Infectious complications in the child with cancer. III. Prevention

524

April 1981 TheJournalofPEDIATRICS

Infectious complications in the child with cancer. IlL Prevention Philip A. Pizzo, M.D., B e t h e s d a , M d .

BECAUSE I N Ff~CTiON is the major cause of death in the patient with cancer, considerable attention has been focused on methods for preventing'infectious complications in high-risk patients. This requires a thorough understanding of the factors that heighten the risk for serious infection, including disease- and treatment-related defects of the integumentary and mucosal physical barriers, diminished phagocytic defenses, decreased cellular and humoral immunity, and nutritional deficiency. More than 80% of the infections which occur in the patient with cancer are caused by microorganisms resident in the patient's flora; nearly half of these infecting organisms are acquired by the patient during hospitalization (the most frequent nosocomial isolates are Ps. aeruginosa, E. coli, K. p n e u m o n i a e , and C. albicans). 2~" .24 Hence colonization of the patient by new pathogenic organisms sets the stage for subsequent infectious complications (Fig. 1). Numerous hospital sources contribute to colonization, including staff-to-patient and patient-to-patient transmission, food, air, water, hospital equipment (respirators, vaporizers), and medical and surgical manipulations and procedures. In addition~ the endogenous or acquired microbial flora of the patient can be adversely perturbed by the antibiotics and chemotherapeutic agents frequently employed in cancer treatmentY ~. '-''~Consequently, a primary objective, during the past 15 years, has been to develop methods to suppress or eliminate the endogenous microbial burden, as well as to decrease the acquisition of new hospital-acquired organisms. Because the hospital staff"is one of the major vectors of From the Infectious Disease Section, Pediatric Oncology Br~nch, National Cancer Institute. Part I appeared in the March, 1981, issue and Part 1I appears on page 513 of this" issue. Reprint address: National Cancer Institute, Butlding 10, Room 2B50, Bethesda, MD 20205.

Vol. 98, No. 4, pp. 524-530

microbial transmission among patients, the importance of careful handwashing in reducing the spread of potential pathogens cannot be overemphasized. ~~ Attention to simple hygienic principles should also be reinforced: careful skin cleansing with iodophor S~utions prier to needle puncture, the limited use of indwelling or drainage catheters, careful cleansing of disrupted mticosal or cutaneous surfaces, and antisepsis of equipment (especially vaporizers and respiratory support devices). Care also must be exercised to prevent patients or staff from transmitting an inf&tion to immunocompr0mised patients by appropriate isolation, as with chickenpox. However, some cancer ~atients appear to require more extensive preventiVe programs. Abbreviations used PE: protected environment LAFR: laminar airflow room HEPA: high-efficiencyparticulate-air (filter) TMP/SMX: trimethoprim-sulfamethoxazoie AML: acute myeloid leukemia CMV: cytomegaloviruS, CONTROL OF THE PATIENT'S ENDOGENOUS AND EXOGENOUS MICROBIAL FLORA The total protected environment and other isolation techniques. Theoretically, reduction of the patient's endogenous and exogenous microbial burden should reduce the risk of developing a serious infection, and thus permit the patient to receive optimal or very intensive chemotherapy which might result in longer disease-tree survival. The prevention techniques currently employed vary in complexity from sirfiple single-room isolation to more elaborate systems utilizing air filtration and decontamination (Fig. 2). Tlie most sophisticated of these regimens is the total protected environment. The analysis of the PE provides a yardstick with which to measure the degree of

