Survival can be significantly prolonged for children with cancer, and cures may be anticipated for many. Among the reasons for this improving prognosis are advances in the management of infection, allowing certain patients who would otherwise have died of this complication to survive sufficiently long that effective cancer treatment may be administered. Nevertheless, infection remains the leading proximate cause of morbidity and mortality in most childhood cancers.1
ETIOLOGY, INCIDENCE, AND PATHOGENESIS
While many of the common bacterial infections can now be treated successfully, newer cancer treatments have led to increasingly severe alterations in host defenses. These compromised defenses, longer survival, and the extensive use of antibiotics have led to infections only rarely seen previously. Such "exotic" infections often prove difficult to diagnose aria manage. However, the major infectious threats in cancer remain gram-negative bacillar)' septicemia, Staphylococcus aureus infections, fungal infections, viral hepatitis, and varicella-zoster infections. Most fatal infections occurring in children with cancer are systemic, usually caused by bacteria or fungi. While in the past the likelihood of fatal infection due to fungi was low, there has been an increasing incidence of such infections (particularly candidiasis and aspergillosis) with the advent of modern cancer chemotherapy.
Changing patterns of infection are to be anticipated in the complex setting of cancer, aggressive cancer treatment, and nosocomial infection. For example, before 19605. aureus was the major cause of severe infection in childhood cancer, but in the past decade gram-negative organisms (especially Pseudomonas aeruginosa) were the most frequently isolated pathogens. Recently, staphylococcal and streptococcal infections have again become frequent, and in some centers they have replaced gram-negative organisms as the most frequently isolated bacterial pathogens.2
The incidence and type of infection in childhood cancer depend on the underlying tumor type, stage of disease, intensity of cancer therapy, and a host of other predisposing factors.1 For example, patients with acute myeloid leukemia in relapse have approximately one episode of septicemia every 80 hospital days, whereas children with early stages of malignant lymphoma have septicemia approximately every 1,200 hospital days. These differences are probably related to variation in the level of normal granulocytes and the intensity oí remission-inducing therapy. However, defects in cellular or humoral immunity may account for particular associations between a given tumor and a specific infectious complication - e.g., varicella-zoster in Hodgkin's disease. The cause and frequency of infection also depend on the age of the patient, barrier defenses (skin and mucosal integrity), and obstruction of natural passages. Other predisposing factors are iatrogenic but often unavoidable: immunosuppressive and myelosuppressive drugs, intravenous and urinary catheters, intravenous fluids, needles, respiratory-assist devices, and hyperalimentation procedures. Many infections in children with cancer are in fact caused by hospital-acquired organisms. Organisms are acquired from various sources in the hospital environment, including food, drinking water, humidifiers, and patient-topatient transmission (sometimes via the unwashed hands and contaminated clothing of hospital staff). Certain agents are transmitted via blood products from infected donors, including hepatitis viruses, cytomegalovirus, toxoplasma, and bacteria.
The single most important factor predisposing to infection is granulocytopenia. The incidence and severity of infection are inversely related to the absolute peripheral granulocyte level.3 Furthermore, the response to antibiotic therapy usually depends on a concurrent rise of the granulocyte level during treatment. In addition to quantitatively impaired phagocytosis, children with cancer, particularly the hematologic malignancies, may exhibit qualitative defects in neutrophil function, and these defects may antedate chemotherapy. The contribution of lymphopenia to the incidence of infection is less certain, but it may relate to the occurence of viral and fungal complications. Macrophage function may also be altered, especially in the lymphomas, and this dysfunction may be expected to lower host resistance to facultative intracellular parasites - e.g., Listeria monocytogenes, Mycobacterium tuberculosis, and Cryptococcus neoformans.
Not only are children with cancer often susceptible to infection even before therapy, but host resistance is altered significantly by cancer treatment.4 For example, the corticosteroids alter immunologic response, diminish phagocytosis, and may produce direct tissue toxicity. Cytotoxic chemotherapy contributes to lowered host resistance by inducing leukopenia, humoral and cell-mediated immunosuppression, and ulcerations in mucosal surfaces. Recovery of immune responsiveness after one dose of a single cytostatic agent usually requires 48 to 72 hours, and intensive combination chemotherapy requires rest periods of 10 to 14 days between drug cycles in order to maintain a degree of immunocompetence.
Other aspects of cancer management may lead to infection. Splenectomy, as carried out in the diagnostic staging of Hodgkin's disease, is an important predisposing cause. Postsplenectomy septicemia or meningitis (usually pneumococcal, streptococcal, or due to H. influenzae and often fulminant) occurs in adolescents and young children days to years after laparotomy, may occur without leukopenia, and might be prevented with penicillin prophylaxis or specific bacterial vaccine immunization.5 Finally, infection and its therapy predispose to further infection. Antibiotics alter the normal balance of microbial flora and may thereby allow invasion by an otherwise innocuous organism. Further infections may occur in as many as 50 per cent of children with cancer who receive antibiotics for more than two weeks. Thus, no antibiotic therapy can be given with impunity, and few areas in medical practice require more judgment than the appropriate use of antimicrobial therapy in the child with cancer.
A comprehensive approach to prophylaxis consists of (1) a reduction in pathogen acquisition, (2) avoidance of invasive procedures, (3) a reduction in the number of potential pathogens already colonizing the patient, and (4) improvement of the patient's host defense mechanisms.
