Abstract
Objective
Long COVID has afflicted tens of millions globally leaving many previously-healthy persons severely and indefinitely debilitated. The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications.
Design
Case histories of the first three index events (among others) are presented. Unaware of others with similar remissions, each subject independently completed personal narratives and standardized surveys regarding demographics/occupation, past history, and the presence and respective severity grading of 33 signs/symptoms associated with long COVID, comparing the presence/severity of those symptoms during the pre-COVID, long-COVID, post-vaccination, and post-MCA phases.
Setting
Patient interviews, e-mails and telephone conversations.
Subjects
Three previously healthy, middle-aged, highly-functioning persons, two women and one man (ages 60, 43, and 63 years respectively) who, post-acute COVID-19 infection, developed chronic, unrelenting fatigue and cognitive impairment along with other severe, disabling symptoms. Each then independently reported incidental and unanticipated complete remissions within days of MCA treatment.
Interventions
The casirivimab/imdevimab cocktail.
Measurements and main results
Irrespective of sex, age, medical history, vaccination status, or illness duration (18, 8 and 5 months, respectively), each subject experienced the same complete remission of their persistent disabling disease within a week of MCA infusion. Each rapidly returned to normal health and previous lifestyles/occupations with normalized exercise tolerance, still sustained to date over two years later.
Conclusions
These index cases provide compelling clinical signals that MCA infusions may be capable of treating long COVID in certain cases, including those with severe debilitation. While the complete and sustained remissions observed here may only apply to long COVID resulting from pre-Delta variants and the specific MCA infused, the striking rapid and complete remissions observed in these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions and long COVID from other variants.
Key points
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Question: Considering that long COVID-19 has been devastating for many millions worldwide, what is the proposed pathophysiology and are there any effective treatments?
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Findings: Previously-healthy middle-aged persons who had developed persistent debilitating post-acute SARS-CoV-2 sequelae, each experienced complete remission of their symptoms within days of receiving a specific monoclonal antibody infusion despite relative differences in sex, age, medical history, vaccination status, and long COVID duration.
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Meaning: Certain monoclonal antibody infusions may be capable of reversing severe long COVID. Beyond providing an effective potential treatment for long COVID, these findings have mechanistic implications for treating other post-viral chronic conditions, including future long COVID variants.
Highlights
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Long COVID-19 remains crippling for millions and their families worldwide.
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The first three index cases of therapeutic complete remission are reported here.
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Each full remission occurred within a week monoclonal antibody infusion.
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Remission occurred despite dissimilar past histories, sex, age, illness duration.
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This has mechanistic implications for treating other post-viral chronic conditions.
1
Introduction
SARS-CoV-2 has led to devastating worldwide physical, mental, social, and economic travail, including tremendous loss of life, protracted hospitalizations, and significant attrition of healthcare personnel. However, these well-recognized sequelae are compounded by the troubling, complex and many-faceted complication of “long COVID.”
Most common in adults, long COVID occurs among those hospitalized for acute SARS-CoV-2 infection, but also in those initially experiencing mild or even unnoticed symptoms. The United States (U.S.) Center for Disease Control and Prevention (CDC) has reported that as many as 69% of adult COVID-19 patients will develop long COVID with formal identification/diagnosis occurring about 28 to 128 days after the initial infection and that two-thirds manifest as a new primary complication [ ]. By June 2022, U.S. estimates had reached 25 million persons affected and likely many more. Globally, long COVID is observed in one-third to one-half of cases [ , ]. Lower acuity cases may not be tallied at all.
Depending on reporting entities, the “long COVID” moniker has been applied to a diversity of chronic conditions arising after acute SARS-CoV2 infection [[ ]; Appendix A]. Pathophysiological mechanisms include: 1) architectural tissue destruction such as lung-scarring post-acute COVID-19 pneumonitis or post-thrombotic loss of limbs [ ]; 2) permanent damage to poorly-healing tissues such as taste/smell neurons [ , ]; or 3) dysfunctional immunological/inflammatory response and imbalances leading to auto-immune conditions and/or indiscernible persistent COVID-19 infection processes [ ], with the latter mechanisms resembling myalgic encephalomyelitis/severe chronic fatigue syndrome (ME/CFS).
Recent ME/CFS studies have suggested that long COVID may be related to Epstein-Barr virus (EBV) reactivations [ , ]. Other investigations indicate evidence of persistent COVID-19 harboring in gastrointestinal tracts of long COVID patients [ , ]. These imply either autoimmune conditions [ ] and/or chronic ongoing “occult” infection in gastrointestinal tracts or other anatomic compartments [ , ]. Like ME/CFS, predominant long COVID manifestations are cognitive difficulties (often reported as “mental fog” or “brain fog”) and/or severe fatigue. Postural orthostatic tachycardia syndrome (POTS) and other complications have been described, but severe refractory fatigue occurs in >75% of cases [ , , , , , ].
