(ProQuest: Text stops here in original.)
Infection remains the principal determinant of morbidity and mortality in childhood leukemia. Overwhelming infection was the proximate cause of death in 13 of 17 (80 per cent) of children with leukemia who died during the past year on our oncology service. This experience parallels the experience of others over the last decade.1
Although benign infections are as common in leukemic children as in otherwise healthy children, such selflimited infections must be distinguished from life-threatening infections to which the child with leukemia, or the child with a tumor receiving chemotherapy, is unusually prone. Serious infections occur during periods of myelosuppression with severe granulocytopenia or during periods of immunosuppression associated with defects of humoral and cell-mediated immunity. These groups are discussed separately in terms of variety of pathogens encountered, clinical work-up, and therapy.
INFECTIONS RELATED TO GRANULOCYTOPENIA
The absolute granulocyte count (AGC) is obtained by multiplying total white blood count by the per cent, granulocytes; it is a useful index of the patient's capacity to resist bacterial and certain fungal infections. Granulocytopenia predisposes the patient to sepsis and occurs during initial presentation or periods of bone marrow relapse. It occurs occasionally during remission as a result of bone marrow suppression due to excessive chemotherapy or radiation therapy.2
Over the past year we encountered 29 episodes of sepsis in 20 patients among the 50 children with all forms of leukemia currently being followed. As noted in Figure 1, 21 (72 per cent) of these episodes were associated with an AGC of less than 100/mm.3, and in 24 episodes (83 per cent) the AGC was less than 500/mm.3 As stressed recently by Hughes,3 three of our last 17 patients with newly diagnosed acute lymphoblastic leukemia (on admission blood cultures) had sepsis with Pseudomonas aeruginosa, beta hemolytic Streptococcus Group A, and Moraxella species, all in association with an AGC of 0/mm.3 Our experience also confirms that of Bodey,2 who pointed out that patients with leukemia are at risk for sepsis any time the AGC falls below 500/mmf The risk becomes even greater when the AGC is less than 100/ mm.3; nearly three fourths of our septic patients were in this range.
The five patients in our series who had an AGC above 500/mm.3 represented a different group. All had AGCs over 2,000/mm.3, and four developed sepsis only after experiencing severe debilitating complications. Of these four, three had severe intractable hypoxemia secondary to interstitial pneumonia; two were on respirators. Another child had Escherichia coli and Klebsiella-Aerobacter sepsis after an abdominal exploration for what proved to be 1-asparaginaseinduced hemorrhagic pancreatitis. We concluded that inanition due to severe debilitating illnesses occurring during leukemia increases the risk of sepsis even when the AGC is elevated. Diplococcus pneumoniae was isolated from the fifth child as an outpatient during a bout of otitis media, an event surprisingly common even among ambulatory children without leukemia.4
Pseudomonas aeruginosa. Staphylococcus aureus, Escherichia coli, and Klebsiella-Aerobacter accounted for half of the isolates in the 29 episodes of sepsis (Table 1). Hemophilus influenza, Streptococcus pyogenes, and an unusual variety of less virulent organisms such as Mima polymorpha and Hemophilus aphrophilus comprised the remainder. Four patients developed acute abdominal signs in the course of their terminal illness, and each had two to six anaerobic and /or aerobic gram negative bacterial isolates from a single blood culture. One patient with pneumonia had Streptococcus viridans and Staphylococcus aureus in a single culture.
Figure 1. Relationship between the incidence of bacteremia and the absolute granulocyte count (AGC).
Bacterial sepsis occurring in granulocytopenic patients generally presents with acute severe toxicity malaise, fever, and chills, developing over a day or less. On the other hand, viral, fungal, and parasitic infections in the immunologically suppressed patients usually have an insidious onset (see below). A thorough physical examination with particular attention to hidden sites of infection, including the perineum, is carried out. Skin lesions and fundoscopy may provide valuable clues to the nature of the organisms. The best example is the vesicular ulcer with a gangrenous necrotic base surrounded by erythema - known as pyoderma gangrenosa and usually due to Pseudomonas aeruginosa (Figure 2). Any suspicious skin lesion should be aspirated, cultured, and Gram stained.
