key: cord-0855150-emdj66vj
authors: Kampf, Günter; Brüggemann, Yannick; Kaba, Hani E.J.; Steinmann, Joerg; Pfaender, Stephanie; Scheithauer, Simone; Steinmann, Eike
title: Potential sources, modes of transmission and effectiveness of prevention measures against SARS-CoV-2
date: 2020-09-18
journal: J Hosp Infect
DOI: 10.1016/j.jhin.2020.09.022
sha: d6da70bb79d0b6547c2153d03b0a88ab5a897cfd
doc_id: 855150
cord_uid: emdj66vj

During the current SARS-CoV-2 pandemic new studies are emerging daily providing novel information about sources, transmission risks and possible prevention measures. In this review, we aimed to comprehensively summarize the current evidence on possible sources for SARS-CoV-2, including evaluation of transmission risks and effectiveness of applied prevention measures. Next to symptomatic patients, asymptomatic or pre-symptomatic carriers are a possible source with respiratory secretions as the most likely cause for viral transmission. Air and inanimate surfaces may be sources; however, viral RNA has been inconsistently detected. Similarly, even though SARS-CoV-2 RNA has been detected on or in personnel protective equipment, blood, urine, eyes, the gastrointestinal tract and pets, these sources are currently thought to play a negligible role for transmission. Finally, various prevention measures such as hand washing, hand disinfection, face masks, gloves, surface disinfection or physical distancing for the healthcare setting and public are analysed for their expected protective effect.

the end of the infectious period. In fact, real-time reverse transcriptase PCR results remained positive 6-8 days after the loss of transmissibility [9] . For SARS coronavirus, viral RNA was detectable in the respiratory secretions and stools of some patients after onset of illness for more than 1 month, but live virus could not be detected by culture after week 3 [10] . The inability to differentiate between infective and non-infective (dead or antibody-neutralised) viruses therefore remains a major limitation of nucleic acid detection methods. Despite this limitation, given the difficulties in culturing infectious virus from clinical specimens during a pandemic, using viral RNA load as a surrogate remains plausible for generating careful clinical hypotheses.

The association between viral load and clinical outcome including severity of symptoms is still poorly characterized although the majority of studies reported an association between higher viral loads and more severe symptoms [11] [12] [13] [14] [15] [16] [17] [18] [19] .

Transmission dynamics of SARS-CoV-2 are heterogeneously [20] . Numerous individual infection clusters in particular in Asia with variable size have been reported [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] .

Originating from a single travel-associated primary case from China, the first documented chain of multiple human-to-human transmissions of SARS-CoV-2 outside of Asia allowed a detailed study of transmission events and identified several factors (e.g. cumulative face-toface contact, direct contact with secretions or body fluids of a patient, personal protective equipment) to classify contacts as low or high risk [32] . Furthermore, factors such as immune suppression, increased disease severity and viral load, asymptomatic individuals, the practice of seeking care at multiple healthcare facilities, frequent inter-hospital transfer, large numbers of contacts and prolonged duration of exposure facilitate transmission [33] . Household transmission is also common [34] . Superspreading is regarded as a normal feature of disease spread and has also been described with SARS-CoV-2 [35, 36] . Importantly, a recent study observed that transmission clusters occurred in many, predominantly indoor settings and most clusters involved fewer than 100 cases, with the exceptions being in healthcare (hospitals and elderly care), large religious gatherings, food processing plants, schools, shopping, and large co-habiting settings (worker dormitories, prisons and ships) [31] . Given the predominately mild, non-specific symptoms, infectiousness before symptom onset the successful containment of COVID-19 relies on stringent and urgent surveillance and infection-control measures.

Based on the definition of the WHO a confirmed case is a person with laboratory confirmation (detection of viral genomic material) of SARS-CoV-2, irrespective of clinical signs and symptoms [37] . Asymptomatic coronavirus infections have been described before [38] and might together with pre-symptomatic spread form a potential source of COVID-19 infections acquired in a social or nosocomial context [26, [39] [40] [41] [42] [43] [44] . In February 2020, a total of 44,672 confirmed cases were reported for China with a proportion of 1.2% of asymptomatic cases [45] . Data from the first of April based on more rigorous testing of contact persons suggest in a small cohort of 166 new cases a proportion of 78% as asymptomatic cases [46] . Irrespective of the frequency of asymptomatic carriers, they are considered to be important for the transmission of the disease [47] . Various studies reported SARS-CoV-2 infections, originating from asymptomatic carriers during close contacts such as household contacts or residents of a long-term care skilled nursing facility [43, [48] [49] [50] [51] [52] . Importantly, several studies have reported that viral RNA loads in pre-symptomatic, asymptomatic and symptomatic patients do not differ significantly [53] [54] [55] . Others have reported no transmission from 455 contacts (patients, family members, hospital staff) to asymptomatic carriers and concluded that the infectivity of some asymptomatic carriers may be weak [56] .

