Issue #110: From acute COVID disease phase to recovery, or Long COVID

Written by Nobel Laureate Professor Peter Doherty

As discussed over the past couple of weeks (#108, #109), it’s reasonable to think that some of the variability in Long COVID (LC) will reflect what happened during the acute phase of the disease. Those who required hospitalization may, after discharge, be suffering persistent health impairment as a consequence of severe damage to body organs, especially the lungs, heart and kidney. Such effects, which may at least partly resolve with compensatory tissue repair over time, are likely to be most apparent for those who required ICU support. Post Intensive Care Syndrome (PICS) is well known for other conditions, including severe influenza.

What’s more mysterious is the debilitating LC syndrome seen in people who experience a relatively mild, initial course of symptoms, that either does not resolve or can become worse with time. Overall, the LC experience does not look to be as bad for this latter group (See Figures 1 and 2 here), as ‘initially mild’ LC (IMLC) tends to describe the experience of younger people, and can progress to be a very debilitating condition, it is a major problem for both the individual and for society.

So far, though, we’ve not seen a lot of analysis regarding possible treatments that separate these ‘post-hospitalization Long COVID’ (PHLC) and IMLC cohorts. Though there will undoubtedly be overlap, could it be that the likelihood of some therapeutic intervention being effective will be much higher for the IMLC set?

While the process of virus replication in our respiratory tract, heart, kidneys and so forth can lead to cell death, much of the damage - and the symptoms we experience - reflects the actions of our immune cells (and their secreted products) as they divide and differentiate in our lymphoid tissue (#85), then exit into the blood and extravasate into sites of infection. Normally, if this virus-specific immune response achieves pathogen elimination, we will soon start to feel better and life will go back to normal. We’re all familiar with that scenario from our regular encounters with the 100 or more viruses (rhinoviruses, paramyxoviruses, adenoviruses, enteroviruses, ‘human’ coronaviruses etc) that cause ‘coughs and sneezes’, or even ‘flu-like’ symptoms.

The path to recovery begins (#95) when no new cells become infected (to start replicating the virus) because any free-floating virus particles (virions) are tagged and neutralised by specific antibodies (or immunoglobulins, Igs). Then, the active disease process normally comes to an end as the existing virus-producing ‘factories’ are eliminated by ‘killer’ CD8+ T cells (or some Ig-mediated mechanism). In short order, the foreign ‘antigens’ (virus proteins or peptides) and cell debris are soon ‘engulfed and destroyed’ by macrophages. The result is there’s no continuing antigen stimulation to drive the further secretion of those somewhat toxic ‘immune mediators’, the chemokines and cytokines. Once these molecules are no longer in excess in local tissue sites and in the blood that circulates through our brain, we feel a lot better.

This has of course been the COVID-19 experience for most of us, especially if we are younger. At the time of initial SARS-CoV-2 entry via the upper respiratory tract, those who received two doses of the adenovirus-vectored AstraZeneca vaccine or the Pfizer or Moderna mRNA vaccines (both deliver the spike protein of the original Wuhan strain) will already have greatly expanded populations (from a few naïve precursors #87) of memory B cells, CD4+ ‘helper’ T cells and CD8+ killer’ cells that are available for rapid recall (#93). Terminally differentiated (B cell lineage) plasma cells will be sitting in bone marrow and pumping out SARS-CoV-2-specific IgG antibodies. Most of this IgG will be circulating in the blood, though a little (plus some secreted IgA) may be present in the mucus bathing the superficial epithelial layer of the nasal mucosa.

The changes in successive SARS-CoV-2 variants have led to a progressive drop in the efficacy of neutralizing IgGs and IgAs generated following two doses of the standard vaccines, with any evidence of immediate, Ig-mediated protection falling-off greatly after the Delta strain gave way to Omicron. That can be compensated to some extent by a third or fourth vaccine shot, which does seem to bring up some neutralising Igs to Omicron. What may not have changed much however are the spike peptides recognized by ‘memory’ CD4+ and CD8+ T cells, (#34) that can play a major part in recovery. Is that why vaccination tends to keep us out of hospital?

Over the past few weeks (#105-109) we’ve been asking whether prior vaccination stops us from developing LC. Not surprisingly, when vaccines prevent SARS-Cov-2 infection we don’t get LC, so there is a protective effect there. However, when we do suffer a ‘breakthrough’ infection with one or other Omicron or (through 2021) earlier SARS-CoV-2 variant, it seems that vaccination provides only partial protection against the development of at least some LC symptoms.

What is happening here? An obvious question is whether the immune response has in some sense failed to clear the virus, so that the immune cells are continuing to be stimulated by antigen.

Next week, we’ll focus on the possible link between LC and virus persistence, which may be most relevant to the situation for those in the IMLC category.