The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections

Samuel E Jones; Fahrisa I Maisha; Satu J Strausz; Vilma Lammi; Brian E Cade; Anniina Tervi; Viola Helaakoski; Martin E Broberg; FinnGen; Jacqueline M Lane; Susan Redline; Richa Saxena; Hanna M Ollila

doi:10.1016/j.ebiom.2023.104630

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections

EBioMedicine. 2023 Jul:93:104630. doi: 10.1016/j.ebiom.2023.104630. Epub 2023 Jun 8.

Authors

Collaborators

FinnGen:
Aarno Palotie, Mark Daly, Bridget Riley-Gills, Howard Jacob, Dirk Paul, Slavé Petrovski, Heiko Runz, Sally John, George Okafo, Nathan Lawless, Heli Salminen-Mankonen, Robert Plenge, Joseph Maranville, Mark McCarthy, Margaret G Ehm, Kirsi Auro, Simonne Longerich, Anders Mälarstig, Katherine Klinger, Clement Chatelain, Matthias Gossel, Karol Estrada, Robert Graham, Robert Yang, Chris O Donnell, Tomi P Mäkelä, Jaakko Kaprio, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Anne Pitkäranta, Taneli Raivio, Jani Tikkanen, Raisa Serpi, Tarja Laitinen, Veli-Matti Kosma, Jari Laukkanen, Marco Hautalahti, Outi Tuovila, Raimo Pakkanen, Jeffrey Waring, Bridget Riley-Gillis, Fedik Rahimov, Ioanna Tachmazidou, Chia-Yen Chen, Heiko Runz, Zhihao Ding, Marc Jung, Shameek Biswas, Rion Pendergrass, Margaret G Ehm, David Pulford, Neha Raghavan, Adriana Huertas-Vazquez, Jae-Hoon Sul, Anders Mälarstig, Xinli Hu, Åsa Hedman, Katherine Klinger, Robert Graham, Manuel Rivas, Dawn Waterworth, Nicole Renaud, Ma En Obeidat, Samuli Ripatti, Johanna Schleutker, Markus Perola, Mikko Arvas, Olli Carpén, Reetta Hinttala, Johannes Kettunen, Arto Mannermaa, Katriina Aalto-Setälä, Mika Kähönen, Jari Laukkanen, Johanna Mäkelä, Reetta Kälviäinen, Valtteri Julkunen, Hilkka Soininen, Anne Remes, Mikko Hiltunen, Jukka Peltola, Minna Raivio, Pentti Tienari, Juha Rinne, Roosa Kallionpää, Juulia Partanen, Ali Abbasi, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Heiko Runz, Sanni Lahdenperä, Shameek Biswas, Natalie Bowers, Edmond Teng, Rion Pendergrass, Fanli Xu, David Pulford, Kirsi Auro, Laura Addis, John Eicher, Qingqin S Li, Karen He, Ekaterina Khramtsova, Neha Raghavan, Martti Färkkilä, Jukka Koskela, Sampsa Pikkarainen, Airi Jussila, Katri Kaukinen, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Mark Daly, Ali Abbasi, Jeffrey Waring, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, Tim Lu, Natalie Bowers, Rion Pendergrass, Linda McCarthy, Amy Hart, Meijian Guan, Jason Miller, Kirsi Kalpala, Melissa Miller, Xinli Hu, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Oili Kaipiainen-Seppänen, Johanna Huhtakangas, Nina Mars, Ali Abbasi, Jeffrey Waring, Fedik Rahimov, Apinya Lertratanakul, Nizar Smaoui, Anne Lehtonen, Coralie Viollet, Marla Hochfeld, Natalie Bowers, Rion Pendergrass, Jorge Esparza Gordillo, Kirsi Auro, Dawn Waterworth, Fabiana Farias, Kirsi Kalpala, Nan Bing, Xinli Hu, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Riitta Lahesmaa, Nizar Smaoui, Coralie Viollet, Susan Eaton, Hubert Chen, Rion Pendergrass, Natalie Bowers, Joanna Betts, Kirsi Auro, Rajashree Mishra, Majd Mouded, Debby Ngo, Teemu Niiranen, Felix Vaura, Veikko Salomaa, Kaj Metsärinne, Jenni Aittokallio, Mika Kähönen, Jussi Hernesniemi, Daniel Gordin, Juha Sinisalo, Marja-Riitta Taskinen, Tiinamaija Tuomi, Timo Hiltunen, Jari Laukkanen, Amanda Elliott, Mary Pat Reeve, Sanni Ruotsalainen, Dirk Paul, Natalie Bowers, Rion Pendergrass, Audrey Chu, Kirsi Auro, Dermot Reilly, Mike Mendelson, Jaakko Parkkinen, Melissa Miller, Tuomo Meretoja, Heikki Joensuu, Olli Carpén, Johanna Mattson, Eveliina Salminen, Annika Auranen, Peeter Karihtala, Päivi Auvinen, Klaus Elenius, Johanna