As summarized in Table I , the proportions of asymptomatic SARS-CoV-2 cases at the time point of testing have been determined for different cohorts of patients. In hospitalized patients it was described to range be between 5.0% and 27.8% [57] [58] [59] [60] . In a long-term care facility, it was quite high with 56.5% [61] . In family clusters it was found between 25% and 57.1% [62, 63] . In 171 children in China the proportion was 15.5% [64] . Among Japanese nationals evacuated from Wuhan by chartered flights it was 30.8% in contrast to German nationals with 1.8% [65, 66] . On board of a cruise ship asymptomatic carriers were detected in 50.5% of the cases. The delay-adjusted asymptomatic proportion, however, was only 17.9% [67] . In Iceland, a proportion of 3.6% of the general population (13080 out of 364000 inhabitants) were investigated. Overall, 100 of them (0,8%) were positive with a proportion of 43% asymptomatic carriers. Among inhabitants with a high risk for infection the proportion of asymptomatic cases was only 7% [68] . Overall, asymptomatic SARS-CoV-2 infections seem to account for up to 56% of SARS-CoV-2 infections in selected cohorts, suggesting a significant factor for the rapid progression of the COVID-19 pandemic [53, 69, 70] .

For comparison, the prevalence of asymptomatic influenza virus carriage (total absence of symptoms) ranged from 5.2% to 35.5% and subclinical cases (illness that did not meet the criteria for acute respiratory or influenza-like illness) between 25.4% to 61.8% [71] . With MERS a proportion of 9.5% of 1010 cases was asymptomatic [38] .

Follow-up examinations, however, indicate that the majority of initially tested asymptomatic cases (70.8% -100%) develop moderate but detectable clinical symptoms over time and therefore should be considered as pre-symptomatic. Only in a small group of patients, no symptoms or radiological findings became apparent, but were described as potentially infectious for up to 29 d (Table II) [72] .

Of note, patients with negative PCR result prior to discharge may also become transient asymptomatic carriers again. One patient, for example, was retested positive for SARS-CoV-2 during the 2 weeks quarantine after discharge [73] . Two healthcare workers (HCWs) were also tested (throat swab) after discharge (COVID-19) and were weakly positive in 2 of 7 samples and positive in 1 of 7 samples (case 1 sampled over 10 d), and weakly positive in 1 of 8 samples and positive in 1 of 8 samples (case 2 sampled over 8 d) [74] . However, these results have to be interpreted with caution as currently applied PCR methods can lead to fluctuating results in weakly positive samples due to detection limits of the assays. Indeed, a single case was described with low viral RNA loads or negative RT-qPCR results, despite a SARS-CoV-2 infection confirmed by the presence of anti-SARS-CoV-2 specific antibodies [75] . Importantly, a systematic meta-analysis of different cohort studies observed that asymptomatic patients with COVID-19 seems to correlate with young age and social activity [76, 77] . In particular, future studies aiming to understand the contribution of young aged patients such as children to asymptomatic transmission of SARS-CoV-2 should be prioritised [78] . In summary, the prevalence of asymptomatic SARS-CoV-2 infection and duration of pre-symptomatic infection are not well understood, as asymptomatic individuals are not routinely tested. Studies on the immune response of asymptomatic carriers are lacking, which could contribute to a better characterization of the protective factors under natural conditions [79] .

Several sources have been described that could possibly be involved in SARS-CoV-2 transmission based on the detection of viral RNA. These include the respiratory tract, air contamination, the gastrointestinal tract, eyes, inanimate surfaces, personnel protective equipment, pets, and rather less likely blood and the urinary tract.

SARS-CoV-1 has been frequently associated with droplet-based transmission [80, 81] . Likewise, person-to-person transmission has been assumed for SARS-CoV-2 very early [21] . Importantly, a more efficient transmission of SARS-CoV-2 compared to SARS-CoV-1 has been suggested, due to active pharyngeal viral shedding while symptoms are still mild and typical of upper respiratory tract infection [7] . Table III summarizes the frequency and magnitude of SARS-CoV-2 viral RNA loads in respiratory tract samples obtained from COVID-19 patients.

The viral RNA load with SARS-CoV-2 can be as high as 11.1 log10 cpm (Table III) . It seems to be particularly high in the early and progressive stage of disease [16] or two days before and one day after symptom onset [82] . However, in some cases RNA could still be found up to 51 days after the first positive test with negative results in-between [15, 83] . Influenza A virus RNA has even been released for up to 70 d with negative results in-between although infectious virus was only detected for 5 d after symptom onset [84] . Age was also associated with high viral RNA load [15] . Most studies observed decreased viral RNA loads over time [5, 7] . One study shows that SARS-CoV-2 was detected by culture in 19 out of 25 clinical samples (nasopharyngeal swab) from COVID-19 patients [6] . The viral RNA load detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients [5] . It is important to differentiate between detection of RNA and the isolation of infectious virus in cell culture. PCR for RNA of SARS-CoV-2 does not distinguish between infectious virus and non-infectious nucleic acid. Thus, interpretation of duration of viral shedding and infection potential should be based on viable virus from cell culture and needs to be carefully evaluated when solely based on PCR results.

