Septicemia in association with acute lymphoblastic leukemia

May 1979 The Journal of P E D I A T R I C S

715

Septicemia in association with acute lymphoblastic leukemia Fifty consecutive episodes of septicemia were studied in 41 children who had acute lymphoblastic leukemia. Seventy-six percent of these episodes occurred when the absolute granulocyte count was 200/mm 3 or less and were caused by gram-negative enteric and gram-positive mucocutaneous bacteria. In eight patients, Streptococcus pyogenes was isolated at the time when A L L was diagnosed. Multiple anaerobic and aerobic isolates from a single blood culture were associated with abdominal distress, whereas Streptococcus pneumoniae and Hemophilus influenzae septicemia occurred in association with respiratory illnesses. When patients with severe compromise of anatomic barriers or respiratory disease were excluded, 94% of all patients with septicemia had an AGC of less than 200/mm :~. The data provide guidelines for treatment for febrile patients with A LL based upon the A GC, the phase of the disease, and on the presence of associated respiratory or abdominal findings.

Robert R. Chileote, M.D.,* Chicago, Ill., and Robert L. Baehner, M.D., Indianapolis, Ind.

INFECTION is the principal cause of morbidity and mortality in patients with leukemia. 1 In acute lymphoblastic leukemia, remission is induced in more than 90% of children'; effective maintenance therapy produces a median survival in excess of five years? Septicemia, however, presents formidable diagnostic and therapeutic difficulties despite advances in antimicrobial therapy for patients with cancer? We studied 50 episodes of septicemia in children with ALL to determine which bacteria are responsible and to delineate more precisely the relationship between the neutrophil levels and the risk for septicemia. From the Department of Pediatrics, Wyler Children's Hospital and the Pritzker School of Medicine of The University of Chicago, and the Department of Pediatrics, Division of Pediatric Hematology/ Oncology, James Whitcomb Riley Hospital for Children, and the lndiana University School of Medicine. Supported in part by PHS Grant A1 10892-04, CA 13809-5, American Cancer Society, Illinois Division, Grant 76-38 and by a grant from the James Whitcomb Riley Memorial Association. *Reprint address: Box 97-Wyler Children's Hospital 950 E. 59th St. Chicago, 1L 60637.

0022-3476/79/500715+04500.40/0 9 1979 The C. V. Mosby Co.

MATERIALS AND METHODS The 50 episodes of septicemia occurred during the last three years among 75 children who had ALL. None had had splenectomy or had received prophylactic antibiotics. Vincristine, prednisone, and L-asparaginase were used for induction of the first remission, followed by intratheeal methotrexate, intrathecal methotrexate and cranial radiation, or craniospinal radiation for central nervous system prophylaxis. Daily 6-mercaptopurine, weekly methotrexate, and monthly vincristine and prednisone pulses were administered as maintenance therapy. Maintenance medications were adjusted to keep the total white count at Abbreviations used ALL: acute lymphoblastic leukemia AGC: absolute granulocyte count approximately 2,500 WBC/mm ~. When relapse occurred, various combinations of vincristine, prednisone, L-asparaginase, cytosine arabinoside, methotrexate, cyclophosphamide, and adriamycin were used for reinduction. White cells were enumerated with a hemocytometer. Differential estimates were based on 200 cells or; when the neutrophil count was extremely low, on the number of

Vol. 94, No. 5, pp. 715-718

7 16

Chilcote and Baehner

The Journal Of Pediatrics May 1979

30-

2503

__

2o.

la.i

I13. - 15. I.IJ O~ It.

o

c~

IO-

z

5-

O"

0

50

I00

I

I

150 200

I

250

I

I

300 350 AGC

I

400

I

450 5()0

I//I

>500

Figure. Number of instances of septicemia in neutropenic patients with acute lymphoblastic leukemia, grouped according to absolute granulocyte count.

