• Host defense mechanisms
• Nonspecific (no memory) – Mechanical and physical barriers, antimicrobial substances, mucus membranes, normal flora.
• Extracellular or Humoral – Immunoglobulins (opsonic activity, secretory IgA, activate complement), iron deprivation, complement
• Cellular – cell-mediated (T cell, monocyte, NK cells); phagocyte-mediated (Circulating phagocytes – neutrophils, eos, basos, monos; fixed tissue macrophages).
• Other contributing factors include age, malnutrition, and deficiency of trace elements (zinc).
• Disease States that Affect Host Defenses
• Diabetes Mellitus – Patients with IDDM have impaired nonspecific defense mechanisms, including alteration of skin and skin flora due to vascular disease and neuropathy. Patients with diabetes are particularly predisposed to infections due to Staph aureus.
• Chronic Renal Failure – Patients with chronic renal failure who are on chronic dialysis are predisposed to infection predominately because of compromised local defense mechanisms (peritoneal catheters, skin colonization, exposure to multiple antibiotics).
• Alcoholism and Cirrhosis – Patients with chronic alcohol abuse are predisposed to pulmonary infections such as pneumococcal pneumonia and tuberculosis. The combination of compromised nonspecific defense mechanisms (aspiration, depressed cough reflex), as well as specific host defense abnormalities may be contributory.
• Collagen Vascular Diseases – May cause a deficiency of complement Þ impaired chemotactic responses and depressed bactericidal activity.
• Immunosuppressive Drug Therapy
• High dose corticosteroids are associated with impaired neutrophilic granulocyte activity (bacterial infections with staph, gram negatives and fungal infections with candida and Aspergillus) as well as depressed cell mediated immune mechanisms (granulomatous infections and infections due to intracellular micro-organisms).

• Incidence of infection in cancer is extremely high. Infection related deaths account for 60% of deaths in leukemia and lymphoma and nearly 40% of deaths in solid tumors. The single most important factor predisposing to bacterial infection in cancer patients is granulocytopenia (specifically, neutropenia).
• Other factors which may contribute are dysfunction of cellular and humoral immunity, abnomalities of mucosal barriers, obstruction of renal or biliary systems, altered CNS function and iatrogenic causes like cannulae and catheters.
• Granulocytopenia may be functional (as in AML, CML or solid tumors) or quantitative (caused by radiation, chemotherapy and steroids). The most important aspect is the quantitative component when dealing with cancer.
• In most cases of acute leukemia, aplastic anemia, or myelosuppressive therapy for cancer, the incidence of infection is inversely related to the absolute number of circulating granulocytes. ß granulocytes Þ Ý incidence of infection.
• The importance of granulocytic phagocytic defense against bacterial infection is reflected by the fact that nearly 70% of infections in the acute leukemias are bacterial in origin (Staphylococci, E. Coli, and other gram-negatives) accounting for approx. 75% of total infections; Candida and other fungal infections account for 20%, viruses 5%.
• Recently there has been an increase in gram positive infections. Factors promoting this phenomenon include: intensive, prolonged chemotherapy, the increased use of indwelling catheters and subcutaneous ports, the disruption of the GI tract mucosa associated with neutropenia, and the utilization of prophylactic antibiotics against gram-negative pathogens.

Host Defense Defect	Microorganisms Commonly Causing Infection	Common Underlying Conditions
Impaired antibody function	Streptococcus pneumoniae, Hemophilus influenzae type B, Neisseria meningitidis, Enteroviruses	Congenital and acquired hypoglobulinemia, B-cell malignancies, AIDS
Defects in complement (CLL, multiple myeloma, chemotherapy)	Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria spp (encapsulated bugs)	Congenital and acquired hypocomplementemic states, hypocomplementemic vasculitis
Depressed cell-mediated immunity (Hodgkin’s, CLL, Steroids, Malnutrition)	Mycobacteria, Listeria monocytogenes, Nocardia asteroids, Salmonella, fungi (including Pneumocystis carinii), Toxoplasma gondii, Strongyloides stercoralis, herpes group viruses, measles (intracellular pathogens)	AIDS, transplant recipients, lymphoma, prolonged corticosteroid therapy, congenital defects
Decrease in the number of fully functional granulocytes (neutropenia)	Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, oral bacterial flora, Aspergillus spp, Candida spp (extracellular pathogens)	Myeloproliferative disorders, cytotoxic chemotherapy, congenital disorders

