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Blood Tests to Be performed, and why.

 

One could select many tests, in pursuit of the many symptoms found in those experiencing the "long-term" variant of COVID-19. These clinical findings and their prevalence have been effectively summarized in this meta-analysis article. The list is similar to the symptomatic findings presented last year on our site, LTCOVID.com These symptoms that emerged from our previous questionnaire have been summarized on this page.

 

The selected analytes will focus on those that may prove most useful in evaluating this study's intervention using light.

 

 

  C - Reactive protein (CRP)  

 

 

The following summary is found at this link: https://pubmed.ncbi.nlm.nih.gov/28722873/

 

Aspects of CRP with a potentially important link to our study have been highlighted.

 

 

"C-reactive protein (CRP) was discovered by Tillett and Francis in 1930. The name CRP arose because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the "c" carbohydrate antibody of the capsule of pneumococcus.

CRP is a pentameric protein synthesized by the liver, whose level rises in response to inflammation. CRP is an acute-phase reactant protein that is primarily induced by the IL-6 action on the gene responsible for transcription of CRP during the acute phase of an inflammatory/infectious process. There is some question of whether dysregulation of the role of CRP in the clearance of apoptotic cells and cellular debris plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but this has not been definitively demonstrated. It has been demonstrated to have some protective properties in animal studies on lung tissue in alveolitis by reducing neutrophil-mediated damage to the alveoli and protein leakage into the lung.

CRP has both proinflammatory and anti-inflammatory properties. It plays a role in the recognition and clearance of foreign pathogens and damaged cells by binding to the phosphocholine, phospholipids, histone, chromatin, and fibronectin. It can activate the classic complement pathway and also activates phagocytic cells via Fc receptors to expedite the removal of cellular debris and damaged or apoptotic cells and foreign pathogens. This can become pathologic, however, when it is activated by autoantibodies displaying the phosphocholine arm in auto-immune processes, such as idiopathic thrombocytopenic purpura (ITP). It can also worsen tissue damage in certain cases by activation of the complement system and thus inflammatory cytokines.

As compared to the erythrocyte sedimentation rate, which is an indirect test for inflammation, the levels of CRP rise and fall rapidly with the onset and removal of the inflammatory stimulus respectively. Persistently elevated CRP levels can be seen in chronic inflammatory conditions such as chronic infections or inflammatory arthritides such as rheumatoid arthritis.

There are numerous causes of an elevated C-reactive protein. These include acute and chronic conditions, and these can be infectious or non-infectious in etiology. However, markedly elevated levels of CRP are most often associated with an infectious cause (an example of pathogen-associated molecular pattern recognition). Trauma can also cause elevations in CRP (alarmin response). More modest elevations tend to be associated with a broader spectrum of etiologies, ranging from sleep disturbances to periodontal disease."

 

Another reference for CRP, including normal and abnormal levels seen.

 

Pertinent to CRP findings in those with COVID-19, one can find many references. The following selected reference serves well:

 

C-reactive protein and clinical outcomes in patients with COVID-19

 

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  Lactate Dehydrogenase (LDH)  

 

A detailed summary from a biochemical perspective is found here.

 

Though not very specific, elevated LDH levels are taken as a sign of tissue damage or disease.

Normally, it is part of the process of converting sugars into energy.

 

Strenuous exercise will also increase LDH.

 

Normal levels of LDH in the blood can vary depending on the lab, but usually range between 140 units per liter (U/L) to 280 U/L for adults and tend to be higher for children and teens. In cerebrospinal fluid, normal levels are: 70 U/L or lower for newborns. 40 U/L or lower for adults.

 

In the setting of COVID-19, increased LDH levels have been reported to signal clinical deterioration in several studies. Here is one such study.

 

 

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  Inorganic Phosphate (Pi)  

 

Our analysis of results from our questionnaire of COVID-19 sufferers last October 2020, included a review of the probable importance of Inorganic Phosphate (Pi) for this population.

