Altered mental status and pronounced febrile response after second mRNA-1273 (Moderna) COVID-19 vaccine administration in a patient with previously documented COVID-19 infection

A 54-year-old man who was previously found to be COVID-19 positive received two doses of mRNA-1273 (Moderna) vaccine 4 weeks apart, as recommended by the manufacturer. He was brought to the emergency department 1 day after second dose of the vaccine with altered mental status, headache and high fever. The patient was hospitalised for 2 days and managed with supportive care. He completely recovered with return of mental status to baseline and resolution of fever.

Pathophysiology of Fever and Application of Infrared Thermography (IRT) in the Detection of Sick Domestic Animals: Recent Advances

Body-temperature elevations are multifactorial in origin and classified as hyperthermia as a rise in temperature due to alterations in the thermoregulation mechanism; the body loses the ability to control or regulate body temperature. In contrast, fever is a controlled state, since the body adjusts its stable temperature range to increase body temperature without losing the thermoregulation capacity. Fever refers to an acute phase response that confers a survival benefit on the body, raising core body temperature during infection or systemic inflammation processes to reduce the survival and proliferation of infectious pathogens by altering temperature, restriction of essential nutrients, and the activation of an immune reaction. However, once the infection resolves, the febrile response must be tightly regulated to avoid excessive tissue damage. During fever, neurological, endocrine, immunological, and metabolic changes occur that cause an increase in the stable temperature range, which allows the core body temperature to be considerably increased to stop the invasion of the offending agent and restrict the damage to the organism. There are different metabolic mechanisms of thermoregulation in the febrile response at the central and peripheral levels and cellular events. In response to cold or heat, the brain triggers thermoregulatory responses to coping with changes in body temperature, including autonomic effectors, such as thermogenesis, vasodilation, sweating, and behavioral mechanisms, that trigger flexible, goal-oriented actions, such as seeking heat or cold, nest building, and postural extension. Infrared thermography (IRT) has proven to be a reliable method for the early detection of pathologies affecting animal health and welfare that represent economic losses for farmers. However, the standardization of protocols for IRT use is still needed. Together with the complete understanding of the physiological and behavioral responses involved in the febrile process, it is possible to have timely solutions to serious problem situations. For this reason, the present review aims to analyze the new findings in pathophysiological mechanisms of the febrile process, the heat-loss mechanisms in an animal with fever, thermoregulation, the adverse effects of fever, and recent scientific findings related to different pathologies in farm animals through the use of IRT.

Triazol-phenyl antipyretic derivatives inhibit mPGES-1 mRNA levels in LPS-Induced RAW 264.7 macrophage cells

Background:: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) production, which plays an important role in the regulation of febrile response. In our previous work, ligand-based pharmacophore models, built with mPGES-1 inhibitors, were employed to identify a novel series of compounds that reduce the febrile response in rats. Objectives:: Evaluate the mechanism of action of the most active compound (1). Methods:: For in vivo assays, rats were pretreated with the antipyretic compounds 1-8, 30 min before LPS injection. For in vitro assays, RAW 264.7 macrophage cells were incubated with the antipyretic compounds 1-8 for 1 hour before LPS stimu-lus. After 16 h, quantitative real-time PCR was carried out. Additionally, the PGE2 concentration in hypothalamus was quantified by ELISA and the inhibitory effect of N-cyclopentyl-N'-[3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)phenyl]ethanediamide (1) over human COX-2 enzymatic activity was determined with a COX Colorimetric Inhibitor Screening Assay Kit. Results:: Compound 1 and CAY10526 have comparable efficacy to reduce the febrile response when injected i.v. (com-pound 1: 63.10%, CAY10526: 70.20%). Moreover, compound 1 significantly reduces the mPGES-1 mRNA levels, in RAW264.7 cells, under inflammatory conditions. A chemically-similar compound (8- ) also significantly reduces the mRNA levels of the gene target. On the other hand, compounds 6 and 7, which are also somewhat similar to compound 1, do not, significantly, impact mPGES-1 mRNA levels. Conclusions:: PGE2 concentration reduction in hypothalamus, due to compound 1 central injection, is related to decreased mPGES-1 mRNA levels but not to COX-2 inhibition (IC50> 50 μM). Therefore, compound 1 is a promising lead for inno-vative antipyretic drug development.

