First-in-Human Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Rapidly Developed SARS-CoV-2 Therapeutic Antibody, AOD01, in Healthy Adults.

INTRODUCTION: AOD01 is a novel, fully human immunoglobulin (Ig) G1 neutralizing monoclonal antibody that was developed as a therapeutic against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AOD01 in healthy volunteers. METHODS: Intravenous doses of AOD01 were evaluated in escalating cohorts [four single-dose cohorts (2, 5, 10, and 20 mg/kg) and one two-dose cohort (two doses of 20 mg/kg, 24 h apart)]. RESULTS: Twenty-three subjects were randomized to receive AOD01 or a placebo in blinded fashion. A total of 34 treatment-emergent adverse events (TEAEs) were reported; all were mild in severity. Related events (headache and diarrhea) were reported in one subject each. No event of infusion reactions, serious adverse event (SAE), or discontinuation due to AE were reported. The changes in laboratory parameters, vital signs, and electrocardiograms were minimal. Dose-related exposure was seen from doses 2 to 20 mg/kg as confirmed by Cmax and AUC0-tlast. The median Tmax was 1.5-3 h. Clearance was dose independent. Study results revealed long half-lives (163-465 h). Antidrug antibodies (ADA) to AOD01 were not detected among subjects, except in one subject of the two-dose cohort on day 92. Sustained ex vivo neutralization of SARS-CoV-2 was recorded until day 29 with single doses from 2 to 20 mg/kg and until day 43 with two doses of 20 mg/kg. CONCLUSIONS: AOD01 was safe and well tolerated, demonstrated dose-related PK, non-immunogenic status, and sustained ex vivo neutralization of SARS-CoV-2 after single intravenous dose ranging from 2 to 20 mg/kg and two doses of 20 mg/kg and show good potential for treatment of SARS-CoV-2 infection. (Health Sciences Authority identifier number CTA2000119).

Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

PURPOSE: To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes. MATERIALS AND METHODS: Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT > MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT > 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression. RESULTS: Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT > MIC and 44% for 100%fT > 5 × MIC. Failure to achieve 40-50%fT > MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT > 5 × MIC within 48 h was significantly associated with shorter length of hospital stay. CONCLUSION: Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

Strongyloides Hyperinfection Associated with Enterococcus faecalis Bacteremia, Meningitis, Ventriculitis and Gas-Forming Spondylodiscitis: A Case Report.

An elderly Singaporean male with no travel history was hospitalized for fever and altered mental status. Blood cultures grew Enterococcus faecalis, and given a preceding history of steroid use and peripheral eosinophilia, Strongyloides hyperinfection was suspected. Stool specimens were positive for Strongyloides stercoralis larvae over four days, and larvae were also isolated in an early morning nasogastric aspirate specimen prior to initiation of ivermectin. A cerebrospinal fluid examination was consistent with partially treated bacterial meningitis and ventriculitis was demonstrated on neuroimaging. In view of a persistent fever, a further imaging evaluation was performed, which demonstrated bilateral pneumonia as well as the unusual finding of gas-forming emphysematous spondylodiscitis and left psoas abscesses. Despite the early suspicion of Strongyloides hyperinfection, commencement of appropriate antibiotics and anti-helminthics, microbiological clearance of bacteremia as well as clearance of S. stercoralis from the stool, the patient still succumbed to infection and passed away 11 days after admission.

Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans.

Leaves of the Epimedium plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined Epimedium prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized Epimedium prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial. Serum samples were collected over a 48-h period and analyzed by liquid chromatography-tandem mass spectrometry and non-compartmental pharmacokinetic modelling. Epimedium prenylflavonoid extracts were well tolerated and no adverse effects were observed. The principle metabolites detected in the serum were icariside II and desmethylicaritin. Icariside II had a T max of between 4.1 - 4.3 h, reaching a maximum AUC0→∞ of 23.0 (17.5, 29.9) h×ng/mL (median [IQR: interquartile range]) with the highest dose of the Epimedium prenylflavonoid. On the other hand, desmethylicaritin had a delayed T max of 24.1 - 24.4 h and reached a maximum AUC0→∞ of 126.1 (62.4, 202.9) h×ng/mL. The median maximum plasma concentration and AUC0→∞ of desmethyliciaritin showed an increase with higher doses of the Epimedium prenylflavonoid (p < 0.05). Icariin, icariside I, and icaritin levels were below detection limits. Levels of Epimedium prenylflavonoid metabolites observed in this study were consistent with levels demonstrated to have anti-osteoporotic effects in cellular and animal studies. Coupled with the favorable safety profile of the extract observed, further studies are required to explore the utility of Epimedium prenylflavonoid extracts to prevent osteoporosis in postmenopausal women.

Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model.

COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib. WBA was measured at intervals until 8 hours post-dose (by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units after 72 hours incubation). Celecoxib had no activity alone in the WBA assay (cumulative WBA over 8 hours post-dose: 0.03 ± 0.01ΔlogCFU, p = 1.00 versus zero). Celecoxib did not increase cumulative WBA of standard TB drugs (mean cumulative WBA -0.10 ± 0.13ΔlogCFU versus -0.10 ± 0.12ΔlogCFU for TB drugs alone versus TB drugs and celecoxib; mean difference -0.01, 95% CI -0.02 to 0.00; p = 0.16). The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay.

Activity of faropenem with and without rifampicin against Mycobacterium tuberculosis: evaluation in a whole-blood bactericidal activity trial.

Background: Faropenem has in vitro activity against Mycobacterium tuberculosis (Mtb) and shows synergy with rifampicin. We tested this in a whole-blood bactericidal activity (WBA) trial. Methods: We randomized healthy volunteers to receive a single oral dose of faropenem (600 mg) with amoxicillin/clavulanic acid (500/125 mg) ( n = 8), rifampicin (10 mg/kg) ( n = 14) or the combination rifampicin + faropenem + amoxicillin/clavulanic acid ( n = 14). Blood was drawn at intervals to 8 h post-dose. Drug levels were measured using LC-tandem MS. WBA was measured by inoculating blood samples with Mtb and estimating the change in bacterial cfu after 72 h. Trial registration: ClinicalTrials.gov (NCT02393586). Results: There was no activity in the faropenem + amoxicillin/clavulanic acid group (cumulative WBA 0.02 Δlog cfu; P = 0.99 versus zero change). There was a suggestion of a trend favouring the rifampicin + faropenem + amoxicillin/clavulanic acid group at 8 h (cumulative WBA -0.19 ±âŸ0.03 and -0.26 ±âŸ0.03 Δlog cfu in the rifampicin and rifampicin + faropenem + amoxicillin/clavulanic acid groups, respectively; P = 0.180), which was significant in the first hour post-dose ( P = 0.032). Faropenem C max and AUC were 5.4 mg/L and 16.2 mg·h/L, respectively, and MIC for Mtb H37Rv was 5-10 mg/L. Conclusions: Faropenem is not active when used alone, possibly due to inadequate plasma levels relative to MIC. However, there was a suggestion of modest synergy with rifampicin that may merit further testing in clinical trials.

Combined use of irinotecan with histone deacetylase inhibitor belinostat could cause severe toxicity by inhibiting SN-38 glucuronidation via UGT1A1.

SN-38, the active metabolite of irinotecan, and histone deacetylase inhibitors (HDACis) such as belinostat, vorinostat and panobinostat, have all been shown to be deactivated by glucuronidation via UGTs. Since they all compete for UGTs for deactivation, we aimed to investigate the inhibitory effect of various HDACis on the glucuronidation of SN-38. This inhibitory effect was determined by measuring the formation rate of SN-38 glucuronide after SN-38 incubation with human recombinant UGT1A isoforms (1A1, 1A6, 1A7 and 1A9) and pooled human liver microsomes (HLM, wild type, UGT1A1*1*28 and UGT1A1*28*28 allelic variants), with and without HDACis. The data showed that belinostat at 100 and 200 µmol/L inhibited SN-38 glucuronidation via UGT1A1 in a dose-dependent manner, causing significant decrease in Vmax and CLint (p < 0.05) from 12.60 to 1.95 pmol/min/mg and 21.59 to 4.20 µL/min/mg protein respectively. Similarly, in HLMs, Vmax dropped from 41.13 to 10.54, 24.96 to 3.77 and 6.23 to 3.30 pmol/min/mg, and CLint reduced from 81.25 to 26.11, 29.22 to 6.10 and 5.40 to 1.34 µL/min/mg protein for the respective wild type, heterozygous and homozygous variants. Interestingly, belinostat at 200 µmol/L that is roughly equivalent to the average Cmax, 183 µmol/L of belinostat at a dose of 1,400 mg/m2 given intravenously once per day on days 1 to 5 every 3 weeks, was able to inhibit both heterozygous and homozygous variants to same extents (~64%). This highlights the potential clinical significance, as a large proportion of patients could be at risk of developing severe toxicity if irinotecan is co-administered with belinostat.

Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI.

BACKGROUND: Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. METHODS: Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. RESULTS: SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype. CONCLUSION: Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT00808184.

Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults.

OBJECTIVES: Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions. METHODS: Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days. After a 14 day washout, subjects were switched over to rifampicin (600 mg)/isoniazid (300 mg) or rifampicin (600 mg) daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters and evaluate relationships between parameters and demographic factors, and metabolic enzyme, transporter and transcriptional regulator genotypes. Allometric scaling of clearance and volume of distribution terms based on body weight was applied. RESULTS: A one-compartment model in which absorption was described by a transit absorption model best described the rifampicin data. 25-Deacetyl-rifampicin pharmacokinetic data were best described by a two-compartment model linked to the rifampicin model. None of the investigated covariates significantly influenced the disposition of rifampicin and 25-deacetyl-rifampicin. The apparent clearance of rifampicin and 25-deacetyl-rifampicin was estimated at 10.3 [relative standard error (RSE) 5.6%] and 95.8 (RSE 10%) L/h, respectively, for 70 kg adults. CONCLUSIONS: The pharmacokinetics of rifampicin and its main metabolite were characterized. Prospective studies with a larger number of participants, including patients, are needed to validate the results of this study.

Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

Pharmacokinetics of ertapenem in outpatients with complicated urinary tract infections.

OBJECTIVES: Ertapenem is a broad-spectrum carbapenem antibiotic used to treat severe bacterial infections. In view of its dosing convenience, it is increasingly used as outpatient therapy. The objective of this study was to determine the pharmacokinetics and renal disposition of ertapenem in outpatients with complicated urinary tract infections. METHODS: Ertapenem was administered as a daily intravenous infusion of 1 g over 30 min. At steady-state, blood and urine samples were collected over one dosing interval. Drug concentrations in serum and urine were determined using a validated liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was used to characterize ertapenem serum and urine profiles. The likelihood of the standard dosing achieving a favourable pharmacokinetic-pharmacodynamic exposure was evaluated using Monte Carlo simulations. RESULTS: Ten adult male patients were studied. Concentration-time profiles of ertapenem in both serum (r(2) =0.997) and urine (r(2) =0.982) were captured satisfactorily. Mean values for volume of distribution, clearance and elimination t½ were 4.8 L, 0.7 L/h and 6.1 h, respectively. A high ertapenem concentration (>128 mg/L) could be attained in the urine at 40% of the dosing interval. CONCLUSIONS: The pharmacokinetics of ertapenem in serum and urine were characterized. Our simulations suggested that a sufficiently high ertapenem concentration could be achieved in urine to overcome low to intermediate resistance. Clinical investigations to validate our findings are warranted.

CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.

We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1-day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry. The population pharmacokinetic study was conducted using NONMEM. Demographics, clinical characteristics, and genetic polymorphisms were screened as covariates. A two-compartment model for MDZ and two sequential compartments representing 1OHM and HMG best described the data. The CYP3A5*3 and total bilirubin level significantly influenced MDZ clearance. The population typical MDZ clearance for CYP3A5*3 expressers was 22% lower than non-expressers. Baseline bodyweight was a statistically significant covariate for clearance and distribution volume of 1OHM. Creatinine clearance was positively correlated with HMG clearance. Our data indicate that CYP3A5*3, total bilirubin, bodyweight, and creatinine clearance are important predictors of MDZ and metabolite pharmacokinetics. Further studies in more patients are needed to explore the links between the identified covariates and the disposition of MDZ and its metabolites.

