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1.
Clin Lung Cancer ; 21(2): 114-126.e3, 2020 03.
Article in English | MEDLINE | ID: mdl-31839534

ABSTRACT

The impact of oncologic treatment for (non)-small-cell lung cancer (NSCLC and SCLC, respectively) on cognition is relevant when deciding which treatment is the most preferable option, especially when curation is not possible. A systematic search of Medline and EMBASE for studies on the effect of treatment on cognition in patients with lung cancer was performed. A total of 39 longitudinal articles were included. Study populations were heterogeneous with regards to stage and treatment type. In the 7 studies concerning SCLC, the median age of patients was between 59 and 68 years. Eighty-six percent of these studies had a loss to follow-up > 10%. Six studies used objective tests to assess cognition. Objective measurements showed a negative effect on attention, memory, and fluency after treatment. Thirty-three studies concerning NSCLC were included. The mean age of patients was between 53 and 77 years. Seventy percent of these studies included patients with stage III and IV NSCLC. Over one-half of the studies had a high rate of loss to follow-up. Eighty-eight percent used objective scales to assess cognitive functioning. Subjective decline of cognitive functioning up to 11.1% was experienced, with recovery at 4 to 6 months. Objective measurement of attention showed improvement over the course of chemotherapy. In SCLC, there is a significant negative effect on attention, memory, and fluency. In NSCLC, the longer term impact of treatment on both subjective and objective cognitive functioning appears limited. Thus, there is no evidence directing treatment choice for NSCLC based on longer term cognitive deficits. Further research is needed to precisely assess the impact of lung cancer treatment on cognition.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cognition Disorders/pathology , Lung Neoplasms/drug therapy , Cognition Disorders/chemically induced , Humans , Lung Neoplasms/pathology , Prognosis
2.
BMC Infect Dis ; 19(1): 17, 2019 Jan 07.
Article in English | MEDLINE | ID: mdl-30612559

ABSTRACT

BACKGROUND: Guidelines recommend macrolides and fluoroquinolones in patients hospitalized with community-acquired pneumonia (CAP), but their use has been associated with cardiac events. We quantified associations between macrolide and fluoroquinolone use and cardiac events in patients hospitalized with CAP in non-ICU wards. METHODS: This was a post-hoc analysis of a cluster-randomized trial as a cohort study; including patients with a working diagnosis of CAP admitted to non-ICU wards without a cardiac event on admission. We calculated cause-specific hazard ratio's (HR's) for effects of time-dependent macrolide and fluoroquinolone exposure as compared to beta-lactam monotherapy on cardiac events, defined as new or worsening heart failure, arrhythmia, or myocardial ischemia during hospitalization. RESULTS: Cardiac events occurred in 146 (6.9%) of 2107 patients, including heart failure (n = 101, 4.8%), arrhythmia (n = 53, 2.5%), and myocardial ischemia (n = 14, 0.7%). These occurred in 11 of 207 (5.3%), 18 of 250 (7.2%), and 31 of 277 (11.2%) patients exposed to azithromycin, clarithromycin, and erythromycin for at least one day, and in 9 of 234 (3.8%), 5 of 194 (2.6%), and 23 of 566 (4.1%) exposed to ciprofloxacin, levofloxacin, and moxifloxacin, respectively. HR's for erythromycin, compared to beta-lactam monotherapy, on any cardiac event and heart failure were 1.60 (95% CI 1.09;2.36) and 1.89 (95% CI 1.22;2.91), respectively. HR's for levofloxacin and moxifloxacin, compared to beta-lactam monotherapy, on any cardiac event were 0.40 (95% CI 0.18;0.87)and 0.56 (95% CI 0.36;0.87), respectively. Findings remained consistent after adjustment for confounders and/or in a sensitivity analysis of radiologically confirmed CAP (n = 1604, 76.1%). CONCLUSIONS: Among patients with CAP hospitalized to non-ICU wards, erythromycin use was associated with a 68% increased risk of hospital-acquired cardiac events, mainly heart failure. Levofloxacin and moxifloxacin were associated with a lower risk of heart failure. Although our study does not fully exclude confounding bias, findings remained largely unchanged in crude, adjusted, and sensitivity analyses. These findings may caution the use of erythromycin as empirical therapy in these patients. TRIAL REGISTRATION: The original trial was retrospectively registered under ClinicalTrials.gov Identifier NCT01660204 on August 8th, 2012.


