hypogammaglobulinemia and complement factor 3 (C3) deficiency. Impaired degranulation occurs in Chédiak-Higashi syndrome and in use of antimalarial drugs and corticosteroids.

Disorders of Microbial Killing

Chronic Granulomatous Disease of Childhood

Chronic granulomatous disease occurs as an X-linked or autosomal recessive disorder characterized by decreased ability of neutrophils to produce hydrogen peroxide. The different forms of the disease are associated with different enzyme deficiencies that interfere with energy production at the cellular level.

The disease becomes manifest in the first few years of life, chiefly in males, and is characterized by recurrent infections of skin, lungs, bone, and lymph nodes. Patients are susceptible to diseases caused by organisms such as staphylococci and Serratia that produce catalase, which destroys the small amount of hydrogen peroxide produced in cells and leads to failure of bacterial killing.

The diagnosis may be established by (1) absent nitroblue tetrazolium dye reduction by neutrophils in vitro; (2) decreased bacterial killing curves by neutrophils in test systems; and (3) histologic examination of involved tissue, which shows granuloma formation occurring as a second line of defense against organisms that normally would be removed by the acute inflammatory response.

Myeloperoxidase Deficiency

Myeloperoxidase acts with hydrogen peroxidase and halide to effect bacterial killing. Deficiency of myeloperoxidase is a rare cause of clinically significant failure of neutrophil function.

Granulocytic Leukemia

Neutrophils, monocytes, or both are increased in number in granulocytic leukemias (cancers of cells of the myeloid series; Chapter 26: Blood: III. the White Blood Cells), but they usually function abnormally. The number of normally functioning noncancerous neutrophils is usually greatly decreased in granulocytic leukemia.

Congenital (Primary) Immunodeficiency

All types of congenital immunodeficiency are rare.

Severe Combined Immunodeficiency

Severe combined immunodeficiency disease (SCID) is one of the most severe forms of congenital immunodeficiency. It is characterized by a defect of lymphoid stem cells (① in Figure 7-1) that leads to failure of development of both T and B lymphocytes. The thymus fails to descend normally from the neck into the mediastinum and is almost devoid of lymphocytes, as are lymph nodes (Figure 7-2B), spleen, gut-associated lymphoid tissue, and peripheral blood. Immunoglobulins are absent in serum (Table 7-1).

Failure of both cellular and humoral immunity causes a variety of severe infections early in life, with death usually resulting in the first year. Infections due to viral, fungal, bacterial, and protozoal organisms occur (Table 7-2).

Severe combined immunodeficiency probably represents several different inherited diseases, all characterized by failure of differentiation of stem cells. Most patients have the autosomal recessive form (Swiss-type); a few patients have the X-linked recessive form. More than half of patients with the autosomal recessive form lack the enzyme adenosine deaminase (ADA) in cells. Conversion of adenosine to inosine cannot occur, with the result that adenosine and its lymphotoxic metabolites accumulate. The absence of ADA in amniotic cells permits prenatal diagnosis. Treatment consists of bone marrow transplantation. Gene therapy, to introduce the ADA gene onto chromosome 20 has resulted in clinical improvement in a small group of patients. A few patients with severe combined immunodeficiency lack nucleoside phosphorylase and inosine phosphorylase, leading to similar metabolic deficits.

Thymic Hypoplasia (DiGeorge Syndrome)

Congenital failure of development of the thymus (② in Figure 7-1) results in lack of T lymphocytes in the blood and T cell areas of lymph nodes (Figure 7-2C) and spleen. The total lymphocyte count in peripheral blood is decreased. Patients show signs of deficient cell-mediated immunity and suffer from severe viral, mycobacterial, and fungal infections during infancy (Table 7-2). B lymphocyte development and number are usually normal. T helper cell activity is absent, but serum immunoglobulin levels are usually normal (Table 7-1).