J o u r n a l P r e -p r o o f A strict distinction between droplet versus airborne transmission routes for infections is not possible [85] . Virus transmission via droplets and aerosols enables many viruses to spread efficiently between humans [86] . Airborne transmission is defined as the transmission of infection by expelled particles of comparatively small in size and which can remain suspended in air for long periods of time [87] . The World Health Organization uses a particle diameter of 5 ߤm to delineate between airborne (≤5 ߤm) and droplet (>5 ߤm) transmission [88] . Transmission of infectious diseases by the airborne route is dependent on the interplay of several factors, including particle size (i.e., particle diameter) and the extent of desiccation [87] . Particle desiccation is a critical variable and depending on environmental factors as even large, moisture laden droplet particles desiccate rapidly [87] . For example, Wells showed that particles begin desiccating immediately in a rapid fashion upon air expulsion: particles up to 50 ߤm can desiccate completely within approximately 0.5 seconds [89] . Rapid desiccation is a concern since the smaller and lighter the infectious particle, the longer it will potentially remain airborne. Hence, even when infectious agents are expelled from the respiratory tract in a matrix of mucus and other secretions, causing large, heavy particles, rapid desiccation can lengthen the time they remain airborne (the dried residuals of these large aerosols, termed droplet nuclei, are typically 0.5-12 ߤm in diameter) [87] . Of further concern, very large aerosol particles may initially fall out of the air only to become airborne again once they have desiccated [87] . One of the challenges facing practitioners, particularly in an enclosed building, is that even large-sized droplets can remain suspended in air for long periods. The reason is that droplets settle out of air onto a surface at a velocity dictated by their mass [87] . If the upward velocity of the air in which they circulate exceeds this velocity, they remain airborne. Hence, droplet aerosols up to 100 ߤm diameter have been shown to remain suspended in air for prolonged periods when the velocity of air moving throughout a room exceeds the terminal settling velocity of the particle [87] .

Respiratory virus shedding can occur via sneezing, coughing or talking. Sneezing distributes approximately 40,000 particles (droplets or airborne microorganisms) per sneeze, coughing approximately 710 particles per cough, and talking approximately 36 particles per 100 words [87] . Using highly sensitive laser light scattering observations a recent study describes that loud speech can emit thousands of oral fluid droplets per second [90] , indicating that normal speaking may also contribute to virus transmission in stagnant air. Most of the 40,000 large droplet particles caused by a single sneeze will desiccate immediately into small, infectious droplet nuclei, with 80% of the particles being smaller than 100 ߤm [3] . The transmission of infectious diseases via airborne or droplet routes may further also depend on the frequency of the initiating activity. A single sneeze may produce more total infectious particles, while overall coughing may potentially be a more effective route of airborne transmission (e.g. during infection with Coxsackievirus A) [91] . Coronavirus-infected humans coughed on average 17 times over 30 min during exhaled breath collection [92] . Given that dry cough is also a common symptom of COVID-19 patients [93] , it may therefore contribute to potential airborne transmission of this pathogen. In this context, airborne transmission has been considered to be possible in a cluster of infections in a restaurant with air conditioning [94] .

Few studies are available to evaluate the role of air for transmission of SARS-CoV-2, most of them obtained in hospitals with COVID-19 patients. From the data shown in Table IV viral copies were only detected in large air volumes of 9000 L with a larger proportion on ICU (35% detection rate) compared to general wards (12.5% detection rate). In smaller volumes such as 90 L, 1,200 L or 1.5 m 3 no virus was detected. Even directly in front of a COVID-19 patient it was not possible to detect the SARS-CoV-2 RNA in the air [95] . The viral RNA loads of the first confirmed case were 3.3×10 6 copies per mL in the pooled nasopharyngeal and throat swabs and 5.9×10 6 copies per mL in saliva on the day of air sampling [95] . The air samples of 1000 L were collected at a distance of 10 cm at the level of patient's chin while the patient performed 4 different manoeuvres (i.e., normal breathing, deep breathing, speaking "1, 2, 3" continuously, and coughing continuously) while putting on and putting off the surgical mask were all undetectable for SARS-CoV-2 RNA [95] . Nosocomial transmission of SARS-CoV-2 by an airborne route has been described to be very unlikely [96] . Nonetheless, SARS-CoV-2 can remain infectious in air for 3 h measured in a Goldberg drum with a decline of viral load from 3.5 log10 to 2.7 log10 per litre of air [97] . In a subset of 4 study participants with a symptomatic seasonal coronavirus infection but without any coughing during the 30 min exhaled breath collection no coronavirus RNA was detected in respiratory droplets or aerosols [92] .

