Severity Of Respiratory Virus Infection Research Articles

2721. Respiratory Virus Infections Following CAR T-cell Therapy: Risk Factors and Outcomes

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy is a novel cancer therapy which functions by engineering patients’ own cells to target a malignancy. The preparative lymphodepleting chemotherapy and cell versus tumor effect create a novel, dynamic state of immunocompromise. Respiratory viruses have been found to be the predominant late infectious complication, but little is known about specific risk factors and outcomes of these infections. Methods We retrospectively identified adult patients who received CD19-directed CAR T-cell therapy at our center and followed them up to two years post-infusion (or until disease progression, death, or February 2022 — whichever came first). We undertook structured chart review using REDCap. Descriptive statistics were used where indicated. An adapted ordinal scale was used to assess the severity of respiratory virus infections (RVIs) (PMCID: PMC9278199). Results We found 73 patients who met search criteria. Of those, 23 patients (32%) developed an RVI, and their baseline characteristics are listed in Table 1. There were 38 episodes of RVI with an average of 1.65 episodes per affected patient. The median time from infusion to RVI was 180 days. The etiologic agent for the majority of RVIs was either unknown or rhino/enterovirus (Figure 1). The median ordinal score for RVI severity was 1, corresponding to ambulatory management for most (Figure 2). However, 24% of patients required a higher level of care. In patients where serial NAATs were performed, the duration of viral shedding was a median of 33 days (IQR 32 – 39). Immediately prior to infection the median IgG was 370 mg/dl (IQR 292 – 566), ANC was 1690 cells/μL (IQR 873 – 3165), and ALC was 480 cells/μL (IQR 285 – 703). 10 (43%) patients were treated with IVIG and 4 (17%) patients received antivirals. Many patients did not seek care for their RVIs or sought care outside of the Hematology/Oncology clinic. The RVI diagnosis relied on the impression of the treating physician at the time the patient presented with symptoms, or when the patient described past symptoms for which they did not present to the Hematology/Oncology clinic for care. Additionally, sometimes a full panel of respiratory viral nucleic acid amplification testing was done and negative (possibly false negative due to a collection issue or non-tested virus). Other times only COVID/FLU/RSV testing was done. Other times no respiratory virus panel was done. “Unknown” is a clinical syndrome of respiratory viral infection encompassing patients either without nucleic acid amplification testing being performed or with negative testing. The Ordinal Scale for EHR Use* was used to rank the severity of each instance of RVI. Possible rankings included 1, 3, 5, 7, 9, or 11. None of the RVIs met the criteria for 9 (organ support) or 11 (death). *Khodaverdi M, Price BS, Porterfield JZ, Bunnell HT, Vest MT, Anzalone AJ, Harper J, Kimble WD, Moradi H, Hendricks B, Santangelo SL, Hodder SL; N3C Consortium Collaborators. An ordinal severity scale for COVID-19 retrospective studies using Electronic Health Record data. JAMIA Open. 2022 Jul 9;5(3):ooac066. doi: 10.1093/jamiaopen/ooac066. PMID: 35911666; PMCID: PMC9278199. Conclusion There is a high burden of delayed RVI in patients who receive CAR T-cell therapy, and these infections can lead to severe illness requiring hospitalization. Clearance of virus was delayed, with duration of shedding lasting at least one month for most. Many CAR T-cell therapy patients had lower immunoglobulin G and lymphocyte counts prior to RVI. Further research is needed to understand the best treatment and prevention strategies for RVIs in this population. Disclosures All Authors: No reported disclosures

Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection

BackgroundLower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses.ResultsHere, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1−/− recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7− TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection.ConclusionsThis study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.

Airborne fine particles drive H1N1 viruses deep into the lower respiratory tract and distant organs.

Mounting data suggest that environmental pollution due to airborne fine particles (AFPs) increases the occurrence and severity of respiratory virus infection in humans. However, it is unclear whether and how interactions with AFPs alter viral infection and distribution. We report synergetic effects between various AFPs and the H1N1 virus, regulated by physicochemical properties of the AFPs. Unlike infection caused by virus alone, AFPs facilitated the internalization of virus through a receptor-independent pathway. Moreover, AFPs promoted the budding and dispersal of progeny virions, likely mediated by lipid rafts in the host plasma membrane. Infected animal models demonstrated that AFPs favored penetration of the H1N1 virus into the distal lung, and its translocation into extrapulmonary organs including the liver, spleen, and kidney, thus causing severe local and systemic disorders. Our findings revealed a key role of AFPs in driving viral infection throughout the respiratory tract and beyond. These insights entail stronger air quality management and air pollution reduction policies.

