Long Covid May Not Be Caused by Covid-19 Virus

By Pat Anson, PNN Editor

An immune system response to the COVID-19 virus has been suspected as a possible cause of Long Covid, a poorly understood disorder that causes chronic fatigue, brain fog, insomnia, chest pain and other symptoms long after the initial infection.  

But a small new study in the UK suggests that Long Covid may not be an inflammatory immune reaction to the SARS-CoV-2 virus. Instead, the body appears to be responding to the activation of dormant viruses many of us already have in our systems.

"Long Covid occurs in one out of 10 COVID-19 cases, but we still don't understand what causes it,” said Laura Rivino, PhD, Senior Lecturer at the University of Bristol's School of Cellular and Molecular Medicine. “Several theories proposed include whether it might be triggered by an inflammatory immune response towards the virus that is still persisting in our body, sending our immune system into overdrive or the reactivation of latent viruses such as human cytomegalovirus (CMV) and Epstein Barr virus (EBV)."

Rivino and her colleagues collected and analyzed blood samples from 63 Covid patients with mild, moderate or severe symptoms who were hospitalized at the start of the pandemic -- before vaccines were available – and tested them again 3, 8 and 12 months after their admission.  

Their findings, published in the journal eLife, show that patients with severe symptoms had significant dysfunction in their T-cell profiles after three months. T-cells are white blood cells released by the immune system to fight bacteria and viruses.

Further analysis showed there was no rapid increase in immune cells targeting SARS-CoV-2, but there was an increase in T-cells targeting CMV -- a common virus that is usually harmless but can stay in the body for life once you’re infected with it. That suggests that the prolonged T-cell activation observed at three months in severe patients may not be driven by SARS-CoV-2, but instead may be "bystander driven" by dormant viruses that were reactivated.  

"Our findings suggest that prolonged immune activation and long COVID may correlate independently with severe COVID-19. Larger studies should be conducted looking at both a larger number of patients, including if possible vaccinated and non-vaccinated COVID-19 patients,” said Rivino. "Understanding whether inflammation and immune activation associate with long COVID would allow us to understand whether targeting these factors may be a useful therapy for this debilitating condition."

The good news for Covid long haulers is that after 12 months, the T-cell levels of patients with severe Covid symptoms were similar to those of patients who experienced mild and moderate symptoms – suggesting that severe cases can resolve over time.

Long Covid May Affect Genes Involved in Pain Signaling

By Pat Anson, PNN Editor

About 16 million people in the United States have Long Covid, a poorly understood disorder that causes body aches, headaches, fatigue, insomnia, brain fog and other symptoms long after an initial infection with COVID-19. For some, the symptoms are mild, but for other they are so severe they become disabling.

Why do some people quickly recover from Covid, while about one in five have lingering symptoms?

A new animal study found that thousands of genes involved in nervous system function are affected by SARS-CoV-2, and may cause lasting damage to dorsal root ganglia, the spinal nerves that carry pain and other sensory messages to the brain. Scientists believe that genetic damage may be what causes Long Covid.

“Several studies have found that a high proportion of Long Covid patients suffer from abnormal perception of touch, pressure, temperature, pain or tingling throughout the body. Our work suggests that SARS-CoV-2 might induce lasting pain in a rather unique way, emphasizing the need for therapeutics that target molecular pathways specific to this virus,” explains co-author Venetia Zachariou, PhD, chair of pharmacology, physiology & biophysics at Boston University’s Chobanian & Avedisian School of Medicine.

Zachariou and her colleagues infected hamsters with SARS-CoV-2 and studied how it affected the animals’ sensitivity to touch, both during the initial infection and after the infection had cleared. Then they compared the effects of SARS-CoV-2 to those triggered by an influenza A virus infection, and were surprised by what they found.

In the hamsters infected with Covid, researchers observed a slow but progressive increase in sensory sensitivity over time – one that differed substantially from influenza A infections, which caused a sudden hypersensitivity that returned to normal once the initial infection ended.

