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KEY POINTS
Current knowledge
• Human coronaviruses frequently cause as ymptomatic to mild or moderate upper respiratory tract infections although at a lower rate, severe cases can occur mainly in children, elderly, and immunocompro mised adults, usually during cold seasons. Currently, there is scarce information on the epidemiology of HCoVs in adults in Argentina.
Contribution of this article to current knowledge
• Human coronaviruses cause about 10% of upper respiratory tract infections cases in ambulatory adult patients attending to a clinic in Buenos Aires, Argentina, even beyond the winter months, showing also an alternating circulation pattern between alphacoronavirus and betacoronavirus.
Seven species of coronaviruses can cause hu man infections: endemic human coronavirus (HCoV)-NL63, HCoV-229E, HCoV-HKU1, HCoV-OC43, SARS-CoV-1, MERS-CoV and SARS-CoV-2; the first two are alpha coronavirus and the re maining 5 are betacoronavirus1. The four HCoV (229E, NL63, OC43 and HKU1) have been asso ciated with upper respiratory tract infections (URTI) during non-pandemic times. The incuba tion period is, on average, 2 days, and the peak of symptoms and virus shedding is 3 or 4 days after inoculation2. These HCoV cause from as ymptomatic to mild, moderate and, at a lower rate, severe illness occurring mainly in children, elderly, and immunocompromised adults. Re infections are common since infections usually do not provide solid immunity2,3. During the COVID-19 pandemic the incidence of respira tory viruses, including HCoV, experienced a sig nificant decrease due to mitigation strategies implemented to contain SARS-CoV-24,5. In this sense, the decreased prevalence of HCoV infec tions, which predominates in pediatric popula tions, might be related to the periods of school attendance restriction. In addition, since most of the epidemiological studies on HCoV are per formed in pediatric and hospitalized patients and, as these viruses are usually not included in the routine diagnostic testing, knowledge about HCoV epidemiology in adults is scarce, in Ar gentina and worldwide. Therefore, we decided to perform this study aiming to characterize the epidemiology and clinical aspects of HCoV in ambulatory adults during COVID-19 pandemic times.
Materials and methods
This is a descriptive, prospective, longitu dinal study performed in a private hospital in La Plata, Buenos Aires, Argentina between No vember 2020 and October 2022. All consecutive patients attending to the clinic that were non-hospitalized adults suffering from an URTI epi sode with a confirmed viral diagnosis of OC43, NL63, HKU1 or 229E through nasal swabs were included in the study. The viral diagnosis was made using the Biomerieux BioFire FilmArray® Respiratory EZ Panel 2.1 that performs a real time nested multiplex polymerase chain reac tion (PCR) designed to detect 15 virus including the four endemic HCoV, SARS-CoV-2, Adenovi rus, Human Metapneumovirus, Rhinovirus/En terovirus, Influenza A y B, Parainfluenza Virus 1-4, Respiratory Syncytial Virus (RSV), and 4 bac terial respiratory pathogens (Bordetella paraper tussis, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae). A subgroup of patients underwent clinical evaluation between days 3 and 5 and on day 30 after the viral diagnosis; a repeated nasal multiplex PCR was carried out on the day 3-5 visit.
Statistical analysis was performed with IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp. Categorical variables were analyzed through fre quencies and percentage. Continuous variables were analyzed with Kolmogorov-Smirnov test in order to evaluate normality in which case, mean and standard deviation were used. On the other hand, median and interquartile range (IQR) was performed for those which did not meet that cri terion.
This study was performed with the approval of the Institutional Review Board and followed its ethics procedures. Informed consent was ob tained from all study participants.
Results
During the study period 458 ambulatory pa tients of at least 18 years-old were evaluated successively for an acute episode of URTI. From this cohort of patients, 153 (33.4%) were positive for SARS-CoV-2, 56 (12.2%) for Rhinovirus/ Enterovirus, 44 (9.6%) for HCoV, 15 (3.2%) for RSV, and 10 (2.1%) for Influenza A. The 44 pa tients (9.6%) positive for endemic HCoV includ ed the following types: 14 (31.8%) 229E, 13 (29.5 %) OC43, 11 (25.1%) HKU-1, and 6 (13.6%) NL63. Co-detections with other viruses were found in 5 (11.4%) cases at baseline: three with Rhinovi rus/Enterovirus, one each with Adenovirus and Parainfluenza 4. These 44 patients had a mean age of 41.5 years (range: 20 to 72 years) and 25 (56.8%) were women. The most common comor bidities were obesity (BMI above 30 kg/m2) and hypertension in 7 (15.9%) and 5 (11.4%) subjects, respectively (Table 1).
Tabla 1 Epidemiological and clinical characteristics of 44 patients with human coronaviruses infection
The distribution of the different HCoV ac cording to epidemiological weeks and seasons is shown in Figure 1. During spring-summer and autumn-winter seasons, we documented 16 (36.4%) and 28 (63.6%) HCoV cases, respectively. Alphacoronavirus 229E and NL63 were identified mainly in the winter of 2021 and 2022, respectively. HKU-1 infections occurred both, in sum mer and winter, while OC43 was detected only in spring 2021.
