PEDIATRICS Vol. 122 No. 1 July 2008, pp. e26-e32 (doi:10.1542/10.1542/peds.2007-1510)
ARTICLE |
Risks of Invasive Pneumococcal Disease in Children With Underlying Chronic Diseases
a Departments of Epidemiology Research
b Bacteriology, Mycology, and Parasitology, Statens Serum Institut, Copenhagen, Denmark
c Viral Epidemiology Branch, Division of Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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OBJECTIVE. The risk of invasive pneumococcal disease is increased among children with some chronic diseases. The objective of this study was to quantify the risk of invasive pneumococcal disease in a wide range of chronic diseases.
PATIENTS AND METHODS. Cases of invasive pneumococcal disease among children (aged 0–17 years) were identified from 1977 through 2005 by using a national surveillance program in Denmark. Rate ratios were assessed in a case-control study by using 10 age- and gender-matched controls per case. Chronic diseases were defined a priori.
RESULTS. Among 1655 children with invasive pneumococcal disease, 19% had a history of chronic disease, according to our definition, versus 5% of controls. An increased risk of invasive pneumococcal disease was observed for children followed >30 days after initial hospital contact for a chronic disease, but it was also increased in children with 
5 hospital contacts for any other reason. Children with a history of cancer, chronic renal disease, splenectomy, and transplantation were particularly susceptible to invasive pneumococcal disease. Adjusted for number of hospital contacts, the risk for children with other types of chronic disease was 1.4-fold more than for those with hospital contacts for any reason.
CONCLUSIONS. Cancer, chronic renal diseases, splenectomy, and transplantation were strongly associated with an increased risk of invasive pneumococcal disease in children. For children with other chronic diseases, their excess risk seemed to be attributable mostly to frail children having repeated hospital contact rather than their underlying condition.
Key Words: pneumococcal infections • epidemiology • comorbidity • invasive procedures • disease susceptibility • case-control studies
Abbreviations: IPD—invasive pneumococcal disease • RR—rate ratio • CNS—central nervous system • ICD—International Classification of Diseases • CI—confidence interval • aRR—adjusted rate ratio
Invasive pneumococcal disease (IPD) occurs in children with chronic diseases at rates that greatly exceed those of the general population. Between 11% and 44% of children with IPD have been reported to have an underlying chronic disease.1–5 Furthermore, the fatality rate for children with IPD has been found to be 4 times higher if they also have an underlying chronic disease.6 Children with chronic diseases also have a high frequency of recurrent IPD.7,8 Specific chronic conditions reported to be associated with an increased IPD risk include anatomic or functional asplenia,9,10 congenital and acquired immunodeficiency,11–13 anatomic abnormalities,3 asthma,14 and nephrotic syndrome.15 Children who undergo invasive surgeries such as cochlear implants16,17 and bone marrow or solid organ transplantation18,19 are also at increased risk of IPD. These associations are based largely on IPD case series or epidemiologic studies that were limited by a modest number of patients.
In a large population-based case-control study nested in the Danish population, we evaluated the association between IPD and selected chronic disease conditions and invasive surgery among children by using unique nationwide disease registers and comparing IPD cases with age- and gender-matched subjects in the general population. We also examined how the association was modified by the number of hospital (inpatient and outpatient) contacts before IPD, time since first hospital contact for chronic disease or invasive surgery, and age at IPD.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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Data were obtained by linking 4 Danish national data sources (the Danish Streptococcus Database,20 the Danish Civil Registration System,21 the Danish Medical Birth Registry,22 and the National Register of Patients23) by means of the unique personal identification number that is assigned to all residents in Denmark. A matched case-control design was nested in the Danish population, of which 1210566 were below 18 years of age on January 1, 2006. The study was approved by the Danish Data Surveillance Authority (No. 2004-41-4345).
