Dissertations / Theses on the topic 'Respiratory severity severity'

Clinicians use several oxygen-based indices in intensive care units as surrogates to determine the condition of the patient’s lung and verify monitoring progress. Examples of these oxygen indices include the ratio of arterial oxygen tension to inspired oxygen fraction (PaO2/FiO2 ratio); arterial/alveolar oxygen tension ratio (PaO2/PAO2); alveolar–arterial oxygen tension difference (PA-aO2); respiratory index (RI= (PA-aO2)/PaO2), and content-based venous admixture (Qs/Qt). One of the issues with this approach is that these indices fail to take into consideration several additional external pulmonary physiological factors and, as such, these indices could potentially mislead clinicians. This thesis explores the nature of the oxygen-tension-based indices response and examined the effect that varying certain external pulmonary factors, such as FiO2, PaCO2, Hb, respiratory rate, oxygen consumption, cardiac output, and respiratory quotient, had on PaO2 using virtual subjects and patients’ data to quantify oxygenation defect through a combination of mathematics, different diseases, and pathophysiology. There were one or two approaches that could lead us to the answer, and many dead end routes. Eventually, the research produced a new index that was compared and validated using two approaches. First, on virtual subjects with lung pathologies that were commonly seen in the intensive care unit and then on real clinical data that was obtained from the intensive care unit. The results of these validation investigations indicated that the proposed index is more robust and resistant to variations in certain external pulmonary factors than the PaO2/FiO2 ratio. As such, there is a strong indication that it may help to improve the quality of patient care provided. The feasibility of manually calculating and applying this newly proposed index in the ICU is an issue that merits further exploration. Theoretically, if the newly proposed index was found to be practicable, it could improve the healthcare provided; reduce the cost of unnecessary blood work, and save time and effort. However, due to the time it takes to calculate crPaO2 manually, the use of medical technology and computer applications is desirable.

The molecular mechanisms underlying susceptibility to severe respiratory syncytial virus (RSV) infection remain poorly understood. Herein, we report on the role of osteopontin (OPN) in regulation of RSV infection in human epithelial cells and how interleukin-1 beta (IL-1β), a cytokine secreted soon after RSV infection, when persistently expressed can induce OPN expression leading to increased viral infection. We first compared OPN expression in two human epithelial cell lines: HEK-293 and HEp-2. In contrast to HEp-2, HEK-293 expresses low levels of pro-caspase-1 resulting in decreased IL-1β expression in response to RSV infection. We found a correlation between low IL-1β levels and a delay in induction of OPN expression in RSV-infected HEK-293 cells compared to HEp-2. This phenomenon could partially explain the high susceptibility of HEp-2 cells to RSV infection versus the moderate susceptibility of HEK-293 cells. Also, HEK-293 cells expressing low levels of pro-caspase-1 exhibit decreased IL-1β expression and delayed OPN expression in response to RSV infection. HEK-293 cells incubated with human rIL-1β showed a dose-dependent increase in OPN expression upon RSV infection. Also, incubation with rOPN increased RSV viral load. Moreover, HEp-2 cells or mice infected with a mucogenic RSV strain RSV-L19F showed elevated levels of OPN in contrast to mice infected with the laboratory RSV strain rA2. This correlated with elevated levels of OPN following infection with RSV-L19F compared to rA2. Together, these results demonstrate that increased OPN expression is regulated in part by IL-1β, and the interplay between IL-1β and OPN signaling has a pivotal role in the spread of RSV infection.

<p> INTRODUCTION: Although recent studies have found that the lower respiratory tract microbiome was different in asthmatics compared to non-asthmatics in adults, the microbiome of asthmatic people with and without asthma exacerbation has not been well investigated. </p><p> OBJECTIVES: The primary objective of the study was to compare the abundance and diversity of the respiratory tract microbiome in children with and without asthma exacerbation. </p><p> METHODS: This was a cross sectional study where asthmatic children from 5-18 years old were recruited at the emergency department at LeBonheur Children&rsquo;s Hospital, Memphis, TN. Recruited children were further grouped by asthma exacerbation level and asthma severity level. Induced sputum samples and nasopharyngeal swabs were collected to analyze the microbiome in the two sources with Illumina based sequencing. The primary outcome to measure was the microbiome abundance and diversity of specific taxa in the two sites with or without current asthma exacerbation. The secondary outcome to measure was the microbiome abundance and diversity of specific taxa in the two sites with various levels of asthma severity. The additional outcome to measure was the specific microbial taxa in the two sites associated with an increased or decreased risk of asthma exacerbation or severity. </p><p> RESULTS: 51 children from 5-10 years old were recruited. The relative abundance of 9 taxa (e.g. Moraxella) were significantly higher in nasopharyngeal samples, and the relative abundance of 26 taxa (e.g. Streptococcus) were significantly higher in induced sputum samples. No significant difference in abundance and diversity was found with various asthma exacerbation and severity levels in either of the two sites. No specific taxon was significantly associated with an increased or a decreased risk of asthma exacerbation or severity. </p><p> CONCLUSION: Microbiome composition differed significantly in induced sputum samples compared to nasopharyngeal samples. No significant change of microbial abundance and diversity in the two sites was associated with asthma exacerbation or severity. No specific taxon in the two sites was associated with an increased or a decreased risk of asthma exacerbation or severity. Larger, comparative studies need to be performed to discover subtle difference in future.</p><p>

The lung was recently identified to consist of a complex microenvironment made up of microorganisms that interact with one another and the host cells via direct and indirect interactions. As a result, understanding the dynamic of the microbiome in chronic respiratory diseases has become the focus of pulmonary researches. In cystic fibrosis (CF), chronic infections are a comorbidity associated with the genetic disorder. Recently, it was noted that the interactions of the fungus, Aspergillus fumigatus, and the bacterium, Pseudomonas aeruginosa together contribute to more severe disease outcomes in CF patients. In vitro co-cultures show that P. aeruginosa and A. fumigatus can affect one another’s growth and pathogenicity, but very few studies have attempted to model interactions of these microorganisms in vivo. Based on clinical and basic research, we developed a co-exposure model in which we could compare non-allergic and allergic animals co-exposed to Pseudomonas aeruginosa and Aspergillus fumigatus. While both groups had significant neutrophilia and production of acute phase response cytokines and chemokines, the allergic co-exposed group had a greater mortality with 34.8% of the animals expiring by 24h in comparison to 12.5% for the non-allergic co-exposed animals and 100% survival in the controls. A contributing factor to the more severe disease outcomes in the allergic co-exposed group is the increase in eosinophilic inflammation and IL-17A production, which only occurs when both microorganisms are viable. In addition, it was found that viable P. aeruginosa but not A. fumigatus causes interstitial inflammation, significant neutrophilia, and even death during co-exposures. The decline in health of animals co-exposed to the fungus and bacteria could be attributed not only to the host’s inflammatory response, but also to the spatial and temporal co-localization in the lung. To address this, we performed in vitro studies finding an aggregation of the microorganisms that could also be identified in vivo. This current research emphasizes the need for in vivo studies on polymicrobial interactions.<br>ND Agricultural Experiment Station; National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R155AI137886

Introduction Airway remodelling describes the histopathological changes in tissue architecture observed in obstructive lung diseases such as asthma and may have a negative impact on lung function. These changes do not appear to be treated by current asthma treatments. Changes observed during airway remodelling include increased thickness of airway smooth muscle (ASM) layer and enhanced extracellular matrix (ECM) deposition. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, which facilitate tissue remodelling via ECM protein degradation. Matrix metalloproteinase-1 (MMP-1) and mast cells are present in the airways of patients with asthma (but not in healthy people). MMPs expression is highly regulated in lungs and is increased in disease states. My project aimed to assess MMP-1, -2 and -9 expression and activity in asthma airways. Furthermore, the underlying mechanism of MMP-1 activation and subsequently its role in airway remodelling and worsening asthma severity was investigated in the context of asthma exacerbation, which is thought to be an exaggerated lower airway inflammatory response to an environmental exposure such as respiratory virus infection. Methods Patients with stable asthma and healthy controls underwent spirometry, methacholine airway (PC20 ) challenge, exhaled nitric oxide (FeNO) test, bronchoscopy/bronchial washings and primary airway smooth muscle (ASM) cell cultures. A second asthma group (mild to moderate severity) and controls had symptom scores, spirometry and bronchoalveolar lavage (BAL) before and after rhinovirus inoculation. ECM was prepared from decellularised primary ASM cultures. MMP-1 protein levels and activity were assessed in bronchial fluid samples by enzyme-linked immunosorbent assay (ELISA), western blotting and fluorescent activity assay. ASM cell growth was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) reduction assay and cell counts. Bronchial fluid gelatinase (MMP-2 and -9) expression and activity was assessed by gelatin zymography. Results MMP-1 and MMP-9 expression was enhanced in both stable asthma and during asthma exacerbations, whilst MMP-2 expression was only increased during asthma exacerbations. MMP-1 can be activated by tryptase, which is an inflammatory product of mast cell degranulation. Activated (degranulated) mast cells enhanced proliferation of both control and asthma ASM cells via the production of a pro-proliferative ECM in vitro and the proliferative effect was dependent on MMP-1. In patients with asthma, mast cells numbers within ASM bundles were associated with ASM growth. MMP-1 protein levels were related to bronchial reactivity and MMP-1 activity increased during asthma exacerbations, where its levels were related to exacerbation severity. Conclusion This study suggests that MMP-1 plays an important role in asthma pathophysiology and that ASM/mast cell interactions contribute to asthma severity by transiently increasing MMP-1 activation, ASM growth and airway responsiveness. Moreover, there is increased expression of MMP-2 and -9 during asthma exacerbations compared with stable asthma. As both MMP-2 and -9 act as mediators of inflammation (Okada, S. et al., 1997) (Elkington, P.T.G., 2006) and tissue remodelling (Oshita, Y. et al., 2003), an increase in gelatinolytic activity linked to MMP-2 and MMP-9 is also likely to play a significant role in the pathophysiology of asthma exacerbations.

Skeletal muscle dysfunction and wasting are major comorbidities of chronic obstructive pulmonary disease (COPD) and lung cancer (LC). Despite that the lower limb muscles are usually more severely affected, the respiratory muscles may also experience structural and functional abnormalities in COPD. Muscle dysfunction negatively impacts on the patients’ quality of life by impairing their exercise tolerance even of daily life activities. Several molecular mechanisms are involved in the etiology of COPD muscle dysfunction. In this regard, we hypothesized that oxidative stress may be a trigger of enhanced muscle proteolysis and dysfunction in the limb muscles of cachectic patients bearing two different respiratory conditions such as COPD and LC, and that epigenetic events may be involved in the pathophysiology of COPD muscle dysfunction of both respiratory and limb muscles.<br>La disfunció muscular esquelètica i la pèrdua de massa muscular són dues manifestacions sistèmiques freqüents en malalties com la Malaltia Pulmonar Obstructiva Crònica (MPOC) i el Càncer de Pulmó (CP). Malgrat que en els malalts amb MPOC, els músculs perifèrics sovint es veuen més greument afectats, els músculs respiratoris també mostren alteracions estructurals i funcionals. La disfunció muscular que pateixen aquests pacients afecta negativament la seva qualitat de vida, no només reduint la seva tolerància a l’exercici físic sinó també a les seves activitats quotidianes. Diferents mecanismes moleculars estan implicats en la etiologia de la disfunció muscular en la MPOC. La nostra hipòtesi és que l’estrès oxidatiu podria ser un desencadenant de l’augment de proteòlisi i disfunció muscular en els músculs perifèrics de pacients amb caquèxia associada a processos respiratoris com ara la MPOC i el CP. Els mecanismes epigenètics podrien estar també implicats en la fisiopatologia de la disfunció muscular en la MPOC.

