COVID-19 Long-haul Syndrome (Post COVID Syndrome): Symptoms, Treatment and I-RECOVER Protocol

Up to 80% of patients experience prolonged illness after COVID-19. LHCS (Long Haul COVID Syndrome) is not only seen after the COVID infection but it is being observed in some people that have received vaccines. 

According to a recent study of Mayo Clinic patients who had COVID-19, about 75% of the people suffering long COVID symptoms — defined as persistent symptoms even six months after recovery — are women.

LHCS may persistent for months after the acute infection and almost half of patients report reduced quality of life. Patients may suffer prolonged neuropsychological symptoms, including multiple domains of cognition. (Ref, Ref)

What are some common symptoms of post COVID syndrome? Their typical symptoms can include:
  • Headaches
  • Sleep difficulties
  • Hair loss
  • Smell disorder
  • Decreased appetite
  • Cognitive (ability to think) issues
  • Erratic heartbeat 
  • Chest pain
  • Fatigue
  • Gastrointestinal issues
  • Intolerance to physical or mental activity
  • Low-grade fever
  • Muscle and joint pain
  • Shortness of breath
NB: A syndrome is not a disease. It’s a group of signs and symptoms that may accompany more than one specific disease. In this case, the syndrome affects some people who have contracted the virus that causes COVID-19 and can mimic the symptoms of other, seemingly unrelated diseases.

COVID-19 long haulers report that these symptoms flare up unpredictably. They are often in different combinations and can be debilitating for days and weeks at a time. 

In one Italian study, COVID-19 long-haulers experienced fatigue, shortness of breath, joint pain, and chest pain, in that order. None of the patients in that study had a fever after their acute illness had passed. However nearly half of them reported their quality of life had suffered.

A puzzling feature of the LHCS syndrome is that it is not predicted by initial disease severity; post-COVID-19 frequently affects mild-to-moderate cases and younger adults that did not require respiratory support or intensive care. [411] The symptom set of LHCS is in majority of the cases very similar to the chronic inflammatory response syndrome (CIRS)/ myalgic encephalomyelitis/chronic fatigue syndrome.[411] An important differentiating factor from CIRS is the observation that LHCS continues to improve on its own albeit slowly in majority of the cases. Another important observation is that LHCS includes more young people compared to severe COVID that affects older people or persons with comorbidities. Furthermore, the similarity between the mast cell activation syndrome and LHCS has been observed, and many consider post-COVID to be a variant of the mast cell activation syndrome.[413] 

The LHCS syndrome in highly heterogenous and likely results from a variety of pathogenetic mechanisms. The following theories have been postulated to explain LHCS: [411] 
1. Ongoing respiratory symptoms (SOB, cough, reduced effort tolerance) may be related to unresolved organizing pneumonia (activate pulmonary macrophages). 
2. Monocyte activation syndrome. Persistence of viral debris in monocytes results in an ongoing immune response in an attempt by the immune system to clear the offending protein(s) and viral RNA fragments. 
3. The neurological symptoms may be related micro- and/or macrovascular thrombotic disease which appears to be common in severe COVID-19 disease.[414] Brain MRIs’ 3 months post-infection demonstrated micro-structural changes in 55% of patients. [415] In addition, features of encephalopathy may be related to encephalitis and auto-reactive brain antibodies [416] as well as severe cerebral vasoconstriction. [417] The brain microvasculature expresses ACE-2 receptors and SARS-CoV-2 “pseudovirons” may bind to the microvascular endothelium causing cerebral microvascular inflammation and clotting.[418]. 
4. An unmasking of mast cell activation syndrome (MCAS), or triggering of mast cell activation syndrome. Mast cells are present in the brain, especially in the median eminence of the hypothalamus, where they are located perivascularly close to nerve endings positive for corticotrophin releasing hormone.[419] Following stimulation, mast cells release proinflammatory mediators such as histamine, tryptase, chemokines and cytokines which may result in neurovascular inflammation.[419] The “brain-fog”, cognitive impairment and general fatigue reported in long-COVID may be due to mast cell related neurovascular inflammation.

Clinical signs and symptoms can be grouped in the following clusters. The reason for this grouping is to allow organ specific targeted therapy/individualized therapy. 
1. Respiratory: shortness of breath, congestion, persistent cough, etc. 
2. Neurological/psychiatric: brain fog, malaise, tiredness, headaches, migraines, depression, inability to focus/concentrate, altered cognition, insomnia, vertigo, panic attacks, tinnitus, anosmia, phantom smells, etc. 
3. Musculoskeletal: myalgias, fatigue, weakness, joint pains, inability to exercise, post-exertional malaise, inability to perform normal activities of daily life (ADL’s).
4. Cardiovascular: Palpitations, arrhythmias, Raynaud like syndrome, hypotension, and tachycardia on exertion. 
5. Autonomic: Postural tachycardia syndrome (POTs), abnormal sweating. 
6. GIT disturbance: Anorexia, diarrhea, bloating, vomiting, nausea, etc. 
7. Dermatologic: Itching, rashes, dermatographia 
8. Mucus membranes: Running nose, sneezing, Burning and itchy eyes. 

FLCCC I-Recover Protocol

Given the lack of clinical trials of long-haul COVID-19 syndrome, these recommendations are based on the abnormal changes within the body associated with the COVID-19 disease and post viral illnesses along with the collective experience of FLCCC members.

