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The Long Haul COVID-19 Syndrome (LHCS) is characterized by prolonged malaise, headaches, generalized fatigue, sleep difficulties, hair loss, smell disorder, decreased appetite, painful joints, dyspnea, chest pain, and cognitive dysfunction. Up to 80% of patients experience prolonged illness after Covid-19. LHCS is not only seen after the COVID infection but it is being observed in some people that have received vaccines (likely due to monocyte/microglia activation by the spike protein from the vaccine). LHCS may persist 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. 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. The symptom set of LHCS is in the majority of the cases very similar to the chronic inflammatory response syndrome (CIRS)/ myalgic encephalomyelitis/ chronic fatigue syndrome. An important differentiating factor from CIRS is the observation that LHCS continues to improve on its own albeit slowly in the majority of cases. Another important observation is that LHCS includes more young people compared to severe COVID, which 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. The LHCS syndrome is highly heterogeneous and likely results from a variety of pathogenetic mechanisms. Furthermore, it is likely that delayed treatment (with ivermectin, etc.) in the early symptomatic phase will result in a high viral load which increases the risk and severity of LHCS. The following theories have been postulated to explain LHCS:

  1. Ongoing respiratory symptoms (SOB, cough, reduced effort tolerance) may be related to unresolved organizing pneumonia (activated pulmonary macrophages).

  2. Monocyte and microglia activation. The persistence of viral debris (spike protein?) in monocytes and microglia results in an ongoing inflammatory 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. Brain MRIs 3 months post-infection demonstrated micro-structural changes in 55% of patients.In addition, features of encephalopathy may be related to encephalitis and auto-reactive brain an- tibodies [517] as well as severe cerebral vasoconstriction. [518] The brain microvasculature expresses ACE-2 receptors and SARS-CoV-2 “pseudovirions” may bind to the microvascular endothelium causing cerebral micro-vascular inflammation and clotting.

  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 corticotropin-releasing hormone. Following stimulation, mast cells release pro-inflammatory mediators such as histamine, tryptase, chemokines, and cytokines which may result in neurovascular inflammation. The “brain fog”, cognitive impairment, and general fatigue reported in long-COVID may be due to mast cell-related neurovascular inflammation.

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 did not receive adequate antiviral treatment (e.g., ivermectin, etc.) during the acute symptomatic phase and adequate anti-inflammatory/macrophage repolarization therapy (e.g., corticosteroids, statins, omega-3 fatty acids, fluvoxamine, ivermectin, etc.) during the acute phase of COVID-19 are much more likely to develop the Post-COVID-19 Syndrome.

In patients with ongoing respiratory symptoms, chest imaging is suggested (preferably a chest CT scan). Those with unresolved pulmonary inflammation (organizing pneumonia with ground glass opacification) should be treated with a course of corticosteroids. Low-dose prednisolone/ methylprednisolone (10 mg/day) for six weeks is suggested. However, the patients’ symptoms and CRP should be followed closely as a dose escalation may be required in those who respond poorly. 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 of pattern with decreased residual volume and DLCO. These patients should be referred to a pulmonologist with expertise in pulmonary fibrosis. Anti-fibrotic therapy may have a role in these patients, 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. [364] Similar to patients who have recovered from septic shock, a prolonged (many months) immune disturbance with elevated pro-and anti-inflammatory cytokines may contribute to the LHCS. This is likely the consequence of monocyte activation syndrome and monocyte repolarization therapy is therefore indicated. Activated microglia may contribute to the neurological symptoms characteristic of LHCS. 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 the expression of pro-resolving lipids including Protectin D1 and Resolvin D4.