Although upper respiratory tract infections (URTI) are the most frequent illness among humans, insufficient evidence exists to determine if exercise training during an URTI may prolong or intensify an URTI. The purpose of this investigation was to determine the effect of exercise training on the severity and duration of URTI symptoms. Following serological screening, those subjects who were rhinovirus 16 (RV 16) antibody-free completed a graded exercise test. Thirty-four individuals (ages 18-29 years) of moderate fitness (between 32 ml/kg"1/miri 1- 60 ml/kg 1/min"1) were randomly assigned to the exercise group (EX) while 16 individuals of similar age served as a nonexercise control group (CTL). All subjects were inoculated with RV 16 on two consecutive days. EX subjects completed 40 minutes of supervised exercise at 70% of heart rate reserve within 18 hours of each inoculation and then exercised every other day for the next eight days (total of six exercise sessions). Immediately following each exercise period subjects completed a symptom checklist. EX subjects were strongly encouraged to abstain from any additional physical activity while the CTL group was encouraged to be as sedentary as possible for ten days beginning the first day of inoculation. Prior to the first inoculation and every 12 hours afterwards all subjects completed a 13 item symptom severity checklist and a physical activity log (e.g., minutes of walking, and hours of work). Used facial tissues were collected and weighed during these same reporting periods. One-way analysis of variance indicated that there! was no significant difference between groups with respect to additional physical activity. Two-way analysis of variance indicated that there were no significant differences in either the severity or duration of an URTI (symptom scores, mucous weights) between the EX and CTL groups for any given day. Further, no significant differences were observed between the pre and post exercise symptom scores for the EX group. These results suggests that moderate exercise training during a rhinovirus-caused URTI does not appear to alter the severity and duration of the illness. This was the first study to examine the influence of exercise on symptom severity and duration during an URTI. Additional studies should be performed utilizing various exercise prescriptions (e.g. intensity, frequency and duration), subject populations (e.g. younger and older), and fitness levels (e.g. sedentary, and highly fit).<br>School of Physical Education

Respiratory Syncytial Virus (RSV) is a major cause of bronchiolitis and pneumonia in infants, immunocompromised and the elderly in both developed and developing countries. Re-infections are common and G protein variability is one mechanism to overcome herd immunity. This is illustrated by the appearance of the BA genotype with a 60 nucleotide duplication dominating the subtype B genotypes in epidemics worldwide. To investigate the evolution of subtype A and B in South Africa (SA) since 2002 the genetic variability in the G protein was analysed in all recent strains isolated over four years (2006-2009) in SA hospitals. Bayesian analysis revealed a replacement of all subtype B genotypes previously identified in SA with the BA genotype since 2006, while subtype A genotypes identified in previous years are still circulating. The evolutionary rate of the SA BA genotype was shown to be 2.305 x 10-3 nucleotide substitutions/site/year while subtype A was shown to have 3.382 x 10-3 substitutions/site/year and drift was evident. The most recent common ancestor (MRCA) of the SA BA viruses was determined to date back to 1997. All SA BA isolates clustered with the BA-IV sub-genotype and the appearance of new sub-genotypes within this branch may occur if drift continues. Sequencing of the complete G protein of selected BA SA strains revealed an additional 6 nucleotide deletion. When comparing G protein variability with disease severity, the dominating subtype/genotype in each season was also the subtype/genotype that was associated with increased hospitalizations. No direct association between G protein variability and disease severity was seen. Subtype/genotype switching was evident over the four years most probably because of herd immunity. G protein variability may play a role in RSV‟s ability to re-establish annual epidemics by allowing immune evasion. Certain substitutions or alterations may enhance the fitness of viruses as is evident with the BA strains that replaced all other B genotypes previously identified in SA. The G protein‟s ability to accommodate such substantial changes and facilitate immune evasion may complicate vaccine development. It remains to be seen if this BA genotype will remain dominant or if the dominance will eventually fade because of herd immunity. Subtyping of RSV strains over the four years identified G protein PCR amplicons significantly reduced in size in 2 out of 209 clinical specimens. Sequence analysis revealed subtype B strains lacking nearly the entire G protein ectodomain in one HIV positive and one HIV exposed child hospitalized with pneumonia. G protein deletion mutants replicate effectively in vitro but have not been detected in nature. This study suggests that RSV clinical strains that lack most of the G protein gene may occur in immunocompromised patients with lower respiratory tract infection (LRTI). The molecular mechanism whereby this occurs is not clear, however reduced immune pressure in these patients may allow these strains to utilise the F protein for binding and replication. Further characterization of such strains may elucidate the replication and pathogenic potential, however low viral load and long term storage of specimens complicated the isolation of such strains. Acquisition of the 60 nucleotide duplication appeared to have improved the fitness of the BA viruses and more recent subtype B strains may need to be included in experimental vaccines to evaluate their efficacy in the current setting of evolved circulating strains. In addition, the association of clinical strains lacking most of the G protein with LRTI may have implications for the utilisation of certain attenuated strains in immunocompromised children. RSV is unique among paramyxoviruses in having two non-structural (NS) proteins that play a major role in inhibiting the host‟s immune response. Sequence and quantification analysis of these proteins were performed to determine its role in disease severity. We were unable to attribute specific protein polymorphisms with differences in disease severity but identified genome heterogeneity (quasispecies) within patients which may have an influence on the NS protein function, and also have an influence on the innate immune response and thus an effect on disease severity. When comparing patients with mild and severe disease, higher expression levels of NS1 were seen in the hospitalized group compared to the out-patient group, supporting our hypothesis that increased levels of NS may lead to enhanced suppression of the interferon pathway and in effect result in more severe disease. However, the opposite was found for NS2 with higher expression levels in the mild group. Genetic variability within the gene-end and gene-start sequences were not seen thus could not explain the differences in expression levels observed, although variability within the promoter area may need to be investigated.<br>Dissertation (MSc)--University of Pretoria, 2012.<br>Medical Virology<br>MSc<br>Unrestricted

Aims: to establish the prevalence of RSV and HMPV in Yemeni children with ARI, describe the risk factors for disease severity, the cytokine (IL6, TNF-a, IL7, IL 10, IL12 and INF-y) and chemokine (IL8 and RANTES) concentrations in children with RSV and/or HMPV and their association with disease severity. To determine serum micronutrients and C- reactive protein concentrations in children with RSV and/or HMPV with mild and severe ARI. Methodology: Children <2 years old with signs and symptoms of ARI attending a reference hospital in Sana'a, Yemen, were enrolled during 2002 and 2003. RSV and HMPV were identified using RT-PCR. Children with mild/moderate (P02 :-f : 88%) hypoxia were compared to those with severe hypoxia (pO2 < 88%). Cytokines and chemokines were measured by ELISA. Inductive Coupled Plasma Mass Spectrometry was used to measure zinc, selenium and copper and a High Performance Liquid Chromatography to measure serum vitamins A and E concentrations. Results: RSV was identified in 40%, HMPV in 7% and RSV/HMPV co-infections in 4% of the children. Group A was the predominating RSV. The period with high RSV and HMPV incidence occurred from December to March but both viruses were detected throughout the study. Single RSV and HMPV infections were undistinguishable clinically and dual infections were common. The factors independently associated with an increased risk of severe hypoxia due to RSV were age :53 months, the child not having his/her vaccines up to date, the presence of a smoker at home and using a cooking fuel other than gas. In contrast, only age <_ 3 months, having a history of recurrent ARI and using a source of fuel other than gas were the only risk factors found to be independently associated with an increased risk of severe HMPV. RSV and HMPV infections in infants differ significantly in regard to the type of induced immune response elicited and coinfections modified the production of cytokines. Young age modifies immune responses against the infections. There was an inverse association of IL7 with hypoxia due to RSV. Micronutrients deficiency is widespread in our study population (especially with RSV) and was associated with disease severity and inflammatory stress with an inverse relationship between zinc and copper concentrations and zinc/copper ratios of children with RSV and HMPV. Conclusion: RSV and HMPV are important causes for ARI in Yemen. This thesis describes the immunological mechanisms observed in RSV and HMPV infections and the risk factors associated with disease severity. This information can be used to inform the development of curative and preventive strategies for acute respiratory infections and for the monitoring of curative interventions. Micronutrient deficiencies are highly prevalent in children with ARI and micronutrient supplementation may decrease the risk for developing severe RSV and HMPV disease.

Obstructive sleep apnea (OSA) is estimated to affect 2 to 4 percent of the adult population (Young T 1993, Skomro and Kryger 1999). However, an estimated 80 to 90 percent of adults with moderate to severe OSA may be clinically undiagnosed. Identification of those at risk and their subsequent diagnosis is, obviously, of great concern to clinicians. This investigation included three distinct research aims, which were the following: (1): In order to establish reliability of hemodynamic measures to be used during exercise testing, a study was conducted on the acetylene single-breath cardiac output (Qc) technique in 15 healthy subjects. This was completed in order to establish reliability of exercise Qc and total peripheral resistance (TPR), these responses could then be investigated acutely in the context of evaluating the relation of these measures to markers of disease in OSA patients. (2): The primary research aim was to describe the extent to which graded exercise testing may reveal abnormalities in hemodynamic function in obstructive sleep apnea (OSA) patients, particularly with respect to cardiac output (Qc), mean arterial pressure (MAP), and TPR that may be related to polysomnography (PSG) markers of OSA severity. Cardiorespiratory and hemodynamic responses that were evaluated included the following: peak oxygen consumption (VO2pk), end-tidal carbon dioxide production (PETCO2), end-tidal oxygen pressure (PETO2), heart rate (HR), blood pressure (systolic = SBP and diastolic = DBP), rate pressure product (RPP), TPR and its derivatives including MAP and Qc, in OSA patients. A global biochemical marker of vascular function, 24-hour urinary nitrite/ nitrate elimination was also determined for each patient. (3): The last aim was included in order to provide qualitative information concerning treatment, subjective sleep and daytime function, and physical activity levels of the OSA patients in this investigation as well as to give insights into the special challenges and potential for doing trials involving nCPAP and physical exercise training with OSA patients. Results from this study can be used to improve clinical evaluation procedures as well as to better understand underlying mechanisms relative to the link between cardiovascular disease and OSA<br>Ph. D.