The most common presenting symptoms were nasal congestion (77.3%), rhinorrhea (63.6%), cough (59.1%), headache (50%), sore throat (50%), malaise (45.5%), sneezing (40.9%), joint or muscle pain (34.1%), fever (13.6%), nau sea (9.1%), dyspnea (9.1%) and diarrhea (6.8%). Most of the patients (86.3%) had at least 3 of these symptoms. Diarrhea was only seen in pa tients with OC43 infection. The median dura tion of symptoms was 4 days (IQR: 3-5 days). No hospitalizations or deaths were observed during the 30-days of follow-up and only one patient required treatment with oral antibiotics.
Between days 3 and 5 of follow-up, 33 (75%) patients underwent clinical assessment and a repeated multiplex PCR assay and 19 (57%) had positive PCR for the same HCoV found initially, with codetection of two other viruses (Adenovi rus and Rhinovirus). The rate of persistence was 71%, 58%, and 46% for HKU1, OC43 and 229E, re spectively, and among the 6 patients with NL63, only one had a follow-up test which resulted positive.
Forty-one subjects (93%) reported receiving at least one dose of SARS-CoV-2 vaccine although in 19 (43%) of them more than 6 months had elapsed since the last administration. Seven subjects (15.9%) informed a prior diagnosis of COVID-19 disease, 3 of which occurred in the last 6 months.
Discussion
This prospective observational study evalu ated ambulatory adults with symptomatic in fection caused by HCoV in Argentina during two consecutive seasons at the time of ongoing COVID-19-related transmission mitigation mea sures. These results are relevant as there is a sig nificant scarcity of epidemiological and clinical data of HCoV infection in ambulatory adults. We found that almost 10% of the patients present ing with URTI were positive for endemic HCoV; this prevalence is higher than that reported in Scotland between 2005 and 2017, where 5.3% of more than 12 000 outpatients with URTI were positive for HCoV6.
We found that type 229E was the most prev alent HCoV detected, as it has been previously shown by the Center for Disease Control and Prevention in the United States when consider ing only the adult population7. Similarly, a pro spective study in Michigan found that 229E was the most prevalent HCoV in adults between 18- 49 years of age8. Of note, in the same study, 229E and NL63 types were both associated with high er odds of severe and mild illness, respectively, compared with the other 3 HCoV8. In the current report, we could not detect any difference in dis ease severity between the four HCoV infections, having all patients good clinical outcome with no hospitalizations.
We observed a peak of HCoV cases in spring/ summer 2021/2022 (36.4%) after lifting mitiga tion measures applied to contain COVID-19 pan demic. This peak has been reported for almost all non-SARS-CoV-2 respiratory viruses except Rhinovirus / Enterovirus5. Interestingly, these HCoV appear to follow a pattern of circulation, where one type of alfa-HCoV predominates in one season and one beta-HCoV in the following; it was speculated that the 1-year lasting cross-immunity between alfa-HCoV (229E and NL63) and beta-HCoV (HKU1 and OC-43) might deter mine this alternating pattern6,7. Along with this, we observed that 229E (alfa-HCoV) predomi nated in the 2021 winter, OC43 (beta-HCoV) in the 2021 spring / 2022 summer, and NL63 (alfa- HCoV) and HKU1 (beta-HCoV) in the 2022 win ter season. Even though the typical prevalence of HCoV infections in the community follows the influenza pattern with peaks in each win ter, circulation of any of these HCoV out of the cold seasons has been described3, particularly in recent studies looking at the prevalence of respi ratory viruses after removing the COVID-19-re lated restrictions4,5. Of note, we found a rate of HCoV persistence by PCR test of almost 60% at days 3 to 5 of illness, which correlates with the mean viral shedding of HCoV in children of 6.4 days9.
The majority of the subjects had at least one dose of a SARS-CoV-2 vaccine and only few (15.9%) reported prior diagnosis of COVID-19 dis ease. Even though previous HCoV infection may diminish the severity of COVID-19 disease10,11, there is no data on how vaccination against SARS-CoV-2 might impact on HCoV infections. Nevertheless, prospective epidemiological stud ies including serological evaluation are required to better define the potential cross-immunity among the different HCoVs and SARS-CoV-2.
The presenting symptoms and the benign evolution of this cohort do not differ from those described by others3. Diarrhea was present only in patients with OC43 infection, which has been closely related to human enteric coronavirus12. Only one subject received a course of antibiot ics in this cohort of patients; the rapid multiplex PCR assay is a useful diagnostic tool for decreas ing inadequate antibiotic prescriptions in this setting13.
The main findings of this report include: a) endemic HCoV caused a significant propor tion of URTI among adult outpatients during COVID-19-related restrictions times in a city in Argentina, b) 229E was the prevalent HCoV type, and c) an alternating pattern of circu lation between alfa-HCoV and beta-HCoV was described. However, the enrollment of a relatively small number of patients from one medical center and the lack of comparison with patients suffering from other respirato ry viruses are among the main limitations of the study. More prospective local evidence is required to better characterize the evolution, the patterns of prevalence, and the burden of the disease of HCoV among adults in the out patient setting.
