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Role of Chlamydia pneumoniae in acute chest syndrome of sickle cell disease
Role of Chlamydia pneumoniae in acute chest syndrome of sickle cell disease S c o t t T. Miller, MD, M a r g a r e t R. H a m m e r s c h l a g , MD, Keith Chirgwin, MD, S r e e d h a r P. Rao, MD, Patricia Roblin, MS, M a u r e e n Gelling, RN, Tziporah Stilerman, PA-C, Julius S c h a c h t e r , PhD, a n d Gail Cassell, PhD From the Departments of Pediatrics and Medicine, State University of New York-Health Science Center at Brooklyn; the Department of Laboratory Medicine, Universityof California, San Francisco, and the Department of Microbiology, University of Alabama, Birmingham Children with sickle cell disease and a c u t e chest syndrome were investigated for infection with Chlamydiapneumoniae and Mycoplasmapneurnoniae. Of 30 patients who had 32 episodes of a c u t e chest syndrome, four (13%) had C. pneumoniae isolated from the nasopharynx; two of these also had serologic e v i d e n c e of acute infection, and one had positive n a s o p h a r y n g e a l isolates on two subsequent occasions during the course of I year with stable, e l e v a t e d titers of anti-C, pneumoniae IgG, suggesting chronic infection. Two patients with n e g a t i v e cultures had serologic e v i d e n c e of infection with C. pneumoniae. None of 32 cultures for M. pneumoniae were positive, and although anti-M. pneumoniae IgM d e v e l o p e d in two patients, one of these patients had e v i d e n c e of C. pneumoniae infection (positive culture and seroconversion). We c o n c l u d e that C. pneumoniae infection is prevalent in our sickle cell p o p u l a t i o n with acute chest syndrome. Until further studies clarify the p a t h o p h y s i o l o g i c signifi c a n c e of C. pneumoniae infection, we believe that early inclusion of erythromycin as antimicrobial therapy for a c u t e chest syndrome seems reasonable. (J PEDIATR1991;118:30-3)
"Acute chest syndrome" is a term used to describe fever and new pulmonary findings in persons with sickle cell disease. 1-3 Infection, particularly that due to Streptococcus pneumoniae, was believed to be the predominant cause of ACS in a large group of patients described in 1971, 4 but more recent studies in both adults l, 2 and children 5 have failed to document an infectious agent in the majority of ACS episodes. Because pulmonary infarction is an uncommon occurrence in children with ACS, 4 it seems likely that infectious agents that are not readily identifiable by routine microbiologic techniques may be responsible for at least some episodes of ACS in children with SCD. One such agent is Chlamydia pneumoniae (formerly Submitted for publication July 12, 1990; accepted Aug. 23, 1990. Reprint requests: Scott T. Miller, MD, Department of Pediatrics, State University of New York-Health Science Center at Brooklyn, Box 49, 450 Ctarkson Ave., Brooklyn, NY 11203. 9/20/24942
30
termed T W A R ) , a new species recently demonstrated to be distinct from Chlamydia trachomatis, a common cause of sexually transmitted disease, neonatal inclusion conjunctivitis, and pneumonia, and from Chlamydia psittaci, the etiologic agent of psittacosis. 6, 7 C. pneumoniae appears to ACS SCD
Acute chest syndrome Sickle cell disease
]
be a common cause of community-acquired pneumonia not previously searched for in patients with ACS. 7 The purpose of this investigation was to determine whether C. pneumoniae is prevalent in our pediatric SCD population with ACS and, if so, to determine what clinical features are associated with C. pneumoniae infection. METHODS An attempt was made to investigate all children admitted to Kings County Hospital with SCD and both clinical
Volume 118 Number 1
Acute chest syndrome of sickle cell disease
31
Table. Patients with evidence of C. pneumoniae infection: Clinical and serologic data Patient No.