Reduction in pathogen acquisition should begin by limiting hospitalization when outpatient facilities can be utilized. When hospitalization is essential, overcrowding in wards and intensive-care units must be avoided. The hospital staff must carefully wash their hands before and after patient contact. This oncerespected requirement has been widely ignored in the antibiotic era. Hexachlorophene rapidly kills staphylococci but not gramnegative organisms or fungi. For the latter microbes, iodine-containing compounds should be used. Hospital food is almost always contaminated with a variety of organisms; well-cooked food should be served whenever possible. Water for drinking and bathing and other potential sources of contamination (ice machines, sitz baths, bathtubs) should be cultured frequently. Other prophylactic techniques include the culturing of respirator equipment, the use of fresh platelets, and careful surveillance of blood donors.
The total avoidance of invasive procedures is impossible, but we recommend that intravenous catheters not be used except during hemorrhage or septic shock. Scalp-vein needles should be changed frequently, and all intravenous tubing should be changed daily. New tubing should be employed after every blood-product infusion, and no intravenousfluid bottle should be left in place for more than 24 hours.
To reduce the total number of organisms already colonizing the patient requires care of the skin and mucous membranes and oral hygiene. Patients with positive tuberculin skin tests or x-ray evidence of old tuberculosis should be placed on isoniazid regimen during prolonged chemotherapy. Passive immunization immediately after exposure to measles and varicella is usually appropriate, as is the use of immune serum globulin after exposure to viral hepatitis. Active immunization with appropriate killed influenza vaccines should also be undertaken.
Finally, an attempt should be made to augment host defense mechanisms. The major goal is to treat the tumor so that phagocytic, immunologic, hemostatic, and body barrier defenses return to normal. In the absence of these defenses, the patient should be encouraged to obtain adequate nutrition and exercise, the air should be of proper temperature and humidity to maintain nasopharyngealpulmonary toilet, and other underlying diseases (such as diabetes and congestive heart failure) should be controlled. Obstruction of natural passages by tumor (such as bronchus, ureter, or eustachian tube) almost always leads to infection. An attempt should be made to relieve all such obstructions at once, through the use of local radiation therapy or other modalities.
Figure 1. A small perianal abscess, from which Klebsiella was cultured, progressed rapidly to this massive slough of anal and rectal tissue. The patient was a five-year-old boy receiving chemotherapy for acute myeloid leukemia in relapse.
The diagnosis of infection in children with cancer begins with knowledge of the kinds of infection common within each tumor type and the conditions under which these infections occur. Thus, the infection to be initially considered in a granulocytopenic patient with acute leukemia and de novo fever is bacterial septicemia, often arising from a nidus in the lungs, pharynx, or rectum (Figure 1). In patients with protracted fever, particularly those who have been in relapse for some time, infection due to Candida or Aspergillus should be considered. The febrile, granulocytopenic patient with a malignant lymphoma may have bacterial septicemia, but consideration should be given as well to cryptococcosis, listeriosis, disseminated zoster, nocardiosis, and Pneumocystis carinii pneumonia. Further clues to diagnosis include the presence of catheters, hyperalimentation lines, bloodproduct transfusions, damaged intravenous equipment or humidifiers, and neighboring infected patients whose pathogenic organisms may have been transmitted.
The importance of immediate and appropriate cultures, especially of the blood, cannot be overemphasized. Blood cultures should be done in duplicate (separate venipunctures) and placed in appropriate media, including media that will sustain anaerobes. Use of a pour plate (1 ml. of blood in 9 ml. of liquid agar) may speed diagnosis. Cultures of skin lesions, sputum, urine, stool, and spinal fluid (when indicated) must be done before antibiotics are begun and should include a two-tube anaerobic system.
Further specific diagnostic techniques include transtracheal aspiration, fiberoptic bronchoscopy with bronchial brushing, and lung biopsy or aspirate for pneumonic infiltrates. Skin biopsy may permit the diagnosis of herpes zoster, disseminated fungus infections, and bacterial sepsis.
The characteristic ecthyma of Pseudomonas infection (Figure 2) should always suggest underlying bacteremia. In the presence of periorbital edema, proptosis, or headache, mucormycosis should be sought in a nasal biopsy specimen.
Candida infection frequently disseminates following invasion of the oropharynx, esophagus, or gastrointestinal tract. In the presence of dysphagia or retrosternal pain, a barium study may reveal Candida esophagitis, and fiberoptic esophagoscopy with biopsy may reveal unsuspected pathogens - e.g., herpes simplex.
Among the new and important diagnostic techniques are those that employ radioisotopic imaging. For example, gallium-67 citrate concentrates in areas of infection when administered intravenously, and focal accumulation of the isotope may be demonstrated by scintiscanning. The technique depends on the affinity of the isotope for leukocytes, but we have found scans to be positive even when the peripheral granulocyte count is less than 100/cu. mm. (Figure 3).6 It should be noted, however, that gallium also concentrates in neoplastic tissue. Thus, in the child with cancer, the chief value of this method may be in the exclusion of an abscess if the scan is negative or in indicating the need for further studies if the scan is positive. The use of several radioisotopes, each with different characteristics, may be of particular value in diagnosing and localizing infection in the child with cancer. An especially promising technique is the infusion of indium-Illlabeled autologous leukocytes for localization of abscesses.7
Figure 2. The typical ecthyma caused by P. aeruginosa. The patient was a 14-year-old girl with underlying Pseudomonas septicemia. She had been receiving combination chemotherapy for acute myeloid leukemia in relapse; these lesions were noted in the setting of fever and granulocytopenia.
