Stem cells derived from the BM, peripheral blood or umbilical cords of autologous or allogeneic donors are used for transplantation.1 Hematopoietic SCT is now considered the standard of care for several well-defined congenital or acquired hematological and immunological conditions, as well as certain chemosensitive, radiosensitive or immunosensitive malignancies.2, 3 Despite advances in care, SCT is associated with significant morbidity, mortality and hospital resource utilization.4, 5 Recipients of SCT are at an increased risk for a variety of infections at various phases of transplantation, which is associated with significant morbidity and mortality. Guidelines exist for preventing infectious complications in SCT recipients.6, 7, 8 The oral cavity contains a variety of microorganisms including bacterial, viral, fungal and parasitic species.9, 10, 11 Certain pathological oral conditions such as periodontitis or gingivitis may lead to life-threatening systemic diseases and infections.9, 10, 11 Optimal oral care before and after transplantation is critical in the management of these patients.12 Current national estimates and the impact of pre-existing oral conditions, such as acute or chronic periodontitis or gingivitis, in SCT recipients who are subject to myeloablative and immunosuppressive regimens on outcomes, specifically infectious risk, is unclear. The objectives of the present study are to examine the prevalence of gingivitis and periodontitis in hospitalized stem cell transplant recipients in the United States and to examine the impact of presence of gingivitis and periodontitis on hospitalization outcomes.
The current study is a retrospective analysis of the Nationwide Inpatient Sample (NIS) for the years 2004 to 2010.13 This study was granted ‘exempt’ status by the Institutional Review Board of the College of Dentistry – The University of Iowa. All patients who underwent stem cell transplant procedures were selected. Primary outcomes included hospital charges, length of stay and occurrence of infectious complications. As the current study included data from multiple years, hospital charges were inflation adjusted to year 2010 levels. Infectious complications examined included septicemia, bacteremia, mycoses and post-operative pneumonia. A composite binomial variable (presence or absence of any one of the four infectious complications) was created and used as the outcome variable. Secondary outcomes included occurrence of stomatitis/mucositis and oral thrush. Independent variables of interest in the current study were presence of gingivitis or periodontitis. Gingivitis and periodontitis were identified by using ICD-9-CM codes for these conditions in the secondary diagnoses fields. The codes used included: acute gingivitis (ICD-9-CM diagnoses codes of 523.00 and 523.01); chronic gingivitis (523.10 and 523.11); acute periodontitis (523.30, 523.31, 523.32 and 523.33); and chronic periodontitis (523.40, 523.41 and 523.42). Multivariable linear regression analysis was used to examine the association between hospital charges (dependent variable) and presence of gingivitis/periodontitis (independent variable). In a similar way, the association between length of stay (dependent variable) and presence of gingivitis/periodontitis was also examined. Hospital charge and length of stay data were highly skewed. To account for skewing, hospital charges and length of stay were log transformed and used as the outcome variable. The estimates were exponentiated and re-transformed to obtain percentage change in charges and length of stay and change from the overall mean values. Multivariable logistic regression analysis was used to examine the association between occurrence of infectious complications (dependent variable) and presence of gingivitis/periodontitis. In all regression models, the effects of age, sex, race, type of admission, co-morbid burden, type of stem cell transplant and hospital region were adjusted. Co-morbid burden was computed by summing the presence of 29 different chronic co-morbid conditions in this cohort of patients. The co-morbid conditions examined included: AIDS, alcohol abuse, deficiency anemias, rheumatoid arthritis/collagen vascular diseases, chronic blood loss anemia, congestive heart failure, chronic pulmonary disease, coagulopathy, depression, diabetes—uncomplicated, diabetes—with chronic complications, drug abuse, hypertension, hypothyroidism, liver disease, lymphoma, fluid and electrolyte disorders, metastatic cancer, neurological disorders, obesity, paralysis, peripheral vascular disorders, psychoses, pulmonary circulatory disorders, renal failure, solid tumor without metastasis, peptic ulcer disease, valvular disease and weight loss. Effects of clustering of outcomes within hospitals were adjusted. All tests for associations were two sided; a P-value of <0.05 was deemed to be statistically significant. Statistical tests were conducted using SAS Version 9.3 software (SAS Institute, Cary, NC, USA).