Heart Rate Variability (HRV) currently is utilized when assessing the risk of mortality in individuals suffering from coronary heart disease or diabetic neuropathy. Research has shown that patients with Obstructive Sleep Apnea (OSA) also show a decrease in HRV, as well as an increase in sympathetic drive characterized by an increase in the low-frequency component of HRV. HRV, in conjunction with other indicators, may represent a non-invasive, low cost method for the confirmation of severity of OSA in some patients and therefore may represent an additional tool for the assessment of risk in these individuals. This becomes especially true when urinary catecholamines, fitness level, and quality of life (QOL) assessment are included. The purpose of this study was to determine if a correlation exists between severity of OSA as assessed by respiratory distress index (RDI) and the selected measures HRV, fitness, QOL, and catecholamine output. Subjects were 6 men and 5 women who were recently diagnosed with OSA by polysomnographic (PSG) study. HRV and blood pressure was measured during two consecutive trials consisting of 512 heartbeats. Catecholamine levels were determined by HPLC following 24-hour urine collection. Fitness levels were established following cycle ergometer testing and QOL following questionnaire completion. Subjects with lower weight, BMI, and neck circumference had significantly higher parasympathetic influence as analyzed through the amount of high frequency component of HRV (r =.738, .726, .789, respectively; p<0.05). Respiratory distress index (RDI) was negatively related to the average heart rate (HR=RR average, r = -.610, p<0.05), while the amount of total sleep (r = .657, p<0.05) and REM sleep (r = .739, p<0.01) increased as HR increased. The average HR was correlated to the predicted VO2max (r = .677, p<0.05). When the frequency components of HRV, fitness, QOL, and catecholamines were combined, the association to RDI increased dramatically (r = .984, p = .02). The results indicate that as the severity of OSA increases, markers of fitness, QOL, and sleep decrease. There is also an inverse relationship between autonomic function and severity of OSA. It is concluded that HRV and fitness levels are inversely related to the severity of OSA, and that these measures may be developed into a risk assessment tool for use in OSA patient evaluatio<br>Master of Science

The objective of this research was to investigate the relationship between ante mortem assessments of disease severity and the gross pathological manifestations of disease observed during necropsy. Many clinical assessments are subjective, the hypothesis under investigation is that these correlate with the pathological progression of the disease in the animal. Bronchopneumonia due to Pasteurella haemolytica A1 in calves, Actinobacillus pleuropneumoniae infection in pigs, and Mycoplasma gallisepticum infection of chickens were investigated. The diseases were induced by experimental infection and animals were closely monitored. Both graphical and statistical methods were used to correlate ante mortem measures of disease severity with each other and with post mortem measures of gross pathological lesions and bacteriological isolation of the infecting organism. Calves showed highly correlated relationship between ante mortem and post mortem indicators of disease severity. For pigs, the relationship between clinical variables and gross pathology was much less clear and varied between the three serotypes of Actinobacillus pleuropneumoniae used (serotypes 3, 5a, 9). In chickens, there were few clinical signs evident until the pathology compromised the physiological reserve capacity of the airsacs. Beyond this "threshold", rapid increases in respiratory auscultation score, mycoplasma isolation and serological response were all indicators of increasing gross pathological changes. The relationships between ante mortem assessments of disease severity and the gross pathological lesions recorded at necropsy were usually non-linear and differed for each pair of variables correlated. The relationships between clinical variables being used as indicators of disease severity and the post mortem pathological measures need to be clearly understood for each variable before conclusions concerning the disease severity, prognosis or, in treated animals, efficacy predictions can be made.

INTRODUÇÃO: As infecções do aparelho respiratório inferior (IARI) constituem importante causa de morbi-mortalidade nas crianças abaixo dos cinco anos de idade e são responsáveis por um grande número de hospitalizações. Os vírus são os seus principais agentes causadores. A maioria das IARI, na criança, tem um único agente viral identificado. Com o advento de técnicas moleculares, tornou-se possível a identificação de mais de um agente viral numa mesma amostra de secreção respiratória. No que diz respeito à gravidade da doença entre crianças infectadas por um único vírus em relação às crianças infectadas por dois ou mais vírus (coinfecção), a literatura científica revela-se conflitante. No presente estudo, os autores comparam a gravidade da infecção entre um ou mais agentes virais em crianças até 24 meses de idade hospitalizadas com infecção aguda do aparelho respiratório inferior e os possíveis fatores associados à evolução clinica. CASUÌSTICA E MÉTODOS: em estudo de coorte retrospectivo foram analisadas 304 crianças hospitalizadas com infecção respiratória aguda no período de fevereiro a novembro de 2005. Foram avaliadas as características demográficas dos pacientes (idade, sexo), diagnóstico de alta, presença de fatores de risco para gravidade (prematuridade, displasia broncopulmonar, cardiopatia, imunodepressão, neuropatia) e os seguintes desfechos de gravidade: tempo de internação, necessidade e tempo de oxigênio, necessidade e tempo de internação em UTI, necessidade e tempo de ventilação mecânica. A técnica de PCR ou RT-PCR foi utilizada para identificação de oito vírus respiratórios: vírus sincicial respiratório (VSR), metapneumovírus humano (MPV-h), parainfluenza 1, 2 e 3 (PIV), Influenza A e B (IV A e B) e adenovírus (AdV). RESULTADOS: Foram identificados agentes virais em 219 (72%) crianças sendo que 158 (72%) crianças apresentaram infecção por um único agente viral (IU) e 61 (28%) apresentaram co-infecção (CI). O VSR foi o vírus mais freqüente em ambos os grupos. No grupo IU, o VSR esteve presente em 121 amostras (76,6%), seguido do AdV em 20 amostras (12,6%) e pelo MPV-h em 11 amostras (7%). No grupo CI, o agente mais identificado em associação com o VSR foi o AdV, presente em 24 amostras (39%) seguido do MPV-h em 16 amostras (26%). Não foi encontrada diferença entre os grupos IU e CI quanto à idade (p=0,66), sexo (p=0,84), história de prematuridade (p=0,87). A distribuição das infecções virais, segundo o mês de ocorrência, foi semelhante nos grupos IU e CI, predominando nos meses de abril, maio e junho. As infecções virais foram mais frequentes nas crianças menores de 1 ano de idade tanto no grupo IU como no grupo CI. A bronquiolite foi o diagnóstico mais freqüente em ambos os grupos (42% IU e 33% CI). Não houve diferença, entre os dois grupos, quanto à necessidade de UTI (p=0,12), necessidade de oxigênio (p=0,71), necessidade de ventilação mecânica (p=0,35), tempo de internação (p=0,18), tempo de UTI (p=0,8), tempo de ventilação mecânica (p=0,8), tempo de oxigênio (p=0,81). CONCLUSÃO: A gravidade das infecções virais do aparelho respiratório inferior em lactentes hospitalizados foi semelhante tanto em pacientes com coinfecção como nos pacientes com infecção por um único agente.<br>BACKGROUND: Lower acute respiratory tract infections are a major cause of morbidity and mortality in children under five years of age and lead to a large number of hospitalizations. Acute bronchiolitis and pneumonia correspond to the main manifestations of these infections and viruses are the major ethiologic agents. Whether the infections caused by one or more virus are associated with the disease severity is still controversial . OBJECVIVES: to compare the severity of the infection by one or more viral agents in children up to 24 months of age hospitalized with acute lower respiratory tract infection and the possible associated factors with clinical outcome. PATIENTS AND METHODS: A retrospective study of 304 children hospitalized with acute respiratory disease from February to November 2005. We evaluated the demographics (age, sex), disease severity risk factors (prematurity, bronchopulmonary dysplasia, heart disease, immunosuppression, neuropathy, absence of breastfeeding) and the following outcomes: lengh of hospitalization, oxygen therapy, admission in the ICU, need of mechanical ventilation. The PCR or RT-PCR was used to identify eight respiratory viruses: respiratory syncytial virus (RSV), human metapneumovirus (h- MPV), parainfluenzavirus 1, 2 and 3 (PIV), influenza A and B (IV A and B) and adenovirus (AdV). RESULTS: Viral agents were identified in 219 (72%) children. Among them 158 (72%) were infected with a single viral agent and 61 (28%) had co-infection. RSV was the main ethiologic agent in 121 samples (76.6%) in the patients with a single agent , followed by AdV in 20 samples (12.6%) and the h-MPV in 11 samples (7%). In the patients with co-infection, the most common association was the RSV and AdV (39%) followed by the RSV and h-MPV (26%). There was no statistically significant difference between the group with single viral agent and the group with co-infection regarding age (p=0.66), gender (p=0.84), history of prematurity (p=0.87) and history of breastfeeding until 6 months of age (p=0.36). The monthly distribution of viral infections was similar in both groups, predominantly in April, May and June. Children under one year of age were the most afected by acute lower respiratory tract infection in both groups. Bronquiolitis was the most frequent diagnosis in both groups. There was no difference between the groups regarding the need for ICU (p=0.12), oxygen requirement (p=0.71), need for mechanical ventilation (p=0.35), length of hospitalization (p= 0.18), ICU stay (p= 0.8), duration of mechanical ventilation (p=0.8), oxygen therapy (p=0.81). CONCLUSION: In children hospitalized with acute respiratory low tract infection caused by one or more type of virus configure the same disease severity profile.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome in Europe. After inhalation of virus shed by bank voles, the virus systemically targets the vascular endothelium leading to vascular dysfunction and leakage. Many patients with PUUV infection experience cardiopulmonary manifestations but the underlying mechanisms have not been determined. The aims of the studies presented were to describe cardiopulmonary manifestations, investigate pathogenetic mechanisms including presence of virus in the lungs and the local immune response in PUUV infection. The results showed cardiopulmonary involvement of varying severity in almost all studied patients. High-resolution computed tomography frequently revealed vascular leakage into the lungs or pleural cavities. Pulmonary function tests generally showed reduced gas diffusing capacity, evidenced in patients as dyspnea, poor oxygenation and frequent need of oxygen treatment. Among patients who were not fully recovered at 3 months follow-up, remaining decreased gas diffusing capacity was highly common. Echocardiography revealed mainly right heart dysfunction which was related to manifestations within the lungs, in terms of increased estimated pulmonary vascular resistance, mild to moderate pulmonary hypertension, and reduced right ventricular systolic function in patients with more pronounced lung involvement, as indicated by need of oxygen treatment. Analyses on bronchoalveolar lavage (BAL) and bronchial biopsies revealed a highly activated cytotoxic T cell (CTL) response in the lungs. The CTL response was not balanced by the expansion of regulatory T cells and high numbers of CTLs were associated with more severe disease. PUUV RNA was detected in almost all patients’ BAL samples and the viral load was inversely correlated to the number of CTLs. Three patients presenting with severe and fatal cardiopulmonary distress were also described. Autopsies revealed PUUV protein in vascular endothelium in all investigated organs, including the heart and lungs, along with a massive CTL response mainly in the lungs. In conclusion, cardiopulmonary involvement of varying severity was present in almost all patients with PUUV infection. Cytotoxic immune responses could contribute to disease development but also help in clearing the infection. Long lasting fatigue after hantavirus infection may be explained by remaining manifestations within the lungs.

