BACKGROUND:Enterohemorrhagic HUS (eHUS), triggered by Shiga toxin (STX), is a thrombotic microangiopathy and major cause of acute kidney injury (AKI) in children. Of those hospitalized, ~65% require dialysis, while others may suffer seizures, neurocognitive deficits from cerebral ischemia, other organ failure ( ~ 30%), and death (3-5%). Long-term sequelae include chronic kidney disease, hypertension, insulin-dependent diabetes, and neurocognitive impairment. No therapeutic agents are effective and/or approved by the Food and Drug Administration, or similar bodies. METHODS:We have identified two potential therapeutic targets-mannose-binding lectin-2 (MBL2) of the lectin complement pathway and clotting factor XIa (FXIa) of the intrinsic coagulation pathway. We previously reported the importance of MBL2 in a mouse model of Shiga Toxin-induced kidney injury, using 3F8, a mouse anti-human MBL2 antibody, and procoagulant activity in an endothelial monolayer model. We now report important roles for both clotting factor XI and MBL2 in this model, employing 3G3, a humanized anti-FXIa antibody, and 3F8 together. RESULTS:The antibody combination is superior to either antibody alone in reducing glomerular platelet deposition, and to 3F8 in reducing fibrin deposition. Only the combination is effective in lowering AKI, hemolysis, and weight loss. CONCLUSION:The antibody combination may have therapeutic application in affected children. IMPACT:Enterohemorrhagic hemolytic uremic syndrome causes acute renal failure in 65% of affected children, seizures and neurocognitive deficits from cerebral ischemic events in 3-5%, other organ system failure in 20-30%, and death in 3-5%. There presently exists no specific therapy, only supportive care. We have found in our mouse model of Shiga Toxin-induced kidney injury that monoclonal antibodies against the mannose binding lectin-2 (MBL2) of the lectin complement pathway, and factor XI/XIa of the contact coagulation pathway show clear benefit used singly, but even greater benefit in combination. The combination offers promise for an effective first specific therapy.

Irahara, Takayuki; Watanabe, Eizo; Ozaki, Masayuki; Tsuda, Masanobu; Kajita, Yuka; Terashima, Tsuguaki; Katsuki, Ryusuke; Tanabe, Subaru; Hirayama, Yuuji; Ooishi, Dai; Kato, Kosuke; Kuge, Yuuji; Kotouge, Kazuki; Ishizu, Keisuke; Kato, Ryoichi Author Information

Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.

Kounis syndrome is defined as the concurrence of acute coronary syndrome and a condition related to mast cell activation, including anaphylaxis and anaphylactoid. A 58-year-old male hemodialysis patient underwent enhanced computed tomography (CT) using the radiocontrast medium, iopamidol for investigation of a kidney tumor. Two minutes after the administration of iopamidol, he developed respiratory symptoms and chest pain. Five minutes after that, disturbed consciousness and low blood pressure were observed. On the other hand, he did not demonstrate urticaria and swelling of the skin. A 12lead electrocardiogram (ECG) and echocardiogram suggested the presence of cardiac ischemia. Therefore, he was diagnosed with Kounis syndrome caused by radiocontrast media. Eighteen minutes after this, he received an intramuscular injection of adrenaline (0.3 mg), and his vital signs stabilized and his ECG, echocardiogram, and symptoms improved. Without undergoing emergency coronary angiography (CAG), he was hospitalized and closely monitored. The next day, his symptoms had not worsened, and he underwent hemodialysis at his local hospital. The allergen radiocontrast media could be injurious and not sufficiently excreted if administrated for patients on weekly hemodialysis with radiocontrast medium-induced Kounis syndrome manifesting; hence, indication for emergency CAG in radiocontrast medium-induced Kounis syndrome should be cautiously evaluated by close observation.