Age (yr)
Hgb
Chest radiography
Po2 (mm Hg)
Transfused
Serology Date
IgG
IgM
1/13/89 5/23/89 8/25/89 tl/7/89 1/25/90 4/25/88 5/19/88
16 128 0 0 32 64 128 128 0 0
0 0 0 0 0 0 0 0 0 0
16 128 0 16
0 32 0 16
Comments
Culture positive 1
9
SC
LLL
88
No
2
16
SS
Bilateral effusion
78
Yes
3
15
SS
LUL
59
Yes
4
5
SS
LUL
67
Yes
SS
RML, LLL Interstitial
73
Yes
5/6/89 5/23/88 4/14/89
Anti-M. pneumoniae IgM 1:320 Anti-M. pneumoniae IgM 1:20 Pos. C. pneumoniae culture Pos. C. pneumoniae culture Pos. C. pneumoniae culture Hematocrit, 21%; reticulocytes, 0.4%
Culture negative 5
9
8/28/89 11/17/89 6 8 SS 75 Yes 5/18/88 8/10/89 Hgb, Hemoglobin;LLL, left lower lobe;LUL, left upper lobe;RML, right middlelobe. and roentgenographic findings compatible with ACS. We obtained nasopharyngeal culture specimens for isolation of Chlamydia and Mycoplasma pneumoniae, and acute and convalescent sera for isolation of C. pneumoniae and M. pneumoniae antibodies. Additional investigations to document an infectious origin of ACS were done at the discretion of the admitting physicians. Chlamydia cultures were grown in cycloheximide-treated HeLa 229 cells pretreated with dextran-diethylaminoethyl (DEAE). At least four serial passages were done with each specimen. Positive cultures were confirmed by fluorescent antibody staining with a specific anti-C, pneumoniae monoelonal antibody (Washington Research Foundation, Seattle, Wash.). Sera were collected, frozen at - 7 0 ~ C, and shipped in batches to the appropriate laboratory. Serologic studies for C. pneumoniae were performed by the microimmunofluorescence test at the University of California, San Francisco. Nasopharyngeal specimens for isolation of M. pneumoniae were inoculated in SPAN media and frozen at - 7 0 ~ C. Cultures were then inoculated on SP4 agar and incubated for 1 month in carbon dioxide at 37 ~ C. Identification of M. pneumoniae was confirmed by fluorescent staining with an M. pneumoniae conjugate. Serum antibody to M. pneumoniae was detected with the use of an indirect enzyme immunoassay. Mycoplasma cultures were grown and serologic studies performed at the University of Alabama. RESULTS Between February 1988 and August 1989, a total of 30 children admitted to Kings County Hospital Center with SCD and ACS were investigated. Two patients had two episodes of ACS during the study period. Children with ACS
included 21 with homozygous sickle cell anemia, eight with sickle-hemoglobin C disease, and one with sickle-/3thalassemia. Ages ranged from 14 months to 15 years (median 5]/2 years); two children were less than 2 years of age. Of 25 patients more than 2 years of age for whom information is available, 19 (76%) had received pneumococcal vaccine; 23 (82%) of 28 were receiving prophylactic penicillin. All but one patient had fever and puhnonary infiltrates (29 lobar, 2 interstitial) visible on chest radiographs at some time during the course of hospitalization; one patient had bilateral pleural effusions without consolidation. Blood for bacterial culture was obtained from all patients and was sterile in all cases. Nasopharyngeal aspirates for viral isolation, obtained from nine patients, were positive in two; one grew both respiratory syncytial virus and cytomegalovirus, and another grew influenza B virus. One additional patient with concurrent aplastic crisis was acutely infected with human parvovirus B19 (B19 antigen, DNA, electron microscopy, and anti-B19 IgG and IgM all positive). Chlamydia pneumoniae was isolated from the nasopharynx of four children; serologic and clinical data are presented in the Table. Two patients (1 and 2) had a fourfold or greater rise in anti-C, pneumoniae IgG, suggesting acute infection, although patient 2 also had specific IgM against M. pneumoniae. Patient 4 had a positive nas0pharyngeal culture but no detectable anti-C, pneumoniae antibody immediately and 1 year later. Patient 3 had C. pneurnoniae isolated from the nasopharynx three times during a l-year period; he had stable anti-C, pneumoniae IgG titers. None of the culture-positive patients had detectable anti-C. pneumoniae IgM. Of the remaining 26 culture-negative patients, 22 had at
32
Miller et al.
