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Effect of underlying disease and age on pneumococcal serotype distribution
Effect of Underlying Disease and Age on Pneumococcal Serotype Distribution
STEVEN BARRY RICHARD
J. WEISHOLTZ, J. HARTMAN, B. ROBERTS,
M.D. MD. M.D.
New York, New York
From the Division of Infectious Diseases, Department of Medicine, New York Hospital-Cornell Medical Center, New York, New York. This work was presented in part at the 22nd Annual International Conference on Antimicrobial Agents and Chemotherapy, Miami Beach, Florida, October 4-6, 1982. Dr. Hartman is a recipient of a Teacher-Scientist Award from the Andrew W. Mellon Foundation, New York, New York, Requests for reprints should be addressed to Dr. Steven J. Weisholtz, Division of Infectious Diseases, Department of Madlcine, New York Hospttal-Ccmell Medical Center, 525 East 68th Street, New York, New York 16921. Manuscript accepted October 14, 1982.
The hospital records of 264 patients with 277 episodes of pneumococcal bacteremia occurring at New York Hospital-Cornell Medical Center over the period 1970 to 1960 were examined to determine whether serotype distribution varied with the underlying disease or age of the patient. The patients were placed into three groups according to their underlying disease. Group A consisted of ail patients with significant impairment of their immune system. Group B included those patients with underlying conditions that were not associated with immune deficiency. Group C comprised those patients considered to be normal hosts. Overall, 64 percent of blood isolates were serotypes included in the vaccine. In Group A, only 73 percent of these isolates were vaccine types, compared with 65 percent in Group B and 97 percent in Group C (differences significant at p
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TABLE I
SEROTYPE DISTRIBUTION-WEISHOLTZ
ET AL
Serotype Distribution of 277 Episodes of Pneumococcal Bacteremia Occurring in 264 Patients Number and Percent of Bacteremic Episodes 1976-1960 Adults ---ChildrenAdults Number Number Percent Number Percent Percent
1970-1975 Children* Number Percent
Total Number
Percent
Vaccine types+ Nonvaccine types
20 2
91 9
74 19
80 20
39 3
93 7
99 21
83 17
232 45
84 16
Total
22
100
93
100
42
100
120
100
277
100
Includes all patients less than 15 years old. + Includes types 1, 2, 3, 4, 6, 7, 8, 9, 12, 14, 18, 19, 23, l
and 25.
to the immunizing pneumococcal antigen [IO-161, poor opsoniting ability despite adequate antibody titers [ 17,181, or infection with a pneumococcal type that is not included in the vaccine. Surveillance studies have indicated that 68 to 90 percent of pneumococcal blood isolates are included in the present vaccine formulation [3,19-221. However, to date, no patient population has been systematically studied to determine whether the incidence of pneumococcal bacteremia due to vaccine serotypes varies with underlying disease or age of the patient. There is some evidence to suggest that in certain patients at higher risk for the development of pneumococcal infection, a disproportionately greater number of nonvaccine serotypes may be recovered during episodes of pneumococcal bacteremia [8,9,23]. In this retrospective study, pneumococcal blood isolates recovered over the past decade from a large university hospital were examined to determine whether these high-risk patients differed from the normal population in the number and type of pneumococcal serotypes encountered. In addition, host factors that affect the clinical course of pneumococcal bacteremia were analyzed. The results suggest that patients with significant impairment of host immune defenses are at greater risk for the development of pneumococcal
bacteremia with nonvaccine
serotypes.
PATIENTS AND METHODS The microbiology records of patients with pneumococcal bacteremia between January 1970 and December 1980 were reviewed. All isolates were identified and subsequently typed in the Microbiology Laboratory at New York Hospital using antiserum obtained from the State Serum Institute, Copenhagen, Denmark. All isolates were divided into those that were and were not included in the current 1Cpolyvalent pneumococcal vaccine. The present vaccine formulation includes types 1, 2, 3, 4, 6A, 7F, 8, 9N, 12F, 14, 18C, 19F, 23F, and 25. Although the typing serums provided by the Danish Serum Institute are type-specific for most pneumococcal serotypes, typing serums 6, 7,9, 12, 18, 19, and 23 are actually polyvalent group serums reacting with several capsular types. For example, the Danish group 7 antiserum reacts with four different but antigenically related serotypes-7F, 7A, 78, and 7C, or American types 51,7, 48, and
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50. No specific-factor serum samples were available in this study to identify specific pneumococcal types within these groups. Therefore, throughout this report, the Danish nomenclature was used, and antigenically related serotypes were placed together under the group serum types. Antigenic cross-reactivity within these serotype groups has been demonstrated [24]. A total of 295 episodes of pneumococcal bacteremia in 281 patients occurred during this time period, and all but four were serotyped. Hospital charts of 264 patients with 277 typed pneumococcal bacteremia isolates were available for detailed analysis. Of the typed isolates not included in this report, four were nonvaccine types and 10 were vaccine types. The hospital records of each patient with a serotyped pneumococcal blood isolate were reviewed to ascertain age, sex, date of admission, outcome, underlying disease, and pneumococcal vaccination status. Patients were then grouped according to their underlying disease. Group A consisted of all patients with underlying conditions generally accepted to be associated with significant impairment of host immunity. This group included persons with multiple myeloma (11 episodes), other malignancies being treated with chemotherapy or radiotherapy (40 episodes), end-stage renal disease while undergoing hemodialysis (13 episodes), sickle cell anemia (five episodes), nonmalignant conditions requiring splenectomy (four episodes), severe diabetes mellitus with acidosis (three episodes), nephrotic syndrome (one episode), significant alcohol abuse as manifested by hepatic dysfunction (seven episodes), postnecrotic cirrhosis (two episodes), and other diseases requiring long-term immunosuppressive therapy, such as systemic lupus erythematosus, asthma, and renal transplantation (20 episodes). Group B included those patients with underlying conditions not clearly associated with significant host immune impairment. The majority of patients in Group B had significant pulmonary disease as their primary illness, and they accounted for 28 episodes of pneumococcal bacteremia. The remaining patients in Group B had a variety of other conditions, including coronary artery disease, inactive solid tumors, mild renal insufficiency (creatinine less than 2.5 mg/IOO ml), burns, intermittent drug or alcohol abuse, mild diabetes mellitus (glucose less than 250 mg/lOO ml), scleroderma, rheumatoid arthritis, sickle trait, Parkinson’s disease, mental retardation, Kawasaki’s disease, hypothyroidism, nonspecific anemia, and pregnancy or recent delivery. Patients in Group C were considered to be normal hosts. Patients with more than one underlying condition were grouped according to the pre-
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Distribution of Serotypes of Streptococcus pneumoniae Isolated from 277 Episodes of Pneumococcal Bacteremla
TABLE II
Serotvasof Isolate
Children’
Vaccine Types 1 ,-.