No genetic defect has been identified in thymic hypoplasia. Thymic hypoplasia in DiGeorge syndrome is part of a more severe abnormality of development of the third and fourth pharyngeal pouches. The latter condition is marked by absent parathyroid glands, abnormal aortic arch development, and abnormal facies. When the parathyroids are absent, profound hypocalcemia causes early death. Thymic hypoplasia has been successfully treated with transplantation of human fetal thymus, which restores T cell immunity.

T Lymphopenia (Nezelof's Syndrome)

Nezelof's syndrome represents a cluster of poorly defined deficits of T cell number and function thought to result from abnormalities of T cell maturation in the thymus. The DiGeorge syndrome is distinguished from Nezelof's syndrome by its characteristic association with abnormalities of other structures derived from the third and fourth pharyngeal pouches.

Bruton's Congenital Agammaglobulinemia

Bruton's agammaglobulinemia is an X-linked recessive disorder seen mostly in male infants and characterized by failure of development of B lymphocytes (③ in Figure 7-1). Pre-B cells (CD10-positive) are present, but mature B lymphocytes are absent in the peripheral blood and B cell domains in lymph nodes, tonsils, and spleen. Reactive follicles and plasma cells are absent in lymph nodes (Figure 7-2D). Serum immunoglobulins are markedly decreased or absent. The thymus and T lymphocytes develop normally, and cell-mediated immunity is intact (Table 7-1). The total lymphocyte count in peripheral blood is normal because T cells, which typically represent 80–90% of blood lymphocytes, are present in normal numbers.

Failure of humoral immunity leads to development of infections in the infant after passively transferred maternal antibody levels decrease, usually in the second half of the first year of life (Table 7-2). Treatment with frequent injections of immune globulin is effective.

Common Variable Immunodeficiency

Common variable immunodeficiency includes several different diseases characterized by decreased levels of some or all of the immunoglobulin classes. Peripheral blood lymphocytes, including B cell numbers, are usually normal. Plasma cells are usually decreased, suggesting defective B lymphocyte transformation (④ in Figure 7-1). In some cases, an excess of suppressor T cells has been described (⑤ in Figure 7-1), particularly in an acquired form of the disease that develops in adult life. Variable inheritance patterns have been described in a minority of cases. The deficient humoral immune response leads to recurrent bacterial infections and giardiasis (Table 7-2). Treatment with prophylactic gamma globulin injections is less satisfactory than in Bruton's agammaglobulinemia.

Isolated IgA Deficiency

Selective deficiency of IgA is the most common immunodeficiency, occurring in about one in 1000 individuals. It is due to a defect in the terminal differentiation of IgA-secreting plasma cells (④ in Figure 7-1); in some patients, it is associated with abnormal suppressor T lymphocytes (⑤ in Figure 7-1).

Most patients with IgA deficiency are asymptomatic. A few demonstrate increased incidence of pulmonary and gastrointestinal infections because they lack the mucosal IgA. Most IgA-deficient individuals develop anti-IgA antibodies in their plasma. These antibodies may react with IgA present in transfused blood and cause type I hypersensitivity reactions (Chapter 8: Immunologic Injury).

Immunodeficiency Associated with Inherited Diseases

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome is an X-linked recessive disease characterized by eczema, thrombocytopenia (decreased platelets in blood), and immunodeficiency. T lymphocyte deficiency may develop in the course of the disease, and serum IgM levels are low. Patients develop recurrent viral, fungal, and bacterial infections. There is a high incidence of lymphoma.

Ataxia-Telangiectasia

Ataxia-telangiectasia is an autosomal recessive disease characterized by cerebellar ataxia, skin telangiectasia, and deficiencies of T lymphocytes, IgA, and IgE. There appears to be a defect in deoxyribonucleic acid (DNA) repair mechanisms, with multiple breaks especially involving chromosomes 7 and 11 (T cell receptor genes). Lymphoma may occur.

Bloom's Syndrome

Bloom's syndrome, which is also autosomal recessive, manifests other defects in DNA repair. Immunoglobulin deficiency and lymphoma are common.

