Long Covid Weekly #81: NIH Injects life into Long Covid funding, Covid evolving in immunocompromised patients & more!
Hi everyone,
Sorry about the late send-out this week!
In this edition, we cover a range of topics, including the National Institutes of Health's efforts to bolster Long Covid research, the impact of Long Covid on children in the US, and the efficacy of different treatments for Long Covid symptoms.
The NIH funding is actually from the pandemic emergency fund, as Ravi pointed out here. This means that this is not a continuous yearly budget for Long Covid, which is needed for a disease of this magnitude. However, as many who work in government know, allocating a fixed budget can be a slow and arduous process that can take years to move into effect. My hope is by the time this budget runs out we will be seeing a full budget in place!
Another piece I wanted to highlight from this week was from Article: SARS-CoV-2 evolution during prolonged infection in immunocompromised patients. Specifically, I wanted to highlight this section below:
‘Two of the patients received mAb (Monoclonal Antibody) treatments (bebtelovimab or sotrovimab), which target the SARS-CoV-2 spike protein to neutralize the virus (37, 39). In both cases, mAb-resistant mutations replaced the dominant amino acid by the next timepoint following antibody administration … These findings are consistent with previous reports where mAbs were administered and resistance was detected’
The virus becoming more resistant over time to these antibodies is highly concerning. Do we know if this holds for anti-virals like Paxlovid?
Media
SUMMARY:
NIH announced an additional investment of $515 million over the next four years into the RECOVER Initiative to study Long COVID, which affects 1 in 9 adults in the United States who have recovered from COVID-19.
The RECOVER Initiative involves large-scale observational studies with nearly 90,000 participants, aiming to deepen understanding of Long COVID and identify effective treatments through clinical trials.
Recent studies supported by RECOVER have provided insights into how COVID-19 affects gene expression, long-term symptoms in individuals with comorbidities, persistence of the virus in tissues, and immune system changes in Long COVID.
My Take:
This is a great step, however it is a bandaid not a permanent solution. There needs to be an allocated budget. In my opinion, these things probably take a lot of time, so by the time this budget runs out, this might be resolved.
SUMMARY:
About 6 million US children may be experiencing long COVID, with symptoms affecting various body areas.
Children with more severe initial COVID-19 illness are at higher risk for developing long COVID, with symptoms like loss of smell, brain fog, and mental health conditions.
Research into long COVID in children is ongoing, led by the US National Institutes of Health's RECOVER Initiative.
SUMMARY:
UMass Chan researchers are exploring the potential link between long COVID and neurodegenerative diseases, such as Alzheimer's and Parkinson's.
They are investigating the molecular consequences of long COVID using a human cerebral organoid platform previously employed in herpes virus studies.
The research aims to determine if SARS-CoV-2 infection in brain organoids produces similar neurological signatures to those observed in Alzheimer's disease.
The team is working to identify new strategies to limit viral replication and develop treatments for severe COVID-19.
The PolyBio Research Foundation award provides $250,000 over one year for this research, which is part of the Long Covid Research Consortium's efforts to study core biological drivers of long COVID and its long-term effects on health.
My Take:
This research is crucial as it sheds light on the potential long-term neurological consequences of COVID-19, especially in relation to neurodegenerative diseases.
Article: Long COVID patients need scientific ambition, not defeatism | Gavi, the Vaccine Alliance
SUMMARY:
The article discusses the challenges posed by Long COVID and ME/CFS, highlighting the need for scientific ambition and research efforts to address these complex conditions.
The authors emphasize the biological basis of these illnesses and the importance of proper funding for biomedical research.
Long COVID research has revealed fundamental biological changes in patients, with potential disease mechanisms identified.
The parallels between Long COVID and ME/CFS suggest shared underlying mechanisms, signaling the need for comprehensive understanding and targeted treatments.
The historical neglect and psychologization of ME/CFS have underscored the importance of approaching these conditions with a scientific perspective.
My Take:
The authors can all be found on Twitter!
Article: How Long COVID takes a toll on relationships: Washington Post
Summary:
While much has been written about the physical health challenges of long covid, less is known about how the debilitating condition affects relationships.
