CME INDIA Presentation by Dr N K Singh, Admin.

It is said that COVID patients get betrayed by their own Immune systems. Nobody knows the way virus behaves. Most do recover but may young patients have died. Multiple comorbidities mixed patient recovered and obese at age 90 recovered. Many sudden deaths have been reported. Prediction of the disease course is one of the the most important issues in COVID-19.

We are still in search of unique predictors to know the outcome.

What we have identified so far?

Haematological

• Lymphocyte count
• Neutrophil count
• Neutrophil–lymphocyte ratio (NLR)

Inflammatory

• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)
• Procalcitonin (PCT)

 Immunological

• Interleukin (IL)-6
• IL-10
• IL-6/IL-10 Ratio

 Biochemical

• D-dimer
• Troponin
• Creatine kinase (CK)
• Aspartate aminotransferase (AST)
• Ferritin
• LDH

New laboratory biomarkers (Might be some role)

• Homocysteine
• Angiotensin II

Surrogate markers of infection

• Ferritin
• LDH
• C-reactive protein (CRP) correlated to IL-6

Concept of IL-6/IL-10 Ratio: New predictor might be very useful

• Interleukin (IL)-6, is pro-inflammatory.
• IL-10, is anti-inflammatory.
• The levels of both are altered in severe COVID-19 patients.
• New concept is that do not focus solely on increased baseline levels of IL-6 in COVID-19, it may be more useful to view longitudinal inflammatory biomarker levels as features of a more comprehensive shift in metabolic and inflammatory balance.
• Alterations in cytokine balance predict clinical progression.
• It can be used to guide decision making.
• More informed prognosis could help determine when to escalate or de-escalate care.
• It is applicable to patients both in the ICU and on the ward.

Dublin-Boston Scoring System

• Helps in predicting which COVID-19 patients will develop severe infection.
• Developed by researchers from RCSI, Harvard University, Beaumont Hospital in Dublin and the Brigham and Women’s Hospital in Boston.
• The changes in the ratio of IL-6 and IL-10 over time – the researchers developed a point system where each 1-point increase was associated with 5.6 times increased odds for a more severe outcome.
• The ratio of IL-6 to IL-10 significantly outperforms measuring the change in IL-6 alone.
• This is the first COVID-19 specific prognostic scores now available to guide clinical decision-making.
• The Dublin-Boston score now accurately predicts how severe the infection will be on day 7. We have to measure the patient’s blood for the first four days.
• Then we see the 4-day change in IL-6:IL-10 ratio.
• Each 1-point increase in the score is associated with 5.6 times increased odds for a more severe outcome.
• Treatment strategies addressing the underlying cause of changes in IL-6 and IL-10 are more likely to be successful, with the Dublin-Boston score.
• It can represent a viable means of assessing the response to therapy.

Quickly Refreshing IL-6 – It is like bad cholesterol LDL

• Interleukin-6 (IL-6) has important roles in both innate and adaptive immunity.
• IL-6 can be produced by a variety of different cell types, including macrophages, endothelial cells, and T cells.
• This production can be initiated in response to microbial invasion or other cytokines, such as tumour necrosis factor (TNF).
• As part of the innate immune system, IL-6 acts on hepatocytes to induce expression of C-reactive protein (CRP), fibrinogen, and serum amyloid A, also known as the acute phase response.
• Within the adaptive immune response, IL-6 plays a key role in activating antibody-producing B cells to proliferate, leading to an enhanced antibody response.
• Elevated in patients with infection, sepsis, and septicaemia.
• IL-6 concentrations appear to correlate with severity of sepsis.
• Elevations in IL-6 also appear to be associated with more localized infections, numerous chronic inflammatory disorders, including RA, SLE, ankylosing spondylitis (and inflammatory bowel disease (IBD)).
• Normal Value < or =1.8 pg/mL.
• Circulating levels of the master pro-inflammatory cytokine IL-6 are elevated in patients with COVID-19.
• Use of isolated IL-6 measurement as a COVID-19 prognostic tool, or as a means of evaluating clinical response to treatment, is hindered by several factors:
  1. IL-6 levels within the same patient vary significantly over the course of any given day.
  2. The magnitude of the IL-6 response to infection is, in absolute terms, also variable between patients.
  3. The presence of immunometabolism comorbidities such as obesity can also influence circulating IL-6 levels and IL-6 release.
• It is worth remembering that although IL-6 may contribute to organ injury and death in sepsis syndromes, it is also required for innate immunity and microbial clearance.
• Imprecise inhibition of the pro-inflammatory effects may therefore represent a double-edged sword.

Quickly Refreshing IL-10 – It is like good cholesterol HDL

• Remember it as – The Master Regulator of Immunity to Infection.
• IL-10 has emerged as a key immunoregulator during infection with viruses, bacteria, fungi, protozoa, and helminths, ameliorating the excessive Th1 and CD8⁺ T cell responses.
• IL-10 is an anti-inflammatory cytokine that maintains the balance of the immune response.
• It allows the clearance of infection while minimizing damage to the host.
• IL-10 can also dampen the harmful immune responses elicited in autoimmunity and allergy.