Long COVID has striking similarities with the CFS following reactivation of other latent viral infections such as cytomegalovirus (CMV), EBV, herpes type 6, and herpes zoster [[ , , , ]; Appendix A]. Long COVID CFS could be a persistent low-grade endothelialitis complicated by maladapting imbalances in complex immune responses and resulting multi-organ mitochondrial dysfunction [Appendix A]. Among persons hospitalized with COVID-19, half develop one or more IgG auto-antibodies, including those that attack cytokines, while others produce anti-nuclear antibodies similar to various autoimmune diseases [ ]. Apolipoprotein A-1 antibodies are found in up to 93% of patients. In certain patients, some of the antibodies identified work against HCRTR2 sites, the receptor that binds to orexin (hypocretin), thus possibly explaining long COVID interference with wakefulness, energy, and appetite issues [ ].
Case reports of COVID-19 vaccination mitigating long COVID-19 could also indicate augmented immune responses helping to neutralize harboring viruses and/or displace dysfunctional antibodies attached to cells [ ]. Either way, vaccinations only reduced symptomatology and did not fully-reverse the illness.
Therefore, a compelling observation, being reported here, is how incidental use of a specific monoclonal antibody (MCA) treatment was able to completely-reverse the profound chronic fatigue and “brain fog” of long COVID within days of administration. In each case, MCA infusions were intended to help prevent worsening of the chronic conditions following new COVID-19 exposures. Having experienced and accepted their longstanding illnesses as permanent COVID-19 sequelae, neither medical personnel, the patients, nor their families had anticipated improvements, let alone complete remissions.
To remain concise while also documenting this profound clinical observation in detail, the first three index cases (among many others) are being used because, by themselves, each persuasively illustrate this serendipitous observation. In all three cases, long COVID symptoms had been severely debilitating and unrelenting (for 18 months in one case), yet each person had the same complete (and sustained) rapid remission within 5–7 days of MCA administration regardless of age, sex, medical history or duration of long COVID.
2
Methods and materials
This project is compliant with the 1975 Helsinki Declaration and received human subjects review from the Florida Department of Health (FDOH) Ethics and Human Research Protection Program (IRB protocol #2022–065, Principal Investigator, Paul E. Pepe, MD, MPH) which determined exempt status and waiver of informed consent (latest approval, 08/25/2022). Nonetheless, each person, whose case histories are described here, did eagerly provide consent to report their cases to help others.
To better capture and compare individual experiences in a relatively standardized fashion, each were, independently, given the same set survey that assessed demographics and medical history [ Table 1 ] and scored 33 signs/symptoms associated with long COVID-19 [ Table 2 ]. Symptom severity and impact were graded as: 0 (“symptom not present”); 1–3 (“some impact on daily life”); 4–6 (“significant impact on daily life”); and 7–10 (“severe impact on daily life and ability to function”). Scores were provided for the following phases: 1) before COVID; 2) during long COVID; 3) post-COVID vaccinations; and 4) post-MCA treatment [ Tables 1-2 ; Fig. 1 ].
| Patient Number | Patient 1 | Patient 2 | Patient 3 |
|---|---|---|---|
