NEW CHALLENGES IN INTERNAL MEDICINE

0025-7125/92 $0.00

+

.2D

INFECTIONS IN THE COMPROMISED HOST Salvador Alvarez, MD

The compromised (immunocompromised) host is a term frequently used to describe an individual who has one or more deficiencies in the defense mechanisms. This person is particularly susceptible to infections, which are called "opportunistic infections." 12 The type of infection and the etiologic agents that cause disease have extended beyond those thought to commonly result in disease in the normal host. Some of these organisms, which are considered nonpathogens or which rarely cause disease in other than markedly immunocompromised hosts, also are called "opportunistic." There are many diseases that commonly predispose individuals to develop opportunistic infections. The type of infection and the etiologic agent are related to the different defense mechanisms that the body has against infections. The normal defense mechanisms against infection include (1) normal skin and mucous membranes, (2) humoral immunity, (3) phagocytic system, and (4) cellular immunity (Table 1). NORMAL MECHANISMS OF HOST DEFENSE

The skin and the mucous membranes are the first-line mechanism of defense in all patients. They act as a major barrier against invasive organisms. 9 The presence of mucus in the respiratory and gastrointestinal tract facilitates focal elimination or the containment of foreign material. These primary barriers assume a greater importance in patients whose secondary host mechanisms, such as cell-mediated immunity, From the Infectious Disease Section, Department of Internal Medicine, Ochsner Clinic of Baton Rouge, Baton Rouge, Louisiana THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 5· SEPTEMBER 1992

1135

1136

AL V AREZ

Table 1. DEFENSE MECHANISMS AGAINST INFECTION

Cellular immunity Humoral immunity Antibody production Complement system Phagocytic system Normal skin and mucous membranes

antibody production, or phagocytosis, are impaired. 17 Other nonspecific mechanisms of defense include ciliary motion, gastric acidity, intestinal motility, and the presence of lysozymes and lactoferrin in saliva and tears that help to protect against infections.5 When the mucous membranes are broken down by chemotherapeutic agents or by the presence of catheters, patients are at increased risk for infectious complications. Other nonspecific mechanisms of defense include the presence of normal flora in the gastrointestinal tract that protects against the overgrowth of unusual organisms. The breakdown of these protective mechanisms, secondary to the use of broad-spectrum antibiotics, also can predispose patients to develop opportunistic infections. 4 INFECTIONS IN PATIENTS WITH HUMORAL IMMUNODEFICIENCY

Patients with defects in the humoral immune system have a decreased ability to form immunoglobulins or specific antibodies. 10 The complement deficiencies are also included in this group of patients.]] Table 2 summarizes the specific types of infections related to defects in the humoral immune system. Depending on the nature of the deficiency, the lack of antibody can range from the absence of all classes of immunoglobulins to a deficiency of a single immunoglobulin or a specific antibody. This group of patients usually presents with recurrent sinopulmonary tract infections with encapsulated bacteria and, infrequently, with gram-negative organisms. These infections can be severe and result in bacteremia, meningitis, or cellulitis.](j Recurrent or chronic gastrointestinal infections may lead to the development of a malabsorption syndrome, such as the presence of giardiasis in the intestinal tract of patients with a selective deficiency of the IgA.IO Some of the humoral immunodeficiencies can be associated to a Tcell defect deficiency with abnormalities in the cellular immunity. These patients will present with combined cellular and humoral defects. III As far as the complement deficiencies, these can be present in the classic or alternate pathway. Almost all the complement components and regular protein deficiencies have been described. The later components of the complement pathway (CS, C6, C7, CS, and C9) are associated with recurrent infections, particularly those caused by Neisseria meningitidis and Neisseria gonorrhoeae. ll The use of intravenous immunoglobulin preparations in the last

INFECTIONS IN THE COMPROMISED HOST

1137

Table 2. SPECIFIC TYPES OF INFECTIONS RELATED TO DEFECTS IN THE HUMORAL IMMUNITY Disorder Complement deficiency

Antibody deficiency

Disease C1 deficiency, C1 q deficiency (SLE, glomerulonephritis), C1 inhibitor (hereditary angioedema) C2, C3,C4, CS, C6, Cl, CB, C9 deficiencies Alternative pathway (SS disease, splenectomy) Factor B deficiency Selective IgA, IgM, and IgG subclass deficiencies, X-linked hypogammaglobulinemia, transient hypogammaglobulinemia of infancy Common variable hypogammaglobulinemia X-linked immunodeficiency disease (mixed), Nezelof sydrome, ataxia telangiectasia, Wiskott-Aldrich syndrome, short limbed dwarfism