Other aspects influencing droplet or airborne transmission are temperature and humidity because they correlate with the spread of and deaths associated with COVID-19 [98] [99] [100] . In China, the number of confirmed cases increased with higher temperature and higher humidity in most of the provinces [101, 102] . COVID-19 lethality significantly worsened (4 times on average) with environmental temperatures between 4 °C and 12 °C and relative humidity between 60% and 80% [103] . Biktasheva et al., however, described that the COVID-19 mortality correlates with low air humidity, probably caused by a lower resistivity of dry or very dry mucous membranes [104] . Huang et al. described that 60% of all COVID-19 cases are found in places with an air temperature between 5 °C and 15 °C [105] . In Brazil a 1 °C increase in temperature has been associated with a decrease in confirmed cases of 8% [106] . In Wuhan and Xiaogan temperature was the only meteorological parameter constantly but inversely correlated with COVID-19 incidence [107] . At low temperature and low humidity, droplets tend to remain suspended in air [108] . High relative humidity will increase the droplet sizes due to the hygroscopic growth effect, which increases the deposition fractions on both humans and the ground [109] . Overall, a seasonal pattern of COVID-19 is very likely.

SARS-CoV-2 aerosolized from infected patients and deposited on surfaces could remain infectious outdoors for considerable time during the winter in many temperate-zone cities, with continued risk for re-aerosolization and human infection [110] . Conversely, SARS-CoV-2 should be inactivated in the environment relatively fast during summer in many populous cities of the world, indicating that sunlight should have a role in the occurrence, spread rate, and duration of coronavirus pandemics [110] . Simulated sunlight has been described to rapidly inactive SARS-CoV-2 [111, 112] .

Indoor transmission of SARS-CoV-2 is much more likely compared to outdoor transmission [113] . In a closed seafood market, the risk of a costumer to acquire SARS-CoV-2 infection via the aerosol route after 1 h exposure in the market with one infected shopkeeper was about 2.23 × 10 − 5 . The risk rapidly decreased outside the market due to the dilution by ambient air J o u r n a l P r e -p r o o f and became below 10 − 6 at 5 m away from the exit [114] . Outdoor, these virus particles are very strongly diluted by the open air [115] .

Some patients displayed diarrhoea at the beginning or during the course of infection suggesting that SARS-CoV-2 may also affect the gastrointestinal tract. Viral RNA was detected in a proportion between 9.1% and 100% in COVID-19 patients with up to 8.1 log10 viral copies per g (Table V) . One study including 46 patients with 16 of them reporting gastrointestinal manifestations (35%) reported diarrhea as the most common symptom (15%), followed by abdominal pain (11%), dyspepsia (11%), and nausea (2%) [116] . Analysing two groups of overall 12 patients, none of the stool samples resulted in successful virus isolation in cell culture, irrespective of viral RNA concentration [7, 117] . In contrast, one study described the successful isolation of virus by cell culture from 2 out of 3 patients [118] . Of note, another study showed higher viral RNA loads in fecal samples of mildly symptomatic or asymptomatic children compared to nasopharyngeal swabs [119] . These results indicate the possibility of fecal-oral transmission or fecal-respiratory transmission through aerosolized feces. Furthermore, the presence of SARS-CoV-2 RNA in bile juice was reported from one patient and speculated that RNA in fecal specimens may partly originate from bile juice [120] . Finally, a recent study suggested that detectable SARS-CoV-2 RNA in the digestive tract could be a potential warning indicator of severe disease [121] , however further evidence will be needed.

Transmission of SARS-CoV-2 through the ocular surface was considered to be possible [122] . Conjunctivitis has been reported in a patient in the middle phase of COVID-19, the conjunctival swab specimens remained positive for SARS-CoV-2 on 14 and 17 days after onset and were negative on day 19 [123] . Another study showed among 30 COVID-19 patients that the virus was detected in tears and conjunctival secretions only in the one patient with conjunctivitis [124] . Furthermore, in another group of 38 COVID-19 patients two of them were identified with positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens, a total of 12 patients had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions [125] . In addition, no virus was detected on the conjunctiva in 5 other COVID-19 patients [11] . One patient was described with persistent conjunctivitis with viral RNA detection until day 27 after symptom onset and confirmation of infectious virus in the first RNA-positive ocular sample [126] . Even though the virus can be detected rarely in the conjunctival sac at very low levels [127, 128] , there is no evidence that it can replicate locally [129] . That is why the conjunctiva were considered not to be the preferred gateway into the respiratory tract [130] .