Common symptoms such as fatigue, brain fog and dizziness can make it difficult for someone with long Covid to help with household chores, go out on dates or be physically intimate. As a result, experts say many long Covid patients struggle with strained relationships.
The article discusses how long Covid adds unpredictability to relationships, and can act like a “third person” in relationships.
Research
DEFINITIONS:
3C-like protease: An enzyme that SARS-CoV-2 uses to help process viral polyproteins, which is a target for antivirals like ensitrelvir.
Primary analysis population: The pre-specified subset of patients used for assessing the primary endpoint, in this case those treated within 72 hours of symptom onset.
Adverse event: An undesired medical event experienced by a patient in a clinical trial, regardless of causality.
HDL cholesterol: High-density lipoprotein, a lipoprotein that carries cholesterol from tissues to the liver. A decrease is considered an adverse effect.
SUMMARY:
As part of the regulatory approval process for ensitrelvir, this phase 3 trial included a larger sample size and focused on the efficacy and safety of ensitrelvir in a population of patients with mild to moderate COVID-19.
The primary endpoint of the trial was the time to resolution of a composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, including a sore throat, stuffy or runny nose, cough, low energy or tiredness, and feeling hot or feverish.
Patients were followed up for 28 days, and the outcomes were compared between the ensitrelvir and placebo groups.
The trial demonstrated a significant reduction in the time to resolution of key COVID-19 symptoms with ensitrelvir treatment in patients presenting within 72 hours of disease onset.
The most common adverse event observed was a decrease in high-density lipoprotein levels, which was noted to be higher in the ensitrelvir groups compared to placebo.
The overall safety profile of ensitrelvir was favorable with no treatment-related serious adverse events reported.
The findings of this trial suggest that ensitrelvir could be a potential treatment option for patients with mild to moderate COVID-19, especially when administered early in the course of the disease.
DEFINITIONS:
Patient Health Questionnaire-9 (PHQ-9): A validated 9-item screening tool for depressive symptoms.
Neuro-QOL: A validated patient-reported outcome measure assessing cognitive symptoms like concentration, memory, processing speed.
Non-probability sampling: A sampling method where not every individual has a known, non-zero chance of being selected, limiting generalizability.
SUMMARY:
This study examined the prevalence and correlates of self-reported cognitive symptoms in individuals with post-COVID-19 condition (symptoms persisting >2 months after acute infection) compared to those who recovered fully.
Data came from two waves of a 50-state U.S. internet survey conducted in late 2022 to early 2023 with 14,767 respondents reporting prior confirmed COVID-19.
Of the 1,683 respondents meeting criteria for post-COVID-19 condition, 56.7% reported experiencing at least one cognitive symptom daily (e.g. trouble concentrating, slowed thinking), compared to only 27.1% of those without post-COVID-19 condition.
Among those with post-COVID-19 condition, more daily cognitive symptoms were associated with younger age, female gender, and lower income levels.
More cognitive symptoms also correlated with greater depressive symptom severity on the PHQ-9, greater self-reported functional impairment in daily life, and lower likelihood of full-time employment - associations that persisted after adjusting for depressive symptoms. Authors pointed out that this does not infer a causal relationship between depression and Long Covid.
The authors conclude that cognitive issues are highly prevalent in post-COVID-19 condition, often co-occur with depressive symptoms, and are linked to significant functional impairment. They recommend screening for and addressing cognitive symptoms as part of the public health response to post-COVID-19 condition.
My Take (Amy):
One limitation that the authors noted is that the PHQ-9 - a screening tool for depression - includes some items that may also capture COVID-19 somatic symptoms rather than features of major depression per se. For example, fatigue and motor slowness.
I think about this every time I fill out a PHQ-9: Does the test conclude I’m depressed when I report severe “slow speech” and “fatigue”?
DEFINITIONS:
Long-lived plasma cells (LLPCs): Stable plasma cells in the bone marrow responsible for durable antibody responses.
Extrafollicular immune response: Activation of B-cells outside of lymphoid follicles, leading to short-lasting antibodies.