Infection Bacterial infection, Neisseria infection associated to SLE, nephritis, immune-complex disorders

Recurrent bacterial infections with encapsulated organisms and gramnegative giardiasis

SLE = systemic lupus erythematosus, SS = sickle cell disease.

few years has changed both the treatment and the outcome of many patients with humoral defects. These preparations can be given in large quantities to reconstitute normal serum globulins and provide better protection against infections. 16 INFECTIONS IN PATIENTS WITH CELLULAR IMMUNITY DEFECTS

The defects in the cellular mediated immunity are a complex series of interactions between the T-cell lymphocytes and the macrophages. 6 Many of the cellular immune disorders are a component of mixed Tand B-cell defects (Table 3). As a result of this, the affected individuals are susceptible to encapsulated bacteria and other pathogens associated with humoral defects. Another group of cellular immunodeficiencies contains those considered to be acquired, and they are divided into three large groups. The first includes many diseases, such as malignancies, renal insufficiency, and diabetes mellitus, as outlined in Table 3. The most common malignancies associated with cellular immunodeficiency are primary lymphomas and leukemias. However, other diseases, such as non-Hodgkin's lymphomas, mycosis fungoides, and Sezary syndrome, are also associated with cellular immune deficiencies. 14 Second, many therapeutic modalities for malignancies or other diseases can produce a profound depression in the cellular immune system. Cyclophosphamides, for example, can deplete the circulating T lymphocytes and inhibit the T-cell function and proliferation. Other antineoplastic agents have an antimicrobial effect that impairs the

1138

ALVAREZ

Table 3. SPECIFIC TYPES OF INFECTIONS RELATED TO DEFECTS IN THE CELLULAR IMMUNITY Disorder

Congenital

Acquired • Infections

• Drugs • Diseases

Disease

Nezelof syndrome, chronic mucocutaneous candidiasis, ataxia telangiectasia, WiskottAldrich syndrome, DiGeorge syndrome, X-linked agammaglobulinemia, cartilage-hair hypoplasia

Infection

Candidiasis, intracellular bacterial infections, virus (CMV, HS, HZV), Pneumocystis carinii, toxoplasma

Measles, chicken pox, mumps, influenza, yellow fever, infectious mononucleosis, viral vaccine (MMR, rubella), tuberculosis, leprosy, brucellosis, typhoid fever, coccidioidomycosis, malaria, filariasis, HIV Cytotoxic agents, corticosteroids, radiation therapy, cyclosporine, procainamide Lymphomas, Hodgkin's disease, renal failure, diabetes mellitus, squamous cell carcinoma of head and neck, sarcoidosis, malnutrition, cystic fibrosis

MMR = measles, mumps, rubella; HIV = human immunodeficiency virus; CMV = cytomegalovirus; HS = herpes simplex; HZV = herpes zoster virus.

normal flora of the gut. Radiation therapy impairs the delayed hypersensitivity and corticosteroids reduce the circulating number of lymphocytes, impair delayed hypersensitivity, and alter lymphocyte-macrophage interactions. 14 The deleterious effects of these drugs are most apparent in transplant patients in whom the infection is directly related to the duration and the degree of immunosuppressive therapy they have received. Third, many infectious diseases have an associated deficiency in the cellular immune system, making the patients more susceptible to intracellular pathogens. It is well-known that some acute viral infections, such as cytomegalovirus or Epstein-Barr infections, are associated with immunologic defects. Other diseases, such as leprosy, tuberculosis, and brucellosis, also have been associated with evidence of decrease in the cellular immune system. 14 The human immunodeficiency virus and the acquired immunodeficiency syndrome (AIDS) present with multiple defects in the immune system, and they are associated with a great variety of infections, including Pneumocystis carinii, toxoplasmosis, mycobacterial disease, herpes simplex and zoster, Cryptosporidium, and Isospora belli. 13