A study analysed human post-mortem eyes for the expression of ACE2 (the receptor for SARS-CoV-2) and TMPRSS2. In all samples the expression of ACE2 and TMPRSS2 was detected in the conjunctiva, limbus, and cornea, with especially prominent staining in the superficial conjunctival and corneal epithelial surface [131] . In contrast, another study from Germany found no relevant conjunctival expression of the ACE2 receptor on mRNA and protein levels [132] . In summary, the detailed pathophysiology of ocular transmission of SARS-CoV-2 remains not completely understood [133] and both the presence of viral particles in tears and conjunctiva, and the potential for conjunctival transmission remains controversial [134] . In conclusion, spread of COVID-19 from ocular secretions cannot be ruled out but seems to be very unlikely.

Indirect transmission of COVID-19 has been assumed to be possible via fomites although direct evidence is currently not available [135] . In hospitals some data were collected to describe the frequency of detection of SARS-CoV-2 RNA on inanimate surfaces in the immediate patient surrounding. The detection rate was variable on ICU surfaces (0% -75%), in isolation rooms (1.4 -100%) and on general wards (0% -61%). The mean virus concentration per swab were 4.4 -5.2 log10 on ICUs and 2.8 -4.0 log10 on general wards. A positive correlation between patient viral RNA load and positivity rate of surface samples was described [136] . However, on cleaned and disinfected surfaces viral RNA could mostly not be detected (Table VI) . Detection of viral RNA on the floor is indicative for sedimentation of contaminated droplets.

Surfaces outside the COVID-19 patient room were also investigated. On ICU the virus was rarely detected as "weak positive" on the floor and on door knobs in 3 buffer rooms, 6 dressing rooms and a nurse station (6 of 84 samples; 7.1%) [137] . On the general ward the virus was rarely detected on the patient floor (23 samples; one "weak positive" result on the computer mouse or keyboard) and never detected on doorknobs and the floor in 3 buffer rooms and 5 dressing rooms (52 samples) [138] . Viral RNA could be detected even 28 d after discharge of COVID-19 on surfaces of pagers and in drawers of the isolation wards. The relevance of finding, however, is not clear because it is not known if infectious virus was present at that time [139] .

In a microbiology laboratory the detection rate on surfaces was 18.2%. In the domestic environment of SARS-CoV-2 carriers the detection rate on surfaces was overall low (0% -3.4%; Table VI) .

It has to be mentioned that in most studies only PCR was performed for RNA. But detection of viral RNA on surfaces does not provide any information about viral infectivity or viability [140] . New findings from a COVID-19 cohort in Gangelt, Germany, and with cases in Italy provide data on the detection of infectious SARS-CoV-2 on surfaces. Although viral RNA was detected in 3.4% of 119 surface samples in 21 households of confirmed COVID-19-cases and on 7.7% of sampled surfaces around COVID-19-cases in Italy, infectious SARS-CoV-2 was not found in any sample [141, 142] . Similar findings were described with SARS-CoV and influenza-virus. In Canada, a total of 85 samples from inanimate surfaces were taken in a SARS-hospital. Viral SARS-CoV RNA was present in 5.6% of samples, but none of the samples revealed infectious virus [143] . In Thailand and Taiwan RNA of SARS-CoV was detected on 27.7% of 94 surface samples in a SARS-hospital or in a SARS-ward; in none of the samples infectious SARS-CoV was found [144] . Similar data were reported from 90 households with proven H1N1 influenza virus infections in children. Viral RNA was detected on 17.8% of inanimate surfaces but virus could never be cultured [145] .

In cell culture studies, SARS-CoV-2 has been described to remain infectious on stainless steel and plastic for 3 -4 d, on glass and banknote for 2 d, on wood for 1 d, all with a decrease of viral infectivity with time [97, 146] . In the close surrounding of COVID-19 patients in hospitals SARS-CoV-2 RNA is detected more frequently compared to surfaces outside the patient rooms but samples were so far consistently negative for infectious virus. If infectious SARS-CoV-2 may be detected in a relevant amount on various surfaces in the public when only a short exposure to potentially infected, may be even asymptomatic people exists, is currently unknown but very unlikely. Surfaces in air planes or trains in coughing or sneezing distance for potentially infected long-distance travellers may theoretically have a higher risk for contamination.

The RNA of SARS-CoV-2 has so far mainly been found on PPE used by healthcare workers on ICU (0% -50%), mainly on shoes and gloves. In other settings PPE was only very rarely contaminated with SARS-CoV-2 (Table VII) . All studies performed PCR assays for SARS-CoV-2 RNA detection.

