Post-COVID Phenotypic Manifestations are Associated with New-Onset Psychiatric Disease: Findings from the NIH N3C and RECOVER Studies.

Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective EHR cohort study of 1,603,767 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 65 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28-120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There was a significant association between six categories and newly diagnosed anxiety, mood, and psychotic disorders, with odds ratios highest for cardiovascular (1.35, 1.27-1.42) PASC-AMs. Secondary analysis revealed that the proportions of 95 individual clinical features significantly differed between patients diagnosed with different psychiatric disorders. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings. Funding: NCATS U24 TR002306.

Increased risk of psychiatric sequelae of COVID-19 is highest early in the clinical course.

Background: COVID-19 has been shown to increase the risk of adverse mental health consequences. A recent electronic health record (EHR)-based observational study showed an almost two-fold increased risk of new-onset mental illness in the first 90 days following a diagnosis of acute COVID-19. Methods: We used the National COVID Cohort Collaborative, a harmonized EHR repository with 2,965,506 COVID-19 positive patients, and compared cohorts of COVID-19 patients with comparable controls. Patients were propensity score-matched to control for confounding factors. We estimated the hazard ratio (COVID-19:control) for new-onset of mental illness for the first year following diagnosis. We additionally estimated the change in risk for new-onset mental illness between the periods of 21-120 and 121-365 days following infection. Findings: We find a significant increase in incidence of new-onset mental disorders in the period of 21-120 days following COVID-19 (3.8%, 3.6-4.0) compared to patients with respiratory tract infections (3%, 2.8-3.2). We further show that the risk for new-onset mental illness decreases over the first year following COVID-19 diagnosis compared to other respiratory tract infections and demonstrate a reduced (non-significant) hazard ratio over the period of 121-365 days following diagnosis. Similar findings are seen for new-onset anxiety disorders but not for mood disorders. Interpretation: Patients who have recovered from COVID-19 are at an increased risk for developing new-onset mental illness, especially anxiety disorders. This risk is most prominent in the first 120 days following infection. Funding: National Center for Advancing Translational Sciences (NCATS).

Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults.

The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 microg of vaccine by ID or IM route; 15 microg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 microg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine.

Airway toxicity of house dust and its fungal composition.

House dust is an important source of different toxic metabolites as well as allergens, including those of fungal origin, in the indoor environment. A bio-assay employing 1-day-old chick tracheas was used to characterize airway effects of 2-butanone and dimethylsulphoxide (Me2SO) extracts of 23 dust samples collected from water damaged (13) and control (10) Danish schools. Direct microscopical analysis of samples, followed by cultivation on dichloran 18 % glycerol agar at 25 degrees C for 10 days to establish their mycoflora, was performed. The in vitro ciliostatic potential of the chloroform-extractable endo- and exometabolites of 41 representative fungal isolates was determined. Nine dust extracts in 2-butanone (2 from damp rooms) or 10 (6) in Me(2)SO showed some ciliostatic activity in the 3-days' experiment. Fungal composition of dust from buildings with leakage was almost identical with that from undamaged houses, as well as the fungal colony counts from the damp schools and the control samples. Aspergillus spp. were prevalent in the samples - 31 or 40 % of all fungi, followed by Penicillium spp. and Cladosporium cladosporioides. Alternaria spp., Chaetomium spp., Mucor spp., Mycelia sterilia, Paecilomyces variotii, Rhizopus sp., Ulocladium sp. and yeasts were each isolated in less than 8 % of the fungal content. No Aspergillus flavus isolate (8 in total) was aflatoxigenic,em>in vitro. Alternaria spp., Aspergillus spp., Botrytis cinerea, Penicillium spp., C. cladosporioides, Chaetomium spp. and Ulocladium sp.; in total, 88 % of all fungi tested, produced ciliostatically active metabolites. These toxigenic strains were also present in 4 dust samples from controls and 5 dust samples from water damaged buildings. Extracts of these dust samples were also toxic in bioassay. There were bio-detectable concentrations (10-20 microg of extracts/ml of the organ culture medium) of toxic compounds in house dust. Contribution of fungal metabolites to its toxic effect should be studied further.

Volatile metabolites from indoor molds grown on media containing wood constituents.

Since volatile mold metabolites are used for the detection of mold growth in buildings, it was interesting to determine whether different indoor mold species show different affinity for the major components of wood, a common building material. Growth and volatile metabolites were studied when Aspergillus versicolor, Penicillium chrysogenum, and P. palitans were grown on laboratory substrates containing the major wood constituents cellulose, xylan and lignin. Microbial volatile organic compounds (MVOCs) were characterized by thermal desorption/gas chromatography/mass spectroscopy. Growth and volatile metabolites varied considerably and there appeared to be complementary substrate specificities for P. chrysogenum, and P. palitans grown on cellulose and xylan. The failure of A. versicolor to produce characteristic MVOCs when grown on media containing wood constituents suggests that systems using volatile metabolites to detect microbial growth in buildings may be fundamentally unreliable for the detection of this species.