The definition of most viral illnesses depends on a combination of clinical signs, serology, culture, and light or electronmicroscopic examination. For serology, acute and convalescent sera should be obtained 14 to 21 days apart. Since chemotherapy may alter the serologic response, titers should also be obtained at the time of the first rise in white cell count after the suspected viral episode. Fluids and tissues should be placed immediately in viral infusion broth and cultured promptly, preferably without freezing or refrigeration. Vesicle fluid and cerebrospinal fluid can be examined by the electron microscope. This technique provides rapid information about the virus group, but definitive identification depends on culture, which may take up to six weeks.
Figure 3. A gallium-67 citrate scintiscan demonstrating an area of uptake consistent with the diagnosis of psoas abscess (arrow). The patient was a 1 2-year-old boy with aplastic anemia who at the time of this positive scan had a peripheral granulocyte count of less than 100/cu. mm.
The immunosuppressed or myelosuppressed cancer patient cannot respond to infection with the usual signs of inflammation. Rectal abscesses may appear trivial yet seed bacteria into the blood. Potentially fatal pulmonary infiltrates may seem minor in extent on x-ray or physical examination. Pharyngitis may occur without adenopathy or exudate, and urinary-tract infections may occur in the absence of dysuria or pyuria. Despite the absence of significant physical signs and symptoms, we believe that daily (or even more frequent) examinations, encouraging the febrile child to report seemingly trivial complaints, and repeated chest x-rays will usually identify the primary site of infection within a few days of its onset, whether or not primary infection has resulted in sepsis. Helpful clues include a history of anal tenderness, bacteria in the unspun urine (Gram stained despite a lack of pyuria), or retinal lesions suggestive of the endophthalmitis associated with Candida or Aspergillus dissemination. Candida in the urine, in the absence of a urinary catheter, may reflect invasive candidiasis, especially when pseudohyphae are seen.
FEVER OF UNKNOWN ORIGIN
Our approach to fever of unknown origin depends on the foregoing discussion of etiology, frequency, and predisposing factors; in other words, the physician must recognize likely possibilities.
More than 70 per cent of granulocytopenic cancer patients have infection as the source of de novo fever (over 101 degrees) - frequently bacterial sepsis, pneumonia, or cellulitis. Since the median survival with inappropriate therapy of sepsis is less than three days, immediate steps must be taken whenever a de novo febrile episode occurs in a granulocytopenic patient and before culture results become available. The child should undergo a complete history and physical examination, with emphasis on sites of high probability (catheters, obstructions, infusions, etc.) and an awareness that the usual signs of inflammation may be absent. Chest x-rays should always be done, since pneumonia may occur without physical findings. Gram stains and cultures of all suspicious lesions, as well as two or three sets of blood cultures, should be performed. Surveillance cultures of nose, throat, urine, and stool will identify the organisms colonizing the patient.
Following these procedures and generally no later than four hours after the initial temperature elevation, the child with significant granulocytopenia and de novo fever of undetermined origin should be given empiric broad-spectrum antibiotics. No one regimen is known to be superior to others, since few comparative trials have been conducted and patterns of infection often vary between institutions. We currently recommend combination therapy with gentamicin (6 mg./kg. per day, given intravenously every six hours over 15 minutes); carbenicillin (500 mg./kg. per day, given intravenously every six hours over 10-to-15 minutes); and cephalothin (170 mg./kg. per day, given intravenously every four hours over 15 minutes). This combination will cover most gram-negative bacilli (including P. aeruginosa), S. aureus, other possible gram-positive organisms, and most anaerobes (including many Bacteroides species but not B. fragilis).
Where Pseudomonas infections are uncommon, gentamicin and cephalothin may suffice. In children with poor renal function, gentamicin and a semisynthetic penicillin should be employed in preference to gentamicin and cephalothin. (Gentamicin blood levels should be measured in all children receiving this drug, with or without renal dysfunction, to ensure therapeutic and nontoxic dosages). These antibiotic combinations are additive and often synergistic.
The antibiotics are continued, and daily examinations and frequent chest x-rays are repeated until the site and organism(s) are documented. If no site and no organism is discovered within seven days, the patient may not have a bacterial infection. If the child's condition has worsened despite antibiotics and cultures remain negative, the possibility of fungal infection becomes very real. If, however, the patient has clinically improved (and defervesced) even though cultures and examinations remain unrevealing, the antibiotic combination should be continued.
A critical dilemma occurs when the patient's cultures and examinations remain negative and he neither improves nor deteriorates. In this situation, the antibiotics might be discontinued after one week of empiric treatment, with the patient then observed meticulously and cultured repeatedly; antibiotics should be resumed immediately at the earliest sign of deterioration. Although certain patients may in fact have an occult bacterial infection and worsen if the antibiotics are discontinued after one week and before recovery from granulocytopenia, children may also suffer from cumulative toxicity and superinfection when antibiotic therapy is protracted. If the initial cultures did reveal an etiologic organism, the antibiotics should be modified appropriately as indicated below.
Most pediatric oncology centers report that P. aeruginosa, Klebsielh pneumoniae, and Escherichia coli represent the majority of the agents isolated in bacterial infection, followed by S. aureus, group D streptococcus species, and Serratia marcescens. As noted previously, patterns of infection among cancer patients are subject to change, and there is evidence that gram-positive infections are again occurring commonly and in some centers equaling or exceeding the gram-negative organisms in frequency. The genus of the infecting organism varies to a certain degree with the primary site of infection - e.g., Bacteroides with rectal lesions, Enterobacter or Erwinia with contaminated infusions, and Candida species or group D streptococcus species following hyperalimentation.