least one serum specimen available for analysis; 11 had paired sera, although time intervals between specimens varied considerably. In two patients (Nos. 5 and 6), there was a fourfold increase in anti-C, pneumoniae IgG titers, although there was a substantial delay in obtaining convalescent serum from patient 6. One culture-negative patient with only a single serum specimen available had a titer of anti-C, pneumoniae IgG of 1:32. M. pneumoniae was not isolated from any of the patients. Of 18 patients, two (11%) had serologic evidence of infection, but one of these patients also had a positive Culture for
C. pneumoniae. DISCUSSION Evidence of infection with C. pneumoniae was found in six children with SCD during 32 episodes of ACS, an infection rate of 19%. The only previously published study of C. pneumoniae infection that used culture as well as serologic studies involved university students 8 and included neither children nor (specifically) patients with SCD. Serologic surveys, however, have suggested that C. pneumoniae is pathogenic in hematologically normal children.7, 9 The prevalence of C. pneumoniae infection in our children with SCD is comparable to that reported in the non-sickle-cell population.7, 10 In the study from the University of Washington health service, 8 all culture-positive patients had serologic evidence of acute infection; in fact, serologic methods were deemed superior to culture techniques for documenting acute infection. This was not the case in our population or in a population of persons without sickle cell disease studied concurrently.1~In fact, one of our patients who had a fourfold rise in anti-C, pneumoniae IgG also had a high (1:320) IgM titer against M. pneumoniae, which dropped appropriately in convalescent serum drawn 3 months later. Data on this patient might be interpreted as evidence of concurrent infections or, perhaps, nonspecific polyclonal B cell activation in response to Chlamydia, Mycloplasma, or some other pathogen. One of our patients had stable, elevated titers of anti-C. pneumoniae IgG and also positive nasopharyngeal cultures on three occasions during the course of 1 year. These data suggest that there can be chronic, asymptomatic infection with C. pneumoniae, as is known to occur in genital infection caused by C. trachomatis.ll Studies using sequential cultures in persons with or without symptoms have not been reported and need to be done for confirmation. One culture-positive patient had no detectable antibody imme-. diately or 1 year later; the significance of this finding is not yet clear. Further studies are required to clarify the epidemiologic features of C. pneumoniae, but it seems likely that it is
The Journal of Pediatrics January 1991
pathogenic in at least some children with ACS and should be considered in decisions regarding appropriate therapy for ACS. Antimicrobial therapy has usually been directed against S. pneumoniae, to which patients with SCD have increased susceptibility.12, 13 In a large series of patients reported from Miami in 1971,4 8.5% of patients with ACS had positive blood cultures and an additional 42% had potentially pathogenic bacteria isolated from the throat or sputum; 83% of these isolates were S. pneumoniae, and it was speculated on the basis of clinical findings that a substantial number of culture-negative patients may also have been infected. However, more recent studies in adult patients 1, 2 suggest that pneumococcal isolates are extremely uncommon and that pulmonary findings are largely due to pulmonary infarctions. Even in children, who are probably less susceptible than adults to pulmonary infarction,4 bacterial infection is now a relatively uncommon cause of ACS. In only 6 of 37 Jamaican children with ACS who had blood culture specimens drawn were pathogens isolated; three were S. pneumoniae. 