; 4 6 (fi, 7 (c, 8 9 (e, 12 (E, 14 18 (E, 19 (l9J, 23 (23J 25 Subtotal
6B)z 7A, 78,7C) 9A. 9L, 9V) 12A) 18A, 188, 18F) 19A, 19B, 19C) 23A, 238)
Nonvaccine Types 10 13 15 16 17 20 24 Other& Subtotal Total
4
Adufts
Numberof fsolatesRecovered Grout At GroupB 0 0 7 8 14 8 3
12 0 22 17 15 12 19 20 6 20
4 5 6 10 5 0 77
4 0 7 10 2 2 13 9 3 12 4 8 7
GroupC
Total
8 0 8 6 3 4 4 8 0 14 4 9 5 0 73
12 0 22 24 19 14 20 24 7 31 14 27 17 232
11 7 13 9 0 59
173
1 0 0 1 0 1 0 2 5
6 2 5 6 4 3 2 12 40
12 29
2 14
0 0 2
7 2 5 7 4 4 2 14 45
64
213
106
96
75
277
14 8
82
Includes all patients less than 15 years old. 7 See text for description of groups. $ Polyvalent serum that includes several antigenically related serotypes within the group. The underlined type is present in the vaccine. § Includes two each of types 22.33.35, and 41 and one each of types 5, 11,29,34,38, and 46. l
dominant condition. These groupings were made without prior regard to the serotype of the pneumococcal isolates. Patients were subsequently stratified according to age, with the pediatric group considered as children under 15 years of age. All data were analyzed using the chi-square method. RESULTS Over the past 11 years, 295 episodes of pneumococcal bacteremia occurred in 281 patients at the New York Hospital. Complete microbiologic and clinical data were available for 277 of these episodes occurring in 264 patients (Table I). The average annual rate of bacteremia varied from 19 per year from 1970 to 1975 to 32 episodes per year from 1976 to 1980; 77 percent of the episodes occurred in adults and the remainder in children. Overall, 84 percent of pneumococcal isolates were serotypes included in the present 14-polysaccharide pneumococcal vaccine. This proportion remained relatively constant throughout the 1 l-year study period. However, the percentage of vaccine serotypes was higher in pediatric patients than in adults (92 versus 81 percent, p
accounted for about two thirds of the total (Table II). No isolates of vaccine serotype 2 were identified during the study period. Types 16, 10, 15, 17, and 20 were the most common nonvaccine isolates, representing 59 percent of all nonvaccine isolates and 10 percent of the total. Different serotype distributions occurred in the pediatric and adult age groups. Types 3, 9, 14, 8, and 4 were the most frequent isolates in adults, compared with types 19, 14, 23, 18, and 4 in children. Relation of Serotype Distribution to Underlying Disease. Table Ill shows the distribution of vaccine and
nonvaccine pneumococcal serotypes to various host factors. Of the 264 patients with available records, 73 percent had some underlying disease; 37 percent of the patients were in Group A, 35 percent in Group B, and 27 percent in Group C. The proportion of nonvaccine isolates recovered from Group A was significantly higher than that found in the other two groups. Among patients in Group A, 27 percent of the isolates were nonvaccine types, compared with 15 percent in Group B and only 3 percent in Group C (p
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DISTRIBUTION-WEISHOLTZ
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TABLE III
Relation of Seroiype Distribution to Underlying Disease in 277 Episodes of Pneumococcal Bacteremia Number of Isolates (Percent of Total) in Each Group Nonvaccine Serotypes ._~ Total Number Percent Children Adults Number
Vaccine Serotypes Grow’
Children+
Adults
Group A Group B Group c
15 17 27
62 65 46
Total
59
173
77 a2 73 232
Total .~
Percent
73 a5 97
3 0 2
26 14 a
29 14 2
27: 15: 3:
a4
5
40
45
16
See text for description of groups. t Includes all patients less than 15 years old. t Significant at p
groups separately, although the number of nonvaccine serotypes recovered from pediatric patients was too small to make analysis meaningful. Different individual serotypes predominated in Group A patients (Table II). Types 6, 19, 7, and 4 were the most common isolates in that group, compared with the other groups in which types 14,8,9, and 19 were most often identified. Several serotypes appeared to have a special predilection for immunocompromised patients. Types 11, 13, 15, and 33 were identified only among patients in Group A and more than half of the isolates of types 6, 7, and 10 were recovered from these high-risk patients. In general, the nonvaccine isolates were more commonly identified among patients with underlying diseases. Of the nonvaccine isolates, 64 percent were recovered from Group A, 31 percent from Group B, and only 5 percent from Group C. Among adult patients, no nonvaccine isolates were found in Group C. Vaccine serotypes, on the other hand, were evenly distributed among the three groups. Hematologic malignancy, occurring in 33 episodes of pneumococcal bacteremia, was the most common disease found in Group A. Among these patients, 33 percent of the isolates were nonvaccine types. Four episodes occurred in patients with Hodgkin’s disease, seven in patients with non-Hodgkin’s lymphoma, four in patients with chronic lymphocytic leukemia, 12 in patients with dysproteinemias, and six in patients with acute leukemia. All patients were receiving chemotherapy for active disease at the time of the occurrence of bacteremia and nine were neutropenic. Three patients with Hodgkin’s disease and one with nonHodgkin’s lymphoma also had undergone splenectomy. Pneumococcal bacteremia was not found in any patient with lymphoma or leukemia in remission and no longer receiving chemotherapy. Of the 18 patients with solid tumors, all had metastatic disease, and 11 were receiving chemotherapy or radiation at the time of the occurrence of bacteremia; 22 percent of their isolates were nonvaccine types. One fourth of the isolates recovered from patients who were undergoing long-term hemodialysis and almost half of the isolates from paatric