Definition and Ascertainment of Cases and Controls
IPD was defined as the isolation of Streptococcus pneumoniae from a normally sterile site. Cases were selected from the Danish Streptococcus Database, a database established as part of a national surveillance program of IPD among patients hospitalized in Denmark since 1938.20 To ensure complete registry information of hospital contacts, available only since January 1, 1977, we included only subjects who were born in Denmark on or after January 1, 1977, diagnosed between January 1, 1977, and May 1, 2005 (the end of follow-up), and living in Denmark at the time of diagnosis. Multiple births were excluded because of small sample size. The index date (date of IPD diagnosis) was based on the date that the sample was obtained.
Since 1968, the Danish Civil Registration System has kept daily updated demographic information on all residents in Denmark.21 From this registry we sampled 10 random population controls per case (n = 15373), each matched on gender and exact date of birth. Controls were selected by risk-set sampling from subjects at risk in the Danish population at the time that disease occurred in the index case, allowing rate ratios (RRs) to be reported.24 As with cases, controls had to be singleton births born in Denmark and be at risk of IPD (ie, be alive without a previous diagnosis of IPD and living in Denmark) at the index date of the corresponding case. These inclusion criteria were not included in the initial risk-set sampling, which is why there were 7% fewer controls than 10 per case in the final study population. Cases were eligible to be controls as long as they were at risk (ie, until the first date of IPD diagnosis). Controls were assigned an index date equal to the date of diagnosis of the corresponding case and required to be IPD-free up to that point. For purposes of adjustment, we obtained the number of siblings at the index date from the Danish Civil Registration System and birth weight from the Danish Medical Birth Registry, complete since 1973.
Chronic Disease
Information about chronic disease was extracted from the National Register of Patients, which contains information on admissions, treatments, and discharge diagnoses of all patients treated in Danish hospitals since 1977.23 Outpatient and emergency department hospital contacts have also been recorded in this registry since 1995. Children without a chronic disease recorded in this system were assumed to have no chronic disease. We selected chronic diseases that either had previously been shown to be associated with IPD or might plausibly be associated with infection with or impaired immunologic responses to S pneumoniae (eg, genetic conditions, anatomic abnormalities, problems with immunity). We included cancer (hematologic and nonhematologic cancer), renal disease (congenital renal malformation; chronic renal disease including chronic glomerulonephritis, nephrosis, and chronic renal insufficiency), neurologic disease (congenital malformation of the central nervous system [CNS]; epilepsy; cerebral palsy; hydrocephalus), heart disease (congenital heart disease; chronic heart disease including valve disease, cardiomyopathy, conduction disturbances, cardiac failure), genetic disease (chromosomal abnormality; inborn error of metabolism), immunologic/metabolic disease (hemolytic anemia including thalassemia and sickle cell disease; autoimmune disease including inflammatory polyarthritis and systemic autoimmune disease; congenital immunodeficiency; diabetes), lung disease (chronic airway disease including chronic obstructive lung disease, emphysema, and cystic fibrosis; asthma; congenital respiratory malformation system), and gastrointestinal disease (congenital gut malformation; esophageal disease including reflux and stenosis). Together, these conditions are described as "chronic disease" in this report. In addition, because surgery might be associated with exposure, we examined surgical procedures including neurologic, heart, thoracic, and abdominal surgery. Procedures that involved splenectomy and transplantation (solid organ or bone marrow) were analyzed separately. Together, these conditions are described as "invasive surgery." The specific International Classification of Diseases (ICD) codes are provided in Appendix I. The date of the first hospital contact for a condition within these selected diagnosis codes was considered the date of first hospital contact leading to a diagnosis of chronic disease or date of invasive surgery. Thus, children with >1 condition contributed with risk time for each chronic disease or invasive surgery. To evaluate the effect of hospital contact, analyses that adjusted for the total number of hospital contacts were performed. The total number of hospital contacts was defined as the sum of every hospital contact (excluding contact relating to a normal birth) registered at a Danish hospital >2 days before the index date, including admissions and outpatient and emergency department visits. Hospital contacts had to be separated by 1 day to count as a new contact.
