Utilidade da determinação consecutiva da proteína C reactiva no follow-up da pneumonia adquirida na comunidade

Resumo: A pneumonia adquirida na comunidade (PAC) é a principal causa de morte devido a doença infecciosa no mundo ocidental, sendo responsável por um número superior a 20 hospitalizações/ano por mil habitantes.As guidelines internacionais preconizam a antibioterapia combinada, como seja a associação de um β-lactâmico e de um macrólido no tratamento inaugural da PAC grave. Tal facto implica a utilização de cuidados de saúde oneroso e o consumo elevado de antibióticos, contribuindo, assim, para o aparecimento de resistências bacterianas.Nos EUA, os custos do tratamento da PAC excedem os doze biliões de dólares e, em muitos países desenvolvidos, observa-se um aumento da resistência aos macrólidos.Uma vez determinada a etiologia da PAC, a antibioterapia direccionada para o agente patogénico em causa pode ser iniciada. No entanto, até agora, não foi encontrada um biomarcador suficientemente sensível e específico para orientar a terapêutica inaugural, devendo ser criados protocolos com essa finalidade.Os autores do presente trabalho estudaram a relevância da determinação consecutiva da proteína C reactiva (PCR) no follow-up de doentes com PAC, avaliando o valor preditivo da normalização tardia dos níveis séricos da PCR relativamente ao risco de administração de antibioterapia inapropriada e a um prognóstico desfavorável.Trata-se de um estudo prospectivo multicêntrico controlado conduzido em cinco hospitais universitários holandeses, entre Junho de 2000 e Julho de 2003, sobre a eficácia clínica da instituição empírica de terapêutica antibiótica intravenosa ou oral na PAC.A PAC foi definida pela presença de, pelo menos, dois sintomas de infecção respiratória baixa aguda antes da admissão hospitalar e de um infiltrado pulmonar âde novoâ ou em progressão na radiografia do tórax. A classificação como grave está relacionada com um score no índice de gravidade PSI â Pneumonia severity index >90 ou de acordo com a definição da American Thoracic Society.Foram excluídos indivíduos com pneumonia intersticial, fibrose quística, colonização a gram negativos devido a lesão estrutural do aparelho respiratório, esperança de vida 25c/min; Sat O2 <90% por oximetria de pulso; PaO2 <55mmHg), instabilidade hemodinâmica, alteração súbita do estado de consciência, admissão numa unidade de cuidados intensivos ou morte nos 3 primeiros dias após a admissão. A falência tardia foi decretada pela deterioração clínica ou complicações, incluindo a morte, necessidade de ventilação mecânica, reintrodução de antibioterapia IV após instituição de antibióticos orais, readmissão por infecção pulmonar após alta hospitalar ou pirexia após melhoria inicial no período de follow-up.O atraso na normalização da PCR foi definido por um declínio < 60% nos níveis da PCR no dia 3 e < 90% no dia 7.Foram englobados 289 doentes com uma idade média de 69,7±13,8 anos. Os scores dos índices PSI e APACHE II foram respectivamente 112,4±25,7 e 13,8±4,6. Outras patologias estavam presentes em 180 indivíduos: I cardíaca congestiva, neoplasia, doença cerebrovascular, I renal crónica, doença hepática e doença pulmonar obstrutiva crónica (DPOC). O nível sérico médio da PCR na admissão foi de 174mg/l, tendo sido ligeiramente inferior nos doentes submetidos a antibioterapia em ambulatório (135mg/l) e nos indivíduos sob corticoterapia inalatória (146mg/l). Não se verificou associação entre os níveis da PCR e as características demográficas ou a presença de comorbilidade. Cerca de 232 (80,3%) doentes receberam um β-lactâmico em monoterapia como terapêutica empírica inicial e 47 (16,3%) terapêutica combinada de um β-lactâmico com um macrólido.Em 122 (89,1%) dos 137 doentes com etiologia confirmada, a antibioterapia empírica foi considerada adequada. Um total de 20 indivíduos (6,9%) morreram durante o período de follow-up e 9 foram transferidos para uma unidade de cuidados intensivos.O diagnóstico etiológico foi estabelecido em 137 (47,4%) doentes, sendo o S. pneumoniae o mais frequente (19% dos casos). Os valores da PCR mais elevados foram observados nos doentes infectados por S. pneumoniae (278mg/l) seguido pela L. pneumophila (247mg/l), H. influenzae (214mg/l), S. aureus (187mg/l), Enterobacteriaciae (129mg/l), C. pneumoniae (115mg/l), M. catarihalis (64mg/l) e M. pneumoniae (49mg/l). Doentes infectados com agentes patogénicos múltiplos tinham um valor médio da PCR, na admissão, de 213mg/l. Os doentes com etiologia desconhecida tinham uma concentração média, na admissão, inferior aos indivíduos com confirmação bacteriológica (140mg/l versus 209mg/l).A determinação da PCR foi efectuada na admissão em todos os indivíduos, em 264 (91,3%) no dia 3 e em 210 no dia 7 do internamento. O declínio médio da PCR foi de 38,4% até ao dia 3 e de 80,9% na primeira semana de follow-up. Os doentes com tratamento antibiótico inapropriado tinham uma normalização mais lenta dos níveis da PCR. O declínio <60% no dia 3 e <90% no dia 7 estava associado a um maior risco de terapêutica empírica inadequada. Os doentes com atraso na normalização dos níveis de PCR na primeira semana apresentavam uma taxa de mortalidade superior, mas tal facto não foi estatisticamente significativo.Doentes com atraso na normalização da PCR no dia 3 tinham um ligeiro aumento do risco de apresentar falência terapêutica precoce ou tardia, mas tal facto não foi estatisticamente significativo

