Benjamin T. Galen

EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production.

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.

Meningoencephalitis due to Gemella haemolysans

Gemella haemolysans is an uncommon but described cause of invasive disease in humans. We report a case of meningitis due to G. haemolysans that did not grow in cerebrospinal fluid culture, demonstrating a potential role for direct 16S rRNA gene PCR and sequencing in culture-negative cerebrospinal fluid when bacterial meningitis is suspected.

Ultrasound-Guided Peripheral Intravenous Catheters to Reduce Central Venous Catheter Use on the Inpatient Medical Ward

Purpose: The traditional technique of placing a peripheral intravenous (IV) catheter is successful in most cases on inpatient wards. However, when the traditional method fails, a central venous catheter may be placed to maintain IV access. These catheters are associated with risks including central line–associated bloodstream infection. Methods: We evaluated the effectiveness and acceptability of an ultrasound-guided peripheral IV service to reduce the number of newly placed central venous catheters on an inpatient ward. Central venous catheters were counted daily on intervention and control wards using a standard protocol, and rates of newly placed catheters were compared using a Poisson regression model. Nurses were surveyed to assess acceptability and perceived benefit. Results: We found a reduction in the rate of newly placed central venous catheters on the intervention unit compared with the control unit at 90 days: mean 0.47 versus 0.67 newly placed central venous catheters/day, but the difference was not significant (P = .08). Nurses were in favor of the ultrasound-guided IV service, with perceived benefit to their patients. Conclusion: Ultrasound-guided peripheral IV might reduce unnecessary central venous catheters on general inpatient wards. A portable ultrasound used for this purpose was found to be acceptable by nursing staff.

Is pocket ultrasound ready for prime time

Th e recent trial by Biais and colleagues adds to a growing body of literature supporting point-of-care ultrasound in the critical care setting [1]. Th e authors demonstrate that, in the hands of two expert users, a newer pocket-sized device was comparable with conventional ultrasound machines for several key echocardiographic parameters. Clearly in the right hands, the Vscan™ (GE Healthcare, Wauwatosa, WI, USA) is a promising tool, but we must be cautious not to extra polate these data to non-expert users. Th e novelty and convenience of pocket ultrasound should not distract from the requirement for proper training in medical school or for postgraduate medical education [2]. Th e emphasis must be on adequate training in a defi ned skill set within the scope of practice for a given specialist before pocket ultrasound becomes a management tool at the bedside. Furthermore, the device’s limitations must also be delineated. Th e Vscan™ has a single-phased array transducer, which is suitable for cardiac and abdominal windows, but the absence of a linear probe limits the use of this device for ultrasound-guided vascular access. For instance, in the medical ICU setting, the Vscan™ has great potential to guide bedside procedures such as thoracentesis and paracentesis but at this time is not appropriate to aid in central line placement. Th e authors do not directly bring cost into their discussion, but an advantage of the pocket device is that it retails at nearly one-quarter of the price of the comparison machine used in their trial. Th ese various ben efi ts and limitations must be taken into consideration when determining whether the Vscan™ is cost-eff ective for a given clinical setting.

In support of residency training at an academic veterans hospital.

To the Editor: Recently, we presented Clever and colleagues’ report1 to our peers at Cardiff University Journal Club. It was met with enthusiasm and sparked much debate, as all of us had experienced communication skills training using simulated patients in our first year of medical school and had taken real patient histories during later clinical placements. Thus, our encounters were similar to those of the first-year students described by Clever et al, who had developed their skills by communicating with both outpatients and simulated patients.

Post-test probability according to prevalence.

To the Editor:— The impact of disease prevalence on post-test disease probability cannot be understated and Agoritsas, et al. demonstrate clearly that their survey population tends towards overestimation of disease probability given a positive test result: the majority of respondents in each category chose the 95–99.9% option. The authors assert that incorporating disease prevalence (or prior probability) is not intuitive to clinicians and they propose as evidence the observation that physicians who were not provided with prevalence data in their study still “guessed” at post-test probability. However, it is unclear to the reader if these subjects even had the option in their survey to reply “cannot be determined,” since Table 1 indicates that 100% of these respondents did in fact select a post-test probability. Conclusions drawn from this arm of the study are therefore limited. This trial underscores the limitations of teaching arithmetic-based Bayesian calculations to medical trainees, since such statistical calculations are clinically cumbersome to implement if only because the terminology used to evaluate laboratory tests is not intuitive. The concepts are, however, quite intuitive and it has been shown that 95% of physicians who do take into consideration test characteristics in interpreting results do so in a “informal direct method”1. Rather than thinking in terms of ratios, odds, or nomograms, it is ideal to know which tests are good for ruling out and which are good for ruling in and when to use them. Leaving the mathematical heavy lifting to those who develop evidence-based guidelines in diagnostics permits clinicians to utilize Bayesian principles at the bedside without their knowing it. A good example is the extensive work done to optimize d-dimer testing and imaging in evaluating a patient for PE2,3. The trial by Agoritsas et al. reminds us that clinicians do need this structure in order to properly use and interpret diagnostic tests.

