Long Covid Treatments

Part of the challenge of finding a treatment is finding a good diagnosis of the problem. What is the Long Covid problem anyway? Long Covid seems a lot like a continuation of the active infection minus the virus shedding. This post examines some of the basic toxicology outcome measures that may or may not lead us to an understanding and ultimately a treatment.

Cytokine profiles

McFarland and coauthors have made a case for how inflammatory cytokines can lead to nociceptor sensitization in dorsal root ganglia.[1] The dorsal root ganglion, as you may recall, is the nodule containing the cell bodies of afferent neurons of the dorsal root. Afferent neurons contact somatosensory end organs in the skin, deep tissue and viscera.

the Dx

Clinical trials of treatments of active Covid infections have proposed monitoring IL-1β, IL-10, IL-6, IL-18. IL-1β , IL-6, tumor necrosis factor (TNF), and other cytokines were listed as drivers of Long Covid chronic pain. [1] IL-10 is generally considered anti-inflammatory, but has been argued to be pro-inflammatory in Covid-19, cancer, and autoimmune diseases. [2] If the damage is done, what is the point of measuring cytokines as an outcome measure? Long Covid has been proposed to be an autoimmune disease. [3]

Reference [3] did not mention anti-NMDA receptor antibodies in Covid patients but we have covered thie phenomenon elsewhere on this website. When it comes to chronic pain, it is all about PGE2 that comes after inflammatory cytokines. One question not answered by this review is if auto antibodies binding to their targets sets off a new cytokine storm of diagnostic value.

The Rx

In an animal model mouse pindpaws were intraplantar injected with PGE₂ or saline in control for 14 consecutive days [4]. After that mice had free access to running wheels for 28 days or were forced to remain sedentary. [4] During the expercise period mechanical hyperalgesia was measured by the electronic von Frey method.[4]

The images shown n Figure 2 are only a small sampling of a remarkable study. [4] The authors did not attempt to establish a molecular mechanism of exercise induced analgesia. They discussed anti-inflammatory cytokines and the endocannabinoid system as possibilities. Likewise, we do not know if PGE2 DRG sensitization or NMDA auto antibodies are the cause of hyperalgesia. Whether Long Covid hyperalgesia is the result of PGE2 induced modifications of the DRG or auto antibodies, exercise therapy if human patients can be convinced to walk or run 6 km per day like the mice.

Complete blood counts and more

While Long Covid is hitting the peer reviewed literature, there really hasn’t been the extensive work linking parameters uncovered by the complete blood count to symptoms. One study that we know about has followed CBC parameters up to 21 days after symptom onset. [5] At present we are not aware if neutrophil counts stay high and lymphocyte counts stay low in those with the Long Covid syndrome. One would hope that as new treatments for Long Covid undergo clinical trials, CBC will be part of the toxicology tests of an agent on a new population. A complete blood count and all the associated blood chemistry has been conducted on a 57 year old man who presented with autoimmune hepatitis. [5]

We may be required to obtain complete blood counts when testing Cu(I)NA₂ on a new population. If we suspect an autoimmune disease, we may want think about sub typing lymphocytes.

Liver Enzymes

The same study reported liver enzymes in the serum of the 57 year old male Long Covid patient.[6]

parameter	patient	reference range
Alkaline phosphatase	48 U/l, repeat 29 U/l	39–117 U/l
Aspartate aminotransferase	137 U/l, repeat 371 U/l	0–40 U/l
Alanine aminotransferase	106 U/l, repeat 246 U/l	0–44 U/l
GGT	655 U/l	0–65 U/l
Prothrombin time	10.4 seconds	9.1–12 seconds
International Norm. Ratio	1	0.8–1.2
Partial thromboplastin time	28 seconds	24–33 seconds
Total iron binding capacity	271 μg/dl	250–450 μg/dl
Iron	222 μg/dl	38–169 μg/dl
Iron saturation	82%	15–55%
Ferritin	860 ng/ml, repeat 3,275 ng/ml	30–400 ng/ml
Erythrocyte sedimentation rate	66 mm/hr	0–30 mm/hr
Haemoglobin A1c	5.90%	4.8–5.6
Anti-smooth muscle Ab	83 units	Positive >30 units
Anti-mitochondrial Ab	174.5 units	Positive >24.9 units
Anti-double-stranded DNA Ab	14 IU/ml	Positive >9 IU/ml
Anti-soluble liver antigen Ab	4.4 units	Negative 0–20 units

The authors concluded that this male had auto immune cirrhosis. [7] Liver enzymes are clearly elevated. It is not really clear if the antibodies against smooth muscle proteins contributed to the cirrhosis or if these antibodies affected other organs. Albumin, produced by the liver, was within the reference rage (not shown). Immunoglobins were elevated. Future studies with Cu(I)NA₂ to to treat long Covid should include normal blood work that includes liver enzymes. Indeed studies in humans (5-FU toxicity) and rodents (fatty liver model) have shown that Cu(I)NA₂ mitigates liver damage.