Rather than repeating those topics here, a link to the related page on our LTCOVID.com site will be of practical use. It can be viewed at this link: Inorganic Phosphate - A Syndromic Approach: Respiratory Alkalosis and Hypophosphatemia.

 

The above information once reviewed, should leave one with a clear sense of why Inorganic Phosphate (Pi) has been selected for inclusion in the objective data obtained through labwork of samples from enrollees in our protocol. Hypophosphatemia-induced Cardiomyopathy is a topic that should also be of more than passing interest, especially for endurance athletes participating in the present work. The topic of virally-acquired myocarditis (heart muscle inflammation) appears with increasing frequency.

 

This is an appropriate place to mention that while we are committed to the importance of inorganic phosphate to energy generation at a cellular level, we feel that the energetics problem suffered by most with "long-term" COVID-19 occurs upstream to incorporation of phospate. Part of the electron transport chain has been hijacked by the virus and left broken or damaged after the virus is no longer present. As explained elsewhere, that component is the principle target of the present study's intervention using specific wavelengths of light.

 

Supplementing low phosphate levels when present, may not be fully effective as long as key electron transport chain components remain damaged. Normal levels of cellular energetics may not be obtained, or only very slowly over prolonged periods, if this is not first addressed.

 

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  Haptoglobin (Hp)  

 

Red blood cells contain hemoglobin (Hb) as the iron-containing oxygen carrier. 

When red cells become old (senescent) and eventually break down, hemoglobin fragments are released into the circulation. These have a toxic effect. 

 

Haptoglobin (Hp) binds this free hemoglobin, reducing its toxic oxidative effects.

The usual rate of chronic destruction of red cells normally, does not overpower the ability of usual haptoglobin levels in dealing with demand. So Hp levels remain normal. 

 

Red cells can also break down in various disease states, apart from the normal breakdown seen with aging cells. One can summarize these as hemolytic anemias reflected in diminished red cell mass.

 

During hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades.

 

So usually, as hemolytic breakdown increases, haptoglobin levels will drop because it is being used up in the process of controlling increases in free hemoglobin in the plasma.

 

Here is a useful review of these interactions of haptoglobin (Hp).

 

In pursuing evidence for hemoglobin damage due to COVID-19, this has also been studied in this illness as presented here.

 

 

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  Complement C3   

 

C3 is the central component of the complement activation system, a vital component of the immune response system. It can be activated through 3 different pathways, converting inactive proteins into functional fragments. This complex response system is well summarized in this resource. It represents an innate immune response tool which responds to platelet activation and/ or contact with antibody molecules.

 

Local inflammation, thrombosis and tissue damage also result from activation of the complement system. Therefore its relation to COVID-19 cases and the present study, since it behaves as an overactive complement-mediated disease.

 

In COVID-19 patients Complement C3 has been identified as a unique risk factor for disease severity.

 

In COVID-19, complement inhibition is being pursued as a way of reducing tissue damage.

 

 

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  Interleukin 6 (IL-6)  

 

Interleukin-6 is one of several, (here numbered 1 to 23), proteins or glycoproteins.

 

Their name arose from the observation that they function in communication between (inter) white blood cells (leukocytes).

 

They are a vital part of the machine that is the ever-vigilant human immune system.

 

One can find that a tremendous amount of research has been done to define the widespread role of the 17 to 20 different human interleukins in normal immune functioning. They can also malfunction at times, leading to auto-immune diseases in which cells produce substances that attack human cells when no such attack is indicated. In this specific domain, and others relating to chronic diseases such as psoriasis, much remains unknown about interleukin-6 (IL-6) activities. Nevertheless, a great deal is known about specific structure-function relationships of this molecule.