A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein.

There is concern that ingestion of dietary phytoestrogens may increase risk of estrogen receptor alpha (ERα)-positive breast cancer. The prenylflavone icaritin, a phytoestrogen consumed in East Asian societies for its perceived beneficial effects on bone health, stimulated the growth of breast cancer (MCF-7) cells at low concentrations. Although acting like an estrogenic ligand, icaritin exerted an unexpected suppressive effect on estrogen-stimulated breast cancer cell proliferation and gene expression at higher concentrations. Like estradiol, icaritin could dose-dependently destabilize ERα protein. However, destabilization of ERα by the estradiol/icaritin combination was profound and greater than that observed for either compound alone. Microarray gene expression analyses implicated aryl hydrocarbon receptor (AhR) signaling for this suppressive effect of icaritin. Indeed, icaritin was an AhR agonist that competitively reduced specific binding of a potent AhR agonist and increased expression of the AhR-regulated gene CYP1A1. When AhR was knocked down by small interfering RNA, the suppressive effect of icaritin on estradiol-stimulated breast cancer cell growth and gene expression was abolished, and ERα protein stability was partially restored. Similarly in an athymic nude mouse model, icaritin restricted estradiol-stimulated breast cancer xenograft growth and strongly reduced ERα protein levels. Overall, our data support the feasibility for the development of dual agonists like icaritin, which are estrogenic but yet, through activating AhR-signaling, can destabilize ERα protein to restrict ERα-positive breast cancer cell growth.

Population pharmacokinetics of modafinil and its acid and sulfone metabolites in Chinese males.

BACKGROUND: Modafinil is a psychostimulant used to treat excessive sleepiness. The aim of this study was to develop a population pharmacokinetic model of modafinil and its major metabolites in Chinese male adults and to identify covariates that predict variability in disposition. METHODS: Eighty healthy volunteer subjects were randomized to 4 oral dose groups: 3 doses of 50 mg of modafinil, 3 doses of 100 mg of modafinil, 2 doses of 200 mg of modafinil plus 1 dose of placebo, or 3 doses of placebo (each dose given 8 hourly). Blood samples were collected up to 58 hours post-first dose for plasma concentrations of modafinil and its metabolites. Pharmacokinetic data analyses were performed using noncompartmental and compartmental approaches. The population pharmacokinetic study was conducted using the nonlinear mixed-effects model software, NONMEM, and validated using the bootstrap, crossvalidation and visual predictive check approaches. RESULTS: Data were best described by a 5-compartment model: 2 compartments for modafinil (first-order absorption from gut compartment) and 1 each for modafinil acid and modafinil sulfone. A covariate analysis identified body weight as influencing volumes of the central and peripheral compartments for modafinil. All the parameters were estimated with good precision (relative standard error < 39%). The visual predictive check found that the final pharmacokinetic model adequately predicted observed concentrations of all 3 molecular species. The authors developed dosing schedules to achieve minimum trough plasma modafinil concentrations of 3 mcg/mL. CONCLUSIONS: A robust population pharmacokinetic model for modafinil and its metabolites was developed for the first time. Based on this model, individualized dosing based on weight is now possible.

Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometric method.

Raltegravir is a highly efficacious inhibitor of HIV integrase. Large pharmacokinetic variability has been reported in clinical trials and this could be due to glucuronidation of raltegravir, the only reported metabolism pathway. In order to precisely evaluate and monitor the raltegravir and raltegravir glucuronide simultaneously, a novel, sensitive and robust liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of raltegravir and raltegravir glucuronide in human plasma. A simple protein precipitation with acetonitrile was utilized for plasma sample preparation prior to analysis. Baseline chromatographic separation was achieved on a ZORBAX Eclipse XDB-C8 using gradient elution mode. The run time was 9 min at a constant flow rate of 0.4 ml/min. The mass spectrometer was operated under a positive electrospray ionization condition. Excellent linearity (r(2) ≥ 0.9997) was achieved for raltegravir and raltegravir glucuronide in the range of 2-2000 nmol/l. The average recovery of raltegravir and raltegravir glucuronide was 105.8% and 102.2%, respectively. The precision (coefficient of variation) was 1.6-6.6% for raltegravir and 2.1-6.9 for raltegravir glucuronide, respectively. The accuracy was 98.6-106.1% for raltegravir and 96.3-100.3% for raltegravir glucuronide. The plasma samples were tested to be stable after nine freeze-thaw cycles and exposure to room temperature for 24 h. This well-validated assay was applied for the quantification of raltegravir and raltegravir glucuronide in plasma samples within 24 h after a single oral dose of 400 mg raltegravir in six healthy subjects.