Suggestions for antibiotic therapy when a given pathogen has been identified include the following: Carbenicillin (or ticarcillin), used in combination with gentamicin, is highly effective in treating P. aeruginosa. With the advent of this synergistic combination, mortality due to Pseudomonas sepsis declined. The combination of cephalothin and gentamicin is synergistic for many Klebsiella isolates. The same combination is additive for virtually all other gram-negative infections, including those caused by Enterobacter species, E. coli, and Serratia. Amikacin should be used for gentamicin-resistant gram-negative infections. The semisynthetic penicillins are the treatment of choice for infections caused by S. aureus, and clindamicin is the agent of choice for anaerobes with demonstrable resistance to penicillin - e.g., B. fragilis. With regard to other organisms, it is probably best to utilize bactericidal drugs of the penicillin type whenever possible.
The early empiric use of broad-spectrum antibiotic combinations in febrile cancer patients with granulocytopenia has been exceedingly effective. For example, about 55 per cent of all patients who prove to have gramnegative sepsis will survive their episode of infection. Moreover, if the granulocyte level recovers normally from chemotherapeutic suppression (in less than two weeks), the survival rate in gram-negative sepsis may be as high as 80 per cent. On the other hand, if the granulocyte level does not recover within two weeks, fewer than 30 per cent of children with gram-negative sepsis will survive.
The duration of antibiotic treatment in documented severe bacterial infections varies with the state of the host's defenses. In general, treatment should continue for one week after clinical (and cultural) resolution if the patient is not granulocytopenic during this week. If granulocytopenia does persist, about two weeks of therapy after resolution of infection seems warranted. Longer therapy is, of course, necessary for certain infections, such as osteomyelitis.
Invasive fungal infections are an important cause of morbidity and mortality in children whose host defenses have been altered by their primary disease, by immunosuppressive therapy, by antibiotics, or by the use of indwelling intravenous and urinary cathers.1 The increasing incidence of fungal disease is primarily due to candidiasis, aspergillosis, and mucormycosis, and the frequency of these three infections is well correlated with increasingly intensive cancer chemotherapy. For example, at the National Cancer Institute there has been at least a 15-fold increase in the incidence of fatal aspergillosis during the past 20 years. Two other fungal infections, histoplasmosis and cryptococcosis, are seen more frequently in patients with cancer than in the general hospital population, but these infections do not appear to be increasing in frequency and are not well correlated with modern chemotherapy.
Candidiasis: Candidiasis is the most frequent fungal infection seen in patients with cancer. The spectrum of infection ranges from localized forms (e.g., thrush and urinary-tract infection), through extensive gastrointestinal infections, to invasive visceral infections (e.g., meningitis, renal disease, septicemia, pneumonitis) and widespread dissemination. C. albicans is the usual species implicated, but other species have been isolated. In the child with cancer, it is likely that any species of Candida may be a pathogen. The more superficial forms of infection are relatively easy to diagnose with the use of direct visualization, culture, and, when appropriate, biopsy. However, deep fungal infections and dissemination are difficult to diagnose with assurance. It should be remembered that Candida is a normal inhabitant of the gastrointestinal tract and mouth; therefore, cultural identification per se is inadequate for diagnosis unless the culture is obtained from involved tissue or from sites not normally harboring the fungus. Serologic tests for Candida have not proved useful.
Recently, emphasis has been placed on careful attention to ocular complaints and repeated ophthalmoscopic examination to detect Candida endophthalmitis, a striking physical finding predictably leading to the diagnosis of disseminated disease (Figure 4). Localized candidiasis and even candidemia do not often lead to disseminated candidiasis in a general hospital population. However, in cancer patients receiving chemotherapy, candidemia is a far more serious situation, since it almost always results in dissemination. All cancer patients with candidemia should receive systemic antifungal chemotherapy with amphotericin B. It is also our belief that febrile, leukopenic cancer patients who are found to be colonized throughout the gastrointestinal tract (i.e., both the mouth and stool) have a very high likelihood of dissemination. We treat all such children with amphotericin B. However, both in isolated candidemia and in gastrointestinal or other local colonization, the courses of treatment are briefer (two to three weeks) than in established deep visceral disease.
Figure 4. A well-demarcated retinal lesion associated with C. albicans endophthalmitis. The patient had a non-Hodgkin's malignant lymphoma and disseminated candidiasis, which was demonstrated following detection of this characteristic retinal lesion.
Aspergillosis: Aspergillosis is the second most common fungal infection in children with cancer. In terms of serious deep visceral infections, this organism may rapidly be approaching candidiasis in frequency. A. fumigatis is the species most frequently isolated in human infection; as with Candida, however, it is unwise to consider any Aspergillus species nonpathogenic in a child with cancer. The hallmark of aspergillosis in the child with cancer is tissue invasion rather than the saprophytic or allergic forms of the disease. Invasive aspergillosis commonly affects the respiratory tract, and pulmonary lesions are detected in virtually all patients. X-ray findings are not diagnostic, but multiple nodular infiltrates, often progressing rapidly and crossing fissures, are very suggestive of the disease.
