key: cord-0708961-x3calf45
authors: Roh, K. H.; Kim, Y. K.; Kim, S.-W.; Kang, E.-R.; Yang, Y.-J.; Jung, S.-K.; Lee, S.-H.; Sung, N.
title: Coinfection with Respiratory Pathogens in COVID-19 in Korea
date: 2020-12-19
journal: nan
DOI: 10.1101/2020.12.18.20248449
sha: 3a3e5bb28389d823ca205d28a20cfb9abf74f446
doc_id: 708961
cord_uid: x3calf45

Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in upper and lower respiratory specimens and coinfection with other respiratory pathogens in patients with coronavirus disease 2019 (COVID-19) were investigated. From the study subjects (N = 258) retrospectively enrolled when confirmed as SARS-CoV-2 positive, nasopharyngeal (NPS), oropharyngeal swabs (OPS), and sputum specimens were restored for retesting SARS-CoV-2 and detecting respiratory pathogens. Majority of the study subjects (95.7%, N = 247) were confirmed as SARS-CoV-2 positive using NPS/OPS specimens, suggesting that the upper respiratory specimen is most valuable in detecting SARS-CoV-2. Coinfection rates in COVID-19 patients (N = 258) with respiratory pathogens were 9.7% (N = 25); 8.5% (N = 22) respiratory viruses and 1.2% (N = 3) Mycoplasma pneumoniae, an atypical bacterium. Of the respiratory virus coinfection cases (N = 22), 20 (90.9%) were co-infected with a single respiratory virus and 2 (0.8%) (metapneumovirus/adenovirus and rhinovirus/bocavirus 1/2/3/4) with two viruses. Respiratory viruses in single viral coinfection cases with SARS-CoV-2 were as follows: non-SARS-CoV-2 coronaviruses (229E, NL63, and OC43, N = 5, 1.9%), rhinovirus (N = 4, 1.6%), metapneumovirus (N = 3, 1.2%), influenza A (N = 3, 1.2%), respiratory syncytial virus A and B (N = 3, 1.2%), and adenovirus (N = 2, 0.8%). No mixed coinfections with respiratory viruses and M. pneumoniae were found. In conclusion, the diagnostic value of utilizing NPS/OPS specimen is excellent, and, as the first report in Korea, coinfection with respiratory pathogens were detected at a rate of 9.7% in patients with COVID-19.

Mycoplasma pneumoniae, an atypical bacterium. Of the respiratory virus coinfection 48 cases (N = 22), 20 (90.9%) were co-infected with a single respiratory virus and 2 (0.8%) 49 (metapneumovirus/adenovirus and rhinovirus/bocavirus 1/2/3/4) with two viruses. 50 Respiratory viruses in single viral coinfection cases with SARS-CoV-2 were as follows: 51 non-SARS-CoV-2 coronaviruses (229E, NL63, and OC43, N = 5, 1.9%), rhinovirus (N = 52 4, 1.6%), metapneumovirus (N = 3, 1.2%), influenza A (N = 3, 1.2%), respiratory syncytial 53 virus A and B (N = 3, 1.2%), and adenovirus (N = 2, 0.8%). No mixed coinfections with 54 respiratory viruses and M. pneumoniae were found. In conclusion, the diagnostic value 55 of utilizing NPS/OPS specimen is excellent, and, as the first report in Korea, coinfection 56 with respiratory pathogens were detected at a rate of 9.7% in patients with COVID-19.

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The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 Introduction 75 COVID-19, caused by the infection of SARS-CoV-2, was identified as a cluster of 76 pneumonia cases in Wuhan, China, in December 2019 , and has spread to other countries 77 since then, resulting in 42 million cases and over 1.1 million deaths globally as of October 78 25, 2020 (1). 79 In Korea, a Chinese female from Wuhan, China, was identified as the first COVID-80 19 case on January 19, 2020, during the quarantine inspection at Incheon airport (2).