Subject(s)
Community-Acquired Infections/drug therapy , Fluoroquinolones/adverse effects , Heart Diseases/chemically induced , Macrolides/adverse effects , Pneumonia, Bacterial/drug therapy , Aged , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Cohort Studies , Community-Acquired Infections/microbiology , Female , Fluoroquinolones/therapeutic use , Hospitalization , Humans , Macrolides/therapeutic use , Male , Middle Aged , Retrospective Studies , beta-Lactams/therapeutic use
3.
Lung ; 195(5): 627-634, 2017 10.
Article in English | MEDLINE | ID: mdl-28631153

ABSTRACT

INTRODUCTION: An important step in improving research and care for the oldest patients with lung cancer is analyzing current data regarding diagnostic work-up, treatment choices, and survival. METHODS: We analyzed data on lung cancer from the Netherlands Cancer Registry (NCR-IKNL) regarding diagnostic work-up, treatment, and survival in different age categories; the oldest old (≥85 years of age) versus those aged 71-84 (elderly) and those aged ≤70 years (younger patients). RESULTS: 47,951 patients were included in the 2010-2014 NCR database. 2196 (5%) patients were aged ≥85 years. Histological diagnosis was obtained significantly less often in the oldest old (38%, p < 0.001), and less standard treatment regimen was given (8%, p < 0.001) compared to elderly and younger patients. 67% of the oldest old received best supportive care only versus 38% of the elderly and 20% of the younger patients (p < 0.001). For the oldest old receiving standard treatment, survival rates were similar in comparison with the elderly patients. In the oldest old, no survival differences were found when comparing standard or adjusted regimens for stage I and IV NSCLC; for stage III, oldest old receiving standard treatment had longer survival. No oldest old patients with stage II received standard treatment. CONCLUSION: Clinicians make limited use of diagnostics and invasive treatment in the oldest old; however, selected oldest old patients experienced similar survival rates as the elderly when receiving some form of anticancer therapy (standard or adjusted). More research is needed to further develop individualized treatment algorithms.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Palliative Care/statistics & numerical data , Radiotherapy/statistics & numerical data , Small Cell Lung Carcinoma/therapy , Surgical Procedures, Operative/statistics & numerical data , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung/surgery , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Neoplasm Staging , Netherlands , Small Cell Lung Carcinoma/diagnosis , Small Cell Lung Carcinoma/mortality , Small Cell Lung Carcinoma/pathology
4.
Clin Lung Cancer ; 18(6): 660-666.e1, 2017 11.
Article in English | MEDLINE | ID: mdl-28320638

ABSTRACT

BACKGROUND: Because of the time-consuming aspect of geriatric assessments, cancer specialists are seeking shorter screening tools to distinguish fit and frail patients. We analyzed the predictive value of the Geriatric 8 (G8) and Identification of Seniors at Risk for Hospitalized Patients (ISAR-HP) in elderly patients with lung cancer. PATIENTS AND METHODS: From January 2014 to April 2016, the data from patients with lung cancer aged > 70 years at 2 teaching hospitals in the Netherlands were included in a database. The patients were classified as potentially frail if they had a G8 of ≤ 14 or ISAR-HP of ≥ 2. RESULTS: Of the 142 included patients (median age, 77 years; interquartile range, 73-82 years), 108 (76%) were potentially frail. After correction for possible confounders, the potentially frail patients had a significantly greater risk of 1-year mortality (hazard ratio [HR], 4.08; 95% confidence interval [CI] 1.67-9.99; P = .02). Higher disease stage (HR, 1.72; 95% CI, 1.40-2.12; P < .001) was also a significant predictor of mortality; however, initial treatment (standard or otherwise) and age were not. When using both screening instruments separately, an impaired score on the G8 and higher disease stage were the variables remaining in the regression analyses (HR for impaired G8, 3.01; 95% CI, 1.35-6.72; P < .001). Patients with impaired scores on the ISAR-HP and G8 had more geriatric impairments than did patients with only an impaired G8 score. CONCLUSION: G8 screening is useful for the prognostication of elderly patients with lung cancer and could be used in combination with ISAR-HP to increase specificity at the cost of sensitivity. Using the ISAR-HP as the only screening tool would be insufficient.


