Infectious complications in the child with cancer. I. Pathophysiology of the compromised host and the initial evaluation and management of the febrile cancer patient

T H E J O U R N A L OF

PEDIATRICS M A R C H

MEDICAL

19 8 1

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Number 3

PROGRESS

Infectious complications in the child with cancer. I. Pathophysiology of the compromised host and the initial evaluation and management of the febrile cancer patient Philip A. Pizzo, M . D . , B e t h e s d a , M d .

INFECTION remains the major cause of death in the patient with cancer, primarily as a consequence of the profound alterations of normal host defenses which result from the malignancy, its treatment, or b o t h ? ~ An understanding of the impaired host defenses which occur in the cancer patient, and the interaction of these defects with the endogenous and exogenous microbial flora (Fig. 1) is essential if early recognition, effective treatment, and prevention of serious infectious complications are to be accomplished. THE BIOLOGY AND PATHOPHYSIOLOGY OF THE COMPROMISED HOST

Integumentary and mucosal barriers. The skin and mucosal surfaces constitute the primary defense of the host against invasion by endogenous and acquired microorganisms. The integrity of this physical barrier can be From the Infectious Disease Section, Pediatric Oncology Branch, National Cancer Institute. Parts II and II1 will appear in'the April, 1981, issue. Reprint address: National Cancer Institute, Building t0. Room 2B50, Bethesda. MD 20205.

disrupted by the tumor (e.g., local invasion or obstruction) or by its treatment (surgery, intravenous needles, radiation, and chemotherapy-induced dermatitis or mucositis). These lesions provide a nidus for microbial colonization, a focus for local infection, and a portal for systemic invasion. Phagocytic defenses. The neutrophil and the monocytemacrophage are the major cellular defenses against most Abbreviations used PMN: polymorphonuclear leukocyte GvHD: graft-vs-host disease R1A: radioimmunoassay ELISA: enzyme-linked-immunosorbent assay DIC: disseminated intravascular coagulopathy HEENT head, eyes, ears, nose, throat TMP/SMX trimethoprim-sulfamethoxazole PCP: Pneumocystis carinii pneumonia CAT: computed axial tomography RE: reticuloendothelial PHA: phytohemagglutinin FUO: fever of unknown origin RSV: respiratory syncytial virus CMV: cytomegalovirus GI: gastrointestinal

Vol. 98, No. 3, pp. 341-354

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The Journal of Pediatrics March 1981 THE COMPROMISED HOST

Fig. t. Interrelation of the treatment- and disease-induced alterations of host defenses which delineate the compromised host.

bacteria and fungi. ~ ' Whether disease related or a consequence of therapy, the degree and duration of granulocytopenia (defined as an absolute granulocyte count of less than 500 polymorphonuclear leukocytes and bandforms/ #1) is inversely related to risk of serious infection? In addition to quantitative defects, qualitative abnormalities of neutrophil function have been described in cancer patients. These include defects in chemotaxis, phagocytosis, bactericidal capacity, and the absence of the respiratory burst which usually accompanies phagocytosis? ~ Cancer chemotherapy may also produce defects of neutrophil function. Corticosteroids, for example, can decrease phagocytosis and neutrophil migration) The combination of prednisone with vincristine and aspariginase or 6-mecaptopurine and methotrexate has been shown to produce a significant decrease in the phagocytic and killing capability of leukocytes? Although the mechanism is not clear, bactericidal activity may also be transiently impaired within the three months following craniospinal irradiation in patients with leukemia, '~ and may thus contribute to the infectious complications which may occur.

The macrophage-monocyte system provides residual phagocytic capacity during periods of severe neutropenia,

since the mature macrophage is more resistant to cytotoxic chemotherapy than the granulocyte. Furthermore, the activated macrophage is also associated with T lymphocytes as an effector of cell-mediated immunity, and is an important defense against mycobacteria, Listeria, Brucella, and several fungi, protozoans, and viruses? Cellular and humoral immunity. Patients with lymphoid malignancies (especially Hodgkin disease) have significant alterations of cell-mediated immunity (anergy, decreased PHA responsiveness)." These defects are further aggravated by chemotherapy (glucocorticosteroids), making such patients susceptible to certain viral (herpes zoster) or fungal (Cryptococcus) infections. Cytotoxic chemotherapy has significant adverse effects on both B- and T-cell functions, resulting in diminished opsonizing activity, inadequate agglutination and lysis of bacteria, and deficient neutralization of bacterial toxins.-' Impaired antibody production has been described in untreated patients with chronic lymphocytic leukemia, multiple myeloma, and Hodgkin disease?'-' Suppressor lymphocytes may contribute to impaired antibody production in patients with multiple myeloma and Hodgkin disease 1:~ and may also relate to the fungal infections which occur in some of these patients. TM In experimental animals, the glucocorticoid-induced defects in lymphocyte function and decreased neutralizing-antibody formation contribute to the increased likelihood of lethal fungal, protozoan, and viral infections. Although a similar deficiency of immunoglobulin production is uncommon in children with acute lymphocytic leukemia, '~' many of the drugs commonly used have significant B-cell cytotoxicity and may contribute to impaired antigenic responsiveness.

TM

While various components of complement are important for host defense, including opsonization, chemotaxis, anaphylatoxin generation, and serum bactericidal activity, infectious sequelae specifically related to complement defects have not been described in cancer patients. However, the potential importance of serum complement is illustrated by its role in the successful treatment of experimental disseminated candidiasis. '7 The retieuloendothelial system and splenectomy. The spleen serves as an efficient mechanical filter and as a source of opsonizing activity early in an infection. Splenectomized patients manifest diminished antibody production when challenged with particulate antigens, are deficient in tuftsin (the phagocytosis promoting peptide), and have decreased levels of IgM and properdin. Consequently, splenectomized patients (patients with Hodgkin disease) are at increased risk of septicemia, usually with Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae. 1~ Septicemia in these patients is