During the study period, a total of 101 462 patients underwent SCT procedures in hospitals across the United States. Of these, about 0.22% had gingivitis/periodontitis. Characteristics of patients having SCT procedures with and without gingival/periodontal conditions are presented in Table 1. About 64% of those with gingivitis/periodontitis were males (compared with 58.7% among those without gingivitis/periodontitis). Whites comprised 53.1% of those with gingivitis/periodontitis (compared with 73.3% of those without gingivitis/periodontitis). Mean age of those with gingivitis/periodontitis was 40.3 years (compared with 44 years among those without gingivitis/periodontitis). The mean charge for those with gingivitis/periodontitis was $397 518, whereas the mean charge for those without gingivitis/periodontitis was $270 943. Mean length of stay for those with gingivitis/periodontitis was 34.4 days, whereas the mean length of stay for those without gingivitis/periodontitis was 26.3 days. Infectious complication rate among those with gingivitis/periodontitis was 52.1% (compared with 32.8% among those without gingivitis/periodontitis). Each of the individual infectious complications (septicemia, bacterial infections, mycoses and post-operative pneumonia) occurred more frequently among those with gingivitis/periodontitis compared with those without gingivitis/periodontitis. Stomatitis/mucositis was present in 33.6% of patients with gingivitis/periodontitis (compared with 31.3% in those without gingivitis/periodontitis). Oral thrush was present in 4.6% of those with gingivitis/periodontitis (compared with 3.3% in those without gingivitis/periodontitis).
Estimates of the multivariable linear (for hospital charges and length of stay) and multivariable logistic (for in-hospital mortality) regression analyses are summarized in Table 2. Following adjustment for confounders such as age, sex, race, type of admission, co-morbid burden, type of stem cell transplant procedure and hospital region, those with gingivitis/periodontitis were associated with significantly higher hospital charges (estimate is 0.2754, $85 991 change from mean, P=0.002) when compared with those without gingivitis/periodontitis. Following adjustment for confounders, those with gingivitis/periodontitis were associated with significantly longer length of stay in hospital (estimate is 0.2101, 6.1 days change from mean, P=0.002) compared with those without gingivitis/periodontitis. Those with gingivitis/periodontitis were also associated with significantly higher odds for any of the infectious complications (odds ratio=2.02, 95% confidence interval=1.11–3.67, P=0.02) compared with those without gingivitis/periodontitis.
The current study used a nationally representative database of hospitalizations to examine the impact of gingival and periodontal conditions on outcomes in patients undergoing SCT procedures. Results of this study show that the presence of gingival and periodontal conditions is associated with significantly increased hospital charges, longer length of stay in hospitals and higher odds for infectious complications among this cohort of patients. SCT (either allogenic or autogenic sources) is a standard of care in the treatment of congenital or acquired hematological/immunological conditions and certain malignancies.2, 3 Patients who undergo these therapies are under an immunosuppressive regimen as part of engraftment of transplanted stem cells. In the immunosuppressive phase, patients suffer neutropenia and thromcytopenia that puts them at an increased risk for variety of infections leading to post-graft complications.
Pre-transplant dental evaluation is recommended and is the standard of care at several institutes.14 The low prevalence (0.22%) of gingivitis/periodontitis in our cohort compared with the general population is likely a reflection of optimal dental workup and clearance before SCT. Dental evaluation and extraction of teeth with advanced periodontitis or optimal treatment of gingivitis have been advocated before SCT to prevent infections and septicemia in transplant recipients. However, to our knowledge, no study to date has conclusively shown a relationship between gingivitis/periodontitis and development of infectious septicemia and/or mortality after hematopoietic SCT. The present study addresses this knowledge gap to an extent by showing an increased risk of infectious complications in stem cell transplant recipients with associated gingivitis/periodontitis.
If untreated, periodontal conditions could lead to destruction of the tooth-supporting structures with tooth loss being the final outcome. In addition, due to the intricate connection that exists between oral cavity and the rest of the human systems, periodontal disease can have a widespread systemic effect in the human body. Interestingly, a recent prospective evaluation demonstrated that the incidence of bacteremia following SCT during the neutropenia phase was higher in patients with untreated periodontal disease than patients with healthy periodontium.15 Hence, any pre-existing untreated conditions such as gingivitis and/or periodontitis in patients undergoing SCT might increase the susceptibility to post-transplant complications due to infections.
This study is subject to several limitations. The nature of the study precludes us from definitively establishing a cause and effect relationship. Hospital discharge data sets are prone to having coding issues. Any systematic errors in coding for different diagnoses or procedures could yield biased estimates. Behavioral factors are not captured in the NIS and hence these were not examined. Finally, a host of factors (such as donor type, conditioning regiment and other uncaptured patient-related variables) could influence outcomes. The retrospective nature of the study and the limitations associated with use of large secondary hospital discharge databases precluded us from conducting a more comprehensive risk adjustment for outcomes.
These study results show that presence of gingival and periodontal conditions is associated with higher hospital charges, longer length of stay in hospitals and higher odds for developing infectious complications. Considering the significant impact that pre-existing periodontal conditions have on the morbidity and financial burden, our study is in agreement with the current guidelines that recommend thorough dental evaluation and treatment, before and after SCT therapy. The results of this study also emphasize the importance of ongoing interdisciplinary collaborative efforts in the care of such complex patients to optimize outcomes.