The Ochsner Journal 12:202–210, 2012 Ó Academic Division of Ochsner Clinic Foundation

Managing Infection in Cancer Patients and Other Immunocompromised Children

Russell W. Steele, MD

Division of Infectious Diseases, Department of , Ochsner Clinic Foundation, New Orleans, LA The University of Queensland School of , Ochsner Clinical School, New Orleans, LA

bial is used for defined infections, the use of the ABSTRACT highest dosages considered safe and longer durations are Children on immunosuppressive therapy for cancer or organ warranted. transplantation are very similar to those with primary in that all are highly predisposed to infection with all types of pathogens—ie, bacteria, viruses, fungi, and parasites—and are highly likely to experience the reactivation INTRODUCTION of microbial agents, particularly viruses, while they are patients, both children and adults, have immunosuppressed. For this reason, early recognition and a very high incidence of infection, resulting from the treatment are critical for optimal chances of survival and immunodeficiency that is iatrogenically introduced 1,2 minimal morbidity. The selection of initial empiric therapy for during their management (Table 1). This circum- these patients when febrile is based on the type of immune stance is an unavoidable consequence of advances suppression (eg, neutropenia and cellular immunity) and other in cancer treatment that have resulted in greatly predisposing factors such as the presence of central venous increased survival and overall cure. Chemotherapeu- lines (CVLs). Much of our clinical approach to prophylactic and tic regimens for cancer patients, directed at inhibiting definitive antimicrobial therapy for children with cancer and tumor replication, are toxic to all elements in bone marrow, including immunologically competent white suspected infection comes from our experiences in managing blood cells. In addition, patients with a variety of children with . For this reason, the diseases are kept alive for longer periods of time present review examines aspects of management of all using extraordinary supportive measures that offer a patients with primary or acquired immunodeficiency. Consis- much greater chance for eventual colonization with tent infections in all of these patients include bacteremia in multiresistant or unusual microorganisms as well as those with CVLs, Pneumocystis jirovecii pneumonia, primary eventual overt infectious disease. The infectious and reactivation infection with herpes group viruses, and agents that cause such infections are often opportu- opportunistic fungi. nistic organisms. For each medical intervention in Some infections in well-defined groups of immunosuppressed these fragile patients, the must calculate hosts are frequent enough to warrant prophylactic therapy; in risk-benefit factors and anticipate adverse events.3 most cases, the duration of such therapy is well defined. Some common complications involve local factors Excessive continuation is likely to lead to colonization and related to diagnostic or therapeutic procedures and to infection with antibiotic-resistant organisms. When antimicro- the placement of indwelling catheters, cannulae, or other foreign bodies. Such factors set the stage for colonization with opportunistic pathogens, which may Address correspondence to then account for significant morbidity and mortality. Russell W. Steele, MD Most patients with diseases that result in second- Ochsner Children’s Health Center ary immunodeficiency receive blood or blood prod- 1315 Jefferson Hwy. ucts during the course of their therapy. The New Orleans, LA 70121 transmission of infectious diseases to these patients Tel: (504) 842-5153 represents a significant risk, particularly for patients Fax: (504) 842-5647 who receive multiple transfusions (Table 2).4 Potential Email: [email protected] blood donors are not screened for many of these Keywords: Bacteremia, cancer, fever, immunodeficiency, infection, agents. Hepatitis is the best-understood and most neutropenia carefully monitored disease, whereas recent litera- ture5 incriminates cytomegalovirus as an agent that is The author has no financial or proprietary interest in the subject increasingly likely to cause severe illness. Blood matter of this article. donors are often asymptomatic for infectious agents