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characteristically fulminant and associated with large numbers of organisms in the bloodstream. The incidence of postsplenectomy septicemia ranges from 1.4 to 20% in cancer patients and is especially dangerous in patients who are also receiving chemotherapy.' .... However, bacteremia occurs even when patients are not granulocytopenic, suggesting that splenectomy is an important independent risk factor for cancer patients. Splenectomy does not appear to enhance the risk for most nonbacterial infections (herpes zoster).'-'" The role of prophylactic antibiotics and bacterial vaccines for splenectomized patients is considered subsequently. Nutrition. Malnutrition, a frequent sequel to childhood cancer and its treatment, further contributes to the loss of integrity of the integumentary and mucosal barriers, impairs phagocytosis, decreases macrophage mobilization, and depresses lymphocyte function) 1 Hence the anorexia and cachexia associated with cancer necessitates aggressive nutritional support (elemental diets, supplements, parenteral alimentation). ~2 Microbial flora-colonization and synergy. Unperturbed, the endogenous microbial flora exists as a carefully balanced synergistic microenvironment within the host. Nonetheless, 86% of the infections which occur in cancer patients arise from the endogenous flora, although 47% of the infecting organisms are acquired by the patient during hospitalization (the most frequent nosocomial isolates are Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Candida albicans). 23 Certain acquired biotypes of Enterobacteriaceae are more likely to colonize the host, ~' whereas acquisition of Ps. aeruginosa is especially important since 40 to 68% of newly colonized patients may develop septicemia during subsequent periods of granulocytopenia. Numerous factors or hospital sources may contribute to colonization of the patient, including staff-to-patient and patient-to-patient transmission (most frequently due to poor handwashing techniques), food, air, water, special equipment (respirators or humidifiers), and medical or surgical procedures, espedally intravenous therapy? 5 Furthermore, the endogenous microbial flora can also be perturbed by antibiotic and chemotherapeutic agents. ~6 When these microbial alterations occur in conjunction with other host defects, infectious sequelae may result. Interactions among different components of the endogenous microflora (viruses with bacteria or protozoa) may result in alterations of the "rificroenvironment and consequent infectious complications (synergestic gangrene of Meleney, or Toxoplasma gondii and Pneumocystis carinii with cytomegalovirus). ~6 Bone marrow transplantation and graft-vs-host disease. Patients undergoing allogeneic bone marrow transplantation for aplastic anemia or hematologic malignancy are

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additionally compromised by total body irradiation, intensive cytotoxic chemotherapy, and the sequelae of GvHD. During the immediate post-transplant period when patients are severely granulocytopenic, bacterial and fungal infections pose the major threat. ~; Following bone-marrow engraftment, interstitial pneumonitis represents the most serious infectious complication. Approximately half of the patients undergoing allogeneic bone marrow transplantation develop interstitial pneumonia, particularly recipients who have a hematologic malignancy compared to aplastic anemia (62 vs 35%). The pneumonia characteristically occurs within three months of transplantation (the median time of onset is 50 days post-transplantation) and is lethal in 65% of the patients. The cytopathic effects of cytomegalovirus can be observed in nearly half of the lungs of these patients. Patients who are seronegative to CMV have a consistently lethal outcome while patients capable of raising their complement fixation titer to CMV above 1:64, either just before or immediately following transplantation, demonstrate less mortality. ~ Attempts to prevent this interstitial pneumonitis with prophylactic adenine arabinoside have been unsuccessful?' Both active and passive immunization of high-risk patients are under investigation.:"' The lymphocytic reaction attendent to GvHD may also result in necrosis of target organs. For example the lung may become such a target organ and has been associated with a severe lymphocytic bronchitis, often secondarily infected with Ps. aeruginosa.:" T H E I N I T I A L E V A L U A T I O N OF T H E C A N C E R P A T I E N T W I T H F E V E R OR INFECTION Fever is common in cancer patients and may occur during 45 to 60% of hospital days. Only rarely can fever be attributed directly to the malignancy (the Pel-Ebstein fever of Hodgkin disease). The majority (55 to 70%) of fevers occurring in cancer patients appear to have an infectious etiology, especially when the patient is granulocytopenic? ........... To complicate this further, fever (and the risk of infection), is a nearly constant sequel of severe granulocytopenia26 The detection of infection and the initial management of the febrile-granulocytopenic patient is complicated by two factors: (1) The presence of granulocytopenia markedly alters the host's inflammatory response, making it difficult to detect the presence of infection? 7 (2) An undetected and untreated infection can be rapidly fatal in the granulocytopenic cancer patient. In the absence of a clinically overt infectious focus (pneumonia, cellulitis) we have not been able to define any factors (including the underlying malignancy, prior therapy, degree of the fever, or neutropenia) which can reliably

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APPROACH TO THE FEBRILE-GRANULOCYTOPENIC PATIENT t Initial Evaluation

History Physical Examination Chest Radiograph Urinalysis Blood Cultures Biopsyand Cultureof SuspiciousLesions

Day I Initial Management Day 3-7

1

Subsequent Therapy

el/ Empiric Broad§ "l,.. Antibiotics Documented infection Feverof Unknown Origin

Fig. 2. Initial evaluation of the febrile neutropenic cancer patient is followed by the expeditious introduction of empiric broad-spectrum antibiotic therapy. The subsequent management depends on whether the initial evaluation revealed an infectious etiology.

differentiate the patient with an occult infectious etiology for the fever from the patient in whom no focus can ultimately be defined. Hence, it is imperative to evaluate the febrile-granulocytopenic patient expeditiously and then to immediately initiate empiric broad-spectrum antibiotic therapy (Fig. 2). Several observations and guidelines can be offered to facilitate the initial evaluation and subsequent management of these patients. Infectious agents. Bacteria are responsible for most of the acute infections which occur in granulocytopenic patients. While virtually any organism (even presumed nonpathogens) can be the cause of an infection, the gram-negative bacilli (especially E. coli, K. pneumoniae, and Ps. aeruginosa) predominate in most institutions. Gram-positive bacteria (especially Staphylococcus aureus and the streptococci) are also isolated frequently. Surprisingly, anaerobic organisms are an infrequent cause of infection in cancer patients. The relative distribution of these organisms varies from institution to institution. Several centers have recently observed a decrease in Pseudomonas isolates, while other institutions have noted an increase in the isolation of gram-positive organisms (especially S. aureus)? ~ This shift is reminiscent of the pattern of infection which was described in caricer patients during the 1950s and early 1960s. Antibiotic sensitivity patterns may also vary among institutions, probably due to the selective pressure of excessive or indiscriminate use of antibiotics. Hence, it is imperative that physicians remain aware of possible changes in the microbial distribution and antibiotic sensitivity patterns at their institution(s). Fungal infections (especially Candida, Aspergillus, and mucormycosis) have been observed with increasing frequency, especially in patients with prolonged ( > 7 days)