The usual physical signs of inflammation may be blunted or even lost in these patients because of leukopenia. Fever and toxicity require that pharyngeal, urine, stool, spinal fluid, and two separately-drawn blood samples be obtained for aerobic, anaerobic, and fungal cultures. Once cultures have been taken the patient should immediately be given broad spectrum antibiotic coverage.
CLINICAL MANAGEMENT OF SEPSIS IN THE GRANULOCYTOPENIC HOST
Our practice has been to administer gentamicin 5 mg. /kg. /day, carbenicilHn 500 mg. /kg. /day, and oxacillin 200 mg. /kg. /day, in three to four doses. If the organism proves to be gram negative, oxacillin is discontinued and carbenicillin and gentamicin are continued until identification and antibiotic sensitivities are available. Separately administered doses of gentamicin and carbenicillin may be synergistic in the treatment of Pseudomonas infection.5'6 If Pseudomonas aeruginosa is not found, we discontinue carbenicillin. Oxacillin alone provides adequate coverage for penicillinase-producing Staphylococcus aureus. Clindamycin as well as penicillin and chloramphenicol are useful adjuncts in anaerobic or mixed bacterial infections arising from the bowel.7 For Streptococcus and Pneumococcus, penicillin suffices; ampicillin is used for Hemophilus influenzae. Antibiotic coverage for other organisms is determined by sensitivity patterns.
If no organism is isolated within three days or the organism is one of the usual contaminants such as Staphylococcus epidermidis or Propionibacteria acne (up to 20 per cent of our positive cultures), antibiotics are suspended and the patient is observed and recultured. Occasionally, despite negative or equivocal cultures, the clinician may elect to continue antibiotics in view of a therapeutic response. It is often in this situation, however, that the conditions needed for the emergence of pathogenic fungi or gram negative bacteria are provided.
It is prudent to confirm in vitro antibiotic susceptibility patterns by exposing patient's bacteria to measured dilutions of the patient's serum. This determination, termed minimum inhibitory dilution (MID), may show that the patient's actual antibiotic levels fall short of an adequate MID of 1:2 or greater needed for in vivo killing. For a variety of reasons, including high fluid intake to prevent hyperuricemia, inherent inaccuracies in estimating optimal drug doses in small children, and miscalculations of dose, antibiotic levels may be unexpectedly low. In patients with renal impairment, gentamicin dosage may need reduction in accordance with serum creatinine. Gentamicin levels are monitored to avoid exceeding the 10 meg. /ml. concentration associated with oto-toxicity.
Bacterial Isolates from Twenty Children with Bacteremia
Figure 2. Characteristic skin lesion of pyoderma gangrenosa due to Pseudomonas aeruginosa developing on the arm of a patient being treated for staphylococcal sepsis.
The importance of continuing communication between the hospital laboratory and the clinician cannot be overemphasized. The potency of the newer aminoglycosides, semisynthetic penicillins, and cephlosporins allows excellent broad spectrum coverage, but the liability of complications from overgrowth by resistant bacteria and fungi demands that coverage be tailored to in vitro sensitivity results.
Often a change in the patient's course warrants reculturing and shifting the specific antibiotic coverage. For example, the appearance of the pyoderma gangrenosum lesion seen in Figure 2 heralded the onset of Pseudomonas septicemia in a child being treated for staphylococcus septicemia. Localized purulent accumulations are drained. Specific therapy is continued for 7 to 10 days or until the patient is afebrile for three days.
The development of septic shock in leukopenic patients continues to carry a grave prognosis, but survival is possible and depends upon aggressive treatment. Early recognition of peripheral circulatory underperfusion with loss of blood pressure, decreased renal output, or deterioration of sensorium should lead to immediate attempts to restore circulatory volume by transfusion of plasma.