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tients who had undergone renal transplantation were nonvaccine serotypes. Among the nine patients with cirrhosis, 44 percent had bacteremias with nonvaccine types. No particular characteristics, such as splenectomy or neutropenia, could be found in any of these patients to distinguish those in whom pneumococcal bacteremia with nonvaccine serotypes developed. Patients with significant pulmonary disease accounted for 29 percent of the episodes of pneumococcal bacteremia among Group B adults. The proportion of nonvaccine serotypes recovered from these patients was 17 percent, a figure comparable with that found in the remainder of Group B. Effect of Age on Serotype Distribute. Vaccine serotypes were more common in the pediatric group (92 percent) than among adults (8 1 percent; p
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Outcome of 277 Episodes of Pneumococcal Bacteremia
TABLE IV
Category Age Group <2 years old 2- 14 years old
15-59
years old
Number (Percent) 01 Infection-Related Deaths 2 (6) 2(6’XjLl
p
20 (16) p <0;1
L6b years old Serotype of Isolate Vaccine type Nonvaccine type Underlying Disease+ Group A Group B Group C Total
43 (18) 9 (20)
p
52 (19)
Rows may not equal 100 percent due to noninfection-related t See text for description of groups. l
Total
29 (91) 30 (94)
32 (100)’ 32 (100)
90 (81)
111 (100)
72 (71)
102 (100)
190 (82) 34 (76)
232 (100) 45 (100)
79 (75) 74 (76) 88 (92)
106 (100) 96 (100) 75 (100)
221 (80)
277 (100)
I
28 (27) (
24 (23) .---I 22 (23) 6 (8) -
Number (Percent) 01 Survivors
deaths.
malignancy and/or splenectomy, as opposed to those with end-stage renal disease, nephrotic syndrome, or immunosuppressive treatment without malignancy, appeared to be at greater risk of dying from pneumococcal bacteremia. These patients in general had more intensive chemotherapy and probably more severe impairment of their host immune defenses. Patients in Group B with cardiac and/or pulmonary disease also had a high mortality rate (27 percent), probably reflecting their older age and decreased cardiopulmonary reserve. Certain serotypes accounted for the majority of infection-related deaths. In adults, vaccine types 4 and 6 were associated with the highest mortality rate (44 and 38 percent, respectively). Types 3, 4, 6,8, and 19 accounted for three fourths of the deaths caused by vaccine serotypes and almost half of all deaths. Nonvaccine types 10, 17, and 24 accounted for six of the nine deaths that occurred from nonvaccine type pneumococci, but only 12 percent of the overall infection-related deaths. COMMENTS Eighty-four percent of pneumococcal blood isolates recovered over an 1 l-year period at the New York Hospital were types included in the present 14-antigen pneumococcal vaccine. This distribution is comparable with that reported previously in several surveillance studies carried out in different geographic areas over the past 20 years [3,19-221. Whereas the overall percentage of vaccine types was similar in each of these studies, the frequency of specific serotypes varied from institution to institution. It is not clear what factors contribute to this variability, but it may be related
to the nature of the study population, geographic and local differences, variations in infecting serotypes over time, as well as sampling error. For example, no type 2 isolates were recovered, even though this type was a predominant cause of pneumococcal disease in earlier periods [20]. Other recent surveillance studies report a similar finding [ 19,251. It would appear from this study that both age and underlying disease influence pneumococcal serotype distribution and, in particular, the relative importance of vaccine versus nonvaccine types as the cause of bacteremic disease. Vaccine serotypes were more commonly identified in the pediatric age group than among adults. In addition, the specific serotypes recovered varied in their frequency between the two age groups. Types 3, 9, 14,8,4, and 6 predominated among adults, whereas types 19, 23, 14, 18, and 4 were the most common serotypes recovered from children less than 15 years old. These findings are consistent with those of other studies [ 191. Although differences between adults and children in serotype distribution exist, the elderly do not appear to differ from younger adults in the incidence of bacteremia due to vaccine serotypes when underlying disease is taken into account. And although similar findings have recently been reported [22], other findings suggest that among institutionalized elderly patients, there is a higher incidence of nonvaccine type pneumococcal infection [9]. These discrepancies may be explained by differences in patient population and the rate of pneumococcal vaccination, the lack of control for underlying disease, and the fact that primarily nonbacteremic isolates were examined in the latter study. Underlying disease also had an important effect on