Because of the propensity of this fungus to invade blood vessels and produce in situ thrombosis and infarction, clinical syndromes and x-ray findings consistent with pulmonary emboli are also frequently seen. Strategic vascular invasion by aspergillus has also produced the Budd-Chiari syndrome, renal papillary necrosis, and cutaneous infarction (Figure 5). The gastrointestinal tract and brain are other common sites of involvement.
Antemortem diagnosis is extremely difficult. Few patients have positive cultures; even when cultures are positive, they are not diagnostic, since they may be found in patients without significant fungal infection. More aggressive approaches to diagnosis, such as lung biopsy, must be utilized early in the course oí the illness. Prompt diagnosis may allow initiation of treatment with amphotericin B early enough for it to be successful. Serologic testing for aspergillosis in cancer patients has not been useful. Blood cultures are rarely, if ever, positive.
Mucormycosis: Although mucormycosis complicates cancer with some frequency, it still remains much less common than aspergillosis and candidiasis. Occasionally children exhibit all or part of the classic triad of orbital cellulitis, sinusitis, and diabetic acidosis; but disseminated, pulmonary, and gastrointestinal forms predominate in these patients. Antemortem diagnosis is exceedingly difficult, and even cultures taken of the affected organs at autopsy are often negative. Serologic testing has not been helpful, and the diagnosis therefore rests on identification of the fungus in tissue. Lung biopsy would seem to be the only way to secure the diagnosis of mucormycosis with any frequency; it should be strongly considered if the clinical picture is appropriate and if the patient's condition allows such a procedure. The Mucorales, like aspergilli, invade blood vessels and cause widespread vascular thrombosis with infarction and hemorrhage (Figure 6).9
Figure 5. Cutaneous infarction associated with infection by A. fumigatis. The patient was a 10year-old girl with acute lymphoid leukemia who developed this lesion at the site of an intravenous needle track. The primary infection led to fatal desseminated aspergillosis.
Cryptococcosis: Cryptococcosis is an acute or chronic meningeal, pulmonary, or disseminated mycosis caused by C. neoformans. The portal of entry is thought to be the respiratory tract, and pneumonitis is probably the initial form of the illness. The pulmonary infection may be subtle and the chest x-ray nondiagnostic. Dissemination of the infection appears to occur from the respiratory tract via asymptomatic hematogenous spread to the central nervous system. The neurologic symptoms may be acute or insidious. Thus, such symptoms as intermittent headache, lethargy, and ataxia should always prompt a lumbar puncture and a search for cryptococci.
India-ink staining of the spinal fluid yields the diagnosis in about half of the cases. Definitive diagnosis usually rests on culture of the organisms, which may require relatively large quantities of cerebrospinal fluid. As a consequence, serologic studies have assumed considerable importance; unlike the fungal infections previously discussed, these serologic assays are extremely reliable in cryptococcosis. Immunologic detection of cryptococcal antigen in the blood or spinal fluid is indicative of systemic cryptococcosis, but the presence of antibody to cryptococcal polysaccharide is less specific.
Histoplasmosis: Histoplasma capsulatum may produce disseminated disease with involvement of the reticuloendothelial system, the lungs, liver, and/or the central nervous system. Even in endemic areas, it tends to be an infrequent cause of disseminated mycosis in childhood cancer. Nevertheless, recognition is important, since histoplasmosis is one of the most easily treatable of disseminated fungal infections. The diagnosis rests on cultural isolation or histopathologic identification. In contrast to the situation with most of the other mycoses, blood and bone- marrow cultures will be positive in as many as 50 per cent of patients with disseminated disease. Careful examination of the gums and buccal mucosa for evidence of indolent ulceration may also provide a clue to the diagnosis.
Figure 6. Vascular thrombosis with infarction and hemmorhage due to infection with Mucorales. The patient was a 25-year-old woman with acute lymphoid leukemia refractory to chemotherapy who developed disseminated mucormycosis, of which this skin lesion was one manifestation.
Treatment of fungal infections: Amphotericin B is the treatment of choice for all five of the disseminated mycoses commonly occurring in children with cancer. The intravenous dosage employed at the National Cancer Institute is 0.5 mg./kg./day. If rapid progression of the mycosis is noted, the incremental steps can be escalated to achieve maximum dosage within one day. The side effects of systemically administered amphotericin B are legion, but the fever and chills may be modified by hydrocortisone. Often six- to 12-week courses (with total doses of 2.0-3.0 gm.) are necessary for eradication of deep fungal infections. Flucytosine is a new systemic antifungal drug that is readily absorbed from the gastrointestinal tract. The dose is 37.5 mg./kg., given every six hours. It is additive or slightly synergistic with low-dose, intravenously administered amphotericin B. The combination is probably the treatment of choice for cryptococcal and Candida meningitis, and it offers promise in treatment of systemic candidiasis and cryptococcosis.10
PNEUMOCYSTIS AND TOXOPLASMA INFECTIONS
While the taxonomy of P. carinii remains unclear, it is a leading cause of severe interstitial pneumonia in the child with cancer. In contrast to other infectious complications, P. carinii pneumonia occurs with equal frequency during remission or relapse of the underlying disease. Immunosuppressive therapy per se (especially corticosteroids) seems to be the major predisposing factor. The incidence of P. carinii pneumonia varies considerably among different institutions, with some hospitals reporting none at all, and others with an incidence ranging as high as 20 per cent. This suggests that patient-to-patient spread may be significant. Although some patients may have a one-to-two-week prodrome, most commonly there is a rapidly progressive syndrome of fever; tachypnea; dry, nonproductive cough; and cyanosis. Other hallmarks include significant hypoxemia and the presence of diffuse interstitial infiltrates, usually emanating from the perihilum on chest x-ray (Figure 7). Less commonly, the chest x-ray may show a unilateral or even lobar distribution.