Sex Hormones Regulate Innate Immune Cells and Promote Sex Differences in Respiratory Virus Infection.

Sex differences in the incidence and severity of respiratory virus infection are widely documented in humans and murine models and correlate with sex biases in numbers and/or functional responses of innate immune cells in homeostasis and lung infection. Similarly, changes in sex hormone levels upon puberty, pregnancy, and menopause/aging are associated with qualitative and quantitative differences in innate immunity. Immune cells express receptors for estrogens (ERα and ERβ), androgens (AR), and progesterone (PR), and experimental manipulation of sex hormone levels or receptors has revealed that sex hormone receptor activity often underlies sex differences in immune cell numbers and/or functional responses in the respiratory tract. While elegant studies have defined mechanistic roles for sex hormones and receptors in innate immune cells, much remains to be learned about the cellular and molecular mechanisms of action of ER, PR, and AR in myeloid cells and innate lymphocytes to promote the initiation and resolution of antiviral immunity in the lung. Here, we review the literature on sex differences and sex hormone regulation in innate immune cells in the lung in homeostasis and upon respiratory virus infection.

Lung Transplantation in Children. Specific Aspects

Lung transplantation has become in recent years a therapeutic option for infants with terminal lung disease with similar results to transplantation in adults. In Spain, since 1996 114 children lung transplants have been performed; this corresponds to 3.9% of the total transplant number. The most common indication in children is cystic fibrosis, which represents between 70-80% of the transplants performed in adolescents. In infants common indications are interstitial lung disease and pulmonary hypertension. In most children a sequential double lung transplant is performed, generally with the help of extracorpo-real circulation. Lung transplantation in children presents special challenges in monitoring and follow-up, especially in infants, given the difficulty in assessing lung function and performing transbronchial biopsies.There are some more specific complications in children like postransplant lymphoproliferative syndrome or a greater severity of respiratory virus infections. After lung transplantation children usually experiment a very important improvement in their quality of life. Eighty eight per cent of children have no limitations in their activity after 3 years of transplantation. According to the registry of the International Society for Heart & Lung Transplantation (ISHLT) survival at 5 years of transplantation is 54% and at 10 years is around 35%.

Trasplante pulmonar en niños. Aspectos específicos

Lung transplantation has become in recent years a therapeutic option for infantswith terminal lung disease with similar results to transplantation in adults.In Spain, since 1996 114 children lung transplants have been performed; this corresponds to3.9% of the total transplant number.The most common indication in children is cystic fibrosis, which represents between 70-80% of the transplants performed in adolescents. In infants common indications areinterstitial lung disease and pulmonary hypertension.In most children a sequential double lung transplant is performed, generally with the help ofextracorporeal circulation. Lung transplantation in children presents special challenges in monitoring and follow-up, especially in infants, given the difficulty in assessing lung function and performing transbronchial biopsies.There are some more specific complications in children like postransplant lymphoproliferative syndrome or a greater severity of respiratory virus infections .After lung transplantation children usually experiment a very important improvement in their quality of life. Eighty eight per cent of children have no limitations in their activity after 3 years of transplantation.According to the registry of the International Society for Heart & Lung Transplantation (ISHLT) survival at 5 years of transplantation is 54% and at 10 years is around 35%.

Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice

BackgroundCigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.MethodsBALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.ResultsInflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.ConclusionSmoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.

Air Pollution and Respiratory Viral Infection

Despite current regulations, which limit the levels of certain air pollutants, there are still a number of adverse health effects that result from exposure to these agents. Numerous epidemiological studies have noted an association between the levels of air pollution and hospital admissions for a variety of different health reasons, including a number of respiratory diseases, as well as increased morbidity and mortality associated with various respiratory conditions and diseases. Because of the large impact respiratory virus infections have on morbidity and even mortality, it is important to understand whether and how exposure to common air pollutants could exacerbate the susceptibility to and severity of respiratory virus infections. This review focuses on current epidemiological and experimental studies, which have examined the association between and effect of air pollutants and respiratory viral infections, as well as potential mechanisms associated with these effects. Examined in this review are U.S. Environmental Protection Agency (EPA) “criteria” pollutants nitrogen dioxide (NO2), ozone (O3), and particulate matter (PM), as well as indoor pollutants such as environmental tobacco smoke (ETS) and combustion products of biomass fuels. Although a number of studies indicate associations between exposure to air pollutants and increased risk for respiratory virus infections, potential mechanisms mediating these effects are largely unexplored. Therefore, additional studies, both epidemiologic and mechanistic, are necessary to increase our understanding of how exposure to air pollutants could affect respiratory virus infections, especially in populations already at risk of developing significant morbidity/mortality after infections with respiratory viruses.