| Age (years) | 60 | 43 | 63 |
| Sex (M/F) | F | F | M |
| Date of COVID Diagnosis | Mar-2020 | Jan-2021 | May-2021 |
| Positive COVID PCR Test – Y or N (Yes or No) | N/A | N/A | Y |
| Rapid Antigen Test Positive (Y or N) | N/A | Y | N/A |
| Antibody Test Positive (Y or N) | Y | N/A | N |
| Clinical Diagnosis (Y or N) | Y | Y | Y |
| Hospitalized (Y or N) | N | N | N |
| Vaccinated (Y or N) | Y | Y | N |
| If Yes, Which Vaccine(s) | Pfizer | Pfizer | N/A |
| If Yes, When Vaccine(s) | Jan 2021, Feb 2021 | Mar 2021, Apr 2021 | N/A |
| Any Improvement/Worsening After Vaccination (Y or N) | N | Y | N/A |
| Height (′ = foot; ʺ = inches) | 5′6ʺ | 5′5ʺ | 5′11ʺ |
| Weight (pounds) | 125 | 132 | 280 |
| Past Medical Problems / Possible COVID Risk Factors | HTN | Anemia | DM, HTN |
| Date of Monoclonal Antibodies Administration | Oct-2021 | Sep-2021 | Oct-2021 |
| Pre-COVID (Baseline) Symptom Score for Patient 1, 2 and 3 | Symptom Score During Long COVID Phase for Patient 1, 2 and 3 | Post-Vaccine Symptom Score for Patient 1, 2 and 3 | Symptom Score 1 week after MAC Treatment for Patient 1, 2 and 3 | |
|---|---|---|---|---|
| Symptom | ||||
| Physical Fatigue (Lack of energy) | 0, 1, 0 | 7, 10, 9 | 7, 9, N/A | 1, 2, 0 |
| Exercise Intolerance (Distance walked/Ability to climb stairs) | 0, 0, 0 | 9, 10, 9 | 9, 10, N/A | 1, 1, 0 |
| Muscle Aches/Bone Aches | 2, 0, 0 | 7, 8, 5 | 7, 8, N/A | 2, 3, 0 |
| Low Muscle Tone | 3, 2, 0 | 8, 9, 9 | 8, 9, N/A | 6, 7, 0 |
| Joint Pain | 2, 0, 0 | 8, 8, 0 | 8, 8, N/A | 1, 0, 0 |
| Chest Pain | 0, 0, 0 | 7, 0, 0 | 7, 0, N/A | 0, 0, 0 |
| Heart Racing/ Palpitations | 1, 0, 0 | 5, 9, 0 | 5, 8, N/A | 1, 0, 0 |
| Shortness of Breath | 0, 0, 0 | 7, 10, 0 | 7, 7, N/A | 0, 0, 0 |
| Dizziness Upon Standing | 0, 0, 0 | 2, 9, 5 | 2, 7, N/A | 0, 0, 0 |
| Dizziness at Rest | 0, 0, 0 | 2, 10, 0 | 2, 7, N/A | 0, 0, 0 |
| Nausea/Motion Sickness | 0, 0, 0 | 3, 6, 0 | 3, 7, N/A | 0, 1, 0 |
| Balance Issues | 0, 0, 0 | 2, 8, 7 | 2, 6, N/A | 0, 3, 0 |
| Brain Fog/Difficulty Concentrating | 0, 2, 0 | 7, 10, 5 | 7, 8, N/A | 2, 2, 0 |
| Cognitive fatigue (easily tired with cognitive tasks) | 0, 1, 0 | 7, 9, 5 | 7, 7, N/A | 1, 1, 0 |
| Difficulty with Memory | 0, 2, 0 | 8, 10, 5 | 8, 8, N/A | 1, 2, 0 |
| Speech Issues (struggle to find words) | 0, 0, 0 | 7, 7, 5 | 7, 2, N/A | 1, 0, 0 |
| Headache | 1, 2, 0 | 3, 9, 0 | 3, 3, N/A | 1, 2, 0 |
| Emotional Lability | 0, 1, 0 | 3, 6, 5 | 3, 6, N/A | 0, 1, 0 |
| Nerve Pain/ Paresthesia | 6, 0, 0 | 9, 7, 0 | 9, 6, N/A | 6, 0, 0 |
| Vibration Sensations | 0, 0, 0 | 5, 8, 0 | 5, 8, N/A | 0, 0, 0 |
| Tremors | 0, 0, 0 | 0, 4, 0 | 0, 1, N/A | 0, 0, 0 |
| Tinnitus | 0, 0, 0 | 0, 2, 0 | 0, 2, N/A | 0, 0, 0 |
| Noise Intolerance (Sensitive to sound) | 0, 0, 0 | 0, 6, 0 | 0, 6, N/A | 0, 0, 0 |
| Sensory Sensitivity (Sensitive to touch) | 0, 0, 0 | 3, 5, 0 | 3, 5, N/A | 0, 0, 0 |
| Decreased/Altered Sense of Smell | 3, 0, 0 | 5, 7, 0 | 5, 5, N/A | 5, 1, 0 |
| Decreased/Altered Sense of Taste | 1, 0, 0 | 5, 7, 0 | 5, 5, N/A | 5, 1, 0 |
| Vivid Dreams/Nightmares (Ongoing) | 0, 1, 0 | 7, 7, 0 | 7, 2, N/A | 0, 1, 0 |
| Difficulty with Sleep/Unrestful Sleep | 2, 2, 0 | 8, 6, 0 | 8, 6, N/A | 3, 4, 0 |
| Rashes | 0, 1, 0 | 0, 6, 0 | 0, 3, N/A | 0, 1, 0 |
| Heat Intolerance (Unable to tolerate warmer temperatures) | 2, 2, 0 | 5, 8, 0 | 5, 8, N/A | 3, 2, 0 |
| Pale Skin | 0, 1, 0 | 6, 10, 0 | 6, 10, N/A | 0, 1, 0 |
| Fever (Relapsing) | 0, 0, 0 | 3, 0, 0 | 3, 0, N/A | 0, 0, 0 |
| Total Score | 23, 18, 0 | 158, 231, 69 | 158, 187, 69 | 40, 36, 0 |
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