Model Monday's: Diana Moldovan
Understanding Persistent COVID-19 Symptoms: Study Explores Early Indicators Of Long COVID
In a recent study posted to the medRxiv* server, researchers investigated early biomarkers of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) in a household-based cohort of individuals intensively sampled during the acute phase of coronavirus disease 2019 (COVID-19).
Study: Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection. Image Credit: Horth Rasur/Shutterstock.Com 
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Specifically, they investigated the persistence of SARS-CoV-2 antigens and immune dysregulation as the two mechanisms driving PASC.
BackgroundPrevious studies following up with COVID-19 patients early during the acute phase of illness focused on shorter-term outcomes, relatively small study populations, and less frequent sample collection time points.
Some recent studies have found an association between PASC and prolonged viral clearance plus distinct early immune signatures. A study identified subgenomic RNA in tissue sites at autopsy for up to six months post-COVID-19.
Another study showed that PASC patients had increased levels of some inflammatory markers for at least a year following infection, e.G., interleukin-6 (IL-6), IL-1B, and tumor necrosis factor-alpha (TNF-), but not those who fully recovered.
Nearly 1 in 10 US adults who have had COVID-19 also reported having PASC, i.E., persistent symptoms in the months following the acute phase of the illness. As its pathogenesis remains unclear, there is a need for more studies investigating the mechanisms contributing to this condition.
About the studyIn the present study, researchers enrolled 136 participants within five days of their first SARS-CoV-2-positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test result. They asked all the study participants to self-collect nasopharyngeal samples up to 21 times in the first 28 days after symptom onset.
A study interviewer administered clinical questionnaires to all the participants to gather key sociodemographic, medical history, quality-of-life, symptomatology, and vaccination data. Symptom items covered 32 pre-selected symptoms.
The team also collected their blood samples at enrollment and multiple other time points, i.E., days 9, 14, 21, 28, and four and eight months post-symptom onset. They considered a patient had PASC if they reported having new or worsening symptoms since the diagnosis of SARS-CoV-2 infection at their fourth-month visit.
Eventually, they compiled all data to compare viral and host immunity markers in the patient's plasma over the complete duration of acute illness.
The former comprised quantity of viral ribonucleic acid (RNA) load, its infectious component, the time duration of its persistence, and plasma SARS-CoV-2 nucleocapsid (N)-antigen level, whereas the latter included IL-6/10, TNF-α, interferon-alpha (IFN-α)/IFN-γ, interferon-gamma inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), and Spike (S) receptor binding domain (RBD) immunoglobulin G (IgG).
They used quantitative RT-PCR targeting N and envelope (E) genes of the SARS-CoV-2 genome to assess viral RNA titers in the samples and a conventional plaque assay to quantify its infectious viral titers. Likewise, they used a cytopathic effect (CPE) in Vero113 hACE2-TMPRSS2 cells to measure SARS-CoV-2 infectivity.
The team used a logistic regression model followed by marginal effects to calculate adjusted risk ratios (aRR) and compare non-infectious and infectious viral shedding and viral load from RT-PCR of nasal samples.
Since viral load and antibody results were presented non-linearly, the team log-transformed the results for comparison. Moreover, they restricted antibody analyses to unvaccinated participants. Furthermore, the researchers graphically summarized the differences in the distribution and magnitude of each analyte evaluated in this study.
ResultsOf 136 study enrollees, 104 completed at least one visit after they developed PASC. They contributed at least one nasal sample for infectious viral titer and viral RNA load testing.
However, only 80 of 104 participants provided blood samples for SARS-CoV-2 N-antigen and inflammatory marker testing.
The median age of participants in this diverse study cohort was 35.5 years, and 77% had no pre-existing diseases. Most participants had infection by a pre-Omicron strain of SARS-CoV-2, and 65% had not received a SARS-CoV-2 vaccine before that.
During the acute illness duration, 96 out of 104 participants had at least one symptom with an average of nine symptoms, with the most common acute symptoms being fatigue, cough, rhinorrhea, headache, and sore throat.
The most important finding of this cohort study was that early viral dynamics and adaptive immune responses were the key early biological determinants of PASC, suggesting that individuals who could control viral replication and ongoing viral persistence likely quickly recovered from infection early and never experienced PASC. Thus, it seems justified to evaluate giving early antiviral therapy to mitigate PASC development in the future.