Subject(s)
Geriatric Assessment/methods , Lung Neoplasms/pathology , Mass Screening/methods , Aged , Aged, 80 and over , Early Detection of Cancer , Female , Hospitalization , Hospitals, Teaching , Humans , Male , Neoplasm Staging , Netherlands , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Regression Analysis , Risk , Sensitivity and Specificity
5.
Lung ; 195(2): 225-231, 2017 04.
Article in English | MEDLINE | ID: mdl-28280921

ABSTRACT

BACKGROUND: Decision-making for older patients with lung cancer can be complex and challenging. A geriatric assessment (GA) may be helpful and is increasingly being used since 2005 when SIOG advised to incorporate this in standard work-up for the elderly with cancer. Our aim was to evaluate the value of a geriatric assessment in decision-making for patients with lung cancer. METHODS: Between January 2014 and April 2016, data on patients with lung cancer from two teaching hospitals in the Netherlands were entered in a prospective database. Outcome of geriatric assessment, non-oncologic interventions, and suggested adaptations of oncologic treatment proposals were evaluated. RESULTS: 83 patients (median age 79 years) were analyzed with a geriatric assessment, of which 59% were treated with a curative intent. Half of the patients were classified as ECOG PS 0 or 1. The majority of the patients (78%) suffered from geriatric impairments and 43% (n = 35) of the patients suffered from three or more geriatric impairments (out of eight analyzed domains). Nutritional status was most frequently impaired (52%). Previously undiagnosed impairments were identified in 58% of the patients, and non-oncologic interventions were advised for 43%. For 33% of patients, adaptations of the oncologic treatment were proposed. Patients with higher number of geriatric impairments more often were advised a reduced or less intensive treatment (p < 0.001). CONCLUSION: A geriatric assessment uncovers previously unknown health impairments and provides important guidance for tailored treatment decisions in patients with lung cancer. More research on GA-stratified treatment decisions is needed.


Subject(s)
Clinical Decision-Making , Geriatric Assessment , Lung Neoplasms/therapy , Aged , Aged, 80 and over , Cognitive Dysfunction/complications , Comorbidity , Female , Health Status , Humans , Lung Neoplasms/complications , Male , Mobility Limitation , Nutritional Status
6.
Lung ; 194(6): 967-974, 2016 12.
Article in English | MEDLINE | ID: mdl-27650509

ABSTRACT

BACKGROUND: Lung cancer is predominantly a disease of the elderly: half of all newly diagnosed patients are over 70 years old. Older patients and those with comorbidities are underrepresented in clinical trials; scientific communities have addressed this issue since the end of the 20th century. We set out to determine the characteristics of the selection of patients in lung cancer trials that are currently recruiting. METHODS: We searched The United States National Institutes of Health (NIH) clinical trial registry ( www.clinicaltrials.gov ) on April 23, 2015 for currently recruiting phase I, II, or III clinical trials in lung cancer. Trial characteristics and study objectives were extracted from the registry website. RESULTS: Of the 419 trails selected in this overview, 88 % explicitly or implicitly excluded elderly patients. Patients were excluded based on stringent organ selection in 76 % of the trials, based on performance status (57 %) and based on age (13 %). The median number of placed restrictions per trial was seven. In the 2 % of the trials that were exclusively designed for elderly patients only fit patients were included. CONCLUSION: In this overview of current lung cancer trials registered in the NIH clinical trial registry, we found that elderly patients and those with comorbidities are often excluded from participation in clinical trials. Therefore, it is difficult for physicians and their frail patients to properly evaluate the efficacy and safety of current treatment options. More research that includes the elderly and those with comorbidities is urgently needed.