Blood SARS-CoV-2 RNA has occasionally been detected in blood of COVID-19 patients, i.e. in 1 of 5 patients on days 7, 8, 9 and 12 after onset of disease [11] , in 5 of 23 COVID-19 patients (21.7%) [15] , in 0 of 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection [54] , or in 3 of 307 samples (1.0%) obtained from 205 COVID-19 patients [147] . SARS-CoV-2 RNA can very rarely (in 4 of 2430 samples) be detected in plasma during routine screening of blood donors considered to be healthy population [148] . Detection of SARS-CoV-2 RNA in blood is considered a strong indicator for further clinical severity [149] . So far, no cases of transmission due to transfusion of blood products have been reported for SARS-CoV, MERS-CoV, and SARS-CoV-2, and clinically ill patients are not considered as blood donors [54] . Therefore, no immediate risk can be derived for the transfusion system [54] . Based on the existing evidence, transmission of COVID-19 by handling potentially contaminated blood products (laboratory technician) or by contact with blood e.g. from a wound to intact skin is very unlikely.

SARS-CoV-2 RNA has occasionally been detected in urine swabs from patients. In 9 patients with confirmed SARS-CoV-2 infections one of the patients was positive for viral RNA in urine [150] . This observation is supported by observations among 12 SARS-CoV-2 positive children with 2 of them positive for viral RNA in urine (17%) [119] . Importantly, infectious virus could be detected from urine in one COVD-19 patient [151] . However, other studies with a total of 47 patients [7, 15, 152] failed to detect SARS-CoV-2 RNA in urine. These data indicate that urine might be a potential source of infection but further evidence is needed.

There is evidence that the main entry receptor of SARS-CoV-2, ACE2, is expressed in cells of the reproductive system [153, 154] . However, one study with 23 COVID-19 patients in the acute (12 patients) and recovery phase (11 patients) failed to detect viral RNA in semen [155] , indicating a low probability of sexual transmission through semen.

SARS-CoV-2 RNA has temporarily been detected in breast milk samples in one study in one of two infected mothers with approximately 10 5 viral copies per mL [156] . Similarly, the presence of viral RNA was reported in breast milk of an actively breastfeeding mildly symptomatic COVID-19 patient raising the possibility of a potential transmission from breast milk [157] .

So far, no evidence for transmission of the virus from pet animals to humans exists [158] . However, Shi et al. reported that ferrets and cats were highly susceptible to SARS-CoV-2, while dogs had a low susceptibility and livestock including pigs, chickens, and ducks were not susceptible to the virus, under experimental conditions [159] . One of 22 cats (France) and two of 10 cats (Wuhan) of COVID-19 patients has been described to have a SARS-CoV-2 infection with mild respiratory and digestive symptoms whereas all 11 dogs (France) and 8 of 9 dogs (Wuhan) were SARS-CoV-2 and serologically negative [160, 161] . Interestingly, viral transmission between cats has been observed [159] . Out of six naïve cats (three subadults and three juveniles), each exposed to a SARS-CoV-2 inoculated cat, transmission occurred in two cats (one cat of each age group). Similar findings were reported by Halfmann et al. [162] . This indicates that cats, being common companion animals, might theoretically transmit the virus to other animals and humans. However, there is so far no clear evidence that cat-to-human transmission of SARS-CoV-2 can occur.

Several practices are recommended with the aim to limit further transmission of SARS-CoV-2 in clinical practice but also public settings. These include hand washing, hand disinfection, wearing of face masks and gloves, disinfection of surfaces and physical distance. Based on an integrated theoretical and statistical analysis of the influence of individual variation in infectiousness on disease emergence it has been suggested that individual-specific control measures outperform population-wide measures [35] .

A hand soap solution (1:49) has been described to have some effect (≥ 3.6 log10 reduction of viral infectivity) against SARS-CoV-2 in 5 min [146] . For healthcare workers hand washing is only useful when hands are visibly soiled [163] . Although SARS-CoV-2 has never been detected on hands of the public population yet, it seems reasonable to assume that the hand contamination by droplets from others may take place in the public with an unknown viral load. Apart from avoiding hand-face-contacts in general, hand washing is first choice for the decontamination of hands, especially after returning home from public places with many close contacts to potentially infected people.

Ethanol and iso-propanol inactivate SARS-CoV-2 at concentration between 30% and 80% (both v/v) in 30 s [164] . Both WHO-recommended hand rubs based on 75% iso-propanol or 80% ethanol (both v/v) also inactivate SARS-CoV-2 in only 30 s [164] . Similar results were obtained with a propanol-based hand rub against SARS-CoV [165] . On clean hands use of an alcohol-based hand rub is first choice in healthcare for the decontamination of hands due to the better activity against nosocomial pathogens including bacteria and yeasts and a better dermal tolerance [163] . It may also be useful for COVID-19 patients, e.g. before leaving the patients room for examinations. In this situation it is reasonable to recommend a hand disinfection in order to reduce potential transmission by direct hand contacts. The routine use of alcohol-based hand rubs for the general population should be discouraged, since there are currently no clear indications when to use them. It may be useful if a contamination of hands with SARS-CoV-2 is likely and a hand washing facility is not available. Otherwise the widespread use of alcohol-based hand rubs may even enhance the shortage of the products in patient care which should be avoided by all means [166] .

