Staphylococcus aureus causes an assortment of infections that range from mild skin infections to bacteremia or necrotizing pneumonia. Patients with S. aureus infections may suffer poor outcomes such as extended hospital stay and death. The goal of this study was to improve outcomes of patients with S. aureus infections by examining microbial characteristics of S. aureus associated with poor clinical outcomes, and comparative effectiveness of S. aureus treatment options for patients with S. aureus infections. Additionally, methods to prevent S. aureus infections among hospitalized patients were assessed. We performed a two-hospital retrospective cohort study to identify microbial characteristics, patient characteristics, or antimicrobial treatments that were predictors of mortality or length of stay among patients with methicillin-resistant S. aureus (MRSA) pneumonia. We found increased age (> 54 years) (hazard ratio [HR]: 4.49; 95% confidence interval [CI]: 1.64-12.33), intensive care unit (ICU) admission (HR: 5.25; CI: 1.52-18.21), and having a hospital-onset pneumonia (HR: 0.32; CI: 0.13-0.75) were associated with mortality while admission to the ICU (odds ratio [OR]: 7.34; CI: 3.58-15.04), increased age (> 54 years) (OR: 2.27; CI: 1.19-4.35), having a hospital-onset pneumonia (OR: 3.60; CI: 1.26-10.28), and receiving vancomycin (OR: 10.85; CI: 3.68-32.00) were predictors of increased length of stay. None of the tested microbial characteristics were associated with poor outcomes. We also completed a multicenter retrospective cohort study to compare the effect of beta-lactams versus vancomycin (both empiric and definitive therapy) on mortality for patients with methicillin-susceptible S. aureus (MSSA) bacteremia who were admitted to Veteran Affairs Medical Centers. We found an increased hazard of mortality for patients who received empiric treatment with a beta-lactam compared with vancomycin (HR: 1.19, 95% CI: 1.00-1.42). However, we observed a protective effect among patients who received definitive treatment with a beta-lactam compared with vancomycin (HR: 0.66; CI: 0.50-0.87). In 2007, 2009-2011, we administered surveys that focused on the implementation of the Institute for Healthcare Improvement's (IHI) MRSA bundle to reduce hospital-onset MRSA infections to infection preventionsts who worked in Iowa hospitals. By the end of the study period, most hospitals implemented a hand hygiene program (range: 87%-94%), placed infected (range: 97%-100%) or colonized patients (range: 77%-92%) on contact precautions, performed active surveillance culturing to identify colonized patients, and monitored the effectiveness of environmental cleaning (range: 23%-71%; P < 0.001). To improve patient outcomes, physicians should provide beta-lactams for definitive treatment of patients with MSSA bacteremia. However, the most effective method to improve outcomes is to prevent S. aureus infections from occurring. This study provides benchmark data that infection prevention staff in rural hospitals throughout the U.S. can use to compare their practices with Iowa hospitals.

We have read with interest the short communication published by Segovia-Juarez et al., 2020 in Respiratory Physiology & Neurobiology establishing that high altitude reduces the infection rate of COVID-19 but not the case fatality rate in the Peruvian setting. We support this hypothesis, however there could be an important number of under registered deaths on account of a low rate of diagnostic tests performed per inhabitant and mostly in symptomatic patients (Pasquariello and Stranges, 2020). / Revisión por pares