Although the studies were performed on animals, researchers say they align with the acute and chronic symptoms caused by Covid in humans. They hope further studies on human genes and sensory pathways affected by the Covid virus will lead to new treatments for Long Covid and conditions such as ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome),

“We hope this study will provide new avenues for addressing somatosensory symptoms of long COVID and ME/CFS, which are only just now beginning to be addressed by mainstream medicine. While we have begun using this information by validating one promising target in this study, we believe our now publicly available data can yield insights into many new therapeutic strategies,” adds Zachariou. 

The study findings appear online in the journal Science Signaling.

The federal government’s Covid public health emergency officially ends this week, but the impact of the pandemic will likely be felt for years to come.

Long Covid Research Could Lead to New Treatments for Chronic Pain

By Pat Anson, PNN Editor

About a third of people infected with Covid-19 develop long-term symptoms, such as headaches, persistent muscle pain, joint pain, stomach pain, chest pain and respiratory discomfort. Three years into the pandemic, scientists are finally beginning to understand what causes long covid and how to possibly treat it.

In studies on hamsters infected with Covid-19, researchers at the Icahn School of Medicine found that the virus left behind a gene expression signature in the animals’ dorsal root ganglia – a cluster of nerves in the spinal cord that transmit pain signals from the body to the brain. The signature matched gene expression patterns seen in other forms of chronic pain.

“A significant number of people suffering from long COVID experience sensory abnormalities, including various forms of pain,” said Randal (Alex) Serafini, an MD/PhD candidate. “We used RNA sequencing to get a snapshot of the biochemical changes SARS-CoV-2 triggers in a pain-transmitting structure called dorsal root ganglia.”

Serafini presented his findings at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics in Philadelphia. 

The symptoms experienced by hamsters infected with Covid-19 closely mirrored those of people. Researchers say the hamsters showed a slight hypersensitivity to touch early after the infection, which became more severe over time.

They performed similar experiments with the Influenza A virus to determine if other RNA viruses promote a similar response. Influenza A caused an early hypersensitivity that was more severe, but began to fade after a few days. Four weeks after recovering from the flu, the hamsters had no signs of long-term hypersensitivity.

In contrast, hamsters infected with SARS-CoV-2-showed more hypersensitivity, reflecting symptoms of chronic pain. The pain sensitivity remained even after the hamsters recovered from the initial Covid-19 infection. Further research found that SARS-CoV-2 downregulates the activity of several previously identified pain regulators and a protein called interleukin enhancer binding factor 3 (ILF3) — a potent cancer regulator.

Based on these findings, the researchers hypothesized that mimicking the acute effects of ILF3 could serve as a new pain treatment strategy. To test this theory, they gave laboratory mice suffering from inflammation a clinically tested anti-cancer drug that inhibits ILF3 activity. The drug was very effective at treating their pain.

“Our findings could potentially lead to new therapies for patients suffering from acute and long COVID, as well as other pain conditions,” said Serafini. “We think therapeutic candidates derived from our gene expression data, such as ILF3 inhibitors, could potentially target pain mechanisms that are specific to COVID patients, both acutely and chronically.

“Interestingly, we saw a few cancer-associated proteins come up as predicted pain targets, which is exciting because many drugs have already been developed to act against some of these proteins and have been clinically tested. If we can repurpose these drugs, it could drastically cut down therapeutic development timeline.”

Serafini and his colleagues are now working to identify other compounds that could be repurposed to treat pain, while also keeping an eye out for new compounds that might inhibit ILF3 activity.

“Our study also shows that SARS-CoV-2 causes long-term effects on the body in drastically new ways, further underscoring why people should try to avoid being infected,” he said.

Another study has suggested that long covid appears to be the result of an overactive immune system. Australian researchers identified biomarkers of a sustained inflammatory response in the blood samples of long covid patients – suggesting their immune systems were activated by the virus, but then failed to turn off.

Other studies have found similarities between long covid and autoimmune conditions such as lupus and myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS).  

In addition to widespread body pain, long covid symptoms include fatigue, cognitive impairment and difficulty sleeping.