Paola M. Soccal

New Respiratory Enterovirus and Recombinant Rhinoviruses among Circulating Picornaviruses

Increased genomic diversity of these viruses is demonstrated.

Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain.

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of several diseases of the CNS, that share common pathophysiological processes, such as blood-brain barrier (BBB) disruption, oxidative stress, remodeling of the extracellular matrix (ECM) and inflammation. In ischemic brain injury, MMPs are implicated in various stages of the disease. Early after the onset of ischemia, MMPs contribute to the disruption of the BBB leading to vasogenic edema and to the influx of leucocytes into the CNS. The ability of MMPs to digest the basal lamina of capillaries increases the risk of hemorrhagic transformation of the ischemic tissue. During the acute ischemic phase, maintenance of the ECM is essential for neuronal survival. However, ECM degradation and its reconstitution are critical to tissue recovery. MMPs as a key modulator of ECM homeostasis play a role in the cascades leading to neuronal cell death and tissue regeneration. This pleiotropic implication of MMPs in brain injury has open new areas of investigation, which should lead to innovative therapeutic strategies. Yet MMPs may have a detrimental or beneficial role depending on the stage of brain injury. Simple therapeutic strategies based on MMP inhibition have thus little chance to favorably alter prognosis.

A Prospective Hospital-Based Study of the Clinical Impact of Non–Severe Acute Respiratory Syndrome (Non-SARS)–Related Human Coronavirus Infection

Abstract Background. In addition to the human coronaviruses (HCoVs) OC43 and 229E, which have been known for decades to cause infection in humans, 2 new members of this genus have recently been identified: HCoVs NL63 and HKU1. Their impact as a cause of respiratory tract disease in adults at risk for complications needs to be established. Methods. We prospectively assessed the clinical impact of coronavirus infection (excluding cases of severe acute respiratory syndrome) among hospitalized adults. All patients with respiratory disease for whom bronchoalveolar lavage was performed were screened by reverse-transcriptase polymerase chain reaction for the presence of all 4 HCoVs. Results. HCoV was identified in 29 (5.4%) of 540 bronchoalveolar lavage fluid specimens from 279 subjects (mean age, 51 years; 63% male). HCoV OC43 was identified most frequently (12 isolates), followed by 229E (7 isolates), NL63 (6 isolates), and HKU1 (4 isolates). In all, 372 (69%) of 540 bronchoalveolar lavage fluid specimens were negative for bacteria, and 2 persons were coinfected with other respiratory viruses. Transplantation was the most common underlying condition. Of the 29 patients who had HCoV identified in their bronchoalveolar lavage fluid specimens, 9 (31%) were hospitalized in the intensive care unit, 22 (76%) presented to the hospital with acute respiratory symptoms, 16 (55%) presented with cough and/or sputum, 13 (45%) presented with dyspnea, 16 (55%) had experienced prior respiratory infection, and 18 (62%) had a new infiltrate that was visible on chest radiograph. The most frequent final diagnosis was a lower respiratory tract infection. Conclusions. The recently discovered HCoVs NL63 and HKU1 contribute significantly to the overall spectrum of coronavirus infection. Our study also suggests that coronaviruses contribute to respiratory symptoms in most cases.

Risk Assessment of Tuberculosis in Immunocompromised Patients. A TBNET Study

RATIONALE In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. OBJECTIVES This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. METHODS Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. MEASUREMENTS AND MAIN RESULTS Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. CONCLUSIONS Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials.gov (NCT 00707317).

Respiratory viruses in bronchoalveolar lavage: a hospital-based cohort study in adults

Background: The epidemiology of respiratory viruses and their potential clinical impact when recovered in lower respiratory specimens has not been established in the hospital setting. A study was performed to investigate the association between positive viral detection and respiratory infection in an at-risk population. Methods: 299 adult patients who underwent bronchoalveolar lavage (BAL) procedures were enrolled in a hospital-based prospective cohort study. Descriptive epidemiology is presented of 17 different respiratory viruses detected by reverse transcription-polymerase chain reaction assays in BAL fluid specimens. Multivariate analysis was conducted to identify the clinical characteristics independently associated with the presence of virus. Results: Of 522 BAL fluid specimens analysed, 81% were collected in adult transplant recipients or other immunocompromised patients. Overall, PCR assays identified viral nucleic acid in 91 BAL fluid samples (17.4%). Similar rates of virus-positive BAL fluid were found in the different subpopulations studied (p = 0.113). Coronaviruses were the most frequent (32.3%), followed by rhinovirus (22.6%), parainfluenza (19.5%), influenza (9.7%), respiratory synctial virus (8.6%), human metapneumovirus (4.2%) and bocavirus (3.1%). Multivariate analysis using mixed models showed that respiratory viral infections were associated with a lack of antibiotic treatment response (OR 2.2, 95% CI 1.2 to 4.1) and the absence of radiological infiltrate (OR 0.3, 95% CI 0.2 to 0.8). In lung transplant recipients in whom a respiratory infection was suspected, the respiratory viral detection rate was 24.4% compared with 13.8% overall in other patients (p = 0.02). Conclusions: In this cohort of hospitalised adults, respiratory viruses detected in BAL fluid specimens were associated with respiratory symptoms, absence of radiological infiltrates and a poor response to antibiotic therapy.