It is our practice to rapidly infuse plasma, followed by fresh whole blood, when available, until peripheral perfusion (as judged by skin temperature and vital signs) is restored. A central venous catheter is inserted as soon as possible and fluids are slowed if an accurate central venous pressure (CVP) reaches 10 to 12 cm. of water.
The persistence of shock despite a high CVP or overt congestive heart failure is ominous and generally suggests irreversible myocardial damage. Recovery is then unlikely, but beta adrenergic agents such as isoproteranol and massive doses of corticosteroids have been advocated.8 Bleeding may continue after restoration of circulatory volume and replacement of grossly depleted clotting factors (fresh frozen plasma 10 ml. /kg., platelet transfusion one unit /13 pounds, and 1.0 mg. of vitamin K intravenously). If coagulation studies indicate ongoing intravascular consumption, heparin (50 to 100 units/ kg.) given every four hours may be indicated.
The mortality rate from sepsis, in our experience, is 30 per cent. Generally, failure to respond to antibiotics is attributable to the continued granulocytopenia of intractable leukemic relapse. Massive central nervous system bleeding, gastrointestinal hemorrhage, and pulmonary edema often accompany the terminal events.
Hospitalized patients with granulocytopenia and infection are placed in single rooms but are not rigidly isolated as the demonstrated value of these procedures in children does not seem to warrant the psychological and observational sacrifices involved. Hand washing by those caring for the patient is emphasized. Attempts to combat infection by infusions with compatible granulocytes, isolation in "life islands," and the use of prophylactic antibiotics have been tried but have not been notably successful.8'9 As our understanding of the immune system advances and the technology of these procedures improves, however, they may hold promise.
INFECTIONS DUETO DYSFUNCTION OF LYMPHOCYTE-MEDIATED IMMUNITY
Most of the commonly used drugs for the treatment of leukemia also cause immunosuppression. Corticosteroids, vincristine, 6-mercaptopurine, methotrexate, cyclophosphamide, and cytosine arabinoside have profound effects on the patient's ability to recognize foreign antigens and to mount a hypersensitivity response.
Defects of both humoral (B cell) and cellular (T cell) immunity have been observed analogous to congenital immunodeficiency diseases. Circulating B lymphocytes can be identified by special immunologic tests to show that they possess IgG receptor sites on their surface and give rise to immunoglobulin-producing cells in the germinal follicles of peripheral lymph nodes.
On the other hand, T lymphocytes predominate in the peripheral blood (80 per cent of all lymphocytes) and are responsible for skin test reactivity and graft rejection. They undergo blastogenic transformation into "atypical lymphocytes" when exposed to macrophages and antigens. During histogenesis, "lymphokinins" are elaborated; these substances include interferon, inhibitors of macrophage migration, and inducers of macrophage phagocytosis.
Immunosuppression is most likely to occur when antineoplastic drugs are used in combination to sustain remission or when irradiation therapy is added to eradicate deep-seated leukemic foci in the central nervous system and abdominal organs once remission has been induced. The necessary extent and intensity of this type of aggressive therapy remains to be defined, but earlier relapse follows its omission.10 In some series, as many as 16 per cent of deaths occur during remission and can be attributed to infection by nonbacterial agents such as Pneumocystis carinii, Herpes viruses. Zoster- Varicella virus, cytomegalovirus, and saprophytic fungi. Such infections are similar to those seen in immunodeficiency states and are not correlated with the AGC. It is likely that immunologic -defects are responsible for their pathogenesis.
Typically, within a week to a few months after treatment of the C.N.S., patients have a combination of intrathecal methotrexate and cranial irradiation and various "consolidation" programs with high dosage chemotherapy. They are moderately lethargic and febrile, but the acute severe toxicity associated with bacteremia is lacking. The majority develop interstitial pneumonia and have tachypnea, loose stools, and cough that develops over a period of days to weeks. Rales are not audible but signs of diminished pulmonary compliance ("stiff lung"), such as sternal and intercostal retractions, become evident. As respiratory distress develops the chest x-ray film may show an infiltrate in one or more lobes, but generally a classical picture of interstitial pneumonia does not develop until later in the course of illness (Figure 3).