INTRODUÇÃO: Apesar dos avanços terapêuticos, a asma grave (AG) persiste relacionada com alta morbidade e custos de saúde. Diversos fenótipos já foram descritos, porém faltam dados a respeito de como esses fenótipos respondem a diferentes intervenções e quais são as melhores ferramentas para avaliá-los. Além disso, debate-se se é possível alcançar o controle em todos pacientes com AG, questionando sua clássica definição de reversibilidade completa. O objetivo deste estudo é descrever e correlacionar os achados de tomografia computadorizada de alta resolução (TCAR) de tórax em pacientes com AG, principalmente com fenótipo de obstrução persistente (OP), e identificar preditores do controle da asma após tratamento padronizado em centro de referência. MÉTODOS: Foram recrutados pacientes com AG não controlada para receber 2 semanas de corticosteroide oral (CO) e 12 semanas de formoterol+budesonida. Avaliações incluíram ACQ, espirometria, pletismografia e teste de washout de nitrogênio com respiração única (SBN2), em três momentos (basal, após CO e final de 12 semanas). OP foi caracterizada como VEF1/CVF < 0,70 após CO. Para avaliação da TCAR do tórax, utilizou-se software quantitativo incluindo a área de parede (AP), espessura de parede (EP) brônquica e Pi10 (área da parede de uma via aérea teórica com lúmen de 10mm de perímetro) para posterior comparação com dados funcionais. RESULTADOS: Entre os 51 pacientes que completaram o protocolo, 13 (25,5%) atingiram controle da asma. A única variável identificada como preditora de controle foi menor ACQ basal. Baseado no comportamento do FEF25-75, VR/CPT e a inclinação da fase 3 do SBN2, tanto a prova de função pulmonar completa como washout de nitrogênio demonstraram o envolvimento das pequenas vias aéreas nos pacientes com AG com diferentes níveis de gravidade relacionado à obstrução ao fluxo aéreo. Impactação mucoide associou-se a aumento no VEF1 após CO (23 ± 18% versus 8 ± 20% - p=0,017). Não houve diferença quanto à presença de bronquiectasia, EP brônquica aferida qualitativamente e padrão em mosaico na variação do VEF1. O valor médio do Pi10 foi de 4,0 ± 0,26 mm e da AP% do brônquio segmentar apical do lobo superior direito (RB1) foi de 66 ± 4%. O VEF1 mostrou uma correlação inversa tanto com Pi10 quanto com o RB1 AP% (r=-0,438, p=0,004 e r=-0,316, p=0,047, respectivamente). OP esteve presente em 77,4% dos pacientes asmáticos graves apesar do tratamento padronizado e associou-se a maior espessamento das vias aéreas. CONCLUSÕES: Impactação mucoide foi o principal preditor qualitativo tomográfico de ganho funcional após CO, enquanto Pi10 e AP% do RB1 correlacionaram-se com VEF1, sugerindo que, mesmo no subgrupo de pacientes com AG, a TCAR pode ter papel como ferramenta prognóstica. Além disso, apesar do tratamento padronizado, alta proporção de pacientes com AG permaneceu com OP ao fluxo aéreo e pior controle dos sintomas. O envolvimento das pequenas vias aéreas e remodelamento brônquico caracterizado pelo aumento da sua espessura foram os principais componentes destes resultados por se correlacionaram com a gravidade da obstrução ao fluxo aéreo<br>INTRODUCTION: Despite advances in asthma treatment, severe asthma (SA) still results in high morbidity and use of health resources. Several phenotypes have already been described but there are still lack of data regarding how these phenotypes respond to different interventions and which are the best tools to evaluate them. There still debate if all severe asthma patients can achieve control or maintain the classical asthma´s definition of a full reversible airway disease. The aim of this study is to describe and correlate thorax high-resolution computed tomography (HRCT) findings in SA patients, mainly with persistent obstruction phenotype, and to identify predictors related to asthma control after a standardized treatment in a reference center. METHODS: Non-controlled SA patients were enrolled to receive 2 weeks of oral corticosteroids (OC) and 12 weeks of formoterol+budesonide. They were evaluated according to ACQ, spirometry, pletismography and single breath nitrogen washout test (SBN2), at baseline, after OC trial and at the end of 12 weeks. Persistent obstruction (PO) was characterized as FEV1/FVC < 0.70 after OC course. Using quantitative software to evaluate thorax HRCT performed at the end of the study, wall area (WA), wall thickness (WT) and Pi10 (wall area for a theoretical airway with 10mm lumen perimeter) were analyzed and compared with function data. RESULTS: Among 51 patients that completed the protocol, 13 (25.5%) achieved asthma control. The only variable identified as predictor of asthma control was lower baseline ACQ. Based on FEF25-75, RV/TLC and the slope of phase III of SBN2, pletismography and SBN2 maneuvers clearly demonstrated small airway involvement in SA patient with different levels of airflow obstruction severity. The presence of mucoid impaction was associated with significant increase in FEV1 after OC (23 ± 18% versus 8 ± 20% - p=0.017). No difference was found regarding bronchiectasis´ presence, qualitative bronchial wall thickness nor mosaic pattern in the FEV1 variation. The mean pi10 was 4.0 ± 0.26 mm and the right upper lobe apical segmental bronchus (RB1) WA% was 66 ± 4%. Baseline FEV1% predicted presented a significant inverse correlation with both Pi10 and RB1 WA% (r = -0.438, p = 0.004 and r = -0.316, p = 0.047, respectively). 77.4% of severe asthmatic patients had PO despite standardized treatment and presented higher airway thickness. CONCLUSIONS: Mucoid impaction was the main HRCT´s predictor to oral corticosteroid response in this non-controlled severe asthmatic patients group. Pi10 and RB1 WA% correlated to baseline lung function supporting the evidence that, even in a subset of severe asthmatic patients, CT findings can be used as a prognostic tool. Despite optimal treatment and close follow-up, a high proportion of severe asthmatic patients will persist with airflow limitation and poor symptoms control. Small airway involvement and airway remodeling characterized as bronchial thickness are main components that explain our findings since they were related to the severity of persistent obstruction

Introduction: Epidemiological studies have indicated that 5-38% of influenza like illnesses (ILI) develop into severe disease due to, among others, factors such as; underlying chronic diseases, age, pregnancy, and viral mutations. There are suggestions that dual or multiple virus infections may affect disease severity. This study investigated the association between co-infection between influenza A viruses and other respiratory viruses and disease severity. Methodology: Datum for samples from North West England tested between January 2007 and June 2012 was analysed for patterns of co-infection between influenza A viruses and ten respiratory viruses. Risk of hospitalization to a general ward ICU or death in single versus mixed infections was assessed using multiple logistic regression models. Results: One or more viruses were identified in 37.8% (11,715/30,975) of samples, of which 10.4% (1,214) were mixed infections and 89.6% (10,501) were single infections. Among patients with influenza A(H1N1)pdm09, co-infections occurred in 4.7% (137⁄2,879) vs. 6.5% (59⁄902) in those with seasonal influenza A virus infection. In general, patients with mixed respiratory virus infections had a higher risk of admission to a general ward (OR: 1.43, 95% CI: 1.2 – 1.7, p = <0.0001) than those with a single infection. Co-infection between seasonal influenza A viruses and influenza B virus was associated with a significant increase in the risk of admission to ICU/ death (OR: 22.0, 95% CI: 2.21 – 219.8 p = 0.008). RSV/seasonal influenza A viruses co-infection also associated with increased risk but this was not statistically significant. For the pandemic influenza A(H1N1)pdm09 virus, RSV and AdV co-infection increased risk of hospitalization to a general ward, whereas Flu B increased risk of admission to ICU/ death, but none of these were statistically significant. Considering only single infections, RSV and hPIV1-3 increased risk of admission to a general ward (OR: 1.49, 95% CI: 1.28 – 1.73, p = <0.0001 and OR: 1.34, 95% CI: 1.003 – 1.8, p = 0.05) and admission to ICU/ death (OR: 1.5, 95% CI: 1.20 – 2.0, p = <0.0001 and OR: 1.60, 95% CI: 1.02 – 2.40, p = 0.04). Conclusion: Co-infection is a significant predictor of disease outcome; there is insufficient public health data on this subject as not all samples sent for investigation of respiratory virus infection are tested for all respiratory viruses. Integration of testing for respiratory viruses’ co-infections into routine clinical practice and R&D on integrated drugs and vaccines for influenza A&B, RSV, and AdV, and development of multi-target diagnostic tests is encouraged.