Suspects with respiratory symptoms and/or a history of travel to other countries, including 82 China, were asked to test for SARS-CoV-2 infection, causing exponential growth by 83 conducting real-time PCR (RT-PCR) tests to identify COVID-19 using emergency use 84 authorized (EUA) in vitro diagnostics (IVD) assays (3). 85 For the fast and accurate diagnosis of SARS-CoV-2 using IVD assays, the 86 selection of appropriate types of specimens collected from patients at the right time would 87 be an important factor (4). It has been reported that lower respiratory specimens such as 88 bronchoalveolar lavage fluid and sputum have been recommended as the best clinical 89 respiratory specimens for detecting SARS-CoV-2 (5, 6). Viral loads of SARS-CoV-2 were 90 higher in nasal swabs than those in throat swabs collected from symptomatic COVID-19 91 patients (7). The Centers for Disease Control and Prevention recommended upper 92 respiratory specimens as acceptable for initial diagnostic testing of SARS-CoV-2 in the 93 types of nasopharyngeal swab (NPS), oropharyngeal swab (OPS), nasal swab, and saliva 94 (8). Simultaneous collection and placement of NPS and OPS in a universal transport 95 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 6 medium (UTM) tube using two sets of swabs is recommended to increase sensitivity in 96 real-time polymerase chain reaction (RT-PCR) assays in Korea, as long as the supply of 97 flocked swabs is not limited (9). We analyzed the number of patients with COVID-19 that 98 were confirmed as positive using NPS/OPS by measuring the detection rates of SARS-99 COV-2 among the patients diagnosed during the screening process in the first outbreak 100 of the disease in Korea.

The IVD assays for detecting SARS-CoV-2 were not incorporated for testing 102 coinfections with other respiratory pathogens at the time of screening COVID-19 suspects.

Recently, coinfections in COVID-19 have been reported not to neglect infections by other 104 respiratory pathogens in addition to . This suggests that 105 simultaneous testing for coinfections between SARS-CoV-2 and other respiratory 106 pathogens would be required to provide a better patient treatment during the COVID-19 107 pandemic (15).

Among the respiratory pathogens, including tuberculosis, virus and bacteria have 109 been predominantly reported as coinfection agents in COVID-19, as seen in the previous 110 influenza pandemic (10, 12, 16, 17) . 

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The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 In this study, we simultaneously detected frequently reported respiratory viruses 117 and atypical bacteria in clinical specimens collected from patients with COVID-19 to 118 identify coinfection rates using RT-PCR-based commercial assays. Upper (NPS and OPS) 119 and lower (sputum) respiratory tract specimens were employed to investigate the 120 coinfections with respiratory pathogens when COVID-19 was confirmed as positive during 121 the screening process.

This study reports simultaneous detection of SARS-CoV-2 and coinfection with 123 respiratory pathogens (viruses and atypical bacteria) using commercially available RT-124 PCR assays among COVID-19 patients confirmed during the first outbreak in Korea. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint containing a UTM to increase test sensitivity (9, 18, 19) . 149 We reviewed the request forms and enrolled study subjects who were COVID-19 150 positive for fever ( > 37.5°C) and cough because these two respiratory symptoms were 151 reported as the most common (10, 16). The respiratory specimens (UTM containing 152 NPS/OPS as upper respiratory specimen and sputum as lower respiratory specimen) of 153 the study subjects were restored from storage freezers (-70°C) and applied to extract 154 nucleic acids to reconfirm SARS-CoV-2 and detect respiratory pathogens simultaneously. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 Specimen preparation and nucleic acid extraction 157 Specimens collected from the enrolled study subjects were subjected to nucleic 158 acid extraction as described below for detecting SARS-CoV-2 and respiratory pathogens. 

To detect SARS-CoV-2, a commercial RT-PCR assay (Allplex TM 2019-nCoV Assay, 175 Seegene Inc., Seoul, Republic of Korea) was employed in this study. Briefly, the extracted 176 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 nucleic acids (8 µL) were mixed with reagents of the commercial RT-PCR assay, such as 177 primers and probes for specifically detecting three target genes of the virus [envelope 

The nucleic acids extracted from the specimens of the study subjects were also 185 applied to simultaneously detect respiratory pathogens using commercially available CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

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The statistical significance of the difference in detection rates of respiratory 199 pathogens was analyzed using the Chi-square test or Fisher's exact test. The mean value Ethics statement 206 We retrospectively analyzed the request forms and RT-PCR assay results of the 207 study subjects, which were exempted from informed consent. This study was approved CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

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Study subject enrollment 218 A total of 258 study subjects with fever and cough were enrolled in this study. After subjects who were SARS-CoV-2 positive and had fever (higher than 37.5°C) and cough 226 were enrolled.

The mean age ± standard error of the mean (SEM) of the study subjects was 48.5 indicates that SARS-CoV-2 was mostly detected at the age of 40-59 y in this study.