Encephalopathy with somnolence and nonspecific encéphalographie changes developed in two of our patients; it cleared over several weeks leaving no apparent sequelae. However, multifocal leukoencephalopathy and herpes encephalitis have been reported in other autopsy series.1 Nonspecific maculopapular skin rashes and fever occasionally confound the clinician until lesions characteristic of varicella-zoster evolve. Death can result from dissemination of the virus or from secondary bacterial infection.
Figure 3. Chest x-ray film from a child with acute lymphoblastic leukemia complicated by severe interstitial pneumonia. There are diffuse bilateral interstitial and alveolar changes. No microorganisms were demonstrated before or after death.
Because of the wide spectrum of fungal, protozoan, or viral agents involved, no single or combination treatment is feasible. Moreover, the efficacy of the highly toxic drugs used to eradicate these infections remains to be proved. Immunologic unresponsiveness often precludes accurate serologic diagnosis, and culture techniques are in the early stages of development. Thus, extensive efforts to define the exact nature of the infection and to histologically demonstrate the organism are warranted.
If the arterial P02 in room air drops to 70 mm. Hg. or below, a diagnostic lung aspiration is indicated. A #21 scalp vein needle is rapidly inserted into the lung and withdrawn under negative pressure provided by a syringe.11 The one or two drops of aspirate are stained with methanamine silver for Pneumocystis, candida, and aspergillus. Gram's and Wright's stains are also carried out to identify bacteria, viral inclusions, and the cellular composition of the inflammatory reaction. The remainder of the aspirate is cultured using appropriate fungal, bacterial, and viral media. Up to one third of these patients develop partial pneumothorax after this procedure, and preparations for x-ray and chest tube insertion should be made beforehand. Endobronchial brushings and open or closed lung biopsy have also been advocated as a means for obtaining tissue. Indications for biopsy of other organs are not clear and depend on the availability of subspecialty services and the physicians' judgment.
Therapy is largely supportive. Immunosuppressive antileukemic drugs are discontinued or modified. During the severe stages of interstitial pneumonitis management is best carried out in an intensive care unit. Repeated arterial blood gases are necessary to monitor oxygen supplementation, and mechanical ventilators may be required to support the patient's respirations. Because of various physiologic adaptations governing oxygen delivery, profound degrees of hypoxemia may develop before cyanosis is evident. Falling arterial Pq2, rising PcO2' and acidosis may presage sudden respiratory deterioration and allow the physician sufficient time to prepare the child for intubation and mechanical ventilation. Specific microbial therapy is still experimental, but the administration of pentamidine isethionate may be advantageous if Pneumocystis carinii is identified.12 Five of our last seven patients with interstitial pneumonia over the past year have survived. Pneumocystis was demonstrated in only one patient, and, despite eradication of the organism with pentamadine, the patient expired from hypoxemia and severe pulmonary fibrosis. Causative agents were not identified in the others.
Amphotericin B, beginning at 0.1 mg. /kg. /day, is indicated for disseminated mycoses including candida, but the antemortem diagnosis of visceral fungal infections is extremely difficult.13'14 The efficacy of cytosine arabinoside and adenine arabinoside for treatment of disseminated varicellazoster and herpes virus infections remains moot,13 but clinical trials are in progress. If the drugs are used, low doses of 10 mg. /m.2 given by intravenous push, followed by 10 mg./m.2/day by continuous intravenous infusions, seem most effective with the least side effects.
MIXED IMMUNOLOGIC DEFECTS AND INFECTION
Although most serious infections fall into either the severe granulocytopenia or impaired lymphocyte group, there are a number of patients for whom this may be an oversimplification. For example, craniospinal irradiation in doses low enough to prevent granulocytopenia both alters lymphocyte function and the ability of leukocytes to kill ingested bacteria.17 This largely unexplored area presents difficult clinical problems of combined immunosuppression and granulocytopenia.