14 These children, however, had not received pneumococcal vaccine or penicillin prophylaxis, the latter having subsequently been shown to reduce the risk of pneumococcal infection in young children with SCD. 15 In a series of 102 children from Philadelphia, 5 in which 90% of the patients had been immunized against pneumococcus and 25% were receiving prophylactic penicillin, only 5% of the patients had bacterial pneumonia as confirmed by positive blood culture, latex agglutination, or urine polysaccharide counterimmunoelectrophoresis. An additional 7% had positive sputum cultures; one third of all these proven or suspected bacterial infections were due to S. pneurnoniae. Viral pneumonia was diagnosed in 8% of the patients. M. pneumoniae infection was diagnosed serologically in 16% of the patients overall but in 45% during the autumn months. An infectious etiologic agent could not be identified in the remaining 64% of the children. It may be that some of these ACS episodes were due to C. pneumoniae infection. Serologic studies have indicated that C. pneumoniae usually causes a relatively mild, prolonged illness,7 although it may be more virulent in elderly persons and in young children.7,9 Our findings suggest that children with SCD may be significantly compromised by C. pneumoniae infection. Similarly, M. pneumoniae, which also generally causes a mild illness in normal persons, can cause serious infection in those with SCD. 16 Patients with SCD do not, however, appear to have an increased incidence of infection in comparison with hematologically normal persons. 7, 10 One of our patients with ACS had evidence of acute infection with human parvovirus B19. This association has been noted by us and others. 14, 17It remains unclear whether pulmonary findings are directly related to infection of pul-
Volume 118 Number 1
monary tissue by the virus or perhaps, instead, represent pulmonary infarctions caused by m a r r o w hypoplasia, worsening anemia, a n d subsequent impaired oxygen delivery. W e conclude t h a t a comprehensive epidemiologic study of A C S is required; this should include analysis for infection by C. pneumoniae and h u m a n parvovirus B19, as well as pathogens searched for previously by Poncz et al. 5 and others. Longitudinal case-control studies are also needed to determine the incidence of a s y m p t o m a t i c or chronic infection by C. pneumoniae. It seems clear t h a t C. pneumoniae is a p a t h o g e n in at least some children with A C S and t h a t diagnosis based on clinical findings is not possible. Rapid diagnosis in a clinical laboratory is not readily available, and given the high incidence of M. pneumoniae infection in some series of A C S patients, it seems p r u d e n t to include erythromycin early in the t r e a t m e n t of A C S to provide both anti-Chlamydia and anti-Mycoplasma coverage.
Acute chest syndrome of sickle cell disease
6.
7. 8.
9.
10.
11. 12.
13. REFERENCES
1. Charache S, Scott JC, Charache P. "Acute chest syndrome" in adults with sickle cell anemia. Arch Intern Med 1979;139:679. 2. Davies SC, Luce P J, Win AA, et al. Acute chest syndrome in sickle cell disease. Lancet 1984;1:36-8. 3. Charache S, Lubin B, Reid C, eds. Management and therapy of sickle cell disease. Bethesda Md.: National Institutes of Health publication No. 89-2117, 1989:20-1. 4. Barrett-Connor E. Acute pulmonary disease and sickle cell anemia. Ann Rev Respir Dis 1971;104:159-65. 5. Poncz M, Kane E, Gill FM. Acute chest syndrome in sickle cell
14.
15.
16.
17.
