International hospitals and healthcare facilities face catastrophic financial challenges related to the COVID-19 pandemic. The American Hospital Association estimates a financial impact of $202.6 billion in lost revenue for America's hospitals and health systems, or an average of $50.7 billion per month. Furthermore, it could cost low- and middle-income countries ∼ US$52 billion (equivalent to US$8.60 per person) each four weeks to provide an effective health-care response to COVID-19. In the setting of the largest daily COVID-19 new cases in the US, this burden will influence patient care, surgeries, and surgical outcomes. From a global economic standpoint, The World Bank projects that global growth is projected to shrink by almost 8% with poorer countries feeling most of the impact, and the United Nations projects that it will cost the global economy around 2 trillion dollars this year. Overall, a lack of preparedness was a major contributor to the struggles experienced by healthcare facilities around the world. Items such as personal protective equipment (PPE) for healthcare workers, hospital equipment, sanitizing supplies, toilet paper, and water were in short supply. These deficiencies were exposed by COVID-19 and have prompted healthcare organizations around the world to invent new essential plans for pandemic preparedness. In this paper we will discuss the economic impact of COVID on US and international hospitals, healthcare facilities, surgery, and surgical outcomes. In the future the US and countries around the world will benefit from preparing a plan of action to use as a guide in the event of a disaster or pandemic.

Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6–deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.

We screened bronchoalveolar lavage (BAL) fluids from COPD-E (chronic obstructive pulmonary disease-Emphysema) and control subjects using a 120 Ab cytokine array and demonstrated that adiponectin was highly expressed in BAL in COPD-E. An adiponectin ELISA confirmed that adiponectin was highly expressed in BAL in COPD-E compared with smokers and healthy control subjects. Immunohistochemistry studies of lung sections from subjects with COPD-E demonstrated that airway epithelial cells expressed significant levels of adiponectin and adiponectin receptor (AdipoR) 1 but not AdipoR2. In vitro studies with purified populations of human lung A549 epithelial cells demonstrated that they expressed both adiponectin and AdipoR1 (but not AdipoR2) as assessed by RT-PCR, Western blot, and immunohistochemistry. Lung A549 epithelial AdipoR1were functional as incubation with adiponectin induced release of IL-8, which was inhibited by small interfering RNA to AdipoR1. Using a mouse model of COPD, tobacco smoke exposure induced both evidence of COPD as well as increased levels of adiponectin in BAL fluid and increased adiponectin expression by airway epithelial cells. As adiponectin expression in adipocytes is dependent upon NF-κB we determined levels of adiponectin in tobacco smoke exposed CC10-Cretg/IkkβΔ/Δ mice (deficient in the ability to activate NF-κB in airway epithelium). These studies demonstrated that CC10-Cretg/IkkβΔ/Δ and wild-type mice had similar levels of BAL adiponectin and airway epithelial adiponectin immunostaining. Overall, these studies demonstrate the novel observation that adiponectin and functional AdipoR1are expressed by lung epithelial cells, suggesting a potential autocrine and/or paracrine pathway for adiponectin to activate epithelial cells in COPD-E.

The fungal allergen, Alternaria, is specifically associated with severe asthma, including life-threatening exacerbations. To better understand the acute innate airway response to Alternaria, naïve WT mice were challenged once intranasally with Alternaria. Naïve WT mice developed significant BAL eosinophila following Alternaria challenge when analyzed 24 hours later. In contrast to Alternaria, neither Aspergillus nor Candida induced BAL eosinophilia. Gene microarray analysis of airway epithelial cell brushings demonstrated that Alternaria-challenged naïve WT mice had an over 20 fold increase level of expression of “Found in Inflammatory Zone 1” (FIZZ1/Retnla), a resistin-like molecule. Lung immunostaining confirmed strong airway epithelial FIZZ1 expression present as early as 3 hours after a single Alternaria challenge that persisted for at least 5 days and was significantly reduced in STAT6-deficient, but not PAR-2-deficient mice. Bone marrow chimera studies revealed that STAT6 expressed in lung cells was required for epithelial FIZZ1 expression, while in contrast, STAT6 present in bone marrow derived cells contributed to airway eosinophilia. Studies investigating which cells in the non-challenged lung bind FIZZ1 demonstrated that CD45+CD11c+ (macrophages and dendritic cells) as well as collagen-1 producing CD45 negative cells (fibroblasts) can bind to FIZZ1. Importantly, direct administration of recombinant FIZZ1 to naïve WT mice led to airway eosinophilia, peribronchial fibrosis, and increased thickness of the airway epithelium. Thus, Alternaria induces STAT-6 dependent acute airway eosinophila and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. This may provide some insight into the uniquely pathogenic aspects of Alternaria-associated asthma.

Objectives Eosinophilic esophagitis (EoE) is a disorder characterized histologically by tissue eosinophilia. Sialic acid–binding immunoglobulin-like lectin (Siglec-F) is a receptor highly expressed on mouse eosinophils and mediates eosinophilic apoptosis. We investigated whether administration of an anti-Siglec-F Ab would reduce esophageal eosinophilic inflammation and remodeling in a mouse model of egg ovalbumin (OVA)–induced EoE. Subjects and Methods Three groups of mice were studied (no OVA, OVA + anti-Siglec-F Ab, and OVA + isotype control Ab). Mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA. Levels of esophageal eosinophils and features of remodeling (angiogenesis, vascular endothelial growth factor expression, deposition of fibronectin, basal zone hyperplasia, and fibrosis) were quantitated by immunohistochemistry and image analysis. Results Administration of an anti-Siglec-F Ab to OVA-challenged mice significantly reduced levels of esophageal eosinophils, down to levels noted in non-OVA-challenged mice. The anti-Siglec-F Ab also reduced features of OVA-induced remodeling, including angiogenesis, basal zone hyperplasia, and fibronectin deposition. The reduced angiogenesis in anti-Siglec-F Ab-treated mice was associated with reduced numbers of vascular endothelial growth factor–positive cells in the esophagus. The anti-Siglec-F antibody did not significantly reduce esophageal fibrosis as assessed by trichrome staining. Conclusions Administration of an anti-Siglec-F antibody significantly decreased the number of eosinophils in the esophagus in a mouse model of OVA-induced EoE. The reduction in eosinophilic inflammation was associated with a significant decrease in levels of angiogenesis, deposition of fibronectin, and basal zone hyperplasia. Studies in this pre-clinical model of EoE suggest that Siglec-F (and its human paralog Siglec-8) may be novel therapeutic targets to reduce eosinophilic inflammation in EoE.