Complement Deficiency

Deficiency of various complement factors has been described; these disorders are all rare. C2 deficiency is the most common. C3 deficiency clinically resembles congenital agammaglobulinemia and is characterized by recurrent bacterial infections during infancy. Deficiency of early complement factors (C1, C4, and C2) is associated with the development of autoimmune diseases, notably systemic lupus erythematosus. Deficiency of the late complement factors (C6, C7, and C8) predisposes to development of recurrent infections caused by Neisseria.

Secondary & Acquired Immunodeficiency

Immunoparesis of varying degree is fairly common. It occurs most often as a secondary phenomenon in various diseases (Table 7-3) and is rarely a primary disease.

Acquired Immune Deficiency Syndrome (AIDS)

Incidence

(Figure 7-3.) AIDS has become the most common immunodeficiency disease in the United States since it was first recognized in 1981 in Los Angeles. Subsequent retrospective studies indicate that cases may have occurred around the world as long ago as 1960. It is believed that more than 20 million persons, many of whom are infants, are infected with HIV (human immunodeficiency virus). Approximately 5 million persons have symptomatic AIDS. There were 60,000 deaths due to AIDS in the United States in 1995, and AIDS is now the leading cause of death in American young adult males. Internationally, the disease is most common in Southeast Asia and sub-Saharan Africa.

Definition

AIDS was initially defined by the centers for disease control and prevention (CDC) on the basis of the occurrence of certain opportunistic infections and cancer indicative of impaired mediated immunity. The definition has been revised (most recently in January 1993) to incorporate the results of HIV antibody testing and CD4 (helper T cell) levels (Table 7-4). A presumptive diagnosis of AIDS—based on the presence of certain strong indicator diseases—may still be made in the absence of a positive HIV antibody test (Table 7-4).

Etiology and Pathogenesis

AIDS is caused by an ribonucleic acid (RNA) retrovirus called human immunodeficiency virus (HIV)—previously called human T cell lymphotropic virus type III (human T cell lymphotropic virus (HTLV) III) and lymphadenopathy-associated virus (LAV). Different strains of HIV are beginning to appear, with definition based on the env (envelope) protein: M is the common strain. Strains O and E may not be detected by tests currently in use. A second closely related virus (HIV-2) has recently been described in Africa with cases also reported elsewhere, including the United States. HIV-2 produces a very similar disease. The primary targets of viral attack are helper (CD4-positive) T lymphocytes. The virus uses the cell surface CD4 receptor molecules for its entry. Other cell types that share common epitopes with the T lymphocyte receptor—eg, macrophages and cells in the central nervous system—are also susceptible to infection with HIV.

The entry of HIV into T lymphocytes may result in (1) acute destruction of the cell, which contributes to a progressive depletion of CD4 cells at a rate of approximately 80,000/μL/yr; or (2) latent infection, with insertion of the proviral genome into the host DNA. Infection of humans with HIV is almost invariably associated with the appearance of anti-HIV antibodies in the serum, usually within 6 months after infection (Figure 7-4). These antibodies are not protective, and HIV viremia persists despite their presence. Detection of anti-HIV antibodies and viral isolation from the blood or infected cells are important diagnostic tools (Figure 7-4; Table 7-5).

Transmission

HIV infection is essentially a sexually transmitted disease, with transmission also occurring through direct injection into the blood by intravenous drug users or less often by transfusion of blood products (Figure 7-3). The risk of transmission by other body fluids such as saliva and tears is very low despite the presence of HIV in such fluids. The risk of infection of health care workers is also low, although a few cases of HIV infection have been reported after accidental blood spills and needle sticks. The risk of infection by casual contact with an infected person is almost nil.

