(Acta Paediutr Jpn 1991; 33: 564
- 572)
Infectious Complications in Childhood Leukemia Takuo Hirotsu, M.D. and Jun-ichi Akatsuka, M.D. Department of Pediatrics, The Jikei Universit!. School of Medicine. Tokyo
Since children with acute leukemia have prolonged periods of severe neutropenia due to the disease itself or its intensive chemotherapy, they often develop life-threatening infectious complications. A protected environment and prophylactic antibiotics for patients with severe neutropenia have been shown to decrease the incidence of infectious morbidity. In spite of the high mortality rate of infections, on the other hand, their diagnosis is not well established because the percentage of microbiological detectability by blood culture is low. The differentiation of infections may be possible by using some supplementary measures and particular laboratory parameters. Febrile neutropenic patients with leukemia should promptly receive empiic treatment with combinations of two or three broad-spectrum antibiotics that are bactericidal and synergistic toward the presumed pathogens, or with antifungal drugs if patients are resistant to antibiotics, as well as supportive measures such as granulocyte transfusion, intravenous gamma-globulin and granulocyte colonystimulating factor. Key Words Childhood leukemia, Neutropenia, Protected environment, Prophylactic antibiotics, Empiric treatment, Fever of unknown origin
introduction As intcnsive therapies for childhood leukemia have recently progressed [I]. the number ol' patients expericncing prolonged and profound neutropenia with an attendant high risk of infection has also increased. As well as preventing infection by means of a protected environment and prophylactic antibiotics, it is therefore important to vigorously seek out causes of infection by culture and non-culture methods. including some supplementary meas~~~
Received Ma! 10. 1991 C'orreymndence address: Takuo Hirotw. M.D.. Depaninent of Pediatrics. The Daisan Hospital. The Jikri UniLerhity School of' Medicine. 11-1. Izumihon-cho 4chome. Komae-shi. Tokyo 201, Japan
ure\ and particular laboratory parameters. and t o initiate antibiotic therapy promptly or t o use various adjuncts to such therapy. I n this paper. we briefly describe and discuss the prophylaxis and the management and treatment of infections in these children. Our findings are based upon clinical experience in our University Hospital, the study of the research group of' the Japanese Ministry of Health and Welfare, and a study conducted by the Tokyo Children's Cancer Study Group.
I. Protected Environment and Prophylactic Antibiotics Two hundred and ninety-seven febrile episodes in 82 children with acute leukemia were analyz.ed retrospectively at our institute during the eight years from 1969 to 1977 [2] (Study
Infectious complications in childhood leukemia ( 145) 565 No. I in Table 3). This study revealed that most of these infections developed from organisms such as Escherichia coli, Pseudomonus ueruginosu, Klehsiellu pneumoniue, Stuphjdococcus aureus, Streptococcus species, and Cundidu species colonizing along the alimentary and upper respiratory tracts, resulting in oral infection, pneumonia, esophagitis, colitis or perianal lesions. These infections seemed to be caused by the patient's endogenous microbial flora o r by microorganisms acquired from the hospital environment during therapy. Therefore, prevention of infection in neutropenic patients with acute leukemia has included attempts to decrease exposure to these exogenous and endogenous potential pathogens through isolation of the patients and elimination of their intestinal flora. On the other hand, the frequency of infection in patients receiving leukemic chemotherapy is directly related to the duration of neutropenia, and inversely related to the number of circulating granulocytes. Accordingly, for all children who are receiving antileukemic therapy, the protected environment and prophylactic antibiotics should be started one week before the
neutrophil count is predicted to decrease below 500ipl. and ended when the neutrophil count recovers to above 5OOjpl.
I . Protected environment Different reverse isolation techniques have been used in clinical medicine in order to protect patients with high susceptibility to infection. Pathogen-free rooms, ultra-clean wards and sterile cubicles have been designed, but they are very expensive and the patients who are cared for in these rooms sometimes develop psychological problems. We thus designed our isolation units with regular single rooms. The details of our method [3] for maintaining a protected environment in our pediatric ward are summarized in Table I.