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Table 1. Iatrogenic Predisposition to Infection Table 3. Primary Immunodeficiency Syndromes in Order of Frequency Local factors; mucosal and skin lesions Drugs (eg, cyclophosphamide) Usual Age Procedures (intravenous administration, cutdown, bone at Diagnosis Gender marrow biopsy) Transient 6-12 months Both Surgical wounds Urinary catheters of infancy Intravascular devices (intravenous, intraarterial, central venous Selective immunoglobulin A 4-16 years Both pressure, Swan-Ganz catheters, etc) deficiency Respiratory support (ventilator, intermittent positive pressure Common variable All ages Both breathing, etc) hypogammaglobulinemia Transfusion-transmitted disease Chronic mucocutaneous 1-2 years Both Splenectomy candidiasis Hospital-acquired resistant bacteria (caused by inadequate Cyclic neutropenia All ages Both handwashing) X-linked 6-12 months Male hypogammaglobulinemia (Bruton type) Ataxia telangiectasia 3-5 years Both at the time of phlebotomy. When the recipient of Chronic granulomatous 2 years Primarily male blood products is immunocompromised, additional disease care should be taken in screening donors and Severe combined 9 months Both providing follow-up medical examination of donors immunodeficiency as a routine aspect of the recipient’s care. Additional Wiskott-Aldrich syndrome 1-2 years Male problems of transfusion therapy are pulmonary 3 months Both edema from volume overload, hemolytic reactions, (DiGeorge syndrome) and other incompletely understood febrile reactions. Complement deficiencies All ages Both

Table 2. Infections Transmitted by Blood Transfusions PRIMARY IMMUNODEFICIENCY Bacterial Determining the incidence of primary immunode- Bacterial sepsis ficiency syndromes is difficult because many of the Endotoxemia more severe forms may result in early infant death Brucellosis before a diagnosis. One British study estimated that 1 Syphilis in 50 child deaths was a result of immune dysfunc- 6 Salmonellosis tion. Realistically, primary care only Viral occasionally encounter the more severe defects. Cytomegalovirus More common deficiencies, such as transient hypo- Epstein-Barr virus gammaglobulinemia of infancy and selective immu- Hepatitis A, B, and C viruses (now rare) noglobulin A (IgA) deficiency, are familiar to clinicians. Measles virus Most primary immunodeficiency syndromes pre- Rubella virus sent during infancy or early childhood, with the most Colorado tick fever virus notable exceptions being common variable hypo- Human immunodeficiency virus (now rare) gammaglobulinemia, cyclic neutropenia, and com- Other plement deficiencies that may not become clinically Toxoplasmosis apparent until later in life. The deficiencies of the latter Babesiosis components of complement components 5-8 are not Malaria seen until adolescence or early adulthood with the Leptospirosis presentation of recurrent meningococcal and gono- Filariasis coccal disease. Immunodeficiency syndromes and Trypanosomiasis their usual age at diagnosis are summarized in Table Chagas disease 3. Creutzfeldt-Jakob variant (not established) The approach to therapy varies according to the specific defects demonstrated (Table 4). The most

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Table 4. Therapeutic Approaches to Immunodeficiency Table 5. Most Common Causes of Secondary Syndromes Immunodeficiency in Children