Approach to Treatment: 

The treatment approach should be individualized according to the grouping of clinical signs and symptoms. However, in general, it is likely that patients who received inadequate antiviral treatment (ivermectin) during the acute symptomatic phase and inadequate anti-inflammatory/macrophage repolarization therapy (corticosteroids, statins, omega-3 fatty acids, fluvoxamine, ivermectin, etc) during the acute phase of COVID are much more likely to develop the post-COVID syndrome. In patients with ongoing respiratory symptoms chest imaging is suggested (preferably a chest CT scan). Those with unresolved pulmonary inflammation (organizing pneumonia) should be treated with a course of corticosteroids (prednisone) and closely followed. A CRP should be measured, and extended corticosteroids (titrated to the CRP) offered to these patients. Similar to patients who have recovered from septic shock, [420] a prolonged (many months) immune disturbance with elevated pro- and antiinflammatory cytokines may contribute to the LHCS. This is likely the consequence of monocyte activation syndrome and monocyte repolarization therapy is therefore indicated. In addition, a cytokine panel may allow targeted anti-inflammatory therapy (Maraviroc in patients with high CCR5 levels) . It should be noted that much like omega-3 fatty acids, corticosteroids have been demonstrated to increase expression of pro-resolving lipids including Protectin D1 and Resolvin D4.[421] An unknown number of patients who have recovered from COVID-19 organizing pneumonia will develop pulmonary fibrosis with associated limitation of activity. Pulmonary function testing demonstrates a restrictive type pattern with decreased residual volume and DLCO.[406] These patients should be referred to a pulmonologist with expertise in pulmonary fibrosis. Anti-fibrotic therapy may have a role in these patients, [380-383] however additional data is required before this therapy can be more generally recommended. As discussed above, the serotonin receptor blocker cyproheptadine may reduce the risk of pulmonary fibrosis. [256]

How to treat COVID long haulers symptoms: FLCCC I-Recover Protocol

Although numerous reports describe the epidemiology and clinical features of post-COVID syndrome, studies evaluating treatment options are glaringly sparse. Indeed, the NICE guideline for managing the long-term effects of COVID-19 provide no specific treatment recommendations. In general, while the treatment of ‘Long COVID” should be individualized, the following supplements may have a role in the treatment of this disorder. 

long haul syndrome

First-line treatment based on the FLCCC I-Recover Protocol.
  • Ivermectin has been reported to have a role in the treatment of post-COVID-19 syndrome. A dose of 0.2-0.4 mg/kg day for 3-5 days, followed by once or twice weekly dosing for ongoing symptoms for up to 4 weeks. Discontinue after 2 - 4 weeks if all symptoms have resolved. A repeat course is recommended in those who respond poorly or relapse once the treatment is stopped. The anti-inflammatory properties of ivermectin may mediate this benefit.
  • If inadequate response to ivermectin: Prednisone 0.5mg/kg daily for 5 days, 0.25mg/kg for 5 days followed by 0.12 mg/kg for 5 days. Patients with persistent organizing pneumonia may require higher doses for a more prolonged period of time. 
  • If presenting with neurological symptoms i.e. poor concentration, mood disturbance. Fluvoxamine 50 -100 mg day for 15 days. Monitor response closely as some patients will respond poorly to this medication. Teens and young adults who are prescribed fluvoxamine can experience acute anxiety which needs to be monitored for and treated by the prescribing clinician to prevent rare escalation to suicidal or violent behavior. 
Supplements recommended to support the therapy

Omega-3 fatty acids: Vascepa, Lovaza or DHA/EPA 4 g day. Omega-3 fatty acids play an important role in the resolution of inflammation by inducing resolvin production. [154,155] 
• Melatonin 2- 5 mg at night (slow release/extended release) with attention to sleep hygiene. 
• Vitamin D3 1000-3000 u/day 
• Vitamin C 500 mg BID (vitamin C inhibits histamine).[62] 

Other Supportive Therapies

• Functional rehabilitation with light aerobic exercise paced according to individual capacity.[411] 
• Behavioral modification and psychological support may help improve survivors’ overall well-being and mental health. [423]

Second-line approach (after poor response to first-line protocol) and treatment of suspected mast cell activation

Choose a type 1 (loratadine or cetrizine) and type II antihistamine (famotidine) along with a mast cell stabiliser (rupadatadine, quercetin or luteoline).

Second line:
  • montelukast 10 mg/day (for mast cell activation syndrome). Caution as may cause depression in some patients. 
  • SSRIs (selective serotonin reuptake inhibitors) e.g. fluvoxamine, fluoxetine (prozac).
Find health care providers (US):

COVID long haulers chances of dying

Researchers are learning new details about the long-term effects of COVID-19. A new study shows COVID-19 "long haulers" have a significantly higher chance of dying months after their infection.

According to the paper in Nature, COVID survivors have a 59 percent higher risk of death within six months of contracting the virus. This comes amid growing recognition of the long-term issues caused by Covid. “When we are looking at the acute phase, we’re only pretty much looking at the tip of the iceberg,” Ziyad Al-Aly, the researcher responsible for leading the study, told Bloomberg. Al-Aly and his fellow researchers have uncovered a host of conditions affecting survivors, including breathing difficulties, nervous system disorders, and musculoskeletal pain. They also found that “long haulers” are more likely to use antidepressants and pain meds. “We worry about potential spikes in suicide or potential spikes in overdose of opioids,” said Al-Aly, who said he hoped the research would help inform future treatment of long-haul COVID survivors.


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For details of other reference links mentioned above, check out REFERENCES (page 43 onwards).



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