Long-COVID is associated with sustained biochemical disturbances especially elevated levels of D-dimers and Ferritin

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A new study led by researchers from Columbia University-USA along with support of scientists from the Zan Mitrev Clinic-North Macedonia and University of Florence-Italy has found that Long-COVID is associated with sustained biochemical disturbances especially elevated levels of D-dimers and Ferritin.

The Study team aimed to evaluate the incidence of Post-Acute Sequelae of COVID-19 or PASC (Long COVID) in previously hospitalized COVID-19 patients and compare the admission and follow-up levels of biochemical parameters stratified according to baseline clinical severity.
 
A total of 168 COVID-19 patients previously hospitalized at the Zan Mitrev Clinic in Skopje, North Macedonia, with matched laboratory data at baseline and follow-up clinical visit > 30 days post-discharge, were stratified according to National Institute of Health clinical severity guidelines as mild, moderate, severe or critical according to admission clinical presentation. The study team assessed the incidence of PASC and compared the biochemical profile.
 
The median hospitalization and clinical follow-up period were 11 (9-20) and 53 (30-105) days. The overall incidence of PASC was 56.5% (95/168); most PASC cases were confined to the severe sub-group (61/101, 61.4%).

Contrary to mild and moderate cases and a healthy “non-COVID-19” control cohort, the team observed that severe COVID-19 cases experienced sustained biochemical disturbances, most notably elevated D-dimers and Ferritin of 600 ng/ml (283-1168) and 432 ng/ml (170-916), respectively.
 
The study findings found that previously hospitalized severe COVID-19 patients are more likely to experience Post-Acute Sequelae of COVID-19 and prolonged biochemical disturbances, evident by abnormal values of D-dimers and Ferritin.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.09.02.21262599v1
 
Many past studies have repeatedly demonstrated that a large percentage of individuals with a prior SARS-CoV-2 infection exhibit lingering symptoms such as fatigue, dyspnoea, and impaired pulmonary function, particularly amongst those with a history of severe COVID-19.
 
The biochemical parameters of long-COVID patients with prior mild, moderate, or severe COVID-19 that resulted in hospitalization were tracked in detail n this study, finding a characteristically dysregulated immune and inflammatory response in the most seriously ill.
 
The study involved a total of 168 COVID-19 patients that had been hospitalized for at least three days and had robust laboratory data available were recruited for the study. All donated further blood specimens for testing on average two months later.
 
The study findings showed that 56.5% of all participants reported long-COVID symptoms at the time of second sampling, and as the participants were categorized based on disease severity at the time of admission and during their stay at hospital the group note that 63.54% of those with long-COVID had previously been diagnosed with severe COVID-19, compared with around 20% each of those classed as mild or moderate, respectively.
 
It was found that 60.4% of those that had previously suffered from severe COVID-19 developed long-COVID, while 47.4% and 58.6% of patients with mild or moderate COVID-19 developed long-COVID, respectively, according to clinical assessment of symptoms.
 
However unlike other studies or Long COVID News, this finding suggests that there is no significant correlation between disease severity and the probability of developing lingering symptoms. Those with prior severe illness made up a more significant proportion of those with long-COVID in the sample.
 
It should be noted however that the participants in this study were each hospitalized for at least three days, and thus results are likely to be skewed towards individuals more likely to experience poorer health.
 
Detailed biochemical testing of severe COVID-19 patients now with long-COVID demonstrated upregulated ferritin, D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), and interleukin(IL)-6 levels at later time points, with the most severe cases also displaying dysregulated white blood cell profiles.

It was also found that in those with mild to moderate COVID-19 only D-dimer levels were slightly elevated, with all other tested parameters returning to baseline by the second sampling.
 
Importantly more elevated levels of D-dimer and ferritin were observed amongst the severely ill at hospital admission and at later time points, as has been reported in other studies, with ferritin, in particular, exhibiting extremely high levels, in particular, the severely ill.
 