Subject(s)
Clinical Trials as Topic/methods , Lung Neoplasms/therapy , Patient Selection , Adult , Age Factors , Aged , Aged, 80 and over , Comorbidity , Health Status , Humans , Middle Aged , Registries , Young Adult
7.
Lung ; 194(4): 647-52, 2016 08.
Article in English | MEDLINE | ID: mdl-27287676

ABSTRACT

BACKGROUND: Scientific communities focusing on cancer research have urged for the development of trials that address patient-centered outcome measures instead of solely focusing on cancer as a disease-centered process. This is important for a patient with lung cancer because of the rapid course of disease and generally poor prognosis. We set out to determine the characteristics and study objectives of the current clinical trials in pulmonary malignancies. METHODS: The United States National Institutes of Health clinical trial registry was searched on April 23rd 2015, for currently recruiting phase I, II, or III clinical trials in lung cancer. Trial characteristics and study objectives were extracted from the registry website. RESULTS: Of the 419 clinical trials included in this review, patient-centered outcome measures are investigated in a minority of the trials. Outcome measures as quality of life, functional capacity, and health care utilization are included in a small number of trials (20, 4, and 2 % respectively). Treatment completion is included in 1 % of the trials. Research goals are most frequently toxicity (78 %) and progression-free survival (76 %). CONCLUSION: Patient-centered outcome measures are included in a minority of the currently recruiting clinical trials in pulmonary malignancies. If we do not investigate these outcome measures, it is not possible to increase our knowledge of the optimal treatment, as this should aim to optimize the patient's wellbeing as well as the course of disease. One option could be to incorporate combinations of patient- and disease-centered endpoints, for instance by using overall treatment utility or quality-adjusted outcome measures.


Subject(s)
Clinical Trials as Topic/statistics & numerical data , Health Services/statistics & numerical data , Health Status , Lung Neoplasms/therapy , Patient Reported Outcome Measures , Quality of Life , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Biomedical Research , Clinical Trials as Topic/standards , Disease-Free Survival , Goals , Humans , Middle Aged , Registries , Research Design , United States , Young Adult
8.
Clin Lung Cancer ; 17(5): 341-349.e3, 2016 09.
Article in English | MEDLINE | ID: mdl-27349507

ABSTRACT

Lung cancer is predominantly a disease of the elderly: one half of all newly diagnosed patients will be > 70 years old. In the Netherlands, > 12,000 new cases are diagnosed annually. We sought to assemble all available evidence on the relevance of a geriatric assessment for lung cancer patients. A systematic Medline and Embase search was performed for studies in which a geriatric assessment was used to detect health issues or that had addressed the association between a baseline geriatric assessment (composed of ≥ 2 of the following domains: cognitive function, mood/depression, nutritional status, activities of daily living, instrumental activities of daily living, polypharmacy, objectively measured physical capacity, social support and frailty) and outcome. A total of 23 publications from 18 studies were included. The median age of patients was 76 years (range, 73-81 years). Despite generally good Eastern Cooperative Oncology Group performance status, the prevalence of geriatric impairments was high, with the median ranging from 29% for cognitive impairment to 70% for instrumental activities of daily living impairment. Objective physical capacity and nutritional status, as items of the geriatric assessment, had a consistent association with mortality. The information revealed by a geriatric assessment led to changes in oncologic treatment and nononcologic interventions. The present review has demonstrated that a geriatric assessment can detect multiple health issues not reflected in the Eastern Cooperative Oncology Group performance status. Impairments in geriatric domains have predictive value for mortality and appear to be associated with treatment completion. It would be useful to develop and validate an individualized treatment algorithm that includes these geriatric domains.


Subject(s)
Geriatric Assessment/methods , Health Status , Lung Neoplasms/pathology , Activities of Daily Living , Aged , Aged, 80 and over , Cognition , Health Status Indicators , Humans , Nutritional Status , Predictive Value of Tests
9.
N Engl J Med ; 372(14): 1312-23, 2015 Apr 02.
Article in English | MEDLINE | ID: mdl-25830421

ABSTRACT

BACKGROUND: The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy. METHODS: In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS: A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS: Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).


Subject(s)
Anti-Bacterial Agents/therapeutic use , Fluoroquinolones/therapeutic use , Macrolides/therapeutic use , Pneumonia, Bacterial/drug therapy , beta-Lactams/therapeutic use , Administration, Oral , Adult , Aged , Community-Acquired Infections/drug therapy , Community-Acquired Infections/mortality , Cross-Over Studies , Drug Therapy, Combination , Female , Humans , Intention to Treat Analysis , Length of Stay , Male , Middle Aged , Pneumonia, Bacterial/mortality
11.
J Clin Virol ; 41(2): 116-21, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18096430

