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Pneumocystis Infection in Children

National Trends and Characteristics in the United States, 1997–2012

Inagaki, Kengo, MD*; Blackshear, Chad, MS; Hobbs, Charlotte V., MD*

The Pediatric Infectious Disease Journal: March 2019 - Volume 38 - Issue 3 - p 241–247
doi: 10.1097/INF.0000000000002119
Original Studies
Free
SDC

Background: Although the epidemiology of immunocompromising condition in children has evolved over time, updated epidemiology of pediatric pneumocystis infection in the United States is not available.

Methods: We performed a retrospective analysis using the Kids’ Inpatient Database, a nationally representative sample of US pediatric hospital discharges collected in 1997, 2000, 2003, 2006, 2009 and 2012. Pneumocystis cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification, code 136.3 among children 0–18 years of age. Demographic data of cases with and without mortality were compared.

Results: We identified 1902 [standard error (SE): 95] pneumocystis cases during the study period. The pneumocystis hospitalization rate decreased from 7.5 (SE: 0.91) to 2.7 (SE: 0.31) per a million US children from 1997 to 2012 (63.2% decrease). Cases with HIV infection decreased from 285 (SE: 56) cases in 1997 to 29 (SE: 7) cases in 2012, whereas hematologic malignancy and primary immunodeficiency became more prominent. Infants were the most commonly affected [510 cases (SE: 40)]. All-cause in-hospital mortality was 11.7% (SE: 1.3%) and was particularly high among cases with hematopoietic stem cell transplant [32.4%(SE: 7.1%); P < 0.001].

Conclusions: Pneumocystis infection in children showed a marked decrease from 1997 to 2012 in the United States, largely driven by the reduction in HIV-associated cases, and cases with non-HIV illnesses became more prominent. Hematopoietic stem cell transplant–associated cases had particularly high mortality. Clinicians should be aware of high-risk groups that may benefit from chemoprophylaxis, particularly in infancy.

*Department of Pediatrics

Department of Data Science, University of Mississippi Medical Center, Jackson, Mississippi.

Accepted for publication May 6, 2018.

The authors have no funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Kengo Inagaki, MD, Department of Pediatrics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. E-mail: kinagaki@umc.edu.

Pneumocystis pneumonia is a life-threatening infection occurring mainly in immunocompromised hosts. Pneumocystis had been recognized as a pathogen of severe pneumonia in infants and patients with malignancy and primary immunodeficiency before HIV became prevalent.1–4 However, a dramatic rise in the number of pneumocystis cases has occurred in the 1980s, coinciding with the arrival of HIV epidemic in the United States.5 , 6 Since then, advances in HIV medicine have been met with a substantial decline in the incidence of pediatric HIV infection.7 , 8 On the other hand, the incidence of other immunocompromising conditions, such as leukemia, has been stable in children,9 and the diagnosis rate of primary immunodeficiency has reportedly increased.10 In adult populations, the incidence of pneumocystis infection is reportedly increasing among non-HIV immunocompromised hosts.11 , 12 Availability of newer agents or stronger chemotherapy in treating cancer and autoimmune/inflammatory conditions may also result in shift in the populations at risk.11 , 13 , 14 Although changing epidemiology of immunocompromising conditions in children can directly impact the incidence of pneumocystis infection, epidemiologic data on pneumocystis in children are scarcely available, likely because of its relative rarity. Recognition of the populations at risk would be an important step in mitigating the burden of this disease. In this study, we aimed to describe the epidemiologic trend of pneumocystis infection in children from 1997 to 2012, using a nationally representative database.

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MATERIALS AND METHODS

Study Design

We performed a retrospective analysis of serial cross-sectional data using the Kids’ Inpatient Database (KID) from 1997, 2000, 2003, 2006, 2009 and 2012 (www.hcup-us.ahrq.gov/kidoverview.jsp),15 compiled by the Healthcare Costs and Utilization Project of the Agency for Healthcare Research and Quality. The KID is the largest publicly available all-payer pediatric inpatient care database in the United States, released every 3 years since 1997 with the data from 2012 being the latest. The data contains a stratified sample of 10% of uncomplicated in-hospital births and 80% of other pediatric discharges from hospitals in participating states (Table, Supplemental Digital Content 1, http://links.lww.com/INF/D189, which shows the states included in the KID in each data year, and https://www.hcup-us.ahrq.gov/db/availability_public.jsp). Discharge records in the KID are weighted using poststratification on hospital ownership/control, bed size, teaching status, rural/urban location and US region, with the addition of a stratum for freestanding children’s hospitals in proportion to the total number of newborn or nonnewborn discharges, allowing for obtaining national estimates. The authors who had direct access to the KID data completed Healthcare Costs and Utilization Project data use agreement training. Per communication with the Institutional Review Board of the University of Mississippi Medical Center, this study was classified as nonhuman subjects research.