Syndrome Therapy Acquired Splenectomy deficiency immunodeficiency Poor nutrition DiGeorge syndrome Bone marrow transplantation syndrome Other malignancies (thymic aplasia) Sickle cell disease Autoimmune disease Nezelof syndrome Antimicrobial therapy, bone Leukemia Immunosuppressive chemotherapy (thymic hypoplasia) marrow transplantation Nephrotic syndrome Wiskott-Aldrich syndrome Bone marrow transplantation Down syndrome Ataxia telangiectasia Fresh plasma, antibiotics Chronic mucocutaneous Ketoconazole, fluconazole candidiasis suppressive therapy occasionally require Ig supplementation until approx- deficiency imately 18 months of age. Hypogammaglobulinemia Intravenous immunoglobulin replacement Defects in neutrophil function must be followed Selective immunoglobulin Antibiotics closely and treated with antibiotics, especially during Adeficiency acute infectious episodes. Thus, close communica- Complement deficiencies Antibiotics, fresh plasma, tion between patient or parent and physician be- meningococcal vaccine comes the most important aspect of management. T and B cell deficiency Severe combined Bone marrow transplantation SECONDARY IMMUNODEFICIENCY immunodeficiency The suppression of immunologic function with Phagocytosis resulting increased susceptibility to infection may Hyperimmunoglobulin E, Antibiotics result from a number of primary diseases (Table 5). Job syndrome This circumstance is more common in adults than in Chronic granulomatous Antibiotics, interferon, bone children because of the higher incidence of malig- disease marrow transplantation nancy and the greater use of immunosuppressive Neutropenia Antibiotics, granulocyte colony chemotherapy for a variety of diseases. Acquired stimulating factor, immunodeficiency syndrome is the most common granulocyte transfusions predisposing factor in children. More than 2% of all hospitalized children demon- strate secondary immunodeficiency.6 Recognition and treatment of these host defense abnormalities difficult deficiencies to manage are those with T have therefore become a very important aspect of lymphocyte or combined T and B lymphocyte hospital practice. Secondary deficiency is actually abnormality, for which bone marrow transplantation much more common than primary immunologic usually represents definitive therapy. Selective B disorders, even in infants and children, and is usually lymphocyte deficiencies with hypogammaglobulin- managed by primary care physicians with consulta- emia are treated with immunoglobulin replacement tive support. and are best managed by primary care physicians. The recognition of associations between specific Intravenous preparations of human serum Ig are infectious processes and primary disease offers readily available for therapy, generally given at a important guidance to diagnosis and treatment (Table dosage of 400 mg/kg monthly. These treatments 6). All of these should be well understood by should be used only for patients with documented physicians caring for pediatric patients. hypogammaglobulinemia accompanied by recurrent clinical infection or with demonstrated inability to Neutropenia produce specific following antigenic chal- Congenital neutropenias may present either in lenge (eg, tetanus). The physiologic hypogamma- childhood or during the adult years and include globulinemia, apparent at 3-6 months of age, does benign neutropenia and variants thereof, cyclic not require supplemental Ig and must be distin- neutropenia, and infantile genetic agranulocytosis.7 guished from the transient hypogammaglobulinemia These syndromes are secondary to the inadequate seen in infancy. The latter deficiency represents a production of granulocytes. Although a large spec- delay in normal synthesis after maternal IgG trum of clinical consequences has been described, is no longer at protective levels; these infants most patients do not experience a significantly

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Table 6. Unusual Pathogens and Disease Entities Associated Table 7. Susceptibility Staging for Neutropenia Secondary to With Secondary Immunodeficiency Immunosuppressive Chemotherapy

