key: cord-0783461-91degx30 authors: Calum, H; Sode, LP; Pedersen, M title: Status: nosocomial transmission and prevention of SARS‐CoV‐2 in a Danish context date: 2021-05-29 journal: APMIS DOI: 10.1111/apm.13160 sha: 58a4d9db13c275e23c8c79d7aa1d4bbe379ca6a0 doc_id: 783461 cord_uid: 91degx30 The unexpected pandemic with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has challenged the health care sector as regards preventing and controlling the virus from spreading between patients and hospital personnel. The massive spread of the pandemic has led State authorities to introduce restrictions on society and public behavior unprecedented in modern times. First, we describe the Danish effort regarding standard precautions, personal protective equipment, and disinfection in the health care setting with Denmark as an example. As regards number of coronavirus disease 2019 (COVID‐19) related hospital submissions, deaths, and infected health care workers Denmark is not the hardest hit country compared to others. This cannot be explained by hardness of the restrictions alone. Several aspects concerning the person‐to‐person spread of SARS‐CoV‐2 are not fully understood and require more experimental studies. The dogma is that virus transmission happens through either respiratory droplets or contact routes. However, it is likely not the whole truth, as we describe scenarios where droplets and/or direct contact cannot alone explain how all patients were infected. Aspects of the physiology of airborne transmission is considered, as several parameters are in play beyond particle size and respiratory rate. These are ozone concentration, ambient temperature, and humidity. In a hospital environment these factors are not necessarily all controllable, making infection prevention and control a challenge. The envelope is lipid bilayer membrane, which can be susceptible to destruction by dry heat, organic solvents, and detergents (6) . The virus uses the angiotensin converting enzyme 2 (ACE2) receptors to enter the human cells and the protease TMPRSS2 (Transmembrane Protease Serine type 2) facilitates the further internalizations process. The presence of ACE2 receptors is Accepted Article ubiquitous, since the receptor is present in the central nervous system, conjunctivae gastrointestinal system, lung, heart, kidney, and testes (7) . The size of SARS-CoV-2 is 120 nm. Knowledge about the transmission route is essential to prevent the virus from spreading (7) . The SARS-CoV-2 belongs together with SARS-CoV and MERS-CoV to the Betacoronavirus genus. The genome sequence homology between SARS-CoV and SARS-CoV-2 is 80% and between SARS-CoV-2 and MERS-CoV 50% (7) . The genome of SARS-CoV-2 has 96,2% similarity to CoV-TaTG13 from bats (8) . The respiratory illness, COVID-19, has a span in symptomatology from asymptomatic to severe pneumonia with Acute Respiratory Distress Syndrome. The median incubation period is 5.1 days and the majority of infected patients have symptoms within 12 days (9) . Basic reproduction number (R 0 ) is estimated to 2,2 -2,6 (10). The mortality of COVID-19 seems lower as compared to SARS and MERS, i.e. 2,1%, 9,2%, and 34,4% respectively. The mortality rate is highest among elder and patients with comorbidity (10) . During the initial stage of the pandemic Denmark and other countries had no official standard of care for neither oxygen nor medical treatment for COVID-19. The treatments were based on experiences from China and Italy. Initially the treatment consisted of high flow nasal oxygen or ventilation. After some months this was combined with dexamethasone and antiviral therapy with This article is protected by copyright. All rights reserved Remdesivir (11, 12) . Anticoagulation therapy was added due to thrombosis and coagulation abnormalities in patients with severe COVID-19 disease (13) . In the beginning, the overall strategy in Denmark was a containment policy which aimed to delay the epidemic by means of diagnostics, isolation as well as quarantine of patients and close contacts. When WHO in marts 2020 declared a pandemic, the Danish Health Authority has launched a mitigation strategy with the aim of preventing spread of infection to health care workers (HCW) and patients (14). The medical professional guidance has been conducted by The Danish Health Authority, Statens Serum Institute (SSI), and the National Center for Infection Control (CEI) These three organizations have published guidelines and recommendations aimed to prevent the virus to spread, protect individuals at risk for severe disease acquiring the virus, and that the impact on the Health care system due to the increased demand was not overstretched. A central discussion was how far droplets could travel though air. According to WHO, the distinction between droplets and aerosols begins below 5 µm. However, some authors use Accepted Article other droplets size cutoffs and implies that droplets are able to stay long in the air without evaporation (15 and FFP3-masks during clinical procedures of high risk, as did they temporarily dispense from the 3-hours' time limit for use of the two masks during the peak of the Danish epidemic. In cleaning the hospital area, the recommended products were Accepted Article water and soap, alcohol or a chlorine solution of a minimum of 1.000 parts per million. Cleaning staff were required to wear PPE when cleaning and managing hospital waste (17). In Denmark the isolation of the COVID-19 patients is discontinued either if the patient has been symptom free for 48 hours or in the case of the intensive care unit patient when the patient is fever-free without antipyretics for 48 hours and has two negative SARS-CoV-2 Nucleic Acid Amplification Tests from both pharynx and trachea 24 hours apart (18). This differs from the WHO guideline (19) . However, the experiences in the Danish health sector has shown that the guideline is highly operational. that all individuals who were tested positive for SARS-CoV-2 were Accepted Article asked to track down recent contacts with other persons, so they could be tested 4,6, and 8 days after the day of contact. 