Patients who were 18 years of age or younger were included in the analysis. Records with pneumocystis infection were identified by searching for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of 136.3 (pneumocystosis) in any of the diagnoses listed in the database. Patient-level information including age, sex, race, discharge year and in-hospital all-cause mortality was provided by the database. We used International Classification of Diseases, Ninth Revision, Clinical Modification, codes to identify the following clinical conditions in the pneumocystis infection cases (Table, Supplemental Digital Content 2, http://links.lww.com/INF/D190): HIV infection, hematologic malignancy, primary immunodeficiency, brain tumor or malignant solid tumor, hematopoietic stem cell transplant (HSCT), solid-organ transplant and autoimmune/inflammatory disorders.

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Statistical Analysis

Data from January 1 to December 31 in 1997, 2000, 2003, 2006, 2009 and 2012 were collected and analyzed. The rate of pneumocystis hospitalization per a million US children was estimated as the weighted case number divided by the population estimates as of July 1st of each study year obtained from the US census bureau.16

Demographic characteristics and underlying conditions were compared between pneumocystis cases with and without in-hospital all-cause mortality. Bivariate analysis of categorical variables was performed with Pearson χ2 test. Multivariable analysis with logistic regression using variables that reached statistical significance on bivariate analysis was planned; however, this was not performed because only one variable from the bivariate analysis attained statistical significance. Temporal trends in the mortality among pneumocystis cases were assessed using linear regression including year as a continuous predictor variable and mortality as a response variable.17 Temporal changes in the association between each underlying condition and mortality were assessed by developing a series of logistic regression models including interaction terms between each condition and year variable and mortality as a response variable.

Data were analyzed using R software version 3.2.3 (R Foundation for Statistical Computing; Vienna, Austria) and Stata software version 14.1 (StataCorp; College Station, TX). We used svy command in Stata to account for the sampling design of the KID. Presented values are weighted values unless otherwise specified. Cells with <10 observations in tables were omitted from presentation after the Healthcare Costs and Utilization Project recommendation to avoid the risk of identification of individuals. We used 2-sided significance level of 0.05 in all analyses.

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RESULTS

Temporal Trend of Pneumocystis Infection

We identified 1902 [standard error (SE): 95] cases of pneumocystis infection during the study period. The pneumocystis hospitalization rate decreased from 7.5 (SE: 0.91) to 2.7 (SE: 0.31) per a million US children from 1997 to 2012 (63.2% decrease; Fig. 1). The decrease was particularly more substantial during the earlier years in the study period, especially between 1997 and 2000 (Fig. 1).

FIGURE 1

FIGURE 1

HIV was the most common underlying disorder for pneumocystis infection in the study period from 1997 to 2012, with a total of 627 (SE: 64) cases [33.0%(SE: 2.4%); Table 1]. The number of pneumocystis cases with HIV showed approximately 10-fold decrease during the study period from 285 (SE: 56) cases [51.2% (SE: 5.2%) of all cases in the year] in 1997 to 29 (SE: 7) cases [13.4% (SE: 2.9%) of all cases in the year] in 2012 (Fig. 2). On the other hand, the number of cases without HIV remained relatively stable (Fig. 2). As a result, HIV was the second common underlying disorder after hematologic malignancy in 2006 and the third common underlying disorder after hematologic malignancy and primary immunodeficiency in 2009 and 2012 (Fig., Supplemental Digital Content 3, http://links.lww.com/INF/D191).

TABLE 1

TABLE 1

FIGURE 2

FIGURE 2

The decrease of HIV-associated cases was particularly accentuated among children younger than adolescence age (<13 years of age); cases in these younger children decreased from 231 (SE: 42) in 1997 to <10 in 2009 and 2012, whereas in older children, the case numbers were 54 (SE: 18) in 1997 and 19 (SE: 6) in 2012, respectively. The decrease in younger children was the most substantial during the earlier years in the study period, particularly between 1997 and 2000 (Fig., Supplemental Digital Content 4, http://links.lww.com/INF/D192).

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Age Distribution of Pneumocystis Infection

Infants (<12 months of age) were the most commonly affected age group during the study period, with the case number of 510 (SE: 40) [26.8%(SE: 1.6%); Table 1; Fig. 3]. This was followed by 1 year of age that had 151 (SE: 21) cases [7.9% of all cases (SE: 1.0%)] and 18 years of age that had 148 (SE: 18) cases [7.8% of all cases (SE: 0.9%)], respectively (Fig. 3). The rest of the age groups had similar number of cases (Fig. 3). The age distribution was generally similar in different time points, and infants were the dominant age category throughout the study period.