Leukemia Disseminated chickenpox Absolute Predisposition Pneumocystis jirovecii pneumonia Neutrophil to Bacterial Herpes simplex Count/mm3 Infection Candida sp. sepsis 1000 Little Ecthyma gangrenosum > 500-1000 Mild (Pseudomonas, <500 Moderate (50%) Aeromonas spp.) <100 anticipated >7 days Severe (100%) Aspergillus sp. pneumonia Sickle cell Pneumococcal meningitis, bacteremia disease and pneumonia Salmonella sp. osteomyelitis Normal neutrophil counts are generally in the Nephrotic Pneumococcal peritonitis range of 2,000-5,000/mm3, with variations by age, syndrome Disseminated chickenpox gender, and race. Although neutropenia is defined as an absolute neutrophil count of <1,500/mm3 in- Down Pneumococcal pneumonia , creased infection is not observed until a neutrophil syndrome Hepatitis count is <1,000/mm3. The absolute neutrophil count Splenectomy Pneumococcal sepsis is an important objective parameter for making clinical Diabetes Malignant otitis externa decisions about immunosuppressed patients with (Pseudomonas sp.) fever (Table 7). Offering antibiotics to febrile patients 3 Phycomycosis (mucormycosis) with a neutrophil count of <500/mm pending results Listeriosis of culture has become a fairly standard protocol. During periods of anticipated transient neutrope- nia, such as during induction therapy for cancer, increased propensity for infection. Inadequate pro- patients may benefit from granulocyte transfusions. duction of neutrophil precursors may also be a Such transfusions may be impractical unless the consequence of nutritional deficiencies, including period of neutropenia is 6 weeks, but under these vitamin B12 and folate, or secondary to infectious defined conditions benefits from such transfusions processes such as typhoid fever, infectious mononu- have been demonstrated.8 cleosis, and viral hepatitis. More common than congenital neutropenias are neutropenic states sec- Neutropenia and Fever ondary to the use of cytotoxic drugs in cancer The most common clinical circumstance in which therapy, autoimmune disease, and the excessive the physician must make decisions for the immuno- destruction of granulocytes (either as inherited disor- compromised host involves fever in the neutropenic ders, because of hypersplenism, or a result of artificial patient. In pediatrics, this individual is most likely a heart valves or hemodialysis). child with leukemia who is neutropenic secondary to More recently described7 is an autoimmune chemotherapy administered during treatment of the process in which antibodies, directed at neutrophils, oncologic process. Such patients are not only produce profound neutropenia. These autoantibodies neutropenic, but their remaining granulocytes func- are often seen in conjunction with autoimmune states tion poorly in mechanisms of phagocytosis and such as lupus erythematosus and Felty syndrome. In bacterial killing, unlike other neutropenic states (eg, such cases, infectious diseases are difficult to congenital neutropenia) in which remaining neutro- manage and account for observed high mortality. phils function normally. This function problem ac- Granulocyte transfusions are of no benefit because counts for the increased susceptibility of neutropenic antineutrophil antibodies destroy donor cells. cancer patients over those with neutropenia of other The clinical approach for patients with neutropenia etiologies. More common pathogens causing infec- secondary to immunosuppressive chemotherapy tion in childhood leukemia are listed in Table 8.9 consists of careful monitoring for infectious episodes The best indicator of susceptibility to systemic and early institution of antimicrobial therapy. Once bacterial disease is the absolute neutrophil count. A acute infection is documented, these patients must be count of <500/mm3 in a febrile patient dictates treated for longer periods because eradicating bac- empiric antimicrobial therapy10 (Table 9). If therapy teria without the help of the host’s granulocyte killing is not instituted and blood cultures are obtained daily capacity is extremely difficult. for 5 days, 50%-80% will eventually demonstrate

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Table 8. Documented Etiology of Infection in Childhood Table 10. Continued Management of the Neutropenic Patient Leukemia After 3 Days of Intravenous Antibiotics

Bacterial 75% Afebrile and etiology identified Staphylococcus epidermidis 50% Adjust to most appropriate management. Staphylococcus aureus 15% Afebrile and etiology not identified Escherichia coli 3% Low risk Pseudomonas aeruginosa 2% Oral antibiotics: ciprofloxacin plus amoxicillin-clavulanate Klebsiella/Enterobacter sp. 1% ANC >500/mm3 at day 7: stop Others 4% Intermediate risk (ANC <500/mm3 at day 7) Viral 20% Clinically well: stop antibiotics when afebrile 5 days. Varicella-zoster virus 7% High risk (unstable or ANC <100/mm3) Herpes simplex virus 5% Continue same intravenous antibiotic(s). Cytomegalovirus 5% Others 3% ANC, absolute neutrophil count. Fungal 5% Candida albicans 4% chest x-ray and lumbar puncture to be performed if Others 1% central nervous system infection cannot be ruled out clinically. Baseline liver enzymes, renal function studies, and serum electrolytes should also be obtained prior to beginning antimicrobial therapy. bacteremia. If antibiotics are not started until a positive The selection of antibiotics must obviously provide culture is obtained, mortality is more than 80%. coverage for the most likely pathogens, yet be Low-risk patients may receive initial oral or intrave- particularly directed at the most difficult-to-treat nous empirical antibiotics in a clinic or hospital setting organisms. In most settings, Pseudomonas aerugino- (Tables 10 and 11).11,12 Ciprofloxacin plus amoxicillin- sa represents the most resistant potential organism. clavulanate in combination is currently recommended 9 Presently no clinical evidence demonstrates that for oral empirical treatment. one particular combination from the list in Table 9 is Diagnostic evaluation should include cultures of more efficacious than another. Monotherapy is pre- blood, urine, and any other areas of suspicion, with ferred unless Staphylococcus aureus is a major consideration. Table 9. Initial Management of the High-Risk Febrile Finally, the duration of recommended therapy Neutropenic Patient is different from that for routine infections; treat-