Inadequate PPE including facemask at the beginning of the epidemic in China has resulted in infections and deaths among healthcare workers [167, 168] . Unprotected patient care with long and close contacts was also later a major risk for healthcare workers to acquire COVID-19 [169] . In COVID-19 cases face masks can at least reduce the viral spread. In 17 individuals with a symptomatic seasonal coronavirus infection a surgical face mask was able to reduce the proportion of viral RNA detection in droplets from 30% to 0% and in aerosols from 40% to 0% during 30 min exhaled breath collection suggesting a protective effect when worn by infected patients [92] . In another study 4 COVID-19 patients coughed 5 times in front of a petri dish (20 cm distance) with a surgical mask, a cotton mask or without a mask. Without a mask 2.6 log10 viral copies per mL were detected, with a surgical mask it was 2.4, and with a cotton mask 1.9 log10 viral copies per mL [170] . Household transmission was more likely when the primary case and other household members did not wear a mask at home resulting in the possibility of unprotected transmission [171] . Data on a protective effect of face masks when only worn by healthy subjects in an endemic COVID-19 setting are not available. Despite these results it was shown in South Korea that none of 35 HCWs with close contacts to a COVID-19 patient developed symptoms or were PCR positive in the nasopharynx although they only wore a surgical mask for more than ten minutes during activities including aerosol-generating procedures such as intubation [172] . In addition, one study could show that a 4 days surgical mask partition between cages reduces the risk of noncontact transmission between artificially infected and naïve golden Syrian hamsters [173] .

Importantly, a used face mask worn by a SARS-CoV-2 spreader will be contaminated. After only 5 coughs all surgical or cotton face masks worn by COVID-19 patients were contaminated on the outer surface whereas samples from the inner surface were mostly negative [170] . Chin et al. found that the virus can remain infectious or detectable for up to 7 days on the outer layer of a surgical mask, on the inner layer for 4 days [146] . Although the results are only based on three independent triplicates, this finding should have implications for the re-use of face masks in a shortage situation [166] .

Wearing a face mask is recommended for healthcare workers in case of suspected or confirmed COVID-19 patients [2, 174] although it was described in Hong Kong that 11 of 413 HCWs had unprotected exposure to confirmed COVID-19 cases, none of these were infected [95] . Wearing a face mask may also be useful for HCWs when mild respiratory symptoms occur because in the Netherlands 4.1% of such healthcare workers were positive for SARS-CoV-2 [175] . Even universal masking in hospitals by healthcare workers has been proposed although the expected effect was described as marginal [176] .

Suspected and confirmed COVID-19 cases should wear a face mask to prevent the spread of infectious droplets [2] .

So-called mass masking has been proposed as a considerable option [177, 178] . Many countries have recommended or legally ordered the use of fabric masks or face coverings for the general public. The WHO, however, acknowledged that the widespread use of masks by healthy people in the community setting is not yet supported by high quality or direct scientific evidence and that there are potential benefits and harms to consider [179] . But in areas of known or suspected widespread community transmission and limited or no capacity to implement other containment measures, governments should encourage the general public to wear masks in specific situations and settings [179] . Some recent studies suggest that general face mask usage by the healthy population in the community reduces the risk of transmission [180, 181] . But in order to evaluate only the effect of masks worn by healthy people in the community on the prevention of transmission in a country or region, some relevant variables with a proven impact on transmission should have been considered for the study period: the seasonal effect on the incidence (similar weather conditions), the main mode of transmission during the period of observation (mainly local clusters or mainly transmission in buildings or mainly transmission in the public), the total number of new cases in the observation period (mass masking in a region with 1 new case per day may have a different effect compared to a region with 10.000 new cases per day) and the extent of community lockdown (the less people are in the public the less likely a protective effect of general masks can be expected). In an endemic population scenario without restrictions regarding physical distance and close or long face-to-face contacts it may indeed be useful, especially for the part of the population which has a high risk for a severe COVID-19 infection. It is, however, a controversial debate among the scientific community if any additional protective effect by mass masking is expectable if a minimum distance between people is assured (e.g. 2 m) and contacts are only of short duration.

Gloves can partially prevent the contamination of the hands with specific pathogens or all types of bioburden [182] . However, at the same time wearing gloves is associated in hospitals with a lower compliance in hand hygiene [183, 184] . Use of gloves is recommended for HCWs in specific patient care activities, e.g. when soiling of the hands is expected and when caring for COVID-19 patients [2, 163] . If there is any protective effect by wearing gloves by the general population in the public is speculative. One aspect is that wearing gloves may result in more awareness too reduce face hand contacts. And yet it seems reasonable not be encourage the general population to routinely wear gloves in the public.