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infection control which can be achieved when a comprehensive reduction of the patient's endogenous and exogenous flora is attempted. The total pi'otected environment utilizes a laminar airflow room, the essential feature of which is a wall of high-efficiency particulate-air filters, capable of removing particles from the air which are larger than 0.3 /x, with a greater than 99.97% efficiency. The HEPA filters are placed behind an end wall of the room, through which air passes one way toward the opposite end of the unit, out and around a self-sanitizing plastic enclosure, and along the existing room walls toward a return plenum (Fig. 3). When all surfaces of the room are completely disinfected, and if all objects which enter the facility are steam or gas autoclaved, a relatively sterile environment can be achieved. -~ In order to avoid contamination, patients entering the LAFR must be fully decontaminated, usually with 0ral nonabsorbable antibiotics, cutaneous antiseptics, orificial antibiotics, and a semisterile diet. This environment results in a significant reduction of the patieni's microbial burden. It takes one to three weeks for the regimen to become fully effectivE, and in order to maintain a state of decontamination, patients must continue on the antibiotic and antisepsis regimen throughout the period of isolation. Furthermore, there are certain body sites (especially the oropharynx) which are very difficult to effectively decontaminate, and certain organisms (especially Candida albicans) which resist eradication with currently available antimicrobial agents, irrespective of site. These limitations reduce the efficacy of the PE. Nonetheless, more than a dozen clinical evaluations during the last decade have shown a significant reduction in the incidence of serious infections when protbundly granulocytopenic patients are treated in a PE, as compared with patients treated in a regular hospital setting. However, PE patients still have 5 to 25% the number of serious infections found in comparably treated control patients. ~', ~ Most of these infectiofis Occur during the first four weeks of isolation, presumably prior {o maximum microbial suppression. The inability of the PE regimen to eliminate the resident microbial flora from all body sites is a serious limitation, since more than threequarters of t-he infections which occur in PE patients are due to these persistent organisms. Accordingly, the improved control of infection observed when patients were treated with orally absorbed trimethoprim-sulfamethoxaz01e in addition to nonabsorbable antibiotics is encouraging and may indicate a role for systemic antibiotic prophylaxis in conjunction with the PE regimen. ~ While the PE regimen reduces the incidence of bacterial and fungal infections, no protection is afforded against the clinically important latent herpesviruses (herpes sim-

Infectious complications in the child with cancer. H I

IN FECTION ~

525

COLON IZATION

ENDOGENOUS MICROBIAL FLORA

EXOGENOUS MICROBIAL FLORA

FOOD AIR

WATER CONTACTS

Fig. 1. Sources of infection in the compromised host. plex,

herpe s

zoster,

cytomegalovirus)

or

protozoa

(P. carinii). This is particularly relevant for patients who

are undergoing allogeneic bone marrow transplantation in the treatment of aplastic anemia or leukemia and who are at risk for both acute bacterial and fungal infections, as Well as severe interstitial pneumonia with CMV. m ' ' Although this is not strictly a failure of the PE regimen per se, CMV pneumonitis nonetheless serves to limit the successful outcome of the procedure. Clearly, a more successful decontamination program, as well as effective antiviral therapy, is necessary to improve the overall utility of the PE regimen in preventing a wide range of serious infections. However, even if this were accomplished, the PE stili has several other formidable limitations. The costs of an isolation unit are significant. Currently, a commercially available semiportable LAFR (Fig. 3) which can be installed in a standard hospital room costs approximately $30,000. Room preparation for LAFR installation (exclusive of major reconstruction) adds another $5,000 to 8,000. Provision must be made for a sterile supply service, sterile kitchen, microbiology laboratory, as well as highly skilled nurses and trained dietary, housekeeping, and maintenance personnel. Many consumable supplies (sterile gowns, masks, linens, disinfectants, and antibiotics) add to the daily cost, Tl~e psychological impact of continued isolation on the patient must also be Considered. While most studies have described only minimal psychological complications, this is probably related tO the increased availability of occupational, psychological, and physical therapists who contribute to the support of the patient? 7~ Our experience with children (even when younger than 5 years of age) confirms the psychological acceptability of the PE regimen. 1~6 However, since these patients clearly require continued support by both family and professional staff, this must also be included in the cost accounting. Potential adverse effects related tO the suppression of the endogenous microbial flora must also be considered.

526

Pizzo

The Journal of Pediatrics April t981

SIMPLE

~ COMPLEX

STANDARD PHYSICAL ISOLATION REVERSE WITH ISOLATION HEPA AIR-FILTRATION

PROPHYLACTIC ANTIBIOTICS

PARTIAL DECONTAMINATION

PROPHYLACTIC ANTIBIOTICS PLUS PHYSICAL DECONTAMINATION

PROTECTED ISOLATION HEPA AIR-FILTRATION PLUS PROPHYLACTIC ANTIBIOTICS PLUS PHYSICAL DECONTAMINATION

Fig. 2. Spectrum of infection prevention techniques used for high-risk patients.