Intravenous Monotherapy (preferred) Table 11. Management of Patients With Persistent Fever cefepime (5-7 Days) meropenem or imipenem cilastatin piperacillin-tazobactam Reassess If S aureus or S epidermidis highly suspected add vancomycin Options for management Penicillin-allergic patients 1. Continue initial antibiotics. cephalosporins except immediate-type reaction, then use Stop vancomycin if stable. ciprofloxacin plus clindamycin or aztreonam plus 2. Change antibiotics for progressive disease. vancomycin 3. Add IV fluconazole or liposomal amphotericin B. If gram-negative status is highly suspected Duration of therapy 3 add aminoglycoside Day 7: Afebrile and ANC >500/mm other combinations with aminoglycoside Stop antibiotics. 3 * ticarcillin Day 7: Afebrile and ANC <500/mm * ticarcillin/clavulanic acid Continue oral or IV antibiotics for 14 days and then * azlocillin reassess. * mezlocillin Day 7: Febrile * piperacillin Continue IV antibiotics until afebrile 5 days. Reassess after 3 days (see Tables 10 and 11) IV, intravenous; ANC, absolute neutrophil count.

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Table 12. Treatment of Candidemia in Neutropenic Patients place and usually results from 2 predisposing factors: long-term, broad-spectrum antibiotics and the pres- Stable Patients ence of intravascular access lines. In almost all cases, Fluconazole 12 mg/kg/d IV divided twice a day medically placed catheters or other offending foreign Unstable Patients bodies should be removed to help eradicate this Liposomal amphotericin B 3-5 mg/kg/d IV divided every 24 fungus. Limiting the number of broad-spectrum hours antimicrobial agents used must also be considered. and Table 12 summarizes the management of candide- Fluconazole 12 mg/kg/d IV divided twice a day mia. Fluconazole or liposomal amphotericin B, in When stable, fluconazole relatively low doses and of short duration, is usually Empirical Therapy (including other fungi) effective in treating this infection. In the immunolog- Fungus unlikely: fluconazole ically normal host with candidemia, the removal of the Fungus likely: liposomal amphotericin B, voriconazole, intravascular line is often the only necessary step. posaconazole, micafungin, or caspofungin (all acceptable alternatives) PROPHYLAXIS Some infections in a well-defined group of IV, intravenous. immunosuppressed hosts are frequent enough to warrant prophylactic therapy (Table 13). ment courses depend on the period of fever and granulocytopenia. If a patient shows a return of CUTANEOUS ANERGY peripheral neutrophils after 3 days of therapy, then Transient defects in cell-mediated immunity are intravenous antibiotics could be discontinued and commonly encountered during the course of acute or treatment changed to oral therapy, particularly if chronic illnesses (Table 14). For a variable period of cultures are negative and the patient is afebrile. On time, patients may fail to demonstrate positive the other hand, if fever and granulocytopenia persist, delayed to intradermal skin testing.13 antibiotics are usually continued even after what This lack of reaction presents an enigma to clinicians would normally be considered adequate therapy using a skin test to diagnose a patient’s primary (Table 11). illness. To differentiate global cutaneous anergy, a battery of skin tests might be applied along with the Candidemia test antigen. A positive skin test to a recall antigen The recovery of Candida sp. from the blood of such as tetanus or candida along with a negative skin immunosuppressed patients has become common- test to the pathogen in question would reassure the