BackgroundCoronavirus disease 2019 (COVID-19) features a hypercoagulable state, but therapeutic anticoagulation effectiveness varies with disease severity. We aimed to evaluate the dynamics of the coagulation profile and its association with COVID-19 severity, outcomes, and biomarker trajectories.MethodsThis multicenter, prospective, observational study included patients with COVID-19 requiring respiratory support. Rotational thromboelastometry findings were evaluated for coagulation and fibrinolysis status. Hypercoagulable status was defined as supranormal range of maximum clot elasticity in an external pathway. Longitudinal laboratory parameters were collected to characterize the coagulation phenotype.ResultsOf 166 patients, 90 (54%) were severely ill at inclusion (invasive mechanical ventilation, 84; extracorporeal membrane oxygenation, 6). Higher maximum elasticity (P=0.02) and lower maximum lysis in the external pathway (P=0.03) were observed in severely ill patients compared with the corresponding values in patients on non-invasive oxygen supplementation. Hypercoagulability components correlated with platelet and fibrinogen levels. Hypercoagulable phenotype was associated with favorable outcomes in severely ill patients, while normocoagulable phenotype was not (median time to recovery, 15 days vs. 27 days, P=0.002), but no significant association was observed in moderately ill patients. In patients with severe COVID-19, lower initial C3, minimum C3, CH50, and greater changes in CH50 were associated with the normocoagulable phenotype. Changes in complement components correlated with dynamics of coagulation markers, hematocrit, and alveolar injury markers.ConclusionsWhile hypercoagulable states become more evident with increasing severity of respiratory disease in patients with COVID-19, normocoagulable phenotype is associated with triggered by alternative pathway activation and poor outcomes.

【目的】COVID‐19肺炎の炎症と栄養代謝動態の特徴を明らかにし, 治療的介入の可能性につき考察する. 【対象と方法】当院救急ICUにCOVID‐19肺炎の診断で入室した患者28名につき, 炎症や栄養代謝に関する血液検査や間接熱量測定にて得られたデータを分析した. 【結果】COVID‐19重症度の内訳は中等症18例, 重症10例であった. 重症は全例に挿管管理を要し4例にvv‐ECMO管理を要した. 炎症データは重症で有意に高くリンパ球数が重症で有意に低下していた（p=0.005）. 栄養代謝ではCONUT値およびPGC‐1α濃度が重症で有意に高値であった（p=0.03, 0.003）. 間接熱量測定を行い得た5例では通常肺炎と比して脂質酸化量が低く呼吸商は高い傾向があった.【結語】COVID‐19肺炎では重症度に応じて高度炎症および免疫麻痺状態に陥っており, 栄養学的リスクも高いことが示唆された. また特有の栄養代謝動態の変化があり栄養療法において考慮すべきと思われた.

Background: Although early enteral nutrition (EN) plays a key role in managing patients after cardiac surgery, only a few studies have evaluated the effects of multidisciplinary team rounds (MDTR) in an intensive care unit (ICU) on the outcomes of cardiac surgery. We launched the MDTR in June 2020 and investigated its effect on clinical outcomes and nutritional management after cardiac surgery. Methods: A retrospective observational study was conducted in a single ICU. This study included 160 patients admitted to the ICU. The patients were divided into the Conventional and MDTR groups according to their MDTR status. The postoperative hospital stay (PoHS) and EN initiation process were compared between the two groups. Results: No significant difference was observed in the PoHS between the two groups (median: 15 days in the Conventional group and 14 days in the MDTR group). Multiple regression analysis indicated that MDTR was associated with shortened PoHS (regression coefficient: −4.65 days). The time to EN initiation was significantly shorter without increasing EN-related complications in the MDTR group (28.2 vs. 22.5 hours). Conclusion: MDTR could be associated with the shortening of PoHS; it allows the early and safe provision of EN for patients after cardiac surgery. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000044240).

The prevalence of magnesium imbalance in critically ill children is very high. However, its significance in the development of acute kidney injury (AKI) and mortality remains unknown. In this retrospective observational study from 2010 to 2018, the pediatric-specific intensive care database was analyzed. We included critically ill children aged > 3 months and those without chronic kidney disease. Patients were diagnosed with AKI, according to the Kidney Disease Improving Global Outcomes (KDIGO) study. We calculated the initial corrected magnesium levels (cMg) within 24 h and used a spline regression model to evaluate the cut-off values for cMg. We analyzed 28-day mortality and its association with AKI. The interaction between AKI and magnesium imbalance was evaluated. The study included 3,669 children, of whom 105 died within 28 days, while 1,823 were diagnosed with AKI. The cut-off values for cMg were 0.72 and 0.94 mmol/L. Both hypermagnesemia and hypomagnesemia were associated with 28-day mortality (odds ratio [OR] = 2.99, 95% confidence interval [CI] = 1.89–4.71, p < 0.001; OR = 2.80, 95% CI = 1.60–4.89, p < 0.001). Hypermagnesemia was associated with AKI (OR = 1.52, 95% CI = 1.27–1.82, p < 0.001), while neither hypermagnesemia nor hypomagnesemia interacted with the AKI stage on the 28-day mortality. Abnormal magnesium levels were associated with 28-day mortality in critically ill children. AKI and hypermagnesemia had a strong association. “A higher resolution version of the Graphical abstract is available as Supplementary information”.