For example, a decrease in the peripheral leukocyte count, diminished granulocyte colony-stimulating factor, and altered humoral and cellular immunity, have been described in germ-free animals? 77, 17, The extent to which similar problems might be encountered in human beings is unknown. The antibiotic decontamination schedule may have an adverse effect on the absorption of nutrients, 17~ and the suppressed flora may also affect the absorption and metabolism of certain chemotherapeutic agents (methotrexate). 1~~ Hence, the relative benefits of infection control accrued by the PE must be carefully balanced against its cost, utility, and potential toxicity. For the patient with Cancer, the major utility relates to whether the reduced incidence of infection permits the administration of chemotherapy or radiation therapy which might result in increased remission and survival rates. Clinical trials utilizing the PE have been conducted, or are in progress, evaluating the treatment of adults with leukemia, lymphoma, and solid tumors and of children with a variety of malignancies. Unfortunately , the evaluation of many of these trials is limited by small numbers of patients, variation in the age and sex of the patients, differences in the therapeutic regimens, and a lack of appropriate controls. Nonetheless, several conclusions can be inferred. Patients treated in the PE for initial induction therapy of acute myeloid leukemia have failed to demonstrate a consistent improvement in remission rate or duration, or in survival, even though infectious complications have been reduced. 2~ For these patients, the limiting factor appears to be the effectiveness of currently available chemotherapy rather than infection prevention capability. Whether very intensive chemotherapy, in conjunction with autologous or aliogeneic bone marrow transplantation, will be more successful in eradicating residual leukemia cells and hence prolong remission duration in patients who have achieved initial remission is unknown, but the poor iong-term survival of patients with AML justifies this very intensive treatment approach. Should this strategy be successful, and if the problem of CMV pneumonia which has been associated with allogeneic bone marrow transplantation can be controlled with either new antiviral agents or interferon, the PE regimen will be useful in the treatment of acute myelogenous leukemia.

Several solid tumors seen in children have a favorable response to initial combination chemotherapy but also have a high recurrence rate, raising the possibility that early intensive chemotherapy might eliminate tumor cells resistant to lower dosages of chemotherapy. Since hematologic toxicity is a major limitation of intensive chemotherapy, the PE permits the delivery of such therapy. We recently evaluated the role of very intensive chemotherapy in children with solid tumors which had become refractory to standard dosage chemotherapy. These studies confirmed that it was possible to isolate children in a PE, and that this isolation resulted in a significant reduction in the incidence of infections during prolonged granulocytopenia. While more than half of these patients showed a complete or partial response to the intensive chemotherapy, the duration of response was prolonged (greater than two years) in only 10%. Nonetheless, that some of these patients achieved unmaintained long-term remissions suggests that such drug schedules are capable of overcoming drug resistance in some patients. ~-' Consequently, this strategy is now being exploited in the primary treatment of patients with metastatic Ewing sarcoma and rhabdomyosarcoma prior to the development of drug resistance. Results from these trials are preliminary but encouraging. In summary, while the initial trials evaluating the PE for adults with acute leukemia showed a significant reduction in the incidence of serious infections during profound granulocytopenia, no consistent benefit in the response rate or duration could be demonstrated for patients who received standard chemotherapy. Current experience with very intensive chemotherapy regimens, however, suggests a potential therapeutic benefit. This experience includes patients with AML who are treated with ablative chemotherapy plus allogeneic or autologous bone marrow transplantation, as well as adults and children undergoing intensive chemo- and radiotherapy regimens for the initial treatment o f lymphomas and certain solid tumors. Should these studies confirm a benefit from early intensive therapy (as measured by significantly prolonged disease-free remission), the infection control benefits of the PE will be well established. Nonetheless, PE facilities are Unlikely to be widely available and hence simpler methods of infection control must be sought. Standard single room reverse isolation

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Infectious complications in the child with cancer, l l I

527

Fig. 3. Semi-portable laminar airflow room housed within a standard single bed hospital room: A, the LAFR unit (sterile area); B, visitor area (not sterile); C, cross section of the entire single-bed hospital room housing the LAFR; D, HEPA filter wall (the arrows indicating the unidirectional airflow); E, air intake and blower system which pmnps air through the HEPA filters; F, plastic or glass barrier which separates the sterile LAFR from the outer anteroom (B); G, patient controls for nurse call, TV; H, control panel for the LAFR unit; /, air outflow area from the LAFR.