granulocytopenia. Unfortunately, these infections are difficult to diagnose and treat, and a high index of suspicion is essential to permit early intervention. ~' 4,, Sites of infection. The lung is the most frequent site of serious infection, followed by soft tissues (especially perirectal cellulitis), mucosal infections, and septicemia. Urinary tract infections are less common in children and adolescents than in adults, and central nervous system infections remain unusual. Specific host-susceptibility. Certain cancer patients have specific disease-related or treatment-induced defects which place them at risk for specific infectious complications (altered cellular immunity places the patient with Hodgkin disease at risk for herpes zoster infection or cryptococcal meningitis). Patients with hematologic malignancies or lymphomas have generally been considered to be at greater risk for bacterial and fungal infections than are patients with solid tumors. However, we have observed that as treatment schedules for patients with solid tumors have become more intensive and the duration of granulocytopenia more prolonged, the incidence, distribution, and outcome of the infections in these patients have become indistinguishable from the pattem in patients with leukemia. Diagnostic evaluation. Since the classic signs and symptoms of infection are likely to be absent, the examining physician must take a careful history and perform a scrupulous physical examination, being especially attentive to subtle signs of inflammation. Moreover, the physical examination may need to be repeated frequently, especially when no source of the infection is initially discernable. Since the endogenous flora accounts for 86% of the infecting organisms, ~ surveillance cultures (nose, throat, urine, and stool) should be considered along with at least two blood cultures (I?om different venipunctures). Suspicious skin or other lesions should be aspirated or biopsied, and should be Gram stained and cultured. If an intravenous needle or catheter is in place when the patient first becomes febrile, it must be considered a potential focus and should be removed and cultured. A chest radiograph should also be performed as part of the initial patient evaluation. Even with a comprehensive evaluation, an infectious etiology is initially demonstrated in only 50 to 70% of febrile-granulocytopenic patients. 3.... Moreover, a definitive diagnosis may take days (presumably because of the low microbial innoculum); some infections cannot be unequivocally diagnosed. In the future, it may be possible to employ rapid diagnostic methods which are nonculture dependent (RIA, ELISA, or counterimmunoelectrophoresis techniques for antigen detection). Nuclear scintiscanning in the neutropenic patient has been disappointing,

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but may be successful when performed with in vitro-or in vivo-labeled granulocytes. 4~ At present, our technology does not always ensure early accurate diagnosis; therefore, following the initial evaluation, it is imperative to initiate broad-spectrum antibiotic therapy until the cause of the fever is more specifically discerned (Fig. 2). Empiric antibiotic therapy. The morbidity and mortality of infection is clearly reduced when empiric broadspectrum antibiotic therapy is initiated immediately after the expeditious evaluation of the febrile-neutropenic cancer patient, whether or not a bacterial infection can be initially documented. ~ ~3 The particular antibiotic regimen selected for empiric therapy should satisfy the following criteria: The drug combination should be effective against the major pathogens observed at the particular hospital; the combination should be synergistic (or at least additive) and should contain at least one bactericidal agent (especially in neutropenic patients)4~; the agents chosen should have the least possible organ toxicity; and the blood levels should be carefully monitored. Most institutions utilize either a two- or three-drug combination, generally consisting of a cephalosporin, a semisynthetic penicillin, or both, and an aminoglycoside. Recent studies have compared the therapeutic efficacy of twoand three-drug combinations, including newer antibiotic agents (cephazolin, cephamandole, ticarcillin, tobramycin, amikacin), but to date a clear superiority of one antibiotic combination has not been clearly established. We presently use a three-drug combination, KGC: Cephalothin [(Keflin] 170 mg/kg/day, iv, every 4 hours), gentamicin (6 mg/kg/day, iv, every 6 hours) and carbenicillin (500 mg/kg/day, iv, every 4 hours). Following the initial evaluation and institution of empiric antibiotic therapy in the febrile-neutropenic cancer patient, the subsequent management depends on the identification (or the lack of identification) of the etiology for the fever and the duration of neutropenia (Fig. 2). Since 1976, we have prospectively evaluated 652 episodes (in 271 patients) of fever (defined as three oral temperature elevations above 38~ during a 24-hour period, or a single oral temperature elevation of 38.5 ~ or higher) and neutropenia ( < 500 PMN//d). A documented source of infection was found within the first seven days in 329 (51%) of these episodes. The remaining episodes (49%) had no detectable infectious etiology and were classified as FUO. The management of specific infections and l~atients with FUO is considered subsequently. THE MANAGEMENT OF SPECIFIC INFECTIOUS COMPLICATIONS Septicemia. Approximately one-fifth of the febrile episodes which occur in granulocytopenic cancer patients are