33
disease: etiolt)gy and clinical correlates. J PEDIATR 1985; 107:861-6. Grayston JT, Kuo CC, Campbell LA, et al. Chlamydiapneumoniae sp. nov. for Chlamydia sp. strain TWAR. Int J Syst Bacteriol 1989;39:88-90. Grayston JT. Chlamydia pneumoniae, strain TWAR. Chest 1989;95:664-9. Grayston JT, Kuo CC, Wang SP, et al. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986;513:161-8. Saikku P, Ruutu P, Leinonen M, et al. Acute lower respiratory tract infection in Filipino children associated with Chlamydia TWAR antibody. J Infect Dis 1988:158:1095-7. Chirgwin K, Roblin P, Gelling M, et al. Infection with Chlamydia pneumoniae (TWAR) in Brooklyn. J Infect Dis (in press). Hammerschlag MR. Chlamydial infections. J PED1ATR 1989; 114:727-34. Barrett-Connor E. Bacterial infection and sickle cell anemia: an analysis of 250 infections in 166 patients and a review of the literature. Medicine 1971;50:97-112. Zarkowsky HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglobinopathies. J PEDIATR 1986;109:579-85. DeCeulaer K, McMullen KW, Maude GH, et al. Pneumonia in young children with homozygous sickle cell disease: risk and clinical features. Eur J Pediatr 1985;144:255-8. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593-9. Shulman ST, Bartlett J, Clyde WA, et al. The unusual severity of mycoplasmal pneumonia in children with sickle cell disease. N Engl J Med 1972;287:164-7. Rao SP, Miller S, Cohen B, et al. Does human parvovirus cause acute chest syndrome in sickle cell disease [Abstract]? Pediatr Res 1988;23:345A.
"Acute chest syndrome" is a term used to describe fever and new pulmonary findings in persons with sickle cell disease. 1-3 Infection, particularly that due to Streptococcus pneumoniae, was believed to be the predominant cause of ACS in a large group of patients described in 1971, 4 but more recent studies in both adults l, 2 and children 5 have failed to document an infectious agent in the majority of ACS episodes. Because pulmonary infarction is an uncommon occurrence in children with ACS, 4 it seems likely that infectious agents that are not readily identifiable by routine microbiologic techniques may be responsible for at least some episodes of ACS in children with SCD. One such agent is Chlamydia pneumoniae (formerly Submitted for publication July 12, 1990; accepted Aug. 23, 1990. Reprint requests: Scott T. Miller, MD, Department of Pediatrics, State University of New York-Health Science Center at Brooklyn, Box 49, 450 Ctarkson Ave., Brooklyn, NY 11203. 9/20/24942
30
termed T W A R ) , a new species recently demonstrated to be distinct from Chlamydia trachomatis, a common cause of sexually transmitted disease, neonatal inclusion conjunctivitis, and pneumonia, and from Chlamydia psittaci, the etiologic agent of psittacosis. 6, 7 C. pneumoniae appears to ACS SCD
Acute chest syndrome Sickle cell disease
]
be a common cause of community-acquired pneumonia not previously searched for in patients with ACS. 7 The purpose of this investigation was to determine whether C. pneumoniae is prevalent in our pediatric SCD population with ACS and, if so, to determine what clinical features are associated with C. pneumoniae infection. METHODS An attempt was made to investigate all children admitted to Kings County Hospital with SCD and both clinical
Volume 118 Number 1
Acute chest syndrome of sickle cell disease
31
Table. Patients with evidence of C. pneumoniae infection: Clinical and serologic data Patient No.