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pneumococcal serotype distribution. Patients with compromised immune defenses (Group A) had a significantly lower proportion of vaccine serotypes (73 percent) than did the remainder of the study population (90 percent). This finding was more striking when compared with findings in those patients with no underlying disease (Group C), in which 97 percent of the bacteremic isolates were vaccine types. In fact, among adults, no nonvaccine serotypes were identified in Group C. In addition, entirely different individual serotypes predominated in Group A compared with the other groups. For several reasons, the results of this study were probably not influenced by the few doses of pneumococcal vaccine administered during the last three years of the study period when the vaccine was available (1978 to 1980). Only three patients, all from Group A, were known to have been vaccinated before their episode of pneumococcal bacteremia. Two of these patients had infection with vaccine types and one had a nonvaccine type bacteremia. In addition, the percentage of vaccine types isolated before November 1977 (82 percent), when the pneumococcal vaccine first became available, was comparable with that occurring since that time (83 percent). Lastly, the average yearly rate of pneumococcal bacteremia before the introduction of the vaccine was 23 episodes per year, compared with 36 episodes per year in subsequent years. It is conceivable that pneumococcal vaccination may prove to be a significant factor affecting serotype distribution, but this could not be tested in our study due to the smaller number of patients vaccinated. Several previous studies of pneumococcal infection in high-risk populations appear to support our finding that nonvaccine serotypes have a predilection to cause bacteremia in patients with significant underlying disease. A 36 percent proportion of nonvaccine serotypes was identified among 60 cancer patients with pneumococcal bacteremia collected from 1955 to 198 1 at Memorial Hospital in New York [23]. Similar results were reported in a recent Centers for Disease Control survey of pneumococcal blood isolates from unvaccinated, immunosuppressed patients [8], as well as in a study of institutionalized, chronically ill, elderly patients with pneumococcal pneumonia and bacteremia [9]. However, a control group of normal patients was not included in any of these studies. Types 6,19, and 7 were the most common serotypes isolated from patients in Group A in our study. In the Memorial Hospital study [ 231, types 6, 19, and 18 were the predominant serotypes in their group of patients with malignancy. Other small studies analyzing patients with sickle cell disease [26] and renal transplant recipients [27] found no specific type predilection for underlying disease.
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Several possible explanations for the higher proportion of nonvaccine type bacteremia in immunocompromised patients can be suggested. The pneumococcal polysaccharide antigens display various degrees of immunogenicity and evoke variable antibody responses when administered to both normal [3,28] and impaired hosts [ 10-161. Although it has not been specifically studied, the nonvaccine serotypes may be less immunogenic in immunocompromised hosts and may thus be more virulent in this high-risk group. Particularly in patients with asplenia or other diseases of the reticuloendothelial system, a brisk and substantial antibody response to infecting pneumococci appears to be essential to a competent host defense 171. It would appear that, in general, the nonvaccine serotypes are less invasive than the more commonly isolated vaccine types. It is reasonable to anticipate that immunocompromised patients would be more susceptible to these less virulent pneumococcal types. A second factor that might affect type-specific predominance in patients with various underlying diseases is variation in the requirements for opsonization of different serotypes 129,301. The manner in which specific pneumococcal types behave in complement- or antibodydeficient serum remains to be defined. It should be noted that since no specific “factor serum” samples were available during this study, it was not possible to separate those serotypes antigenically related to vaccine types but not actually in the vaccine (that is, 6B, 9V, 18F, 19A, and so forth). In a recent study [ 191, types 6B, 9V, and 19A were very common, representing 6.1, 4.7, and 3.3 percent, respectively, of all isolates recovered. If those “related types” had been included with the nonvaccine serotypes, our results may have been somewhat different. However, since the majority of type 6 and 19 isolates were recovered from patients in Group A, the adjusted proportion of nonvaccine type bacteremia in immunocompromised patients may actually be significantly higher. In conclusion, this report emphasizes the importance of underlying disease and age in the distribution of pneumococcal serotypes causing bacteremia. It has previously been shown ]6,25,31-331, and has been confirmed in this study, that these parameters also have a profound effect on the outcome of pneumococcal infection. The higher percentage of nonvaccine serotypes identified in immunocompromised patients may be one factor limiting expected vaccine efficacy in this high-risk group. However, poor antibody responses to immunizing antigens [ 10-161, as well as ineffectual clearance of infecting organisms [ 17,181, probably play a more important role in maintaining the persistently high morbidity and mortality rates from pneumococcal infection in these high-risk patients.