Without treatment, the mortality of the patient with P. carinii pneumonia is 100 per cent. Immediate therapeutic intervention is essential, but since 50 per cent of patients with the syndrome of interstitial pneumonia may have another infection (bacterial, viral, or fungal), definitive diagnosis is critical. Unfortunately, noninvasive procedures are unreliable, and diagnosis can be established with assurance only by examination of infected tissue. Open lung biopsies have the highest diagnostic yield but carry the attendant morbidity of thoracotomy. In expert hands a closed needle aspiration of the lung will permit diagnosis of P. carinii with an accuracy of 85 per cent and with minimal morbidity. Tissue should be stained with Giemsa- Wright, toluidine blue, or Gomori's methenamine silver nitrate to demonstrate the organisms.
When instituted early, therapy is effective in 75 per cent of cases, with clinical improvement beginning after two to five days. Pentamidine and trimethoprim-sulfamethoxazole appear to be equally effective in the treatment of P. carinii pneumonia. While the experience with pentamidine is more extensive, nearly 50 per cent of treated patients have serious side effects. Trimethoprim-sulfamethoxazole (Bactrim® or Septra®) is effective in adults and children and has the advantage of minimal toxicity.11 We therefore believe it to be the treatment of choice. The dose of trimethoprim is 20 mg./kg./day and that of sulfamethoxazole 100 mg./kg./day; the combination is given every six hours for 14 days orally or intravenously. This combination of drugs is also uniquely effective for the chronic prophylaxis of patients at high risk of developing P. carinii pneumonia (e.g., leukemic children receiving long-term remission maintenance chemotherapy). However, since the drug may inhibit tetrahydrofolate reductase, its possible interaction with cancer therapeutic agents (such as methotrexate) must be studied more fully before one can recommend it for routine prophylactic use.
Figure 7. P. carinii pneumonia in a boy with acute lymphoid leukemia. The leukemia had been in remission for two years, and monthly pulses of maintainance chemotherapy had been continued. The roentgenographs picture is characteristic of a diffuse interstitial infiltrate emanating from the perihilar regions, but it is not specific for P. carinii pneumonitis.
Toxoplasmosis is caused by the obligate intracellular protozoon Toxoplasma gondii. In patients with cancer, this organism tends to produce a serious disseminated infection, due to defects in cellular immunity that permit recrudescence of latent infection. The disseminated infection involves the heart, liver, kidneys, and especially the brain.12 The clinical findings in such cases usually reflect signs of encephalitis or cerebral mass lesions. Pulmonary infiltrates, fever, hepatosplenomegaly, and lymphadenopathy are also common. Serologic testing is useful if a rising antibody titer can be demonstrated. Isolated high titers are not diagnostic, however, since many multiply transfused patients have extremely high titers. Histopathologic changes in affected lymph nodes of patients with acute acquired toxoplasmosis are remarkably distinctive and virtually diagnostic. The therapy of choice is pyrimethamine (14.5 mg./sq. M., given orally every day) and sulfadiazine (600 mg./sq. M., given orally every six hours) for 28 days; these agents have a synergistic effect.
The ubiquitous viral illnesses (such as those caused by rhinoviruses, adenoviruses, and enteroviruses) are generally no more frequent or more severe in patients with cancer than in the general population. However, children with altered defenses are less able to contain infection caused by the herpes viruses, vaccinia, and measles than are well children. The reason for frequent dissemination and prolonged replication of these viruses in such children is not clear, but it may in part relate to inadequate production of interferon by leukopenic patients.
Since children with cancer may not be able to contain certain viral infections, they should not be immunized with the live virus vaccines; such children should instead be passively protected whenever exposed to illnesses that can be prevented or modified with appropriate gamma globulin. Thus, children with malignant diseases, including those in remission but still on maintenance chemotherapy, should not be immunized against measles, mumps, rubella, or smallpox or receive the live, attenuated Sabin polio vaccine. Children with Hodgkin's disease, who may have a chronic cellular immune defect not related to chemotherapy, should probably not receive these immunizations even after they complete chemotherapy. Specific antiviral therapy is still in its infancy. There is no evidence at this time that any antiviral agent has lifesaving effect against any of the viral complications of cancer.
Varicella-zoster: Illness caused by varicellazoster is usually recognized clinically and confirmed quickly with standard assays. This virus produces varicella as a primary infection; zoster represents activation of the latent varicella-zoster virus in patients who have previously had varicella (Figure 8). Fulminant varicella (usually with pneumonia) occurs more frequently in children receiving cancer therapy than in normal children. As many as one-third of leukemic children who contract varicella or zoster may in fact develop disseminated disease. In this group, mortality can be as high as 20 per cent. Varicella may be prevented or modified in children with cancer if high-titer specific antibody (zoster immune globulin, or ZIG) is given within 72 hours of exposure. The single intramuscular dose is 0.2 ml./kg. (maximum: 5 ml.). Cessation of cancer therapy before the onset of lesions, if possible, also appears to lessen the risk of dissemination.
