Real-time polymerase chain reaction (RT-PCR) is used to detect severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic. Researchers discovered that the viral load peaks with the onset of symptoms and gradually wanes off by the third week, after the development of antibodies.
The Centers for Disease Control and Prevention (CDC) recommends isolation for 14 days following exposure to COVID-19. However, several studies have recently indicated that for some patients, the infectivity persists for several weeks. These studies have suggested that the infection timeline varies from person to person due to the difference in age, immunity, and disease severity.
In most cases, infectivity does not persist beyond 10 days of the onset of COVID-19 symptoms. This is confirmed by RT-PCR, where no trace of total RNA or subgenomic RNA are detected after the above-stated period. In rare cases that involve immunocompromised adults, prolonged infectivity has been reported. Thereby, more research on how SARS-CoV-2 affects this vulnerable population is extremely vital. More specifically, the sequential dynamics of viral infectivity and the development of SARS-CoV-2 variants in immunocompromised patients, especially children, is an area that is under-researched.
New research, published on medRxiv* preprint server, has reported the effect of prolonged SARS-CoV-2 infection in immunocompromised children and young adults. In this study, multiple nasopharyngeal samples from three patients were obtained from the Children's Hospital Los Angeles (CHLA) between May 7 and November 21, 2020. All three patients, including two children and one young adult, were diagnosed with B-cell acute lymphoblastic leukemia (ALL). Their brief case histories are mentioned below.
Patient 1 - female under 5 years of age. She was diagnosed with B-cell ALL and was treated with chemotherapy. She consistently tested SARS-CoV-2 positive RT-PCR for an extended period.
Patient 2 - male between 20-25 years of age. He was diagnosed with B cell ALL six months before his first SARS-CoV-2 positive RT-PCR. He was hospitalized multiple times with extremely severe health conditions. For several weeks he showed positive SARS-CoV-2 RT-PCR with consistently high viral loads. He remained SARS-CoV-2 RT-PCR positive even at the time of the publication of the research.
Patient 3 - is a male under 5 years of age. He was diagnosed with high-risk B-cell ALL 7 months before SARS-CoV-2 infection. He underwent an array of treatments for both diseases over a long period of time. He tested RT-PCR negative on the 196th day.
Clinical timeline of symptoms, hospital admissions, and treatment. Timelines for patient 1 (A), patient 2 (B), and patient 3 (C) are labelled by date from initial positive RT-PCR (day 0). Colored bars indicate time periods where patients were symptomatic, required supplementary oxygen, or received treatment (Remdesivir or convalescent plasma). The phases of chemotherapy are also shown.
Researchers reported that among these patients, two showed significant intra-host SARS-CoV-2 mutational accumulation and host immune responses that may have contributed to the course of their disease. They also found virus replication in patient 2 (up to 144 days) and patient 3 (up to 162 days). The subgenomic RNA was also easily detected during the period of infection. Therefore, it is vital to regularly monitor immunocompromised patients who are SARS-CoV-2 positive for a more extended period. Such studies could help us predict the ability of the virus to replicate and develop new variants continuously.
Scientists are mainly intrigued by the SARS-CoV-2 B.1.1.7 variant owing to its high level of infectivity. Compared to the reference SARS-CoV-2 sequence, B.1.1.7 has acquired 17 mutations, 8 of which are in the spike gene. Such reports raise concerns because long-term replication within an immunocompromised host could develop more infective variants. In the current study, researchers have found mutations in several regions within the spike gene. They observed a V70P mutation in patient 3 (day 162), which coincides with B.1.1.7 variant. Similar mutations in the spike gene (N440D, E484A, and E484K) were also reported in other persistently infected, immunocompromised patients.
The analysis of the patients' antibody responses was conducted, where, patient 1 with limited active replication of the virus showed high levels of ACE2-RBD blocking antibodies. However, both patients 2 and 3 showed poor antibody responses associated with prolonged replication of SARS-CoV-2 in the host. In general, all three patients had higher levels of antibodies targeting RBD and subgenomic transcripts S1 were more than N. Researchers found that levels of antibodies of patient 2, treated with two courses of remdesivir and several infusions of convalescent plasma, waned quickly.
The current study concluded that immunocompromised children and young adult patients are a highly vulnerable group. This group can develop many virulent variants owing to their prolonged period of infection. It is, therefore, essential to monitor such immunocompromised groups to prevent further development of infectious variants that could prolong the pandemic. One limitation of this study is the small case series. More research is needed to understand the influence of the host in viral clearance and mutation and the study could be conducted using a larger group of infected individuals.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity Thao T Truong PhD, Alex Ryutov PhD, Utsav Pandey PhD, Rebecca Yee PhD, Lior Goldberg MD, MSc, Deepa Bhojwani MD, Paibel Aguayo-Hiraldo MD, Benjamin A Pinsky MD, PhD, Andrew Pekosz PhD, Lishuang Shen PhD, Scott D Boyd MD, PhD, Oliver F Wirz PhD, Katharina Roltgen PhD, Moiz Bootwalla MS, Dennis T Maglinte MS, Dejerianne Ostrow PhD, David Ruble BS, Jennifer H Han MS, Jaclyn A Biegel PhD, Maggie Li ScM, ChunHong Huang MD, Mayala K Sahoo PhD, Pia S Pannaraj MD, MPH, Maurice O'Gorman PhD, Alexander R Judkins MD, Xiaowu Gai PhD, Jennifer Dien Bard PhD medRxiv 2021.02.27.21252099; doi: https://doi.org/10.1101/2021.02.27.21252099, https://www.medrxiv.org/content/10.1101/2021.02.27.21252099v1