2. Prophylactic antibiotics A large number of clinical trials have been conducted to investigate the utility of prophylactic antibiotic regimens in immunocompromised patients. There are two principal methods for prophylactic antibiotic regimens. One is total gastrointestinal decontamination which suppresses not only the potentially pathogenic microorganisms but also the non-
Table I , Protected environment and topical antibiotic prophylaxis
I . Isolation unit and all items placed into the units Sterilized by formalin gas (for 24 hours) Cleaned by benialkonium chloride solution (every day)
2. Steriliiation of patient before entering the units Washed by chlorhexidine solution (0.02C) Putting on a steriliied gown Gargling with povidone iodine solution Spraying with kanamycin plus amphotericin B solution Not allowed to go outdoors without a mask, gown and cap 3. Topical antibiotic regimen Chlorhexidine solution (0.02%aqueous) for cleaning the skin daily Chlorhexidine solution (0.5%)applied to the prepuce or vulva1 and vaginal region Chlorhexidine cream to nasal cavity and auditory canal Amphotericin B (50 mg per 5% glucose 500 ml) added to mouthwash. every 6 hours Inhalation of kanarnycin (20 mgiday) plus amphotericin B ( I mgiday) to upper respiratory tract every 6 hours 4. Food Sterilired with an electric range at 1.400 W for 30 seconds.
5. Steriliiation of all persons before entering into the units Washing hands with chlorhexidine solution (0.02% aqueous) Putting on slippers and gown, mask and cap. all sterilized by formalin gas
Vol. 33 No. 4 August 1991
566 (146)Hirorsu and Akatsuka amphotericin B. Recently. another study (Study No. 4) of the Tokyo Children's Cancer Study Group evaluated the prophylactic usefulness of a combined regimen of arnphotericin B and aztreonam, which is a monobactam antibiotic with a strong bactericidal effect against gramnegative bacteria including Pseudomonus aeruginosa but little o r no suppressive effect on stool anaerobes in children with neutropenia induced by cancer chemotherapy. In the early period after chemotherapy in which the neutrophil counts fell below SOOjpl, amphotericin B was first given orally and. in the late period in which they were below 250/pI. aztreonam at the dose of 100 mg/kg was administered intravenously twice a day with oral amphotericin B, until the neutrophil count again rose to 500jpl (unpublished data).
pathogenic anaerobic part of the flora. The other is selective gastrointestinal decontamination which preserves colonization resistance. Table 2 gives the prophylactic regimens which we have administered in our clinical studies. In a controlled prospective randomized trial of the research group of the Japanese Ministry of Health and Welfare [4] (Study No. 2), we studied the prophylactic effect of a total antimicrobial modulation (TAM) regimen consisting of polymyxin B. kanamycin and amphotericin B. and that of a selective antimicrobial modulation ( S A M ) regimen consisting of trimethoprim-sulfamethoxazole and amphotericin B in children with acute leukemia during induction therapy in a regular single room, and compared the results with historical controls in regular single room isolation only. Based on a previous study (Study No. 3) of the Tokyo Children's Cancer Study Group [5] we t'ormulated a better prophylactic regimen by comparing the three different S A M regimens (A, B and C) with oral highdose
3. Antiviral prophylaxis In principle, prophylactic passive immunization by high-titer gamma-globulin has been used for specific viral infection within six months after complete remission. For example,
Table 2. Prophylactic antibiotic regimens (dose per day) I , Total decontamination (TD) and selective decontamination (SD)"I TD 10 million I1 kg
Pol!ni!sin-B A M P H Svrup* KM S\rup**
200 mg 30mg kg b.i.d.
0.1 Tab./kg 200 mg b.i.d.
2. Oral high-dose A M P H " ' A A M P H Syrup 100mg kg TMP-SMZ 0.1 T a b kg b.i.d
SD
TMP-SMZ*** A M P H syrup
B
C
A M P H Syrup 5 0 m g kg 0.1 T a b kg TMP-SMZ b.i.d.