Statistical Analysis
The associations between chronic diseases, invasive surgeries, and risk of IPD were expressed as RRs estimated in a conditional logistic regression by using SAS (SAS Institute, Inc, Cary, NC) procedure PHREG.24 Chronic disease and invasive surgery were adjusted for each other. Because of the importance of a recent hospital contact, RRs were adjusted for hospital contacts for any reason within the last 3 to 30 days (categories: yes or no). When IPD-positive samples were collected within 2 days of hospital contact, the infection was considered to have been community acquired, whereas when positive samples were collected 3 to 30 days after hospital contact, the infection was considered likely to have resulted from nosocomial infections.25 In addition, RRs were adjusted for birth weight (<1500, 1500–2499, or 2500 g) and number of siblings (0, 1, 2, or 3), both of which have been associated with risk of IPD.26 Additional analyses adjusting for the total number of hospital contacts were made by comparing children with a history of chronic disease to children without a chronic-disease diagnosis who had hospital contact for any reason. For epidemiologic purity, the main analyses required that chronic-disease diagnoses preceded IPD. However, a large number of IPD cases had a chronic disease first noted on the same admission. Given that these chronic conditions most likely preceded the IPD diagnoses, we reanalyzed the RRs by including chronic disease identified at the same hospital contact as the IPD diagnosis. All tests for differences between cases and controls and tests for effect modification were performed as likelihood ratio tests in a conditional logistic regression model.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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There were 1655 cases (59% male) of first-event IPD in the study period. The median age was 1.3 years (interquartile interval: 0.8–3.6 years). Bacteremia was the most common clinical presentation (72%) followed by meningitis (27%) and infection at other sterile sites (1%). Among all IPD case subjects, 19% had a hospital contact for a chronic-disease condition before IPD compared with 5% of the control subjects. Thirty-four children (2.1%) had recurrent IPD disease (>30 days between IPD events), and 22 (65%) of these children had a hospital contact for a chronic condition before their first IPD event. To simplify statistical analyses, only first IPD events were included in the results reviewed here.
For children with hospital contact, time since the first contact for chronic disease or invasive surgery modified the risk of IPD (Fig 1). However, the high risk of IPD after hospital contact stabilized after 30 days, as shown, indicating that hospital contact itself did not affect risk thereafter. Because we focused on the biological relationship between chronic diseases and IPD, hereafter we compare IPD rates in children with and without chronic diseases >30 days after hospital contact, assuming that diagnoses of IPD made within 0 to 2 days of hospital contact represent community-acquired S pneumoniae infections. Thus, IPD rates in children with the first hospital contact for chronic disease (n = 33) or invasive surgery (n = 19) 3 to 30 days before IPD are not presented here.
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Chronic Disease, Invasive Surgery, and Risk of IPD
Unadjusted RRs of IPD in children with a hospital contact for a chronic disease >30 days before IPD were high compared with children without chronic diseases. A history of hospital contact was associated with RRs of >10 for hematologic cancer (RR: 127.5), nonhematologic cancer (RR: 20.1), chronic renal disease (RR: 25.4), congenital immunodeficiency (RR: 14.7), chromosomal abnormality (RR: 10.3), and chronic heart disease (RR: 10.2). Correspondingly, unadjusted RRs of IPD in children who underwent any of the studied invasive surgeries (except abdominal) were also high (RR: >10) compared with children who did not have invasive surgery.
The RRs of IPD in children with a hospital contact for a chronic disease >30 days before IPD were considerably lower when adjustments were made for invasive surgery, recent hospital contact, birth weight, and the number of siblings (Table 1). Children with a history of chronic disease were at a 2.4-fold increased risk of IPD (95% confidence interval [CI]: 2.0–2.9) compared with those without chronic disease. Children with a history of cancer (adjusted RR [aRR]: 19.0 [95% CI: 8.7–41.5]) or chronic renal disease (aRR: 18.9 [95% CI: 2.8–127.1]) were at high risk of IPD compared with children without such a disease. Children diagnosed with 2 chronic diseases (n = 208) were at increased risk of IPD (aRR: 2.1 [95% CI: 1.5–3.1]) compared with those with only 1 chronic disease (n = 867).