(without air-filtration or prophylactic antibiotics) has been frequently employed in an attempt to reduce the acquisition of potential pathogens by leukopenic cancer patients. Because many anecdotal data have suggested that this precaution alone is unlikely to significantly alter airborne transmission ofmicroorganisms or decrease the incidence of infection arising from the endogenous flora, it is not surprising that a prospectively randomized trial of strict reverse isolation vs routine ward care has failed to demonstrate a beneficial effect. 1~ Similarly, the addition of air filtration to standard isolation (without suppression of the host's endogenous flora) has also failed to demonstrate a significant reduction in the incidence of infection.~, Prophylactic antibiotics. The benefit of prophylactic antibiotics to suppress or eliminate the endogenous flora without concomitant physical isolation has also been evaluated. Commonly, nonabsorbable antibiotics (gentamicin, vancomycin, nystatin, polymixin B) in Various combinations are used to achieve gastrointestinal decontamination. While the microbial burden can be reduced, this process is hampered in the nonisolated patient by continued exposure to exogenous organisms from the air, water, food, and physical contacts. Accordingly, although

more than a dozen clinical trials have been conducted, a consistent reduction in infectious complications has not been observed. TM 171,185,~s5 Even if these regimens ultimately proved useful, a disturbing increase in the incidence of aminoglycoside-resistant isolates has been observed in centers where nonabsorbable antibiotics are frequently employed. 187,18~ Consequently, it is recommended that this therapy not be routinely administered, but be restricted to patients in a protected environment so that emergence of resistant organisms can be closely monitored and controlled. Intravenous systemic antibiotics administered on a rotating schedule have also been compared with oral nonabsorbable antibiotics for the prevention of fever and infection. The regimens were comparable, but were most effective when administered in the protected environment.1~9 A new strategy aimed at controlling the microbial flora is the partial or selective decomtamination of the gastrointestinal tract, whereby the aerobic flora is eliminated but the anaerobic flora preserved. ~'~ The residual anaerobic flora appears capable of protecting the host from colonization by potential pathogenic aerobic organisms, and thus may be capable of diminishing the incidence of infection during high-risk periods. This can be accom-

528

Pizzo

plished with a number of oral antibiotics, including naladixic acid, TMP/SMX, polymixin B, and amphotericin. Preliminary observations have demonstrated a significant reduction in the incidence of infection in granulocytopenic patients undergoing selective decontamination with TMP/SMX or naladixic acid plus amphotericin, and warrant further study of these regimens. 1"~ The utility of oral absorbable antibiotics has been suggested by the recent Observation that children receiving TMP/SMX as prophylaxis against Pneumoeystis earinii also h a d a decreased incidence of bacterial infection compared with a control group. "~ Similar benefit was also found in hospitalized adults with leukemia who were randomly assigned to a TMP/SMX- or a placebo-treated group. The TMP/SMX-treated patients had a significant reduction in the incidence of infection (especially bacteremias) during granulocytopenia when compared to the control group (19 vs 39%). T M This regimen appears to be well tolerated, inexpensive, not associated with bacterial or fungal superinfection, and more effective in preventing infection than nonabsorbable antibiotics alone. 17~Because TMP/SMX is not commonly employed for the treatment of serious infections, the emergence of resistance does not represent as significant a threat to patient management as that observed with the nonabsorbable aminoglycosides. We are currently investigating the role of TMP/SMX plus erythromycin as a broad-spectrum oral antibiotic regimen to prevent fever and infection in children with malignancy. Directed at both gram-positive and gram-negative organisms, the combination is being evaluated in a prospective double-blind placebo-controlled trial in outpatients and inpatients. Preliminary observation suggests that this regimen is useful for patients receiving intensive chemotherapy, but further study is necessary? '~ A significant reduction of serious infections can be accomplished with the suppression or elimination of the endogenous flora and the reduced acquisition of new potential pathogens. While the PE has consistently proven to be the most successful of these regimens, such facilities are clearly limited. Hence, the recent studies suggesting benefit from oral absorbable antibiotic prophylaxis and partial decontamination are of interest and may provide less expensive and cumbersome alternatives. Further evaluation of these regimens is important, especially when studied in conjunction with other available methods (cutaneous antisepsis, cooked food diets). It appears that the degree of infection prophylaxis which is necessary is likely to vary according to the relative risk of the patient, permitting a stratification of limited resources. For example, patients undergoing bone marrow transplantation or intensive chemotherapy with an expected duration of granulocytopenia exceeding 25 days may profit from PE