Transmission of HIV during sexual contact occurs at a rate lower than that of gonorrhea or hepatitis B; estimates of the risk associated with a single heterosexual encounter with an HIV-infected partner range from 5% to 15%—compared with 30% in the case of gonorrhea. Estimates of transmission rates between regular (repeat) sexual partners vary: female → male, 10–20%; male → female, 20–50%; male → male, >50%. The risk is increased by the coexistence of other venereal diseases associated with open genital sores. The use of condoms has been recommended as a means of decreasing HIV transmission during sexual contact. Transmission of HIV by blood transfusion and blood products is highly efficient, with the result that more than 90% of individuals transfused with infected blood become infected. Testing for HIV antibody in blood donors has greatly reduced the risk of HIV transmission by transfusion of blood and blood products (eg, factor VIII concentrate used to treat hemophilia).

Individuals at High Risk for HIV Infection

HIV infection occurs in several high-risk groups: (1) Male homosexuals and bisexuals account for over 60% of cases of AIDS in the United States. (2) Intravenous drug abusers account for about 15% of cases. (3) Heterosexual female contacts of male bisexuals and intravenous drug abusers account for less than 10% of cases in the United States, but the proportion is rising rapidly (almost 50% of all new cases in some areas). (4) Patients transfused with blood products—most importantly hemophiliacs and infants—represent an estimated 2% of cases.

The situation is quite different in sub-Saharan Africa, where heterosexual transmission predominates and women and children account for almost half of all cases. Similar trends are being reported from Thailand and other countries. In one study from Kenya, almost 90% of prostitutes tested HIV-positive. The transmission rate from infected mother to infant is in the order of 10–20%.

Manifestations and Stages of HIV Infection

(Table 7-6.)

Incubation Period

The incubation period between infection and the development of AIDS has been calculated in patients infected by blood transfusion—a documented date of inoculation—to be a median of about 4½ years. In sexually transmitted disease, it appears to be longer, ie, 8–10 years. The incubation period is shorter in young children than in adults. During the incubation period, individuals are positive for HIV antibody and may show changes in the peripheral blood lymphocytes (Figure 7-4), but they are asymptomatic. The percentage of asymptomatic HIV-positive individuals who go on to develop AIDS is unknown, but it is thought to be high.

Changes in the Immune System

HIV infection leads to a decrease in the number of helper/inducer (CD4-positive) T cells in the peripheral blood (Table 7-4; Figure 7-4). This may be accompanied by an increase in the number of suppressor/cytotoxic (CD8-positive) T cells, resulting in a decreased CD4:CD8 ratio. These changes in the immune system lead to functional immunodeficiency. The decreased CD4:CD8 ratio is not diagnostic of HIV infection and may occur in several other immunodeficiency states.

AIDS-Related Complex (ARC)

Patients with ARC are HIV-positive and symptomatic but have none of the indicator diseases that are used to define AIDS (Table 7-4). ARC patients complain of fatigue, weight loss, night sweats, and diarrhea and have superficial fungal infections of the mouth, fingernails, and toenails. The best-studied components of ARC are the lymph node abnormalities. In the early stages, infected lymph nodes show marked reactive follicular hyperplasia with characteristic histologic features (Chapter 28: The Lymphoid System: I. Structure & Function; Infections & Reactive Proliferations)—a condition called persistent generalized lymphadenopathy (PGL). HIV can be isolated from the lymph nodes of patients with PGL. At a later stage, lymph nodes show lymphocyte depletion.

AIDS

AIDS is the final phase of HIV infection in which the patient develops one of many opportunistic infections or neoplasms that define the disease (Table 7-4).

Among the opportunistic infections, the following are the most common: P carinii pneumonia, esophageal candidiasis, cytomegalovirus infections, atypical mycobacterial infections, toxoplasmosis of the brain, cryptosporidiosis of the intestine, herpes simplex infections, and papovavirus infection of the brain (progressive multifocal leukoencephalopathy).

Kaposi's sarcoma is a malignant vascular cancer that affects the skin (Figure 7-5) and many internal organs. It is the cancer whose suddenly increased incidence and appearance in a much younger age group caused AIDS to be first recognized in 1981. Since that year, these patients have been shown also to have an increased incidence of high-grade non-Hodgkin's malignant B cell lymphomas, particularly of the central nervous system.