Uvod: Iz rezultata brojnih randomiziranih kliničkih studija proizi&scaron;le su smernice u koijma se navodi da je upotreba neinvazivne ventilacije (NIV), uz farmakolo&scaron;ku terapiju, indikovana kod svih bolesnika sa te&scaron;kom egzacerbacijom hronične opstruktivne bolesti pluća (HOBP), i to sa najvi&scaron;im nivoom preporuke. Dokazano je da se upotrebom NIV-a smanjuje broj intubacija, uz smanjenje mortaliteta ali i skraćenje dužine bolničkog lečenja. S obzirom da je nekada ventilatorna potpora bila pružana isključivo u jedinicama intenzivne nege, a da je kapacitet ovakvih odeljenja gotovo stalno popunjen, postavlja se pitanje adekvatnog okruženja unutar bolnice gde se bezbedno i efikasno može primeniti neinvazivna ventilacija, ali gde se i na vreme mogu prepoznati rani znakovi njene neuspe&scaron;ne primene, nakon čega trebaobezbediti pravovremenu endotrahealnu intubaciju. Stoga su rađene brojne studije u cilju izdvajanja ranih prediktora ishoda neinvazivne ventilacije - kako u cilju ranog prepoznavanja neuspeha NIV-a i omogućavanja pravovremene intubacije, tako i u cilju stratifikacije pacijenata sa različitim stepenom rizika za neuspeh, uz obezbeđivanje adekvatnog nivoa nege i monitoringa za sve bolesnike. Ciljevi: Ciljevi istraživanja su da se utvrdi koji pokazatelji koreliraju sa neuspe&scaron;nim ishodom primene neinvazivne mehaničke ventilacije kod bolesnika sa te&scaron;kom egzacerbacijom hronične opstruktivne bolesti pluća, kako bi se kreirao prognostički model ishoda lečenja, te da se se na osnovu prognostičkog modela stratifikuju bolesnici prema stepenu rizika za neuspeh NIV-a i u skladu sa njim predloži adekvatan stepen monitoringa, odnosno kliničko okruženje za bezbedno i efikasno pružanje ventilatorne potpore. Metodologija: U Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici sprovedeno je prospektivno opservaciono istraživanje u trajanju od 39 meseci, u koje je uključeno 250 konsekutivnih bolesnika hospitalizovanih zbog te&scaron;ke egzacerbacije HOBP-a sa respiratornom acidozom. NIV je primenjen u modu pritiskom podržane ventilacije ventilatorima marke Covidien tipa Airox Supportair, uz upotrebu oronazalne maske. Početni parametri su podrazumevali upotrebu ekspiratornog pozitivnog pritiska u disajnim putevima - EPAP-a od 5 cm H2O i inspiratornog pozitivnog pritiska u disajnim putevima IPAPa od 12 cm H20, koji su u potom titrirani ka ciljnim vrednostima IPAPa od 15-20 cmH2O, a u skladu sa kliničkim odgovorom. Za svakog bolesnika evidentirani su: pol, starost, ranija primena dugotrajne oksigenoterapije u kućnim uslovima, primena NIV-a tokom prethodnih hospitalizacija, komorbiditeti preko Charlson indeksa, vreme proteklo od početka hospitalizacije do započinjanja NIV-a, vrednosti pH, bikarbonata, PaCO2 i PaO2 u gasnim analizama arterijske krvi pre započinjanja NIV-a, inicijalna SpO2 i odnos PaO2/FiO2, zatim promena vrednosti pH, PaCO2 i PaO2 u gasnim analizama arterijske krvi sat vremena nakon početka primene NIV-a, inicijalni vitalni parametri - srčana frekvenca, respiratorna frekvenca, stanje svesti procenjeno Glazgov koma skalom (GCS), telesna temperatura, sistolni arterijski pritisak, diureza, a potom zbirni modifikovani ranoupozoravajući bodovni skor (MEWS-modified early warning score), prisustvo i opseg konsolidacija na radiogramu grudnog ko&scaron;a, saradnja bolesnika, te mesto primene NIV-a. Kao primarni ishod istraživanja definisan je neuspeh neinvazivne mehaničke ventilacije: intubacija ili smrtni ishod u toku hospitalizacije uzrokovan respiratornom insuficijencijom. Svaki potencijalni prediktor neuspeha je prvo evaluiran uz pomoć univarijantne analize, a potom su svi faktori rizika za koje je univarijantnom analizom utvrdjena statistička značajnost analizirani uz pomoć multivarijantne logističke regresije, u cilju utvrdjivanja adekvatnih statističkih modela. Rezultati: Od ukupno 250 bolesnika NIV je uspe&scaron;no primenjen kod 164 bolesnika (65.6%). Ukupno 139 (59.3%) bolesnika bilo je mu&scaron;kog pola, a prosečna starost svih ispitanika bila je 67 godina. Bolesnici sa neuspe&scaron;nim ishodom NIV-a imaju, prema univarijantnoj analizi: statistički značajno veće vrednosti Charlson indexa (p=0.002, OR 1.293, 95%CI 1.103-1.516), konsolidacije u &ge;2 kvadranata (p=0.000, OR 5.384, 95%CI 2.487-11.655), duže vreme od početka hospitalizacije do započinjanja NIV-a (p=0.0034, OR 1.005, 95%CI 1.000-1.009), tahikardiju (p=0.031, OR 2.292, 95%CI 1.080-4.864), vrednost GCS &le;11 (p=0.042, OR 1.000, 95%CI 0.165-0.969), veći MEWS skor (p=0.000, OR 1.708, 95%CI 1.410-2.068), niže vrednosti inicijalnog pH (p=0.004, OR 0.002, 95%CI 0.000-0.147), slabiju saradnju (p=0.000, OR 2.102, 95%CI 0.145-0.339). Mesto gde je sprovedena NIV je značajno uticalo na ishod &ndash; &scaron;anse za neuspe&scaron;an ishod su bile dvostruko veće kod bolesnika ventiliranih na op&scaron;tem odeljenju (p=0.006, OR 2.102, 95%CI 1.236-3.574). Kao nezavisni prediktori neuspeha nakon multivarijantne logističke regresije pokazali su se vrednosti Charlson-ovog indexa (p=0.043, OR 1.246, 95%CI 1.007-1.541), MEWS skora (p=0.010, OR 1.394, 95%CI 1.083-1.795), inicijalne vrednosti pH (p=0.030, OR 0.642, 95%CI 0.430-0.958) i stepena saradnje (p=0.000, OR 0.230, 95%CI 0.141-0.376). Zaključci: Bolesnici sa visokim vrednostima Charlson-ovog indeksa (preko 6 bodova) i MEWS-ovog skora (preko 4 boda), te niskom inicijalnom pH vredno&scaron;ću arterijske krvi (ispod 7.29) i niskim stepenom saradnje (manjim od 4) su bolesnici koji imaju povi&scaron;en stepen rizika za neuspe&scaron;an ishod primene neinvazivne ventilacije. Bolesnici visokog stepena rizika treba da se zbrinjavaju i neinvazivno ventiliraju na odeljenjima poluintenzivne i intenzivne nege, dok se bolesnici sa manjim stepenom rizika mogu inicijalno neinvazivno ventilirati i na op&scaron;tim odeljenjima, uz adekvatan monitoring i nadzor obučenog osoblja.<br>Introduction: Clinical guidelines that have evolved from the results of numerous randomized clinical trials state that the use of non-invasive ventilation (NIV), in addition to pharmacological therapy, is necessary in all patients wih severe exacerbation of chronic obstructive pulmonary disease (COPD) - at the highest level of recommendation. It has been proven that the use of NIV leeds to reduction in mortality, intubation rates, and the length of stay in hospitals. Since ventilatory support in past was only delivered in intensive care units, and bearing in mind that their capacities are limited, there is a question of an adequate setting within a hospital where NIV can be used safely and efficiently, and where potential early signs of failure will be timely recognized and patient intubated, if necessary. Consequently, the studies were performed in order to identify early predictors of NIV outcome &ndash; in order to recognize NIV failure and necessity for transition towards invasive ventilation, but also in order to stratify the patients according to the level of risk, which will then dictate the necessary level of care and monitoring. Goals: This research is aimed at identification of parameters that correlate with failure of non-invasive ventilation in patients with severe exacerbation of COPD, in order to create prognostic model of outcome, which will then enable stratification of patients according to the risk of NIV failure. The model is to be used in order to determine adequate level of care and monitoring, that is, a setting within a hospital, for provision of efficent and safe ventilatory support for all patients. Methods: This 39-month prospective observational study was performed at the Institute for Pulmonary Diseases of Vojvodina in Sremska Kamenica, which included 250 consecutive patients hospitalized due to severe exacerbation of COPD with respiratory acidosis. NIV was applied as pressure support mode of ventilation with the ventilators brand Covidien, type Airox Supportair, with oro-nasal mask. Initial parameters were: expiratory positive airway pressure &ndash; EPAPof 5 cm H2O and inspiratory positive airway pressure - IPAP of 12 cm H20, which were further adjusted towards the IPAP of 15-20 cmH2O, or according to the clinical response. The following data were recorded for each patient: sex, age, earlier longterm oxygen therapy, NIV episode during the previous hospitalizations, co-morbidities through Charlson index, time elapsed from admission to NIV initiation, initial blood gas values: pH, bicarbonates, PaCO2 and PaO2, initial SpO2 and PaO2/FiO2, the subsequent changes inthe blood gas values after one hour: pH, PaCO2 and PaO2, initial vital signs - heart rate, respiratory rate, consciousness level by Glasgow coma scale (GCS), body temperature, sistolic blood pressure, urine output, and then modified early warning score - MEWS, presence of consolidation on chest X-ray, tolerance, setting where NIV was applied. Primary outcome was NIV failure defined as endotracheal intubation or death during hospitalization caused by respiratory failure. All variables were first tested with univariate analysis, and those with statistical significance were further subjected to multivariate logistic regression, in order to generate an adequate statistical model. Results: Amongst the total of 250 patients, NIV was successfully applied in 164 patients (65.6 %). There were 139 (59.3%) male patients, and average age was 67. According to the univariate analysis, patients with NIV failure had: higher Charlson index (p=0.002, OR 1.293, 95%CI 1.103-1.516), consolidation in &ge;2 quadrants (p=0.000, OR 5.384, 95%CI 2.487-11.655), longer time from admission to NIV initiation (p=0.0034, OR 1.005, 95%CI 1.000-1.009), increased heart rate (p=0.031, OR 2.292, 95%CI 1.080-4.864), GCS &le;11 (p=0.042, OR 1.000, 95%CI 0.165-0.969), higher MEWS score (p=0.000, OR 1.708, 95%CI 1.410-2.068), lower initial pH (p=0.004, OR 0.002, 95%CI 0.000-0.147), poorer tolerance (p=0.000, OR 2.102, 95%CI 0.145-0.339). The setting were NIV was applied influenced the outcome &ndash; odds for NIV failure were twice as high for the patients on general wards (p=0.006, OR 2.102, 95%CI 1.236-3.574). After the multivariate logistic regression, the following variables were identified as independent predictors of outcome: Charlson index (p=0.043, OR 1.246, 95%CI 1.007- 1.541), MEWS score (p=0.010, OR 1.394, 95%CI 1.083-1.795), initial pH (p=0.030, OR 0.642, 95%CI 0.430-0.958) and tolerance (p=0.000, OR 0.230, 95%CI 0.141-0.376). Conclusions: Patients with higher Charlson index (&gt; 6 points) and MEWS score (&gt;4 points), lower initial pH (&lt;7.29) and tolerance (&lt;4) are at a higher risk for nonivasive ventilation failure. High-risk patients should be admitted and ventilated at high dependency or intensive care units, while the low-risk patients may receive non-invasive ventilatory support on general wards, with adequate monitoring and under the trained staff supervision.