 

IL-6 is also known as B-cell stimulatory factor 2 or BSF-2, and interferon beta-2, and has had other names as well, usually based in discovery of specific functions. It is a cytokine (the word means ‘cell mover’), involved in many biological functions such as driving the differentiation of B cells into cells that secrete immunoglobulins (antibodies). It also drives nerve cell differentiation and activates certain hepatocyte functions in the liver. The gene for IL-6 is located at chromosome 7p21 in humans.

 

IL-6 can be produced by several different cell types including fibroblasts, B cells, macrophages, and endothelial cells lining blood vessels. It stimulates several types of leukocytes (White Blood Cells). It stimulates liver cells to rapidly produce Acute Phase Proteins.

 

IL-6 directs B-cells (a type of white blood cell) to differentiate into plasma cells that produce antibodies.

 

In driving such events normally, one might find levels of IL-6 in the blood plasma of 0 to 30 pg (picograms) par mL. Measured levels in serum are normally 1-5 pg/mL. Levels rise rapidly in response to infection. Strenuous physical/ muscular activity also increases IL-6 levels. Increased levels of IL-6 influence the levels of reactive oxygen species in muscle. Overexpression of IL-6 can lead to oxidative stress in muscle tissues.

 

IL-6 signaling is involved in several aspects of cardiovascular biology and related illnesses such as obesity, insulin resistance and atherosclerosis.

 

IL-6 plays a central role in host defense through immune and hematopoetic (blood cell forming) activities that make it critical to the induction of the ‘acute phase response’ when the organism is under attack. It is at the foundation of inflammation as a defense mechanism.

 

Adding to its complex roles, IL-6 often displays hormone-like properties affecting metabolism through the neuroendocrine system with effects on lipid metabolism, iron transport and insulin resistance.

 

It drives immune homeostasis and health, responding during infection, but also is found participating in autoimmunity, cancer and chronic diseases. Rheumatoid arthritis and other joint diseases are involved with IL-6. These diseases are almost never seen in IL-6 deficient laboratory animals. In moving from an acute to chronic disease, IL-6 actions change the inflammatory infiltrate from polymorphonuclear leukocytes (PMNs) to monocytes and macrophages. This also brings the acute phase of inflammation under control, avoiding tissue damage.

 

IL-6 levels are elevated in complicated cases of COVID-19, and associated with adverse clinical outcomes.

 

Of particular interest to the present study, IL-6 mediates certain mitochondrial activities. Increased IL-6 increases mitochondrial reactive oxygen species (ROS) production. This is mediated via opening of the mitochondrial transition pore (mPTP). These effects are also seen in aging and obesity. IL-6 has a protective effect on astrocyte mitochondria in a septic condition, reducing damage, maintaining mitochondrial DNA, and mitochondrial biogenesis and viability.

 

IL-6 has been suggested as a mediator of the neuropsychiatric symptoms of “long-term” COVID-19.

 

The present study’s intervention with specific wavelengths of light should be usefully paired to identification of changes, if any, in levels of IL-6 at specific points as defined in the protocol.

 

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  Procalcitonin (proCT)  

 

 

We first measured serum and urine calcitonin in patients with acute inflammation (large burns) in 1982. That study confirmed elevated levels and suggested the possibility of a pulmonary origin due to inhalational injury. 

 

The same samples, carefully preserved, were subsequently used in 1992 to measure procalcitonin levels which were also found to be elevated. And in a follow-up study at a mean of 8.2 years after their initial injuries, some still had chronically elevated calcitonin and procalcitonin values, taken as evidence of late pulmonary sequelae.

 

Subsequent to those early studies, procalcitonin became a frequently measured marker for pulmonary, and more generally, septic involvement with infection. Endotoxin and the importance of procalcitonin are presented here. The evolution of procalcitonin as a marker and mediator of sepsis is reviewed here.

 

Pertinent to the present study, does procalcitonin measurement have a role in managing those with COVID-19? Are abnormal levels found and how should these be interpreted?

 

Serum levels of proCT are elevated in COVID-19 and are proportional to the severity of the disease (duration of mechanical ventilation for example) and overall mortality rates as well.