A M P H Syrup 50mgikg 0. I T a b / kg TMP-SMZ b.i.d. Inhalation**** A M P H for IV use I mg KM 2 0 m g t.i.d.
3. Anreonam and A M P H
0 A regimen o r C regimen of oral high-dose A M P H
0 A n r e o n a m 100 mg; kg (intravenous) b.i.d. plus A regimen o r C regimen of oral highdose A M P H
* amphotcricin R (maximum dose: 3 glday), ** Kanamycin, *** Trimethoprim 80 mg plu, Sulfamethoxaiole 40 mg.
**** Dissolved
in 10 ml of distilled water for injection
Artu Paediutr Jpn
Infectious complications in childhood leukemia (147) 567 varicella zoster immune globulin (VZIG) should be given at the dose of I vial/ 10 kg within 72 hours of exposure to varicella or herpes zoster. VZIG is also recommended for patients who either have a negative history of varicella infection or are sero-negative. Prophylaxis against cytomegalovirus infection with intravenous high-titer gammaglobulin is administered at the dose of 100 to 200 mg/ kg [6]. On the other hand, varicella-susceptible leukemic children who are in remission should receive the varicella virus vaccine.
tions, and skin lesions became less frequent in the prophylactic antibiotics group (Table 3). 2. Microbiological documentation of infections The causative organisms were isolated in only 20% of these cases. Gram-negative rods such as Escherichia coli, Pseudomonas aeruginosa and Klehsiella pneunioniae, and varicella zoster. chicken pox and Pneumocytis carinii were isolated less frequently in the prophylactic antibiotics group. However, the isolation of grampositive rods such as Staph.vlococcus aureus. Staphylococcus epidermidis and Streprococcus species, and of Candida and Aspergillus species, increased in incidence after prophylaxis in spite of oral administration of anti-fungal agents (Table 4).
II. Prophylactic Effects and Changes in Infection Episodes Tables 3 and 4 summarize the results of prophylactic effects in prospective studies conducted as previously mentioned.
111. Approach to Diagnosis of Fever of
1. Frequency and site of infections The frequency of infectious episodes was less than 1.0 per patient in the prophylactic antibiotics group, as compared with more than 1.0 in the control group which did not have prophylactic antibiotics. However, there was no difference in the frequency of suspected sepsis, fever of unknown origin or sepsis between the two groups. On the other hand, respiratory infections such as pneumonia, anorectal lesions, urinary tract infec-
Unknown Origin The key to treatment of infectious diseases is always to identify the causative organism as soon as possible. However, as has already been mentioned, the episodes of fever of unknown origin and suspected sepsis were most frequently encountered in patients with acute leukemia receiving chemotherapy. A large proportion of neutropenic leukemic patients who become febrile will not have a
Table 3. Frequency of infections during initial therapy 1 III 1969- 1977 non
Study no. Study period Prophylactic regimen
2 141 1980- 1985 non TD SD
3 ‘(1 1987- 1988 A B C
4 I989 @
0
~
No. of patients
82
Sepsis Suspected sepsis Fever of unknown origin Pneumonia Upper respiratory infection Alimentary tract infection Urinary tract infection Skin infection Others
36
1
18
75 35 55 44 8 23 21
26
23
20
51
33
57
75
5 7 6 I 0 0 0 I 2
3 5 3 I 0 0 0 0 1
2 8 4 0 1 0 0 0 0
7 II 2 9 7 0 3 1
5 8 13 0 4 2 0 4 0
0 I 4 0 0 0 0 0 I
3 24 6 5 6 3
10
I 0 I
Total
297
26
22
13
15
50
36
6
49
Infectious episodes/patient
2.4
1.4
0.8
0.5
0.7
0.9
1.0
0.1
0.6
Vol. 33 No. 4 August 1991
(27001)L
Infectious complications in childhood leukemia (149) 569 Table 5. Approach to diagnosis of fever of unknown origin I ) Scoring system to predict the possibility of bacterial infection (Kamiya et al)'"'' 0 I 2 3 4
CRP ( + ) 0 ESR (mmlhr) I°C a day 3) C R P > 6 m g i d l ( 3 + ) 4) neutrophil count
- 572)
Infectious Complications in Childhood Leukemia Takuo Hirotsu, M.D. and Jun-ichi Akatsuka, M.D. Department of Pediatrics, The Jikei Universit!. School of Medicine. Tokyo