Vaccination is one of the most successful public health interventions in history, and is estimated to save lives of 3 million children globally each year. Ongoing surveillance is warranted to identify further evolution of the epidemiology of vaccine preventable diseases, and to evaluate the effects of vaccines provided. This dissertation aims to explore the impact of vaccines on disease burden, and effectiveness of diagnostic tools for two important infectious diseases; pneumonia and tuberculosis (TB). The first study employed a large electronic health record data, Massachusetts Health Disparities Repository (MHDR), to evaluate impact of 13-valent conjugated pneumococcal vaccine (PCV13) on all-cause pneumonia among children who receive primary care at Boston Medical Center (BMC). We extracted all-cause pneumonia cases diagnosed at both inpatient and outpatient settings among children younger than 8 years of age. Using interrupted time-series regression analysis monthly rates estimated for years after (2011–2013) implementation of PCV13 were compared to expected rates calculated from pre-PCV13 era (2007–2009). The year of PCV13 introduction (2010) was excluded. We also extracted cases of urinary tract infection and evaluated as control outcome. At the end of 2013 compared to prePCV13 era, among children younger than 2 years of age there was a 35.3% (95% CI 5.4–65.3) reduction in all-cause pneumonia cases. In children with comorbidity, pneumonia declined by 38.8% (95% CI 11.1 to 65.4) in those younger than 2 years of age, and 28.7% (95% CI 2.9 to 54.5) in those 2 to 8 years of age. The results of this study contribute to the growing body of evidence supporting the benefit of indirect protection with conjugated vaccines, and emphasize the importance of high sustainable vaccine coverage rates. The second and the third studies used data from the Tuberculosis Epidemiologic Studies Consortium (TBESC) Study-1, a 10-site collaboration of academic institutions and state and local TB control programs that is funded and administered by the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention (CDC). The second study evaluated the impact of Bacille Calmette Guérin (BCG) vaccination, which continues to be the only vaccine available for prevention of TB, on tuberculin skin testing (TST) results. Using the data collected TBESC Study-1 between September 2012 and September 2014, we examined the association between BCG vaccination and TST positivity. Logistic regression models were used to calculate adjusted prevalence ratios (PR) and 95% confidence intervals (CI). Prior BCG vaccination had no impact on the TST results once adjusted for history of household contacts (adjusted PR 1.0, 95% CI 0.4–1.5). The results of this study add further evidence that BCG vaccination has little impact on TST results in children, particularly in older age groups. The third study examined the cost-effectiveness of three different screening strategies compared to no screening for latent tuberculosis infection (LTBI) in a population with high proportion of foreign-born individuals who have different risk levels for developing TB. In this study, everyone was tested with using all available tools for LTBI: TST, and interferon-gamma release assays (IGRAs) during their enrollment visit. We used decision tree analysis and Markov models to compare TST only, IGRA only, TST followed by IGRA among those who were TST positive, and no screening strategies. Regardless of the assumptions and tests used, screening provided better health outcomes such as less TB cases and less TB related mortality compared to no screening. The incremental cost-effectiveness ratio (ICER) of TST followed by IGRA compared to no screening was $75,094 per QALY gained. The results of this study suggest that prioritizing certain groups for targeted LTBI screening such as foreign-born individuals, and using TST followed by IGRA can maximize the impact of public health resources allocated to eradicate TB in the U.S. The findings from these studies will contribute to the further understanding of the impact of the vaccines and the changing epidemiology of vaccine-preventable diseases providing more insight to formulate new strategies to improve overall health of children.