In proportion to the assiduousness of the culture technique, multiple agent infections are becoming more apparent. Gram negative sepsis with disseminated candidiasis, Pneumocystis pneumonia complicated by staphylococcal pneumonia, and synergistic deep bacterial gangrene with multiple agents all have been seen recently in debilitated patients. Progress may depend less on the development of new agents to treat the variety of offending ubiquitous pathogens than on ways to reconstitute the host's immunologic defenses once the balance has swung too far in favor of the microbes.
Laboratory Evaluation of Infection in Acute Leukemia
GENERAL PROPHYLACTIC PROCEDURES
Attention to certain common but often overlooked procedures may prevent serious infection in the leukemic child. Intravenous needles, cutdowns, catheters, nasal packs, and ulcers of the skin and mucous membranes require daily examination for possible secondary bacterial or fungal infection. Nutrition is often a problem during periods of prolonged relapse or infection, and occasionally peripheral or central hyperalimentation is needed.
Vigilance against skin infections, thrush, periodontal disease (a dentist attends our clinic), urinary tract infection, and other sites of recurrent infections of childhood is especially important in the child with leukemia. Impetigo merits an intramuscular benzathine penicillin trial and a search for family contacts. Urinary tract infections are treated 10 days with sulfasoxozole or ampicillin and follow-up cultures.
Little is gained by isolation of the child from other children during periods of relative health unless they will be clearly at risk to exposure to varicella, rubeola, or epidemic influenza. School attendance is encouraged and should be one measure of the success of antileukemic therapy. Physical education and summertime activities are generally not restricted during remission unless there are specific orthopedic contraindications.
Modification of chemotherapy dosage is frequently required during benign viral infection to prevent severe leukopenia or mucous membrane ulcerations. Repeat blood counts and oral inspection are necessary during the next two weeks. The use of prophylactic antibiotics during a viral illness is not helpful.
Zoater immune globulin or plasma obtained from individuals with high titer of zoster antibody may prevent or lessen the severity of illness due to varicella if given to the patient within the first two days after household exposure.15 During periods of remission, the child should receive active killed vaccine immunizations in accordance with current American Academy of Pediatrics recommendations. However, inoculation with live virus preparations such as polio, rubeola, rubella, mumps, influenza, and smallpox vaccinations is contraindicated at all times. Skin testing with intermediate strength PPD (stabilized) and endemic fungal disease antigens such as histoplasmin or coccidiodin is routinely carried out on all patients undergoing induction. Any degree of reactivity at 48 to 72 hours is investigated further before steroids or immunosuppressant chemotherapy is begun.
When blood transfusions are indicated for anemia, it is best to use packed red blood cells which have been frozen in glycerol since, the risk of hepatitis,16 engraftment of lymphocytes, and transfusion reactions may be lessened. Platelet concentrates should be administered for bleeding due to thrombocytopenia.
Early diagnosis and treatment of serious infections in children with leukemia can alter morbidity and mortality. Each episode of illness with fever represents a diagnostic challenge and requires careful, complete clinical investigation based on history, physical examination, and laboratory data as outlined in the checklist in Table 2. It is often difficult to separate benign infections from those that may become lifethreatening. Serious infections are best handled in pediatric centers where a staff experienced in the care of childhood leukemia and its many complications is available.
1. Hughes, W. T. Fatal infections in chldhood leukemia. Amer. J. Dis. Child. 122 (1971). 283293.
2. Bodey. G. P.. Buckley, M.. and Sathe. Y. S. Quantitative relationships between circulating leukocytes and infections in patients with acute leukemia. Ann. Intern. Med. 64 (1966), 32T-340.
3. Hughes. WT. and Smith. DR. Infection during induction of remission in acute lymphocytic leukemia. Cancer 31 (1973). 1008-1014.
4. McGowan, J. E., Jr., Bratton, L., Klein....
Bacterial Isolates from Twenty Children with Bacteremia
Laboratory Evaluation of Infection in Acute Leukemia