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Weinkelstein JA, Drachman RH: Deficiency of pneumococcal opsonizing activity in sickle cell disease. N Engl J Med 1968; 279: 459-466. Giebink GS, Foker JE, Kim Y, Schiffman G: Serum antibody and opsonic response to vaccination with pneumococcal capsular polysaccharide in normal and splenectomized children. J Infect Dis 1980; 141: 404-412. Broome CV, Facklam RR, Allen JR, Fraser DW, Austrian R: Epidemiology of pneumococcal serotypes in the United States, 1978-1979. J Infect Dis 1980; 141: 119-123. Finland M, Barnes MW: Changes in occurrence of capsular serotypes of Streptococcus pneumoniae at Boston City Hospital during selected years between 1935 and 1974. J Clin Microbial 1977; 5: 154-166. Jacobs NM, Lerdkachormusk S, Metzger WI: Pneumococcal bacteremia in infants and children: a ten year experience at Cook County Hospital with special reference to the pneumococcal serotypes isolated. Pediatrics 1979; 64: 298-300. Broome CV, Facklam RR: Epidemiology of clinically significant isolates of Streptococcus pneumoniae. Rev Infect Dis 1981; 3: 277-280. Folland D, Armstrong D, Seiden S. Blevins A: Pneumococcal bacteremia in patients with neoplastic disease. Cancer 1974; 33: 845-849. Schiffman G: Chemistry and immunochemistry of the pneumococcal polysaccharide vaccine with special reference to cross-reactions and immunologic factors. Rev Infect Dis 1981; 3(suppl): S18-S26. Mufson MA, Kruss DM, Wasil RE, Metzger WI: Capsular types and outcomes of bacteremic pneumococcal disease in the antibiotic era. Arch Intern Med 1974; 134: 505510. Seeler RA, Metzger W, Mufson MA: Diplococcus pneumoniae infection in children with sickle cell anemia. Am J Dis Child 1972; 123: 8-10. Linneman CC Jr, First MR: Risk of pneumococcal infections in renal transplant patients. JAMA 1979; 241: 26192621. Weibel RE, Vella PP, McLean AA, Woadhaus AE, Davidson WL, Hillman MR: Studies in human subjects of polyvalent pneumococcal vaccines (39894). Proc Sot Exp Biol Med 1977; 156: 144-150. Gudcian JC, Christenson GD, Fine DD: The role of opsonins in recovering from experimental pneumococcal pneumonia. J Infect Dis 1980; 142: 175-189. Fine DP: Pneumococcal type associated variability in alternate complement activation. Infect lmmunol 1975; 12: 772778. Schwartz JS: Pneumococcal vaccine: clinical efficacy and effectiveness. Ann Intern Med 1982: 96: 208-220. Austrian R, Gold J: Pneumococcal bacteremia with especial reference to bacteremic pneumonia. Ann Intern Med 1964; 60: 759-776. Landesman S, Schiffman G: Assessment of antibody response to pneumococcal vaccine in high risk populations. Rev Infect Dis 1981;3(suppl): Sl84-196.
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STEVEN BARRY RICHARD
J. WEISHOLTZ, J. HARTMAN, B. ROBERTS,
M.D. MD. M.D.
New York, New York
From the Division of Infectious Diseases, Department of Medicine, New York Hospital-Cornell Medical Center, New York, New York. This work was presented in part at the 22nd Annual International Conference on Antimicrobial Agents and Chemotherapy, Miami Beach, Florida, October 4-6, 1982. Dr. Hartman is a recipient of a Teacher-Scientist Award from the Andrew W. Mellon Foundation, New York, New York, Requests for reprints should be addressed to Dr. Steven J. Weisholtz, Division of Infectious Diseases, Department of Madlcine, New York Hospttal-Ccmell Medical Center, 525 East 68th Street, New York, New York 16921. Manuscript accepted October 14, 1982.
The hospital records of 264 patients with 277 episodes of pneumococcal bacteremia occurring at New York Hospital-Cornell Medical Center over the period 1970 to 1960 were examined to determine whether serotype distribution varied with the underlying disease or age of the patient. The patients were placed into three groups according to their underlying disease. Group A consisted of ail patients with significant impairment of their immune system. Group B included those patients with underlying conditions that were not associated with immune deficiency. Group C comprised those patients considered to be normal hosts. Overall, 64 percent of blood isolates were serotypes included in the vaccine. In Group A, only 73 percent of these isolates were vaccine types, compared with 65 percent in Group B and 97 percent in Group C (differences significant at p
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TABLE I
SEROTYPE DISTRIBUTION-WEISHOLTZ
ET AL
Serotype Distribution of 277 Episodes of Pneumococcal Bacteremia Occurring in 264 Patients Number and Percent of Bacteremic Episodes 1976-1960 Adults ---ChildrenAdults Number Number Percent Number Percent Percent
1970-1975 Children* Number Percent
Total Number
Percent
Vaccine types+ Nonvaccine types
20 2
91 9
74 19
80 20
39 3
93 7
99 21
83 17
232 45
84 16
Total
22
100
93
100
42
100
120
100
277
100
Includes all patients less than 15 years old. + Includes types 1, 2, 3, 4, 6, 7, 8, 9, 12, 14, 18, 19, 23, l
and 25.
to the immunizing pneumococcal antigen [IO-161, poor opsoniting ability despite adequate antibody titers [ 17,181, or infection with a pneumococcal type that is not included in the vaccine. Surveillance studies have indicated that 68 to 90 percent of pneumococcal blood isolates are included in the present vaccine formulation [3,19-221. However, to date, no patient population has been systematically studied to determine whether the incidence of pneumococcal bacteremia due to vaccine serotypes varies with underlying disease or age of the patient. There is some evidence to suggest that in certain patients at higher risk for the development of pneumococcal infection, a disproportionately greater number of nonvaccine serotypes may be recovered during episodes of pneumococcal bacteremia [8,9,23]. In this retrospective study, pneumococcal blood isolates recovered over the past decade from a large university hospital were examined to determine whether these high-risk patients differed from the normal population in the number and type of pneumococcal serotypes encountered. In addition, host factors that affect the clinical course of pneumococcal bacteremia were analyzed. The results suggest that patients with significant impairment of host immune defenses are at greater risk for the development of pneumococcal
bacteremia with nonvaccine
serotypes.