Zoster usually occurs as an endogenous reinfection and is particularly common among children with Hodgkin's disease. ZIG does not appear to benefit patients with zoster, but adenine arabinoside, a purine nucleoside inhibitor of DNA synthesis, hastens cutaneous healing and has no significant toxicity. It is not yet clear whether the drug aborts dissemination. The dose is 10 mg./kg./ day by continuous intravenous infusion for five days; one must weigh the somewhat shorter healing time against the necessity of hospitalization for intravenous treatment.13
Figure 8. Herpes zoster infection confined to the typical dermatome distribution. The patient was a five-year-old boy with alveoler rhabdomyosarcoma of the prostrate. Although this lesion was extensive, the boy was treated with adenine arabinoside and recovered quickly.
Herpes simplex (herpesvirus hominis): Children with cancer may develop an extensive cellulitis or mucocutaneous lesion caused by Herpes simplex. Occasionally the virus causes a disseminated disease or encephalitis, with or without skin lesions. In the immunosuppressed patient, herpes simplex may also cause an isolated esophagitis and/or necrotizing tracheobronchitis and bronchopneumonia. Esophagitis must be distinguished from monilial disease by esophagoscopy and biopsy, and pneumonia must be diagnosed by lung biopsy. There is no specific antiviral therapy available for the treatment of extensive mucocutaneous herpes, but studies on the use of adenine arabinoside are under way and this drug appears to be effective in H. simplex encephalitis.
Cytomegalovirus: Illness caused by cytomegalovirus (CMV) is poorly understood and usually not diagnosed with assurance. Infection is apparently ubiquitous, since 60 to 80 per cent of normal adults have antibody to the virus. CMV illness appears to consist of primary infection, endogenous reinfection, or exogenous reinfection. Cancer patients who excrete the virus in urine or saliva appear to have more episodes of pneumonitis or fever with rash than those who are not excretors. However, the relationship of virus excretion, viremia, serologic response, and clinical illness is not at all clear. There is no specific antiviral therapy for CMV illness. CMV alone can cause significant pulmonary disease, but lung biopsy (or aspirate) usually reveals it to be accompanied by other agents (especially P. carinii). CMV is demonstrated in the lung by histology or culture.
Vaccinia: In children with cancer, heteroinoculation or autoinoculation with vaccinia can lead to extensive local or generalized disease (Figure 9). Vaccinia immune globulin and methisazone (Marboran®), a thiosemicarbazone, have been used in the treatment of these complications with anecdotal efficacy, but no controlled studies have been reported. The oral dose of methisazone is 200 mg./kg. initially, followed by 50 mg./ kg. every six hours for three days.
Figure 9. Extensive infection of the vulvar area with vaccinia. The patient was a seven-year-old girl with acute lymphoid leukemia who emigrated from Cuba to the United States. Although this patient was exempted from vaccination, she was heteroinoculated by a sibling. The child was treated with Morboran® and had an uneventful recovery.
Measles: The rubeola virus may cause fatal giant cell pneumonia in children, with or without an exanthem. The virus may persist for long periods in the respiratory tract of such patients, whereas it is not recoverable from normal children 48 hours after disappearance of the rash. Passive immunization within 24 to 48 hours after exposure appears to be effective in preventing or modifying the disease, using at least 0.25 mUkg. of gamma globulin.
Influenza: Because of the multitude of influenzal strains and the inherent genetic instability of this family of myxoviruses, active immunization is only sporadically successful. Influenza vaccines usually have minimal toxicity, however, and their use should be encouraged in the child with cancer in anticipation of epidemic disease.
Viral hepatitis: Viral hepatitis is responsible for considerable morbidity in children with cancer. There are at least two variants of this illness, types A and B, caused by two distinct agents.14 Non- A, non-B variants have also been identified. Type A (infectious hepatitis) is characterized by a short incubation period, a significant degree of contagion, and a short period of abnormal transaminase activity. Type B (serum hepatitis) has a long incubation period, prolonged transaminase elevation, and usually greater severity than type A. Type A hepatitis is usually transmitted orally, but blood is also infective; thus, hepatitis after transfusion can be due to type A, type B, or other variants. Type B hepatitis is usually transmitted parenterally, but nonparenteral spread also occurs. Immunologic tests for virus antigens (and related antibodies) have reached a high degree of precision for types A and B. A long-term carrier state is uncommon in normal patients with acute type B hepatitis, but type B viral antigens may persist in up to 50 per cent of children with leukemia or lymphoma without necessarily implying active liver disease. Currently available tests do not detect all type B carriers (or non- A, non-B variants). Thus, negative blood tests do not guarantee that virus will not be transmitted.
The essence of hepatitis management is prevention. Transfuse the least amount of blood possible, use only volunteer Australia (Hb8) antigen- negative donors, enforce hygienic practices in all patient-staff interactions (including needle precautions), and wear gloves to draw blood. There is a risk of transmission of hepatitis to oncology patients from carriers among the hospital staff, and vice versa. Since type B hepatitis can be transmitted nonparenterally, the same isolation constraints should apply as in the case of type A. Significant protection agaginst icteric type A hepatitis is associated with the use of standard immune serum globulin (0.02=0.04 ml./kg.), but it is uncertain whether potential late sequelae of anicteric hepatitis are prevented. A hyperimmune globulin preparation (HBIG) is effective in reducing the incidence of type B hepatitis in several high-risk situations. Immune serum globulin may also be effective after low-level exposure. Immunoprophylaxis need not be given to persons who currently have circulating anti-Hbs, nor is hyperimmune globulin routinely indicated in the prophylaxis of transfusion-associated hepatitis, since 90 per cent of cases are not caused by the hepatitis B virus.