In sepsis-associated coagulopathies and disseminated intravascular coagulation, relative platelet reductions may reflect coagulopathy severity. However, limited evidence supports their clinical significance and most sepsis-associated coagulopathy criteria focus on the absolute platelet counts. To estimate the impact of relative platelet reductions and absolute platelet counts on sepsis outcomes. A multicenter retrospective observational study was performed using the eICU Collaborative Research Database, comprising 335 intensive care units (ICUs) in the United States. Patients with sepsis and an ICU stay > 2 days were included. Estimated effects of relative platelet reductions and absolute platelet counts on mortality and coagulopathy-related complications were evaluated. Overall, 26,176 patients were included. Multivariate mixed-effect logistic regression analysis revealed marked in-hospital mortality risk with larger platelet reductions between days one and two, independent from the resultant absolute platelet counts. The adjusted odds ratio (OR) [95% confidence intervals (CI)] for in-hospital mortality was 1.28[1.23–1.32], 1.86[1.75–1.97], 2.99[2.66–3.36], and 6.05[4.40–8.31] for 20–40%, 40–60%, 60–80%, and > 80% reductions, respectively, when compared with a < 20% decrease in platelets ( P < 0.001 for each). In the multivariate logistic regression analysis, platelet reductions ≥ 11% and platelet counts ≤ 100,000/μL on day 2 were associated with high coagulopathy-related complications (OR [95%CI], 2.03 and 1.18; P < 0.001 and P < 0.001), while only platelet reduction was associated with thromboembolic complications (OR [95%CI], 1.43 [1.03–1.98], P < 0.001). The magnitude of platelet reductions represent mortality risk and provides a better signature of coagulopathies in sepsis; therefore, it is a plausible criterion for sepsis-associated coagulopathies.

We retrospectively analyzed data from the Medical Information Mart for Intensive Care-III critical care database to determine whether visually-assessed right ventricular (RV) dysfunction was associated with clinical outcomes in septic shock patients. Associations between visually-assessed RV dysfunction by echocardiography and in-hospital mortality, lethal arrhythmia, and hemodynamic indicators to determine the prognostic value of RV dysfunction in patients with septic shock were analyzed. Propensity score analysis showed RV dysfunction was associated with increased risk of in-hospital death in patients with septic shock (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.99–2.32; P < 0.001). In multivariate logistic regression analysis, RV dysfunction was associated with in-hospital death (OR 2.19; 95% CI 1.91–2.53; P < 0.001), lethal arrhythmia (OR 2.19; 95% CI 1.34–3.57; P < 0.001), and tendency for increased blood lactate levels (OR 1.31; 95% CI 1.14–1.50; P < 0.001) independent of left ventricular (LV) dysfunction. RV dysfunction was associated with lower cardiac output, pulmonary artery pressure index, and RV stroke work index. In patients with septic shock, visually-assessed RV dysfunction was associated with in-hospital mortality, lethal arrhythmia, and circulatory insufficiency independent of LV dysfunction. Visual assessment of RV dysfunction using echocardiography might help to identify the short-term prognosis of patients with septic shock by reflecting hemodynamic status.

