**1. Introduction**

Over the last two years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic with high morbidity and mortality, causing over 426 million infections and almost 6 million deaths up to February 2022 [1]. Clinical courses range from asymptomatic infection to severe disease with need for intensive care unit (ICU) stay and death [2]. Different risk factors for severe COVID-19 have been described and include older age, frailty, and higher burden of comorbidities [3,4]. However, because older and frail patients are often malnourished and have a higher likelihood for low levels in different specific micronutrients [5,6], micronutrient deficiencies could additionally contribute to more severe courses in patients infected with SARS-CoV-2. From a preclinical perspective, the importance of various micronutrients for a functioning immune system has been well

**Citation:** Voelkle, M.; Gregoriano, C.; Neyer, P.; Koch, D.; Kutz, A.; Bernasconi, L.; Conen, A.; Mueller, B.; Schuetz, P. Prevalence of Micronutrient Deficiencies in Patients Hospitalized with COVID-19: An Observational Cohort Study. *Nutrients* **2022**, *14*, 1862. https:// doi.org/10.3390/nu14091862

Academic Editors: Omorogieva Ojo and Amanda R Amorim Adegboye

Received: 30 March 2022 Accepted: 26 April 2022 Published: 29 April 2022

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documented [7–9]. For example, it has been shown that vitamin A plays an important role in maintaining mucosal integrity [10], while zinc plays an essential role in protecting against reactive oxygen and nitrogen species [11,12]. Furthermore, vitamin D increases the excretion of antimicrobial peptides in epithelial lining cells in the respiratory tract [13] and is involved in the modulation of pro- and anti-inflammatory cytokine production [14]. Consequently, deficiencies in micronutrients may lead to higher susceptibility for infections.

With respect to COVID-19, deficiencies in different micronutrients, including vitamin D [15,16], zinc [17,18], and selenium [19,20], have been discussed as risk factors for a more severe disease course, with need for ICU admission and mechanical ventilation, or higher incidence of death. Based on these observations, there has been a call for more wide-spread supplementation of the above-mentioned micronutrients during the COVID-19 pandemic to prevent and improve courses of infected patients [7,21]. This call is particularly timely, since a high prevalence of deficiencies has been reported from different countries, including Switzerland [22,23]. Still, until now, there is insufficient research concerning the association of micronutrients levels with clinical courses of COVID-19.

Herein, we analyzed different micronutrient levels in a COVID-19 cohort and described the distribution of deficiencies, as well as the correlation among levels of different micronutrients. Further, the association between deficiencies in micronutrients and severe progression of COVID-19 disease was investigated.

#### **2. Subjects and Methods**

#### *2.1. Patient Population*

This prospective observational study involved adult patients (≥18 years) hospitalized with a confirmed SARS-CoV-2 infection between 17 March 2020 and 30 April 2020 at the Cantonal Hospital Aarau (Switzerland), a tertiary care hospital. Baseline characteristics of this cohort have been published elsewhere [24]. In brief, patients were included if they had typical clinical symptoms of a SARS-CoV-2 infection (e.g., respiratory symptoms with or without fever and/or pulmonary infiltrates) and a positive real-time reverse transcription polymerase chain reaction test (RT-PCR) taken from nasopharyngeal swabs or lower respiratory tract specimens, according to the World Health Organization (WHO) guidance [25]. Written general informed consent was obtained from all analyzed patients. The study was approved by the local ethics committee (EKZN, 2020-01306) and performed in conformance with the Declaration of Helsinki ethical guidelines. For the present analysis, only patients with a complete micronutrient status were included, whereas patients receiving either an oral or intravenous substitution of the analyzed micronutrients at the hospital before obtaining the blood samples were excluded. Patients taking micronutrient supplements at home were included, as we aimed to display micronutrient status at the time of hospital admission.