The Journal of Pediatrics April 1981

isolation. On the other hand, patients with anticipated periods of granulocytopenia shorter than 25 days are less likely to require PE isolation. METHODS

TO IMPROVE

HOST

DEFENSES

Hematologic support. Coupled with strategies aimed at altering, suppressing, or eliminating the host microbial flora are newer methods for shortening the period of risk of granulocytopenia. One of these is the infusion of cryopreserved autologous bone marrow following the administration of intensive chemotherapy. 1~':~Preliminary results suggest that autotogous bone marrow rescue can shorten the period of granulocytopenia to 25 days or less. This maneuver may lessen the need for patients undergoing intensive chemotherapy to be treated in a PE when autologous bone marrow is available. We are currently testing this hypothesis by randomizing such patients to either a PE or standard hospital setting. Prophylactic granulocyte transfusions have also been employed in severely neutropenic patients to reduce the incidence of infection. Although the initial results in patients following bone marrow transplantation were encouraging, '~ recent studies are equivocal. Collecting adequate numbers of functional granulocytes for effective transfusion remains a major problem. Also, there appears to be a serious risk of alloimmunization with prophylactic granulocyte transfusion programs, which may impede platelet transfusion support, as well as a significant risk of CMV transmission and infection. '~'~.... Consequently, we do not use prophylactic transfusions and restrict the therapeutic use of granulocyte transfusions to neutropenic patients with documented gram-negative septicemia, or to patients with a localized infection which is progressing in spite of appropriate antimicrobial therapy. Recently, immune adjuvants and other agents (lithium carbonate) have been used to shorten the period of drug-induced neutropenia and thus potentially reduce the incidence and severity of infection. 1~'7 Combined with prophylactic antibiotics, these agents may provide an important adjunct to infection prevention. Immunizations. In addition to modulation of the granulocyte and macrophage-monocyte system, methods to improve humoral and cellular immunity have also been sought. Two bacterial vaccines have been evaluated in cancer patients. A lipopolysaccharide Pseudomonas vaccine has been shown to result in a short-lived antibody response and some reduction in infection by Pseudomonas. ~ However, the adverse effects (fever, severe pain at the injection site) associated with its administration and the declining incidence of Pseudomonas infections in cancer patients have limited the use of this preparation.

Volume 98 Number 4

Recently, a pneumococcal polysaccharide vaccine has been tested in splenectomized patients who are at risk for fulminant septicemia. TM The antibody response to this vaccine has been disappointing in patients receiving combination chemotherapy. However, studies designed to assess the benefit of immunization prior to splenectomy and chemotherapy are underway. 19'~ Passive immunization also deserves consideration; high levels of IgG antibody to the O antigen of gram-negative bacilli appear to have a protective effect against infection by these organisms. 2~176 201 We have also observed that cancer patients who die from septicemia due to gramnegative bacteria have a significantly lower level of antibody to the core glycolipid of Enterobacteriaceae. Because there is 98% protection against Ps. aeruginosa in animals vaccinated with the mutant (J5) E. coli 0111, the value of passive immunization with these antibodies is under investigation, with promising preliminary results.20z, z03 The prevention or attenuation of several c o m m o n viral illnesses can be accomplished if i m m u n e serum globulin or high-titer globulin is administered within 72 hours of exposure. ~~ Seronegative patients exposed to hepatitis A, rubeola, rubella, or polio should be given standard i m m u n e globulin. Specific high-titer globulin should be administered to patients exposed to hepatitis B, chickenpox, vaccinia, or mumps. Vaccination against viruses (e.g., influenza) has also been evaluated in cancer patients. Low level antibody responses have generally been observed in patients receiving chemotherapy, rendering active immunization of limited utility. '-'~176 Naturally, the use of live vaccines should be avoided in the cancer patient since they may be associated with serious-immediate and unanticipated delayed toxicity:-~ FUTURE GOALS IN THE EVALUATION, MANAGEMENT, AND PREVENTION OF INFECTIONS The enormous experience gained in the management of infectious complications in cancer patients has resulted in a significant decrease in morbidity and mortality. Nonetheless, infection remains the most common cause of death and a significant impediment to cancer therapy, emphasizing the need for continued improvement. This necessitates a more accurate assessment of the factors which place the patient at risk for infection, as well as improved means for the early detection of occult infection in neutropenic patients. These diagnostic tests should be noninvasive, and specific (e.g., based on the antigenic determinants of the infectious organism). Improved treatment schedules will require develop-

