BLUE FINGERS, EOSINOPHILIC LUNGS: ACUTE EOSINOPHILIC PNEUMONIA FOLLOWING COVID-19 INFECTION

SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Acute eosinophilic pneumonia is a rare illness characterized by eosinophilic infiltration of the lung parenchyma. Cases often present with fever, severe dyspnea, bilateral infiltrates, and eosinophilia on BAL exams. The cause of eosinophilic pneumonia is unknown, but is thought to be related to inhalational exposure of an irritant or toxin. Most cases are responsive to steroid treatment. This case demonstrates acute eosinophilic pneumonia in a patient who recently recovered from COVID-19 pneumonia. CASE PRESENTATION: A 50 year old female with a history of multiple sclerosis, seizure disorder secondary to MS, Irritable Bowel Syndrome, and a distant history of tobacco smoking and opiate dependence on chronic suboxone therapy, presented with dyspnea secondary to respiratory failure. The patient was urged to present by her husband after findings of hypoxia to 79% on room air with cyanosis of the lips and fingers. She recently recovered from COVID-19 1 month prior, at which time she had symptoms of cough productive of red mucus, fever, and exhaustion;but states she never returned to her baseline. With ongoing hypoxia, the patient was intubated for mechanical ventilation. Subsequent bronchoscopy with BAL resulted in a elevated eosinophil count to 76%, with fungal elements and PCR positive for HSV-1. The patient was initiated on high dose glucocorticoid therapy in addition to Acyclovir and Voriconazole. A CT with IV contrast revealed extensive bilateral pulmonary emboli involving the segmental and subsegmental branches throughout both lungs and extension into the right pulmonary artery;the patient was started on anticoagulation. Shortly after beginning glucocorticoid therapy, the patient had significant improvement and was able to be weaned off ventilation to simple nasal cannula. She was able to be safely discharged home with two liters of supplemental oxygen and steroid taper. DISCUSSION: Acute Eosinophilic pneumonia is a rare condition with an unknown acute disease process. The diagnostic criteria for acute eosinophilic pneumonia includes: a duration of febrile illness less than one month, hypoxia with an SpO2 <90%, diffuse pulmonary opacities, and otherwise absence of inciting causes of pulmonary eosinophilia (including asthma, atopic disease, or infection). Diagnosis of eosinophilic pneumonia is attained after meeting clinical criteria with a BAL sample demonstrating an eosinophilia differential of >25%. The mainstay of treatment for this condition is glucocorticoid therapy with most cases resolving rapidly after treatment. CONCLUSIONS: Fewer than 200 cases of acute eosinophilic pneumonia have been reported in medical literature. It is imperative to keep a wide differential as critical illness may be rapidly improved with appropriate therapy. The cause of acute eosinophilic pneumonia is largely unknown, it is unclear what role COVID-19 may have played in the development of this pneumonia. Reference #1: Allen J. Acute eosinophilic pneumonia. Semin Respir Crit Care Med. 2006 Apr;27(2):142-7. doi: 10.1055/s-2006-939517. PMID: 16612765. Reference #2: Nakagome K, Nagata M. Possible Mechanisms of Eosinophil Accumulation in Eosinophilic Pneumonia. Biomolecules. 2020 Apr 21;10(4):638. doi: 10.3390/biom10040638. PMID: 32326200;PMCID: PMC7226607. Reference #3: Yuzo Suzuki, Takafumi Suda, Eosinophilic pneumonia: A review of the previous literature, causes, diagnosis, and management, Allergology International, Volume 68, Issue 4, 2019, Pages 413-419, ISSN 1323-8930 DISCLOSURES: No relevant relationships by Tayler Acton No relevant relationships by Calli Bertschy No relevant relationships by Stewart Caskey No relevant relationships by Shekhar Ghamande No relevant relationships by Tyler Houston No relevant relationships by Zenia Sattar No relevant relationships by Heather Villarreal