Table 13. Prophylaxis for the Immunocompromised Host

Infectious Underlying Disease Agent Prophylactic Regimen Leukemia Pneumocystis Trimethoprim/sulfamethoxazole (TMP/SMX) Primary immunodeficiency jirovecii 5 mg TMP/25 mg SMX per kg per day orally, divided every 24 hours or Severe combined 3 times weekly immunodeficiency DiGeorge syndrome Nezelof syndrome Asplenia Streptococcus Conjugate pneumococcal vaccine at age 2, 4, 6, and 12-15 months; Splenectomy pneumoniae pneumococcal polysaccharide vaccine at 2 years and 5 years later Sickle cell disease PLUS Congenital complement Benzathine penicillin G 1.2 3 106 U intramuscularly every 3 weeks deficiencies (C2, C3, (>60 lb); 600,000 U (<60 lb) every 3 weeks C3b inhibitor, C5) or Penicillin V 250 mg orally twice a day (>60 lb); 125 mg orally twice a day (<60 lb) Chronic granulomatous Staphylococcus TMP/SMX (for immune augmentation) disease aureus 4 mg TMP/20 mg SMX per kg per day orally, divided every 12 hours

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Table 14. Causes of Cutaneous Anergy Table 15. Cellular and Susceptibility Staging of Patients Primary Immunodeficiency Secondary Immunodeficiency Degree of Immunosuppression CD4 Cells/mm3 Acquired immunodeficiency syndrome Severe Malignancy Age (years) Immunosuppressive therapy <1 <700 Autoimmune disease 1-2 <500 Surgery (recent) 2-6 <250 Trauma >6 <100 Burns Moderate Poor nutritional status Age (years) Advanced age <1 700-1,200 Acute disease process 1-2 500-750 Infectious Diseases 2-6 250-500 Bacterial >6100-250 Viral Mild Fungal Age (years) Rickettsial <1 1,200-1,750 Chronic Diseases 1-2 750-1,000 Sarcoidosis 2-6 500-750 Rheumatoid >6250-500 Renal Alcoholism Cirrhosis Diabetes staging system (Table 15), patients can be catego- rized into those who have mild suppression of cellular immunity and those who are severely immunosuppressed. The latter group of patients is physician that this patient can respond to specific at extremely high risk of infection with opportunistic antigens, allowing the physician to interpret the pathogens, particularly fungi and herpes group negative specific skin test as evidence against viruses. disease. However, this reactivity is not absolute— particularly when skin testing for tuberculosis— TRANSPLANT RECIPIENTS because antigen-specific nonreactivity has been Patients who have recently undergone trans- observed. plantation, either bone marrow or solid organs, The phytohemagglutination (PHA) skin test is represent a population with moderate to severe probably the most sensitive test for evaluating anergy; immunodeficiency and a high risk for opportunistic the question of infection would be more rapidly infections. Many infections are caused by reactivat- resolved with this mitogen in the initial skin test ed pathogens present in the host or donor organs battery. Placing other skin tests first would create a at the time of transplant. Etiology varies with timing delay of 2 days while reading these tests before the before or after transplantation and is consistent PHA skin test can be applied as a second step in the enoughtousetiminginrelationtotransplantinthe diagnostic work-up. initial approach to a differential diagnosis (Figure).5 Physicians should monitor patients with diseas- The reactivation of herpes group viruses, particu- esknowntobeassociatedwithcellularimmuno- larly cytomegalovirus, is so common in these deficiency and be alert that such patients are highly patients that obtaining serologic data prior to predisposed to viral and fungal infectious process- transplant to determine previous infection with es. The degree of cellular immunosuppression can these potential pathogens for both recipient and be roughly determined by quantitating T lympho- donor is critical. Prophylactic antiviral and antibac- cyte CD4 subpopulations. This testing for clinical terial therapy is often warranted. management helps direct early and aggressive use of antifungal or antituberculous medication for CONCLUSIONS severely immunosuppressed individuals, often prior Infection in immunocompromised patients offers to receiving final culture results. With the use of a a particular clinical challenge because the patho-

