Click Here to Download this Blog Post –  Long COVID 2025 Part 1

Dr. Nicholas L. DePace, M.D., F.A.C.C.

This is Part 2 of a 5 Part Series about Redefinition of Long COVID

In the New England Journal of Medicine, a pivotal article titled Long Covid Defined, authored by Ely, Brown, and Fineberg et al., was published on July 31, 2024. It describes how the COVID-19 pandemic, while recognized for its deadly acute phase that claimed over one million lives in the U.S. and seven million globally, also gave rise to a lingering public health emergency—Long COVID. The authors emphasized that millions of survivors now suffer from chronic, often disabling symptoms.

Estimating the Scale of Long COVID

Various estimations suggest that Long COVID may affect up to 10% of adults who contracted the virus and 2% who were vaccinated. According to the New England Journal article, survey data shows that around 7% of adults and over 1% of children report symptoms consistent with Long COVID. This equates to approximately 50–60 million people globally who may be suffering from the syndrome.

Defining Long COVID: A Committee-Based Approach

The article introduced a formal definition of Long COVID, developed by a specialized committee. They noted hallmark symptoms such as cognitive impairment, neuromuscular issues, depression, and severe fatigue. Due to the lack of standardized diagnostic criteria, the committee employed a multi-phase process involving systemic engagement, focus groups, and questionnaires to gather comprehensive insights.

Clinical Definition and Symptomatology

According to the committee, Long COVID is an infection-associated chronic condition following SARS-CoV-2 infection. It is defined by a disease course lasting at least three months and may be continuous, relapsing and remitting, or progressively worsening. Long COVID can affect multiple organs and presents with a wide variety of symptoms.

Common symptoms include:

• Shortness of breath and chronic cough

• Persistent fatigue and post-exertional malaise

• Cognitive dysfunction (“brain fog”) and memory issues

• Recurring headaches, lightheadedness, and rapid heart rate

• Sleep disturbances and altered taste or smell

• Gastrointestinal symptoms such as bloating, constipation, and diarrhea

These symptoms are frequently observed in conditions involving dysautonomia—disorders of the autonomic nervous system affecting both the parasympathetic and sympathetic branches.

Viral Triggers and Related Conditions

The symptoms of Long COVID are not unique to SARS-CoV-2. Similar post-viral syndromes have been linked to Epstein-Barr virus, enteroviruses, and others. The committee pointed out that Long COVID can manifest as singular or multiple overlapping conditions.

These include:

• Interstitial lung disease and low oxygen saturation (hypoxemia)

• Heart complications like arrhythmias and cardiovascular disease

• Strokes, blood clots, and kidney dysfunction

• Postural Orthostatic Tachycardia Syndrome (POTS)

• Fibromyalgia and other chronic fatigue-type conditions

• Connective tissue diseases and metabolic disorders such as diabetes and hyperlipidemia

• Autoimmune diseases like lupus, rheumatoid arthritis, and Sjögren’s syndrome

• Mast Cell Activation Syndrome (MCAS)

Click Here to Download this Blog Post –  Long COVID 2025 Part 1

Dr. Nicholas L. DePace, M.D., F.A.C.C.

This is Part 1 of a 5 Part Series about Redefinition of Long COVID

Long Covid: A Chronic Condition Emerging From the Pandemic

In the New England Journal of Medicine, an article was published Long Covid Defined, authored by Ely, Brown, and Fineberg et.al; July 31, 2024.  They describe how the COVID-19 pandemic was a dangerous acute outbreak of infection that killed more than one million people in the United States and seven million worldwide.

Millions Left With Lasting Symptoms

More importantly, the authors emphasize that millions were left with chronic, disabling symptoms post-infection, known as Long Covid. Estimates suggest up to 10% of adults infected and 2% of vaccinated individuals may develop it.

Prevalence Among Adults and Children

The article cites survey data indicating that 7% of adults and more than 1% of children may suffer from Long Covid—translating to 20 to 50 million cases in the U.S. and 60 million globally.

A New Definition for Long Covid

A committee defined Long Covid as an infection-associated chronic condition lasting at least three months after SARS-CoV-2 infection. It may follow a continuous, relapsing, remitting, or progressive course and affect one or more organs.

They used a multiphase process of systemic engagement and information gathering and included focus groups, questionnaires and so forth.

The committee stated that long Covid is an infection-associated chronic condition that occurs after the SARS-CoV-2 infection and is present for at least three months as a continuous, relapsing, and remitting or progressive disease state that affects one or more organs.

Common Symptoms and Clinical Manifestations

Key symptoms include cognitive impairment, neuromuscular issues, depression, and severe fatigue. Additional symptoms include shortness of breath, persistent cough, post-exertional malaise, brain fog, fast heart rate, sleep disturbances, and gastrointestinal issues like bloating and diarrhea.

Link to Dysautonomia and Other Viral Triggers

These are symptoms that we see very commonly in people with dysautonomia or autonomic dysregulation syndromes, that is, abnormalities of the autonomic nervous system involving either or both branches, the parasympathetic and sympathetic systems.

Other viruses are known to cause these symptoms, including Epstein-Barr, enteroviruses, and so forth.  The symptoms are not specific for Covid in a post-viral syndrome.

However, the committee went on to state that singular multiple conditions, such as interstitial lung disease, low oxygen levels or hypoxemia, heart disease and arrhythmias, strokes and blood clots, kidney disease and racing heart rate when standing (postural orthostatic tachycardia syndrome), and other forms of dysautonomia and chronic fatigue-type syndromes can be present.

They discussed fibromyalgia, connective tissue disease disorders, hyperlipidemia, diabetes, and autoimmune disorders, such as lupus, rheumatoid arthritis, and Sjögren’s disease.  They even discussed mast cell activation syndrome as being operative in a long Covid syndrome.