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due to septicemia (defined as one or more positive blood cultures in association with fever), with the mortality rate ranging from 25 to 40%. 4..... ~'...... ~" '~ Polymicrobial septicemia must always be considered and carries an especially high mortality (~_ 70%). '~ Since septicemia in the febrilegranulocytopenic cancer patient cannot be reliably diagnosed by physical examination (the fever pattern and the presence of chills are not consistent), rapid evaluation and the initiation of empiric antibiotic therapy is essential. ':' In our hands, this approach has resulted in a significant decrease in the morbidity and mortality (15%) f r o m septicemia. Although the degree of initial neutropenia is not of prognostic significance, the time during which the white blood count remains low may be related to outcome. The antibiotic therapy of the patient with septicemia depends on the sensitivity of the microbial isolate. For patients with gram-negative septicemia, an aminoglycoside (gentamicin, tobramycin, amikacin) is generally combined with a semisynthetic penicillin (carbenicillin, ticarcillin). This combination is important since an aminoglycoside alone is inadequate in the neutropenic patient, and the use of a semisynthetic penicillin alone may result in the development of microbial resistance (especially by Ps. aeruginosa). It is also imperative to monitor antibiotic levels (especially the aminoglycosides) initially and then at least weekly in order to minimize so-called breakthrough bacteremia, and to decrease antibiotic-induced organ toxicity. The treatment of a gram-negative isolate which is resistant to the initial antibiotic regimen poses a major therapeutic dilemma. We have successfully employed the parenteral or oral fixed combination formulation of trimethoprimsulfamethoxazole (dose calculated as 20 mg/kg/day of the trimethoprim component, every 8 hours) for some of these patients. Treatment of gram-positive septicemia is successfully accomplished with a cephalosporin or with a penicillinase-resistant penicillin (oxacillin, methicillin). The possibility of methicillin-resistant staphylococci or other resistant organisms (Corynebacteria) should also be considered and if necessary, the therapy appropriately modified (generally by instituting vancomycin 44 mg/kg/day, iv, every 8 hours). We have recently observed a 41% incidence of second (gram-negative) septicemic episodes in patients remaining granulocytopenic for more than seven days who were treated initially with a single (narrowspectrum) antibiotic for gram-positive septicemia. In contrast, none of the granulocytopenic patients who were treated for gram-positive septicemia with broad-spectrum antibiotics developed second bacterial infections, suggesting that the broad-spectrum antibiotic regimen used in

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these patients may have provided systemic prophylaxis during the prolonged granulocytopeniaf Patients who become afebrile during therapy, and whose granulocytopenia resolves, appear to be adequately treated with 10 to 14 days of antibiotics, irrespective of the particular organism(s) responsible. On the other hand, patients whose septicemia is associated with organ complications (deep cellulitis or osteomyelitis) may require four to six weeks of antimicrobial therapy. The management of the patient with persistent granulocytopenia who remains febrile after a week of putatively appropriate antibiotic therapy is a perplexing problem. In these cases, the possibility of a second (occult) infection which is incompletely sensitive to the antibiotic regimen or the development of a superinfection must be considered. However, the withdrawal of antibiotic therapy in these initially infected and still febrile-granulocytopenic patients is associated with a significant recurrence rate (approximately 40%) of septicemia (generally with the same organism or with an organism sensitive to the original antibiotic regimen). This suggests that continued antibiotic therapy is beneficial? ~ We are currently exploring the risks and benefits of continued antibiotic therapy in patients with continuing granulocytopenia and fever. We are also studying the addition of empiric antifungal therapy for such high-risk patients, with encouraging results. In addition to antibiotic therapy, white blood cell transfusions may be of benefit to some patients with documented gram-negative septicemia, especially when the duration of granulocytopenia exceeds seven days.'" Fortunately, cardiovascular compromise secondary to endotoxemia has become less frequent with early, aggressive antibiotic therapy. However, should signs of cardiovascular compromise develop, close monitoring is essential (including central venous and pulmonary wedge pressures), along with respiratory support and vigorous fluid and acid-base management, including adrenergic receptor-blocking agents (dopamine), vasopressor (norepinephrine), or vasodilating agents (isoproterenol), to maintain an adequate cardiac output and to avoid irreversible lactic acidosis? ~ Evaluation of the efficacy of highdose corticosteroid analogs in the treatment of septic shock remains controversial because of the variations in the underlying disease, site of infection, infecting organism(s), and response to other therapies. Nonetheless, a recent prospective, randomized analysis has suggested that a single dose of methylprednisolone (30 mg/kg) or of dexamethasone (3 mg/kg), administered as soon as the blood pressure drops, results in a significant reduction in mortality (38.4 vs 10.4%), suggesting that high-dose steroids may be important in the early management of bacteremic shock, r,'

The Journal of Pediatrics March 1981

Coagulation abnormalities are also frequently associated with septicemia. They include a lowered platelet count, prolonged prothrombin and partial thromboplastin time, and a reduced level of fibrinogen. Patients who remain normotensive or who respond to initial antishock measures generally do not have significant bleeding sequelae associated with these abnormalities. However, disseminated intravascular coagulopathy may occur in patients who remain hypotensive in spite of vigorous hydration with plasma expanders. Consumption coagulopathy in these patients may respond to factor replacement and heparin (50 to 100 units/kg, iv every 4 hours).:'~ Some episodes of septicemia in the cancer patient may be iatrogenic, associated with intravenous catheters or parenteral alimentation fluids; or may be secondary to surgical procedures (sigmoidoscopy, dental operations gastrointestinal or genitourinary endoscopy, or catheterization)2 :~ ~'~ Streptococcus viridens, S. aureus, Erwinia, S. marscesens, anaerobes, or C. albicans are most often isolated in such patients. The patient may be nongranulocytopenic and therapy is generally successful if the nidus of infections is removed and appropriate therapy instituted. HEENT infections. Oral mucositis. Ulceration of the oral mucosa frequently occurs with several commonly used chemotherapeutic agents (methotrexate, actinomycin-D, adriamycin), Colonization of drug-induced lesions by the indigenous aerobic or anaerobic oral flora (or both) may result in local infection, and in the neutropenic patient may provide a portal for septicemia. The vigorous use of mouth-cleansing salts and solutions (bicarbonate, hydrogen peroxide) may help to decrease or control the mucositis. Unfortunately, the oral mucosa is a difficult site to decontaminate fully, and several organisms (C. albicans) are particular problems. While oral candidiasis is predominantly a superficial infection, in severely neutropenic patients it may serve as a portal for systemic invasion. Oral nystatin is of only minimal benefit; patients with more extensive oral candidiasis may respond to a short course of amphotericin B (0.5 mg/kg/day for 7 days). Recent experience with clotrimazole troches (50 rag, 5 times daily) are promising. In addition to bacterial and fungal infections of the oropharynx, certain viruses (especially herpes simplex) may be significant pathogens, but treatment has been generally disappointing. Otitis media. While the common middle ear pathogens (S. pneumonia, S. pyogenes, H. influenzae) may be the cause of otitis media in children with cancer, gramnegative organisms (Klebsiella, Pseudomonas) must be considered when the patient is neutropenic, and broad-