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Children with a history of invasive surgery were at increased risk of IPD compared with children who had not had invasive surgery (aRR: 2.4 [95% CI: 1.9–3.1]) (Table 2). Children who underwent splenectomy (aRR: 14.4 [95% CI: 1.3–154.2]) or transplantation (aRR: 14.3 [95% CI: 3.0–68.5]) were particularly susceptible.
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Analyses that included chronic diseases first noted during the same hospital contact as the IPD diagnosis did not change the pattern of the results, although the risks increased. The aRR of IPD in children with a history of chronic disease compared with those without chronic disease was 3.3 (95% CI: 2.8–3.9). Compared with children without such diseases, the aRRs in the main chronic-disease groups were 41.7 (95% CI: 19.3–90.0) for cancer, 5.1 (95% CI: 1.9–13.2) for renal disease, 3.0 (95% CI: 2.1–4.3) for neurologic disease, 2.7 (95% CI: 1.9–3.9) for heart disease, 2.7 (95% CI: 1.4–5.3) for genetic disease, 2.2 (95% CI: 1.0–4.8) for immunologic/metabolic disease, 1.8 (95% CI: 1.3–2.4) for lung disease, and 1.8 (95% CI: 1.1–2.8) for gastrointestinal disease.
For children aged 0 to 2 years, the aRR of IPD in children with chronic disease compared with children without chronic disease was 2.3 (95% CI: 1.8–3.0), whereas for children aged >2 years it was 2.6 (95% CI: 2.0–3.4) (P = .48). Similar results were observed for invasive surgery.
Since 1995 data from outpatient and emergency department hospital contacts were also available in addition to all hospital admissions. Analyses that only included children with IPD from 1977 to 1994 resulted in an aRR of IPD in those with chronic disease of 3.3 (95% CI: 2.4–4.5), whereas the aRR in children with invasive surgery was 1.7 (95% CI: 1.1–2.5).
History of Chronic Disease, Number of Hospital Contacts, and Risk of IPD
The effect of the number of hospital contacts was examined for children with and without a history of chronic disease. IPD rates for children without hospital contact before IPD were used as the comparison group. Because the risks in children with cancer, chronic renal disease, splenectomy, or transplantation were exceptionally high, they were analyzed separately from children with other chronic diseases. Figure 2 illustrates the relationship between frequency of hospital contact and group. The children who had a condition within the group of conditions at exceptionally high risk of IPD had high risks at every hospital contact compared with children without hospital contact. In children with other chronic diseases and children without a history of chronic disease, risk increased with the number of hospital contacts compared with children without hospital contact.
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After adjusting for the number of hospital contacts, IPD risks in children who had chronic diseases (other than the exceptionally high group) were only slightly higher than in those with a hospital contact for any other reason (aRR: 1.4 [95% CI: 1.1–1.8). Overall, the aRR of IPD for children with a history of
5 (n = 318) hospital contacts for any other reasons was 3.4 (95% CI: 2.4–4.9) compared with children with no previous hospital contact. Examination of the specific diagnoses listed in the children without a history of chronic diseases who had 5 hospital contacts revealed a wide variety of diagnoses, and IPD risk did not seem to be especially concentrated in any specific diagnostic category (data not presented). |
DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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In this study we estimated the relative risk of IPD in children associated with a wide variety of chronic diseases or in children who had undergone invasive surgery. Compared with the general population of children, certain chronic diseases, specifically cancer, renal diseases, splenectomy, and transplantation, had exceptional risk. However, for other chronic diseases, risks were little higher than for children with any reason for hospital contact. Our study indicates that, except for certain high-risk chronic diseases, IPD risk increases with the number of hospital contacts for any reason. The most likely explanation is that there is a relatively higher proportion of frail individuals among children with repeated hospital contacts. Iatrogenic infections, more invasive procedures, and better access to definitive diagnoses all contribute to the higher risks for persons with hospital contacts for any reason. We speculate that children with chronic diseases other than those few conditions with exceptional risks have a slightly higher rate (1.4-fold) because they are somewhat more ill or subjected to more invasive procedures than the average child without a chronic disease. Thus, the causes for the increased IPD risk reported with many chronic diseases in not likely to be specific to the underlying chronic-disease condition. The exceptionally high IPD risk for children with cancer or renal diseases and those undergoing splenectomy or transplantation is similar to risks reported elsewhere.9,15,18,19,27 Each of these conditions is associated with primary or treatment-related immunodeficiency, including steroids and other forms of generalized immunosuppression. It seems probable that immune resistance to S pneumoniae was compromised in these patients.