Infectious complications in the child with cancer. H I

529

ment of less toxic antimicrobial agents in conjunction with better methods for bolstering host defenses. The role of i m m u n e adjuvants and other agents to shorten the duration of granulocytopenia may lessen the period of risk and the morbidity associated with infection. Improved (and more simple) preventive methods are most important, including methods lbr altering the degree of host compromise, and methods for decreasing the endogenous microbial flora. Clearly the most significant challenge is the development of effective cancer treatment methods which are tumor specific and which do not produce the significant compromise of host defenses which results in infectious complications. The author expresses gratitud e to Ms. Kay Robichaud and to Drs. F. Bia, P. Peebles, and S. Schimpff for helpful advice and criticism in the preparation of this manuscript.

REFERENCES* 170, Knittle MA, Eitzman DV, and Baer H: Role of hand contamination of personnel in the epidemiology of gramnegative nosocomial infections, J PEDIATR86:433, 1975. 171. Levine AS, Siegel SE, Schrclber AD, et al: Protected environments and prophylactic antibiotics. A prospective controlled study of their utility in the therapy of acute leukemia, N Engl J Med 288:477, 1973. 172, Enno A, Catovsky D, Darrell J, et al: Co-trimoxazole for the prevention of infection in leukemia, Lancet 2:395, 1978. 173, Buckner CD, Cliff RA, and Sanders JE: Protective environment for marrow transplant recipients. A prospective study, Ann Intern Med 89:893, 1978. 174. Winston DJ, Crale RP, Meyer DV, et al: Infectious complications of human bone marrow transplantation, Medicine 58:1, 1979. 175. Dietrich M: Reverse isolation and gut decontamination in the management of cancer patients, Eur J Cancer 15:45, 1979. 176. Sussman EJ, Hollenbeck AP, ttersh SP. et al: Separationdeprivation and childhood cancer: A conceptual re-evalu-. ation, in Kellerman J, editor: Psychosocial aspects of childhood cancer, Springfield, Ill, Charles C Thomas, Publisher (in press). 177. Metcalf D, Foster R, and Pollard M: Colony stimulating activity of serum from germ-free normal and leukemic mice, J Cell Physiol 70:131, 1967. 178. Sell S: Immunoglobulins of the germ-fi'ee guinea pig, J lmmunol 93:122, 1964. 179. Cohen MH, Creaven PJ, Fossieck BE Jr, et al: Effect of oral prophylactic broad spectrum nonabsorbable antibiotics on the gastrointestinal absorption of nutrients and methotrexate in small cell bronchogenic carcinoma patients, Cancer 38:1556, 1976. 180. Zaharko DS, Bruckner H, and Oliverio VT: Antibiotics *References 1 to 89 appeared at the end of Part 1 on page 352 and references 90 to 169 at the end of Part 11on page 521.