Introduzione ed obiettivi dello studio: La distrofia miotonica (DM), la distrofia più comune nell'adulto, è una malattia autosomica dominante caratterizzata da una ampia varietà di manifestazioni multisistemiche. La distrofia miotonica di tipo 1 (DM1) è causata da espansione della tripletta CTG all’estremità 3’ del gene della DM proteina chinasi. Tra le caratteristiche cliniche multisistemiche della DM1 vi è la compromissione respiratoria. Gli obiettivi di questo studio consistevano nel valutare la prevalenza e la gravità dei disturbi respiratori nei pazienti con DM1 al momento della diagnosi e nell'indagare sulla consapevolezza di malattia e di compromissione respiratoria da parte dei pazienti. Pazienti e Metodi: Tra i pazienti ricoverati presso la Clinica Neurologica di Ancona tra settembre 2007 e ottobre 2010 sono stati arruolati tutti i soggetti a cui veniva formulata la diagnosi genetica di DM1 confermata geneticamente. I pazienti sono stati sottoposti ad esame obiettivo generale e neurologico, visita oculistica, radiografia del torace e elettromiografia (EMG). Abbiamo analizzato le caratteristiche cliniche dei pazienti, il motivo che ha portato alla diagnosi, la presenza di sintomi suggestivi di un disturbo respiratorio (come affaticamento, dispnea, cefalea mattutina, ecc.). Tutti i pazienti venivano sottoposti a monitoraggio cardiorespiratorio notturno, spirometria ed emogasanalisi. Miotonia ed ipostenia sono state valutate utilizzando la scala per la disabilità (MDRS) e l'eccessiva sonnolenza diurna è stata determinata mediante la scala di sonnolenza di Epworth (ESS). Sono stati considerati come affetti da alterata funzione polmonare, i pazienti che avevano almeno uno dei seguenti reperti: PaCO2 diurna ≥ 45 mm Hg, capacità vitale forzata (FVC) <80% del predetto, AHI> 10 eventi per ora di sonno, SaO2 <90% per ≥ 5% della notte. L'indicazione alla ventilazione a pressione positiva non invasiva (NIV) veniva posta in presenza di uno tra PaCO2 ≥ 45 mm Hg, saturazione di ossigeno notturna ≤ 88% per 5 minuti consecutivi, FVC <50% del predetto. Risultati: I dati sono stati raccolti su 21 pazienti (11 femmine/10 maschi), età media 39,7 anni (range 19-61 anni). L'EMG mostrava un quadro di distrofia miotonica in tutti i pazienti. Nessuno dei pazienti aveva deformità della gabbia toracica. Il motivo che ha portato alla diagnosi di DM1 è stata la presenza di un parente affetto in 7 casi (33,35%), il fenomeno miotonico in tre (14,3%), il rilievo di iperCKemia agli esami ematici in 2 (9, 5%), ipostenia in 7 (33,35%) e altri motivi (mal di testa e vertigini) in 2 (9,5%). Il 33% dei pazienti risultava avere emogasanalisi, spirometria e monitoraggio cardiorespiratorio notturno nella norma mentre il restante 67% presentava un’alterazione di almeno uno di tali esami. L’indagine che evidenziava compromissione della funzionalità respiratoria era il solo esame notturno in un paziente (5%), la sola spirometria in due pazienti (10%), emogasanalisi ed esame notturno in un paziente (5%), emogasanalisi e spirometria in tre pazienti (15%), spirometria ed esame notturno in tre pazienti (15%), tutti e tre gli esami in 4 pazienti (20%). Dei 14 soggetti con compromissione della funzione respiratoria 9 avevano una situazione così severa da soddisfare i criteri per NIV. Soltanto quattro dei 21 pazienti esaminati, adeguatamente interrogati, riportavano sintomi indicativi di alterazione della funzionalità respiratoria.Uno di questi pazienti non aveva compromissione della funzione respiratoria. Conclusioni: In tre anni, sono stati arruolati 21 pazienti con DM1. E' probabile che l'incidenza di DM1 nella nostra regione sia significativamente più elevata rispetto a quanto ci si possa aspettare in relazione ai dati epidemiologici della letteratura. La maggior parte dei pazienti arruolati aveva prove di funzionalità respiratoria alterate. Non è stata trovata nessuna relazione significativa tra sintomi soggettivi, caratteristiche clinico-demografiche dei pazienti e compromissione respiratoria (p> 0,005). Un tempestivo riconoscimento di una compromissione respiratoria può portare ad un miglioramento della sopravvivenza e della qualità della vita mediante l'applicazione di NIV. L'importanza del monitoraggio della funzione respiratoria nei pazienti affetti da DM1 ha lo scopo di evitare procedure d’urgenza come l’intubazione. In relazione alla disomogeneità del quadro strumentale respiratorio, i tre esami che indagano la funzionalità respiratoria nei pazienti con DM1 andrebbero eseguiti tutti sin dal momento della diagnosi. Le linee guida relative alla indicazione alla NIV non tengono inoltre conto delle differenze che esistono tra le diverse patologie neuromuscolari, sarebbe pertanto necessaria la stesura di linee guida specifiche per ciascuna patologia neuromuscolare ed in particolare per la DM1.<br>Background and purpose: Myotonic dystrophy (DM) is the most common dystrophy in adults. It is an autosomal dominant disease characterized by a variety of multisystemic features. Myotonic dystrophy type 1 (DM1) is caused by trinucleotide expansion of CTG in the myotonic dystrophy protein kinase gene. Clinical manifestations of DM1 include respiratory disorders. The goals of this study were to evaluate the prevalence and the severity of respiratory disorders in DM1 patients at diagnosis and to assess the awareness of the patients about the disease and the respiratory condition. Patients and Methods: Consecutive patients with a genetically confirmed diagnosis of DM1 admitted in Clinica Neurologica of Ancona from September 2007 to October 2010 were enrolled at diagnosis. Patients underwent general and neurological physical examination, ophthalomological assessment, chest X-ray and electromyography (EMG). We analysed the clinical features of patients, the reason that led to diagnosis, the presence of symptoms suggestive of a respiratory disorder (such as fatigue, dyspnea, morning headache, etc). Nocturnal cardiorespiratory monitoring as well as spirometry and blood gases were performed in all DM1 patients. Myotonia and muscle weakness were rated using the five point muscular disability rating scale (MDRS) and excessive daytime sleepness was assessed by the Epworth Sleepiness Scale (ESS). Were regarded as suffering from impaired lung function, patients who had at least one of the following: daytime PaCO2 ≥ 45 mm Hg, forced vital capacity (FVC) <80% predicted, AHI> 10 events per hour of sleep, SaO2 <90% for ≥ 5% of the night. Indication for Noninvasive Positive Pressure Ventilation (NIV) was one of PaCO2 ≥ 45 mm Hg, nocturnal oxygen saturation ≤ 88% for 5 consecutive minutes, FVC< 50% predicted. Results: Data were collected on 21 patients (11 female/10 male), mean age 39,7 years (range 19-61 years). EMG revealed typical myotonic changes in all patients. None of the patients had chest deformity. The reason that led to diagnosis of DM1 was the presence of a sick relative in 7 cases (33.35%), the myotonic phenomenon in 3 (14.3%), detection of iperCKemia to blood tests in 2 (9, 5%), weakness in 7 (33.35%) and other reasons (headache and dizziness) in 2 (9.5%). One third of patients appeared to have normal blood gases, spirometry and nocturnal parameters while the remaining 66,7% had impaired lung function. The impaired lung function test was just the nocturnal cardiorespiratory monitoring in one patient (5%), just the spirometry in two patients (10%), blood gases and nocturnal cardiorespiratory monitoring in one patient (5%), blood gases and spirometry in three patients (15%), spirometry and nocturnal cardiorespiratory monitoring in three patients (15%), all three tests in 4 patients (20%). Of the 14 subjects with impaired respiratory function 9 had a so severe situation to met the criteria for NIV. Only four of the 21 patients properly interrogated reported symptoms suggestive of impaired lung function. One of these patients had no impairment of lung function. Conclusions: We enrolled 21 DM1 patients in three years. Probably the incidence of DM1 in our region is significantly higher than expected according to the literature. The majority of the patients enrolled had evidence of impaired lung function. No significant relationships were found between subjective complaints, clinical-demographic features and respiratory compromission (p>0.005). Timely recognition of a respiratory compromission may lead to improved survival and quality of life by the application of non-invasive ventilatory support. Importance of monitoring respiratory function in patients with DM1 is designed to avoid emergency procedures such as intubation. In relation to the heterogeneity of respiratory involvement features, all the three pneumological tests should be performed in all DM1 patients from the time of diagnosis. The guidelines regarding the indication for NIV don't take into account the differences that exist between the various neuromuscular diseases, is therefore necessary to draw up specific guidelines for each neuromuscular disease and in particular for DM1.

La prévalence de la rhinite allergique (RA) est en augmentation dans le monde entier. Malheureusement, cette maladie est souvent considérée comme triviale, et les patients ont une tendance à ne pas consulter un médecin, malgré le fait que la RA a un impact très important sur leur qualité de vie. Les recommandations ARIA conseillent d’évaluer la sévérité de la maladie avant traitement et le contrôle des symptômes au cours du suivi pour optimiser le traitement, améliorer la qualité de vie des patients, et diminuer le coût de la RA. En analysant des bases de données en vie réelle, nous avons détecté un score simple et pratique qui permet aux médecins d’évaluer la sévérité de la RA et nous avons validé un système pour vérifier le contrôle des symptômes par visual analogue scale (VAS) sur l’écran des smartphones. Cette validation se base sur les données recueillies par l’application pour smartphones « MASK-Air® » et a été réalisé selon les recommandations COSMIN, avec évaluation, de la cohérence interne, de la fiabilité, de la sensibilité, et de l’acceptabilité. Le score pour évaluer la sévérité se base sur les résultats de l’étude Pollin’Air, après comparaison de 5 méthodes de classification des patients (deux types d’analyses en cluster, un score à 17 questions, le score ARPhyS à 5 questions et le VAS). L’évaluation de la sévérité et du contrôle de la RA sont essentielles pour bien gérer les patients, leurs symptômes et leur qualité de vie. Grâce à l’analyse de bases de données en vie réelle, nous avons validé des outils faciles à utiliser et à comprendre, et rapides à compléter, et qui peuvent donc être vraiment utilisés dans la pratique clinique<br>The prevalence of allergic rhinitis (AR) is increasing worldwide. Unfortunately, this disease is often considered as trivial, and patients tend not to consult their physician, and even less a specialist, even though AR has a very significant impact on the quality of life of patients, which translates into a risk of absenteeism and impaired presenteeism. ARIA guidelines recommend evaluating the severity of the disease before treatment and the control of symptoms during follow-up to optimize treatment, improve patients’ quality of life, and reduce the direct and indirect cost of AR. By analyzing real-life databases, we detected a simple and practical score that allows physicians to assess AR severity and we validated a system to verify the control of symptoms by a visual analogue scale (VAS) on smartphone screens. This last validation was based on data collected by the “Allergy Diary / MASK-Air®” application for smartphones of the MASK study. It was carried out according to COSMIN criteria, with an evaluation, among other things, of internal consistency, reliability, sensitivity, and acceptability. The score to assess AR severity is based on the results of the Pollin'Air study, after comparison of 5 methods for patients’ classification (two types of cluster analyses, a 17-question score, the 5-question ARPhyS score and the VAS). Assessing both severity and control in AR is essential to properly manage patients, their symptoms and quality of life. Through the analysis of real-life databases, we validated tools that are easy to use and understand, and quick to complete, therefore meet the essential characteristics to be truly used in clinical practice

碩士<br>國立臺灣大學<br>物理學研究所<br>104<br>Respiratory distress syndrome is one of the main cause of death for premature baby. Its symptoms include difficulty breathing, purple skin, expiratory moan and uncoordinated breathing. It’s mortality rate is highest in the first 48 hours. However, the symptoms are not shown immediately after birth. Some auxiliary examination is required for early detection of RDS. The auxiliary examination includes amniotic fluid examination, bubble test, PG examination, blood examination and chest x-ray(CXR) examination etc. All auxiliary examinations exclude CXR examination have specific numbers for classification, as the number of bubbles in bubble test, the molecule density in PG, amniotic and blood examination. CXR is a qualify but not quantify examination. The four grades classification standard used by NTUH are as follow: 1. If frosted glass pattern appear 2. If vessels are congested. 3. if the boundary between heart and lung, diaphragm and lung disappears. This research tries to numerically describe the RDS level of CXR, hoping to find a quantitative method for CXR classification. Medical image processing is not an easy work, especially for the case involving irregularity disease area. For RDS new born, there will be white out and boundary blurring effect on CXR. It makes most of the methods used for segmentation for adult CXR invalid. New approach must be developed. We use filter that are sensitive to ribs and use edge following technique to find the approximate region of thoracic cage. And by use of the property that spine nodes will be connected to ribs, to segment out the spine region by threshold. By mixing all approaches above, the lung area can be roughly segment out. After calculating the average and variation of selected regions, we see a correspondence (87% correctness) between the numerically grading and the qualitative grading which decided by doctors. It is concluded that it is possible to quantify RDS CXR by image processing.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine in the field of Clinical Microbiology and Infectious Diseases Johannesburg, 2018.<br>Background: Respiratory Syncytial Virus (RSV) is a common cause of upper and lower respiratory tract infections (LRTI), primarily in children having severe disease manifestation. In South Africa, RSV is identified in approximately 25-30% of children hospitalized for LRTI. There is a spectrum of RSV-associated LRTI severity. Understanding associations between immune mediators and RSV-LRTI severity could assist clinicians in the triaging for level of care. Several cytokines have been implicated in RSV-LRTI severity. Aim: Study the associations between cytokine levels from plasma and nasopharyngeal aspirate with RSV infection or RSV-associated LRTI severity in hospitalized infants ranging from 0-12 months of age. The correlation between plasma and nasopharyngeal aspirate cytokine concentrations was also evaluated. Methods: Paired plasma and nasopharyngeal aspirate (NPA) samples were collected from polymerase chain reaction confirmed RSV-infected infants without coinfection with other pathogens that we investigated for. Paired samples were also collected from RSV negative-control infants (n=31) who did not have any respiratory symptoms. Control-infants were scheduled for elective surgery; samples were collected before administration of medication and surgical procedure. RSV associated LRTI episodes were grouped into mild (n=89) and severe RSV-LRTI (n=113) using the Respiratory Index of Severity in Children (RISC) Score. Interferon gamma (IFN-γ), interleukins (IL) IL-1α, IL-1β, IL-4, IL5, IL-6, IL-8, IL-9, IL-10, IL-12(p70)IL-13, macrophage inducing protein (MIP-1α), monocyte chemo attractant protein (MCP-1), tumour necrosis alpha (TNF-α), Regulated on activation, normal T cell expressed and secreted (RANTES) and were measured with multiplex immunosorbent assay using Luminex® technology. Cytokine profiles were evaluated for association of RSV-LRTI severity and between RSV LRTI cases and controls. Results: Comparing hospitalized RSV-associated LRTI to control infants, RSV cases had elevated plasma TNF-α (0.7pg/ml vs. 0.5pg/ml; p=0.007), and IL-10 (1.0pg/ml vs. 0.6pg/ml; p=0.02) concentrations, and reduced plasma MIP-1α (12pg/ml vs. 28pg/ml; p=0.008) and IFN-γ (3pg/ml vs. 5pg/ml; p=0.02) levels. Nasopharyngeal aspirate TNF-α (8.0pg/ml vs. 1.0pg/ml; p=0.01), IL-8 (2682pg/ml vs. 184pg/ml; p=0.002), MCP-1 (287pg/ml vs. 66pg/ml; p<0.001), MIP-1α (27pg/ml vs. 6.7pg/ml; p=0.004) concentrations were elevated in RSV-LRTI cases compared to control infants. Infants hospitalized with severe RSV-associated LRTI (RISC score ≥2) were younger than mild cases (3.9 vs. 4.5 months; p=0.01). In RSV cases, severe RSV-LRTI was associated with increased plasma IFN-γ levels (4pg/ml vs. 3pg/ml) and NPA MIP-1α concentrations (88pg/ml vs. 50pg/ml, mean; all other values medians) compared to mild RSV-LRTI. In a multivariate analysis, NPA MIP-1α levels remained associated with RSV-LRTI (p=0.05), but could not predict RSV-LRTI severity. Conclusion: This study observed that during RSV-associated LRTI, immune response was directed at the respiratory tract. Reduced concentrations of plasma IFN-γ and elevated levels of cytokines in the NPA may suggest that the blood of RSV-LRTI cases had reduced number of IFN-γ producing cells. There was no evidence of distinct Th1 or Th2 type immune response and the cytokines associated with RSV-LRTI severity could not predict the outcome of severe RSV-associated LRTI. Key words: Respiratory Syncytial Virus, Lower respiratory tract infections, Severity, Plasma, Nasopharyngeal aspirate, IFN-γ, MIP-1α, Luminex®<br>LG2018