12 th of May 2020, the Danish Health Authority took over the responsibility for tracking and and contacting close contacts to persons tested positive for COVID-19. Whether these initiatives have been successful is difficult to substantiate scientifically, since no data is available. On October 2 nd 2020, the Danish health authorities released new guideline regarding the spatial distance in public and recommended a distance of at least 1 meter between people, and 2 meters in specific cases (21). Furthermore, the guideline took into consideration, that under certain conditions such as crowded indoors settings with poor ventilation and recirculation of the air, the risk of infection would be increased. In the guideline, the Danish Health Authorities introduced the concept R e . R 0 stands for the basic reproduction number and is pivotal for the political decision makers. R 0 represents the number of secondary cases due to a primary case in absence of immunity or intervention. R e or R t (also known as effective R or varying R) is the average number of secondary cases per infectious case, when initiatives have been launched to curb the pandemic. A pandemic will continue for R 0 and peter out for R 0 (22,23). SARS-> 1 < 1. CoV-2 pandemic have been characterized by asymptomatic cases. It is estimated that over 80% of the cases are asymptomatic (24) . This article is protected by copyright. All rights reserved The contact rate in the asymptomatic group influences the R 0 due to their activity is normal in contrast to symptomatic persons who self-isolate. Intensive testing and trace strategy can provide an estimate of the distribution between asymptomatic cases and symptomatic cases and furthermore, of course provides the opportunity of isolation of "silent spreaders". Srinivasa and coworkers emphasize that calculation of R 0 or R t is difficult and may not be able to capture the real spread. In fact, miscalculation can lead to underestimation of the true value and that testing and trace campaign should be very extensive and thorough (25) . Moreover, In the former Danish guideline, it was emphasized that, there is not scientific documentation for R 0 like measles. On October 29 th 2020 the Danish Health Authority expanded the precaution with wearing masks in public. Concerning the health care sector, a principle of caution demanded the use of masks, when moving in common areas. The rule is still maintained (26) . Brosesau define aerosols as Tellier with the addendum, that the particles differ in size (36) . Bourouiba concludes that aerosols and droplet nuclei are used synonymous (34) and they are suspended in the air for longer time without evaporation providing the possibility for reaching and infecting a susceptible person at a longer distance. Respiratory particles are composed of water, Na + , K + , Cl -, lactate, and glycoproteins. Evaporation is due to the difference in water vapor pressure around the particle surface and the ambient air (37) . Prather and coworkers argued that the terminology must be clarified including the size of the particles (38) , since size is determining the distance to travel. In short, the airborne transmission is characterized by particles below 5 µm and travel distance longer than 1 m, in contrast to the dogma of droplet transmission where a working distance longer than 1 m is considered safe. Below 5 µm, the droplets can reach the alveoli, and close standing persons can have mouth mucosa and eyes exposed. Larger droplets fall very quickly to the ground without evaporation. Moreover, the particles may be able to travel more than 1-2 meters, remain in the air for Günter and colleges concluded that transmission occurred within Furthermore, if evaporation occurs the airborne lifetime expands (57) . The virus RNA load in oral fluid is measured to 2,35 x 10 9 copies per milliliter (2) . It is estimated that the probability is 37% that a droplet with diameter 50 µm contains at least one virion (57) . In line with these observations Edwards et al., found that by breathing persons could be classified into low producers expelling < 500 droplets per liter over six hours, and super producers exhaling > 500 droplets pr. Liter over six hours (58) . Airborne This article is protected by copyright. All rights reserved analyzing the data, it will often be difficult to conclude whether people have been in close contact or the contacts were more distant. Furthermore, Low R 0 does not preclude airborne transmission. Deposited virus-containing secretions may also be reaerosolized by activity such as walking, cleaning the room, and by door opening (60) . Western blotting to find viral antigen was not possible. One study conducted by van Doremalen addressed this challenge using a three-jet Collison nebulizer and fed into a Goldberg drum creating an aerosolized environment. They examined aerosols, plastic, stainless steel, copper, and cardboard and found that SARS-CoV-2 was viable for 3 hours in aerosols. 