ABSTRACT

BACKGROUND: Viral respiratory infections, particularly human rhinovirus (HRV) infections, are the most common cause of asthma exacerbation. HRV infections usually lead to more severe and longer duration of lower respiratory tract (LRT) symptoms in asthmatics than in otherwise healthy individuals. However, the exact mechanism by which viruses contribute to exacerbation of asthma is unknown. OBJECTIVES: The main objective of our study was to investigate the relationship of the enhanced severity of LRT symptoms to viral dynamics or cytokine responses in the upper respiratory tract (URT). STUDY DESIGN: Therefore, we conducted a longitudinal study in which asthmatics and healthy controls were followed during natural viral respiratory tract infections. RESULTS: Our study confirmed that viral respiratory tract infections caused more severe problems of the LRT in asthma patients as compared to healthy controls. However, for all subjects, the severity of LRT symptoms were not related to viral load or prolonged viral shedding in the URT. In addition, we did not detect differences in proinflammatory cytokines in the URT between asthmatics and controls. CONCLUSION: Persistence of the virus, as well as viral load in the URT, may not be associated with the induction and/or persistence of asthmatic symptoms.


Subject(s)
Asthma/complications , Respiratory Tract Infections/physiopathology , Respiratory Tract Infections/virology , Viral Load , Virus Diseases/physiopathology , Viruses/isolation & purification , Adolescent , Adult , Female , Humans , Male , Middle Aged , Severity of Illness Index , Virus Diseases/virology , Virus Shedding , Viruses/classification
12.
Antiviral Res ; 70(2): 75-84, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16490265

ABSTRACT

T helper 1-driven immune responses have been implicated in protective immunity against viral infections. Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a p35 and a p40 subunit that can induce differentiation of naïve T cells towards a T helper 1-response. To determine the role of IL-12 in respiratory tract infection with influenza, p35 gene deficient (p35-/-) and normal wild type mice were intranasally infected with influenza A virus. IL-12 p35-/- mice displayed a transiently enhanced rather than an impaired viral clearance, as indicated by a 10-fold reduction in viral loads on day 8 after infection. Although interferon-gamma levels were significantly lower in the lungs of IL-12 p35-/- mice, their cellular immune responses were not altered, as reflected by similar T cell CD69 expression and influenza-specific T cell recruitment. Our data indicate that endogenous IL-12 impairs viral clearance during the late phase of influenza A virus infection in mice.


Subject(s)
Influenza A virus/immunology , Interleukin-12/deficiency , Interleukin-12/immunology , Orthomyxoviridae Infections/immunology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/virology , Animals , Bronchoalveolar Lavage , Flow Cytometry , Immunoglobulins/blood , Immunoglobulins/immunology , Interleukin-12/biosynthesis , Interleukin-12/metabolism , Lung/immunology , Lung/virology , Mice , Mice, Inbred C57BL , Orthomyxoviridae Infections/blood , Orthomyxoviridae Infections/virology , Respiratory Tract Infections/blood , T-Lymphocytes/immunology , Viral Load
13.
Am J Physiol Lung Cell Mol Physiol ; 290(1): L194-9, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16100290

ABSTRACT

Although influenza infection alone may lead to pneumonia, secondary bacterial infections are a much more common cause of pneumonia. Streptococcus pneumoniae is the most frequently isolated causative pathogen during postinfluenza pneumonia. Considering that S. pneumoniae utilizes the platelet-activating factor receptor (PAFR) to invade the respiratory epithelium and that the PAFR is upregulated during viral infection, we here used PAFR gene-deficient (PAFR-/-) mice to determine the role of this receptor during postinfluenza pneumococcal pneumonia. Viral clearance was similar in wild-type and PAFR-/- mice, and influenza virus was completely removed from the lungs at the time mice were inoculated with S. pneumoniae (day 14 after influenza infection). PAFR-/- mice displayed a significantly reduced bacterial outgrowth in their lungs, a diminished dissemination of the infection, and a prolonged survival. Pulmonary levels of IL-10 and KC were significantly lower in PAFR-/- mice, whereas IL-6 and TNF-alpha were only trendwise lower. These data indicate that the pneumococcus uses the PAFR leading to severe pneumonia in a host previously exposed to influenza A.