Age (yr)
Hgb
Chest radiography
Po2 (mm Hg)
Transfused
Serology Date
IgG
IgM
1/13/89 5/23/89 8/25/89 tl/7/89 1/25/90 4/25/88 5/19/88
16 128 0 0 32 64 128 128 0 0
0 0 0 0 0 0 0 0 0 0
16 128 0 16
0 32 0 16
Comments
Culture positive 1
9
SC
LLL
88
No
2
16
SS
Bilateral effusion
78
Yes
3
15
SS
LUL
59
Yes
4
5
SS
LUL
67
Yes
SS
RML, LLL Interstitial
73
Yes
5/6/89 5/23/88 4/14/89
Anti-M. pneumoniae IgM 1:320 Anti-M. pneumoniae IgM 1:20 Pos. C. pneumoniae culture Pos. C. pneumoniae culture Pos. C. pneumoniae culture Hematocrit, 21%; reticulocytes, 0.4%
Culture negative 5
9
8/28/89 11/17/89 6 8 SS 75 Yes 5/18/88 8/10/89 Hgb, Hemoglobin;LLL, left lower lobe;LUL, left upper lobe;RML, right middlelobe. and roentgenographic findings compatible with ACS. We obtained nasopharyngeal culture specimens for isolation of Chlamydia and Mycoplasma pneumoniae, and acute and convalescent sera for isolation of C. pneumoniae and M. pneumoniae antibodies. Additional investigations to document an infectious origin of ACS were done at the discretion of the admitting physicians. Chlamydia cultures were grown in cycloheximide-treated HeLa 229 cells pretreated with dextran-diethylaminoethyl (DEAE). At least four serial passages were done with each specimen. Positive cultures were confirmed by fluorescent antibody staining with a specific anti-C, pneumoniae monoelonal antibody (Washington Research Foundation, Seattle, Wash.). Sera were collected, frozen at - 7 0 ~ C, and shipped in batches to the appropriate laboratory. Serologic studies for C. pneumoniae were performed by the microimmunofluorescence test at the University of California, San Francisco. Nasopharyngeal specimens for isolation of M. pneumoniae were inoculated in SPAN media and frozen at - 7 0 ~ C. Cultures were then inoculated on SP4 agar and incubated for 1 month in carbon dioxide at 37 ~ C. Identification of M. pneumoniae was confirmed by fluorescent staining with an M. pneumoniae conjugate. Serum antibody to M. pneumoniae was detected with the use of an indirect enzyme immunoassay. Mycoplasma cultures were grown and serologic studies performed at the University of Alabama. RESULTS Between February 1988 and August 1989, a total of 30 children admitted to Kings County Hospital Center with SCD and ACS were investigated. Two patients had two episodes of ACS during the study period. Children with ACS
included 21 with homozygous sickle cell anemia, eight with sickle-hemoglobin C disease, and one with sickle-/3thalassemia. Ages ranged from 14 months to 15 years (median 5]/2 years); two children were less than 2 years of age. Of 25 patients more than 2 years of age for whom information is available, 19 (76%) had received pneumococcal vaccine; 23 (82%) of 28 were receiving prophylactic penicillin. All but one patient had fever and puhnonary infiltrates (29 lobar, 2 interstitial) visible on chest radiographs at some time during the course of hospitalization; one patient had bilateral pleural effusions without consolidation. Blood for bacterial culture was obtained from all patients and was sterile in all cases. Nasopharyngeal aspirates for viral isolation, obtained from nine patients, were positive in two; one grew both respiratory syncytial virus and cytomegalovirus, and another grew influenza B virus. One additional patient with concurrent aplastic crisis was acutely infected with human parvovirus B19 (B19 antigen, DNA, electron microscopy, and anti-B19 IgG and IgM all positive). Chlamydia pneumoniae was isolated from the nasopharynx of four children; serologic and clinical data are presented in the Table. Two patients (1 and 2) had a fourfold or greater rise in anti-C, pneumoniae IgG, suggesting acute infection, although patient 2 also had specific IgM against M. pneumoniae. Patient 4 had a positive nas0pharyngeal culture but no detectable anti-C, pneumoniae antibody immediately and 1 year later. Patient 3 had C. pneurnoniae isolated from the nasopharynx three times during a l-year period; he had stable anti-C, pneumoniae IgG titers. None of the culture-positive patients had detectable anti-C. pneumoniae IgM. Of the remaining 26 culture-negative patients, 22 had at
32
Miller et al.