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Figure. Timetable for infection following transplantation. gens are often unusual, and appropriate treatment 3. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational must begin early in the course of the illness. These Association for Supportive Care in Cancer risk index: a multinational patients also must receive the highest tolerated scoring system for identifying low-risk febrile neutropenic cancer dosages of antimicrobial agents and for maximum patients. JClinOncol. 2000 Aug;18(16):3038-3051. durations. Prophylactic antibiotics should also be 4. Kuehnert MJ, Roth VR, Haley NR, et al. Transfusion-transmitted bacterial infection in the United States, 1998 through 2000. given based on the pathogens likely to reactivate Transfusion. 2001 Dec;41(12):1493-1499. duringthetimeofmoresevereimmunosuppres- 5. Fishman JA. Infection in solid-organ transplant recipients. N Engl sion. J Med. 2007 Dec 20;357(25):2601-2614. 6. Bonilla FA, Bernstein IL, Khan DA, et al; American Academy of REFERENCES , Asthma and ; American College of Allergy, 1. H¨ubel K, Hegener K, Schnell R, et al. Suppressed neutrophil Asthma and Immunology; Joint Council of Allergy, Asthma and function as a risk factor for severe infection after cytotoxic Immunology. Practice parameter for the diagnosis and chemotherapy in patients with acute nonlymphocytic leukemia. management of primary immunodeficiency. Ann Allergy Asthma Ann Hematol. 1999 Feb;78(2):73-77. Immunol. 2005 May;94(5 Suppl 1):S1-S63. Erratum in: Ann 2. Viscoli C, Varnier O, Machetti M. Infections in patients with febrile Allergy Asthma Immunol. 2006 Mar;96(3):504. neutropenia: epidemiology, microbiology, and risk stratification. 7. Sievers EL, Dale DC. Non-malignant neutropenia. Blood Rev. Clin Infect Dis. 2005 Apr 1;40 Suppl 4:S240-S245. 1996 Jun;10(2):95-100.

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8. Dale DC, Liles WC, Price TH. Renewed interest in granulocyte 11. Koh A, Pizzo PA. Empirical oral antibiotic therapy for low risk transfusion therapy. Br J Haematol. 1997 Sep;98(3):497-501. febrile cancer patients with neutropenia. Cancer Invest. 2002; 9. Rolston KV. Challenges in the treatment of infections caused by 20(3):420-433. gram-positive and gram-negative bacteria in patients with cancer and 12. Klastersky J, Paesmans M, Georgala A, et al. Outpatient oral neutropenia. Clin Infect Dis. 2005 Apr 1;40 Suppl 4:S246-S252. antibiotics for febrile neutropenic cancer patients using a score 10. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice predictive for complications. J Clin Oncol. 2006 Sep 1;24(25): guideline for the use of antimicrobial agents in neutropenic 4129-4134. patients with cancer: 2010 Update by the Infectious Diseases 13. Steele RW, Suttle DE, LeMaster PC, Patterson FD, Canales L. Society of America. Clin Infect Dis. 2011 Feb 15;52(4):427-431. Screening for cell-mediated immunity in children. Am J Dis Child. Epub 2011 Jan 4. 1976 Nov;130(11):1218-1221.

This article meets the Accreditation Council for Graduate and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.

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