A few children had >1 chronic disease and, therefore, were counted twice. This was too rare to be analyzed by specific combinations of diseases, but when grouped, persons with >1 condition seemed to have a higher risk than those with only a single condition, perhaps because they were more ill. Two specific factors were strongly associated with high IPD risk. First, risk was very high during the first 0 to 30 days after a hospital contact, probably because IPD was the cause of admission and because of nosocomial infections. By 30 days after hospital contact, IPD risk had stabilized. Thus, this study focused on risk in the period beyond 30 days of hospital contact to better assess the effect of underlying chronic diseases on IPD risk. Second, invasive surgery is a recognized risk factor16,18,19 and is clearly seen in this study. To examine the underlying risk associated specifically with chronic diseases, all analyses were adjusted for invasive surgery.
We expected young age to be a major risk modifier of the association between IPD and chronic disease, because children in the first 2 years of life may be undergoing primary infection,28,29 whereas older children should have already had exposure to pneumococcal antigens.26 We found, however, that for children beyond 30 days from a hospital contact, the relative risk of IPD was similar among young and older children. Most children in the first 2 years had probably already been exposed to S pneumoniae and, thus, had the same immune status as older children. We recently described findings that showed that primary exposure typically occurs in the first few months of life.28
The associations between chronic diseases and IPD that we observed are unlikely to be a result of misclassification. Our study methodology used population-based controls and exposure information from national registries, thereby minimizing selection and recall bias. All cases had had a culture result that was positive for S pneumoniae from a normally sterile site, but we may have missed some cases. A validation study performed on the Danish Streptococcus Database found that 15% of known IPD infections were not reported to this database,30 and in additional cases, S pneumoniae infections may not have been cultured even if present. Similarly, chronic diseases could be misclassified or not identified in the hospital record. However, underreporting of either IPD cases or chronic diseases will likely cause results of this study to be conservatively estimated. The available register data changed in 1995 including also outpatient and emergency department hospital contacts; however, results from analyses restricted to 1977–1994 was not significantly different from results from the entire study period. We were unable to estimate how chronic disease was associated to severity of IPD, because we did not perform chart reviews. Finally, during the study period, the frequency of chronic diseases and invasive surgeries might have changed, and greater numbers of preventive measures may have been used. However, analyses were adjusted for calendar period to reduce cohort effects.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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Every fifth child with IPD in our study had an underlying chronic disease. Specifically, children with cancer or chronic renal disease and those who had undergone splenectomy or transplantation were at particularly high risk, perhaps because each of these conditions is associated with immune suppression. Excluding these children at exceptionally high risk, children with chronic diseases had a 1.4-fold increased risk of IPD compared with children with a hospital contact for any other reason. However, children with repeated hospital contact for any reason are at high risk of contracting IPD, and the increased risk associated with many chronic diseases in most cases is likely to be related to the underlying chronic-disease condition. Our study highlights the need for preventive strategies such as pneumococcal vaccination for children with chronic diseases or invasive surgeries and, indeed any other reasons for repeated hospital contact.