least one serum specimen available for analysis; 11 had paired sera, although time intervals between specimens varied considerably. In two patients (Nos. 5 and 6), there was a fourfold increase in anti-C, pneumoniae IgG titers, although there was a substantial delay in obtaining convalescent serum from patient 6. One culture-negative patient with only a single serum specimen available had a titer of anti-C, pneumoniae IgG of 1:32. M. pneumoniae was not isolated from any of the patients. Of 18 patients, two (11%) had serologic evidence of infection, but one of these patients also had a positive Culture for
C. pneumoniae. DISCUSSION Evidence of infection with C. pneumoniae was found in six children with SCD during 32 episodes of ACS, an infection rate of 19%. The only previously published study of C. pneumoniae infection that used culture as well as serologic studies involved university students 8 and included neither children nor (specifically) patients with SCD. Serologic surveys, however, have suggested that C. pneumoniae is pathogenic in hematologically normal children.7, 9 The prevalence of C. pneumoniae infection in our children with SCD is comparable to that reported in the non-sickle-cell population.7, 10 In the study from the University of Washington health service, 8 all culture-positive patients had serologic evidence of acute infection; in fact, serologic methods were deemed superior to culture techniques for documenting acute infection. This was not the case in our population or in a population of persons without sickle cell disease studied concurrently.1~In fact, one of our patients who had a fourfold rise in anti-C, pneumoniae IgG also had a high (1:320) IgM titer against M. pneumoniae, which dropped appropriately in convalescent serum drawn 3 months later. Data on this patient might be interpreted as evidence of concurrent infections or, perhaps, nonspecific polyclonal B cell activation in response to Chlamydia, Mycloplasma, or some other pathogen. One of our patients had stable, elevated titers of anti-C. pneumoniae IgG and also positive nasopharyngeal cultures on three occasions during the course of 1 year. These data suggest that there can be chronic, asymptomatic infection with C. pneumoniae, as is known to occur in genital infection caused by C. trachomatis.ll Studies using sequential cultures in persons with or without symptoms have not been reported and need to be done for confirmation. One culture-positive patient had no detectable antibody imme-. diately or 1 year later; the significance of this finding is not yet clear. Further studies are required to clarify the epidemiologic features of C. pneumoniae, but it seems likely that it is
The Journal of Pediatrics January 1991
pathogenic in at least some children with ACS and should be considered in decisions regarding appropriate therapy for ACS. Antimicrobial therapy has usually been directed against S. pneumoniae, to which patients with SCD have increased susceptibility.12, 13 In a large series of patients reported from Miami in 1971,4 8.5% of patients with ACS had positive blood cultures and an additional 42% had potentially pathogenic bacteria isolated from the throat or sputum; 83% of these isolates were S. pneumoniae, and it was speculated on the basis of clinical findings that a substantial number of culture-negative patients may also have been infected. However, more recent studies in adult patients 1, 2 suggest that pneumococcal isolates are extremely uncommon and that pulmonary findings are largely due to pulmonary infarctions. Even in children, who are probably less susceptible than adults to pulmonary infarction,4 bacterial infection is now a relatively uncommon cause of ACS. In only 6 of 37 Jamaican children with ACS who had blood culture specimens drawn were pathogens isolated; three were S. pneumoniae. 