Nobuaki Shime

C/EBPβ Is Involved in the Amplification of Early Granulocyte Precursors during Candidemia-Induced “Emergency” Granulopoiesis

Granulopoiesis is tightly regulated to meet host demands during both “steady-state” and “emergency” situations, such as infections. The transcription factor CCAAT/enhancer binding protein β (C/EBPβ) plays critical roles in emergency granulopoiesis, but the precise developmental stages in which C/EBPβ is required are unknown. In this study, a novel flow cytometric method was developed that successfully dissected mouse bone marrow cells undergoing granulopoiesis into five distinct subpopulations (#1–5) according to their levels of c-Kit and Ly-6G expression. After the induction of candidemia, rapid mobilization of mature granulocytes and an increase in early granulocyte precursors accompanied by cell cycle acceleration was followed by a gradual increase in granulocytes originating from the immature populations. Upon infection, C/EBPβ was upregulated at the protein level in all the granulopoietic subpopulations. The rapid increase in immature subpopulations #1 and #2 observed in C/EBPβ knockout mice at 1 d postinfection was attenuated. Candidemia-induced cell cycle acceleration and proliferation of hematopoietic stem/progenitors were also impaired. Taken together, these data suggest that C/EBPβ is involved in the efficient amplification of early granulocyte precursors during candidemia-induced emergency granulopoiesis.

Successful treatment of severe asthma-associated plastic bronchitis with extracorporeal membrane oxygenation

We describe a case of near-fatal asthma requiring extracorporeal membrane oxygenation (ECMO). The patient presented with severe respiratory distress, which was not responsive to conventional pharmacological therapy. The patient also failed to respond to mechanical ventilation and thus was placed on venovenous ECMO for temporary pulmonary support. A fiberoptic bronchoscopy revealed that large amounts of thick bronchial secretions had occluded the main bronchus, which suggested plastic bronchitis secondary to asthma. Aggressive airway hygiene with frequent bronchoscopies and application of biphasic cuirass ventilation for facilitation of secretion clearance were performed to improve the patient’s respiratory status. The patient achieved a full recovery and suffered no neurological sequelae. This case illustrates that aggressive pulmonary hygiene with ECMO is a useful therapy for patients with asthma-associated plastic bronchitis.

Evaluation of semi-quantitative scoring of Gram staining or semi-quantitative culture for the diagnosis of ventilator-associated pneumonia: a retrospective comparison with quantitative culture

BackgroundSemi-quantitative Gram stain and culture methods are still commonly used for diagnosing ventilator-associated pneumonia (VAP), due to its convenience. Only a few studies, however, have assessed the reliability of these methods when compared with quantitative cultures, a current standard for the diagnosis of VAP. The objective of this study was to assess the utility of semi-quantitative scores obtained using Gram stains and cultures of endotracheal aspirates when compared with quantitative cultures in the diagnosis of VAP.MethodsA retrospective chart review of mechanically ventilated patients with clinically suspected VAP in a single intensive care unit was performed. Semi-quantitative scores of Gram stains or culture results were compared with quantitative culture results of endotracheal aspirate for the diagnosis of VAP in 136 samples for 51 patients.ResultsThe semi-quantitative scores of Gram stains and the semi-quantitative culture results significantly correlated with the log value of the quantitative culture results (rs = 0.64 and 0.75). When using a log count ≥6 of quantitative cultures as the reference standard for the diagnosis of VAP, the sensitivity and specificity was 95% and 61% for Gram stain score of ≥1+, and was 42% and 96% for Gram stain score ≥3+, respectively. The sensitivity and specificity was 96% and 40% for the semi-quantitative culture score of ≥2+, and was 59% and 86% for the semi-quantitative culture score of ≥3+, respectively.ConclusionsAbsence of bacteria in semi-quantitative Gram stain and poor growth (≤1+) in semi-quantitative culture method could be utilized to exclude the possibility of VAP, whereas detection of abundant (≥3+) bacteria in semi-quantitative Gram stain could be utilized to strongly suspect VAP.

Mechanically ventilated children with 2009 pandemic influenza A/H1N1: results from the National Pediatric Intensive Care Registry in Japan.

Objective: To outline the characteristics, clinical course, and outcome of pediatric patients requiring mechanical ventilation with influenza A/H1N1 infection in Japan. Design: Prospective case registry analysis. Setting: Eleven pediatric or general intensive care units in Japan. Patients: Consecutive patients infected with A/H1N1, aged from 1 month to 16 yrs old admitted to the intensive care unit for mechanical ventilation between July 2009 and March 2010. Interventions: None. Measurements and Main Results: Eighty-one children, aged 6.3 [0.8–13.6] (median [interquartile range]) years, were enrolled. Seventy-four (91%) had mechanical ventilation with tracheal intubation. Median duration of mechanical ventilation was 4 days (range 0.04–87) and 18 patients (23%) required mechanical ventilation >7 days. Two patients (2%) required extracorporeal membrane oxygenation. The in-hospital mortality was 1%. Forty-one patients (50%) had at least one underlying chronic condition, including 31 with asthma. Associated clinical symptoms and diagnosis were as follows: acute respiratory distress syndrome (9%), asthma or bronchitis (37%), pneumonia (68%) with 8 (14%) having bacterial pneumonia, neurological symptoms (32%), myocarditis (2%), and rhabdomyolysis (1%). Therapeutic interventions include inotropic support (21%), methylprednisolone therapy (33%), and antimicrobial therapy (88%). Multivariate analysis revealed that inotropic support was the only statistically significant factor associated with mechanical ventilation for more than a week (odds ratio 5.5, 95% confidence interval 1.5–20.5, p = .005). Conclusions: The clinical presentations of pediatric patients requiring mechanical ventilation for A/H1N1 in Japan were diverse. In-hospital mortality of this population was remarkably low. Rapid access to medical facilities in combination with early administration of antiviral agents may have contributed to the low mortality in this population.