Standard blood chemistry may be good enough for diagnosing post Covid liver damage. Post Cu(I)NA₂ blood chemistry tests may tell us if we have a treatment.

D-dimer

D-dimer is a degradation product of fibrin, the stuff of blood clots. The presence of D-dimer in the blood is an indication of thrombosis, the formation of a blood clot inside a blood vessel. The first report summarized the clinical assessment of 384 patients reviewed a median of 54 (IQR 47–59) days following hospital discharge with COVID-19. [7] Another study found that Long Covid patients with elevated D-dimer tended to be younger and did not require hospitalization. [8] Did the formation of vascular blood clots prevent deleterious internal bleeding? Was vascular damage in the patients with D-dimers long into recovery also severe enough for vascular smooth muscle proteins to be released into the blood and trigger an auto immune reaction? [6]

If cirrhosis is brought on by damaged blood vessels in the liver, could copper and other nutrient absorption result from damage to blood vessels in the gut? This relates to copper deficiency and eye health problems being brought on by gastric bypass surgery.

A month after the original posting of this post, there have been no new reports of actin auto antibodies in Long Covid to the best of our knowledge. This is probably not something we want to include as a diagnostic of Long Covid and efficacy of Cu(I)NA₂.

Dx

We might ask for information s to whether D-dimer was high during the active covid Infection. This might diagnose that vascular damage probably occurred. We can test serum copper bound to ceruloplasmin or something.

Rx

Lysyl oxidase is needed to cross link collagen in damaged blood vessels.

Post treatment Lyme Disease (PTLD) and Long Covid questionnaires

Our previous experience with the Revised Symptom Impact Questionnaire (SQIR) helped us understand how Cu(I)NA₂ might be acting in a population with a diverse set of symptoms of nerve/muscle discomfort. Long Covid and PTLD share overlapping symptoms. Might there be a better or an additional questionnaire for long Covid? A previous study used four questionnaires to assess PTLD

• Fatigue Severity Scale (FSS) A nine item fatigue metric has summary scores that range from 9 to 63 with a higher score indicating worse fatigue, and with ≥36 indicating clinically relevant levels of fatigue [10]
• Short-Form McGill Pain Questionnaire (SF-MPQ) A 15-item pain metric has summary scores that range from 0 to 45 with a higher score indicating worse pain, and with ≥4 indicating a clinically significant experience of pain [11]
• Pittsburgh Sleep Quality Index (PSQI) This test has summary scores ranging from 0 to 21 with a higher score indicating worse sleep quality, and with ≥6 indicating clinically significant poor sleep quality. [12]
• The Beck Depression Inventory (BDI) is a 21 item depression questionnaire with summary scores ranging from 0 to 63 with a higher score indicating worse depression, and with ≥14 indicating mild, moderate, or severe depression. [13]

The PTLD study concluded that PTLD patients had a lower quality of life than normal controls. [9] These questionnaires may be useful in evaluating Cu(I)NA₂ in the treatment of Long Covid-19 and PTLD. Previous experience has suggested that participants might become impatient with too many questions and not give much thought to the answers. A very old questionnaire from 1977 [14] addresses fatigue, pain, and sleep disturbances. [14] The authors were trying to correlate autonomic nervous system function that included “sweaty palms” and “difficulty breathing” with depression and anxiety. [14] Only 24 questions with scores ranging from “very frequently” to “rare or never” may represent less of a challenge to the participant to thoughtfully answer.