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spectrum antibiotic therapy should be instituted. If the platelet count permits, tympanocentesis should be performed to help guide subsequent therapy. Eye. The eye is rarely the primary site of infection in the cancer patient but may become involved by contiguous extension (periorbital cellulitis, or herpes zoster infection involving the ciliary nerve), or by means of bacteremia (especially with Pseudomonas). Disseminated candidiasis has also been associated with an endophthalmitis, ~ although these lesions may be less apparent during granulocytopenia? ~' Sinuses. Sinusitis in the cancer patient is usually caused by bacteria or fungi. Patients with nasopharyngeal tumors who have obstruction of sinus drainage are at highest risk for acute or chronic episodes. Anaerobic infections deserve special consideration, and biopsy, culture, and initiation of appropriate antibiotic therapy (clindamycin, 30 to 40 mg/kg/day, every 6 hours) are important? 7 Antral windows may be necessary to afford appropriate drainage. Neutropenic patients are at risk for fungal infections (especially Aspergillus spp or mucormycosis)'~ and suspicious cases require early biopsy and antifungal therapy. Pulmonary infections. The pulmonary defense network includes the complex interaction of mechanical factors (air filtration, mucinous and nonspecific secretions, mucociliary clearance) along with humoral (IgA, IgG) and cellular (lymphocyte and macrophage) host factors. The efficiency of this protective system, especially the alveolar macrophage, can be altered by cancer chemotherapy and radiation. Furthermore, when these pulmonary defects are coupled with neutropenia, the mortality of experimental pneumonia approaches 100% in rodents. '~' Similarly, when pneumonia occurs in-the cancer patient in association with neutropenia (and especially septicemia), the mortality may be as high as 80%.4o The lung is the most common site of serious infection in cancer patients. The diagnostic possibilities vary according to the patient's age, underlying malignancy, remission and relapse status, prior and current chemotherapy, radiation therapy, neutrophil count, microbial colonization, and presenting symptoms. Although the ability to detect a pulmonary infiltrate radiographically may be difficult in the neutropenic patient, it is generally possible to place patients into one of four categories according to the type of infiltrate and the degree of neutropenia. Patchy or localized infiltrate without neutropenia. Infection in these patients is generally similar to that in the general population, and may be due to viruses (RSV, parainfluenza, adenovirus), mycoplasma, or bacteria (S. pneumoniae, H. influenzae). Sputum should be cultured and patients are usually treated with penicillin, ampicillin,

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or erythromycin (although resistant organisms must also be considered). The possibility chemotherapy-induced pneumonitis (methotrexate, cyclophosphamide, bleomycin) ~1-~2should also be considered. Patchy or localized infiltrate plus neutropenia. In addition to the organisms noted for nonneutropenic patients, opportunistic gram-negative bacteria (Klebsiella, Pseudomonas) must be strongly considered. Staphylococcal pneumonia can be fulminant, although it is infrequent even in cancer patients with staphylococcal septicemia?:' Initial treatment should include broad-spectrum antibiotics, and if the patient fails to improve (or stabilize) within 72 hours after the initiation of therapy, further evaluation (an open lung biopsy provides the highest diagnostic yield) is mandatory to exclude other potentially treatable organisms. The most likely possibilities are bacteria which may be resistant to the initial antibiotic regimen; fungi (especially Aspergillus, Candida, Cryptococcus, Coccidioides, Histoplasma); Nocardia; and mycobacteria. Viral or protozan infections rarely present as a focal pneumonia. Interstitial pneumonia without neutropenia. The protozoan, Pneumocystis carinii, is the most likely etiologic agent in this group of patients, and infection is most commonly heralded by fever, cough, tachypnea, cyanosis. severe hypoxemia, and alkalosis? 4 Untreated, the mortality of P. carinii pneumonia is virtually 100%. The recent demonstration that PCP responds to trimethoprim-sulfamethoxazole ~' has lessened the need for a pretreatment lung biopsy. We currently initiate oral or intravenous TMP/SMX (20 mg/kg/day as trimethoprim) in patients with suspected PCP. Should the patient fail to respond or stabilize within 72 hours of therapy, lung biopsy is performed to evaluate other diagnostic possibilities (including TMP/SMX-resistant P. carinii). The newly described pneumonitis associated with the Legionnella pneumophilia also deserves consideration, since early therapy with erythromycin may be life-saving? '~ ,,7 Interstitial pneumonia plus neutropenia. In addition to P. carinii and CMV, gram-positive and gram-negative bacteria and several fungi can cause interstitial infiltrates in neutropenic patients. Hence, broad-spectrum antibiotics as well as TMP/SMX are empirically initiated in these patients. Failure of improvement necessitates lung biopsy and consideration of antifungal therapy. Cardiovascular infections. Endocarditis is an infrequent complication of bacteremia in cancer patients, presumably because of the early initiation of empiric antibiotics in these patients? ~ On the other hand, endocarditis may suggest an underlying malignancy (association of Streptococcus boris with colon cancer)?" Gram-negative organisms (Pseudomonas) and fungi (Candida) ~' are the corn-

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mon causes of endocarditis in cancer patients. Myocardial microabscesses occur more frequently (Candida) and myocarditis may be associated with both viruses and protozoa (Toxoplasma). Since bacterial endocarditis is uncommon, protracted courses of antibiotics ( > 3 weeks) are generally unnecessary for the cancer patient with staphylococcal bacteremia who has responded to two weeks of antibiotic therapy/:~ Peripheral vascular infections are also infrequent in cancer patients. However, vascular necrosis is characteristic of certain organisms (Pseudomonas, Aspergillus, Mucor) and may result in a characteristic cutaneous necrosis. Aspergillus can also produce an obstruction of the hepatic vein leading to a Budd-Chiari syndrome? ~ Gastrointestinal tract infections. The host defenses of the normal GI tract include: mechanical factors (peristalsis, secretions, the gastric acidity barrier); the antibacterial lysozymes, bile salts, natural antibodies; the microecologic balance of the indigenous intestinal flora; and the local cell-mediated and humoral (especially secretory IgA) immune factors. In the cancer patient, the normal protective barrier of the GI tract is altered by the underlying disease (local tumor invasion and infiltration), as well as by chemo- and radiotherapy induced mucosal defects. Since the GI tract is a major reservoir of microorganisms, it serves as a portal for systemic infection in the patient with cancer. In addition, several characteristic GI syndromes may occur: Esophagitis. Characterized by dysphagia and burning retrosternal pain, esophagitis is usually associated with fever and neutropenia in a patient already receiving broad-spectrum antibiotic therapy. C. albicans is the most common etiologic agent, although herpes simplex and bacterial organisms can also produce these symptoms/" A characteristic cobblestone appearance of the distal esophageal mucosa is observed on contrast esophagogram, although this pattern does not discriminate among the various diagnostic possibilities. Since a short course of amphotericin B (0.5 mg/kg x 7 days) affords prompt relief for patients who have Candida esophagitis, we empirically institute this therapy in symptomatic patients who have positive esophagograms. Patients who fiiil to improve require esophagoscopy and biopsy. lntra-abdominal infections. In addition to infection with the common intestinal flora, the cancer patient is also at risk for infection with GI pathogens (Salmonellaf' as well as several unique intra-abdominal syndromes: Typhlitis is a necrotizing cellulitis of the cecum, usually presenting acutely with severe right lower quadrant pain. Gram-negative bacilli (especially Pseudomonas) are most commonly responsible, and the mortality is high even with apparently optimal antibiotic management. Surgical