Molecular and Serological Intraocular Fluid Analysis of Coxiella burnetii-seropositive Patients with Concurrent Idiopathic Uveitis

Purpose: Previous studies have suggested a link between Q fever and uveitis. We determined whether Coxiella burnetii causes intraocular infection in C. burnetii-seropositive patients with idiopathic uveitis. Methods: From a retrospective observational case series, paired aqueous humor and serum samples from 10 C. burnetii-seropositive patients with idiopathic uveitis were examined for intraocular antibody production by using the Goldmann-Witmer coefficient and by polymerase chain reaction (PCR). Results: Although intraocular IgG against C. burnetii was detected, no intraocular antibody production was observed (low Goldmann Wittmer coefficients). All PCR results were negative. Conclusions: Uveitis due to an intraocular infection with C. burnetii is unlikely

The Implications of Sequential Investment in the Property Rights Theory of the Firm

In the property rights theory of the firm, control over assets (ownership) affords bargaining power in the case of re-negotiation, providing incentives for parties to make relationship specific investments. The models predict that property rights will be allocated so as to maximise surplus generated from investment. However, these models assume that investments are made simultaneously. In this thesis I extend the standard property-rights framework to allow for sequential investment; the model allows for two investment periods. If a party invests first (ex-ante), they sink their investment before any contracting is possible. The parties that invest second (ex-post) do so after some aspects of the project are tangible, so that they can contract on (at least some) of their investment costs. As well as being empirically relevant, sequencing has several important theoretical implications. First, if a party gets to invest second, then – ceteris paribus – it has a greater incentive to invest. Second, the investment of parties that invest first are affected by a more than one influence. Anticipating higher ex-post investment, they can have a greater incentive to increase their investments. However, higher ex-post investment leads to greater costs being borne by the ex-ante investors (via the cost sharing contracts); this reduces ex-ante incentives to invest. Overall either effect can dominate so that ex-ante investment can either increase or decrease as a result of sequential investment. Third, as noted, sequencing of investment provides the possibility to (partially) contract on ex-post investment and costs. This is an additional method of providing incentives to invest, beyond the allocation of property rights themselves. Consequently, ex-post investors can be protected (and be provided incentives to invest) via these contracts, whereas ex-ante investors –who can not contract on their investments at all – are more likely to require the protection of property rights (through the allocation of asset ownership). The addition of sequential investment alters some of the predictions of the standard models. For example, previously the literature found that if all assets are complements at the margin all agents should have access to all assets (Bel (2005)). However, when investment sequencing is possible, making a control structure more inclusive (increasing the number of agents who have access to assets) can reduce the incentives of the ex-ante investors, decreasing overall surplus; this is because increasing the property rights of ex-post investors increases the marginal costs borne by ex-ante investors, effectively reducing their claim on surplus, diminishing their incentives to invest. This result contradicts Bel (2005), and shows that even when all assets are complimentary at the margin allocating access rights can be detrimental to incentives. Furthermore, if assets are substitutes at the margin then transfer of assets from ex-ante investors to ex-post investors can increase ex-ante investment and surplus. This counter intuitive result can occur in the case when decreasing ex-post investment is necessary to provide an incentive to ex-ante investors to increase their investments.Discipline of Economic