Schleutker, Esa Pitkänen, Nina Mars, Mark Daly, Relja Popovic, Jeffrey Waring, Bridget Riley-Gillis, Anne Lehtonen, Margarete Fabre, Jennifer Schutzman, Natalie Bowers, Rion Pendergrass, Diptee Kulkarni, Kirsi Auro, Alessandro Porello, Andrey Loboda, Heli Lehtonen, Stefan McDonough, Sauli Vuoti, Kai Kaarniranta, Joni A Turunen, Terhi Ollila, Hannu Uusitalo, Juha Karjalainen, Esa Pitkänen, Mengzhen Liu, Heiko Runz, Stephanie Loomis, Erich Strauss, Natalie Bowers, Hao Chen, Rion Pendergrass, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Sirkku Peltonen, Leena Koulu, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, David Choy, Rion Pendergrass, Dawn Waterworth, Kirsi Kalpala, Ying Wu, Pirkko Pussinen, Aino Salminen, Tuula Salo, David Rice, Pekka Nieminen, Ulla Palotie, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Ulvi Gursoy, Vuokko Anttonen, Kirsi Sipilä, Rion Pendergrass, Hannele Laivuori, Venla Kurra, Laura Kotaniemi-Talonen, Oskari Heikinheimo, Ilkka Kalliala, Lauri Aaltonen, Varpu Jokimaa, Johannes Kettunen, Marja Vääräsmäki, Outi Uimari, Laure Morin-Papunen, Maarit Niinimäki, Terhi Piltonen, Katja Kivinen, Elisabeth Widen, Taru Tukiainen, Mary Pat Reeve, Mark Daly, Niko Välimäki, Eija Laakkonen, Jaakko Tyrmi, Heidi Silven, Eeva Sliz, Riikka Arffman, Susanna Savukoski, Triin Laisk, Natalia Pujol, Mengzhen Liu, Bridget Riley-Gillis, Rion Pendergrass, Janet Kumar, Kirsi Auro, Iiris Hovatta, Chia-Yen Chen, Erkki Isometsä, Hanna Ollila, Jaana Suvisaari, Thomas Damm Als, Antti Mäkitie, Argyro Bizaki-Vallaskangas, Sanna Toppila-Salmi, Tytti Willberg, Elmo Saarentaus, Antti Aarnisalo, Eveliina Salminen, Elisa Rahikkala, Johannes Kettunen, Kristiina Aittomäki, Fredrik Åberg, Mitja Kurki, Samuli Ripatti, Mark Daly, Juha Karjalainen, Aki Havulinna, Juha Mehtonen, Priit Palta, Shabbeer Hassan, Pietro Della Briotta Parolo, Wei Zhou, Mutaamba Maasha, Shabbeer Hassan, Susanna Lemmelä, Manuel Rivas, Aarno Palotie, Aoxing Liu, Arto Lehisto, Andrea Ganna, Vincent Llorens, Hannele Laivuori, Taru Tukiainen, Mary Pat Reeve, Henrike Heyne, Nina Mars, Joel Rämö, Elmo Saarentaus, Hanna Ollila, Rodos Rodosthenous, Satu Strausz, Tuula Palotie, Kimmo Palin, Javier Garcia-Tabuenca, Harri Siirtola, Tuomo Kiiskinen, Jiwoo Lee, Kristin Tsuo, Amanda Elliott, Kati Kristiansson, Mikko Arvas, Kati Hyvärinen, Jarmo Ritari, Olli Carpén, Johannes Kettunen, Katri Pylkäs, Eeva Sliz, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Arto Mannermaa, Eija Laakkonen, Nina Pitkänen, Samuel Lessard, Clément Chatelain, Lila Kallio, Tiina Wahlfors, Jukka Partanen, Eero Punkka, Raisa Serpi, Sanna Siltanen, Veli-Matti Kosma, Teijo Kuopio, Anu Jalanko, Huei-Yi Shen, Risto Kajanne, Mervi Aavikko, Rasko Leinonen, Henna Palin, Malla-Maria Linna, Mitja Kurki, Juha Karjalainen, Pietro Della Briotta Parolo, Arto Lehisto, Juha Mehtonen, Wei Zhou, Masahiro Kanai, Mutaamba Maasha, Zhili Zheng, Hannele Laivuori, Aki Havulinna, Susanna Lemmelä, Tuomo Kiiskinen, L Elisa Lahtela, Mari Kaunisto, Elina Kilpeläinen, Timo P Sipilä, Oluwaseun Alexander Dada, Awaisa Ghazal, Anastasia Kytölä, Rigbe Weldatsadik, Sanni Ruotsalainen, Kati Donner, Timo P Sipilä, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Auli Toivola, Minna Brunfeldt, Hannele Mattsson, Kati Kristiansson, Susanna Lemmelä, Sami Koskelainen, Tero Hiekkalinna, Teemu Paajanen, Priit Palta, Kalle Pärn, Mart Kals, Shuang Luo, Tarja Laitinen, Mary Pat Reeve, Shanmukha Sampath Padmanabhuni, Marianna Niemi, Harri Siirtola, Javier Gracia-Tabuenca, Mika Helminen, Tiina Luukkaala, Iida Vähätalo, Jyrki Tammerluoto, Marco Hautalahti, Johanna Mäkelä, Sarah Smith, Tom Southerington, Petri Lehto