The Prospects for Prevention

The main method of prevention of AIDS currently available is public education about the methods of transmission of HIV. The use of condoms and safe sex practices have been recommended as ways to decrease the risk of infection.

Screening of blood donors for HIV antibody has markedly decreased the incidence of AIDS transmitted by transfusion of blood products. Health care workers, policemen, and firemen routinely take precautions to decrease the risk of becoming infected. The use of gloves, fluid-proof gowns, masks, and safe needle disposal methods should be routine safety precautions for health care workers and others at risk.

The two main directions of research in AIDS are aimed at developing a vaccine that will prevent infection or a drug that will be effective in treatment. Both a vaccine and an effective drug are not apparently in the immediate future.

Course and Treatment of AIDS

AIDS is a disease that relentlessly and invariably progresses to death. Almost all patients are dead 5 years after diagnosis, but many die much sooner. Treated patients continue to develop additional opportunistic infections. Combination therapy with reverse transcriptase inhibitors and protease inhibitors has shown improved survival.

Effects of Immune Deficiency

The immunocompromised host is susceptible to development of various diseases and disorders.

Infections

(Table 7-2.) The development of infections depends on the specific immunodeficiency. T cell deficiency predisposes to infections with viruses, mycobacteria, fungi, and other intracellular organisms such as Pneumocystis carinii and Toxoplasma gondii. B cell deficiency predisposes to pyogenic bacterial infections. These infections reflect the relative importance of cell-mediated and humoral responses in the defense against different microbial agents.

Malignant Neoplasms

Kaposi's sarcoma and malignant B cell lymphomas are the most common malignant cancer that develop in immunodeficient individuals. They occur in patients with HIV infection, Wiskott-Aldrich syndrome, and ataxia-telangiectasia and in patients receiving long-term immunosuppressive therapy after organ transplantation. The occurrence of malignant cancer may be related to the role of the immune response in removing developing malignant cells that arise in the body (failure of immune surveillance; see Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms), or it may be due to sustained immune stimulation of an inadequate immune system in which the usual controls of cellular proliferation are lacking (eg, leading to B cell lymphoma). In some instances, notably ataxia-telangiectasia, immune deficiency is associated with fragility of chromosomes, which is thought to predispose to cancer.

Note that epithelioid thymoma, a primary tumor of thymic epithelial cells, is believed to induce a secondary immunodeficiency (Table 7-1).

Autoimmune Diseases

Autoimmune diseases are more likely to develop in patients with congenital immunodeficiency (Bruton's agammaglobulinemia, common variable immunodeficiency, selective IgA deficiency, and deficiency of early complement factors). The most common autoimmune disorders in these patients are rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, and thrombocytopenia.

Graft-versus-Host Disease

Graft-versus-host disease is a risk in severely T cell-deficient patients who receive viable foreign immunocompetent cells in blood transfusions and bone marrow transplants. The absence of host T cell immunity prevents destruction of these foreign cells, which can then react against the host (Chapter 8: Immunologic Injury). The disease is usually fatal.

Diagnosis of Immune Deficiency

When immune deficiency is suspected, usually because of recurrent or opportunistic infection, the diagnosis may be confirmed by appropriate immunologic studies (Table 7-1). These include (1) determination of serum immunoglobulin and complement levels (Note: deficiency may not become apparent until 3–6 months of age as the level of passively transferred maternal immunoglobulin falls); and (2) studies of peripheral blood lymphocytes, including total lymphocyte count, T and B cell number, and i dentification of lymphocyte subpopulations (eg, helper and suppressor T cells) using monoclonal antibodies. New cytofluorometric techniques facilitate performance of these tests in clinical practice. Other tests such as viral culture and serologic studies (in HIV infection) and enzyme determinations (in severe combined immunodeficiency disease) may be necessary.