Code status documentation at admission in COVID-19 patients: a descriptive cohort study

Objectives The COVID-19 pandemic pressurised healthcare with increased shortage of care. This resulted in an increase of awareness for code status documentation (ie, whether limitations to specific life-sustaining treatments are in place), both in the medical field and in public media. However, it is unknown whether the increased awareness changed the prevalence and content of code status documentation for COVID-19 patients. We aim to describe differences in code status documentation between infectious patients before the pandemic and COVID-19 patients. Setting University Medical Centre of Utrecht, a tertiary care teaching academic hospital in the Netherlands. Participants A total of 1715 patients were included, 129 in the COVID-19 cohort (a cohort of COVID-19 patients, admitted from March 2020 to June 2020) and 1586 in the pre-COVID-19 cohort (a cohort of patients with (suspected) infections admitted between September 2016 to September 2018). Primary and secondary outcome measures We described frequency of code status documentation, frequency of discussion of this code status with patient and/or family, and content of code status. Results Frequencies of code status documentation (69.8% vs 72.7%, respectively) and discussion (75.6% vs 73.3%, respectively) were similar in both cohorts. More patients in the COVID-19 cohort than in the before COVID-19 cohort had any treatment limitation as opposed to full code (40% vs 25%). Within the treatment limitations, 'no intensive care admission' (81% vs 51%) and 'no intubation' (69% vs 40%) were more frequently documented in the COVID-19 cohort. A smaller difference was seen in 'other limitation' (17% vs 9%), while 'no resuscitation' (96% vs 92%) was comparable between both periods. Conclusion We observed no difference in the frequency of code status documentation or discussion in COVID-19 patients opposed to a pre-COVID-19 cohort. However, treatment limitations were more prevalent in patients with COVID-19, especially 'no intubation' and 'no intensive care admission'.Pathophysiology, epidemiology and therapy of agein

Lower respiratory tract infection in the community: associations between viral aetiology and illness course

Objectives: This study determined associations between respiratory viruses and subsequent illness course in primary care adult patients presenting with acute cough and/or suspected lower respiratory tract infection.Methods: A prospective European primary care study recruited adults with symptoms of lower respiratory tract infection between November 2007 and April 2010. Real-time in-house polymerase chain reaction (PCR) was performed to test for six common respiratory viruses. In this secondary analysis, symptom severity (scored 1 = no problem, 2 = mild, 3 = moderate, 4 = severe) and symptom duration were compared between groups with different viral aetiologies using regression and Cox proportional hazard models, respectively. Additionally, associations between baseline viral load (cycle threshold (Ct) value) and illness course were assessed.Results: The PCR tested positive for a common respiratory virus in 1354 of the 2957 (45.8%) included patients. The overall mean symptom score at presentation was 2.09 (95% confidence interval (CI) 2.07-2.11) and the median duration until resolution of moderately bad or severe symptoms was 8.70 days (interquartile range 4.50-11.00). Patients with influenza virus, human metapneumovirus (hMPV), respiratory syncytial virus (RSV), coronavirus (CoV) or rhinovirus had a significantly higher symptom score than patients with no virus isolated (0.07-0.25 points or 2.3-8.3% higher symptom score). Time to symptom resolution was longer in RSV infections (adjusted hazard ratio (AHR) 0.80, 95% CI 0.65-0.96) and hMPV infections (AHR 0.77, 95% CI 0.62-0.94) than in infections with no virus isolated. Overall, baseline viral load was associated with symptom severity (difference 0.11, 95% CI 0.06-0.16 per 10 cycles decrease in Ct value), but not with symptom duration.Conclusions: In healthy, working adults from the general community presenting at the general practitioner with acute cough and/or suspected lower respiratory tract infection other than influenza impose an illness burden comparable to influenza. Hence, the public health focus for viral respiratory tract infections should be broadened. (C) 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Chronic Q fever diagnosis—consensus guideline versus expert opinion