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APPENDIX |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSAPPENDIXREFERENCES |
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Medical diagnoses in the National Register of Patients are listed according to the ICD-831 or ICD-1032: ICD-8 codes 20000–20799 and ICD-10 codes DC81–DC969 for hematologic cancer; ICD-8 codes 14009–19919 and 23000–23999 and ICD-10 codes DC00–DC809, DD00–DD099, and DD37–DD489 for cancer (all except benign); ICD-8 codes 58100–58209 and ICD-10 codes DN03–DN049, DN07–DN079, and DN18–DN199 for chronic renal disease including chronic glomerulonephritis, nephrosis, and chronic renal insufficiency; ICD-8 codes 75309–75319 and ICD-10 codes DQ60–DQ619 and DQ63–DQ639 for congenital renal malformation; ICD-8 codes 74000–74399 and ICD-10 codes DQ00–DQ079 for congenital CNS malformation; ICD-8 codes 34500–34599 and ICD-10 codes DG40–DG419 for epilepsy; ICD-8 codes 34300–34499 and ICD-10 codes DG80–DG839 for cerebral palsy; ICD-8 codes 34793–34799 and ICD-10 codes DG90–DG919 and DG94–948 for hydrocephalus; ICD-8 codes 39400–39699, 42500–42599, and 42700–42729 and ICD-10 codes DI05–DI099, DI34–DI379, DI42–459, and DI50–DI519 for chronic heart disease including valve disease, cardiomyopathy, conduction disturbances, and cardiac failure; ICD-8 codes 74609–74799 and ICD-10 codes DQ20–DQ289 for congenital heart disease; ICD-8 codes 75930–75959 and ICD-10 codes DQ90–DQ99 for chromosomal abnormality; ICD-8 codes 27500–27399 and 27319–27349 and ICD-10 codes DE70–DE839 for inborn errors of metabolism; ICD-8 codes 28200–28399 and ICD-10 codes DD55–DD59 for hemolytic anemia; ICD-8 codes 71200–71259 and 73400–73499 and ICD-10 codes DM05–DM148, DM30–DM356, and DM358–DM368 for autoimmune disease; ICD-8 codes 27500–27599 and 28800–28809 and ICD-10 codes DD70–DD729 and DD74–DD879 for inherent immunodeficiency; ICD-8 codes 25000–25009 and ICD-10 codes DE10–DE149 for diabetes; ICD-8 codes 49000–49209, 51800–51899, and 27309 and ICD-10 codes DJ40–DJ449, DJ47–DJ479, and DE84–DE849 for chronic obstructive lung disease, emphysema, and cystic fibrosis; ICD-8 codes 49300–49309 and ICD-10 codes DJ45–DJ469 for asthma; ICD-8 codes 74809–74929 and ICD-10 codes DQ30–DQ379 for congenital respiratory malformation system; ICD-8 codes 75000–75199 and ICD-10 codes DQ38–DQ459 for congenital gut malformation; and ICD-8 codes 53000–53099 and ICD-10 codes DK20–DK238 for esophageal disease.
Surgical procedures in the National Register of Patients were classified according to the NOMESCO classification of surgical procedures.33 Transplantation was defined as any procedure including "trans" in the description. Surgical procedures were defined by the following codes excluding transplantation: codes 30000–34000 and KF01–KF99 for thoracic surgery; codes 01000–03000, 05000–06000, 30000–35000, 40000–49999, and KAA–KAW for neurologic surgery; codes 34000–35890 and KGA–KGW for heart surgery; and codes 40000–50000 and KJA–KJW for abdominal surgery excluding splenectomy defined by codes 48900–48901 and KJMA.
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FOOTNOTES |
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Accepted Jan 17, 2008.
Address correspondence to Thomas Hjuler, MD, PhD, Statens Serum Institut, Department of Epidemiology Research, 5 Artillerivej, DK-2300 Copenhagen, Denmark. E-mail: tta{at}ssi.dk
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject IPD occurs in children with chronic diseases at rates that greatly exceed those of the general population. A number of specific chronic conditions have been associated with IPD, mainly in IPD case series.
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| What This Study Adds Population-level risk of IPD associated with chronic disease and invasive surgery among children is provided. Furthermore, we evaluated the modifying effect of the number of hospital contacts before IPD, time since first hospital contact, and age at IPD.
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