Ramirez Ramirez, Oscar

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are at an increased risk of infections. Before the COVID-19 pandemic, respiratory syncytial virus (RSV) followed predictable seasonal patterns, which have been recently disrupted. This study aimed to investigate whether severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection is associated with an increased risk of RSV infection in patients with IBD compared with those without a history of SARS-CoV-2 infection. METHODS: This retrospective cohort study used the TriNetX database to identify patients aged 18 years and older with IBD and SARS-CoV-2 infection (IBD-SARS-CoV-2 cohort) during the 2022 and 2023 RSV seasons. A 1:1 propensity score matching was used to compare patients with IBD but no history of SARS-CoV-2 infection (IBD non-SARS-CoV-2 cohort). RESULTS: In the 2022 IBD-SARS-CoV-2 cohort (mean age: 53.7 ± 17.6 years; 59% female; 77% White), the RSV infection risk was 0.47%, higher than 0.19% in the matched IBD non-SARS-CoV-2 cohort (adjusted odds ratio [aOR]: 2.4; 95% CI: 1.5–3.6). The risk was highest 30–60 days after SARS-CoV-2 infection (aOR: 2.9; 95% CI: 1.7–4.9), particularly in those aged 60 years and older (aOR: 2.5; 95% CI: 1.3–4.5). The use of systemic corticosteroids (aOR: 2.3; 95% CI: 1.1–4.6) or immune-modifying therapies (aOR: 3.9; 95% CI: 2–7.1) was associated with higher RSV infection risk. Similar trends were observed during the 2023 RSV season, with no significant differences in RSV-related hospitalizations. DISCUSSION: Adults with IBD have a higher risk of RSV infection after SARS-CoV-2 infection, particularly those receiving steroids or immune therapies. SARS-CoV-2 infection may have contributed to the recent RSV infection surge in this population, warranting further research.

INTRODUCTION: Studies suggest that the generation of durable T-cell immunity following coronavirus disease 2019 (COVID-19) vaccination protects against severe disease. The aim of this study was to measure cell-mediated immune response (CMIR) 1–2 months and 6 months after a third dose of a COVID-19 mRNA vaccine. METHODS: This prospective study (HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease [IBD]) evaluated CMIR at 28–65 days (t 1 ) after dose 2, 28–65 days (t 2 ) (n = 183) and 6 months (±45 days) (t 3 ) (n = 167) after a third dose of an mRNA COVID-19 vaccine. A small cohort had blood sample available 28–65 days (t 4 ) (n = 55) after a fourth dose. Primary outcomes were CMIR at (t 2 ) and (t 3 ). Secondary outcomes included the effect of immunosuppressing IBD medications on CMIR and response at (t 4 ). RESULTS: All patients had measurable CMIR at all time points. CMIR increased at t 2 compared with that at t 1 (median 1,467 responding cells per million (interquartile range [IQR] 410–5,971) vs 313 (94–960) P < 0.001). There was no significant waning in t 2 vs t 3 or significant boosting at t 4 . Those on anti–tumor necrosis factor monotherapy had a higher CMIR compared with those not on this therapy at t 2 (4,132 [IQR 1,136–8,795] vs 869 [IQR 343–3,221] P < 0.001) and t 3 (2,843 [IQR 596–6,459] vs 654 [IQR 143–2,067] P < 0.001). In univariable analysis, anti–tumor necrosis factor monotherapy was associated with a higher CMIR at t 2 ( P < 0.001) and t 3 ( P < 0.001) and confirmed in a multivariable model ( P < 0.001). DISCUSSION: A third dose of a COVID-19 vaccine boosts CMIR, and the response is sustained in patients with IBD.

Cellular mitochondrial function can be assessed using high-resolution respirometry that measures the O2 consumption rate (OCR) across a number of cells. However, a direct measurement of cellular mitochondrial function provides valuable information and physiological insight. In the present study, we used a quantitative histochemical technique to measure the activity of succinate dehydrogenase (SDH), a key enzyme located in the inner mitochondrial membrane, which participates in both the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) as Complex II. In this study, we determine the maximum velocity of the SDH reaction (SDHmax) in individual human airway smooth muscle (hASM) cells. To measure SDHmax, hASM cells were exposed to a solution containing 80 mM succinate and 1.5 mM nitroblue tetrazolium (NBT, reaction indicator). As the reaction proceeded, the change in optical density (OD) due to the reduction of NBT to its diformazan (peak absorbance wavelength of 570 nm) was measured using a confocal microscope with the pathlength for light absorbance tightly controlled. SDHmax was determined during the linear period of the SDH reaction and expressed as mmol fumarate/liter of cell/min. We determine that this technique is rigorous and reproducible, and reliable for the measurement of mitochondrial function in individual cells.

Previously, we reported that airway inflammation mediated by pro‐inflammatory cytokines such as TNFα induces hypercontractility and increased ATP consumption in human airway smooth muscle (hASM). We also found that TNFα induces an increase in maximum O 2 consumption rate as well as mitochondrial biogenesis and an increase in mitochondrial volume density. However, when normalized to mitochondrial volume, maximum O 2 consumption rate per mitochondrion is reduced in hASM after TNFα exposure. Unfortunately, standard respirometry (e.g., Seahorse) measures only the averaged maximum O 2 consumption rate of a large number of cells. In the present study, we used a quantitative histochemical technique to determine the maximum velocity of the succinate dehydrogenase reaction (SDH max ) together with mitochondrial volume density in individual hASM cells. SDH is a key enzyme in the tricarboxylic acid (TCA) cycle as well as complex II in the electron transport chain (ETC), and SDH max reflects the maximum respiratory capacity of individual mitochondrion. We hypothesized that TNFα decreases SDH max per mitochondrion in hASM cells. hASM cells were dissociated from bronchial biopsies obtained during thoracic surgeries in patients with no history of asthma or chronic obstructive pulmonary disease. The hASM cells were treated with TNFα (20 ng/ml) or vehicle (DMSO) for 24 h, and SDH max was measured using a solution containing 80 mM succinate (maximum substrate concentration) and 1.5 mM nitro blue tetrazolium (NBT) as the reaction indicator. As the SDH reaction proceeded, the hASM cells were imaged in 3D (Z optical slice of 0.5 μm) using an oil‐immersion ×60/1.4 NA objective on a Nikon Eclipse A1 laser scanning confocal system. The change in optical density (OD), reflecting the accumulation of NBT diformazan reaction product in the hASM cell, was measured every 15 s over a 10 min period. Based on the Beer‐Lambert equation, the slope of the change in OD was used to determine SDH max expressed as mM fumarate/L tissue/min. To determine mitochondrial volume density, the same hASM cells were also loaded with MitoTracker Green (500 nM) and imaged in 3D. We found that mitochondria were more fragmented after TNFα exposure although mitochondrial volume density increased. When SDH max was normalized to mitochondrial volume, we found that SDH max per mitochondrion decreased in hASM cells, consistent with the reduction in maximum O 2 consumption per mitochondrion that we previously observed. Thus, the increased energetic demand induced by inflammation (TNFα) are met by mitochondrial fragmentation leading to biogenesis and an increase in mitochondrial volume density rather than an increase in mitochondrial respiratory capacity.