The authors also noted that higher antigen burden during the acute infection phase and immune response in response to that burden contributed to the PASC development in the following months.
The first nine days following COVID-19 diagnosis were crucial; thus, a less robust humoral immune response and prolonged shedding of infectious viruses during those nine days likely led to PASC. Other important factors in PASC pathogenesis were viral load and time of antibody development.
ConclusionsAccording to the current study results, all identified early biological determinants of a larger cascade of events during the earliest (acutest) days of SARS-CoV-2 infection appear relevant in PASC pathogenesis.
However, future studies should evaluate the early biological markers identified in this study to elucidate the causal mechanisms of PASC and a better mechanistic understanding of this condition.
Studies should also evaluate whether early interventions, such as antiviral therapies, monoclonal antibodies, or therapeutic vaccination, could alter the magnitude\duration of infectious viruses and the associated immune response to affect PASC development.
*Important notice: 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.
Journal reference:
Understanding The Biological Effects Of SARS-CoV-2 Persistence In Children
In a study published in The Lancet Microbe, researchers analyzed the most recent knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen or ribonucleic acid (RNA) persistence in SARS-CoV-2-infected children.
Study: Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies. Image Credit: FamVeld/Shutterstock.Com
Although the knowledge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its human interaction has advanced a lot since its emergence in December 2019, many unanswered questions regarding the virus could significantly impact both children's and adults' health.
The post-coronavirus disease 2019 (COVID-19) (post-COVID-19) or long COVID condition, where the virus persists in the body, presents one of the biggest hurdles for researchers and patients, including adults and children. The development of long COVID has been associated with a number of biological abnormalities.
Nonetheless, the precise pathogenesis is yet unknown. Presently, the focus is on the persistence of the virus or its components in the human body following initial infection.
About the studyIn the present research, the authors evaluated the current data on potential SARS-CoV-2 persistence in pediatric patients, how it may impact the patient, and how it may result in post-COVID-19 conditions.
The researchers performed a literature review and analyzed studies on the presence of SARS-CoV-2 antigen or RNA in children undergoing surgery, biopsy, or autopsy for either death from the multisystem inflammatory syndrome or COVID-19 or evaluations for post-COVID-19 or other conditions in PubMed.
The review contained 21 articles following the screening and selection of identified studies. The age range of patients who underwent tissue biopsies or autopsies was one day to 17 years.
The team also analyzed why these findings may serve as a basis for future therapeutic and diagnostic studies on SARS-CoV-2 infection. They also included the personal experience of a doctor and patient in the study.
SARS-CoV-2 persistence in adultsStudies evaluating viral persistence and immunopathology in COVID-19 patients that died weeks to months following the initial infection, for any reason, showed compelling evidence that the viral parts could persist in the body.
Recent evidence reveals less efficient or lower SARS-CoV-2 clearance in non-respiratory tissues. Thus, comprehending how SARS-CoV-2 bypasses immune detection is vital for directing future therapeutic methods to promote viral clearance.
In addition, several immunological and anatomopathological studies in immunocompetent and immunocompromised adults demonstrated that SARS-CoV-2 antigens and RNA could persist in pulmonary and extra-pulmonary regions.
These events have been observed in patients with the SARS-CoV-2 pre-Omicron variant infections. Hence, these results might not apply to individuals with the Omicron variant infection.
Nevertheless, since there is proof that even Omicron-infected patients develop post-COVID-19 conditions, until disproven, viral persistence might be a possibility even among newly infected patients.
Presence of SARS-CoV-2 in pediatric populationsOf the 21 studies in the present review, eight articles addressed the post-mortem histopathological results and the SARS-CoV-2 RNA detection by reverse transcription polymerase chain reaction (RT-PCR) in tissues of children who had undergone autopsy due to fatal acute illness complications.
Six publications demonstrated the presence of viral RNA in the central nervous system (CNS) and other organs and tissues. Further, no SARS-CoV-2 RNA was identified in samples of the blood, cerebrospinal fluid (CSF), lungs, or brain tissue of a pediatric patient who died due to acute fulminant cerebral edema associated with COVID-19.