Table I. Frequency of various bacterial agents in 50 episodes of septicemia in children with acute lymphoblastic leukemia

%of No. with septicemias AGC caused by <200~ram 3 this agent

Organism

No. of patients

Pseudomonas aeruginosa Staphylococcus aureus Escherichia coli Klebsiella Streptococcus pyogenes Streptococcus pneumoniae Hemophilus influenzae Mixed Other*

11 10 6 4 5 4 2 5 3

10 6 6 4 4 2 0 3 2

22 20 12 8 10 8 4 10 6

50

37

100

*Mima polymorpha, Hemophilus aphrophilus, Moraxella species.

cells seen on two slides. The AGC was obtained by multiplying the total leukocyte count by the combined percentages of band forms and mature polymorphonuclear neutrophils. When the patient's temperature exceeded 38.5~ at least two blood samples were obtained after preparation of the skin with iodophor; the blood was cultured aerobically (Columbia broth) and anaerobically (thioglycollate). Contamination with Staphylococcus albus (coaguiase-negative) and Propionibacteria acne was found in 20% of the isolates; these organisms were excluded from analyses. Initial antibiotic therapy for all febrile patients consisted of oxacillin 200 m g / k g / d a y and gentamicin 5

mg/kg/day; the gentamicin dose was increased to 7.5 to 10 m g / k g / d a y or more if blood levels obtained four to eight hours after injection did not exceed 2 /~g/ml. Carbenicillin 500 m g / k g / d a y was added initially when the AGC was less than 1,000/mm 3. Patients with positive blood cultures were treated for seven to ten days with a single antibiotic or with a synergistic combination of antibiotics chosen on the basis of sensitivity studies. No granulocyte transfusions were used. Chi square and t tests were used to compare groups. RESULTS Twenty-eight of the 50 episodes of septicemia (56%) resulted in death; the highest mortality was among patients with gram-negative septicemia (85%). On the other hand, all patients whose blood cultures grew Streptococcus pyogenes, Hemophilus influenzae, or Streptococcus pneumoniae survived. No patient developed bacterial meningitis. Granulocytopenia was extremely severe in most instances of proven sepsis. As shown in the Figure, in 74% of the 50 episodes in this study the patient had an AGC of less than 200/mm :~ at the time of septicemia; in 54%, it was less than 50/mm:'. No patient with an AGC of less than 200/mm :~had a significant number of monocytes on the initial peripheral blood smear. The bacteria isolated from patients with septicemia are listed in Table I. The three gram-negative enteric organisms-Pseudomonas aeruginosa, Klebsiella, and E. colitogether accounted for 42% of all infections; the two gram-positive mucocutaneous organism-Staphylococcus aureus and Streptococcus pyogenes-accounted for 30%.

Volume 94 Number 5

Eight cases of septicemia occurred at the time of the initial diagnosis of leukemia. Streptococcus pyogenes (Groups A, B, or C) accounted for five of the eight infections (62%); two infections were caused by Pseudomonas aeruginosa and one was due to Moraxella. All but one episode was associated with an AGC of less than 200/ram ~. No patient in this group died and all attained remission. Streptococcus pyogenes septicemia occurred only at the time of diagnosis and did not develop in any patient after the initiation of chemotherapy (P < 0.01). Gram-negative enteric bacteria accounted for 20 of 37 episodes in the group of patients who had an AGC of less than 200/mm ~, compared to only one of 13 episodes in the group with an AGC greater than 200/mm 3 (P < 0.03). The one infection in the latter group occurred in a patient receiving respirator support to combat severe hypoxemia caused by Pneumocystis carinii interstitial pneumonia. In five patients with abdominal findings, multiple aerobic and anerobic isolates were obtained from a single blood culture (Table II). One patient was found to have severe hemorrhagic pancreatitis at autopsy? The other four patients' infections followed very intensive cancer chemotherapy for intractable relapse and occurred in association with acute abdominal signs due to bowel ulcers or obstriaction; none of these patients survived. Pulmonary infiltrates were found on radiographs in five of the six patients with Streptococcus pneumoniae or Hemophilus influenzae isolates (Table III). In the sixth, a blood culture obtained as part of an evaluation for otitis media and leukocytosis (AGC 16,800/mm :~) was positive for Streptococcus pneumoniae. The patient did well on penicillin given orally, and a repeat blood culture showed no growth. All patients survived. Six patients were receiving ventilatory support at the time of septicemia. All of these patients had intractable hypoxemia (Po2 less than 40 mm Hg) caused by interstitial pneumonia. Both gram-negative and gram-positive organisms were isolated. Thus, if those patients with respiratory illnesses in association with Hemophilus influenzae or Streptococcus pneumoniae isolates and those patients with severe host compromise, such as acute abdominal insult or severe interstitial pneumonia are excluded, there were 33 episodes of septicemia. In all but two (93%) episodes, the septicemia was associated with AGC of 200/mm 3 or less. DISCUSSION Polymorphonuclear neutrophils help defend mucosal and skin barriers against systemic invasion by bacteria. If we exclude those children who had compromise of pulmonary or gastrointestinal anatomic barriers, 93% of