PATIENTS AND METHODS The microbiology records of patients with pneumococcal bacteremia between January 1970 and December 1980 were reviewed. All isolates were identified and subsequently typed in the Microbiology Laboratory at New York Hospital using antiserum obtained from the State Serum Institute, Copenhagen, Denmark. All isolates were divided into those that were and were not included in the current 1Cpolyvalent pneumococcal vaccine. The present vaccine formulation includes types 1, 2, 3, 4, 6A, 7F, 8, 9N, 12F, 14, 18C, 19F, 23F, and 25. Although the typing serums provided by the Danish Serum Institute are type-specific for most pneumococcal serotypes, typing serums 6, 7,9, 12, 18, 19, and 23 are actually polyvalent group serums reacting with several capsular types. For example, the Danish group 7 antiserum reacts with four different but antigenically related serotypes-7F, 7A, 78, and 7C, or American types 51,7, 48, and
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50. No specific-factor serum samples were available in this study to identify specific pneumococcal types within these groups. Therefore, throughout this report, the Danish nomenclature was used, and antigenically related serotypes were placed together under the group serum types. Antigenic cross-reactivity within these serotype groups has been demonstrated [24]. A total of 295 episodes of pneumococcal bacteremia in 281 patients occurred during this time period, and all but four were serotyped. Hospital charts of 264 patients with 277 typed pneumococcal bacteremia isolates were available for detailed analysis. Of the typed isolates not included in this report, four were nonvaccine types and 10 were vaccine types. The hospital records of each patient with a serotyped pneumococcal blood isolate were reviewed to ascertain age, sex, date of admission, outcome, underlying disease, and pneumococcal vaccination status. Patients were then grouped according to their underlying disease. Group A consisted of all patients with underlying conditions generally accepted to be associated with significant impairment of host immunity. This group included persons with multiple myeloma (11 episodes), other malignancies being treated with chemotherapy or radiotherapy (40 episodes), end-stage renal disease while undergoing hemodialysis (13 episodes), sickle cell anemia (five episodes), nonmalignant conditions requiring splenectomy (four episodes), severe diabetes mellitus with acidosis (three episodes), nephrotic syndrome (one episode), significant alcohol abuse as manifested by hepatic dysfunction (seven episodes), postnecrotic cirrhosis (two episodes), and other diseases requiring long-term immunosuppressive therapy, such as systemic lupus erythematosus, asthma, and renal transplantation (20 episodes). Group B included those patients with underlying conditions not clearly associated with significant host immune impairment. The majority of patients in Group B had significant pulmonary disease as their primary illness, and they accounted for 28 episodes of pneumococcal bacteremia. The remaining patients in Group B had a variety of other conditions, including coronary artery disease, inactive solid tumors, mild renal insufficiency (creatinine less than 2.5 mg/IOO ml), burns, intermittent drug or alcohol abuse, mild diabetes mellitus (glucose less than 250 mg/lOO ml), scleroderma, rheumatoid arthritis, sickle trait, Parkinson’s disease, mental retardation, Kawasaki’s disease, hypothyroidism, nonspecific anemia, and pregnancy or recent delivery. Patients in Group C were considered to be normal hosts. Patients with more than one underlying condition were grouped according to the pre-
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Distribution of Serotypes of Streptococcus pneumoniae Isolated from 277 Episodes of Pneumococcal Bacteremla
TABLE II
Serotvasof Isolate
Children’
Vaccine Types 1 ,-.
; 4 6 (fi, 7 (c, 8 9 (e, 12 (E, 14 18 (E, 19 (l9J, 23 (23J 25 Subtotal
6B)z 7A, 78,7C) 9A. 9L, 9V) 12A) 18A, 188, 18F) 19A, 19B, 19C) 23A, 238)
Nonvaccine Types 10 13 15 16 17 20 24 Other& Subtotal Total
4
Adufts
Numberof fsolatesRecovered Grout At GroupB 0 0 7 8 14 8 3
12 0 22 17 15 12 19 20 6 20
4 5 6 10 5 0 77
4 0 7 10 2 2 13 9 3 12 4 8 7
GroupC
Total
8 0 8 6 3 4 4 8 0 14 4 9 5 0 73
12 0 22 24 19 14 20 24 7 31 14 27 17 232
11 7 13 9 0 59
173
1 0 0 1 0 1 0 2 5
6 2 5 6 4 3 2 12 40
12 29
2 14
0 0 2
7 2 5 7 4 4 2 14 45
64
213
106
96
75
277
14 8
82
Includes all patients less than 15 years old. 7 See text for description of groups. $ Polyvalent serum that includes several antigenically related serotypes within the group. The underlined type is present in the vaccine. § Includes two each of types 22.33.35, and 41 and one each of types 5, 11,29,34,38, and 46. l
dominant condition. These groupings were made without prior regard to the serotype of the pneumococcal isolates. Patients were subsequently stratified according to age, with the pediatric group considered as children under 15 years of age. All data were analyzed using the chi-square method. RESULTS Over the past 11 years, 295 episodes of pneumococcal bacteremia occurred in 281 patients at the New York Hospital. Complete microbiologic and clinical data were available for 277 of these episodes occurring in 264 patients (Table I). The average annual rate of bacteremia varied from 19 per year from 1970 to 1975 to 32 episodes per year from 1976 to 1980; 77 percent of the episodes occurred in adults and the remainder in children. Overall, 84 percent of pneumococcal isolates were serotypes included in the present 14-polysaccharide pneumococcal vaccine. This proportion remained relatively constant throughout the 1 l-year study period. However, the percentage of vaccine serotypes was higher in pediatric patients than in adults (92 versus 81 percent, p