The study team speculates that this may be due to unbound iron playing a role in inflammation. They also suggest that sustained LDH levels in the severely ill may be an indication of ongoing lung repair.
 
Also the elevated inflammatory agents such as CRP and IL-6 may result from greater levels of lung damage and hypoxia experienced during illness.
 
Many other past studies have also reported ongoing elevated levels of IL-6 with the presence of pulmonary lesions in those recovering from severe COVID-19, which the study team suggests coincides with the reported greater incidence of long-COVID symptoms in this group.
 
Among the most commonly reported symptoms from the severe group with long-COVID was lung or chest pain, which is reported around half as often by those with prior mild or moderate COVID-19, with fatigue being most commonly reported in 16%, 20%, and 24% of mild, moderate, or severe patients, respectively.
 
Importantly individuals that experienced only mild or moderate COVID-19 and were considered to have long-COVID based on symptoms appear to have been overrepresented in this study, with almost 60% of individuals in any category of severity reportedly experiencing lingering symptoms for as long as three months post-hospitalization.
 
It must be also noted that although the biochemical profile of those with either mild or severe COVID-19 differed substantially during hospitalization and follow-up, those with a history of severe COVID-19 could be differentiated from the mildly or moderately ill by their significantly dysregulated biochemical profile.


Importance of biochemical parameters in COVID19

Several pro-inflammatory cytokines and chemokines were observed in the bloodstream and target tissue of COVID-19 patients. Ferritin is widely known as an acute phase reactant and as a mediator for severe COVID-19 immunological dysfunction. Ferritin may therefore be an active agent not only in a cytokine storm but also a signal of the inflammatory environment. COVID-19. Complex feedback loops may exist between ferritin and cytokines, as cytokines may increase the expression of ferritin, but ferritin can induce the expression of pro and ant inflammatory cytokines.

In this sense the range of hyperferritinemic syndrome could cover COVID-19 with pulmonary involvement (Alunno et al., 2020, Gandini et al., 2020, Kappert et al., 2020). Ferratin is the intracellular reserve of iron, and iron insufficiency is well known. Anemia is distinguished by low ferritin levels. High levels of iron storage imply the presence of several viruses or bacteria in the human body. This can be accomplished by measuring ferritin levels even in the presence of a transient presence of COVID-19.

According to research, high ferritin levels indicate the severity of COVID-19, as COVID patients with particularly high ferritin levels died in 50% of cases. A series of physiological and metabolic changes start immediately after tissue injury are the active phase reaction of an inflammatory process.

The fluctuation in the concentration of certain plasma proteins called acute phase proteins is one of the many systemic symptoms of this acute phase reaction. Most commonly used among them is C-reactive protein, amyloid serum A, haptoglobin, fibrinogen, and ferritin. Serum Ferritin has been extensively investigated as a measure of iron metabolism, however, it has recently shown a great importance in the context of COVID-19 progression as proven by past studies. Ferritin is an acute phase reactant, and, as such, is typically raised in any inflammatory response.

To assess for the most typically seen cytokine storm syndromes laboratory findings include a complete blood count, serum ferritin levels, and liver function tests. Most medical facilities provide these testing (Lino et al., 2021). Tang et al studies found that higher fibrin-relevant (d-dimer and fibrin degradation product) levels were significantly associated with non-surviving COVID-19 patients when compared to survivors, as was the use of low molecular heparin in severe SARS-CoV-2 infected patients with elevated d-dimer or sepsis-induced disseminated intravascular coagulation.

Increased d-dimer levels may be a good predictor of COVID-19 severe and fatal cases in hospital admission (Tang et al., 2020). Similar study has shown that d-dimer has a discriminatory capacity in patients with and without serious COVID-19 forms but does not have mortality data (Henry et al., 2020).