Subject(s)
Influenza A virus , Orthomyxoviridae Infections/complications , Platelet Membrane Glycoproteins/metabolism , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/metabolism , Pneumonia/etiology , Pneumonia/immunology , Receptors, G-Protein-Coupled/metabolism , Streptococcus pneumoniae/immunology , Animals , Bronchoalveolar Lavage Fluid/cytology , Chemokines/metabolism , Cytokines/metabolism , Female , Immunity , Lung/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Osmolar Concentration , Pneumonia, Pneumococcal/pathology , Pneumonia, Pneumococcal/physiopathology , Streptococcus pneumoniae/growth & development , Survival Analysis
14.
Clin Infect Dis ; 40(5): 662-9, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15714410

ABSTRACT

BACKGROUND: Respiratory virus infections have been recognized as important causes of severe pneumonia in patients who have undergone stem cell transplantation (SCT). Reported incidences of respiratory virus infection in adult SCT recipients vary in the literature from 3.5% to 36% when determined by viral culture. However, a more sensitive method to assess the presence of respiratory viruses in the lower airways may be important for delineation of the true incidence of respiratory virus-associated pneumonia and may be essential for guidance on implementation of antiviral therapy and prevention or limitation of nosocomial spread of infection with respiratory viruses. METHODS: To determine the incidence and severity of respiratory tract illness (RTI) and to assess the diagnostic value of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) versus viral culture, 72 SCT recipients were monitored during a 6-month period. RESULTS: A respiratory virus was detected in 21% of episodes of RTI by viral culture and in 63% of RTI episodes by real-time RT-PCR (P<.0001). In lower respiratory tract illness, real-time RT-PCR was much more sensitive than viral culture for detection of respiratory virus (73% vs. 9%; P=.008). The mortality rate for patients with respiratory virus-associated lower respiratory tract illness (25%) was similar to rates reported elsewhere. Respiratory viruses (predominantly rhinovirus) were detected by real-time RT-PCR in 9% of samples obtained from symptom-free SCT recipients at predetermined times by real-time RT-PCR and by viral culture in 1% (P<.0001), indicating that asymptomatic shedding of respiratory viruses also occurs. CONCLUSION: We conclude that, although asymptomatic shedding of respiratory virus occurs, respiratory viruses are frequent causes of RTI in SCT recipients.


Subject(s)
Polymerase Chain Reaction/methods , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/virology , Stem Cell Transplantation , Virus Cultivation/methods , Virus Diseases/diagnosis , Adolescent , Adult , Humans , Middle Aged , Prospective Studies , Sensitivity and Specificity , Virus Diseases/virology
15.
Immunology ; 114(1): 112-20, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15606801

ABSTRACT

T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(-/-)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(-/-) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-gamma (IFN-gamma) levels were similar in the lungs of IL-18(-/-) mice and wildtype mice. Intracellular IFN-gamma staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-gamma production is IL-18-independent during influenza virus infection. Tumour necrosis factor-alpha production by CD4(+) T cells was significantly lower in IL-18(-/-) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection.


Subject(s)
Influenza A virus , Interleukin-18/immunology , Orthomyxoviridae Infections/immunology , Animals , Bronchoalveolar Lavage Fluid/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytokines/biosynthesis , Immune Tolerance , Interferon-gamma/biosynthesis , Interleukin-18/biosynthesis , Interleukin-18/genetics , Lung/immunology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/virology , RNA, Messenger/genetics , Survival Rate , Up-Regulation , Viral Load
16.
J Immunol ; 172(12): 7603-9, 2004 Jun 15.
Article in English | MEDLINE | ID: mdl-15187140

ABSTRACT

Secondary pneumococcal pneumonia is a serious complication during and shortly after influenza infection. We established a mouse model to study postinfluenza pneumococcal pneumonia and evaluated the role of IL-10 in host defense against Streptococcus pneumoniae after recovery from influenza infection. C57BL/6 mice were intranasally inoculated with 10 median tissue culture infective doses of influenza A (A/PR/8/34) or PBS (control) on day 0. By day 14 mice had regained their normal body weight and had cleared influenza virus from the lungs, as determined by real-time quantitative PCR. On day 14 after viral infection, mice received 10(4) CFU of S. pneumoniae (serotype 3) intranasally. Mice recovered from influenza infection were highly susceptible to subsequent pneumococcal pneumonia, as reflected by a 100% lethality on day 3 after bacterial infection, whereas control mice showed 17% lethality on day 3 and 83% lethality on day 6 after pneumococcal infection. Furthermore, 1000-fold higher bacterial counts at 48 h after infection with S. pneumoniae and, particularly, 50-fold higher pulmonary levels of IL-10 were observed in influenza-recovered mice than in control mice. Treatment with an anti-IL-10 mAb 1 h before bacterial inoculation resulted in reduced bacterial outgrowth and markedly reduced lethality during secondary bacterial pneumonia compared with those in IgG1 control mice. In conclusion, mild self-limiting influenza A infection renders normal immunocompetent mice highly susceptible to pneumococcal pneumonia. This increased susceptibility to secondary bacterial pneumonia is at least in part caused by excessive IL-10 production and reduced neutrophil function in the lungs.


