measuring Covid-19 immunity in children with mitochondrial diseases

An article by Eliza M. Gordon-Lipkin et al at the National Institutes of Health (NIH) in the United States, published March 2022 on the medRxiv website, investigated the SARS-CoV-2 serological landscape of families with children suffering from mitochondrial disease (MtD). The paper is entitled “Undiagnosed COVID-19 in households with a child with mitochondrial disease.”

Using a previously developed ELISA assay for measuring SAR-CoV-2 antibodies from dried blood samples collected at home using Mitra^® devices with VAMS^® technology, the NIH research group was able to show the degree of SARS-CoV-2 penetration in these households. They concluded that pediatric MtD study participants were not adversely affected by Covid-19 during the duration of the study but indicated there may be possible concerns in future with long-term neurological damage.  What is Mitochondrial disease?
Mitochondrial disease (MtD) is a group of genetic disorders that target cellular organelles know as mitochondria. Mitochondria are known as the powerhouse of the cell, manufacturing the cellular “energy currency” adenosine triphosphate (ATP), which is used to drive cellular metabolomic pathways.

Despite the nuclear DNA (nDNA) coding for the majority of mitochondrial proteins, for evolutionary reasons, DNA found in mitochondria (mtDNA) also codes for 13 proteins involved with the respiratory chain. Genetic mutations in both nDNA and mtDNA lead to diseases that affect cellular energy production and especially impact organs and tissues, such as nerve cells that have a high demand for cellular energy.  

Mitrochondrial diseases resulting from genetic mutations include Leigh syndrome, Leigh-like Syndrome, mitochondrial depletion syndrome (MDS), MERRF (myoclonus epilepsy with ragged-red fibers) syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis). Unfortunately, occurrence of these mitochondrial diseases can be as high as 1 in 5000 children, with variability of symptoms, and often leading to infant morbidity and premature death.        

Concerns with MtD and Covid-19 

According to the paper by Gordon-Lipkin et al, there is a chance that 80% of children suffering from MtDs experience recurrent or severe infections. Pneumonia and sepsis are frequent causes of death. Furthermore, up to 50% of those suffering from MtDs experience a worsening of their condition over time, sometimes leading to death. For this reason, the NIH team wanted to measure the serological landscape in both MtD study participants and family members and to measure the efficacy of Covid-19 vaccination.  

The group chose to use capillary dried blood samples collected with remote Mitra devices based on VAMS technology, which were included in sample collection kits. The kits were mailed to the participants’ homes to minimize physical contact and unnecessary exposure to the SAR-CoV-2 virus for this vulnerable cohort.  

MtD Study Method and Findings 

• Twenty families, where at least one child (n=22) was affected by an MtD, were recruited.   

• Study participants and family members were requested to collect a Mitra^® (30 µL) finger-stick blood sample at home. The majority complied and 83 dried blood samples were collected throughout the study. 
   
• Samples were then shipped to the NIH laboratories where serological tests were conducted to measure IgG for nucleocapsid (NC), spike protein and the receptor binding domain (RBD).  IgM and IgA levels were also measured for spike and RBD.  
   
• The enzyme linked immunosorbent assay (ELISA), developed for Mitra^® in a previous large-scale study, was employed. 
  
  
• The reason for both NC and Spike / RBD screening was to differentiate natural immunity from vaccination (raised against spike proteins only).   
  
  
• The study was conducted during the 2020/2021 winter when vaccinations had begun 

• Lesions in the central nervous system (CNS) were observed in 82% of the participants (previously identified by MRI); this was a consequence of previous viral infections.
   
• During the study, only 4.8% were clinically diagnosed with Covid-19, but many within the cohort (participants and family members) had raised antibodies against Covid-19, indicating there had been a previous infection). This may have been due to the high rates of Covid-19 infection at the time (>250,000 in a 7-day average).  
  
  
• One third of the working age household members were working onsite (partially or hybrid).  This was considered a risk factor for infection for those sheltering at home.
   
• Although vaccination had begun for children, especially those at risk, among the MtD patients of this study and previous studies there were indications of a general concern and perceived risk of MtD progression due to vaccination. The research group thus recommended “ring vaccination” as a worthwhile risk mitigation strategy. Ring vaccination is an approach that involves vaccinating those around at-risk patients to help prevent infecting those vulnerable individuals.
   
• As seen generally with children, the pediatric patients with MtD did not have any adverse outcomes due to infection or vaccination during the study. The researchers proposed this was due to a number of reasons.   

• First is the researchers proposed that there is reduced angiotensin converting enzyme 2 (ACE2) receptor expression in this cohort (ACE2 is the infection site where SAR-CoV-2 binds). 
  
  
• The researchers also suggested that natural immunity, cross protection from other coronaviruses, frequent vaccinations, and good adherence to risk-mitigating behaviors all contributed to the lack of adverse outcomes in this cohort. For these reasons, they concluded this would lead to a low dose infection in this cohort. 

• The group highlighted that previous reports showed that SARS-CoV-2 can impair mitochondria and, therefore, exacerbate the progression of Covid-19.  They also noted that infected individuals can progress to show neurological symptoms including infection of the central nervous system (which can last for up to 320 days). As a result, there was a concern for neurodegeneration for MtD participants that could be exacerbated by Covid-19 infection.
   
• There were sources of potential bias in the study such as the cohort having access to social media and that inclusion criteria required genetic evidence of MtD.   
  
  
• Finally, the group also noted that the study was conducted when the Alpha variant of SARS-CoV-2 was prevalent. However, both Delta and Omicron mutations had since become dominant. Since these later mutations were somewhat different from the original strain in their disease progression, the group emphasized that this must be taken into consideration when interpreting the findings.     

Study Authors’ Conclusions 

• A high number of previously undiagnosed cases of Covid-19 were seen in homes having children with MtD and, as a result, the study further improved the understanding of the natural history of MtD and the impact of Covid-19.   
  
  
• The home-sampling study provided a template to access understudied populations during Covid-19 and beyond. 

Neoteryx Conclusions 

Although the world is facing many new challenges, for many people, Covid-19 seems to have become a manageable challenge. However, as mentioned in a previous blog [iv], the Coronavirus Pandemic is still with us and as the northern hemisphere heads toward winter there are concerns of new Covid-19 waves. Although successful vaccination programs have protected many individuals from severe disease or death, there is still a concern for those individuals who are at higher risk.

Studies such as this one conducted by the NIH demonstrate the importance of collecting blood samples remotely through home sampling devices and kits to access vulnerable populations and allow for continuing to improve our understanding of this and possible future pandemics. 

This article was summarized for our readers by James Rudge, PhD, Neoteryx Technical Director. This is curated content. To learn more about the important research outlined in this blog, visit the original article on the medRxiv website.

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