The Journal of Pediatrics March 1981 excision of the necrotic tissue (although risky in such patients) has been successful when combined with aggressive supportive management. 7~ Hyperinfection syndrome is manifested by nausea, diarrhea, abdominal pain, fever, and less commonly by dehydration and shock, occurring as a consequence of the invasion and ulceration of the intestinal tract by filariform larvae of Strongyloides stercoralis which undergo maturation (from the rhabditiform stage) as a consequence of chemotherapy. Treatment with thiabendazole (25 mg/ kg/day, in two divided doses, for 2 days) is effective. 73 Clostridial peritonitis in cancer patients can be fulminant and is characterized by fever, tachycardia, and flank tenderness (which may extend to the axilla and thighs). The abdominal wall rapidly becomes ecchymotic and crepitant/~ Aspiration of the cellulitis yields a cherry red fluid; the Gram stain shows the large gram-positive rods of Clostridium. Aggressive therapy with high-dose penicilfin plus clindamycin, chloramphenicol, or an aminoglycoside is essential. Perianal infections. Even minor tears or ulceration of the anorectal mucosa in the neutropenic patient can result in perirectal cellulitis, usually with gram-negative bacteria/:' Fluctuance may be difficult to detect when the patient is neutropenic, but if present the lesion should be aspirated and cultured for both aerobic and anaerobic organisms. In addition to systemic antibiotics, sitz baths, warm peroxide compresses, low bulk diets, stool softeners, and antidiarrheal agents may help promote local healing and prevent further inflammation. In the absence of organization, surgical drainage is difficult and incision may aggravate local healing. Antibiotic therapy should be continued until complete local resolution has occurred, since these lesions can serve as a portal for infection during subsequent courses of chemotherapy and neutropenia. However, patients who do not respond after 72 hours of therapy with a semisynthetic penicillin and an aminoglycoside should also receive more specific antianaerobic therapy (clindamycin or chloramphenicol). Continued lack of response after 48 or 72 hours of specific antianaerobic therapy in the neUtropenic patient is an indication for granulocyte transfusions. Urinary tract infections. The urinary tract is a relatively infrequent site of infection in the child with cancer, although the risk is increased by tumor obstruction, bladder atony due to cord involvement, or catheterization. In addition to bacterial infection, the urinary tract may also become infected with Candidaalbicans (especially in catheterized patients). Generally this is a superficial infection (bladder thrush), and may be treated by instillation of amphotericin B (50 mg in 1 L of dextrose and water per day) into the bladder or with 5-fluorocytosine (100 to 150

Volume 98 Number 3

mg/kg/day, every 6 hours). However, disseminated candidiasis may occur secondarily in neutropenic patients, necessitating early diagnosis (the presence of pseudohyphae in the urine is not diagnostic) and intravenous amphotericin B. Cutaneous infections. The integrity of this primary physical defense barrier is frequently disrupted in the cancer patient (needle punctures, biopsies, surgery, radiation). Consequently, local cutaneous infection with bacteria or fungi is common and may result in disseminated infection during periods of immunosuppression. Vigilant skin cleansing with iodophor solutions is essential prior to any procedure which may permit the introduction of potential pathogens. The skin can also become infected during bacteremia (Ps. aeruginosa, A. hydrophilia, C. equi, S. marcesens); fungemia (Aspergillus, Candida, Mucor, C. neoformans, H. capsulatum); or viremia (herpes simplex, herpes-zoster). Hence, skin lesions may permit the early diagnosis of generalized infection, and fresh lesions should be aspirated (or biopsied) and the material cultured and examined with Gram stain, KOH, and modified acid-fast stain. If a viral process is suspected, the base of a fresh vesicle should be scraped for Tzanck preparation, and if indicated, vesicle fluid cultured and examined by electron microscopy. The diagnosis of vesicular lesions in the cancer patient is not only important for appropriate management, but also permits the physician to decide whether isolation is necessary for the protection of other patients and staff members. Musculoskeletal infections. The musculoskeletal system is an uncommon primary site of infection in cancer patients. Atypical infections such as deep pyomyositis (due to S. aureus or gram-negative organisms) have been described in both neutropenic and nonneutropenic leukemia patients. 7'~ Diagnosis may be difficult because of the minimal fluctuance (even in nonneutropenic patients) associated with these infections, thus necessitating a heightened index of suspicion. Treatment is generally successful when incision and drainage are added to appropriate antibiotic therapy. Crepitance and soft-tissue tenderness should suggest an anaerobic infection, either with Clostridium or with the toxin-producing Bacillus cereus. 77, TM Immediate intervention with debridement and antibiotics is essential, and hyperbaric oxygen may be necessary. Septic arthritis or osteomyelitis in the cancer patient may be due to gram-negative organisms (Pseudomonas, Klebsiella, Salmonella, Eikenella) or fungi (Candida) as well as the more common gram~positive bacterial pathogens. Early detection may be facilitated by bone scanning, but aspiration and culture are essential to define the