Click Here to Download this Blog Post – Treatment in Long COVID Syndrome

For the most part, supportive therapy for Long-COVID symptoms is a keystone, and there is treatment for autonomic dysfunction that may be demonstrated objectively in a laboratory.  As mentioned earlier, volume expanders and oral-vasoactives,  in addition to fluids, electrolytes, compression garments, and  various exercise techniques, have been prescribed for orthostatic intolerance symptoms . Omega-3 fatty acids  and dietary supplementation have been investigated.  It is believed that omega-3 s may help resolve inflammatory  imbalance. L-Arginine has also been proposed as a treatment  modality. Included in the L-arginine pathway is the pro duction of nitric oxide. Nitric oxide maintains or improves  the health and function of endothelial cells and benefits the  immune system, especially in chronic fatigue states.  Various antioxidants, including zinc, have also been  used empirically, but there are no controlled studies to confirm their utility. We have found alpha-lipoic acid, used as an  antioxidant to relieve autonomic neuropathy in populations of  patients diagnosed with type 2 diabetes mellitus,  to be effective in Long-COVID patients. Electrical neuro prostheses stimulating either the parasympathetic (vagus) or  sympathetic nervous system have been known to help relieve  symptoms of autonomic dysfunction. All of these  therapies also effect proper autonomic function to help relieve  Long-COVID symptoms. Vaccination has been suggested as possibly a factor that may ease symptoms of Long COVID. In one large survey, 57% of responders reported an  overall improvement in their symptoms following vaccination,  and around 19% reported an overall deterioration. Mental health conditions may be treated with various psychological  aides, such as cognitive behavioral therapy as well as anti-depressants, including tricyclics. Treatment of liver function  abnormalities, irritable bowel syndrome, dyspepsia, and other  GI symptoms is very challenging. Renal dysfunction should  be followed serially, nephrotoxins avoided, and proper hydration maintained. However, from a large study of fully vaccinated people, 2.6% were found to contract the virus (labeled as  “breakthrough” patients). Among 1497 fully vaccinated  healthcare workers for whom RT-PCR data were available,  39 SARS-CoV-2 breakthrough infections were documented.  Neutralizing antibody titers in case patients during the peri infection period was lower than those in matched uninfected  controls (case-to-control ratio, 0.361; 95% confidence interval,  0.165 to 0.787). Higher peri-infection neutralizing antibody  titers were associated with lower infectivity (higher Ct values).  Most breakthrough cases were mild or asymptomatic, although  19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha)  variant was found in 85% of samples tested. A total of 74%  of case patients had a high viral load (Ct value,<30) at some  point during their infection; however, of these patients, only  17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented. Among fully vaccinated  healthcare workers, the occurrence of breakthrough infections  with SARS-CoV-2 was correlated with neutralizing antibody  titers during the peri-infection period. Most breakthrough  infections were mild or asymptomatic, although persistent  symptoms did occur.

Click Here to Download this Blog Post – SARS-CoV-2 infection [COVID-19]

SARS-CoV-2 infection (COVID-19) is a major pandemic  that is worldwide and itself is causing significant mortality  and morbidity. A subset of patients have presented  with lingering, persistent, or prolonged symptoms for  weeks or months afterwards, regardless of the severity of COVID infection [5–9]. This lingering condition has been  labeled “post-acute sequelae of SARS-CoV-2 infection” syndrome or simply the “post-acute COVID-19 syndrome” or  “long-COVID-19” or just “Long-COVID” or “long haulers  COVID-19” or simply “long haulers” or “post-COVID syndrome”. This has extended the significant worldwide  morbidity from the COVID-19 pandemic. It is estimated that  43% of patients who tested positive for SARS-COVID-19  will remain ill beyond 3 weeks, and this percentage  may continue to rise. This is the subset that constitutes the  Long-COVID syndrome. This does not include those who  are not confirmed with acute COVID-19 that present with  Long-COVID. Myocarditis is a common result of viral  infection usually caused by oxidative stress due to the virus’  attack on the mitochondria in the heart muscle cell.  Oxidative stress also has a significant effect on the nervous  system given that all nerves contain some of the highest  amounts of mitochondria of all cells in the body. Oxidative  stress produced in the mitochondria and cytosol of the heart,  brain, and nervous system cells contributes to dysfunction and aging of the organs. The Cytokine storm  involved in COVID-19 infections is a source of oxidative stress, and there are over 1200  references (circa. 2022) relating oxidative stress to parasympathetic and sympathetic (P&S) dysfunction. Cardiac injury and primary arrhythmia may occur long-term in  Long-COVID patients, but in our experience, these patients  comprise a very small percentage of the Long-COVID population. The majority of Long-COVID patients with lingering cardio-neuro symptoms and disability present with P&S  dysfunction(s). 

This prolonged post-COVID phase, with morbidity and  ongoing symptoms, creates significant burden to the patient  and to the healthcare system and is not completely under stood. Not just quality of life, including mental and cognitive  health, but employment and productivity issues become paramount when the acute, the subacute, and the chronic phases  of COVID-19 occur. The recovery from COVID-19  usually occurs at 7 to 10 days after the onset of symptoms  in mild disease but could take 6 weeks or more in severe or  critical cases. Laboratory abnormalities may be present and  include low lymphocyte counts and elevated inflammatory  markers (e.g., sedimentation rate, C-reactive protein, ferritin, interleukin 1 and 6, and tumor necrosis factor).  Coagulation system abnormalities may occur. Clots may form in the acute phase as well as in the  subacute phase, especially if there is a history of thrombus  formation. The symptoms of Long COVID may be traced to P&S dysfunction and oxidative  stress due to viral infection, including COVID-19 and other  sources.