Prior epidemiological studies that characterized the incidence and implications of MRSA infection have not directly assessed hospitalized children at the national level. By use of active microbiology laboratory surveillance, a 2004–2005 study of 9 US metropolitan areas estimated a relatively high incidence of and a relatively high mortality associated with MRSA infection [13
]. Although this was not an inpatient-based study, 92% of the reported patients required hospitalization. However, most were adults with MRSA bacteremia who had either a current or historical association with a health care setting. Of note, the 5–14-year-old age group from this study [13
] had a 20-fold lower incidence of MRSA infection than that of the entire cohort, which may indicate a fundamentally different epidemiology of MRSA in hospitalized children. Two additional studies employed a large inpatient database to reveal an increase in MRSA infection during 1999–2000 [16
] and during 1999–2005 [14
]. By use of this large inpatient database, it was found that the rate of MRSA infection doubled over time (from 4 to 8 cases per 1000 admissions), coincident with a significant increase in rate of skin and soft-tissue infection caused by MRSA during the same period. However, because patient-specific data were not available, the rates of MRSA infection in these analyses were estimated from the data collected from local microbiology laboratory surveillance, and a pediatric age group could not be identified.
To our knowledge, the present study provides the most comprehensive description to date of the epidemiology and burden of MRSA infection among hospitalized children in the United States. We found that MRSA caused more than one-half of all S. aureus infections treated in freestanding children’s hospitals from 2002 through 2007. During the study period, we identified a steady increase in both the overall incidence of S. aureus infection and the incidence of MRSA infection, whereas the incidence of MSSA infection remained stable. Most of these S. aureus infections were skin and soft-tissue infections, and the in-hospital mortality of patients with S. aureus infection—irrespective of methicillin resistance—was low.
Although our analysis did not distinguish between CA-MRSA and HA-MRSA infections, the observed increase in MRSA infections was likely driven by the recent dramatic emergence of CA-MRSA strains that occurred during the study period. The predominance of skin and soft-tissue infections among the cases of MRSA infection in our study is consistent with this hypothesis, because pediatric skin and soft-tissue infections predominantly originate in the community [8
]. Furthermore, less than one-third of our MRSA-infected patients had complex chronic conditions [17
]. Although complex chronic conditions have not been directly linked to HA-MRSA infection, the relatively frequent hospitalization of children with complex chronic conditions renders them more likely than children without complex chronic conditions to acquire an HA-MRSA infection. Of note, significantly more patients with MRSA infection were black, compared with patients who had MSSA infection. Although the reason for this racial disparity is unclear, it is consistent with previous analyses of CA-MRSA infection [18
] and colonization [21
]. Single-center pediatric studies that documented the impact of the emergence of CA-MRSA infection on the hospitalization of patients also support this hypothesis, confirming both the increased rates of hospitalization over time and the dominance of skin and soft-tissue infection [11
]. Although the present study offers only indirect confirmation of this phenomenon, evidence for the influence of CA-MRSA infections on the epidemiology of nosocomial MRSA infections in hospitals is mounting [22
The mortality rate in our study—including all cases of S. aureus
infection—was 2%. This rate is at odds with the 6.2%– 8.8% mortality rates calculated for MRSA-infected hospitalized patients in the study by Klein et al. [14
] and with the 18% mortality rate that was determined to be the recent national estimate of the MRSA burden by Klevens et al. [13
]. As stated above, the majority of these MRSA-infected patients were adults with bacteremia who required hospitalization. In contrast, most of the patients in our study did not have a complex chronic condition or bacteremia; the majority were previously healthy children with skin and soft-tissue infection. Furthermore, because our study captured all-cause mortality, it is likely that the mortality rates attributable to MRSA infection are even lower than those estimated by our analysis. It is interesting to note that the mortality of patients with MRSA infection was lower than that of patients with MSSA infection. This is consistent with CA-MRSA infections being the primary force behind the upsurge in nosocomial MRSA infections; children with CA-MRSA infection are predominantly healthy children with skin and soft-tissue infections, a population with a lower base-line mortality rate than those hospitalized for chronic illnesses (supported by the higher incidence of complex chronic conditions among children with MSSA infection). In other words, the influx of patients with CA-MRSA infection to the hospital may be diluting the previous baseline mortality associated with MRSA infection (and, in effect, relatively inflating the mortality associated with MSSA infection), not because CA-MRSA infection is less virulent, but because it generally infects healthier patients than does HA-MRSA.
Use of the Pediatric Health Information System database offers the unique advantage of national-level, pediatric data. Specifically, the Pediatric Health Information System database contains patient medical records from >40 large, tertiary care children’s hospitals (i.e., >70% of the freestanding children’s hospitals in the United States) that reside in 17 of the 20 major metropolitan areas, each of which is represented by only 1 hospital in the Pediatric Health Information System. This database provides up to 21 diagnosis codes per hospitalization, which is more diagnosis data per patient than any other administrative data set. This large, data-rich, and geographically diverse database, however, may not be generalizable to non–tertiary care, freestanding children’s hospitals. For example, because of referral bias, the Pediatric Health Information System database may overrepresent the true incidence of some medically complicated or severe infections, including those caused by MRSA. Because of this overrepresentation, the low mortality rate observed in this cohort of referral centers is notable.
Despite these advantages, administrative sources of data such as the Pediatric Health Information System are limited with specific regard to the possibility of miscoded or inaccurate information. The accuracy of ICD-9-M
codes for diagnosis of either S. aureus
or MRSA infection has not been validated for this large population. Although generally specific, ICD-9-CM
–based identification may not have ideal sensitivity. For example, when classifying different sites of S. aureus
infection, our ICD-9-CM
–based approach revealed sites of infection in only two thirds of our cases. However, the reporting of up to 21 discharge diagnosis codes—3-fold more than the national database had used for previous reports of inpatients with S. aureus
]—likely increases our sensitivity relative to the 2 aforementioned studies that used a large inpatient database [14
]. Because of the lack of microbiology laboratory data, we have identified patients with MSSA infection as those with an ICD-9-CM
code for S. aureus
infection but not for MRSA infection in their medical records, taking advantage of the dichotomous nature of S. aureus
infections with respect to methicillin resistance. Although it is possible that some cases of MRSA might have been missed (e.g., a diagnosis code for S. aureus
infection was entered into the patient’s medical record but an additional diagnosis code for MRSA infection was not), it is unlikely that this would occur differentially by year. In support of this assumption, the overall rate of S. aureus
infection increased over time coincident with the increase in the rate of MRSA infection (); if increased vigilance for properly adding diagnosis codes for MRSA to S. aureus
infections over time was the driving force for this increase, the resultant curve would indicate a stable incidence of all S. aureus
infections accompanied by a decrease in MSSA infections and an increase in MRSA infections. Furthermore, both the overall incidence of MRSA infection and the distribution of sites of infection from this analysis are consistent with the observations of related studies that used a variety of case definitions and analyses [13
]. However, a prospective study to identify patient and infection characteristics supported by patient-specific microbiology laboratory data would be the most reliable method to confirm our findings.
In summary, we have identified a recent increase in MRSA infection among hospitalized children. The predominance of skin and soft-tissue infections, their occurrence in primarily healthy children, the low associated mortality, and the contemporaneous increase in CA-MRSA infections suggest that this increased incidence of MRSA infection in hospitalized children is driven by the recent emergence of CA-MRSA strains.