Septicemia in leukemia

7 17

Table II. Patients with blood cultures positive for multiple organisms

Organism

IAGC[

Abdominalfindings

Klebsiella, Escherichia 4,400 Hemorrhagic pancreatitis coli E. coli, Bacterioides cor88 Large bowel ulcers rodens E. coli, Enterobacter cloa- 1,887 Large bowel ulcers cae E. coli, Proteus, S. pneu87 Large bowel obstruction moniae E. coli, Clostridium septi0 Large bowel ulcers cum

Table IlL Findings in association with Streptococcus pneumoniae and Hemophilus influenzae

Organism

AGC

Streptococcus pneumoniae S. pneumoniae S. pneumoniae Hemophilus influenzae H. influenzae S. pneumoniae

440 186 140 633 244 16,800

Respiratory findings Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Otitis media

the septicemic episodes occurred when the AGC was less than 200/mm a. Our data are consistent with the observation that, in neutropenic syndromes, moderately severe granulocytopenia is usually not associated with infection, whereas patients with an AGC below several hundred are at high riskY 8 Similarly, Wolk et ale identified only two instances of sepsis among 141 episodes of fever in patients with ALL; both occurred when the AGC was less than 200/mm 3. In studies of heterogenous groups that included adults or various types of neoplasms, this distinction was not as clear. 1~ The isolation of Streptococcus pneumoniae or Hemophilus influenzae from blood cultures in association with respiratory disease occurred in patients whose AGC was above and below 200/mm:~-consistent with the observation that these organisms can be cultured from nonleukemic, febrile children in the outpatient setting) :~ The relatively benign course in these patients is in contrast, however, to experience with splenectomized patients with lymphoma or leukemia, who may die of overwhelming infection caused by these organisms:" 15 The high frequency of Streptococcus pyogenes as a pathogen in new patients with ALL and its absence as a cause of septicemia later is puzzling, since other centers have noted episodes throughout the course of the illness?~

7 18

Chilcote and Baehner

However, Streptococcuspyogenes is susceptible in vitro to methotrexate, 17 and administration of this medication for craniospinal prophylaxis and maintenance may have had an effect similar to that of prophylactic antibiotics. Septicemia with multiple enteric organisms was associated with abdominal distress and followed extensive chemotherapy. It is likely that disruption of gastrointestinal mucosa was the causative factor. ~ The initial antibiotic therapy of patients who have acute abdominal signs in association with fever and neutropenia probably should include carbenicillin, chloramphenicol, or penicillin, in addition to broad-spectrum antibiotics active against aerobic gram-negative agents. The poor results likely reflect the fact that these patients were in a terminal stage with intractable leukemic relapse. Neutrophil dysfunction has been reported as a consequence of leukemia/9 radiation therapy, 2~and chemotherapy. 2~ These effects apparently do not readily predispose to septicemia since none of the reports link septicemia to the neutrophil dysfunction described. In spite of these observations, patients in relapse develop more infections in a given time than do patients in remission at the same granulocyte level. '~- In our study, most patients were managed as outpatients, protribiting the determination of the duration of any given granulocyte level. Monocytes, a source of a granulopoietin-termed colony-stimulating factor were absent in the peripheral blood of patients with absolute granulocyte counts below 200/ m m 3. This finding may account for the observation by Ragab and associates that the peripheral blood of patients with ALL has diminished capacity to generate colony stimulating factor in tissue culture. ~'~ F u r t h e r studies will be needed to clarify the relationship of this monocytopenia to the failure of granulocyte production. We acknowledge the assistance of John Fischer and Linda Marler for bacteriologic cultures. REFERENCES 1. Hughes WT: Fatal infections in childhood leukemia, Am J Dis Child 128:283, 1971. 2. Ortega JA, and Nesbit ME Jr, Donaldson MH, Hittle RE, et al: LAsparaginase, vincristine and prednisone for induction of first remission in acute lymphocytic leukemia, Cancer Res 37:535, 1977. 3. Miller DR: Prognostic factors in childhood leukemia, J PEDIATR87:672, 19751 4. SchimpffS, Satterlee W, Young VM, et al: Empiric therapy with carbeniciUin and gentamicin for febrile patients with cancer and granulocytopenia, N Engl J Med 284:1061, 1971.