Whether a patient with severe coronavirus disease (COVID-19) will be successfully liberated from mechanical ventilation (MV) early is important in the COVID-19 pandemic. This study aimed to characterize the time course of parameters and outcomes of severe COVID-19 in relation to the timing of liberation from MV. This retrospective, single-center, observational study was performed using data from mechanically ventilated COVID-19 patients admitted to the ICU between 1 March 2020 and 15 December 2020. Early liberation from ventilation (EL group) was defined as successful extubation within 10 days of MV. The trends of respiratory mechanics and laboratory data were visualized and compared between the EL and prolonged MV (PMV) groups using smoothing spline and linear mixed effect models. Of 52 admitted patients, 31 mechanically ventilated COVID-19 patients were included (EL group, 20 (69%); PMV group, 11 (31%)). The patients’ median age was 71 years. While in-hospital mortality was low (6%), activities of daily living (ADL) at the time of hospital discharge were significantly impaired in the PMV group compared to the EL group (mean Barthel index (range): 30 (7.5–95) versus 2.5 (0–22.5), p = 0.048). The trends in respiratory compliance were different between patients in the EL and PMV groups. An increasing trend in the ventilatory ratio during MV until approximately 2 weeks was observed in both groups. The interaction between daily change and earlier liberation was significant in the trajectory of the thrombin–antithrombin complex, antithrombin 3, fibrinogen, C-reactive protein, lymphocyte, and positive end-expiratory pressure (PEEP) values. The indicator of physiological dead space increases during MV. The trajectory of markers of the hypercoagulation status, inflammation, and PEEP were significantly different depending on the timing of liberation from MV. These findings may provide insight into the pathophysiology of COVID-19 during treatment in the critical care setting.

Magnesium imbalance has been reported to be associated with mortality in adults. Acute kidney injury (AKI) is often assumed to be one of the causes of hypermagnesemia. Even though magnesium imbalance seems to be clinically important in both adults and children, it has been ignored for a long time, especially among critically ill children.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Japan has the highest proportion of older adults worldwide but has fewer critical care beds than most high-income countries. Although the COVID-19 infection rate in Japan is low compared with Europe and the United States, by the end of 2020, several infected people died in ambulances because they could not find hospitals to accept them. Our study aimed to examine the Japanese healthcare system's capacity to accommodate critically ill COVID-19 patients during the pandemic. We created a model to estimate bed and staff capacity at 3 levels of pandemic response (conventional, contingency, and crisis), as defined by the US National Academy of Medicine, and the function of Japan's healthcare system at each level. We then compared our estimates of the number of COVID-19 patients requiring intensive care at peak times with the national health system capacity using expert panel data. Our findings suggest that Japan's healthcare system currently can accommodate only a limited number of critically ill COVID-19 patients. It could accommodate the surge of pandemic demands by converting nonintensive care unit beds to critical care beds and using nonintensive care unit staff for critical care. However, bed and staff capacity should not be expanded uniformly, so that the limited number of physicians and nurses are allocated efficiently and so staffing does not become the bottleneck of the expansion. Training and deploying physicians and nurses to provide immediate intensive care is essential. The key is to introduce and implement the concept and mechanism of tiered staffing in the Japanese healthcare system. More importantly, most intensive care facilities in Japanese hospitals are small-scaled and thinly distributed in each region. The government needs to introduce an efficient system for smooth dispatching of medical personnel among hospitals regardless of their founding institutions.

Dear Editor, For health-care workers performing aerosol-generating procedures (AGPs) on patients with coronavirus disease 2019 (COVID-19), airborne personal protective equipment (PPE) and precautions are required. As supplies of PPE have been depleted during the COVID-19 pandemic, new reusable types of equipment are needed to ensure protection. In response to this situation, previous reports have proposed an “Aerosol Box”, which is intended to protect health-care workers while performing AGPs. The original Aerosol Box designed by Dr Hsien Yung Lai consisted of a transparent plastic cube covering a patient’s head, with two access ports for the clinician’s arms. Canelli et al. reported that while the box does protect clinicians during intubation, it restricts hand movements during the airway procedure. Although clinicians and companies have made modifications to the original model to optimize operator ergonomics, in our experience with the Aerosol Box and training manikins, we also had difficulties due to limited clinician range of motion while performing airway procedures. Therefore, we made further modifications to the original model, resulting in a new design that is more of a “shield and tent” than a box. This new equipment consists of a transparent plastic shield with a sloping angled surface and a plastic drape attached to the top and side edges of the shield. The drape incorporates two linear ports—one on each side—through which the clinician’s arms can pass to perform AGPs. The ports are made at the position shown in the Figure 1A, by making a cut in the drape with scissors. The shield is made of transparent polyethylene terephthalate (PET) sheeting. The dimensions of the shield are provided in Figure 1B. The PET shield is bent at an angle of 60° via heat processing. Because the shield is made of a single sheet of PET, it exhibits high strength. Furthermore, PET is not damaged by alcohol disinfection and is reusable after decontamination with a cleansing agent. After use of the equipment, the surface of the shield is cleaned with standard disinfectants approved by the U.S. Environmental Protection Agency for use against emerging viral pathogens, such as quaternary ammonium or ethyl alcohol. The plastic drape is disposable and can be replaced with a plastic garbage bag. We actually used transparent garbage bags with a capacity of 90 L (width 900 mm, height 1,000 mm). We recommend a drape of similar size to fully cover the patient’s face and his/her surroundings. Through our experience in patients with COVID-19, it became evident that this equipment has high versatility and applicability. Further, we have found that the shield and tent do not impede airway procedures. Using the equipment, we have performed AGPs such as intubation, extubation, and