Research Doctorate - Doctor of Philosphy (PhD)<br>The immune system is an essential component of the human body, providing protection against invading pathogens like the respiratory viruses, human rhinoviruses (HRVs) and influenza virus. Numerous alterations occur in the maternal immune system during pregnancy in order to accommodate the presence of a growing fetus. During pregnancy, there is an increased maternal risk for susceptibility to these respiratory virus infections, as well as increased disease severity following infection. The presence of an underlying inflammatory immune disease, like asthma, may lead to an imbalance in maternal immunity, which may further worsen the outcomes in these women following respiratory virus infections. In order to improve the health of both mother and baby, it is first necessary to understand the underlying changes that occur in maternal immunity following respiratory virus infections, as well as the confounding effect that may result from having asthma. In this study, an in vitro system was utilized, in which peripheral blood mononuclear cells (PBMCs) were isolated from pregnant and nonpregnant women, with and without asthma. PBMCs were cultured with different strains of HRVs and influenza, as well as with positive stimuli, and a range of antiviral and inflammatory factors were then measured. The activity of specific cell types was also assessed following viral infection. This study shows that PBMCs from pregnant women have a significant attenuation in their innate antiviral immune response following infection with both HRV and 2009 pandemic swine flu (H1N1pdm09). Alterations were also identified in the number and activity of key antiviral immune cells during pregnancy following H1N1pdm09 infection. Asthma during pregnancy altered maternal immunity, resulting in impaired innate and adaptive antiviral immune responses and an enhanced inflammatory response. In conclusion, this study identifies significant changes that occur in maternal antiviral immunity, which may explain the increased risk for susceptibility to respiratory virus infections in these women. In addition, altered antiviral and inflammatory immunity in pregnant women with asthma provides a plausible explanation for the high prevalence of respiratory virus-induced asthma exacerbations that occur in these women.

碩士<br>長榮大學<br>醫務管理學系(所)<br>100<br>Background：In order to control the rising medical expenditures, the Taiwan Diagnosis Related Groups (Tw-DRGs) was implemented since 2010 to pay for hospitalization expenses, creating financial inducements to encourage healthcare service providers to improve efficiency and to reduce costs. Diseases severity is an important classifying factor in the DRGs classification system, and the explanation of medical expenditures is still having improvable space. Objective： This study aims to use the classification of severity of MS-DRGs to replace the classification of severity of Tw-DRGs version 3.0, so as to simulate the explanation of medical expenditures. Design： This study is a cross-sectional, simulated study. Secondary data was collected from the National Health Insurance Research Database in 2008, including two groups of claims data: Registry for Contracted Medical Facilities and Inpatient Expenditures by Admissions. Patients with respiratory diseases and disorders in the Major Diagnosis Category 4 (MDC4) of Tw-DRGs version 3.0 were categorized based on the severity classification systems of Tw-DRGs version 3.0 and of MS-DRGs respectively. This study calculated and compared the explanation of medical expenditures and the related weights (RW) of the two aforementioned severity classification systems. Furthermore, this study eliminated the outliers of medical expenses, and analyzed again the explanation of medical expenditures. Results： When classifying patients in the Major Diagnosis Category 4 of Tw-DRGs version 3.0 using the severity classification systems in Tw-DRGs version 3.0, the explanation of medical expenditures was 0.4566. Meanwhile, adopting the severity classification system of MS-DRGs resulted in an explanation of medical expenditures of 0.4759, with an increase of 4.23%. After trimming the outliers of medical expenses, the explanation of medical expenditures when adopting the severity classification system of Tw-DRGs version 3.0 was 0.5177 whereas the explanation of medical expenditures was 0.5334 when adopting the MS-DRGs severity classification system, with an increase of 3.03%. Moreover, 43 BaseDRGs altered the severity classification system, 38 RW of BaseDRGs increased deviations; After trimming the outliers of medical expenses, 39 RW of BaseDRGs increased deviations, the result showed a more centralized classification of patients with similar resource consumptions as. Conclusion： The alteration of severity classification systems had impact on the explanation of hospitalization expenses of Tw-DRGs version 3.0. In terms of patients in the Major Diagnosis Category 4 of the Tw-DRGs version 3.0, the change from the two-level classification system of Tw-DRGs version 3.0 to the three-level MS-DRGs system has improved the explanation of medical expenditures.

碩士<br>嘉南藥理科技大學<br>醫療資訊管理研究所<br>96<br>Considerations of beneficiary access and provider equity highlight that is important to address the issue of how to reduce the varying impact of Tw-DRGs pricing policy across hospitals in the past results. In this study, we have undertaken analyses the feasibility of refining Tw-DRGs secondary diagnoses on the basis of the Major Complication and Comorbidity (MCC) adopted by Medicare Severity DRGs (MS–DRGs). Data sources were longitudinal data from Taiwan NHI inpatients database from 2004 through 2006. The subjects with Tw-DRGs 08801, 089, 09101 and 47501 were selected but excluding outlier cases. The differences in costs of care to patients with MCC versus without MCC were compared. Changes to the case mix index were further estimated across hospitals. This study found the cost per admission for each DRGs with MCC patients was higher than that of corresponding DRG without MCC significantly (P <.0001). Geometric mean length of stay per admission for each DRG was longer in the study DRG.s with MCC. CMI increase under the MCC refined Tw-DRGs and health care costs were the highest in public tertiary care institutions that treated a large number of patients with complex conditions. The results suggest that Tw-DRGs reform should incorporate the complication and comorbidity stratification to ensure and maintain equitable payment so that hospitals do not avoid treating expensive cases or are advantaged by treating less costly conditions.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina<br>Acute Bronchiolitis is a viral low respiratory tract infection, affecting children aged less than two years old. Although the evolution is commonly benign acute bronchiolitis is the main cause of hospitalization in infants under six months old. Several studies associate seric levels of vitamin D with increased risk of respiratory tract infections. We did a literature review with the aim to reunite and analyse studies already published about the subject, in order to conclude if it is possible to associate the seric levels of vitamin D at hospital admission with severity criteria of acute bronchiolitis. The bibliographic search, resorting to PubMed and other platforms, considered scientific and review articles published in the last ten years.Higher levels of vitamin D at birth have reduced the risk of acute bronchiolitis at the first year of life in 95%, according to a study in Netherlands. About the association between vitamin D and acute bronchiolitis severity, most studies, although few and with limitations, suggest a significant correlation between the severity of the disease and low seric levels of vitamin D.Acute Bronchiolitis is a viral low respiratory tract infection, affecting children aged less than two years old. Although the evolution is commonly benign acute bronchiolitis is the main cause of hospitalization in infants under six months old. Several studies associate seric levels of vitamin D with increased risk of respiratory tract infections. We did a literature review with the aim to reunite and analyse studies already published about the subject, in order to conclude if it is possible to associate the seric levels of vitamin D at hospital admission with severity criteria of acute bronchiolitis. The bibliographic search, resorting to PubMed and other platforms, considered scientific and review articles published in the last ten years.Higher levels of vitamin D at birth have reduced the risk of acute bronchiolitis at the first year of life in 95%, according to a study in Netherlands. About the association between vitamin D and acute bronchiolitis severity, most studies, although few and with limitations, suggest a significant correlation between the severity of the disease and low seric levels of vitamin D.<br>A bronquiolite aguda (BA) é uma infeção do trato respiratório inferior, que afeta crianças até aos dois anos de idade. Apesar da sua evolução ser maioritariamente benigna, é a principal responsável pelo internamento de crianças até aos seis meses de idade. Diversos estudos relacionam os níveis séricos de vitamina D com risco de infeções do trato respiratório. Foi efetuada uma revisão da literatura com o objetivo de reunir e analisar os estudos já publicados sobre o tema, de forma a concluir se é possível relacionar os níveis séricos de vitamina D à data do internamento com critérios de gravidade da BA. A pesquisa bibliográfica, com recurso ao PubMed e outras plataformas, considerou artigos científicos e de revisão publicados nos últimos dez anos. Níveis mais elevados de vitamina D ao nascimento reduziram o risco da BA no primeiro ano de vida em 95%, segundo um estudo na Holanda. Quanto à relação entre vitamina D e gravidade da BA, a maioria dos estudos existentes, embora poucos e com limitações, sugere uma relação significativa entre a gravidade da BA e níveis séricos baixos de vitamina D.A bronquiolite aguda (BA) é uma infeção do trato respiratório inferior, que afeta crianças até aos dois anos de idade. Apesar da sua evolução ser maioritariamente benigna, é a principal responsável pelo internamento de crianças até aos seis meses de idade. Diversos estudos relacionam os níveis séricos de vitamina D com risco de infeções do trato respiratório. Foi efetuada uma revisão da literatura com o objetivo de reunir e analisar os estudos já publicados sobre o tema, de forma a concluir se é possível relacionar os níveis séricos de vitamina D à data do internamento com critérios de gravidade da BA. A pesquisa bibliográfica, com recurso ao PubMed e outras plataformas, considerou artigos científicos e de revisão publicados nos últimos dez anos. Níveis mais elevados de vitamina D ao nascimento reduziram o risco da BA no primeiro ano de vida em 95%, segundo um estudo na Holanda. Quanto à relação entre vitamina D e gravidade da BA, a maioria dos estudos existentes, embora poucos e com limitações, sugere uma relação significativa entre a gravidade da BA e níveis séricos baixos de vitamina D.