In three studies, pediatric patients with COVID-19-linked pneumonia showed RT-PCR-confirmed viral infection of respiratory tissues.
Furthermore, the authors noted that according to 11 studies in the present research, following an acute SARS-CoV-2 infection, the virus or at least its parts persisted for weeks to months in children's biological fluids and tissues.
In addition, three articles depicted the post-mortem discovery of SARS-CoV-2 RNA in tissues of children with multisystem inflammatory syndrome. One case report demonstrated SARS-CoV-2 nucleocapsid proteins in the intestinal lamina propria of a young girl with ongoing gastrointestinal symptoms three months following acute SARS-CoV-2 infection.
Two articles described RT-PCR-confirmed SARS-CoV-2 persistence in adenoids and palatine tonsils of children with mild or asymptomatic acute infection. Furthermore, another study depicted SARS-CoV-2 RNA detection by RT-PCR in the CSF of a 17-year-old girl with Guillain-Barrè syndrome associated with acute COVID-19.
Two included publications examining the presence of SARS-CoV-2 RNA in tissues of stillborn babies who died following maternal COVID-19 during pregnancy detected viral RNA in their organs. The most frequent anatomopathological observations were associated with intrauterine hypoxia, asphyxia, hemosiderosis, and hepatocellular damage.
An extremely preterm baby who died four days following birth, whose mother had severe acute SARS-CoV-2 infection, had viral RNA in the neonatal liver and heart vascular endothelium, and various placental and neonatal samples.
Potential effects of SARS-CoV-2 or its particles persistenceAlthough the biological impacts of SARS-CoV-2 RNA persistence are uncertain, preliminary data indicate that these viral components could stimulate immune responses. A study found that the CXCR5+ CD8+ T cells may act as SARS-CoV-2 spreaders in various body regions concealing the virus or an inflammation source in long COVID.
Additionally, a pilot study documented that a subgroup of children with post-COVID-19 had an impaired capacity to switch from non-specific to acquired immune responses.
Moreover, evidence suggests that long-term SARS-CoV-2 antigenemia can result in a hyperinflammatory presentation in multisystem inflammatory syndrome and long COVID among pediatric populations.
Although observational studies discovered a spike in new-onset immune-mediated diseases among children with a history of COVID-19, like type 1 diabetes, a clear association and causal impact between SARS-CoV-2 infection and type 1 diabetes is lacking.
Antiviral consideration for pharmacological studies in long COVIDAn oral antiviral agent, nirmatrelvir, targets the SARS-CoV-2 3-chymotrypsin-like cysteine protease enzyme (Mpro), essential to the viral replication cycle. Nirmatrelvir therapy was linked to a lower risk of long COVID. A case series of four long COVID patients demonstrated improved symptoms following treatment with nirmatrelvir.
Other promising treatment options in the long COVID include immunomodulatory drugs lowering chronic inflammation, such as immunoglobulin G4 monoclonal antibody.
Although SARS-CoV-2 vaccination may not be an immunomodulatory therapy, a 2023 systematic review discovered that it has therapeutic impacts on long COVID through rebalancing and boosting the immune system. Nonetheless, no research has been published examining the same effects in pediatric populations.
Comparing long COVID to other viral infectionsA study compared the symptoms of long COVID patients with psychosomatic or psychiatric patients with other infections, such as Ebola, Lyme, influenza, and chikungunya.
These clinical findings show that many people who survived infections may have long-term, detrimental effects on their health. Further, no study indicates that COVID-19 could result in symptoms as severe as post-measles subacute sclerosing panencephalitis.
ConclusionsThe current study shows SARS-CoV-2 could circulate systemically and persist for weeks or months in children, regardless of the severity of the disease. Viral RNA has been found in pediatric patients who died due to critical acute SARS-CoV-2 infection and children with multisystem inflammatory syndrome with mild or asymptomatic COVID-19.
The authors discussed what is presently known about the biological impacts of SARS-CoV-2 persistence on different viral infections and outlined novel scenarios for basic, clinical, and pharmacological research exploration.
A strategy like this will help with post-viral syndrome management and comprehension. The persistence of SARS-CoV-2 RNA following infection is well known. Nevertheless, its impact on immunity, health, and chronic diseases is still not entirely understood.