530

181. 182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

Pizzo

alter methotrexate metabolism and excretion, Science 166:887, 1969. Gale RP: Advances in the treatment of acute myelogenous leukemia, N Engl J Med 300:1189, 1979. Pizzo PA, Levine AS, and Simon R: Utility of laminar air-flow rooms in the delivery of intensive chemotherapy to children with refractory malignancies, Am Assoc Cancer Res 19:82, t978. Maki DG, and Nauseef W: Simple protective isolation in patients with granulocytopenia, in Nelson JD, and Grassi G, editors: Current chemotherapy and infectious disease, Washington DC, 1980, American Society for Microbiology, pp 1091-1092. Dietrich M, Craus W, Vossen J, et al: Protective isolationantimicrobial decontamination in patients with high susceptibility to infection. A prospective cooperative study of gnotobiotic care in acute leukemia patients. I. Clinical results, Infection 5:3, 1977. Storring RA, Jameson B, McElwain TJ, et al: Oral nonabsorbable antibiotics prevent infection in acute nonlymphoblastic leukaemia, Lancet 2:837, 1977. Schimpff SC, Greene WH, Young VM, et al: Infection prevention in acute nonlymphocytic leukemia. Laminar air flow room reverse isolation with oral, nonabsorbable antibiotic prophylaxis, Ann Intern Med 82:351, 1975. Hahn DM, Schimpff SC, and Fortner CL: Infection in acute leukemia patients receiving nonabsorbable antibiotics, Antimicrob Agents Chemother 13:958, 1971. Klastersky J, Debusscher L, Weerts D, et al: Use of oral antibiotics in protected environment unit: Clinical effectiveness and role in the emergence of antibiotic-resistant strains, Pathol Biol 22:5, 1974. Rodgriguez V, Bodey GP, Freireich EJ, et al: Randomized trial of protected-environment prophylactic-antibiotics in 145 adults with acute leukemia, Medicine 57:253, 1978. Guiot HFL, van der Meer JWM, and von Furth R: Partial antibiotic decontamination: An alternative method of infection prevention in patients with severely decreased host resistance, in Nelson JD, and Grassi C, editors: Current chemotherapy and infectious disease, Washington, DC, 1980, American Society for Microbiology, pp 1434-1435. Gurwith M J, Brunton JL, and Lank BA: A prospective controlled investigation of prophylactic trimethoprim/ sulfamethoxazole in hospitalized granulocytopenic patients, Am J Med 66:248, 1979. Pizzo RA, Robichaud K J, and Edwards BK: Randomized clinical trial of Bactrim plus erythromycin (B + E) vs a placebo for preventing fever and infection in granuloeytopenic cancer patients, Interscience Conference on Antimicrobial Agents and Chemotherapy 20:330, 1980. Deisseroth A, and Abrams RA: The role of autologous stem cell reconstitution in intensive therapy for resistant neoplasms, Cancer Treat Rep 63:461-471, 1979.

The Journal o f Pediatrics April 1981

194. Clift RA, Sanders JE, Thomas ED, et al: Granulocyte transfusions for the prevention of infection in patients receiving bone marrow transplantation, N Engl J Med 298:1052, 1978. 195. Schiffer CA, Aisner J, Daly PA, et al: Allo-immunization following prophylactic granulocyte transfusions, Blood 54-766, 1979. 196. Winston DJ, Ho WG, Young LS, et al: Prophylactic granulocyte transfusions during human bone marrow transplantation, Am J Med 68:893, 1980. 197. Lyman GH, Williams CC, and Preston D: The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy, N Engl J Med 302:257, 1980. 198. Pennington JE, Reynolds HY, Wood RE, et al: Use of a Pseudomonas aeruginosa vaccine in patients with acute leukemia and cystic fibrosis, Am J Med 58:629, 1975. 199. Levine AM, Overfurt (3, Fields R, et al: Response to pneumococcal vaccine in patients with Hodgkin's disease, lymphoma and myeloma, Am Assoc Cancer Res 20:686, 1979. 200. Zinner SH, and McCabe WR: Effect of IgM and lgG antibody in patients with bacteremia due to gram-negative bacilli, J Infect Dis 133:37, 1976. 201. McCabe WR, Kaijsen B, Oiling S, et al: Escherichiae coli bacteremia: H and O antigens and serum sensitivity of strains from adults and neonates, J Infect Dis 138:33, 1978. 202. Peter (3, Pizzo PA, and Robichaud K: Possible protective effect of circulating antibodies to the shared core glycolipid (CGL) of enterobacteriaceae in children with malignancy, Soc Pediatr Res 13:466, 1979. 203. Wolf JC, McCutchan JA, and Ziegler EJ: Prophylactic antibody to core lipopolysaccharide in neutropenia, in Nelson JD, and Grassi C, editors: Current chemotherapy and infectious disease, Washington, DC, 1980, American Society for Microbiology, pp 1439-1441. 204. Stiehm ER: Standard and special human serum globulin as therapeutic agents, Pediatrics 63:301, 1979. 205, Gross PA, Lee H, Wolff JA, Hall CB, Minnefore AB, and Lazicki ME: Influenza immunization in immunosuppressed children, J Pediatr 92:30, 1978. 206. Smithson WA, Siem RA, and Ritts RE: Response to influenza virus vaccine in children receiving chemotherapy for malignancy, J PEmx'r• 93:632, 1978. 9 207. Ganz PA, Shanley JD, and Cherry JD: Responses of patients with neoplastic diseases to influenza virus vaccine, Cancer 420:2244, 1978. 208. Davis LE, Bodian D, Price D et at: Chronic progressive poliomyelitis secondary to vaccination of an immunodeficient child, N Engl J Med 297:241, 1977.