Quality of life and psychological status in survivors of severe acute respiratory syndrome at 3 months postdischarge.

BACKGROUND: Little is known about the long-term consequence of severe acute respiratory syndrome (SARS). We carried out an assessment on SARS patients after their recovery from their acute illness. METHOD: Postal survey comprising Health-Related Quality of Life (HRQoL) questionnaires and anxiety and depression measures was sent to them at 3 months' postdischarge. RESULTS: There was a significant impairment in both the HRQoL and mental functioning. Forty-one percent had scores indicative of a posttraumatic stress disorder (PTSD); about 30% had likely anxiety and depression. CONCLUSION: SARS has significant impact on HRQoL and psychological status at 3 months.

1-year pulmonary function and health status in survivors of severe acute respiratory syndrome.

STUDY OBJECTIVES: To characterize the long-term pulmonary function and health status in a prospectively identified cohort of patients who survived the severe acute respiratory syndrome (SARS). DESIGN: Prospective follow-up cohort study. SETTING: University-affiliated hospital. PATIENTS: Ninety-four patients who recovered from SARS were assessed at a uniform time point of 1 year after hospital discharge. MEASUREMENTS: The study included the measurement of static and dynamic lung volumes, the determination of the diffusing capacity of the lung for carbon monoxide (D(LCO)), and a health status evaluation using the St. George Respiratory Questionnaire (SGRQ). RESULTS: Eleven patients (12%) had mild impairment of FVC, 20 (21%) had mild impairment of FEV1, 5 (5%) had mild impairment of the FEV1/FVC ratio, and 17 (18%) had mild impairment of the D(LCO). There was one patient (1%) who had moderate impairment of FVC, one patient (1%) who had moderate impairment of the FEV1/FVC ratio, and three patients (3%) who had moderate impairment of the D(LCO). No pulmonary function abnormalities were detected in 59 patients (63%). Mean scores were significantly higher (ie, worse) than the population norms in the activity (p < 0.001), impacts (p < 0.001), and total (p < 0.001) domains of the SGRQ. CONCLUSIONS: One year after recovery from SARS, persistent pulmonary function impairment was found in about one third of patients. The health status of SARS survivors was also significantly worse compared with the healthy population. The main determinants of morbidity in recovered SARS patients need to be further defined.

Hypocortisolism in survivors of severe acute respiratory syndrome (SARS).

OBJECTIVE: Following the severe acute respiratory syndrome (SARS) outbreak, many survivors were observed to suffer from psychosomatic symptoms reminiscent of various endocrine disorders. Hence, we sought to determine the existence of any chronic endocrine sequelae in SARS survivors. DESIGN, PATIENTS, MEASUREMENTS: Sixty-one survivors of SARS prospectively recruited were analysed for hormonal derangements 3 months following recovery. Patients with pre-existing endocrine disorders were excluded. Any endocrine abnormalities diagnosed were investigated and treated where indicated up to a year. Serial evaluation facilitated characterization of trends and prognostication of any endocrinological aberrations. RESULTS: Twenty-four (39.3%) patients had evidence of hypocortisolism. The hypothalamic-pituitary-adrenal (HPA) axis dysfunction of the majority resolved within a year. Two (3.3%) of the hypocortisolic cohort had transient subclinical thyrotoxicosis. Four (6.7%) were biochemically hypothyroid, being comprised of three with central hypothyroidism and one with primary hypothyroidism. Two of the three with central hypothyroidism had concomitant central hypocortisolism. Eight had subnormal DHEAS levels. CONCLUSIONS: These preliminary findings highlight a possible aetiologic role of SARS-associated coronavirus in causing a reversible hypophysitis or direct hypothalamic effect, with the HPA axis affected more frequently than the HPT axis.