accounted for about two thirds of the total (Table II). No isolates of vaccine serotype 2 were identified during the study period. Types 16, 10, 15, 17, and 20 were the most common nonvaccine isolates, representing 59 percent of all nonvaccine isolates and 10 percent of the total. Different serotype distributions occurred in the pediatric and adult age groups. Types 3, 9, 14, 8, and 4 were the most frequent isolates in adults, compared with types 19, 14, 23, 18, and 4 in children. Relation of Serotype Distribution to Underlying Disease. Table Ill shows the distribution of vaccine and
nonvaccine pneumococcal serotypes to various host factors. Of the 264 patients with available records, 73 percent had some underlying disease; 37 percent of the patients were in Group A, 35 percent in Group B, and 27 percent in Group C. The proportion of nonvaccine isolates recovered from Group A was significantly higher than that found in the other two groups. Among patients in Group A, 27 percent of the isolates were nonvaccine types, compared with 15 percent in Group B and only 3 percent in Group C (p
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TABLE III
Relation of Seroiype Distribution to Underlying Disease in 277 Episodes of Pneumococcal Bacteremia Number of Isolates (Percent of Total) in Each Group Nonvaccine Serotypes ._~ Total Number Percent Children Adults Number
Vaccine Serotypes Grow’
Children+
Adults
Group A Group B Group c
15 17 27
62 65 46
Total
59
173
77 a2 73 232
Total .~
Percent
73 a5 97
3 0 2
26 14 a
29 14 2
27: 15: 3:
a4
5
40
45
16
See text for description of groups. t Includes all patients less than 15 years old. t Significant at p
groups separately, although the number of nonvaccine serotypes recovered from pediatric patients was too small to make analysis meaningful. Different individual serotypes predominated in Group A patients (Table II). Types 6, 19, 7, and 4 were the most common isolates in that group, compared with the other groups in which types 14,8,9, and 19 were most often identified. Several serotypes appeared to have a special predilection for immunocompromised patients. Types 11, 13, 15, and 33 were identified only among patients in Group A and more than half of the isolates of types 6, 7, and 10 were recovered from these high-risk patients. In general, the nonvaccine isolates were more commonly identified among patients with underlying diseases. Of the nonvaccine isolates, 64 percent were recovered from Group A, 31 percent from Group B, and only 5 percent from Group C. Among adult patients, no nonvaccine isolates were found in Group C. Vaccine serotypes, on the other hand, were evenly distributed among the three groups. Hematologic malignancy, occurring in 33 episodes of pneumococcal bacteremia, was the most common disease found in Group A. Among these patients, 33 percent of the isolates were nonvaccine types. Four episodes occurred in patients with Hodgkin’s disease, seven in patients with non-Hodgkin’s lymphoma, four in patients with chronic lymphocytic leukemia, 12 in patients with dysproteinemias, and six in patients with acute leukemia. All patients were receiving chemotherapy for active disease at the time of the occurrence of bacteremia and nine were neutropenic. Three patients with Hodgkin’s disease and one with nonHodgkin’s lymphoma also had undergone splenectomy. Pneumococcal bacteremia was not found in any patient with lymphoma or leukemia in remission and no longer receiving chemotherapy. Of the 18 patients with solid tumors, all had metastatic disease, and 11 were receiving chemotherapy or radiation at the time of the occurrence of bacteremia; 22 percent of their isolates were nonvaccine types. One fourth of the isolates recovered from patients who were undergoing long-term hemodialysis and almost half of the isolates from paatric
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tients who had undergone renal transplantation were nonvaccine serotypes. Among the nine patients with cirrhosis, 44 percent had bacteremias with nonvaccine types. No particular characteristics, such as splenectomy or neutropenia, could be found in any of these patients to distinguish those in whom pneumococcal bacteremia with nonvaccine serotypes developed. Patients with significant pulmonary disease accounted for 29 percent of the episodes of pneumococcal bacteremia among Group B adults. The proportion of nonvaccine serotypes recovered from these patients was 17 percent, a figure comparable with that found in the remainder of Group B. Effect of Age on Serotype Distribute. Vaccine serotypes were more common in the pediatric group (92 percent) than among adults (8 1 percent; p
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Outcome of 277 Episodes of Pneumococcal Bacteremia
TABLE IV
Category Age Group <2 years old 2- 14 years old
15-59
years old
Number (Percent) 01 Infection-Related Deaths 2 (6) 2(6’XjLl
p
20 (16) p <0;1
L6b years old Serotype of Isolate Vaccine type Nonvaccine type Underlying Disease+ Group A Group B Group C Total
43 (18) 9 (20)
p
52 (19)
Rows may not equal 100 percent due to noninfection-related t See text for description of groups. l
Total
29 (91) 30 (94)
32 (100)’ 32 (100)
90 (81)
111 (100)
72 (71)
102 (100)
190 (82) 34 (76)
232 (100) 45 (100)
79 (75) 74 (76) 88 (92)
106 (100) 96 (100) 75 (100)
221 (80)
277 (100)
I
28 (27) (
24 (23) .---I 22 (23) 6 (8) -
Number (Percent) 01 Survivors
deaths.