The researchers suggest that the enormous scientific interest in SARS-CoV-2 presents a unique chance to learn more about the biological, therapeutic, and clinical effects of viral persistence in humans.
Journal reference:
Buonsenso, D., Martino, L., Morello, R., Mariani, F., Fearnley, K. & Valentini, P. (2023) Viral persistence in children infected with SARS-CoV-2: current evidence and future research strategies. The Lancet Microbe. Doi: 10.1016/S2666-5247(23)00115-5. Https://www.Thelancet.Com/journals/lanmic/article/PIIS2666-5247(23)00115-5/fulltext
World Hepatitis Day: Understanding Viral Hepatitis & Pregnancy Risks
World Hepatitis Day - 28th July 2023. (Representational image: Pixabay)
Viral Hepatitis & Pregnancy
What is Hepatitis & its types?
Viral Hepatitis is a systemic infection affecting liver predominantly by any one of the hepatitis viruses. Most common viruses causing Hepatitis are Hepatitis A, B, C, D, E and G. Other less common causes of Hepatitis are caused by Cytomegalovirus, Epstein-Barr virus, Herpes Simplex virus and Falciparum Malaria. 0n exposure to the virus, about two-thirds of patients do not develop any symptoms. Others may develop fulminant and fatal acute infections on one hand, and from subclinical persistent infections to rapidly progressive chronic Liver disease leading to Cirrhosis and Hepatocellular Carcinoma.
How does Viral hepatitis spread?
Hepatitis A (HAV)
It spreads through the feco-oral pathway and is linked to poor sanitary conditions. HAV infection is frequent in underdeveloped countries such as India during childhood, resulting in mild hepatitis and posing little danger during pregnancy.
Hepatitis B (HBV)
HBV is transmitted through needle stick injuries, tattooing, piercing, and contact with contaminated blood and body fluids such as saliva, vaginal and seminal secretions. Acute infection is manifested by flu-like symptoms. Approximately 90% of individuals have spontaneous resolution of acute infection, 5-10% would become chronic carriers.
It is often transmitted from mother to child at birth (perinatal transmission) or through exposure to maternal blood, vaginal secretions during delivery or acquired during breastfeeding. If a patient tests positive for Hepatitis B virus, HBV antiviral medication should be continued during the pregnancy and after delivery.
Pregnant women may experience fatigue, nausea and vomiting, abdominal pain or discomfort, loss of appetite, low-grade fever, dark urine, and joint pain. In addition the routine screening for Hepatitis B is done in pregnant women.
Hepatitis E
HEV can also be transmitted through feco-oral route. Pregnant women with Hepatitis E, especially those in their second or third trimesters, are at increased risk of acute liver failure, foetal loss and death.
How Viral Hepatitis affect pregnant women ?
In most cases , acute or chronic HBV infection in pregnancy is not different from that occurring in non- pregnant women. Outcome of maternal infection is strictly dependent upon the stage of the disease. Patients with advanced disease may develop jaundice, rupture of oesophageal varices, liver failure.
Maternal infection with viral Hepatitis can lead to increased incidence of low birth weight and preterm births. During your pregnancy, pregnant women undergo blood tests for 3 infectious diseases: hepatitis B, HIV and syphilis. Babies born to a mother with hepatitis B have a greater chance of developing chronic hepatitis if they are not properly treated at birth. It is very important that pregnant people know their hepatitis status in order to prevent passing the virus on to their newborn baby during delivery.
What are the preventive measures for Viral Hepatitis?
Improving hygiene conditions and providing safe, clean drinking water helps in preventing HAV and HEV spread. Active screening of high-risk groups for HBV, HCV infection helps in identifying carriers and preventing community transmission.
Awareness about Viral Hepatitis, their modes transmission and preventive measures among community helps to curb these infections.
In addition, screening of blood and blood products, as well as routine testing of tissue and organ donors, are part of the HHBV and HCV infection prevention approach.
Vaccination is the most effective method of preventing HAV and HBV because these are vaccine-preventable diseases.
Dr Dharshitha Varigonda, Consultant General Physician, Apollo Cradle & Children's Hospital, Kondapur.
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