碩士<br>國立臺灣大學<br>流行病學研究所<br>93<br>Background – Patients with severe acute respiratory syndrome (SARS) exhibits signs and symptoms of respiratory and systemic infection that follows with clinical course of varying severity, including death due to acute respiratory distress syndrome (ARDS). In addition to advanced age, comorbidity, and high viral load, genetic predisposition has been postulated to influence the immune response and clinical course. This study aims to identify potential genetic effectors involved in the pathogenesis of SARS. Method – This is a population-based case-control study that enrolled 108 unrelated laboratory-confirmed SARS patients and 333 healthy Taiwanese as reference. Gene products that are known or predicted to be involved in host response were selected for study of polymorphism. SARS patients are divided into 3 groups based on the duration of illness as index for severity: <15 days for mild, 15~28 days for intermediate, and >28 days for severe case. Result – Clinical severity was significantly associated with certain genotype of three SNPs: a nonsynonymous substitution in the coding region of Toll-like receptor 3, TLR3(L412F) and in the promoter regions of TNF receptor-associated factor 6- TRAF6 (A-9423C) and heme oxygenase-1 - HO-1(T-495A). TLR3 is directly upstream to TRAF6 in the interferon-inducing pathway, and the joint effect of TLR3 or TRAF6 in the pathway was considered, termed TLR3-TRAF6. The severe SARS patients had 4.06-folds (95% CI=1.69~9.74, p=0.002) increased odds of possessing any susceptible genotypes of TLR3-TRAF6 (TLR3(6300T/T), TRAF6(-9423C/C) or (A/C)) and 2.77-folds (95% CI=1.69~9.74, p=0.002) of possessing susceptible genotype of HO-1 (HO-1(-495A/A) or (A/T)) than patients with shorter clinical course in a cumulative logit model. This genetic effect is more profound for the younger SARS patients (<40 yr) than the elder group. Conclusion - TLR3 recognizes double-stranded RNA, and together with TRAF6, activates interferon production; HO-1 can protect tissues from immune-mediated injury. Along with our previous report of two interferon-γ- inducible genes, FGL2 - a prothrombinase and CXCL10 - a chemokine activating TH1 response, our results strongly support the hypothesis that genetic predisposition to certain host responses participate in the pathogenesis of severe SARS-CoV infection. Identifying pathways participating in viral pathogenesis can provide insights to formulating therapeutic interventions for SARS, and probably ARDS from other causes.

La papillomatose respiratoire récurrente (PRR) juvénile est causée par les génotypes 6 et 11 du virus du papillome humain (VPH). Cette maladie est caractérisée par des verrues récurrentes généralement au larynx. La forme sévère peut avoir un impact dévastateur sur la santé et la qualité de vie de l’enfant atteint et de sa famille en raison des conséquences des multiples chirurgies nécessaires et du risque d'obstruction des voies respiratoires. Objectif: Examiner les facteurs de risque associés aux manifestations sévères de la PRR. Méthode: Étude rétrospective des 31 cas diagnostiqués entre janvier 1995 et décembre 2008. Les données démographiques, cliniques, génétiques et virologiques ont été évaluées. Des régressions logistiques furent effectuées afin d'évaluer le rôle des variables indépendantes sur la sévérité de la maladie. Résultats: Nos données suggèrent que les facteurs de risque de sévérité de la PRR seraient associés au genre féminin (Rapport de cotes (RC)=2.60, intervalles de confiance (IC) 95% : 0.44-15.44), au fait d’être premier-né (RC=3.51, IC 95% : 0.17-72.32), à un statut économique faible (RC=5.31, IC 95% : 0.17-164.19), à un jeune âge (RC=0.83, IC 95% : 0.68-1.01), à une charge virale élevée (RC=3.81, IC 95% : 0.23-63.16) et aux condylomes chez la mère pendant la grossesse (RC=12.05, IC 95% : 0.97-149.85). Conclusion: La sévérité de la PRR serait le résultat d'une combinaison de déterminants qui favoriseraient la croissance cellulaire particulièrement chez les jeunes enfants. Des mesures préventives et thérapeutiques visant à restreindre la contamination et la réplication du virus pourraient réduire le fardeau de la maladie.<br>Juvenile Recurrent Respiratory Papillomatosis is caused by Human Papillomavirus genotypes 6 or 11. It is characterised by recurring warts most commonly in the larynx. The severe form of the disease has a devastating impact on health and life quality of the child and its family because of the consequences of multiple surgical procedures and the constant risk of airway obstruction. Objectives: To study the risk factors associated with severe forms of RRP. Method: We conducted a retrospective case series of the 31 patients diagnosed between January 1995 and December 2008. We analyzed demographic and clinical variables, as well as viral and host factors. Logistic regressions were performed to evaluate the impact of each of independent variables on the disease severity. Results: Our data suggest that risk factors for severe forms of RRP in children could be associated with female gender (OR=2.60, 95% CI: 0.44-15.44), being first-born (OR=3.51 95% CI: 0.17-72.32), lower socio-economic status (OR=5.31, 95% CI: 0.17-164.19), younger age (OR=0.83, 95% CI: 0.68-1.01), high viral load (OR=3.81, 95% CI: 0.230-63.16) and history of condylomas of the mother during pregnancy, (OR=12.05, 95% CI: 0.97-149.85). Conclusion: The severity of the RRP would be the result of a combination of factors which would favor the cellular growth particularly in the young children. Therapeutics and preventive measures to restrict the contamination and the replication of the virus could reduce considerably the burden of this disease.

Respiratory infection remains a leading cause of morbidity and death in severely immunocompromised febrile neutropenic haematology patients, despite the introduction of numerous prophylactic strategies and advances in diagnosis and treatment. Prognosis is improved if an organism can be isolated and specific therapy commenced as soon as possible. Current practice in this population group is to commence empirical antibiotics and perform flexible bronchoscopy (FB) if temperature does not settle or after patients develop clinical or radiological features suggesting a respiratory source. This delay may result in a lower procedural diagnostic yield due to prior or prolonged anti-microbial treatment, and increased risk of respiratory compromise and procedural complications due to advanced respiratory infections. We hypothesised that proceeding to FB as early as possible after developing febrile neutropenia would improve treatment outcomes. With this randomised, prospective trial, we aim to further define the role of FB with reference to optimal timing of the procedure and its impact on diagnostic yield, future management and complication rate. We also aim to analyse the impact of proven infection on the cytokine profile of immunocompromised patients. Methods: Patients with acute leukaemia, allogeneic bone marrow transplantation or chronic lymphocytic leukaemia (CLL) being treated with Fludarabine/ Mabthera without an obvious non-respiratory source of infection were prospectively randomised into early bronchoscopy or conventional management groups at onset of febrile neutropenia. Bronchoalveolar lavage (BAL) fluid chemokine levels (IP-10, RANTES, MIG, IL-8, MCP-1) were measured using a human Chemokine cytometric bead array (CBA) kit. Results: Thirty-one episodes of febrile neutropenia in 29 patients were analysed; 17 conventional and 14 early. There was an increased yield in fungal growth in the early bronchoscopy group, which was not predicted by prior clinical or radiological changes. However, this had no impact on clinical management in the short-term due to the delayed growth. Overall diagnostic yield was not significantly different between the two groups. Procedural complication rate was negligible overall and there was no difference associated with either group. IP-10 and MIG were significantly lower in those patients who had a fungal pathogen isolated, compared with those study patients who did not (175.17 vs 1157.8, p=0.03, 30.33 vs 247.8, p=0.03 respectively). IP-10 levels were higher in the conventional than early group (1253.0 vs 261.14, p = 0.035) and the study population had higher MCP-1 (734 vs 2.83, p=0.006) and IL-8 levels (606.9 vs 14.25, p=0.00655) than normal controls. Those cases with fungal infection had higher mean MCP-1, RANTES and IL-8 levels than in normal controls (844.0 vs 2.83, p=0.007; 17.5 vs 2.1, p=0.03; 156.0 vs 14.25, p=0.004). Conclusions: Early bronchoscopy as a component of the septic screen in febrile neutropenic patients was feasible and safe. A significant difference in fungal yield was seen in the early bronchoscopy group compared to conventional methods, with a negligible complication rate, but this did not result in a change in immediate clinical management or outcomes.<br>Thesis (M.Clin.Sc.) - University of Adelaide, School of Medicine, 2009

Respiratory infection remains a leading cause of morbidity and death in severely immunocompromised febrile neutropenic haematology patients, despite the introduction of numerous prophylactic strategies and advances in diagnosis and treatment. Prognosis is improved if an organism can be isolated and specific therapy commenced as soon as possible. Current practice in this population group is to commence empirical antibiotics and perform flexible bronchoscopy (FB) if temperature does not settle or after patients develop clinical or radiological features suggesting a respiratory source. This delay may result in a lower procedural diagnostic yield due to prior or prolonged anti-microbial treatment, and increased risk of respiratory compromise and procedural complications due to advanced respiratory infections. We hypothesised that proceeding to FB as early as possible after developing febrile neutropenia would improve treatment outcomes. With this randomised, prospective trial, we aim to further define the role of FB with reference to optimal timing of the procedure and its impact on diagnostic yield, future management and complication rate. We also aim to analyse the impact of proven infection on the cytokine profile of immunocompromised patients. Methods: Patients with acute leukaemia, allogeneic bone marrow transplantation or chronic lymphocytic leukaemia (CLL) being treated with Fludarabine/ Mabthera without an obvious non-respiratory source of infection were prospectively randomised into early bronchoscopy or conventional management groups at onset of febrile neutropenia. Bronchoalveolar lavage (BAL) fluid chemokine levels (IP-10, RANTES, MIG, IL-8, MCP-1) were measured using a human Chemokine cytometric bead array (CBA) kit. Results: Thirty-one episodes of febrile neutropenia in 29 patients were analysed; 17 conventional and 14 early. There was an increased yield in fungal growth in the early bronchoscopy group, which was not predicted by prior clinical or radiological changes. However, this had no impact on clinical management in the short-term due to the delayed growth. Overall diagnostic yield was not significantly different between the two groups. Procedural complication rate was negligible overall and there was no difference associated with either group. IP-10 and MIG were significantly lower in those patients who had a fungal pathogen isolated, compared with those study patients who did not (175.17 vs 1157.8, p=0.03, 30.33 vs 247.8, p=0.03 respectively). IP-10 levels were higher in the conventional than early group (1253.0 vs 261.14, p = 0.035) and the study population had higher MCP-1 (734 vs 2.83, p=0.006) and IL-8 levels (606.9 vs 14.25, p=0.00655) than normal controls. Those cases with fungal infection had higher mean MCP-1, RANTES and IL-8 levels than in normal controls (844.0 vs 2.83, p=0.007; 17.5 vs 2.1, p=0.03; 156.0 vs 14.25, p=0.004). Conclusions: Early bronchoscopy as a component of the septic screen in febrile neutropenic patients was feasible and safe. A significant difference in fungal yield was seen in the early bronchoscopy group compared to conventional methods, with a negligible complication rate, but this did not result in a change in immediate clinical management or outcomes.<br>Thesis (M.Clin.Sc.) - University of Adelaide, School of Medicine, 2009