Chronic Q fever, caused by Coxiella burnetii, has high mortality and morbidity rates if left untreated. Controversy about the diagnosis of this complex disease has emerged recently. We applied the guideline from the Dutch Q Fe­ver Consensus Group and a set of diagnostic criteria pro­posed by Didier Raoult to all 284 chronic Q fever patients included in the Dutch National Chronic Q Fever Database during 2006–2012. Of the patients who had proven cas­es of chronic Q fever by the Dutch guideline, 46 (30.5%) would not have received a diagnosis by the alternative cri­teria designed by Raoult, and 14 (4.9%) would have been considered to have possible chronic Q fever. Six patients with proven chronic Q fever died of related causes. Until results from future studies are available, by which current guidelines can be modified, we believe that the Dutch lit­erature-based consensus guideline is more sensitive and easier to use in clinical practice

Has the Rate of CD4 Cell Count Decline before Initiation of Antiretroviral Therapy Changed over the Course of the Dutch HIV Epidemic among MSM?

Introduction:Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.Methods:Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Diagnosis and treatment of community-acquired lower respiratory tract infections : Strategies for efficient management

Lower respiratory tract infections are an important cause for morbidity and mortality and associated with considerable costs and antibiotic consumption, especially in patients needing hospitalization. The aim of this thesis was to evaluate diagnostic and treatment strategies to decrease costs and control antibiotic use in hospitalized patients. Early identification of patients with high risk a for a complicated course could prevent unnecessary ICU admissions, complications or deaths. However, current definitions of severe CAP do not seem suitable to guide pneumonia management. A new prediction rule based on routine clinical, biochemical and microbiological information was proposed to determine which patients are at risk for early clinical failure. Results of rapid microbiological tests can help in tailoring therapy early in the course of treatment. An algorithm was developed to determine cost savings based on the results of rapid diagnostic testing. Application of this algorithm to a population of patients hospitalised with CAP showed that the use of Gram staining of sputum or urinary antigen testing to diagnose pneumococcal pneumonia will lead to only minimal cost-savings. Cessation of empirically initiated antibiotic treatment may be justified if viruses are identified. Clinical and economical impact of early, rapid and sensitive identification of viral infection by means of novel Taq-man real-time PCR techniques was evaluated in a randomized trial. Diagnostic yield increased as compared to routine diagnostic procedures and viral infections were detected in over 20%, but its use was not associated with reductions in antibiotic use or costs. Hence, real-time PCR should not become part of the routine work-up for every patient, unless the cost-effectiveness can be improved. However, financial investment in rapid tests may outweigh the costs associated with future treatment of infections caused by resistant micro-organisms. Putative beneficial effects of initial combination treatment with a b-lactam antibiotics plus a macrolides or monotherapy with fluoroquinolones are an increased patient survival as compared to with a b-lactam monotherapy; possible disadvantages are increases in antibiotic use and treatment costs. In a systematic review, unequivocal evidence of increased patient survival only mounted form studies with substantial patient prescription bias. Contrary, antibiotic use and treatment costs would increase with about 20%, increasing up to over 50% in patients with moderate CAP, whereas the adequacy of therapy hardly changes. Therefore, the current evidence for the use of combination therapy or treatment with fluoroquinolones in CAP is not strong enough to justify a place in routine clinical practice. In theory, an early switch from intravenous to oral therapy reduces intravenous drug costs and allows an early discharge from hospital, but risks increase in treatment failures and treatment costs outside the hospital. In a study evaluating these factors, a early conversion to oral treatment significantly reduced length of hospital stay and overall costs as compared to a 7-day course of intravenous treatment. There were comparable clinical outcomes. Future steps towards more efficient management may include even shorter courses of antimicrobial treatment and implementation of early switch strategies in clinical practice