Disrupting Six/Eya Signalling as New Therapy for Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease, with a median survival of 2-4 years from the time of diagnosis [1]. It is estimated that the prevalence of IPF in the US is approximately 10-60 cases per 100,000 people, with limited pharmacological therapies available [2, 3]. IPF is a chronic, progressive disease characterized by alveolar injury, increased extracellular matrix (ECM) deposition and resultant alveolar destruction. Macroscopically, this leads to poor lung compliance, impaired trans-alveolocapillary membrane gas exchange and ultimately, end-stage respiratory failure, necessitating lung transplantation [2, 4, 5]. Several non-genetic risk factors, such as male sex, older age, and smoking, increase the risk of developing IPF [4, 6]. More recently, several genetic risk factors for IPF have also been discovered, including a single-nucleotide polymorphism (rs35705950) in the promoter region of MUC5B [7-9], which codes for an essential protein for airway clearance and innate immune response, along with genes associated with telomere maintenance, such as telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) [1, 10].

Assessment of Diverse Biological Indicators in Gulf War Illness: Are They Replicable? Are They Related?

The complex of multiple symptoms known as Gulf War Illness (GWI) continues to affect a substantial number of the nearly 700,000 U.S. veterans who served in the 1990-1991 Gulf War. Despite considerable research, the biological processes underlying veterans symptoms have not yet been clearly elucidated. To develop useful diagnostic tests and effective GWI treatments, it is imperative to establish a more definitive and integrated understanding of GWI pathophysiology. This study was designed to evaluate diverse previously-identified and hypothesized biological alterations associated with GWI in a single, well-characterized sample of Gulf War veterans. Using a case-control design, the protocol included physical and neuropsychological evaluations, brain imaging (MRI, fMRI, DTI), adrenal function tests, and diverse immune, inflammatory, and coagulation measures. Despite ongoing good-faith attempts to operationalize and implement the project over an extended period, data collection was not initiated and there are no study results to report, owing to a variety of internal and external challenges that we were unable to successfully address. For the most recent period of performance, all study updates, preparations, and sample identification were in place for data collection, including protocol revisions to limit in-person contact and related COVID safety precautions. However, recruitment and data collection were not undertaken due to extended public health restrictions in place during the ongoing pandemic. It is therefore necessary, with great regret, that we close the project without performing the study. We acknowledge and extend our sincere appreciation to the USAMRAA CDMRP program for their support as we worked to address project challenges over the duration of the grant period.

Glutamate Receptor and Kynurenine Pathway Functioning in the Pathobiology of Gulf War Illness

This project has 2 aims: (i) examine the involvement in veterans with Gulf War Illness of a neural excitatory state as a consequence of impaired brain immune, neuron and glia functioning using biomarkers obtained from cerebrospinal fluid (CSF) in 1990-1991 Gulf War veterans with (n=46) and without (n=23) GWI, and (ii) examine involvement in veterans with GWI of a neural excitatory state defined as increased glutamatergic receptor functioning by testing the effect of a single infusion of 0.5 mg/kg of N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine on gamma band EEG (for NMDAR target engagement), other EEG markers, and on symptoms of Gulf War Illness in 19 cases. Outcomes will provide evidence of an expected neural excitatory and pro-inflammatory state in cases that could predispose to neuronal damage via NMDAR hyperactivation through kynurenine pathway activation, and will provide evidence in humans of possible effects of temporarily blocking NMDARs with a subanesthetic dose (0.5 mg/kg) of ketamine.

Risk of Hepatocellular Cancer After Virological Cure with Direct Acting Antiviral Agents in Individuals with Hepatitis C