Several studies have shown that ferritin in hospitalized patients has a considerable elevation, but typically not a particular marker for hemophagocytic lymphohistiocytosis. Ferritin is an acute protein that increases in response to a wide range of inflammatory conditions, including malignancies, overload of iron, and liver or kidney diseases (Melo et al., 2021).

Global studies aimed to better understand the pathophysiology of the disease and to analyze how specific laboratory markers help in the COVID-19 process. Recent results revealed that patients with COVID-19 had lower hemoglobin levels and higher levels of ferritin. USA: A study done revealed that ferritin levels were pathologically high in 5700 individuals hospitalized for COVID-19.

Anemia accompanies hyperferritinemia, no matter what underlying diseases are present. When ferritin levels begin to rise, a time bomb of inflammation is likely to be present. Patients with COVID-19 have reported that inflammatory processes also produce high levels of ferritin. In severe cases serum ferritin levels were substantially higher (Bozkurt et al., 2021). A recent meta-analysis of patients with poor composite result showed that ferritin was higher in non-survivor groups and sub-group findings showed a higher ferritin level.


d-dimer

d-dimer is the main fibrin disintegration fragment and is used in the synthesis and degradation of fiber as a biomarker. Healthy people have modest levels of d-dimer in circulation while high levels are detected in thrombosis-related diseases. For the diagnosis, surveillance and treatment of venous thromboembolism, for which d-dimer is commonly employed, extensively investigated.

Many studies have demonstrated that D-dimer is a good marker for coagulation and fibrinolysis activation. Berger et al investigation found that abnormal d-dimer levels were often detected with COVID-19 admission and were associated with an increased risk of critical disease, thrombotic events, acute renal injury, and death (Berger et al., 2020). d-dimer comes from cross-linked fibrin synthesis and lysis and is responsible for coagulation activation and fibrinolysis.

COVID-19 has been reported to be connected with hemostatic anomalies, and significantly high amounts of d-dimer in non-survivors have been recorded (Zhang et al., 2020). d-dimer is one method to spot thrombotic-state. After the creation of the clot, the fibrinolytic system breaks down the mesh. By activating the plasmin enzyme, the D-dimer consists of two D fragmentations of the fibrin. This shows that the bloodstream has demolished fibrin. d-dimer is a coagulation and fibrinolysis activation system.

The d-dimer test is commonly used in clinical practice to rule out deep vein thrombosis and pulmonary embolism and to confirm the diagnosis of disseminated intravascular coagulation. d-dimer level is one step in thrombosis detection used in patients. In early stage of COVID-19 disease studies have shown an increase in d-dimer and fibrinogen levels.

The increase of d-dimer levels by 3 to 4 times is related to poor forecasts. Increasing d-dimer levels in COVID-19 individuals could also be triggered by underlying conditions such as diabetes, cancer, stroke, and pregnancy. In the control and management of COVID-19 the measurement of d-dimer and coagulation parameters at an early stage of the disease can also be important (Rostami and Mansouritorghabeh, 2020). patients with COVID-19 were reported to have a hypercoagulable state, with 71% of patients who died from COVID-19 having satisfied the DIC criteria.

In this context, this means that a total of 71% of patients who died from COVID-19 met the DIC threshold, with the remaining 29% falling short. Furthermore, venous thromboembolism occurred in 25% of patients with severe COVID-19, and in 30% of those patients, pulmonary embolism was identified. COVID-19 individuals with ischemic stroke have also raised D-dimer levels in their blood (He et al., 2021).

Huang et al found from 11 previous studies that an increased d-dimer was related with an increase in composite poor outcome [RR 2.93 (2.14–4.01), p < 0.001]. Furthermore, subgroup analysis revealed that an elevated D-dimer was linked to an increased risk of mortality. This review focused on a few biochemical parameters, such as serum ferritin and d-dimer. Furthermore, documented studies have revealed that CRP, vitamin D levels, and prolactin play a role in detecting COVID-19 in humans.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378068/

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