Since children with acute leukemia have prolonged periods of severe neutropenia due to the disease itself or its intensive chemotherapy, they often develop life-threatening infectious complications. A protected environment and prophylactic antibiotics for patients with severe neutropenia have been shown to decrease the incidence of infectious morbidity. In spite of the high mortality rate of infections, on the other hand, their diagnosis is not well established because the percentage of microbiological detectability by blood culture is low. The differentiation of infections may be possible by using some supplementary measures and particular laboratory parameters. Febrile neutropenic patients with leukemia should promptly receive empiic treatment with combinations of two or three broad-spectrum antibiotics that are bactericidal and synergistic toward the presumed pathogens, or with antifungal drugs if patients are resistant to antibiotics, as well as supportive measures such as granulocyte transfusion, intravenous gamma-globulin and granulocyte colonystimulating factor. Key Words Childhood leukemia, Neutropenia, Protected environment, Prophylactic antibiotics, Empiric treatment, Fever of unknown origin
introduction As intcnsive therapies for childhood leukemia have recently progressed [I]. the number ol' patients expericncing prolonged and profound neutropenia with an attendant high risk of infection has also increased. As well as preventing infection by means of a protected environment and prophylactic antibiotics, it is therefore important to vigorously seek out causes of infection by culture and non-culture methods. including some supplementary meas~~~
Received Ma! 10. 1991 C'orreymndence address: Takuo Hirotw. M.D.. Depaninent of Pediatrics. The Daisan Hospital. The Jikri UniLerhity School of' Medicine. 11-1. Izumihon-cho 4chome. Komae-shi. Tokyo 201, Japan
ure\ and particular laboratory parameters. and t o initiate antibiotic therapy promptly or t o use various adjuncts to such therapy. I n this paper. we briefly describe and discuss the prophylaxis and the management and treatment of infections in these children. Our findings are based upon clinical experience in our University Hospital, the study of the research group of' the Japanese Ministry of Health and Welfare, and a study conducted by the Tokyo Children's Cancer Study Group.
I. Protected Environment and Prophylactic Antibiotics Two hundred and ninety-seven febrile episodes in 82 children with acute leukemia were analyz.ed retrospectively at our institute during the eight years from 1969 to 1977 [2] (Study
Infectious complications in childhood leukemia ( 145) 565 No. I in Table 3). This study revealed that most of these infections developed from organisms such as Escherichia coli, Pseudomonus ueruginosu, Klehsiellu pneumoniue, Stuphjdococcus aureus, Streptococcus species, and Cundidu species colonizing along the alimentary and upper respiratory tracts, resulting in oral infection, pneumonia, esophagitis, colitis or perianal lesions. These infections seemed to be caused by the patient's endogenous microbial flora o r by microorganisms acquired from the hospital environment during therapy. Therefore, prevention of infection in neutropenic patients with acute leukemia has included attempts to decrease exposure to these exogenous and endogenous potential pathogens through isolation of the patients and elimination of their intestinal flora. On the other hand, the frequency of infection in patients receiving leukemic chemotherapy is directly related to the duration of neutropenia, and inversely related to the number of circulating granulocytes. Accordingly, for all children who are receiving antileukemic therapy, the protected environment and prophylactic antibiotics should be started one week before the
neutrophil count is predicted to decrease below 500ipl. and ended when the neutrophil count recovers to above 5OOjpl.
I . Protected environment Different reverse isolation techniques have been used in clinical medicine in order to protect patients with high susceptibility to infection. Pathogen-free rooms, ultra-clean wards and sterile cubicles have been designed, but they are very expensive and the patients who are cared for in these rooms sometimes develop psychological problems. We thus designed our isolation units with regular single rooms. The details of our method [3] for maintaining a protected environment in our pediatric ward are summarized in Table I.