 

In caring for those with more severe forms of this viral disease, as with other illnesses in which critical care unit admission and stay is required, secondary bacterial infections are relatively common (up to 50% of patients in some series). Faced with this fact, physicians often order antibiotics on admission or shortly thereafter. ProCt levels have been used effectively to reduce antibiotic use (or misuse) in patients who do not have secondary bacterial infections. This "stewardship" role of proCT has been well described. At times proCT is paired with CRP measurements with the same goal of optimizing antibiotic therapy decisions.

 

The application of proCT measurements is not always conducted in a systematic or consistent manner, which has also been presented. It's appropriate role is still being defined.

 

A video has even been published to clarify how proCT levels can be usefully applied to antibiotic management.

 

While an important function, associating proCT uniquely as a guide to antibiotic therapy may in fact limit its utility. Our first study of calcitonin in burn patients more than 30 years ago presented strikingly high values that were rather surprising at the time. These pointed towards neuroendocrine functions and anatomic origins in pulmonary tissues that continue to be expanded on today. Here is one example, a "Functional Exploration of the Pulmonary NeuroEndocrine Body (NEB).

 

So the results from studying this substance once again in the present study population of "long-term" COVID-19 enrollees are likely to be quite instructive. This, especially given the controlled comparisons that the study protocol offers.

 

 

  Prolactin (PRL)  

 

Prolactin (PRL) is normally produced by the posterior part of the pituitary gland, and in both women and men. Gender differences are important since levels rise in women during and after pregnancy in support of breast feeding, as the name suggests. 

 

Normal levels might be as follows:

Males: 2 - 18 nanograms/ mL (ng/mL)

Nonpregnant females: 2 - 29 ng/ mL

Pregnant females: 10 - 209 ng/ mL

 

Abnormal levels arise in several clinical situations that will not be fully presented here.

Pertinent to COVID-19 and its "long-term" variant, autoimmune diseases occur more often in females than males, paralleling this distribution in the viral illness of interest. Also of interest, prolactin can be produced in extra-pituitary locations including adipose tissue, brain and immune cells.

Breast tenderness or discharge when not pregnant, headaches and vision problems may prompt head scans looking for a benign pituitary tumor called a prolactinoma.

Prolactin plays an active role in the development of Peripartum Cardiomyopathy where an abnormal cytokine profile is found associated with left ventricular dysfunction and slow recovery.

 

Prolactin has both hormonal and cytokine effects, again a topic of mutual interest for our protocol. Hormonally it relates most often to motherhood and its lactogenic effect. But prolatin has more than 300 known different efects. As an immune modulator, its effects are widely distrubuted through receptors found on monocytes, lymphocytes, macrophages, natural killer cells, granulocytes and thymic epithelial cells. Binding of prolactin to its receptor activates signaling pathways that influence cell proliferation, differentiation into other cells, secretion and cell survival for those cells in the above family. It stimulates B- and T-cells directly. The immune-neuroendocrine network is quite prolactin linked, and quite associated with auto immune diseases as the above reference presents.

 

Enhancement of PRL levels can lead to an increase in survival in many critical conditions, this too with a gender advantage for women.

 

There are many endocrine changes associated with the SARS-CoV-2 illness, including increased prolactin levels. This is not surprising since any form of stress, including infections, will increase prolactin levels. Prolactin modulates immune and inflammatory responses.

 

In those with COVID-19, prolactin can be increased using dopaminergic drugs and even drugs commonly presecribed for nausea such as domperidone/ metaclopromide. "... at least seven little-understood salient observations in coronavirus patients can apparently be explained by considering the role of enhanced PRL."

 

Mechanisms of COVID-19 progression and etiology of symptoms that persist focus more on brain effects than pulmonary effects and are pertinent to our inclusion of prolactin (PRL) in our present protocol focusing on those with the "long-term" variant of COVID-19.

 

 

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  Antibody to SARS-CoV-2 (Ab)