INFECTIONS IN THE COMPROMISED HOST

1139

INFECTIONS IN PATIENTS WITH DEFECTS IN THE PHAGOCYTIC SYSTEM

One of the most important predisposing factors for infection is the presence of granulocytopenia, which has been defined as less than 1000 granulocytes/mL, or more frequently as a total neutrophil count of less than 500 cells/mL. Since the early 1960s, the white blood cell count has been considered the most important factor in the development of infection in cancer patients undergoing chemotherapy. 1 The severity and the likelihood of developing infections are directly related to the total neutrophil count. Patients whose neutrophil count drops below 100 cells/mm have a greater possibility of severe life-threatening infections. The most common cause of granulocytopenia is the use of chemotherapy for the treatment of malignancy. The most common bacterial infections in the febrile neutropenic patient are caused by gram-negative bacteria, especially Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae. However, in the last 10 years, gramTable 4. SPECIFIC TYPES OF INFECTIONS RELATED TO DEFECTS IN THE PHAGOCYTIC SYSTEM Disorder

Neutropenia

Chemotactic defects

Cellular defects

Intracellular killing defects

Opsonic defects

Disease

Chemotherapy, drug reaction, hypersplenism, aplastic anemia, infantile genetic agranulocytosis, cyclic neutropenia, familial benign neutropenia, autoimmune disorders (Felty's syndrome) Genetic deficiencies (C 3 , C5 ), decreased synthesis (cirrhosis, malnutrition), severe burns, circulating immune complexes (RA, SLE, lE), juvenile periodontitis, sarcoidosis, leprosy, alcohol, amphotericin B, tetracyclines Chediak-Higashi syndrome, Job syndrome, neutrophil actin dysfunction, hypophosphatemia, "lazy" leukocyte syndrome Chronic granulomatous disease, peroxidase deficiency, myeloperoxidase deficiency, absence of specific granules, Chediak-Higashi syndrome, G-6-PD deficiency Complement deficiencies, antibody deficiencies, multiple myeloma

Infection

Bacterial infections of the skin, bacteremia, pneumonia, perirectal abscess

Recurrent bacterial infection of skin, pneumonia, lymphadenitis, lung abscess

Staphylococci skin infections, pneumonia, eczema

Staphylococcus aureus infections, skin abscess, septic arthritis

Recurrent infection with encapsulated organisms

RA ~ rheumatoid arthritis. SLE ~ systemic lupus erythematosus, lE G-6-PD ~ glucose-6-phosphate dehydrogenase.

~

immunoelectrophoresis;

1140

ALVAREZ

positive bacteria have become increasingly prevalent and in many centers are the most common bacterial isolates in febrile neutropenic patients. Bacteria such as Staphylococcus aureus and the coagulasenegative staphylococci and streptococci are major pathogens in cancer patients. 7 Most of these organisms that cause infection in the febrile neutropenic patient can be found as a part of the normal flora of the patients, and most of these organisms have been acquired within the hospital environment. 2 Other organisms, such as Candida, Aspergillus, and occasionally Zygomycetes, can become important pathogens in patients who have neutropenia for a prolonged period of time. The major sites of infections in neutropenic patients are the respiratory tract in the form of pneumonia, the skin and soft tissue infections, the perirectal area, and the oral cavity. Many of these infections are associated with the presence of bacteremia. 2 It should also be remembered that the normal signs of inflammation in the neutropenic patient can be masked by the lack of white blood cells, and the clinical manifestations of infections are difficult to detect. 15 It is absolutely necessary that the cancer patient with neutropenia be examined carefully and methodically to try to detect subtle signs of inflammation or other clinical findings to make the diagnosis of the infection. Because sepsis remains a frequent cause of morbidity and mortality in cancer patients undergoing chemotherapy, the use of empiric antibiotics at the onset of a fever has become standard management for Table 5. EVALUATION OF THE IMMUNE SYSTEM Humoral Immunity Complement Antibody

Phagocytic System

Cellular Immunity

CH50, C3, C4, C1 q, and other components Total Iymphocyte count Serum protein electrophoresis Quantitative immunoglobulins Band T cell counts Immunoglobulin synthesis to specific mitogens White blood cell count with differential Chemotaxis Phagocytosis Bactericidal activity Phagocytic activity NBT reduction Degranulation O2 consumption Total lymphocytic count T and B cell counts Skin test (PPD, candida, mumps, tetanus toxoid) Sensitization to DNCB Surface markers Response to mitogens Phytohemagglutinin con A Quantification of Iymphokinins Stimulation of allogenic Iymphocytes Skin graft rejection

NST = nitroblue tetrazolium test, PPO

=

purified protein derivative, ONeS = dinitrochlorobenzene.

