A study offers new clues on why long COVID persists in some individuals.
- Despite the debilitating
nature of long COVID, there is an absence of diagnostic tests and
therapeutic tools for long COVID.
- A new study analyzed blood
samples from long COVID patients and healthy individuals. The findings
suggest a dysregulation of the complement pathway, a part of the immune
system, and the blood clotting pathways in individuals with long COVID at
six months.
- Changes in certain molecules
in these immune and blood clotting pathways were predictive of the
persistence of long COVID symptoms at 6 and 12 months, indicating the
utility of these measures in developing diagnostic tools for long COVID.
- The dysregulation of these
immune and blood clotting pathways suggests that therapies targeting these
pathways could help treat long COVID.
Approximately 10%-20% of individuals with a SARS-CoV-2 infection experience lingering symptoms
beyond three months after symptom onset. These symptoms referred to as long
COVID, can be debilitating, but there is a lack of diagnostic or
therapeutic tools.
A new study published
in Sciencefound that patients experiencing
long COVID symptoms six months after the SARS-CoV-2 infection show
dysregulation of the blood
clotting or coagulation system and the complement pathway, which is a
part of the immune system.
These changes in the
coagulation and immune systems in long COVID patients were shown to predict the
persistence of symptoms at six months. They may have the potential for the
development of diagnostic tools. Moreover, therapeutics to counter the changes
in the blood clotting and immune
system could help alleviate long COVID symptoms.
Dr. Wolfram Ruf, Scientific Director at the Center for
Thrombosis and Hemostasis (CTH), Johannes Gutenberg University, wrote in an
accompanying editorial:
“Although therapeutic
interventions with coagulation and complement inhibitors in acute COVID-19
produced mixed results, the pathological features specific for Long Covid
suggest potential interventions for clinical testing.”
Potential
causes of long COVID
Long
COVID refers to one or more symptoms that persist or develop after the
acute phase of a SARS-CoV-2 infection. Common symptoms of long COVID include
muscle weakness, fatigue, and brain fog.
Tissue damage,
persistent inflammation, production of autoantibodies, and reactivation of
latent virus reservoirs are some factors that have been hypothesized to
cause long COVID. However, the lack of knowledge about the precise mechanisms
underlying long COVID has hampered the development of diagnostic tools and
targeted therapies.
Several studies have
shown that individuals with long COVID show immune
system dysregulation. The present study further examined changes in the
immune system associated with long COVID at six months.
How
does long COVID affect serum protein levels?
The study included 39
healthy participants and 113 individuals with confirmed SARS-CoV-2 infection.
During the 12-month follow-up period after the onset of a SARS-CoV-2 infection,
40 out of the 113 participants with an acute SARS-CoV-2 infection had at least
one persistent symptom at the 6-month follow-up visit.
Serum samples were
collected from the participants during the acute phase of the infection and six
months after the infection. These serum samples were used to quantify changes
in more than 6,500 proteins.
The participants with
long COVID symptoms at six months showed changes in serum proteins belonging to
the complement system compared with healthy individuals or those without long
COVID at six months. The complement system is a part of the innate immune
system, which serves as the first line of defense against germs.
The complement system
activation helps elicit an immune response against pathogens or damaged tissue.
During the activation of the complement pathway, the plasma proteins belonging
to the complement system interact with each other to form a terminal complement
complex. The terminal complement complex binds to the surface of or inserts
into the membrane of pathogens and damaged cells to induce cell death or promote
their removal by engulfment by phagocytes.
Among patients with long
COVID at six months, the researchers found increased activation of the
complement pathway during acute SARS-CoV-2 infection and at six months after
diagnosis. Increased activation of the complement pathway and terminal
complement complex formation in 6-month long COVID patients could lead to
tissue damage.
The proteins in the
complement system can be activated by three distinct pathways, each involving
different types of molecules. The three complement activation pathways include
the classical pathway, the alternative pathway, and the lectin pathway.
Individuals with long
COVID at six months showed increased expression of molecules involved in
forming the terminal complement complex via the activation of the classical and
alternative pathways than those without long COVID or healthy patients.
Long
COVID linked to changes in coagulation system
In addition to the three
complement activation pathways, thrombin, a protein that promotes blood
coagulation, can also cause the activation of the complement pathway and lead
to the formation of the terminal complement complex.
Patients with long COVID
symptoms at the 6-month follow-up showed lower levels of antithrombin III, an
enzyme that inhibits thrombin, during the acute phase and at six months after
the onset of a SARS-CoV-2 infection than healthy individuals. The lower
antithrombin III levels were accompanied by increased expression of markers of
thrombosis, a state characterized by the formation of clots in the absence of
bleeding.
Patients with long COVID
at six months simultaneously showed increased markers for inflammation and
those for thrombosis. The cooccurrence of inflammation and thrombosis is
referred to as thromboinflammation.
Signs of
thromboinflammation observed in individuals with long COVID at six months
included destruction of red blood cells and dysfunction of endothelial cells
that line blood vessels. Moreover, these patients also showed increased markers
of tissue damage in the blood.
These changes associated
with thromboinflammation reflect the dysregulation of the complement system in
patients with 6-month long COVID. The dysregulation of the coagulation system
in long COVID patients also underscores the need for cardiovascular health
assessment.
The researchers found
that changes in specific complement protein levels, coagulation system
biomarkers, and age and body mass index predicted long COVID at 6 and 12
months.
MNT spoke with Dr. Hrishikesh Kulkarni, Assistant Professor of Medicine at
Washington University School of Medicine, who was not involved in the study.
Dr. Kulkarni said:
“By
utilizing an unbiased screen and confirming it using distinct components of the
membrane attack complex by which the complement system damages cells, the
authors demonstrate that persistently increased complement activation is a key
feature of Long COVID. Moreover, their models that incorporate the measurement
of 2 protein ratios improve an already good clinical model comprising of age
and body-mass index, most notably for 12-month Long COVID.”
Activation
of latent viruses in long COVID
The classical complement
pathway is activated upon antibodies binding to viral proteins or
autoantibodies in the body’s tissue. In the present study, the serum from
patients with 6-month long COVID showed increased antibodies against cytomegalovirus, a
type of herpesvirus.
This is consistent with
evidence suggesting that long COVID symptoms may arise, in part, due to
an inflammatory
response to the reactivation of a prior herpesvirus infection. The
persistence of SARS-CoV-2 in some tissues may also produce an immune response.
These results suggest
that binding of the antibodies to proteins from a herpesvirus could contribute
to the activation of the complement system. Besides explaining the increased
complement activation, these results suggest that antivirals targeting the
herpesvirus and SARS-CoV-2 could have the potential to ameliorate long COVID
symptoms.
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