malignancy and/or splenectomy, as opposed to those with end-stage renal disease, nephrotic syndrome, or immunosuppressive treatment without malignancy, appeared to be at greater risk of dying from pneumococcal bacteremia. These patients in general had more intensive chemotherapy and probably more severe impairment of their host immune defenses. Patients in Group B with cardiac and/or pulmonary disease also had a high mortality rate (27 percent), probably reflecting their older age and decreased cardiopulmonary reserve. Certain serotypes accounted for the majority of infection-related deaths. In adults, vaccine types 4 and 6 were associated with the highest mortality rate (44 and 38 percent, respectively). Types 3, 4, 6,8, and 19 accounted for three fourths of the deaths caused by vaccine serotypes and almost half of all deaths. Nonvaccine types 10, 17, and 24 accounted for six of the nine deaths that occurred from nonvaccine type pneumococci, but only 12 percent of the overall infection-related deaths. COMMENTS Eighty-four percent of pneumococcal blood isolates recovered over an 1 l-year period at the New York Hospital were types included in the present 14-antigen pneumococcal vaccine. This distribution is comparable with that reported previously in several surveillance studies carried out in different geographic areas over the past 20 years [3,19-221. Whereas the overall percentage of vaccine types was similar in each of these studies, the frequency of specific serotypes varied from institution to institution. It is not clear what factors contribute to this variability, but it may be related
to the nature of the study population, geographic and local differences, variations in infecting serotypes over time, as well as sampling error. For example, no type 2 isolates were recovered, even though this type was a predominant cause of pneumococcal disease in earlier periods [20]. Other recent surveillance studies report a similar finding [ 19,251. It would appear from this study that both age and underlying disease influence pneumococcal serotype distribution and, in particular, the relative importance of vaccine versus nonvaccine types as the cause of bacteremic disease. Vaccine serotypes were more commonly identified in the pediatric age group than among adults. In addition, the specific serotypes recovered varied in their frequency between the two age groups. Types 3, 9, 14,8,4, and 6 predominated among adults, whereas types 19, 23, 14, 18, and 4 were the most common serotypes recovered from children less than 15 years old. These findings are consistent with those of other studies [ 191. Although differences between adults and children in serotype distribution exist, the elderly do not appear to differ from younger adults in the incidence of bacteremia due to vaccine serotypes when underlying disease is taken into account. And although similar findings have recently been reported [22], other findings suggest that among institutionalized elderly patients, there is a higher incidence of nonvaccine type pneumococcal infection [9]. These discrepancies may be explained by differences in patient population and the rate of pneumococcal vaccination, the lack of control for underlying disease, and the fact that primarily nonbacteremic isolates were examined in the latter study. Underlying disease also had an important effect on
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pneumococcal serotype distribution. Patients with compromised immune defenses (Group A) had a significantly lower proportion of vaccine serotypes (73 percent) than did the remainder of the study population (90 percent). This finding was more striking when compared with findings in those patients with no underlying disease (Group C), in which 97 percent of the bacteremic isolates were vaccine types. In fact, among adults, no nonvaccine serotypes were identified in Group C. In addition, entirely different individual serotypes predominated in Group A compared with the other groups. For several reasons, the results of this study were probably not influenced by the few doses of pneumococcal vaccine administered during the last three years of the study period when the vaccine was available (1978 to 1980). Only three patients, all from Group A, were known to have been vaccinated before their episode of pneumococcal bacteremia. Two of these patients had infection with vaccine types and one had a nonvaccine type bacteremia. In addition, the percentage of vaccine types isolated before November 1977 (82 percent), when the pneumococcal vaccine first became available, was comparable with that occurring since that time (83 percent). Lastly, the average yearly rate of pneumococcal bacteremia before the introduction of the vaccine was 23 episodes per year, compared with 36 episodes per year in subsequent years. It is conceivable that pneumococcal vaccination may prove to be a significant factor affecting serotype distribution, but this could not be tested in our study due to the smaller number of patients vaccinated. Several previous studies of pneumococcal infection in high-risk populations appear to support our finding that nonvaccine serotypes have a predilection to cause bacteremia in patients with significant underlying disease. A 36 percent proportion of nonvaccine serotypes was identified among 60 cancer patients with pneumococcal bacteremia collected from 1955 to 198 1 at Memorial Hospital in New York [23]. Similar results were reported in a recent Centers for Disease Control survey of pneumococcal blood isolates from unvaccinated, immunosuppressed patients [8], as well as in a study of institutionalized, chronically ill, elderly patients with pneumococcal pneumonia and bacteremia [9]. However, a control group of normal patients was not included in any of these studies. Types 6,19, and 7 were the most common serotypes isolated from patients in Group A in our study. In the Memorial Hospital study [ 231, types 6, 19, and 18 were the predominant serotypes in their group of patients with malignancy. Other small studies analyzing patients with sickle cell disease [26] and renal transplant recipients [27] found no specific type predilection for underlying disease.
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Several possible explanations for the higher proportion of nonvaccine type bacteremia in immunocompromised patients can be suggested. The pneumococcal polysaccharide antigens display various degrees of immunogenicity and evoke variable antibody responses when administered to both normal [3,28] and impaired hosts [ 10-161. Although it has not been specifically studied, the nonvaccine serotypes may be less immunogenic in immunocompromised hosts and may thus be more virulent in this high-risk group. Particularly in patients with asplenia or other diseases of the reticuloendothelial system, a brisk and substantial antibody response to infecting pneumococci appears to be essential to a competent host defense 171. It would appear that, in general, the nonvaccine serotypes are less invasive than the more commonly isolated vaccine types. It is reasonable to anticipate that immunocompromised patients would be more susceptible to these less virulent pneumococcal types. A second factor that might affect type-specific predominance in patients with various underlying diseases is variation in the requirements for opsonization of different serotypes 129,301. The manner in which specific pneumococcal types behave in complement- or antibodydeficient serum remains to be defined. It should be noted that since no specific “factor serum” samples were available during this study, it was not possible to separate those serotypes antigenically related to vaccine types but not actually in the vaccine (that is, 6B, 9V, 18F, 19A, and so forth). In a recent study [ 191, types 6B, 9V, and 19A were very common, representing 6.1, 4.7, and 3.3 percent, respectively, of all isolates recovered. If those “related types” had been included with the nonvaccine serotypes, our results may have been somewhat different. However, since the majority of type 6 and 19 isolates were recovered from patients in Group A, the adjusted proportion of nonvaccine type bacteremia in immunocompromised patients may actually be significantly higher. In conclusion, this report emphasizes the importance of underlying disease and age in the distribution of pneumococcal serotypes causing bacteremia. It has previously been shown ]6,25,31-331, and has been confirmed in this study, that these parameters also have a profound effect on the outcome of pneumococcal infection. The higher percentage of nonvaccine serotypes identified in immunocompromised patients may be one factor limiting expected vaccine efficacy in this high-risk group. However, poor antibody responses to immunizing antigens [ 10-161, as well as ineffectual clearance of infecting organisms [ 17,181, probably play a more important role in maintaining the persistently high morbidity and mortality rates from pneumococcal infection in these high-risk patients.
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