SUMMARY:
The study found deficient generation of spike-specific LLPCs in the bone marrow after SARS-CoV-2 infection, impacting antibody responses.
Unlike tetanus, SARS-CoV-2 failed to induce a LLPC compartment in the bone marrow, affecting the durability of antibody responses.
The study suggests that extrafollicular immune responses may hinder the development of durable immune memory in severe COVID-19 cases.
SUMMARY:
This early release from the CDC's Emerging Infectious Diseases attempts to quantify the number of patients who suffer fatigue after a Covid infection.
This community-based cohort study followed over 4,500 adults for an average of 11.4 months after COVID-19 infection. Fatigue developed in 9% of participants. Even among patients not hospitalized for acute COVID-19 or those without comorbidities, the incidence of post–COVID-19 fatigue approached 10% per year.
COVID-19 patients had 1.68 times the risk for fatigue in the follow-up period compared with matched non–COVID-19 controls. The risk for chronic fatigue was even higher: patients with COVID-19 had 4.32 times the risk for chronic fatigue than did controls.
According to the report, 85% of patients who met the PASC definition had fatigue. A substantial percentage of patients with fatigue remain ill for many months with an illness similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a syndrome sometimes seen after infections that is characterized by functional limitations that impair patients’ ability to maintain daily activities and associated with profound fatigue.
Predictors of incident fatigue among COVID-19 patients included female sex, advanced age, and various comorbidities like mood disorders, pain syndromes, and sleep disorders.
Even among younger patients (18–29 years of age), those without comorbidities, and those who were not hospitalized for acute COVID-19, the incidence of fatigue was only slightly reduced.
COVID-19 patients with incident fatigue had worse clinical outcomes, with higher rates of hospitalizations (25.6% vs. 13.6%) and deaths (5.3% vs. 2.3%) compared to those without fatigue. These data point to the importance of COVID-19 infection prevention.
My Take (Amy):
It’s good to see the CDC acknowledging and producing data that helps show the overlap of ME/CFS with Long Covid.
Article: SARS-CoV-2 evolution during prolonged infection in immunocompromised patients
DEFINITIONS:
Immunocompromised: Having a weakened or impaired immune system, often due to medical conditions or treatments that suppress the immune response.
Consensus mutations: Mutations that become the predominant or consensus sequence in the viral population within a host.
Intrahost single nucleotide variants (iSNVs): Genetic variations (single nucleotide substitutions) present within the viral population of an individual host.
Non-synonymous mutations: Mutations that change the amino acid sequence of a protein, potentially altering its structure or function.
Monoclonal antibodies: Laboratory-produced proteins that mimic the immune system's ability to recognize and bind to specific targets (in this case, the SARS-CoV-2 spike protein) to neutralize or block their function.
Remdesivir: An antiviral drug used to treat COVID-19 infections.
SUMMARY:
This paper reports on a study investigating the evolution of SARS-CoV-2 in five immunocompromised patients experiencing prolonged infections.
Four of the five patients likely had true prolonged infections, while one patient appeared to have been reinfected with a different viral strain.
The rates of accumulation of consensus mutations in the viral genomes were higher in the prolonged infection patients compared to contemporaneous community samples of the same viral lineages.
Two patients treated with monoclonal antibodies (bebtelovimab and sotrovimab) rapidly developed mutations in the spike protein known to confer resistance to these antibodies [WOW].
Despite all patients receiving remdesivir treatment, no known remdesivir-resistance mutations were detected.
SUMMARY:
The study provides valuable insights into the long-term effects of HBOT on post-COVID-19 conditions, demonstrating sustained improvements in quality of life, sleep, neuropsychiatric symptoms, and pain severity over an extended period.
These findings suggest that HBOT may be a promising therapeutic intervention for long COVID patients, warranting further investigation and clinical validation.
The hyperbaric oxygen therapy (HBOT) improved cognitive, psychiatric, fatigue, sleep, and pain symptoms in long COVID patients.