The ratio of males and females was 41.1% (N = 106) and 58.9 % (N = 152), 234 respectively. Residence area of the study subjects were predominantly Kyungpook CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint for the E gene came first, RdRP gene second, and N gene third in the Allplex 2019-nCoV 261 assay applied in this study, and the differences (delta) of the mean Ct values for E, RdRP, 262 and N genes between NPS/OPS and sputum were 1.0, 1.0, and 1.5, respectively. The respectively) from those (21.2 ± 0.4, 22.6 ± 0.4, and 24.5 ± 0.4, respectively) in sputum 272 (P < 0.0001) (Fig. 2 B) . However, as shown in Figure 2 C, the mean Ct values (23.2 ± 2.8, 273 24.9 ± 2.6, and 26.0 ± 2.8, respectively) for the E, RdRP, and N genes in the study 274 subjects who were SARS-CoV-2 positive in NPS/OPS but negative in sputum (2.3%, N = 275 6) were significantly lower than those (31.7 ± 1.3, 22.6 ± 1.3, and 24.5 ± 1.2, respectively) 276 who were SARS-CoV-2 positive in sputum but negative in NPS/OPS (4.3%, N = 11) (P ≤ 277 0.0145). The Ct values and viral load of SARS-CoV-2 are inversely proportional; therefore, 278 the viral loads of SARS-CoV-2 in sputum were significantly lower than those in NPS/OPS.

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The viral loads of SARS-CoV-2 may influence the difference in the detection rates of the 280 virus between NPS/OPS and sputum.

The patients in whom NPS/OPS specimens were positive although sputum was 282 not submitted (39.5%, N = 102) (Fig. 1) , the mean Ct values (20.0 ± 0.5, 21.4 ± 0.5, and 283 22.6 ± 0.5, respectively) for E, RdRP, and N genes in NPS/OPS specimen (Fig. 2 D) were and RSV, Adv, and non-SARS-CoV-2 coronaviruses were detected only in sputum (Table   303 1). Notably, four cases of coinfection (two patients with Flu A and two with HRV) provided 304 only NPS/OPS specimens without sputum ( Table 1) . The data in this study suggest that 305 both types of specimens should be employed for detecting coinfections with respiratory 306 pathogens in COVID-19.

All cases of respiratory bacterial coinfection (N = 3; male:female = 2:1) were M. 308 pneumoniae detected in both NPS/OPS and sputum specimens without any other atypical 309 bacteria detected in this study (Table 1) . Additionally, no mixed coinfection of viruses and 310 bacteria among the study subjects was observed.

The ratio of males to females in the coinfection cases was 4:6 ( Table 1) , but no 312 difference in coinfection by sex was observed (P > 0.05), suggesting that both men and 313 women confirmed that COVID-19 would be susceptible to respiratory pathogens at the 314 same level.

The mean age of coinfection cases (N = 25, 9.7%) with respiratory pathogens 316 (both virus and bacteria) was 38.4 ± 3.3 y, which was significantly lesser than the mean 317 age (49.6 ± 1.0) of patients without coinfections (P = 0.0009). The mean ages for viral (N 318 = 22) and bacteria (N = 3) coinfection cases were 39.2 ± 3.6 y and 32.0 ± 6.0 y, 319 respectively, which were not statistically significant (P = 0.4841) ( Table 1) . Most of the 320 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248449 doi: medRxiv preprint coinfection cases resided in Kyungpook Province, except two cases (coinfections of Adv 321 and HRV in Kyunggi Province and Seoul, respectively) ( Table 1) CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 for the genes specific to SARS-CoV-2, higher viral loads of SARS-CoV-2 were observed 354 in NPS/OPS than in sputum (Fig. 2) , which would support the excellent detection rates of 355 SARS-CoV-2 in NPS/OPS (Fig. 1) . This suggests that NPS/OPS would be the most 356 valuable for diagnosing SARS-CoV-2 in molecular diagnosis assays, and it would not be 357 necessary to enforce sampling sputum specimens, especially when the patients were not 358 able to expectorate. However, in previous studies, sputum specimens were considered a 359 better choice than nasal samples for the molecular detection of SARS-CoV-2. Pan et al.

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The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 (6) measured the viral loads of SARS-CoV-2 from two COVID-19 patients at the early 361 stage of onset of symptoms in throat, sputum, urine, and stool. They found that the viral 362 loads were higher in sputum samples than in throat samples, especially in the early days were detected as similar to or sometimes higher than those in sputum using RT-PCR (24).

Coinfection rate in patients with COVID-19 (N = 258) with respiratory pathogens 376 was 9.7% (N = 25) in the current study (Table 1 and (Table 1 ). This suggests that both upper and lower respiratory tract 394 specimens would be recommended to monitor the coinfection with respiratory pathogens 395 in COVID-19. This is consistent with a previous report by Zhu et al. (14) , who suggested 396 that for detecting coinfections with respiratory pathogens in COVID-19, both upper and 397 lower respiratory tract specimens should be collected and considered to test while 398 diagnosing and treating COVID-19.