2. Prophylactic antibiotics A large number of clinical trials have been conducted to investigate the utility of prophylactic antibiotic regimens in immunocompromised patients. There are two principal methods for prophylactic antibiotic regimens. One is total gastrointestinal decontamination which suppresses not only the potentially pathogenic microorganisms but also the non-
Table I , Protected environment and topical antibiotic prophylaxis
I . Isolation unit and all items placed into the units Sterilized by formalin gas (for 24 hours) Cleaned by benialkonium chloride solution (every day)
2. Steriliiation of patient before entering the units Washed by chlorhexidine solution (0.02C) Putting on a steriliied gown Gargling with povidone iodine solution Spraying with kanamycin plus amphotericin B solution Not allowed to go outdoors without a mask, gown and cap 3. Topical antibiotic regimen Chlorhexidine solution (0.02%aqueous) for cleaning the skin daily Chlorhexidine solution (0.5%)applied to the prepuce or vulva1 and vaginal region Chlorhexidine cream to nasal cavity and auditory canal Amphotericin B (50 mg per 5% glucose 500 ml) added to mouthwash. every 6 hours Inhalation of kanarnycin (20 mgiday) plus amphotericin B ( I mgiday) to upper respiratory tract every 6 hours 4. Food Sterilired with an electric range at 1.400 W for 30 seconds.
5. Steriliiation of all persons before entering into the units Washing hands with chlorhexidine solution (0.02% aqueous) Putting on slippers and gown, mask and cap. all sterilized by formalin gas
Vol. 33 No. 4 August 1991
566 (146)Hirorsu and Akatsuka amphotericin B. Recently. another study (Study No. 4) of the Tokyo Children's Cancer Study Group evaluated the prophylactic usefulness of a combined regimen of arnphotericin B and aztreonam, which is a monobactam antibiotic with a strong bactericidal effect against gramnegative bacteria including Pseudomonus aeruginosa but little o r no suppressive effect on stool anaerobes in children with neutropenia induced by cancer chemotherapy. In the early period after chemotherapy in which the neutrophil counts fell below SOOjpl, amphotericin B was first given orally and. in the late period in which they were below 250/pI. aztreonam at the dose of 100 mg/kg was administered intravenously twice a day with oral amphotericin B, until the neutrophil count again rose to 500jpl (unpublished data).
pathogenic anaerobic part of the flora. The other is selective gastrointestinal decontamination which preserves colonization resistance. Table 2 gives the prophylactic regimens which we have administered in our clinical studies. In a controlled prospective randomized trial of the research group of the Japanese Ministry of Health and Welfare [4] (Study No. 2), we studied the prophylactic effect of a total antimicrobial modulation (TAM) regimen consisting of polymyxin B. kanamycin and amphotericin B. and that of a selective antimicrobial modulation ( S A M ) regimen consisting of trimethoprim-sulfamethoxazole and amphotericin B in children with acute leukemia during induction therapy in a regular single room, and compared the results with historical controls in regular single room isolation only. Based on a previous study (Study No. 3) of the Tokyo Children's Cancer Study Group [5] we t'ormulated a better prophylactic regimen by comparing the three different S A M regimens (A, B and C) with oral highdose
3. Antiviral prophylaxis In principle, prophylactic passive immunization by high-titer gamma-globulin has been used for specific viral infection within six months after complete remission. For example,
Table 2. Prophylactic antibiotic regimens (dose per day) I , Total decontamination (TD) and selective decontamination (SD)"I TD 10 million I1 kg
Pol!ni!sin-B A M P H Svrup* KM S\rup**
200 mg 30mg kg b.i.d.
0.1 Tab./kg 200 mg b.i.d.
2. Oral high-dose A M P H " ' A A M P H Syrup 100mg kg TMP-SMZ 0.1 T a b kg b.i.d
SD
TMP-SMZ*** A M P H syrup
B
C
A M P H Syrup 5 0 m g kg 0.1 T a b kg TMP-SMZ b.i.d.
A M P H Syrup 50mgikg 0. I T a b / kg TMP-SMZ b.i.d. Inhalation**** A M P H for IV use I mg KM 2 0 m g t.i.d.