Infectious complications in the child with cancer. I

3 49

etiology. Patients with local skeletal defects, those who have undergone extensive surgery (amputation, soft tissue dissection), or patients with bacteremia or fungemia are considered to be at high risk, and should be carefully observed. Occasionally it may be difficult to differentiate osteomyelitis from tumor (Ewing sarcoma) or radionecrosis. Central nervous system infections. Central nervous system infections are infrequent in pediatric cancer patients, 7~ although the physician should be aware of several unique CNS infections which may occur as a consequence of the underlying disease or its treatment. Meningitis. Splenectomized cancer patients are at increased risk for meningitis. Although meningitis is surprisingly infrequent in neutropenic cancer patients, even minimal symptoms (headache, meningismus, disorientation), should prompt a diagnostic lumbar puncture. Spinal fluid should be cultured for both bacteria and fungi and must be carefully examined with Gram stain and an India ink preparation. Patients with leukemia or lymphoma may have meningitis with Listeria monocytogenes or Cryptococcus neoformans. The presence of grampositive rods in the spinal fluid of cancer patients should suggest the possibility of Listeria and appropriate therapy (intravenous ampicillin and carbenicillin) should be promptly initiated. ~'' If crypotococcal meningitis is suspected (India ink preparation is positive in 50%), the spinal fluid should be cultured and examined for cryptococcal antigen. Therapy includes systemic amphotericin B (0.3 mg/kg/day) in combination with 5-fluorocytosine (150 mg/kg/day, every 6 hours) with a 67% rate of improvement or cure? 1 Brain abscess. The presence of focal CNS findings in the febrile cancer patient suggests brain abscess. In addition to aerobic and anaerobic bacteria, Nocardia and fungi are the most likely causes. The association of pulmonary lesions with focal neurologic findings is suggestive of Nocardia, Aspergillus, Mucor, and Candida." .... Early diagnosis is essential (including EEG, CAT scan, brain scan) since appropriate therapy (sulfadiazine for Nocardia, amphotericin for fungi) may be life-saving. Encephalitis. Herpes simplex, varicella-zoster, and measles are the most likely causes of viral encephalitis. Herpes simplex (which may present with either focal or generalized symptoms) has recently shown encouraging responsiveness to adenosine arabinoside (15 mg/kg/day over 12 hours for 10 days). ~:' In addition to viruses, Toxoplasma gondii has a predilection, in the compromised host, for the CNS, and may result in headache, confusion, seizures, focal neurologic deficits, and cranial nerve palsies. ~4 The patient with toxoplasmosis may also have hepatosplenomegaly, myocarditis, and pneumonitis. The diagnosis of

3 50

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The Journal of Pediatrics March 1981 FEVER AND GRANULOGYTOPENIA

I

Day 0

I '~

Evaluation

I

Documented

Day 7

F G Fever and Granulocytopenia Resolved

L

F+G Febrilebut Granulocytopenia Resolved

Low Risk FUO'sJ

F G+ Afebrile and Granulocytopenic

F+G+ Febrile and Granulocytopenic

LHigh Risk FUO'sJ

Fig. 3. The initial evaluation of fever and granulocytopenia, and the clinical rating of episodes of fever of unknown origin after seven days of empiric antibiotic therapy.

toxoplasmosis may be made by the visualization of the intracellular parasite, by a Sabin-Feldman dye test > 1:1000, or by the presence of specific IgM immunofluorescent antibody. Treatment of toxoplasmosis requires approximately four weeks of pyrimethamine and sulfonamide (with folinic acid) and is successful in 80% of patients?' Shunt infections. Ommaya reservoirs are being used more to deliver chemotherapeutic drugs to patients with established CNS leukemia or malignancy, and in some institutions these reservoirs are being used for the administration of prophylactic CNS therapy. Like any foreign body, these devices represent a potential source for infection. Fortunately, with scrupulous skin antisepsis, the incidence of shunt infections has been less than 10% in our experience. ~:' Furthermore, although shunt infections may occur in a small number of patients (with corynebacteria or Proprionibacterium aches), we have successfully used systemic and intrareservoir antibiotics (four of six patients) as an alternative to reservoir removal, thus permitting uninterrupted shunt usage in these high-risk patients. Dementias. One of the disconcerting sequelae to modem chemotherapy has been leukoencephalopathy..The majority of these dementing processes can be attributed to chemotherapy, especially the combination of radiation and methotrexate)" However, the recent awareness that slow virus infections can produce CNS deterioration in man has raised concern that some dementing processes may have a viral etiology. Adults with lymphoma and symptoms of progressive mental and emotional deterioration (including decreased visual acuity, aphasia, and both sensory and cerebellar signs) may have antibody to the JC

virus suggesting the diagnosis of progressive multifocal leukoencephalopathy) 7 FEVER OF UNKNOWN

ORIGIN

The management of the neutropenic, febrile cancer patient whose initial evaluation has failed to demonstrate an infectious etiology remains a diagnostic and therapeutic dilemma. Continued empiric antibiotic therapy in these patients may obscure an occult infection; may contribute to hypersensitivity reactions, hematologic toxicity, and renal and electrolyte abnormalities; and may increase the risk of developing a resistant microbial flora or superinfection? ~ On the other hand, the premature withdrawal of antibiotics in the granulocytopenic patient may result in significant infectious morbidity and mortality. The FUOs can be divided into low- and high-risk categories (Fig. 3). 4~ The majority (61%) are low risk, as defined by the resolution of neutropenia within seven days following the initiation of empiric antibiotic therapy. None of these patients developed recurrence of fever or other infectious complications when the antibiotics were discontinued at the resolution of neutropenia; hence, a short course of empiric antibiotic therapy appears safe for this group of patients. In contrast, F U O patients with prolonged neutropenia ( > 7 days) should be considered in a high-risk category. In our series, 30% of the episodes were in this category. These patients can be further subdivided into those who become afebrile (but who remain neutropenic) while receiving empiric antibiotic therapy, and patients who remain febrile while receiving antibiotics (Fig. 3). To test the advantages and disadvantages of continued antibiotic therapy in these patients, we randomly assigned high-risk

Infectious complications in the child with cancer. 1

Volume 98 Number 3

PATIENTS RANDOMIZEDTO CONTINUEANTIBIOTICS

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Fig. 4. Infectious complications in afebrile granulocytopenic patients selected at random to discontinue antibiotic therapy after seven days of empiric therapy (lower panel) or to continue antibiotic therapy until the granulocytopenia resolved (upper panel).