The Journal of Pediatrics May 1979

5. Weetman RM, and Baehner RL: Latent onset of clinical pancreatitis in children receiving L-asparaginase therapy, Cancer 34:780, 1974. 6. Crosby WH: How many "polys" are enough? Arch Intern Med 123:722, 1969. 7. Pincus SH, Boxer LA, and Stossel TP: Chronic neutropenia in childhood. Analysis of 16 cases and a review of the literature, Am J Med 61:849, 1976. 8. Howard MW, Strauss RG, and Johnston RB Jr: Infections in patients with neutropenia, Am J Dis Child 131:788, 1977. 9. Wolk JA, Stuart MJ, Stockman JA III, and Oski FA: Neutropenia, fever, and infection in children with acute lymphocytic leukemia, Am J Dis Child 131:157, 1977. 10. Silver RT, Beal GA, Schneiderman MA, et al: The role of the mature neutrophil in bacterial infection in acute leukemia, Blood 12:814, 1957. 11. Boggs DR, and Frei E: Clinical studies of fever and infection in cancer, Cancer 13:1240, 1960. 12. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia, Ann Intern Med 64:328, 1966. 13. Bratton L, Teele DW, and Klein JO: Outcome of unsuspected pneumococcemia in children not initially admitted to the hospital, J PEDIATR90:703, 1977. 14. Donaldson SS, Moore MR, Rosenberg SA, et al: Characterization of postsplenectomy bacteremia among patients with and without lymphoma, N Engl J Med 287:69, 1972. 15. Chilcote RR, Baehner RL, and Hammond D, Investigators and Special Studies Committee of the Childrens Cancer Study Group: Septicemia and meningitis in children splenectomized for Hodgkin's disease, N Engl J Med 295:798, 1976. 16. Dudding B, Humphrey GB, and Nesbit ME: Beta-hemolytic streptococcal septicemias in childhood leukemia, Pediatrics 43:359, 1969. 17. Metcalfe D, and Hughes WT: Effects of methotrexate on group A beta hemolytic streptococci and streptococcal infection, Cancer 30:588, 1972. 18. Bodey GP, Nits BA, and Freireich EJ: Multiple organism septicemia in acute leukemia: analysis of 54 episodes, Arch Intern Med 116:266, 1965. 19. Strauss RR, Paul BB, Jacobs AA, et al: The metabolic and phagocytic activities of leukocytes from children with acute leukemia, Cancer Res 30:80, 1970. 20. Baehner RL, Neiburger RG, Johnson DE, et al: Transient bactericidal defect of peripheral blood phagocytes from children with acute lymphoblastic leukemia receiving craniospinal irradiation, N Engl J Med 289:1209, 1973. 21. Sharbaugh RJ: Effect of cyclophosphamide on in vitro phagocytosis of Staphylococcus aureus, J Infect Dis 134:619, 1976. 22. Ragab AH, Gilkerson ES, and Myers ML: Granulopoiesis in childhood leukemia, Cancer 33:791, 1974.