key: cord-0827253-0ga5rel6 authors: Xing, Quansheng; Li, Guoju; Xing, Yuhan; Chen, Ting; Li, Wenjie; Ni, Wei; Deng, Kai; Gao, Ruqin; Chen, Changzheng; Gao, Yang; Li, Qiang; Yu, Guiling; Tong, Jianning; Li, Wei; Hao, Guiliang; Sun, Yue; Zhang, Ai; Wu, Qin; Li, Zipu; Pan, Silin title: Precautions are Needed for COVID-19 Patients with Coinfection of Common Respiratory Pathogens date: 2020-03-03 journal: nan DOI: 10.1101/2020.02.29.20027698 sha: 0b460e73926eb107001c95c0dfeae2362b4251b0 doc_id: 827253 cord_uid: 0ga5rel6 Background: With the ongoing outbreak of Coronavirus Disease 2019 (COVID-19), infected patients within and beyond the epidemic area, Wuhan, China, showed different epidemiological and clinical characteristics. There is a paucity of data concerning coinfection with other common respiratory pathogens in COVID-19 patients outside of Wuhan. Methods: We conducted a double-centre study recruiting 68 patients with severe acute respiratory coronavirus 2 (SARS-CoV-2) infection confirmed by nucleic acid testing in Qingdao and Wuhan from January 17 to February 16, 2020. Indirect immunofluorescence was performed to detect the specific IgM antibody against common respiratory pathogens in collected acute phase serum. Results: Of the 68 patients with SARS-CoV-2 infection, 30 (44.12%) were from Qingdao. The median age of Qingdao and Wuhan patients were 50 (IQR: 37-59) and 31 (IQR: 28-38) years, respectively, and the majority of patients were female in Qingdao (60.00%) and Wuhan (55.26%). Among COVID-19 patients in Qingdao, 24 (80.00%) of them had IgM antibodies against at least one respiratory pathogen, whereas only one (2.63%) of the patients in Wuhan had positive results for serum IgM antibody detection (P<0.0001). The most common respiratory pathogens detected in Qingdao COVID-19 patients were influenza virus A (60.00%) and influenza virus B (53.33%), followed by mycoplasma pneumoniae (23.33%) and legionella pneumophila (20.00%). While the pattern for coinfection in patients with community-acquired pneumonia in Qingdao was quite different, with a positive rate of only 20.90%. Interpretation: We reported a large proportion of COVID-19 patients with coinfection of seasonal respiratory pathogens in Qingdao, northeast China, which differed greatly from the patients in Wuhan, central China. Precautions are needed when dealing with COVID-19 patients beyond the epidemic centre who have coinfection with other respiratory pathogens. We highly recommend adding SARS-CoV-2 to routine diagnostic testing in capable hospitals to prevent misdetection of the virus. At the beginning of December 2019, a cluster of "pneumonia of unknown aetiology" emerged in Wuhan, Hubei Province, China. The disease has soon developed into an outbreak posing a pandemic threat. Since no causative pathogen was identified at the onset of the disease, it was once called "Wuhan pneumonia" by the health officials and the public. On December 31, 2019, a total of 27 cases were reported; meanwhile, a rapid response team led by the Chinese Centre for Disease Control and Prevention (China CDC) was formed to conduct detailed epidemiologic and aetiologic investigations in Wuhan. 1 Laboratories in Qingdao and Wuhan adopted a similar protocol for detection of IgM- Raw data were entered by two persons (double data entry) who were not aware of the arrangement of study groups. Continuous variables (non-normal distribution) were expressed All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint as median with interquartile range (IQR) and compared with the Mann-Whitney U test; categorical variables were presented as number (%) and compared by χ ² test or Fisher's exact test between Wuhan and Qingdao groups. A two-sided α of less than 0.05 was considered statistically significant. Statistical analyses were done using the SAS software, version 9.4. By February 16, 2020, a total of 68 patients with laboratory-confirmed SARS-CoV-2 infection was included in the final analysis, among whom 30 were from Qingdao and 38 were from Wuhan ( Table 1 All patients had respiratory specimens tested for specific IgM antibodies against IFV-A, IFV-B, RSV, ADV, PIV, MP, LP, CP and COX. Among the 30 patients admitted in Qingdao, 24 patients had IgM antibodies detected against at least one of the above-mentioned pathogens, and the overall positive rate was 80.00% (Table 3) ; whereas only one (2.63%) of the patients in Wuhan had positive results for respiratory pathogens. The most common respiratory viruses detected were IFV-A (60.00%) and IFV-B (53.33%), followed by MP (23.33%) and LP (20.00%). Ages of healthy control group ranged from 20 to 55 years, with a median age of 40 years All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint (IQR: 33-50), and 14 (46.67%) were men. Only 4 people (13.33%) of this group had specific-IgM antibody detected in their serum, suggesting asymptomatic infection with single virus (IFV-B). The total infection rate in healthy control was significantly lower than that in COVID-19 patients (P<0.0001, Table 4 ), and none of the individual in control group showed evidence of combined infection with two or more pathogens. The climatic characteristics of Qingdao and Wuhan from December to January of following year were shown in Table 5 , where differences could be observed between the two cities. Although the climate in Qingdao is drier and colder than Wuhan, major respiratory pathogens circulate in the two cities were quite similar. This is an extended descriptive study on COVID-19 patients between Wuhan and Qingdao, represented as within and beyond the epidemic centre, respectively. Since the early onset of COVID-19 till the specific definition of novel coronavirus (previously known as 2019-nCoV) releasing on January 7, 2020, 4 the term "illness/pneumonia of unknown aetiology" was repeatedly quoted by the health officials and the public during this one-month period. One of the possible explanations for such failure to clearly define the disease is that no causative pathogen could be found at the early stage. We speculated that if any common respiratory pathogen, such as influenza and parainfluenza viruses, RSV, ADV, MP and CP, or the previous emerging novel coronaviruses including SARS-CoV and MERS-CoV, was isolated from body fluids and secretions of the infected patients, related treatment and management could have been implemented in the first place. As such, it was very unlikely that "pneumonia of unknown causes" would still be emphasized, although this might cause delay in the discovery of SARS-CoV-2. Therefore, we assumed that the possibility of coinfection in All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint COVID-19 patients was very rare. Our assumption was led support by two recent studies conducted in Wuhan showing that there was no coinfection of respiratory pathogens in COVID-19 cases. 3, 9 According to our data, the majority of COVID-19 patients in Qingdao were not from the endemic area; they were infected indirectly without a history of traveling to Wuhan. Despite the high coinfection rate in Qingdao patients who had more complicated clinical conditions Here we also compared the geographical and climatic characteristics of Qingdao and Wuhan. Wuhan is located in the centre of southern China and has a subtropical climate; 16, 17 while Qingdao is situated in the coastal area of northern China in the temperate zone, which has a relatively lower humidity than Wuhan. 18 Despite the difference in natural characteristics between the two cities, common respiratory pathogens circulate in Wuhan and Qingdao (including IFV-A, IFV-B, RSV, and ADV) have shown to be generally similar during the peak season of respiratory diseases in wintertime (from January to February). [19] [20] [21] [22] The incidence of coinfection in COVID-19 patients in Wuhan was rather low. Whereas in places with relatively low temperature like northern Qingdao, it is more common to find combined SARS-CoV-2 infection with other seasonal respiratory pathogens. It is not yet known whether this phenomenon also exists in other regions, leaving a gap for future studies. There are limited data to address whether coinfection with other respiratory pathogens would affect All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint the pathogenesis and outcome of severe acute respiratory illnesses like SARS and MERS. [23] [24] [25] [26] [27] Fortunately, SARS-CoV-2 RNA was detected in all of our patients before other respiratory pathogens being detected. Otherwise these COVID- 19 It is notable that there are several limitations of this study. Two critically ill patients and one patient who died in the end were excluded due to lack of aetiological data other than SARS-CoV-2. As of February 16, 2020, there were 60 cases of confirmed SARS-CoV-2 infection in Qingdao, however, we only analysed 30 non-severe cases whose complete aetiological and clinical information was available. The age of patients in Qingdao ranged from 1.5 years to 80 years; whereas patients in Wuhan were all adults as they were medical professional infected through work. Such age difference between the two groups might bring in bias to this study. We performed nucleic acid testing for the confirmation of SARS-CoV-2 infection, while coinfection with other pathogens was detected by serological testing of antibodies. In spite of superior accuracy, PCR-based molecular testing using throat swabs requires more complicated techniques of laboratory personnel with prolonged reporting time, which may not be suitable for emerging cases of SARS-CoV-2. 28,29 Thus, we applied rapid testing of aetiological agents by IIF in collected acute phase serum to guide clinical decision making. Since both the hospitals in Qingdao and Wuhan adopted the same protocol for the diagnosis of coinfection, we believe this will not affect the determination of final outcomes. All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint To test the reliability of serum specific IgM detection, we recruited a control group of normal people without clinical symptoms. The low infection rate in our control population suggested that our method was reliable in early and rapid diagnosis of respiratory infections. However, we were unable to exclude the possibility that coinfection with other respiratory pathogens may make the patients more susceptible to SARS-CoV-2 infection. Specific-IgM antibody could be detected in serum from one week of illness onwards and the amount progressively author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The data are expressed as n (%) or median (IQR). All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint The data are expressed as n (%) or median (IQR). All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint Table 5 All rights reserved. No reuse allowed without permission. author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.02.29.20027698 doi: medRxiv preprint Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle Impact of Ambient Temperature and Relative Humidity on the Incidence of Hand-Foot-Mouth Disease in Wuhan, China Physical and Socioeconomic Driving Forces of Land-Use and Land-Cover Changes: A Case Study of Wuhan City Effects of PM2.5 and PM10 on congenital hypothyroidism in Qingdao, China Epidemiological characteristics of children respiratory tract viral infection in Hubei area Neotropical Anopheles (Kerteszia) mosquitoes associated with bromeliad-malaria transmission in a changing world This study is supported by The National Natural Science Foundation of China (NSFC)