Chronic SARS-CoV-2 Shedding

Chronic viral shedding, a condition where the virus continues to be released from an individual's body long after the initial infection, has been observed in many infectious diseases, including COVID-19.  In such cases, individuals may remain asymptomatic or experience only mild symptoms while the virus persists. It remains detectable in repeated tests over an extended period and can still infect others even in nasal swab is negative. This was evident in our study.  

Recent research by Conway et al. (2024) highlights the possibility of chronic SARS-CoV-2 infection, extending over several months and potentially years. Other studies have documented prolonged asymptomatic infections and extended viral shedding in moderate to severe beyond hospital discharge. Analysis of sequencing data on UK samples taken between 2 November 2020 and 15 August 2022 lead to estimates that 0.1–0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days.

In the pandemic's early stages, Wan et al. (2020) reported two cases of asymptomatic infections among 78 confirmed cases. One individual, a 36-year-old male, ceased shedding the virus after 14 days, while another, a 19-year-old male, continued for up to 21 days

Li et al, 2020 suggested that repeat asymptomatic infections can have a significant impact on viral clearance, potentially leading to prolonged shedding and increased risk of transmission. The median duration of virus shedding in their study was 11.5, 28 and 31 days for presymptomatic, asymptomatic and mildly symptomatic patients. Seven patients (38.9%) continued to shed virus after hospital discharge. Agarwal et al, 2020 highlighted that among patients who were SARS-CoV-2 positive, a subset continued to shed viral RNA for days or even weeks after generating IgG antibodies. 

Later that year, the ECDC Threat Assessment Brief On UK SARS-CoV-2 Variant speculated that the first variant designated with a Greek letter, the Alpha variant (B.1.1.7), may have originated from a single, likely immunocompromised, individual, emphasizing the potential for extended viral shedding and evolution.

Further evidence of chronic COVID-19 cases emerged in subsequent years. Seth-Smith et al. (2023) described a Caucasian man in his 70s with COVID flareup 50 days after initial diagnosis (oligosymptomatic infection). Whole genome sequencing of the virus showed Pango lineage B.1.221 (circulating in the first year of pandemic). Between the first sample and the second from bronchoalveolar lavage fluid 7 weeks later, eight mutations (double the normal rate) were identified, including minor variants, which could be used to estimate the chronology of mutations. Prolonged infection is a common finding in immunocompromised patients, especially in patients with lymphoma after B-cell depleting therapies. It can be difficult to clear the virus from such patients.

An immunocompromised patient from the Netherlands, diagnosed with type 2 diabetes mellitus and chronic lymphocytic leukemia, experienced chronic infection with the Alpha variant for 42 weeks despite undergoing various treatment regimens. Notably, most clinical symptoms disappeared during this period (Munninck et al., 2022).

In symptomatic COVID-19 patients, the median time to SARS-CoV-2 negativity in nasopharyngeal tests was 28 days. Prolonged shedding was particularly observed in older patients, females, and those with a longer interval from symptom onset to hospital admission (Long et al., 2021). Several studies have identified predictors of prolonged viral shedding in SARS-CoV-2 patients. Male sex, delayed hospital admission, and invasive mechanical ventilation were found to be associated with prolonged shedding (Xu 2020). Older age, low albumin levels, and the use of corticosteroids and tocilizumab were also identified as risk factors (Dezza 2021). Additionally, older age and lack of Lopinavir/Ritonavir treatment were independently associated with prolonged shedding, with earlier administration of this treatment shortening the duration of viral shedding (Yan 2020).

In a study involving 51 SARS-CoV-2 infected individuals, including 44 asymptomatic cases (Saurabh et al., 2020), asymptomatic individuals exhibited a median virus persistence duration of 9 days, similar to symptomatic individuals. Approximately one-fourth of asymptomatic individuals (10/44) demonstrated SARS-CoV-2 persistence beyond 2 weeks, with some cases persisting up to 25 days.

Zahn et al. (2021) discovered that patients with mild COVID-19 remained PCR-positive for up to 37 days after symptom onset. Additionally, Omololu et al. (2021) reported ongoing viral replication for over 119 days in a patient with lymphoma and B-cell immunodeficiency.

In a retrospective analysis conducted across Northwestern Medicine Healthcare (NMHC) patients from March to August 2020 (Batra et al., 2022), 405 individuals, constituting 42.2% of the 2,518 hospitalized patients who underwent repeat SARS-CoV-2 RT-PCR at least fourteen days after the initial positive testing, were identified as having persistent viral shedding. This persistence was found to be associated with male sex (albeit weakly, P=0.047), increased BMI (P=0.026), diabetes mellitus (P=0.001), chronic kidney disease (P<0.001), peripheral arterial disease (P=0.044), and exposure to corticosteroids during the initial COVID-19 hospitalization (P=0.003).

Furthermore, persistent viral shedding demonstrated an independent association with the incidence of in-hospital delirium and increased six-month mortality. Among the studied population, 81 individuals (8%) succumbed, 60 of whom (15% of their respective population) were persistent shedders (OR 2.43; 95% CI 1.42, 4.29, P < 0.001).