Practical widely available clinical/biochemical pearls

• Lymphopenia is found in 80% of critically ill adult COVID-19 patients, and only 25% of patients with mild COVID-19 infection(observational). It suggests that lymphopenia may correlate with infection severity (Changes in lymphocyte populations in patients severely affected by COVID‐19 indicate a low T cells count, an increase in naïve helper T cells and a decrease in memory helper T cell).
• Eosinopenia may not be associated with unfavourable progression of COVID-19.
• NLR has been identified as a prognostic biomarker for patients with sepsis. NLR has been shown to be an independent risk factor for severe disease. NLR ≥ 3.5 may indicate COVID-19 infection severity.
• NLR elevation may be due to dysregulated expression of inflammatory cytokines, aberrant increase of pathological low-density neutrophil and the upregulation of genes involved in lymphocyte cell death pathway.
• Platelet count is a simple, cheap, and easily available biomarker and has been independently associated with disease severity and mortality risk in intensive care unit. The number of platelets was reported to be significantly reduced in COVID-19. Patient’s Low platelet count has been associated with increased risk of severe disease and mortality for COVID-19 patients, and can serve as an indicator of clinical disease worsening during hospitalization (Damaged lung tissue and pulmonary endothelial cells may activate platelets in the lungs, resulting in the aggregation and formation of microthrombi, thereby increasing platelet consumption)
• CRP levels are increased in COVID-19 patients and it has been shown that survivors had median CRP values of approximately 40 mg/L, while non-survivors had median values of 125 mg/L, indicating a strong correlation with disease severity and prognosis (Ruan et al., 2020) 
• Ferritin
  • Ferritin is a key mediator of immune dysregulation, especially under extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects, contributing to the cytokine storm.
  • Ferritin levels, either obtained at presentation or the maximum value over admission, are a relatively poor test in predicting the evaluated outcomes, namely all‐cause mortality, new mechanical ventilation. However, ferritin cannot reliably predict several important outcomes.
• LDH
  • LDH is an enzyme implicated in the conversion of lactate to pyruvate in the cells of most body tissues and increased following tissue breakdown.
  • Elevated serum LDH is present in numerous clinical conditions, such as hemolysis, cancer, severe infections and sepsis, liver diseases, hematologic malignancies, and many others.
  • Nowadays, there is much evidence suggesting that the serum LDH levels serve as a non-specific indicator of cellular death in many diseases.
  • An increase in LDH by 62.5 U/L has an acceptable sensitivity and high specificity for a significantly higher probability of disease progression.
  • LDH is a potentially useful follow-up parameter in COVID-19 pneumonia, which might assist in recognition of disease progression and thus help in risk stratification and early intervention.
• Procalcitonin is the pro-peptide of calcitonin devoid of hormonal activity. Under normal circumstances, it is produced in the C-cells of the thyroid gland.
  • In healthy humans, PCT levels are undetectable (< 0.1 ng/mL).
  • During severe infection (bacterial, parasitic, and fungal) with systemic manifestations, PCT levels may rise to over 100 ng/mL, produced mostly by extra-thyroid tissue. PCT is a mediator of inflammation.
  • PCT value remains within reference ranges in patients with non-complicated SARS-CoV-2 infection; any substantial increase reflects bacterial co-infection and the development of a severe form of disease and a more complicated clinical picture.
  • Initial PCT value may be helpful in the determination of illness severity, it may not always be a reliable prognostic indicator.
  • PCT values may be influenced by pre-existing comorbid conditions, such as CKD and congestive heart failure, baseline values may be high.

CME INDIA Learning Points:

• Dublin-Boston score and changes in the IL-6:IL-10 ratio, both predict clinical outcome. These also give an insight into the pathogenesis of COVID-19 inflammation. At present, it does not support attempts to manipulate the ratio directly as a therapeutic target. Neither any online app. is available.
• At present direct manipulation of biomarkers such as the IL-6:IL-10 ratio does not assure improved outcomes.
• In severe disease, WBCs show lymphocytopenia, affecting both CD4+ and CD8+ cells, as well as a decrease in monocytes and eosinophils, and a clear increase in neutrophils and NLR. These simple parameters can be used for early diagnosis and identification of critically ill patients.
• Markedly higher concentrations of ALT, AST, creatinine, CK, LDH, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer are clearly good severity predictors.
• Current clinical practice suggests that the determination of IL-6, D-dimer, LDH, and transaminases in addition to routine laboratory tests, is useful for the stratification of high-risk patients.
• Coagulation abnormalities in PT, aPTT, FDP, and D-dimer, along with severe thrombocytopenia, are associated with life-threatening DIC, which necessitates continuous vigilance and prompt intervention.
• These are in fact not only predictive of disease severity, but also are helpful for the therapeutic management, based on drugs preventing the activation of coagulation processes. A laboratory score, taking into account hematological, inflammatory, biochemical and immunological parameters, would help to stratify COVID-19 positive patients into risk categories, which would be of utmost importance in the clinical setting and therapeutic management.
• Novel biomarkers potentially useful for screening, clinical management, and prevention of serious complications are under investigation. These include Homocysteine, Ang II, Ang-(1-7), Ang-(1-9), and alamandine.

CME INDIA Tail Piece:

How to increase IL-10 is a subject of intense research.

• Good lifestyle with nutritious diet (especially omega 3 fatty acid), Exercise (IL-10 showed a 27-fold increase immediately post-exercise), Yoga, Meditation, good sleep etc. are well known IL-10 inducer.

Source:

1. https://www.jimmunol.org/content/180/9/5771
2. A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19. EBioMedicine, 8 October 2020.

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