Respiratory viruses in lung transplant recipients: a critical review and pooled analysis of clinical studies.

Lung transplant recipients present an increased risk for severe complications associated with respiratory infections. We conducted a review of the literature examining the clinical relationship between viral respiratory infection and graft complications. Thirty‐four studies describing the clinical impact of influenza, respiratory syncytial virus, parainfluenza, human metapneumovirus, rhinovirus, enterovirus, coronavirus, bocavirus or adenovirus were identified. The detection rate of respiratory viral infection ranged from 1.4% to 60%. Viruses were detected five times more frequently when respiratory symptoms were present [odds ratio (OR) = 4.97; 95% CI = 2.11–11.68]. Based on available observations, we could not observe an association between respiratory viral infection and acute rejection (OR = 1.35; 95% CI = 0.41–4.43). We found a pooled incidence of 18% (9/50) of bronchiolitis obliterans syndrome (BOS) in virus‐positive cases compared to 11.6% (37/319) in virus‐negative cases; however, limited number of BOS events did not allow to confirm the association. Our review confirms a causal relationship between respiratory viruses and respiratory symptoms, but cannot confirm a link between respiratory viruses and acute lung rejection. This is related in part to the heterogeneity and limitations of available studies. The link with BOS needs also to be reassessed in appropriate prospective studies.

Titrated sedation with propofol or midazolam for flexible bronchoscopy: a randomised trial

In this study, we questioned whether propofol provided clinical benefits compared with midazolam in terms of neuropsychometric recovery, safety profile and patient tolerance. Patients, aged >18 yrs, were randomised to receive midazolam or propofol, given by non-anaesthetist physicians to achieve moderate levels of sedation as assessed by the electroencephalographic bispectral index (BIS; between 70 and 85). The primary end-point was the time delay until recovery of the BIS above 90. Other end-points included a neuropsychometric continuous performance test (CPT), serious respiratory adverse events, patient tolerance and physician satisfaction. Neuropsychometric recovery was improved in the propofol compared to the midazolam group as evidenced by faster normalisation of BIS index (5.4±4.7 min versus 11.7±10.2 min; p = 0.001) and better results at the CPT. In the midazolam group, 15% of patients presented profound sedation precluding CPT completion and one patient required mechanical ventilatory support. Patient tolerance was significantly better in the propofol group, whereas the operator’s assessment was comparable in both groups. Compared with midazolam, propofol provided a higher quality of sedation in terms of neuropsychometric recovery and patient tolerance. BIS-guided propofol administration represents a safe sedation technique that can be performed by the non-anaesthesiologist.

Diagnostic Yield and Safety of Electromagnetic Navigation Bronchoscopy for Lung Nodules: A Systematic Review and Meta-Analysis

Background: Electromagnetic navigation bronchoscopy (ENB) is an emerging endoscopic technique for the diagnosis of peripheral lung lesions. A thorough analysis of ENBs yield and safety is required for comparison to other sampling modalities. Objectives: To describe ENBs yield and safety profile. Methods: The MEDLINE and EMBASE databases were systematically searched for studies reporting ENBs yield for peripheral lung lesions. Two independent investigators extracted data and rated each study on a scale of methodological quality. Clearly defined performance outcomes were reconstructed and meta-analyzed. Subgroup analysis and meta-regression were used to identify possible sources of study heterogeneity. Results: A total of 15 trials were included (1,033 lung nodules). A positive and definitive diagnosis was obtained after 64.9% of all ENB procedures (95% CI 59.2-70.3). Overall diagnostic accuracy was 73.9% (95% CI 68.0-79.2). Sensitivity to detect cancer was 71.1% (95% CI 64.6-76.8), with a negative predictive value of 52.1% (95% CI 43.5-60.6). Pneumothorax occurred in 3.1% of patients, requiring chest tube drainage in 1.6% of these cases. Original trials identified 6 variables associated with higher ENB yields: nodule location in the upper or middle lobes, nodule size, lower registration error, presence of a bronchus sign on CT imaging, combined use of an ultrasonic radial probe, and catheter suctioning as a sampling technique. Heterogeneity exploration revealed that studies using general anesthesia or rapid on-site cytological evaluation reported better yields. Conclusions: ENB is effective and particularly safe. Prospective studies are needed to clarify the role of several variables conditioning the yield of this technique.

Rhinovirus Genome Variation during Chronic Upper and Lower Respiratory Tract Infections

Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5′UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers.

Upper and Lower Respiratory Tract Viral Infections and Acute Graft Rejection in Lung Transplant Recipients

Abstract Background. Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. Methods. Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction—based assays. Results. BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (P < .001). We observed a significant association between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (P = .012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20–0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. Conclusions. A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infection.