14 These children, however, had not received pneumococcal vaccine or penicillin prophylaxis, the latter having subsequently been shown to reduce the risk of pneumococcal infection in young children with SCD. 15 In a series of 102 children from Philadelphia, 5 in which 90% of the patients had been immunized against pneumococcus and 25% were receiving prophylactic penicillin, only 5% of the patients had bacterial pneumonia as confirmed by positive blood culture, latex agglutination, or urine polysaccharide counterimmunoelectrophoresis. An additional 7% had positive sputum cultures; one third of all these proven or suspected bacterial infections were due to S. pneurnoniae. Viral pneumonia was diagnosed in 8% of the patients. M. pneumoniae infection was diagnosed serologically in 16% of the patients overall but in 45% during the autumn months. An infectious etiologic agent could not be identified in the remaining 64% of the children. It may be that some of these ACS episodes were due to C. pneumoniae infection. Serologic studies have indicated that C. pneumoniae usually causes a relatively mild, prolonged illness,7 although it may be more virulent in elderly persons and in young children.7,9 Our findings suggest that children with SCD may be significantly compromised by C. pneumoniae infection. Similarly, M. pneumoniae, which also generally causes a mild illness in normal persons, can cause serious infection in those with SCD. 16 Patients with SCD do not, however, appear to have an increased incidence of infection in comparison with hematologically normal persons. 7, 10 One of our patients with ACS had evidence of acute infection with human parvovirus B19. This association has been noted by us and others. 14, 17It remains unclear whether pulmonary findings are directly related to infection of pul-
Volume 118 Number 1
monary tissue by the virus or perhaps, instead, represent pulmonary infarctions caused by m a r r o w hypoplasia, worsening anemia, a n d subsequent impaired oxygen delivery. W e conclude t h a t a comprehensive epidemiologic study of A C S is required; this should include analysis for infection by C. pneumoniae and h u m a n parvovirus B19, as well as pathogens searched for previously by Poncz et al. 5 and others. Longitudinal case-control studies are also needed to determine the incidence of a s y m p t o m a t i c or chronic infection by C. pneumoniae. It seems clear t h a t C. pneumoniae is a p a t h o g e n in at least some children with A C S and t h a t diagnosis based on clinical findings is not possible. Rapid diagnosis in a clinical laboratory is not readily available, and given the high incidence of M. pneumoniae infection in some series of A C S patients, it seems p r u d e n t to include erythromycin early in the t r e a t m e n t of A C S to provide both anti-Chlamydia and anti-Mycoplasma coverage.
Acute chest syndrome of sickle cell disease
6.
7. 8.
9.
10.
11. 12.
13. REFERENCES
1. Charache S, Scott JC, Charache P. "Acute chest syndrome" in adults with sickle cell anemia. Arch Intern Med 1979;139:679. 2. Davies SC, Luce P J, Win AA, et al. Acute chest syndrome in sickle cell disease. Lancet 1984;1:36-8. 3. Charache S, Lubin B, Reid C, eds. Management and therapy of sickle cell disease. Bethesda Md.: National Institutes of Health publication No. 89-2117, 1989:20-1. 4. Barrett-Connor E. Acute pulmonary disease and sickle cell anemia. Ann Rev Respir Dis 1971;104:159-65. 5. Poncz M, Kane E, Gill FM. Acute chest syndrome in sickle cell
14.
15.
16.
17.
33
disease: etiolt)gy and clinical correlates. J PEDIATR 1985; 107:861-6. Grayston JT, Kuo CC, Campbell LA, et al. Chlamydiapneumoniae sp. nov. for Chlamydia sp. strain TWAR. Int J Syst Bacteriol 1989;39:88-90. Grayston JT. Chlamydia pneumoniae, strain TWAR. Chest 1989;95:664-9. Grayston JT, Kuo CC, Wang SP, et al. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986;513:161-8. Saikku P, Ruutu P, Leinonen M, et al. Acute lower respiratory tract infection in Filipino children associated with Chlamydia TWAR antibody. J Infect Dis 1988:158:1095-7. Chirgwin K, Roblin P, Gelling M, et al. Infection with Chlamydia pneumoniae (TWAR) in Brooklyn. J Infect Dis (in press). Hammerschlag MR. Chlamydial infections. J PED1ATR 1989; 114:727-34. Barrett-Connor E. Bacterial infection and sickle cell anemia: an analysis of 250 infections in 166 patients and a review of the literature. Medicine 1971;50:97-112. Zarkowsky HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglobinopathies. J PEDIATR 1986;109:579-85. DeCeulaer K, McMullen KW, Maude GH, et al. Pneumonia in young children with homozygous sickle cell disease: risk and clinical features. Eur J Pediatr 1985;144:255-8. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 1986;314:1593-9. Shulman ST, Bartlett J, Clyde WA, et al. The unusual severity of mycoplasmal pneumonia in children with sickle cell disease. N Engl J Med 1972;287:164-7. Rao SP, Miller S, Cohen B, et al. Does human parvovirus cause acute chest syndrome in sickle cell disease [Abstract]? Pediatr Res 1988;23:345A.