Even if a hand contact yields a transient contamination with SARS-CoV-2 on the hands it does not make a difference if the virus is found on the bare or gloved hand; the essential preventive measure in this case is to avoid hand-face contacts and to wash hands when returning from the public. The resident hand flora is even able to provide some colonisation resistance in contrast to the glove [185] . If wearing gloves by the general population has a similar effect on hand hygiene compliance as it has been described for healthcare workers wearing gloves in the public may even have the unwanted effect of less hand washing potentially increasing the risk of transmission via hands.

Some surface disinfectant agents have been described to inactivate SARS-CoV-2 in 30 s such as ethanol and iso-propanol (30% -80%, v/v) [164] . In 5 min household bleach (1:49 and 1:99) and 0.1% benzalkonium chloride were also very effective against SARS-CoV-2 [146] . Limited data from surface samples in COVID-19 settings support their efficacy [186, 187] . In healthcare settings routine cleaning and disinfection of surfaces with which the patient is in contact is recommended [2] . So far, no studies were reported to address if SARS-CoV-2 (viral RNA or infectious virus) may be found on public inanimate surfaces. Disinfection of surfaces in a household with chlorine-or ethanol-based products can reduce the risk of transmission when the primary case has diarrhoea [171] . The frequent use of household disinfectants also results in a remarkable increase of exposures reported to US poison centers, especially via ingestion in the age group between 0 and 5 years [188] . General disinfection of frequently touched surfaces in the public such as shopping carts or door handles is, however, unlikely to add any protective value because even in COVID-19 wards inanimate surfaces were mainly contaminated in the permanent and immediate surrounding of symptomatic patients (detection of viral RNA, not of infectious virus) and only rarely one room away [138] suggesting that the risk to find SARS-CoV-2 on frequently touched surfaces in the public is low. Future research will hopefully clarify the role of public inanimate surfaces for the spread of SARS-CoV-2.

Close and long contacts are probably the main risk for transmission of SARS-CoV-2 from asymptomatic or symptomatic patients to healthy people as shown in clusters in families, a cruise ship, hospitals and nursing homes [189] . The mode of transmission is very likely by droplets during coughing, sneezing or talking. The risk of long and close contacts is supported with experimental data obtained with 8 syrian hamsters which were inoculated with 10 5 viral copies in 100 µL intranasally. 24 h later each hamster was transferred to a new cage with one naïve hamster as close contact. SARS-CoV-2 was detected in nasal secretions, trachea and lung after 4 days in all naïve contact hamsters [190] .

Physical distancing is another option to slow down the spread of SARS-CoV-2. Early data from China suggests that quarantine, physical distancing, and isolation of infected populations can flatten the epidemic [191] . So far, there are no "real-life" data which provide conclusive evidence regarding effectiveness of physical distancing interventions. However, in a simulation model the likelihood of SARS-CoV-2 human-to-human transmission in a Singaporean population was predicted [192] . They could demonstrate that the combined intervention, in which quarantine, school closure, and workplace distancing were implemented, was the most effective compared with the baseline scenario of no interventions, which reduced the estimated median number of COVID-19 infections by 99.3% when R 0 was 1.5, by 93.0% when R 0 was 2.0, and by 78.2% when R 0 was 2.5 [192] . Nevertheless, an evaluation of the effect of physical distancing alone is currently not possible. Maintaining a physical distance of at least 1 m from other individuals is regarded as one of the most effective preventive measures by the WHO [193] .

Günter Kampf has received personal fees from Dr. Schumacher GmbH, Germany, for presentation and consultation. Yannick Brueggemann, Hani E. J. Kaba, Joerg Steinmann, Stephanie Pfaender, Simone Scheithauer and Eike Steinmann have no conflicts of interest. [5] cps = copies per whole swab or sample; cpc = copies per 1000 cells; cpm = copies per ml; *mean; **3 patients with negative RNA test in saliva. 

- [208] cps = copies per swab; cpm = copies per ml; *proportion of room with at least one environmental surface contaminated; **door handles; ***after cleaning and disinfection; ****detection of infectious SARS-CoV-2 was attempted in all samples and was consistently negative; *****only on ventilator tubing before HME filter.

J o u r n a l P r e -p r o o f (133) 11.3%** Unknown [223] cps = copies per swab; *indicating a low viral RNA load; **mainly on the top of the head and the foot dorsum.

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J o u r n a l P r e -p r o o f [196] J o u r n a l P r e -p r o o f [198] *no absolute numbers reported; **first survey; ***second survey two weeks later.J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f samples significantly higher than for nasopharyngeal swab specimens cpm = copies per ml; cpg = copies per g; cps = copies per whole swab; PFU = plaque forming units.