Affiliations

¹ Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Finland.
² Department of Neurology, School of Medicine, Yale University, New Haven, CT, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Finland; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: hanna.m.ollila@helsinki.fi.

Abstract

Background: Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections.

Methods: We used data on insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital records in the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 392,000). We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and performed Mendelian randomization analyses to assess causality.

Findings: Utilizing 23 years of registry data and follow-up, we discovered that insomnia diagnosis associated with increased risk for infections (FinnGen influenza Cox's proportional hazard (CPH) HR = 4.34 [3.90, 4.83], P = 4.16 × 10^-159, UK Biobank influenza CPH HR = 1.54 [1.37, 1.73], P = 2.49 × 10^-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (inverse-variance weighted (IVW) OR = 1.65, P = 5.86 × 10^-7), URI (IVW OR = 1.94, P = 8.14 × 10^-31), COVID-19 infection (IVW OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (IVW OR = 1.47, P = 4.96 × 10^-5).

Interpretation: Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens.

Funding: Instrumentarium Science Foundation, Academy of Finland, Signe and Ane Gyllenberg Foundation, National Institutes of Health.

Keywords: COVID-19; Insomnia; Mendelian randomization; Respiratory infections; Severe infection; Sleep.

MeSH terms

COVID-19* / complications
COVID-19* / epidemiology
Genome-Wide Association Study
Humans
Influenza, Human* / complications
Influenza, Human* / epidemiology
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Public Health
Respiratory Tract Infections* / complications
Respiratory Tract Infections* / epidemiology
Sleep
Sleep Initiation and Maintenance Disorders*

Grants and funding

R35 HL135818/HL/NHLBI NIH HHS/United States