Dx tests to keep or not in active vs Long Covid

• Cytokine profiles were all the 2020 rage with active Covid, but may or may not be worth the cost and health risks of dealing with infectious blood samples. ORF9c certainly adds an interesting twist if Covid-19 can evade our immune systems in Long Covid.
• If Long Covid is auto immune, CBC is a good and inexpensive test to keep.
• If Long Covid is auto immune, liver enzymes are a good and inexpensive test to keep.
• D-dimer is sort of iffy. The publication source pointed to anti-smooth muscle auto-antibodies that went along with D-dimer. The developing Covid literature is simply not supporting this one.
• Quality of Life Questionnaires. Long Covid and PTLD share overlaps. We could ask direct questions as to CDC’s list of active and long Covid symptoms. There is a short and sweet questionnaire that could be informative in conjunction with direct symptom questions that addresses the hypothesis that Cu(I)NA₂ helps autonomic nervous system functions. [13]

References

1. McFarland AJ, Yousuf MS, Shiers S, Price TJ. (2021) Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain. Pain Rep. 2021 Jan 7;6(1):e885. Free PMC article.
2. Lu L, Zhang H, Dauphars DJ, He YW.(2020) A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol. 2021 Jan;42(1):3-5. doi: 10.1016/j.it.2020.10.012. Epub 2020 Nov 2. PMID: 33214057 Free PMC article. Review.
3. Halpert G, Shoenfeld Y. (2021) SARS-CoV-2, the autoimmune virus. Autoimmun Rev. 2020 Dec;19(12):102695. Free PMC article.
4. Sartori, C. R., Pagliusi, M., Jr, Bonet, I., Tambeli, C. H., & Parada, C. A. (2020). Running wheel exercise induces therapeutic and preventive effects on inflammatory stimulus-induced persistent hyperalgesia in mice. PloS one, 15(10), e0240115. https://doi.org/10.1371/journal.pone.0240115 PMC free article
5. Singh, B., Kaur, P., & Maroules, M. (2021). Autoimmune Hepatitis-Primary Biliary Cholangitis Overlap Syndrome Triggered by COVID-19. European journal of case reports in internal medicine, 8(3), 002264. https://doi.org/10.12890/2021_002264 Free PMC article
6. Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS, Heightman M, Hillman TE, Jacob J, Jarvis HC, Lipman MCI, Naidu SB, Nair A, Porter JC, Tomlinson GS, Hurst JR; ARC Study Group. ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax. 2020 Nov 10:thoraxjnl-2020-215818. doi: 10.1136/thoraxjnl-2020-215818. Epub ahead of print. PMID: 33172844; PMCID: PMC7661378. Free PMC article
7. Lanini, S., Montaldo, C., Nicastri, E., Vairo, F., Agrati, C., Petrosillo, N., Scognamiglio, P., Antinori, A., Puro, V., Di Caro, A., De Carli, G., Navarra, A., Agresta, A., Cimaglia, C., Palmieri, F., D’Offizi, G., Marchioni, L., Kobinger, G. P., Maeurer, M., Girardi, E., … Ippolito, G. (2020). COVID-19 disease-Temporal analyses of complete blood count parameters over course of illness, and relationship to patient demographics and management outcomes in survivors and non-survivors: A longitudinal descriptive cohort study. PloS one, 15(12), e0244129. https://doi.org/10.1371/journal.pone.0244129 Free PMC article
8. Townsend L, Fogarty H, Dyer A, Martin-Loeches I, Bannan C, Nadarajan P, Bergin C, O’Farrelly C, Conlon N, Bourke NM, Ward SE, Byrne M, Ryan K, O’Connell N, O’Sullivan JM, Ni Cheallaigh C, O’Donnell JS. Prolonged elevation of D-dimer levels in convalescent COVID-19 patients is independent of the acute phase response. J Thromb Haemost. 2021 Feb 15. doi: 10.1111/jth.15267. Epub ahead of print. PMID: 33587810. Cross Ref
9. Rebman AW, Bechtold KT, Yang T, et al. . The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment Lyme disease syndrome. Front. Med. 2017;4:224 10.3389/fmed.2017.00224 [PMC free article]
10. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. (1989)The Fatigue Severity Scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol46(10):1121–3.10.1001 [CrossRef]
11. Melzack R. (1987)The short-form McGill Pain Questionnaire. Pain 30(2):191–7.10.1016/0304-3959(87)91074-8 [CrossRef]
12. Buysse DJ, Reynolds CF, III, Monk TH, Berman SR, Kupfer DJ. (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 28(2):193–213.10.1016/0165-1781(89)90047-4 [CrossRef]
13. Beck A, Steer R, Brown G. (1996) Beck Depression Inventory – Second Edition Manual. San Antonio: The Psychological Corporation; . [Google Scholar]
14. Neziroglul F, Yaryura-Tobias JA (1977) Development of an Autonomic Nervous System Questionnaire: Diagnostic Aid in Measurement of Anxiety, Depression, and Aggression. ORTHOMOLECULAR PSYCHIATRY, VOLUME 6, NUMBER 3, 1977, Pp. 265-271 [free article]