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).
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.
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)].
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.
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.
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.
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.
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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