Presentation: A 3 month-old male is referred for admission with a 2-day history of fever, having been diagnosed with pneumonia and prescribed a cephalosporin on the previous day. A blood culture obtained at that time is positive for coagulase negative Staphyloccocus. On exam, he is ill-appearing. He has bilateral conjunctivitis that spares the limbus, non-exudative pharyngitis, and a polymorphic truncal rash. There is no appreciable cervical lymphadenopathy or extremity involvement. A chest x-ray demonstrates a round infiltrate of the left upper lobe, and initial labs reveal a white blood count of 17.5, a C-reactive protein (CRP) of 23.9 mg/dL, and a normal comprehensive metabolic panel. His positive blood culture is deemed a contaminant, and antibiotic coverage for community-acquired pneumonia is given with ampicillin. Diagnostic evaluation: On day 5 of illness, his fevers persist despite broadened antibiotic coverage. Further work-up has ruled out viral respiratory pathogens and Epstein-Barr virus as a cause of persistent fevers. Incomplete Kawasaki disease is suspected due to continued fevers, the presence of three clinical criteria, and further increase in his CRP. He lacks other supplemental laboratory criteria, so an echocardiogram is obtained that shows mild dilation of the left anterior descending artery (LAD) of indeterminate significance. A repeat echocardiogram 2 days later reveals progressive dilation of left main coronary artery (LMCA), LAD, and right coronary artery (RCA). Diagnosis: Dilation of the LAD and RCA confirm a diagnosis of incomplete Kawasaki disease. Within 48 hours of treatment with IVIG and high-dose aspirin, the patient is afebrile with resolving symptoms and a declining CRP. He is discharged on the 9th day of illness on low dose aspirin and a cephalosporin to complete an antibiotic course for concurrent pneumonia. Conclusion & Discussion: This case illustrates the importance of maintaining a high index of suspicion for an incomplete presentation of Kawasaki disease, particularly among infants. The American Heart Association’s guidelines were updated in 2017 to improve recognition of incomplete Kawasaki disease, particularly among infants who are more likely to have an incomplete presentation, abnormalities of the coronary arteries, and a delayed diagnosis. The key to this patient’s diagnosis was the presence of a bilateral conjunctivitis that spared the limbus. A bilateral, non-exudative conjunctivitis that spares the limbus has been recognized as a feature suggestive of Kawasaki disease for the better part of four decades; our review of the literature suggests this feature is highly specific to the diagnosis of Kawasaki disease.

Acute lower respiratory tract infections are a leading cause of morbidity and mortality world-wide. Streptococcus pneumoniae (pneumococcus) is the most common bacterial cause of community-acquired pneumonia. Recovery from pneumococcal pneumonia results in the formation of resident memory CD4+ T cells, which act on lung epithelial cells to accelerate immune responses. Alveolar macrophages (AMs) are tissue-resident macrophages localized in the air spaces, where they orchestrate the lung anti-microbial responses. We hypothesized that recovery from pneumococcal pneumonia results in remodeling of the pool of alveolar macrophages, which act in concordance with other immune cells to protect the lungs from future infections. Although AM numbers were unchanged in experienced lungs, their surface phenotype showed significant changes, most prominently an increased MHC-II and a decreased SiglecF. This experienced AM phenotype was regionally-localized and long-lasting. Experienced AMs also exhibited extensive remodeling on the metabolomics and transcriptional level. Experienced AMs demonstrated significant increases in phosphocreatine and its metabolite precursors. The transcriptional analyses also revealed extensive changes. At baseline, experienced AMs exhibited a significant reduction in cell cycle activity and mRNA processing compared to naïve mice. During acute pneumonia, experienced AMs exhibited significant increases in immune signaling and energy metabolism. Moreover, transcriptional data also revealed strong but imperfect enrichment of a signature previously associated with IFN𝛾 signaling and marrow-derived AMs. IFN𝛾 gain and loss of functions experiments corroborated transcriptional data and revealed an essential role for IFN𝛾 in directly driving the AM MHC-II remodeling. Several immune cells produced IFN𝛾, with neutrophils being the most prominent source after the 1st pneumococcal challenge but other cells predominating after the 2nd pneumococcal challenge. CD4+ T cell depletion studies demonstrated that AMs' experienced phenotype was independent of CD4+ T cells. In contrast to naïve mice, lineage-tracing studies demonstrated that marrow-derived AMs predominately constitute the experienced AM pool. Upon experience, both embryonic AMs and marrow-derived AMs demonstrated similar remodeling for both SiglecF and MHC-II on their surfaces. While all AM similarly remodeled independent of their origin, marrow-derived AMs in experienced lungs displayed some differences from their embryonic counterparts, being less phagocytic. In conclusion, recovery from pneumococcal pneumonia remodels the pool of alveolar macrophages to acquire adaptive characteristics. This remodeling involves a combination of recruitment of new cells and trained immunity via IFN𝛾 signaling.