50% tissue-culture infectious dose (TCID 50 ) was reduced from This article is protected by copyright. All rights reserved Otherwise, the airborne transmission, according to WHO, is limited to aerosol generating procedures (AGP) (9) . Understanding the transmission routes enables the health care authorities to initiate precautions to protect the HCW and patients. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved N95. Other face masks are surgical masks (type II/IIR) (Figure 1 ). FFP1 is the mask with the least filter capacity, since they can prevent 80% of particles greater than 0,3 µm. FFP2 and FFP3 are 94% respectively 99% effective in their filter performance (68) Figure 2 . Droplet-or airborne precaution: This article is protected by copyright. All rights reserved Droplet precaution recommended by Danish authorities is based on the assumption that the transmission is -of course -by respiratory droplets. Furthermore, it implies that one should maintain a spatial distance of 1 meter and wearing a mask when having contact with infected or suspected infected patient. Data from the first wave shows that front line HCWs have an increased risk of testing positive and data also indicate that personal protection equipment may reduce that risk (74) . Besides aerosol formation by patients, some medical procedures generate aerosols. These procedures are characterized as highrisk exemplified by mechanical ventilation, tracheostomy, bronchoscopy, airway suctioning, turning the patient to the prone position, disconnecting the patient from the ventilator, and cardiopulmonary resuscitation (74, 75) . First, the US CDC and ECDC recommended respirators in both low-and high-risk situations. The lack of PPE made the two organizations reconsider the guidelines, so masks were protective enough in low-risk situations and respirators were reserved to high-risk This article is protected by copyright. All rights reserved situations according to US CDC. ECDC suggested, that the storage of PPE should determine the use. Only when the respirators are non-accessible, the masks could be substituted. (68). Figure 3a and 3b,FFP3 mask and goggles used when conducting AGP and FFP3 mask and face shield used when conducting AGP. Since the SARS-CoV-2 can spread to the environment due to the droplets falling down because of gravity or due to indirect transmission by patients, disinfection is essential. Disinfectants such as sodium hypochlorite are effective. Also, biocidal agents like alcohols, hydrogen peroxide, benzalkonium are useable. Ethanol reduced SARS-CoV-2 with a 4.0 log 10 ( ≥ 70%) ≥ reduction. Since a toilet can act as reservoir, cleaning is important and the lid should be closed before flushing (33, 76) . Due to the initial shortage of masks in the health care system and the use of cloth masks in the public, the question regarding the cleaning or disinfection and reuse of the mask has been raised. According to recommendation from the US CDC, the cloth mask should be wash daily and can dry in a warm or hot dryer. When washing the cloth mask can be included in the regular laundry and with use of regular detergent. It is of course important to follow the instructions from the producer. Handling the cloth mask correctly is pivotal to prevent transmission. After removal of or touching the mask, the hands should be wash or and sanitizer (78) . This article is protected by copyright. All rights reserved In 2007 in UK, the department of health recommended that HCW should be "bare below the elbows" (BBE). The purpose was to improve the quality of the hand hygiene. Being BBE is define as no sleeves, watches, or hand jewellary. In Denmark, being BBE also includs not wearing wedding rings, long nails or artificial nails The evidence to support the recommendation, seems to lack. Farrington and coworkers evaluated the quality of handwashing among 88 medicals doctors and 61 medical students at a 900-bed teaching hospital in Cornwall. The participants were randomized into non-BBE and BBE, and the quality of handwashing was estamted by using flourescent alcohol-based preparation. The authors concluded that being BBE did not significantly amend the quality of handwashing as compared to non-BBE, and especially did not improve the wrist washing. In Denmark, BBE is mandatory all thought, the evidence for reducing hospital infections is lacking, also regarding trasmission of SARS-CoV-2 (79). SARS-CoV-2 seems highly contagious between humans as the particle size consists of a continuum of different sizes, why protection of health workers is important. The simplicity of droplet This article is protected by copyright. All rights reserved transmission into the dichotomy of large contra small droplets has been challenged and influencing factors like humidity, temperature, individual anatomic physiology, pollutants, interaction, dynamics in the multiphase gas cloud, and airflow make it difficult always to maintain this model, and maybe expand it to a more continuous model such as the multiphase gas cloud model. It seems possible that airborne transmission can occur in selected settings. Since the weight of evidence is growing, further investigation with modern technology and humans as objects would shed light on the transmission by droplets. At the moment there is no clear-cut distinction between the droplet transmission and airborne transmission, movement. In the end, this is not only about protecting HCW but also the population. 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All rights reserved This article is protected by copyright. All rights reserved Accepted Article