3. Anreonam and A M P H
0 A regimen o r C regimen of oral high-dose A M P H
0 A n r e o n a m 100 mg; kg (intravenous) b.i.d. plus A regimen o r C regimen of oral highdose A M P H
* amphotcricin R (maximum dose: 3 glday), ** Kanamycin, *** Trimethoprim 80 mg plu, Sulfamethoxaiole 40 mg.
**** Dissolved
in 10 ml of distilled water for injection
Artu Paediutr Jpn
Infectious complications in childhood leukemia (147) 567 varicella zoster immune globulin (VZIG) should be given at the dose of I vial/ 10 kg within 72 hours of exposure to varicella or herpes zoster. VZIG is also recommended for patients who either have a negative history of varicella infection or are sero-negative. Prophylaxis against cytomegalovirus infection with intravenous high-titer gammaglobulin is administered at the dose of 100 to 200 mg/ kg [6]. On the other hand, varicella-susceptible leukemic children who are in remission should receive the varicella virus vaccine.
tions, and skin lesions became less frequent in the prophylactic antibiotics group (Table 3). 2. Microbiological documentation of infections The causative organisms were isolated in only 20% of these cases. Gram-negative rods such as Escherichia coli, Pseudomonas aeruginosa and Klehsiella pneunioniae, and varicella zoster. chicken pox and Pneumocytis carinii were isolated less frequently in the prophylactic antibiotics group. However, the isolation of grampositive rods such as Staph.vlococcus aureus. Staphylococcus epidermidis and Streprococcus species, and of Candida and Aspergillus species, increased in incidence after prophylaxis in spite of oral administration of anti-fungal agents (Table 4).
II. Prophylactic Effects and Changes in Infection Episodes Tables 3 and 4 summarize the results of prophylactic effects in prospective studies conducted as previously mentioned.
111. Approach to Diagnosis of Fever of
1. Frequency and site of infections The frequency of infectious episodes was less than 1.0 per patient in the prophylactic antibiotics group, as compared with more than 1.0 in the control group which did not have prophylactic antibiotics. However, there was no difference in the frequency of suspected sepsis, fever of unknown origin or sepsis between the two groups. On the other hand, respiratory infections such as pneumonia, anorectal lesions, urinary tract infec-
Unknown Origin The key to treatment of infectious diseases is always to identify the causative organism as soon as possible. However, as has already been mentioned, the episodes of fever of unknown origin and suspected sepsis were most frequently encountered in patients with acute leukemia receiving chemotherapy. A large proportion of neutropenic leukemic patients who become febrile will not have a
Table 3. Frequency of infections during initial therapy 1 III 1969- 1977 non
Study no. Study period Prophylactic regimen
2 141 1980- 1985 non TD SD
3 ‘(1 1987- 1988 A B C
4 I989 @
0
~
No. of patients
82
Sepsis Suspected sepsis Fever of unknown origin Pneumonia Upper respiratory infection Alimentary tract infection Urinary tract infection Skin infection Others
36
1
18
75 35 55 44 8 23 21
26
23
20
51
33
57
75
5 7 6 I 0 0 0 I 2
3 5 3 I 0 0 0 0 1
2 8 4 0 1 0 0 0 0
7 II 2 9 7 0 3 1
5 8 13 0 4 2 0 4 0
0 I 4 0 0 0 0 0 I
3 24 6 5 6 3
10
I 0 I
Total
297
26
22
13
15
50
36
6
49
Infectious episodes/patient
2.4
1.4
0.8
0.5
0.7
0.9
1.0
0.1
0.6
Vol. 33 No. 4 August 1991
(27001)L
Infectious complications in childhood leukemia (149) 569 Table 5. Approach to diagnosis of fever of unknown origin I ) Scoring system to predict the possibility of bacterial infection (Kamiya et al)'"'' 0 I 2 3 4
CRP ( + ) 0 ESR (mmlhr) I°C a day 3) C R P > 6 m g i d l ( 3 + ) 4) neutrophil count