In some cases - such as B cell deficiency (Faxén and Edvinsson, 2023) - it was initially difficult to recognize the persistent disease, leading to a longer duration of illness - between 45 and 242 days for the 4 cases reported. A 25-year-old female with mixed connective tissue disease (MCTD) developed COVID-19 despite being triple vaccinated. She experienced a short clinical improvement after 14 days of symptoms, but after a couple of days, the symptoms returned. After 8 weeks of persistent symptoms with fluctuating fever, cough, and dyspnea, she was assessed at the Infectious Disease Clinic. The PCR for SARS-CoV-2 was positive in the nasopharynx but negative in blood. She experienced 1 week of symptomatic improvement, but then the fluctuating fever, cough, and dyspnea returned and persisted. After treatment she recovered, but during the following 4 months, she was reassessed several times at the Infectious Disease Clinic, and every time she tested negative by PCR for SARS-CoV-2 in the nasopharynx. Eventually, a bronchoalveolar lavage fluid (BALF) showed a positive PCR for SARS-CoV-2 and she recovered after treatment that involved Paxlovid (disease duration: 183 days, BA.2 variant). We note that this situation is surprisingly common in chronic COVID cases - see Peys et al, 2020, Da Silva et al, 2023, Seth-Smith et al, 2023. Case 2 was a 54-year-old female suffering from rheumatoid arthritis (disease duration: 56 days, BA.5). Case 4 was a 52-year-old female with a history of kidney transplantation. Her disease duration was 45 days, BA.5 variant. Case 3 was a 76-year-old male with a history of follicular lymphoma grade II, diagnosed after his first three doses of the vaccine and before his fourth dose. His breakthrough COVID infection was diagnosed one month after the 4th dose and lasted 242 days. The strain was typed to BA.2, which at that time in Sweden was an almost non-existent variant that strongly suggested prolonged SARS-CoV-2 infection with BA.2 rather than reinfection. 

One patient tested positive for covid-19 for 505 days until they died, according to a case presented at the European Congress of Clinical Microbiology and Infectious Diseases in April 2022. A 47 year old woman who underwent CAR-T cell therapy was shedding SARS-Cov2 for 335 days. A 52 year old man undergoing chemotherapy was still shedding virus after 189 days. A 64 year old immunocompetent man was shedding the virus for 169 days after infection. He constantly tested positive till August of 2020, with an exception of two 2-week periods when he tested negative. A 2022 review found that a typical immunocompetent person continues to shed the virus for a month. 

Continuous genomic surveillance in long-term infected persons is essential and wastewater surveillance may be the best method to do it. what is the prevalence of asymptomatic infections?  Depending on the study population, 23.4-74.0% PCR-positive people (who were symptomless SARS-CoV-2 carriers at the time of the investigation) were identified (Jancovics et l, 2023). A 2022 systematic review and meta-analysis published in JAMA Network Open estimated a pooled percentage of 40.50% asymptomatic infections among individuals with confirmed COVID-19. Among the tested population, the asymptomatic rate was lower, around 0.25%. prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus. Prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus. An early innate immune response, particularly a rapid type 1 IFN response, as well as a rapid and broad induction of SARS-CoV-2 specific T cells, characterize asymptomatic infections

A study by Conway et al. (2024) describes waste-water-treatment plant (WWTP) testing in Michigan over > 2 year period which continued to pick up evidence of the Alpha Variant well into 2023.  The authors hypothesize that a chronically infected individual not only shed the Alpha virus for 24-28 months, but over that time the virus accrued numerous mutations in the Spike RBD and NTD. 
Sampling began in July 2021, which was at least seven months after emergence of the Alpha variant. It became clear that even smallest WWTP (estimated population served: 851) consistently produced higher concentrations of SARS-CoV-2 genome copies and could be used in detecting extended viral presence. , indicating that even small wastewater treatment plants can play a crucial role in detecting such prolonged viral presence​.

Several case reports underscore the complexity of this issue. Gigli (2020) reported a 45-year-old woman with prolonged PCR positivity but no significant COVID-19 symptoms. Vaught (2021) described a healthy young adult male with extended live virus shedding despite mild symptoms. Baang (2020) presented a case of chronic COVID-19 in an immunocompromised patient, with ongoing viral replication for at least 119 days. Goh (2022) reported the persistence of residual antigen and RNA of the SARS-CoV-2 virus in the tissues of patients with long COVID.

Clinical, pathological, and epidemiological evidence supports the establishment of SARS-CoV-2 tissue reservoirs, even in asymptomatic individuals. Autopsy studies have isolated infectious virus from multiple organs, indicating wide dissemination and persistence of viral RNA in tissues for extended periods. The gastrointestinal tract emerges as a significant site for viral persistence, with evidence of viral shedding in feces. This highlights the potential for fecal-oral transmission and the importance of studying stool samples in understanding viral persistence. The virus spreads to extra-respiratory sites through mechanisms that are not fully understood but may involve hematogenous spread and infection of immune cells. This dissemination is facilitated by the expression of ACE2 receptors and other co-receptors in various organs. 

The evidence across multiple studies and case reports consistently underscores the phenomenon of chronic viral shedding in COVID-19, particularly in asymptomatic or mildly symptomatic individuals. This shedding, lasting from days to over a year in some cases, poses challenges in managing and containing the virus. The persistence of viral RNA and the evolution of the virus in prolonged infections highlight the need for continuous genomic surveillance and the importance of wastewater surveillance as a tool for detecting extended viral presence. Understanding the dynamics of asymptomatic infections and their contribution to community transmission remains crucial in our ongoing efforts to control and mitigate the spread of COVID-19.



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