What’s the problem?

Anthony Fauci, MD, has said: “Virtually everybody is going to wind up getting exposed and likely get infected.” There’s one reason to avoid this scenario: long COVID.

If Omicron is sooner or later going to infect even just “more than 50 percent,” how many will get long COVID? We can’t know yet, the variant having appeared just three months ago. Hopefully, this more benign variant will cause fewer cases, but even very mild COVID-19 can bring prolonged symptoms.

Definitions: The WHO convened 265 experts worldwide, including many long-haulers, to develop a definition. Here’s the short version: “Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis.”

Another careful study has laid out various subtypes, using a superb data set the authors are continuing to mine.

Numbers: If anything, they’re worsening. One recent review and meta-analysis found that a third of COVID-19 patients still had fatigue six months later, and half the female patients complained of brain fog. Another concluded that most COVID-19 survivors had one or more persistent symptoms after six months. A third estimated that 43 percent of all cases diagnosed worldwide have or have had long COVID, meaning 100 million then, 134 million now.

Vaccination, contrary to early optimism, seems to cut risk only by half, according to studies of health care workers in Israel and app users in the U.K.

Severity: The WHO panel said gently that the symptoms “generally have an impact on everyday functioning.” To get an idea of what that means, check out this article about physician-patients and this one about regular folks.

What’s the solution?

Overviews in journals such as Science and The Lancet regularly conclude that the condition is untreatable aside from analgesics for pain, breathing exercises for faintness and lifestyle moderation for fatigue and shortness of breath.

The one intervention bringing striking improvement for some patients is SARS-CoV-2 vaccination, as reported anecdotally and confirmed by one large international poll. But vaccination makes some patients worse, and we can’t predict which way any individual will respond.
In the last few months, though, some light may finally be appearing at the end of the tunnel. Theories vary, with some overlap:

Tissue damage. Severe COVID-19 can damage the lungs and the heart, leading to long-lasting dysfunction. But many with long COVID were never severely ill, and they often have no readily demonstrable organ dysfunction.

Blood clots. The South African scientist Etheresia Pretorius thinks the secret of long COVID is tiny inflamed clots plugging up the circulatory system and inhibiting organ oxygenation. She thinks that despite few signs of persistent clotting or inflammation, patients’ blood carries inflammatory molecules and auto-antibodies sequestered inside hard-to-detect fibrin amyloid microclots.

In possible support of this theory, one small series found that most long COVID patients with “brain fog” had Tc-99m brain scans suggestive of reduced blood flow. Dr. Pretorius’s group tried a combination of antiplatelet drugs and anticoagulants in 24 patients and claimed in a manuscript that all 24 were cured. These were not unselected long COVID patients, though, but a vaguely-defined subgroup of an 845-patient database.

This seems too good to be true — fortunately, a large controlled trial is planned.

Inflammation. Inflammatory markers such as C-reactive protein are sometimes but not always elevated in long COVID patients, who often had particularly low levels of such markers during their acute phase. Some think nevertheless that inflammation underlies the condition and have turned to corticosteroids as treatment.

In one tiny case series, 9 out of 9 long COVID patients had pro-inflammatory shifts in lymphocytic and monocytic subpopulations, and nearly all their symptoms resolved after a 4-day course of steroids. Again, this seems too good to be true, and, again, a controlled trial is said to be in the works.

Autoimmunity. Severe COVID-19 frequently induces the production of autoantibodies, which can persist in long COVID. One study found autoantibodies more common in women following asymptomatic infections and in men after symptomatic COVID-19, with specific patterns also varying by gender. Still another line of thinking that would suggest treating with steroids.

Some long-hauler clinics prescribe low-dose steroids empirically, but I don’t know of any ongoing trials.

Abnormal immune response. Researchers in London identified distinctive T-cell patterns in long COVID patients that led them to prescribe combined H1/H2 histamine blockade to 49 patients, reporting that 35 of them improved. Antihistamines are now one leg of University College London’s Stimulate-ICP study. Anomalous immune responses might help explain post-vaccine improvement.

Blunted immune response: Case series in Spain and Belgium have reported that patients destined for long COVID had, initially, not just low inflammatory markers but also weak antibody responses. I’ve also heard anecdotal evidence that long COVID patients often produce few antibodies after vaccination.

This poor immune response may make it harder to clear SARS-CoV-2 from the body, allowing it to continue causing direct damage and stimulating the immune system. Fortunately, nasal shedding does not persist, so long COVID patients are not contagious.

Live virus. Here’s more direct evidence of persistent virus. NIH researchers autopsied 44 patients who died weeks or months after COVID-19 diagnoses, looking for viable coronavirus in body tissues. A pre-published manuscript reports detecting SARS-CoV-2 in all 44 cases, scattered through tissues as far-flung as heart, brain, kidney, lymph node, muscle, thyroid, testicle, and ovary. Most of these patients had died from fulminant COVID-19, so the presence of live virus is not surprising. But some died much later, as long as seven months after the acute illness.

These findings are both novel and surprising since the virus has always been thought to disappear quickly except in immunosuppressed patients. None of the autopsied patients were known to have long COVID. But to me, these findings imply the exciting suggestion that antiviral drugs such as Paxlovid could conceivably be useful in treatment.

Susan Levenstein is an internal medicine physician and author of Dottoressa: An American Doctor in Rome.

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