Publications by authors named "Harald S Haugen"

6 Publications

  • Page 1 of 1

Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.

EClinicalMedicine 2021 Mar 27;33:100773. Epub 2021 Feb 27.

Division of Allergy and Infectious Diseases, University of Washington, United States.

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission.

Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility.

Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60,  = 0.047) but not HCQ/AZ (HR=1.25,  = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63-1.64,  = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57-1.45,  = 0.70).

Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection.

Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. ClinicalTrials.gov number NCT04354428.
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http://dx.doi.org/10.1016/j.eclinm.2021.100773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912360PMC
March 2021

Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial.

Ann Intern Med 2021 03 8;174(3):344-352. Epub 2020 Dec 8.

University of Washington, Seattle, Washington (H.C.S., T.T.S., M.L.K., K.K.T., S.M., H.S.H., L.K., M.W., C.C., H.Y.C., J.M.B.).

Background: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.

Objective: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.

Design: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).

Setting: National U.S. multicenter study.

Participants: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.

Intervention: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.

Measurements: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.

Results: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66];  > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively;  = 0.026).

Limitation: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.

Conclusion: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.

Primary Funding Source: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.7326/M20-6519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732017PMC
March 2021

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not.

J Mol Med (Berl) 2009 May 30;87(5):523-36. Epub 2009 Mar 30.

Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charité, Charitéplatz 1, 10117, Berlin, Germany.

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-gamma nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-gamma and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-alpha potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.
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http://dx.doi.org/10.1007/s00109-009-0457-0DOI Listing
May 2009

A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor.

Mol Endocrinol 2006 Feb 6;20(2):414-25. Epub 2005 Oct 6.

ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, Washington 98102, USA.

Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity. In competition studies, unlabeled CGH is a potent competitor for (125)I-TSH binding, whereas unlabeled TSH does not compete for (125)I-CGH binding. Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone. Transgenic overexpression of GPHB5 in mice produces elevations in serum T(4) levels, reductions in body weight, and proptosis. However, neither transgenic overexpression of GPHA2 nor deletion of GPHB5 produces an overt phenotype in mice. In vivo administration of CGH to mice produces a dose-dependent hyperthyroid phenotype including elevation of T(4) and hypertrophy of cells within the inner adrenal cortex. However, the distinctive expression patterns and binding characteristics of CGH suggest that it has endogenous biological roles that are discrete from those of TSH.
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http://dx.doi.org/10.1210/me.2005-0270DOI Listing
February 2006

Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.

Proc Natl Acad Sci U S A 2005 Mar 22;102(9):3389-94. Epub 2005 Feb 22.

Department of Pathology, University of Washington, Seattle, WA 98115, USA.

Members of the platelet-derived growth factor (PDGF) ligand family are known to play important roles in wound healing and fibrotic disease. We show that both transient and stable expression of PDGF-C results in the development of liver fibrosis consisting of the deposition of collagen in a pericellular and perivenular pattern that resembles human alcoholic and nonalcoholic fatty liver disease. Fibrosis in PDGF-C transgenic mice, as demonstrated by staining and hydroxyproline content, is preceded by activation and proliferation of hepatic stellate cells, as shown by collagen, alpha-smooth muscle actin and glial fibrillary acidic protein staining and between 8 and 12 months of age is followed by the development of liver adenomas and hepatocellular carcinomas. The hepatic expression of a number of known profibrotic genes, including type beta1 TGF, PDGF receptors alpha and beta, and tissue inhibitors of matrix metalloproteinases-1 and -2, increased by 4 weeks of age. Increased PDGF receptor alpha and beta protein levels were associated with activation of extracellular regulated kinase-1 and -2 and protein kinase B. At 9 months of age, PDGF-C transgenic mice had enlarged livers associated with increased fibrosis, steatosis, cell dysplasia, and hepatocellular carcinomas. These studies indicate that hepatic expression of PDGF-C induces a number of profibrotic pathways, suggesting that this growth factor may act as an initiator of fibrosis. Moreover, PDGF-C transgenic mice represent a unique model for the study of hepatic fibrosis progressing to tumorigenesis.
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http://dx.doi.org/10.1073/pnas.0409722102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC552940PMC
March 2005

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.

Nat Immunol 2004 Jul 6;5(7):752-60. Epub 2004 Jun 6.

Department of Immunology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, Washington 98102, USA.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
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http://dx.doi.org/10.1038/ni1084DOI Listing
July 2004