Based on a meta-analysis by Lansbury et al. (12) with the previously reported 400 studies regarding types of co-infected respiratory viruses in patients with SARS-CoV-2, 401 the most common co-infecting virus was RSV, followed by Flu A, HRV, PIV, and other 402 coronaviruses. A study in China, which was not included in the meta-analysis, consistently 403 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248449 doi: medRxiv preprint 21 reported that RSV was most commonly detected among the coinfection viruses in COVID-404 19 patients diagnosed between January 19 and February 26, 2020 (15). However, in the 405 USA, Kim et al. (21) and Richardson et al. (25) detected rhinovirus/enterovirus as the 406 most common coinfection agent in their study, followed by RSV among the study subjects 407 enrolled in March 2020. In this study with Korean study subjects enrolled in February 408 2020, the most common respiratory virus as the coinfection agent was HRV [1.9 %, N = (Table 1) .

SARS-CoV-2 and influenza coinfection was relatively rare in three patients (1.2%) 414 among the study subjects (N = 258) ( Table 1) . This finding is also consistent with previous 415 studies, such as 0.54% in Turkey (13), 0.9% (21) and 2.4% (25) in the USA, and from 416 1. 15, 27, 28) .

Among the atypical bacteria tested in this study, only M. pneumoniae was 418 detected at the level of 1.2% (N = 3) of the study subjects (N = 258) ( Table 1 ). In some 419 other studies, however, C. pneumoniae, another atypical bacterium, was nominated as 420 the coinfection agent in patients with 15, 25) .

The coinfection rates in the above studies for M. pneumoniae and C. pneumoniae ranged 422 from 1.6%-4.8% and 2.5%-5.2%, respectively. Lansbury et al. (12) emphasized, in their 423 meta-analysis study, that M. pneumoniae was the most common bacteria detected in 424 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 22 patients with COVID-19 having coinfections with respiratory bacterial pathogens, followed 425 by P. aeruginosa, H. influenza, Klebsiella pneumoniae, and Chlamydophila spp., 426 suggesting that in addition to coinfection by atypical bacteria, other respiratory bacteria 427 were also the candidates as co-infecting agents in COVID-19.

Unlike Kim et al. (21) , who reported no difference in age between coinfection and 429 SARS-CoV-2 only (non-coinfection), the mean ages between them were significantly 430 different in this study (38.4 ± 3.3 y vs. 49.6 ± 1.0 y, respectively; P = 0.0009). This 431 suggested that young ages were more susceptible to coinfection with respiratory 432 pathogens in this study.

The viral loads of SARS-CoV-2 between the patients with coinfection and SARS-

CoV-2 only infection were not significantly different as Ct values for the target genes (E, 435 RdRP, and N) were statistically the same between them when the Allplex 2019-nCoV 436 assay was applied (P > 0.05). This suggests that the viral load of SARS-CoV-2 is not 437 responsible to cause coinfection with respiratory pathogens.

The current study has a few limitations. The effect of coinfection on the treatment 439 outcomes of COVID-19 patients enrolled in this study is unavailable. The study subjects 440 in this study were retrospectively enrolled during the process of screening COVID-19 in 441 the region of the first outbreak in Korea. Thus, the scope of this study was to investigate 442 the coinfection rates of respiratory pathogens among patients with COVID-19, not 443 hospitalized, but diagnosed as positive during the screening process for SARS-CoV-2.

Additionally, the results of the study cannot represent the coinfection rates for the winter 445 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 

All authors have no potential conflicts of interest to disclose for this study. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

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Ct values among the study subjects (N=102) classified as positive for SARS-CoV-597 2 in NPS/OPS even though sputum specimen were not submitted

Ct: Cycle threshold, SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, 600 NPS: Nasopharyngeal swab, OPS: Oropharyngeal swab, E: Envelope protein gene

Nucleocapsid protein gene 602 * indicates significantly different; differences in Ct values of E gene, RdRP gene, and N 603 gene between SARS-CoV-2 positive in NPS/OPS but negative in sputum (N = 6) and 604 negative in NPS/OPS but positive in sputum

The authors appreciate Prof. Doosu Jeon at Busan National University Yangsan 467 Hospital for his critical review and comments. This research was funded in part by the 468

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. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101/2020.12.18.20248449 doi: medRxiv preprint It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The numbers of coinfection cases based on the age distributions were 1 (0.4%), 11 (4.3%), 619 11 (4.3%), and 2 (0.8%) for ages below 20, between 20 and 39, between 40 and 59, and 620 above 60, respectively. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted December 19, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020