292 The effect of pharmacological zinc on oral Salmonella vaccine efficacy

Pharmacological zinc (2,000-3,000 ppm) is commonly fed to nursery pigs to improve health and growth due to its antimicrobial and anti-inflammatory properties. The objective was to test if pharmacological zinc at time of oral Salmonella vaccination impeded vaccine efficacy. Sixty-four weaned pigs (5.1±0.7 kg BW) were used in a 2 x 2 factorial design. The diets were control (CON) or zinc (3,000 ppm for 1 week, 2,000 ppm for 2 weeks, and no additional zinc for 1 week [ZN]). On d 2 pigs were orally vaccinated for Salmonella with 1 of 2 commercially available vaccines, resulting in 4 treatments (CON1, CON2, ZN1, ZN2; n = 16/treatment). On d 28, n = 8 pigs/treatment were randomly selected and enrolled in a S. Typhimurium challenge study. On d 35 post-weaned, all pigs were inoculated with 108 cfu of a field S. Typhimurium isolate. Pig performance, febrile response, fecal shedding and serology was assessed over a 7-d challenge period. On dpi 7 all pigs were euthanized, and colon contents and ileocecal lymph nodes were collected for culture. The effect of nursery diet, vaccine and their interaction was assessed. Pigs were confirmed Salmonella culture positive at dpi 2 and 6 pigs were culture positive from the ileocecal lymph nodes at dpi 7. Salmonella-specific antibody titers (S/P) increased (P < 0.001) from dpi 0 (0.31) to 7 (2.01), and a time-by-vaccine interaction was reported (P < 0.05). Irrespective of diet and vaccine, core temperatures increased from 39.5°C (dpi 0) to 39.7°C (dpi 2) before decreasing (P = 0.02). Over the challenge period, ADG did not differ (0.67, 0.64, 0.61, 0.62 kg/d, CON1, CON2, ZN1, ZN2, respectively, P = 0.654). Furthermore, ADFI and G:F did not differ by diet or vaccine (P >0.05). In conclusion, pharmacological Zn did not inhibit efficacy of oral Salmonella vaccines.

36 Differential haptoglobin responsiveness to a Mannheimia haemolytica challenge altered immunologic, physiologic, and behavioral responses in beef steers

A retrospective analysis of data from a previous study (Kayser et al., J. Anim. Sci. 97:596; 2019) revealed that steers challenged with Mannheimia haemolytica (MH) had divergent serum haptoglobin (HPT) despite having similar leukocyte and temperature responses. In that study, 36 steers (BW 352 ± 23 kg) were fitted with rumen boluses and were fed from electronic bunks to measure DMI and feeding behavior prior to inoculation with saline or MH. Whole blood was collected on days -4, 0, 1, 2, 3, 5, 7, 10 and 14 relative to MH inoculation. The MH steers were retrospectively classified as HPT responsive (RES; n = 9; mean AUC = 62.6 mg/dL/d) or HPT non-responsive (NON; n = 9; mean AUC = 4.5 mg/dL/d). The current objective was to determine if the HPT responsive phenotype altered other immunologic, physiologic, or behavioral responses, compared with saline controls (CON; n = 18). The magnitude of increase in neutrophils (P< 0.01) and total leukocytes (P< 0.05) was greater in RES than NON or CON on d1. All MH-challenged steers experienced a transient febrile response, but temperature was greater (P< 0.01) in RES on days 0 and 4 compared to NON and CON. Intake was depressed in all three groups d0, but magnitude of depression in RES was greater (P< 0.01) than NON or CON, and remained lower (P < 0.01) d 1, 2, 3, 6, and 8. Bunk-visit duration was decreased (P < 0.01) in all MH-challenged steers on day 0, but RES were greater (P < 0.02) than NON and CON d 11 and 12. Correspondingly, bunk-visit eating rate of RES was decreased (P < 0.01) from day 2 - 14. Had this not been a sub-clinical challenge model, the greater reduction in intake and increased leukocyte recruitment may have resulted in performance differences between RES and NON steers. These results suggest that differences in HPT responsiveness may be associated with differences in innate immunocompetence.