351

352

Pizzo

F U O patients to receive or not receive continued antibiotic therapy. The infectious complications in the F U O patients who had become afebrile but who remained neutropenic and who were selected at random on day 7 either to discontinue antibiotics or to continue until their granulocyte count rose above 500/gl are shown in Fig 4. The patients in both groups were completely comparable, were clinically indistinguishable, and had no evidence of infection at the time of randomization. The duration of granulocytopenia is graphically represented for each patient by the upper solid bar and the duration of empiric antibiotics by a hatched bar. All but one of the patients selected to continue receiving antibiotic therapy for the duration of the granulocytopenia (upper panel) remained afebrile and free from infectious complications. In contrast, seven of the 17 patients (41%) selected at random to discontinue antibiotics (lower panel) became febrile or infected again within a median of two days after antibiotic therapy was stopped (P = 0.007). These observations suggest that it is beneficial to continue empiric antibiotics in F U O patients who have become afebrile but who have prolonged neutropenia. Whether these antibiotics should be continued for the duration of the neutropenia or for a conventional (14-day) treatment course is currently under study. The second high-risk F U O group includes patients who continue to remain both febrile and neutropenic after seven days of empiric antibiotics. For these patients, the possibility that the empiric antibiotic regimen is controlling an occult infection must be balanced against the possibility that the antibiotics are inadequate, or that a fungal infection is a primary or secondary complication. In addition to empiric antibiotic therapy, we are evaluating the utility of additional empiric antifungal therapy in these patients; the preliminary results are encouraging. ~' The author expresses gratitude to Ms. Kay Robichaud and to Drs. F. Bia, P. Peebles, and S. Schimpff for helpful criticism in the preparation of this manuscript. REFERENCES 1. Levine AS, Schimpff SC, Graw RG Jr, et ah Hematologic malignancies and other marrow failure states: Progress in the management of complicating infections, Semin Hematol 11:141, 1974. 2. Feigin RD, and Shearer WT: Opportunistic infections in children, J PEDIATR87:507, 677, 852, 1975. 3. Stossel T: Phagocytosis. Clinical disorders of recognition and ingestion, Ann J Pathol 88:741, 1977. 4. Poplack DG, and Blaese MR: The mononuclear phagocytic system, in Stiehm E, and Fulginitti V, editors: Immunologic disorders of infants and children, Philadelphia, 1980, WB Saunders Company, pp 109-126. 5. Bodey GP, Buckley M, Sathe YS, et ah Quantitative relationships between circulating leukocytes and infection

The Journal of Pediatrics March 1981

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Volume 98 Number 3

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disease. Description of an epidemic of pneumonia, N Engl J Med 297:1189, 1977. Klein RS, Recco RA, and Catalono MT, et al: Association of Streptococcus bovis with carcinoma of the colon, N Engl J Med 297:800, 1977. Ihde DC, Roberts WC, Mair KC, et al: Cardiac candidiasis in cancer patients, Cancer 41:2364, 1978. Buss DH, and Scharyj M: Herpes virus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance, Am J Med 66:457, 1979. Han T, Sokal JE, and Neter E; Salmonellosis in disseminated malignant diseases a seven year review (1959-1965), N Engl J Med 276:1045, 1971. Varki AP, Armitage JO, and Flager JR: Typhlitis in acute leukemia. Successful treatment by early surgical intervention, Cancer 43:695, 1979. Rassiga AA, Lowry JL, and Forman WB: Diffuse pulmonary infection due to Strongloides stercoralis, JAMA 230:426, 1974. Wynne JW, and Armstrong D: Clostridial septicemia, Cancer 29:215, 1972. Schimpff SC, Wiernik PA, and Block JB: Rectal abscesses in cancer patients, Lancet 2:844, 1972. Blatt J, Reaman G, and Pizzo PA: Pyomyositis in acute lymphocytic leukemia heralded by cutaneous vasculitis. Two case reports, Med Pediatr Oncol 7:237, 1979. Lehman TJA, Quinn J J, Siegel S, et al: Clostridium septicum infection in childhood leukemia. Report of a case and review of the literature, Cancer 40:950, 1977. Groschel D, Burges MA, and Bodey GP: Gas gangrene-like infection with Bacillus-cereus in a lymphoma patient, Cancer 37:988, 1976.

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Chernik N, Armstrong D, and Posner JB: Central nervous system infections in patients with cancer. Changing patterns, Cancer 40:268, 1977. Lavetter A, Leedom JM, Mathies AW, et al: Meningitis due to Listeria monocytogenes, N Engl J Med 285:598, 1971. Bennett JE, Dismukes WE, Duma RJ, et al: Amphotericin B-ftucytosine in cryptococcal meningitis, N Engl J Med 301:126, 1979. Young LS, Armstrong D, Blevins A, et al: Nocardia asteroides infection complicating neoplastic disease, Am J Med 50:356, 1971. Whitley RJ, Soong SJ, Dolin R, et al: Adenine arabinoside therapy of biopsy-proven Herpes simplex encephalitis, N Engl J Med 297:289, 1977. Remington JS: Toxoplasmosis in the adult, Bull NY Acad Med 50:211, 1974. Bleyer WA, Pizzo PA, Spence AM, et al: The Ommaya reservoir: Newly recognized complications and recommendations for insertion and use, Cancer 41:2431, 1978. Pizzo PA, Poplack DG, and Bleyer WA: The neurotoxicities of current leukemia therapy, Am J Pediatr Hematol/Oncol 1:127, 1979. Narayan O, Penney JB, Johnson RJ, et al: Etiology of progressive multifocal leukoencephalopathy. Identification of papovovirus, N Engl J Meal 289:1278, 1973. Pennington JE: Fever, neutropenia, and malignancy: A clinical syndrome in evolution, Cancer 39:1345, 1977. 988, 1976. Pizzo PA, Robichard K, Simon R, et al: Empiric antifunal therapy for cancer patients with prolonged fever and granulocytopenia, Proc Am Soc Clin Oncol 21:348, 1980.