The long-term evaluation showed similar improvements as the short-term outcomes across most domains of quality of life, sleep quality, neuropsychiatric symptoms, and pain severity after undergoing HBOT sessions.
Clinical benefits of HBOT were preserved even one year after the last HBOT session, suggesting lasting therapeutic effects.
Article: Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID
DEFINITIONS:
Complement system: A complex system of proteins in the blood that plays a crucial role in the immune response, particularly in the recognition and elimination of pathogens and damaged cells.
Complement activation products: Fragments or complexes of complement proteins that are generated during the activation of the complement system, indicating the involvement of specific complement pathways.
Classical pathway: One of the three main complement activation pathways, typically triggered by antibody-antigen complexes.
Alternative pathway: A complement activation pathway that is constantly active at a low level and can be amplified by the presence of foreign or altered surfaces.
Terminal pathway: The final step in the complement activation cascade, leading to the formation of the membrane attack complex (MAC), which can cause cell lysis.
Complement components: Individual proteins that make up the complement system, such as C3, C4, and C5.
Complement regulators: Proteins that modulate or control the activity of the complement system, preventing excessive activation and protecting host cells from damage.
SUMMARY:
This study investigates the role of complement system dysregulation in the pathogenesis of long Covid.
The researchers analyzed various complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals and patients with long COVID.
They found that markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID compared to healthy controls.
Additionally, plasma concentrations of some complement components (C3, C5, C9) and regulators (C1INH, FD, properdin, FH, clusterin) were also altered in long COVID patients.
Combinations of these complement biomarkers, particularly a panel of four activation markers (iC3b, TCC, Ba, and C5a), showed high predictive power for identifying long COVID cases.
The authors suggest that complement dysregulation contributes to the persistent inflammation observed in long COVID and propose that currently available complement inhibitors could be potential therapeutic options for treating this condition.
[Super Technical Article]
DEFINITIONS:
Functional connectivity (FC): The measure of correlated neural activity between brain regions that have shown synchrony in blood oxygen level-dependent (BOLD) signals.
Default mode network (DMN): One of the primary intrinsic networks of the brain responsible for baseline functions like mind wandering and self-referential thoughts.
Salience network (SA): A network including the insular cortex and anterior cingulate that is involved in detecting salient stimuli, pain, and deception.
SUMMARY:
This paper investigates functional connectivity (FC) differences in the brain between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and healthy controls using ultra-high field 7 Tesla MRI.
ME/CFS patients showed reduced FC between the pontine nucleus in the brainstem and cerebellar vermis IX compared to healthy controls during a cognitive Stroop task.
Seed-based analyses revealed reduced FC in ME/CFS patients between the left cuneiform nucleus (part of the reticular activating system involved in sleep/wake cycles) and occipital/cerebellar regions, as well as between the culmen and cerebellum VI.
ME/CFS patients exhibited stronger FC within the default mode network (DMN), particularly between the posterior cingulate cortex and cuneus, suggesting a potential compensatory mechanism.
Duration of illness in ME/CFS correlated positively with FC in salience network hubs like the anterior cingulate cortex, insula, and supramarginal gyrus.
SUMMARY:
Given the substantial prevalence of Long COVID, this study aimed to assess the association of Long COVID with increased risk of mental health disorders using extensive real-world data.
At the start of the study, none of the participants had a recorded mental health disorder. The two cohorts included one group diagnosed with Long COVID, and another group with no known history of COVID-19 or Long COVID.
In the analysis of real-world data, survivors of COVID-19 with Long COVID were 2.5 times as likely to develop a mental health disorder. They were 3.4 times as likely to develop major depressive disorders and 3.4 times as likely to develop generalized anxiety disorders.
These results are specifically applicable to the new incidence of mental health disorders following a Long COVID diagnosis.
I would add some caution to the interpretation of the HBOT paper discussed. The original study included sham HBOT as a control group but only short term followup. Patients who received sham were offered HBOT so could not be included in the long term followup for this study. So the only conclusion is that patients who received HBOT felt better a year later, but there could be any number of reasons for this, and difficult to prove it was the HBOT alone that contributed.
@Brandon,
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