Acute kidney injury (AKI) is a major complication of sepsis that induces acid-base imbalances. While creatinine levels are the only indicator for assessing the prognosis of AKI, prognostic importance of metabolic acidosis is unknown. We conducted a retrospective observational study by analyzing a large China-based pediatric critical care database from 2010 to 2018. Participants were critically ill children with AKI admitted to intensive care units (ICUs). The study included 1505 children admitted to ICUs with AKI, including 827 males and 678 females. The median age at ICU admission was 22 months (interquartile range 7–65). After a median follow-up of 10.87 days, 4.3% (65 patients) died. After adjusting for confounding factors, hyperlactatemia, low pH, and low bicarbonate levels were independently associated with 28-day mortality (respective odds ratio: 3.06, 2.77, 2.09; p values: <0.01, <0.01, <0.01). The infection had no interaction with the three parameters. The AKI stage negatively interacted with bicarbonate and pH but not lactate. The current study shows that among children with AKI, hyperlactatemia, low pH, and hypobicarbonatemia are associated with 28-day mortality.

Objective: The ongoing pandemic coronavirus disease-2019 (COVID-19) infection causes severe respiratory dysfunction and has become an emergent issue for worldwide healthcare. Since COVID-19 spreads through contact and droplet infection routes, careful attention to infection control and surgical management is important to prevent cross-contamination of patients and medical staff. Tracheostomy is an effective method to treat severe respiratory dysfunction with prolonged respiratory management and should be performed as a high-risk procedure Method: The anesthetic and surgical considerations in this case involved difficult goals of the patient safety and the management of infection among health care workers. Our surgical procedure was developed based on the previous experiences of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Results: We described the management procedures for tracheostomy in a patient with COVID-19, including the anesthesia preparation, surgical procedures, required medical supplies (a N95 mask or powered air purifying respirator, goggles, face shield, cap, double gloves, and a water-resistant disposable gown), and appropriate consultation with an infection prevention team. Conclusion: Appropriate contact, airborne precautions, and sufficient use of muscle relaxants are essential for performing tracheostomy in a patient with COVID-19. (C) 2020 Oto-Rhino-Laryngological Society of Japan Inc. Published by Elsevier B.V. All rights reserved.

Background: The indications for independent lung ventilation (ILV) in critical care settings have not been fully clarified, especially because extracorporeal membrane oxygenation (ECMO) is being used increasingly in cases of severe respiratory failure. Case report: A 90-year-old man presented with severe unilateral pneumonia, and despite conventional mechanical ventilation management with use of a single lumen endotracheal tube and high positive endo-expiratory pressure (PEEP), oxygenation and hemodynamics deteriorated. We then performed ILV using a double-lumen endotracheal tube (DLT) and two ventilators, each set at a different respiratory mode. With continuous administration of a neuromuscular blocking agent, the ventilator for the left lung (non-affected lung) was set to pressure-controlled ventilation (PCV) mode, whereas the ventilator for the right lung (affected lung) was set to bi-level mode, 1 breath/min, and high PEEP. ILV and the high PEEP applied to the affected lung prevented hyperinflation of the non-affected lung and increased pulmonary blood perfusion on the non-affected side. Thus, ILV immediately improved oxygenation and hemodynamics by correcting ventilation/perfusion mismatch. Discussion: Although ECMO is a valid treatment option for patients with severe respiratory failure, it is highly invasive intervention. ILV performed with use of a DLT is less invasive and more useful than ECMO. Thus, ILV should be kept in mind as a treatment option, especially in cases of refractory respiratory failure and circulatory failure in which the pathophysiology of the left and right lungs differs markedly.