Mollaret Cells in Recurrent Benign Lymphocytic Meningitis

A 39-year-old woman with 3 prior episodes of aseptic meningitis without identified pathogen in cerebrospinal fluid (CSF) testing presented with 2 days of headache and neck stiffness. Examination was remarkable only for meningismus. Cerebrospinal fluid revealed lymphocytic pleocytosis (775 cells/mL, 82% lymphocytes, 13% monocytes), elevated total protein (90 mg/dL), normal glucose, negative Gram stain, and the presence of herpes simplex virus 2 (HSV-2) DNA on polymerase chain reaction (PCR) amplification. Cytology revealed large monocytes with varied nuclear morphologies, consistent with Mollaret cells (Figure 1). Treatment with intravenous acyclovir led to rapid clinical improvement. Mollaret cells are activated monocytes with convoluted nuclear lobes and abundant cytoplasm with pseudopods that account for their typical “footprint” or “cloverleaf” shapes. Due to fragility of the nuclear and cytoplasmic membranes in vivo, Mollaret cells are infrequently detected after 24 hours from symptom onset in recurrent benign lymphocytic meningitis attacks. They are encountered in up to 90% of cases of recurrent benign lymphocytic meningitis, or “Mollaret meningitis,” which is strongly linked to HSV-2 reactivation from latent virus in sacral sensory ganglia. However, there are reports of Mollaret cells in meningitis secondary to other herpesviruses (eg, herpes simplex virus 1 (HSV-1), varicella zoster virus (VZV)) and West Nile Virus. In addition to virologic testing, CSF should be reviewed for Mollaret cells when evaluating a case of recurrent aseptic meningitis.

Giant left atrium encountered during right-sided thoracentesis

Giant left atrium is an uncommon pathology to encounter during bedside chest ultrasound, but is an important structure to be aware of when considering thoracentesis. This cardiac structure could easily be mistaken for loculated pleural fluid. This case also supports growing evidence that expert users can safely perform thoracentesis without completely reversing therapeutic anticoagulation.

Recurrent rheumatoid pleural effusions complicated by Mycobacterium heckeshornense infection

A 41-year-old man with rheumatoid arthritis (RA) presented with worsening dyspnea and deconditioning. He had recently been treated with adalimumab for rheumatoid pleural effusions but developed non-tuberculous mycobacterial pleurisy due to Mycobacterium heckeshornense. Despite therapy with appropriate anti-mycobacterial agents, he ultimately required video assisted thoracoscopy for decortication. While Mycobacterium heckeshornense has been reported to cause infection in multiple sites including the lung, this is the first case to our knowledge of infection confined to the pleural space. Rheumatoid pleural effusions can be complex and difficult to treat, especially when complicated by mycobacterial infection.

Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium

Respiratory syncytial virus (RSV) persists as a significant human pathogen that continues to contribute to morbidity and mortality. In children, RSV is the leading cause of lower respiratory tract infections, and in adults RSV causes pneumonia and contributes to exacerbations of chronic lung diseases. RSV induces airway epithelial inflammation by activation of the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor. Recently, EGFR inhibition was shown to decrease RSV infection, but the mechanism(s) for this effect are not known. Interferon (IFN) signaling is critical for innate antiviral responses, and recent experiments have implicated IFN-λ (lambda), a type III IFN, as the most significant IFN for mucosal antiviral immune responses to RSV infection. However, a role for RSV-induced EGFR activation to suppress airway epithelial antiviral immunity has not been explored. Here, we show that RSV-induced EGFR activation suppresses IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection, and we implicate RSV F protein to mediate this effect. EGFR inhibition, during viral infection, augmented IRF1, IFN-λ, and decreased RSV titers. These results suggest a mechanism for EGFR inhibition to suppress RSV by activation of endogenous epithelial antiviral defenses, which may be a potential target for novel therapeutics.