INFECTIO;\JS I;\J TilE COMPROMISED !lOST

1141

febrile episodes in the granulocytopenic patient. Empiric antibiotic regimens are designed to provide coverage against both gram-positive and gram-negative organisms. In the past, because of limited spectra of activity of the antibiotics available, standard therapy was the use of at least two antimicrobial agents to achieve the broad-spectrum coverage. Newer antibiotics such as the third-generation cephalosporins (specifically, ceftazidime) have been used for initial empirical therapy in the management of the febrile neutropenic cancer patient with excellent results. 8 Other antimicrobials, such as carbapenems and quinolones, are also being evaluated for initial empiric therapy. IS The present guide to the selection of antibiotics for empiric therapy has been reviewed recently.3 The number of congenital diseases affecting granulocyte formation are also well described and have been associated with recurrent bacterial infections. A summary of these diseases is presented in Table 4. Table 5 summarizes an approach to the evaluation of patients for possible defects in the immune system. References 1. Bodey GP, Buckley M, Sathe YS, et al: Quantitive relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328340, 1966 2. Hathorn JW, PizZQ PA: Infectious complications in the pediatric cancer patients. In PizZQ PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadelphia, JB Lippincott, 1989, pp 837-867 3. Hughes WT, Armstrong D, Bodey GP, et al: Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. A statement by the Infectious Disease Society of American. J Infect Dis 161:381-396, 1990 4. Johanson WG, Pierce AK, Sanford JP: Changing pharyngeal bacterial flora of hospitalized patients. Emergence of gram-negative bacilli. N Engl J Med 281:1l37-1140, 1969 5. Masson PL, Heremens JF, Schonne E: Lactoferrin, an iron binding protein in neutrophilic leukocytes. J Exp Med 130:643-658, 1969 6. Masur H: Infections in immunologically abnormal patients. In Roberts RB (ed): Infectious Diseases: Pathogenesis, Diagnosis, and Therapy. Chicago, Year Book, 1986, pp 246-268 7. McGowan JE Jr: Changing etiology of nosocomial bacteremia and fungemia and other hospital acquired infections. Rev Infect Dis 7 (suppl 3):5357-S370, 1985 8. Pizzo P A, Hathorn JW, Hiemenz J, et al: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 315:552-558, 1986 9. Reichert U, Saint Leger D, Schaeffer H: Skin surface chemistry and microbial infection. Semin Dermatol 1:91-100, 1982 10. Rosen FS, Cooper MD, Wedgwood RJP: The primary immunodeficiencies, parts 1 and 2. N Engl J Med 311:235-300, 1984 11. Ross Se, Densen P: Complement deficiency states and infection: Epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore) 63:243, 1984 12. Rubin RH, Young LS (eds): Clinical Approach to Infection in the Compromised Host. New York, Plenum Press, 1-685, 1988 13. Sande MA, Volberding PA (eds): Medical management of AIDS. Infect Dis Clin North Am 2:285-550, 1988

1142

ALVAREZ

14. Schimpff se Infection in the compromised host~an overview. In Niandel CL, Douglas RJ, Bennett JE (eds): Principles and Practices of Infectious Diseases. New York, John Wiley & Sons, 1985, pp 2258-2265 15. Sickles EA, Creene WH, Wiernik PH: Clinical presentation of infection in granulocytopenic patients. Arch Intern Med 135:715-719, 1975 16. Stiehm ER, et al: Intravenous immunoglobulins as therapeutic agents. Ann Intern Med 107:367, 1987 17. Strominger JL, Tipper DJ: Structure of bacterial cell walls. The lysozyme substrated. In Osserman E, Canfield W, et al (eds): Lysozyme. New York, Academic Press, 1974, pp 169-184 18. Wade Je, Standiford CL, Drusano CL, et al: Potential of Imipenem as single-agent empiric antibiotic therapy for febrile neutropenic patients with cancer. Am J Med 78 (suppl 54):62-72, 1985

Address reprint requests to Salvador Alvarez, MD Infectious Disease Section Mavo Clinic Jacksonville "4500 San Pablo Road Jacksonville, FL 32224