Purpose: The overarching goal of this project is to reduce HCC-related morbidity and mortality in persons with chronic hepatitis C (CHC) who have been virologically cured by direct acting antivirals (DAAs). Aims: 1) Examine determinants of HCC in virologically cured patients and develop a risk prediction model for HCC;2) Conduct a virtual clinical trial using a mathematical model of the natural history of HCC to evaluate benefits vs harms of HCC surveillance;3) Develop an online HCC Simulator. Design: Using cause-specific Cox proportional hazard models for competing risks, we will identify risk factors in a retrospective cohort study of >100,000 patients with DAA-induced SVR. For dynamic risk prediction of HCC, we will use the landmark Cox model. We will use a mathematical model to simulate a virtual trial comparing long-term effectiveness of no surveillance vs routine surveillance. Finally, we will develop an interactive decision support tool. Progress: The project is on target to be completed by 09/30/2022. Findings: 19 predictors for HCC were identified, with the nature of predictor variables changing over time. Metabolic traits predicted HCC;however, viral factors (HCV genotype) was no longer predictive at 24 months after cure. A Mathematical model of the natural history of HCC in DAA-cured CHC patients was developed that led the team to conclude that the burden of HCC will shift from viremic to virologically cured CHC patients, and to older populations. These findings are reported in a manuscript that was accepted by JAMA Network Open and is currently in press.

Lung Injury Etiology, Risk Factors, and Morbidity of Single and Repeated Low-Level Blast Overpressure Exposure

Cardiopulmonary symptoms of shortness of breath and decreased exercise tolerance after return from deployment are a major concern for many veterans of Iraq and Afghanistan. While much of the focus has been on burn pit exposure and particulate matter as causal factors, there is growing evidence supporting a contributing role of blast-related lung injury. Acute blast overpressure (BOP) lung injury resulting in gross injury is well established. This project will address the less known, possible long-term, or latent effects of less severe BOP lung injuries. We plan to target veterans deployed to Iraq and Afghanistan with exposure to blast injuries of varying severity and invite them to participate in a multi-day cardiopulmonary evaluation. Specifically, we hope to characterize the severity and burden of mild BOP lung injury in Iraq/Afghanistan veterans and determine the association between BOP exposure with physiological, peripheral blood, and CTbased markers of cardiopulmonary function.

Direct Regulation of Estrogen Receptor Transcription Activity by NF1

This project centers on the NF1/neurofibromin tumor suppressor, which was best known as a GTPase Activating Protein (GAP)that repress Ras activity. The parent DoD award has successfully defined a new and GAP-independent activity that NF1 is also a transcriptional co-repressor for estrogen receptor (ER) in ER+ breast cancer. While the parent DoD award focused on endocrine therapy resistance caused by NF1 loss, in this Expansion Award, the focus instead is on metastasis, for which currently has no cure. An important feature of ER+ breast cancer metastasis is that greater than 70% of the metastasis is in the bone. We hypothesized that the transcriptional co-repressor role of NF1 is also responsible for driving bone metastasis in ER+ breast cancer. Therefore, the objective of this Expansion Award is to assess NF1s role in metastasis in order to establish a strategy to stop it. We have made progress in accomplish Task1/Aim 1 to fully define NF1-controlled genes that can impact bone metastasis. This was a key part of the data that was just published in the high impact journal Cancer Cell. This award has also supported the launching a Phase-II clinical trial to treat ER+ NF1-depleted breast cancer, and the awards of a SPORE and another DoD Level-2 project. However, in Aim 2 (Tasks 2 and 30) we are dependent on the use of animals to study how NF1-depleted cancer cells interact with the bone, but this line of study has been severely and negatively impacted by COVID-19. We discuss how we plan to overcome this problem in the future.

MYCN Reprograms Neuroblastoma Metabolism

Despite current aggressive regimens, the majority of patients with MYCN amplification die due to drug-resistant disease, and further intensification ofchemotherapy will not significantly improve this outcome. We propose an entirely novel strategy to oppose MYCN oncogenic function in NB: by blockingthe metabolic reprogramming driven by MYCN. Based on our data and the recent literature, our guiding hypotheses are that: a) lipid metabolism is requiredfor NB tumorigenesis, and b) targeting MYCN-driven lipogenesis will effectively block NB tumor growth. We have demonstrated that lipid metabolism is aselective metabolic dependency of MYCN-driven tumors. MYCN drives both fatty acid (FA) synthesis and FA uptake to maintain NB cell survival. TargetingFA uptake effectively blocks NB in vivo tumor growth.