Percutaneous endoscopic gastrostomy (PEG) is currently a popular method of administering enteral feeding. Most of these patients are elderly, debilitated, and chronically ill. They are on a number of medications and have multiple diseases. With impaired consciousness and swallowing disability, these patients are prone to develop pneumonia. In order to identify possible risk factors, we followed 24 men who underwent PEG for the occurrence of pneumonia or until they died. We then analyzed the medical records of these patients for potential risk factors for pneumonia. The presence of esophagitis during PEG placement endoscopy and history of pneumonia prior to PEG were significant risk factors. Advanced age and cerebrovascular accident (CVA) tended to indicate a higher risk of pneumonia. Taking these risk factors into consideration may be beneficial in the management of such patients.

Three Legionella-like organisms isolated from patients with pneumonia are shown to belong to the species Legionella sainthelensi by DNA hybridization studies and to a new serogroup, serogroup 2, by serological studies (ATCC 49322). L. sainthelensi serogroup 2 and L. santicrusis are indistinguishable bu slide agglutination, but are separable on the basis of their cell wall fatty acid profiles. © 1990.

Vitamin D is known to benefit skeletal bone health and prevent rickets in children. Limited evidence exists to support a role of vitamin D in linear growth and stunting, especially in children at high risk for growth faltering, e.g. undernourished low socio-economic status children <5 years. Also, it is unclear if the immunomodulatory benefits of vitamin D impact childhood pneumonia. It is critical to determine whether vitamin D ameliorates stunting and pneumonia, as these conditions are responsible for a high burden of child mortality and morbidity. A secondary analysis of two studies in Ecuador was undertaken to determine the prevalence of vitamin D deficiency and the effect of vitamin D status on growth (height-for-age (HAZ) and weight-for-age (WAZ) z-scores) (n=516) and illness duration in children hospitalized for severe pneumonia (n=348). Serum 25-hydroxyvitamin D (25(OH)D) concentrations of children who participated in a community-based trial (ages 6-36 months) and hospital-based trial (ages 2-59 months) were determined at baseline. Overall, 18.6% of children had serum 25(OH)D levels <17 ng/ml (n=516), 62.2% were stunted (HAZ≤-2), and 65.5% were underweight (WAZ≤-1). Children with 25(OH)D concentrations <17 ng/ml had a higher risk of stunting (HAZ≤-2) than those with concentrations ≥17 ng/ml (ORadj: 2.8; 95%CI: 1.6, 4.7) in logistic regression models. Underweight (WAZ≤-1) children were twice as likely to have 25(OH)D concentrations <17 ng/ml than normal weight children (WAZ>-1) (ORadj: 2.0; 95%CI: 1.2,3.3). Vitamin D deficiency (≤20 ng/ml) did not affect pneumonia duration among hospitalized children in Cox proportional hazard models (HRadj: 1.2; 95% CI: 0.93,1.5). Younger children (2-12 months), underweight children (WAZ≤-2), and children with higher respiratory rates had a longer duration of illness (HRadj: 0.61; 95% CI: 0.43,0.86; HRadj: 0.78; 95% CI: 0.59,1.0; HRadj: 0.97; 95% CI: 0.96,0.99, respectively). Underweight Ecuadorian children are at increased risk for lower serum 25(OH)D concentrations. Low vitamin D status is associated with stunting among undernourished children but not with the duration of pneumonia illness. This indicates that vitamin D may be a modifiable risk factor for stunting, which, if validated in further research, can potentially impart beneficial effects on growth among stunted children in resource limited settings. / 2020-06-30T00:00:00Z

京都大学 / 新制・課程博士 / 博士(社会健康医学) / 甲第24844号 / 社医博第133号 / 新制||社医||13(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 近藤, 尚己, 教授 川上, 浩司, 教授 平井, 豊博 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

No description available.