• Management of infection in cancer patients is dependent on prevention of infection and empiric therapy of fever or suspected infection.
• Prevention includes limiting invasive procedures, protecting environment, suppressing colonization, and surveillance cultures. Short-term mortality may be decreased by these measures, but long-term has yet to be studied. Antibiotic prophylaxis with TMP/SMX and ketoconazole has also been tried as a way to manage but it has been ineffective due to the development of resistance.
• Fever and Suspected Infection – fever in the granulocytopenic patient with cancer must be regarded as a sign of infection. The clinical approach should include the following factors:
• time of the initial disease diagnosis
• history and type of treatment including cytotoxic and or myelosuppressive agents and blood transfusions
• stage of underlying disease
• history of prior infections and recent antibiotic therapy
• travel history
• dietary history
• exposure history
• previous infectious complications and hypersensitivity reactions
• pattern of temperature elevations
• Sources of Infecting Organisms:
• endogenous normal flora (90% of infections)
• exogenous – water (pseudomonas, serratia); air (fungi); contact (staph); food (gram-negative, candida); IV fluids (enterobacter, Aspergillus, Serratia)
• Specific Disease Syndromes in the Neutropenic Host
• Disseminated disease with skin lesions – Presence of varying types of skin lesions; abscesses or vesicles, infarcted skin, ulcers, maculopapular lesions, raise the suspicion for a number of specific bacterial, fungal or viral pathogens. Staphylococcus aureus is the most common bacteria associated with abscesses involving the skin or subcutaneous tissues. Other organisms include: Pseudomonas, E. coli, Klebsiella, Enterobacter, Proteus, Nocardia, Candida, Cryptococcus, the zygomycetes (mucor and rhizopus), Aspergillus, and Herpes simplex/varicella-zoster.
• CNS INFECTION – Listeria is the most common cause of meningitis in the immunocompromised host and is especially common in patients on corticosteroid therapy or in patients with impaired cell mediated function (Hodgkins disease, lymphomas). Other organisms include: Cryptococcus neoformans, Nocardia, Toxoplasma, Aspergillus, and Mycobacterium tuberculosis.
• Syndrome of Head and Neck Infection – Pharyngitis due to Streptococcus is the most common cause of acute pharyngitis. The most common fungal involvement of the head and neck is associated with Candida colonization of the mouth and other mucosal surfaces. Other organisms of head and neck infections include: Staphylococcus aureus , herpes simplex, cytomegalovirus, Aspergillus, and zygomycetes.
• Pulmonary Infiltrates in the Immunocompromised Host – The presentation of fever and pulmonary infiltrates in the compromised host is one of the most common syndromes appreciated. Pneumonia is the most frequent cause of fatal infection in the compromised host. The mortality rate may be three to five times that of the infection at other sites. Most upper airway infections are due to gram-negative organisms. Rate of progression and CXR changes can give clues as to the type of infection.

CHEST X-RAY FINDINGS AND RATES OF PROGRESSION OF DISEASE AS CLUES TO DIAGNOSIS
RATE OF PROGRESSION
Chest X-ray abnormality	Acute	Subacute-Chronic
Consolidation:	Bacterial, hemorrhage Thromboembolic	Fungal, TB, Tumor, Nocardia
Diffuse Interstitial:	Pulmonary edema, ARDS, Bacterial	Viral, Pneumocystis, Drug
Nodular:	(Bacterial, fungal); pulmonary edema	Tumor, Fungal, Nocardia, TB

• Febrile pneumonitis syndrome in cancer patients – 73% due to infection. 27% non-infectious. Of the infectious causes, approximately 33% conventional bacteria, 33% viral or fungal infection, and 33% other including Nocardia and Mycobacteria. Of the non-infectious causes, 33% were due to recurrent tumor, 33% radiation pneumonitis, and the remainder due to pulmonary hemorrhage, pulmonary emboli, pulmonary edema or drug induced pneumonitis.

• Neutropenia (aNC<500) is the single most important factor for infection. Resolution of neutropenia is an important predictor of a good outcome.
• Degree and duration of neutropenia contribute. Patients with ANC<100 have an inordinately high risk of infection, moreover, the risk increases as the duration of neutropenia exists.
• Risk of infection ismodified by immune status (Fever, neutrophil response)
• Combination antimicrobial therapy is essential. Combining antibiotics provides additive or synergistic activity.
• Outcome of combination therapy can be worse if Gram-negative infection, if sensitive to only one drug of combination, or if neutropenia is protracted.
• Continuing empiric antibiotics until resolution of neutropenia reduces the frequency of recurrent infections.
• Empiric antifungal therapy in patients with persistent fever decreases the frequency of fungal infections.