Current approaches to the prevention of infection in the granulocytopenic patient include attempts to decrease exposure to exogenous and endogenous potential pathogens. The techniques employed include the use of sophisticated isolation and air-filtration facilities (laminar air-flow room; Figure 10), topical and orificial antiseptic-antibiotic agents, diets with a low bacterial burden, and antibiotic bowel decontamination. These environmental maneuvers are highly effective in reducing the potential inoculum of ambient microorganisms, and patients who receive cancer chemotherapy in a laminar air-flow room experience fewer severe infections than do patients treated in conventional ward settings.15 Such protection from infection might permit administration of very intensive chemotherapy to patients whose tumors are resitant to conventional doses of anticancer drugs. However, this intensive approach to therapy remains experimental; for this reason, the ultimate untility of protected environments and prophylactic antibiotics in the therapy of childhood cancer remains uncertain.
Figure 10. A semiportable horizontal laminar air-flow isolation room. Air is circulated through high-efficiency particulate air filters from a filter bank at the head of the bed towards the foot of the bed and around a buffer area and is returned through a plenum next to the instrument panel. This highly sophisticated device is used in conjunction with a comprehensive prophylactic antimicrobial regimen. Such rooms are employed in research studies to determine whether "protected environments" reduce the incidence of infection in children receiving cancer chemotherapy, whether a possible reduction in the incidence of infection will permit more intensive chemotherapy to be administered, and, if so, whether a significant prolongation in survival will result.
Even when granulocytopenic, septic patients are treated urgently and vigorously, not all survive, despite recent antibiotic developments. The significant mortality of such patients has prompted efforts to support them with leukocyte transfusions. Instrumentation is available by which one may procure large quantities of normal donor leukocytes. For example, the continuous-flow blood cell separator permits an average four-hour collection of 10.5 billion mature, undamaged granulocytes. This average collection produces a median granulocyte increment in granulocytopenic recipients of 800/cu. mm./ sq. m. New rotor designs for the centrifugation equipment will permit still larger yields. Normal donor granuloctyes collected with the cell separator circulate normally in the nonalloimmunized host and are capable of extravascular migration into inflammatory areas. The more closely a donor and recipient are phenotypically matched for the appropriate leukocyte antigen specificities, the larger the recovery of transfused cells in the recipient.
Recently, a simple and relatively inexpensive leukocyte procurement method has been developed that initially generated considerable enthusiasm, since it could be undertaken in virtually all hospitals at minimal expense. The method, filtration leukapheresis, is based on the fact that granulocytes adhere reversibly to nylon fibers. The method permits the collection of up to 100 billion granulocytes from a single donation. Unfortunately, the collection process damages these granulocytes, permitting degranulation, and may have serious consequences both in the recipient and in the donor. However, recent studies with pharmacologic inhibitors suggest that there may be techniques to prevent this leukocyte damage and still permit the filtration leukapheresis process to have wide applicability.
Several studies indicate that granulocyte transfusions significantly enhance survival in granulocytopenic cancer patients with septicemia. Thus, survival in patients given granulocyte transfusions is greater than in those given only antibiotics.16 However, the benefit of granulocyte transfusions has been seen only in patients whose granulocyte count does not recover spontaneously within one to two weeks after a cycle of chemotherapy. Patients whose granulocyte levels recover normally have an excellent survival with antibiotics alone and do not require leukocyte transfusions. While leukocyte transfusions are definitely an adjunct to antibiotic therapy of septic patients whose granulocyte levels remain lower than 100/cu. mm. for more than two weeks, such patients have usually received very intensive chemotherapy because of the resistance of their tumors to treatment. The prognosis remains poor for such patients even if they survive the intercurrent episode of septicemia.
Infection is the major immediate cause of morbidity and mortality from childhood cancer - particularly gram-negative bacillary septicemia, viral hepatitis, and S. aureus, fungal, and varicella-zoster infections. Unusual infections, such as P. carinii pneumonia, have become increasingly frequent with more aggressive therapy and lengthened survival.
The most important factor predisposing to infection is granulocytopenia, but the incidence and type of infection also depend on the underlying tumor, the stage of disease, and intensity of therapy. The cancer patient often cannot respond to infection with the usual signs of inflammation. In this setting, subtle symptoms and signs are helpful - as are newer diagnostic procedures, such as radioisotopic imaging.
When a de novo fever occurs in a granulocytopenic cancer patient, the usual cause is bacterial sepsis, pneumonia, or cellulitis. Since the median survival with inappropriate therapy is less than three days, broad-spectrum antibiotic therapy must be started at once. The major fungal infections in these patients are candidiasis, aspergillosis, and mucormycosis. P. carinii pneumonia is the leading cause of death in children with leukemia who are in remission, but therapy is effective in 75 per cent of cases. With regard to viral infections, more use should be made of specific passive immunization, such as zoster immune globulin following exposure to varicella. Live virus vaccines should not be used in these patients.
Sophisticated isolation facilities (laminar air-flow rooms) reduce the incidence of infection in patients receiving intensive cancer chemotherapy, but it is not known whether further increasing the intensity of therapy will significantly prolong survival. Leukocyte transfusions are an important adjunct to antibiotic therapy of septic patients whose granulocyte levels remain very low for extended periods.
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