Patterns of volatile metabolites and nonvolatile trichothecenes produced by isolates of Stachybotrys, Fusarium, Trichoderma, Trichothecium and Memnoniella.

We reported previously that trichodiene, a volatile trichothecene derivative, was produced by a Stachybotrys isolate, also known to produce highly cytotoxic, non-volatile, macrocyclic trichothecenes (satrotoxins). We investigated the relationship between the production of trichodiene and various non-volatile trichothecenes for several molds. Volatile metabolites were concentrated by adsorption on Tenax TA and analyzed by GC/MS, while non-volatile metabolites were separated by HPLC, derivatized and analyzed by GC/MS. Stachybotrys chartarum isolates producing macrocyclic trichothecenes secreted significantly larger amounts of trichodiene and other sesquiterpenes than isolates which only produced simple trichothecenes. The amounts of secreted trichodiene were relatively small in all cases. With the exception of Memnoniella, which excreted small amounts of sesquiterpenes, the other isolates produced varying amounts of sesquiterpenes, including trichodiene, as well as simple tricothecenes, no detectable trichodiene, but large amounts of griseofulvin derivatives. In Stachybotrys there is apparently a correlation between trichodiene and macrocyclic trichothecene production. In the remaining isolates, there was no simple relationship between trichodiene and non-volatile trichothecene synthesis. Trichodiene is produced in larger amounts by Stachybotrys isolates, which also produce satratoxins, but it will be difficult to utilize this metabolite to detect toxic isolates in buildings due to the relatively small amounts excreted.

Detection of indoor PCB contamination by thermal desorption of dust. A rapid screening method?

Although PCB in caulking materials has been forbidden for many years in most of Europe, including Denmark, there has been continued interest to measure PCB levels in the air of contaminated buildings and blood of the occupants (Mengon and Schlatter 1993, Fromme et al. 1996, Ewers et al. 1998, Currado and Harrad 1998, Gabrio et al. 2000). The relatively low priority for investigations of this contamination is probably due to the small quantities inhaled compared to exposure via food, and the rapid metabolism of the most volatile congeners demonstrated by low concentrations of all congeners in the blood of exposed persons (Ewers et al. 1998, Gabrio et al. 2000). There is, however, evidence that PCB containing caulking materials have been used even during the '90s (Fromme et al. 1996). In Denmark, it is estimated that 75 t PCB is still in buildings (Organization of Sealant Branch's Manufacturers and Distributors 2000). During an investigation of dust from buildings with excessive microbial growth (including 35 rooms from 9 buildings), the analysis of semivolatile compounds by thermal desorption-GC/MS of samples from a single building surprisingly revealed large amounts of PCBs containing 3, 4 and 5 chlorine atoms, 10-20 times the amounts found in samples from other buildings. Extraction of the dust by SFE followed by GC/ECD analysis for 12 PCB congeners showed that there was approximately 20 times the total PCB concentrations in dust from the polluted building compared to the levels in the other buildings. Subsequent headspace analysis of caulking material from the polluted building revealed this to be the source. Shelf dust functions as a passive sampling medium and, thus, can be used as a screening method to detect PCB and other semivolatile pollution indoors.

Detection of ciliostatic activity in fungal growth on building materials.

Varying ciliostatic activity was found in extracts of biomass from building materials inoculated with pure isolates of some molds previously isolated from buildings. Extracts from growth on materials composed of finely divided cellulose (plaster board and construction cardboard) were more active than those from growth on Rockwool. Extracts of biomass from all three materials demonstrated an activity greater than control samples. Based on the activity observed here, it is conceivable that the measurement of ciliostatic activity of biomass scraped from contaminated building materials could be useful for planning removal strategies.

Volatile metabolites from actinomycetes.

Twenty-six Streptomyces spp. were screened for their volatile production capacity on yeast starch agar. The volatile organic compounds (VOCs) were concentrated on a porous polymer throughout an 8-day growth period. VOCs were analyzed by gas chromatography with flame ionization detection and identified or characterized by gas chromatography-mass spectrometry. A total of 120 VOCs were characterized by retention index and mass spectra. Fifty-three compounds were characterized as terpenoid compounds, among which 18 could be identified. Among the VOCs were alkanes, alkenes, alcohols, esters, ketones, sulfur compounds, and isoprenoid compounds. Among the most frequently produced compounds were isoprene, acetone, 1-butanol, 2-methyl-1-propanol, 3-methyl-3-buten-1-ol, 3-methyl-1-butanol, 2-methyl-1-butanol, cyclopentanone, dimethyl disulfide, dimethyl trisulfide, 2-phenylethanol, and geosmin. The relationship between the excretion of geosmin and the production of spores was examined for one isolate. A good correlation between headspace geosmin and the number of spores was observed, suggesting that VOCs could be used to indicate the activity of these microorganisms in heterogeneous substrates.