Current Practices for Ventilator-Associated Pneumonia Prevention in Japan: A Survey Study

Data given as No. (%) unless otherwise indicated. Figure 1. Charts show the percentage of patients who received the most aggressive follow-up recommendations ( , 3 months with and without interventions). Physicians who were blinded for the radiologic recommendations were asked to give follow-up recommendations according to the Fleischner Society guidelines. Radiologic recommendations included levels 1 and 2. P 5 .0069 for solitary pulmonary nodules and P , .0001 for multiple pulmonary nodules. * P , .05 vs radiologists by contingency table analysis. F/U 5 follow-up.

Invasive pulmonary aspergillosis in a patient presenting with idiopathic systemic capillary leak syndrome

A 54-year-old man presented to our emergency department with fever and dyspnoea. He required vigorous haemodynamic support and mechanical ventilation for hypotensive distributive shock with hypoalbuminaemia, haemoconcentration, rhabdomyolysis and acute renal failure, consistent with idiopathic systemic capillary leak syndrome. Left lung consolidation and hypoxaemia were observed 6 days after admission. Sputum smear revealed the presence of acute angled branching hyphae, consistent with a diagnosis of invasive pulmonary aspergillosis. Antifungal therapy was administered and mechanical ventilation discontinued on day 66. The patient recovered and was discharged from the hospital on day 185.

De-escalation strategies could be applied to a wide variety of infectious settings

To the Editor I appreciated reading the correspondence from Dr. Rolston and colleagues [1] regarding our article entitled ‘‘De-escalation of antimicrobials in the treatment of bacteraemia due to antibiotic-sensitive pathogens in immunocompetent patients’’, recently published in Infection [2], in which we demonstrated the safety of de-escalating antimicrobial strategies in bacteremia due to antibioticsensitive pathogens occurring in patients without apparent immunosuppressive comorbidities. Although our study was limited to patient populations that we believed could be safely managed by narrowing the spectrum of antimicrobials, the question of whether de-escalation can be applied to more immunologically vulnerable patient populations remains to be answered. Dr. Rolston et al. [1] investigated usage patterns of ertapenem and quinolones in 799 cancer patients, slightly more than half of whom suffered from hematologic malignancies. They found that of the patients receiving ertapenem or quinolones, 42 and 74%, respectively, received the agent for de-escalation. They also found that de-escalation was performed not just for bacteremia due to susceptible organisms, but also for other infections due to multiresistant organisms, including multi-drug resistant Enterobacteriacae or Pseudomonas aeruginosa. Although their study did not directly investigate the de-escalation strategy itself in cancer patients (i.e., there are no data on how many patients actually received antibiotic de-escalation, or how different the outcome was due to the de-escalation), the results suggest that considerable numbers of immunocompromised patients with infections due to antibiotic resistant pathogens are candidates for deescalation strategies. One major point of concern in the report by Dr. Rolston and his colleagues is their assessment of de-escalation. There is no doubt that antimicrobial streamlining from combination therapy with broad-spectrum antipseudomonal beta-lactams together with an aminoglycoside or vancomycin, to monotherapy with ertapenem or a quinolone can be called ‘‘de-escalation’’. Each of these two agents, however, still has a relatively broad spectrum of antimicrobial potency. I would therefore suggest that the de-escalation therapy could be taken a step further by using antimicrobials with an even narrower spectrum, such as firstto third-generation cephalosporins or nonantipseudomonal penicillins. The use of such agents might further facilitate appropriate and judicious antimicrobial usage and be associated with a reduced risk of developing antibiotic-resistant infections [3–5]. As Dr. Rolston stated, a wider application of antibiotic stewardship programs [3], in which de-escalation strategies are included as a mainstay, is surely a key to improving the outcomes of infected patients, as well as avoiding antimicrobial overuse and its associated risks. Further large-scale, prospective studies to assess the safety, efficacy, and impact on resistance of de-escalation strategies in immunosuppressed patients, including patients with haematological disorders or undergoing chemotherapy, or on infections due to antibiotic-resistant pathogens, should be considered. N. Shime (&) Division of Intensive Care Medicine, Division of Infection Control and Prevention, Department of Anesthesiology and Intensive Care, University Hospital, Postgraduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan e-mail: shime@koto.kpu-m.ac.jp

Inhaled Nitric Oxide and Clinical Application

Inhaled nitric oxide is a potent pulmonary vasodilator, having clinically useful properties in improving pulmonary gas exchange and reducing pulmonary vascular resistance. It was officially approved for the clinical use in neonatal persistent pulmonary hypertension (PPHN) and has been utilized worldwide since year 1999. Since then, a significant reduction was observed in the rate of application of extracorporeal membrane oxygenation, a costly and invasive procedure, in the treatment of PPHN except for congenital diaphragmatic hernia. For the other various purposes, however, clinical evidence has not yet been confirmed. Clinical significance in prophylactic or therapeutic use for avoiding pulmonary hypertensive crisis (PHC) in children after congenital heart surgery has not yet been clarified, while the possibility remains of rescue use for a lethal PHC attack. Similarly, despite the transient improvement in arterial oxygenation in patients with acute lung injury/acute respiratory distress syndrome, it is not associated with an improvement in clinically significant outcome including mortality. Further studies are clearly needed to confirm its clinical usefulness in various clinical settings, taking into consideration the side effects and high costs as well as for direct comparison or combination with other recently developed potent pulmonary vasodilators including sildenafil or bosentan.