Subject(s)
Interleukin-10/physiology , Orthomyxoviridae Infections/complications , Pneumonia, Pneumococcal/etiology , Animals , Antibodies/pharmacology , Cytokines/analysis , Disease Susceptibility/etiology , Female , Immunity , Interleukin-10/biosynthesis , Interleukin-10/immunology , Lung/chemistry , Lung/microbiology , Lung/pathology , Mice , Mice, Inbred C57BL , Neutrophils/physiology , Pneumonia, Pneumococcal/immunology , Pneumonia, Pneumococcal/mortality , Streptococcus pneumoniae/growth & development , Survival Rate
17.
J Infect Dis ; 189(4): 652-7, 2004 Feb 15.
Article in English | MEDLINE | ID: mdl-14767819

ABSTRACT

During the past years, human coronaviruses (HCoVs) have been increasingly identified as pathogens associated with more-severe respiratory tract infection (RTI). Diagnostic tests for HCoVs are not frequently used in the routine setting. It is likely that, as a result, the precise role that HCoVs play in RTIs is greatly underestimated. We describe a rapid, sensitive, and highly specific quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of HCoV that can easily be implemented in the routine diagnostic setting. HCoV was detected in 28 (11%) of the 261 clinical specimens obtained from patients presenting with symptoms of RTI ranging from common cold to severe pneumonia. Only 1 (0.4%) of the 243 control specimens obtained from patients without symptoms of RTI showed the presence of HCoV. We conclude that HCoVs can be frequently detected in patients presenting with RTI. Real-time RT-PCR provides a tool for large-scale epidemiological studies to further clarify the role that coronavirus infection plays in RTI in humans.


Subject(s)
Coronavirus 229E, Human/classification , Coronavirus Infections/virology , Coronavirus OC43, Human/classification , Coronavirus/isolation & purification , Respiratory Tract Infections/complications , Base Sequence , Coronavirus/genetics , Coronavirus 229E, Human/isolation & purification , Coronavirus OC43, Human/isolation & purification , DNA Primers , Humans , Pneumonia/complications , Polymerase Chain Reaction/methods , Reference Values
18.
Clin Infect Dis ; 34(2): 177-83, 2002 Jan 15.
Article in English | MEDLINE | ID: mdl-11740705

ABSTRACT

We retrospectively analyzed the value of polymerase chain reaction (PCR) for the detection of respiratory viral infections in 43 patients with hematological cancer whose bronchoalveolar lavage (BAL) samples had been stored. In addition, 17 nose-throat (NT) swabs and 29 blood samples had been obtained. PCR was performed to detect parainfluenza viruses 1-3, respiratory syncytial virus, rhinovirus, influenza viruses A and B, enteroviruses, and coronaviruses. Viral cultures or antigen testing of BAL samples revealed 9 respiratory viruses in 8 patients. By use of PCR, 8 more respiratory viruses were detected in another 7 patients, increasing the rate of identification from 19% to 35% (P<.0005). Available NT swabs yielded the same results with PCR as did BAL samples. We conclude that PCR is more sensitive than viral culture or antigen or serologic testing for detection of respiratory viruses in patients with hematological malignancies, and that it offers the possibility for early, more rapid diagnosis.


Subject(s)
Antigens, Viral/analysis , Hematologic Neoplasms/virology , Pneumonia, Viral/virology , Polymerase Chain Reaction/methods , RNA Virus Infections/diagnosis , RNA Viruses/growth & development , RNA Viruses/isolation & purification , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , RNA Viruses/chemistry , RNA Viruses/genetics , RNA, Viral/genetics , Retrospective Studies , Sensitivity and Specificity , Virus Cultivation
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