FIGURE 3

FIGURE 3

Most [191 (SE: 24) cases; 74.4% (SE 3.9%)] pneumocystis cases with primary immunodeficiency occurred in infants, and this was the most common underlying condition overall in infants, followed by HIV infection [132 (SE: 21) cases].

We observed an increase in the case number in adolescents (particularly those 18 years of age). Majority (85; SE: 13) of pneumocystis cases in this age group was HIV-related, followed by hematologic malignancy-related [31 (SE: 8)].

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Mortality Associated With Pneumocystis Infection

Overall all-cause in-hospital mortality of pneumocystis infection was 11.7% (SE: 1.3%; Table 2). The mortality was generally stable throughout the study period (Table 1), with no significant temporal trend over time (P = 0.16). Mortality was not associated with any of the demographic characteristics studied (Table 1). Among the underlying conditions studied, HSCT was associated with higher mortality [32.4% (SE: 7.1%); P < 0.001; Table 1]. We identified no support for temporal changes in the strengths of associations between mortality and the prespecified underlying conditions studied.

TABLE 2

TABLE 2

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Underlying Conditions for Pneumocystis Infection

Some of specific diagnoses were more prominent in each underlying condition category. Acute lymphoblastic leukemia represented most of hematologic malignancy–associated cases [320 cases (SE: 27)], and severe combined immunodeficiency was by far the most common [161 cases (SE: 23)] among primary immunodeficiency–associated cases (Table 2). Brain tumor and musculoskeletal tumors were more common as underlying conditions for pneumocystis infection than other malignant solid tumors (Table 2). Various autoimmune or inflammatory disorders were identified in cases with pneumocystis diagnosis, but systemic lupus erythematosus was the only diagnosis that had ≥10 cases [25 cases (SE: 10); Table 2].

We identified cases without prespecified underlying disorders, but with other diagnoses including aplastic anemia, hemophagocytic syndrome, histiocytosis, chronic kidney disease, chronic liver disease, Sickle cell disease, Cushing syndrome, congenital heart disease and asthma; however, these could not be studied collectively because of the small number of cases.

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DISCUSSION

This study provides population-based estimates of trends in diagnosis and underlying disorders of pediatric pneumocystis infection in the Unites States. Our data indicate that the rate of pneumocystis hospitalization in children (≤18 years of age) decreased by more than half from 1997 to 2012. This decrease was largely driven by a sharp reduction in the HIV-associated cases, making hematologic malignancy the most common underlying disorder for pneumocystis infection, followed by primary immunodeficiency from 2009 to 2012. We also showed that infants were disproportionately affected by pneumocystis infection. HSCT-associated pneumocystis cases had particularly high all-cause in-hospital mortality.

We observed a substantial decrease in the number of pneumocystis infection in children, particularly in the setting of HIV infection. Historically, pneumocystis infection has been closely associated with HIV. In children, mother-to-child transmission is a major mode of HIV acquisition, although it has substantially decreased after 1992 resulting in 95% reduction by 2005,8 secondary to improved prevention methods.7 In our study, the reduction in HIV-related pneumocystis infection was observed mainly in children who would have had mother-to-child transmission, consistent with the epidemiologic evolution of pediatric HIV. It should be noted that the largest reduction in pneumocystis cases occurred in the earlier years of the study period in our study, which follows the national trend of perinatal HIV transmission. HIV-related pneumocystis infection in adolescents also reduced by approximately 65%; this may be related to the availability of more potent and tolerable antiretrovirals and the widespread use of pneumocystis prophylaxis as in the case of adult patients.18

As HIV lost its presence as an underlying disorder for pneumocystis infection in children, non-HIV conditions such as hematologic malignancies and primary immunodeficiency shifted into relative prominence. Notably, approximately 87% of pediatric pneumocystis infection occurred in non-HIV patients in 2012. Therefore, improved control of pneumocystis in non-HIV patients would be an important step in decreasing the burden of this disease in children.