35 Differential haptoglobin responsiveness to a Mannheimia haemolytica challenge altered immunologic, physiologic, and behavioral responses in beef steers

A retrospective analysis of data from a previous study (Kayser et al., J. Anim. Sci. 97:596; 2019) revealed that steers challenged with Mannheimia haemolytica (MH) had divergent serum haptoglobin (HPT) despite having similar leukocyte and temperature responses. In that study, 36 steers (BW 352 ± 23 kg) were fitted with rumen boluses and were fed from electronic bunks to measure DMI and feeding behavior prior to inoculation with saline or MH. Whole blood was collected on days -4, 0, 1, 2, 3, 5, 7, 10 and 14 relative to MH inoculation. The MH steers were retrospectively classified as HPT responsive (RES; n = 9; mean AUC = 62.6 mg/dL/d) or HPT non-responsive (NON; n = 9; mean AUC = 4.5 mg/dL/d). The current objective was to determine if the HPT responsive phenotype altered other immunologic, physiologic, or behavioral responses, compared to saline controls (CON; n = 18). The magnitude of increase in neutrophils (P< 0.01) and total leukocytes (P< 0.05) was greater in RES than NON or CON on day 1. All MH-challenged steers experienced a transient febrile response, but temperature was greater (P< 0.01) in RES on days 0 and 4 compared to NON and CON. Intake was depressed in all three groups d 0, but magnitude of depression in RES was greater (P< 0.01) than NON or CON, and remained lower (P< 0.01) d 1, 2, 3, 6, and 8. Bunk-visit duration was decreased (P< 0.01) in all MH-challenged steers on day 0, but RES were greater (P< 0.02) than NON and CON d 11 and 12. Correspondingly, bunk-visit eating rate of RES was decreased (P< 0.01) from day 2 - 14. Had this not been a sub-clinical challenge model, the greater reduction in intake and increased leukocyte recruitment may have resulted in performance differences between RES and NON steers. These results suggest that differences in HPT responsiveness may be associated with differences in innate immunocompetence.

Further placental pathology in mild COVID-19 of term pregnancy with pathophysiological correlates

Placental pathology related to SARS-COV-2 infection during pregnancy is under investigation, with emerging but still limited and variable data, mainly including changes of fetal and maternal vascular malperfusion. We observed novel pathological findings not previously reported in two term placentas delivered from women mildly affected with COVID-19, with a 2-day and 6-day interval between the onset of symptoms and delivery. The main changes involved the maternal more than the fetal components of the placenta and included a tendency toward thrombosis and fibrin formation, and mild maternal malperfusion. We further observed fibrin degeneration in the intervillous space, the presence of particles of undetermined origin, and mild or moderate maternal decidual inflammatory exudates consisting of monocytes, macrophages, T-lymphocytes, and plasmacytes. Mild inflammation and incipient mural thrombus formation were noted in the fetal vasculature, as well as endothelial vacuolation of the umbilical vessels, not previously described. The maternal changes were more prominent in the case with a relatively longer clinical manifestation-to-delivery interval, and were associated to a prolonged postpartum maternal viral carriage of 30 days and the development of a low-grade febrile response in the neonate. Both infants showed mild morbidity but eventually had a very good outcome. RT-PCR was negative for SARS-CoV-2 RNA in both cases.We concluded that placental involvement in mild COVID-19 of very short duration at term pregnancy suggested the systemic nature of the disease and appeared related to, though not pathognomonic of COVID-19. Fetoplacental vascular changes and endothelial vacuolation associated with mild neonatal morbidity may suggest a possible transplacental impact on the fetus, to be further investigated.