The risk of pneumocystis infection and the effect of prophylaxis is well established in HIV infection, hematologic malignancies, HSCT, solid-organ transplant and certain primary immunodeficiencies such as severe combined immunodeficiency and hyper IgM syndrome.19–25 Universal chemoprophylaxis based on cluster of differentiation (CD) 4 count with trimethoprim-sulfamethoxazole was implemented before our study period for HIV infection,26 and guidelines for primary prophylaxis against pneumocystis has been published for conditions such as hematologic malignancies, HSCT and solid-organ transplant.27–30 Most experts recommend chemoprophylaxis in patients with severe combined immunodeficiency and hyper IgM syndrome,31 which were the 2 most common primary immunodeficiency conditions associated with pneumocystis infection in our study. Chemoprophylaxis against pneumocystis is less well established for malignant solid tumors, and the recommendation is still evolving in this patient population. Chemoprophylaxis has been recommended for those requiring high-dose and prolonged steroid therapy and those with brain tumors,29 , 32 and a more recent guideline for children recommends prophylaxis for all patients in whom lymphopenia is expected to occur.33 Our study identified brain tumor to be a common underlying condition for pneumocystis in children, supporting these recommendations although the specific attack rate could not be determined in this study. Interestingly, malignant musculoskeletal tumor was identified as the second common malignant solid tumor among pneumocystis cases in our study. This association has not been widely recognized and may be worth investigating in the future studies. Organ transplantation of liver, kidney and heart had higher case numbers of pneumocystis among solid-organ transplant patients in our study, possibly reflecting the volume of such transplantations.

Our results reiterated the predisposition of infants to pneumocystis infection, as recognized since mid-20th century.1 , 2 After HIV increased its prevalence, pneumocystis became a leading cause of morbidity and mortality among HIV-infected infants.34 , 35 This seems to remain true in the HIV-infected African children in the modern age.36 It should be noted that the recent pediatric pneumocystis infections occurred predominantly in non-HIV patients in our study. Pneumocystis can be the initial presentation of undiagnosed primary immunodeficiency in infants or younger children,37–39 indicating the importance of maintaining high index of suspicion in treating infants with severe respiratory manifestations.

Pneumocystis infection has historically been associated with a high mortality rate.40–42 Mortality has been reported to be higher among non-HIV population than in HIV population. An adult study from 1996 to 2008 in the United States showed in-hospital mortality of 19% in the HIV-infected and 27% in the non–HIV-infected populations, respectively.43 On the other hand, another adult study conducted in France from 2007 to 2010 showed the mortality rate of 4% in the HIV-infected and 27% in the non–HIV-infected populations, respectively.44 No similar studies in children are available. The mortality rates in our study, at least in the non-HIV cases, may be lower than aforementioned studies. More studies on mortality in children are necessary to confirm our results. Among underlying disorders, HSCT had particularly higher mortality, consistent with previous studies.44

Finally, we observed pneumocystis cases with diagnoses that were not included in the immunocompromising conditions that we prespecified for this study. Most of these diagnoses have not been commonly associated with pneumocystis infection. However, there have been sporadic pneumocystis cases associated with Cushing syndrome and disorders requiring corticosteroid therapy (eg, asthma, nephrotic syndrome), indicating the importance of corticosteroid use as a predisposing factor.45–48 More studies are needed to identify the at-risk populations that are currently not well recognized, given the potentially serious outcomes. In addition, indication for pneumocystis prophylaxis should be kept reassessed as pneumocystis epidemiology evolves. In the United Kingdom, pneumocystis infection increased from 2000–2005 to 2006–2010, mainly in non-HIV population.12 We did not observe such trends in the US children; nonetheless, the epidemiologic trend in this population should be followed.

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Limitations of the Study

Although the use of the KID database enabled us to study a large number of patients to obtain national estimates, this study has limitations. First, case selection needed to rely solely on accurate diagnostic coding, as in the case of any research using administrative data. The golden standard of pneumocystis diagnosis remains microscopic examination of respiratory samples although polymerase chain reaction, despite being non-US Food and Drug Administration approved, may have become increasingly utilized during the study period, which can have increased sensitivity49 but with possible detection of colonization.50 The possibility that the availability of polymerase chain reaction in pneumocystis diagnosis in the later study years influenced our study result cannot be excluded. However, we believe the effect would be minimal because the increased sensitivity of polymerase chain reaction is expected to make the apparent case number higher, although we observed decreased case numbers over time. Second, because the KID contains inpatient data only, we were unable to obtain the total number of the population at risk in each underlying condition category, and total case numbers, rather than incidence, were presented. Third, the KID does not contain records from all states, and the number of participating states has changed during the study period. Although selection bias cannot be completely excluded, we do not expect this to be a major issue as we did not identify any particular geographic patterns of pneumocystis diagnosis. Fourth, the database did not contain data on degree of immunosuppression (such as CD4 count and the use of immunosuppressive agents) and chemoprophylaxis status, which would have provided clinically important information.

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ACKNOWLEDGMENTS

The authors thank Dr April Palmer, MD, at the University of Mississippi Medical Center, who does not have conflict of interest to disclose, for reviewing the draft of the manuscript.

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Keywords:

population-based study; Kids’ inpatient database; immunocompromised hosts

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