COVID-19 Biomarkers: Harvard Study Shows That Rapid Rise In CRP Levels Predicts Respiratory Decline And Outcome In COVID-19 Patients

COVID-19 Biomarkers: Harvard Medical School researchers from Brigham and Women's Hospital-Boston have in a new study found that rapid rise of C-reactive protein (CRP) levels in COVID-19 patients are an indication of increasing respiratory decline and disease severity. According to the study team, CRP can be used as a biomarker to predict outcomes in COVID-19 patients.


 
In this single-center, retrospective cohort analysis of hospitalized COVID-19 patients, the study team investigated whether inflammatory biomarker levels predict respiratory decline in patients who initially present with stable disease.
 
Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 hours of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. The study findings show that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization
 
The study findings were published in the peer reviewed journal: Cell Reports Medicine.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(20)30188-9
 
To most healthcare professionals, predicting the course of a COVID-19 patient's disease after hospital admission is essential to improving treatment.
 
Harvard’s Brigham and Women's Hospital researchers analyzed patients' levels of inflammation, known to be associated with severity of illness, by looking at C-reactive protein (CRP) trends in 100 COVID-19 patients admitted to the hospital.
 
The study team found that a rapid rise in CRP levels during the first 48-to-72 hours of hospitalization was predictive of subsequent respiratory deterioration and intubation, while steadier CRP levels were observed in patients whose condition remained stable.
 
The key findings from the study were:
 
-Rising CRP levels predict intubation in COVID-19 inpatients stable at admission
 
-Early CRP trend outperforms initial CRP level in prediction of respiratory failure
 
-CRP trend outperforms a physiological index (ROX) in prediction of respiratory failure
 
-CRP and IL-6 levels correlate with each other and with hypoxemia (P_aO₂/F_iO₂)
 
Corresponding Author, Dr Edy Yong Kim, MD, PhD from the division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital told Thailand Medical News, “The team realized that whereas a single CRP lab value from hospital admission wasn't very practical as a predictor of who might get sicker, tracking the rate of change from Da y 1 to Day 2 or 3 was a very powerful and very clinically predictive test. Even though all of these patients looked clinically similar upon admission, as early as 24 hours after hospitalization, the immune systems of patients who would go on to the ICU multiple days later were already inflamed, as measured by these biomarkers."
 
The term inflammation is a broad condition that describes the release of chemicals involved in immune responses. CRP tests integrate signals from a number of different proteins involved in inflammation, called cytokines, to provide physicians with a snapshot of a patient's inflammatory activity within a matter of hours.
 
Although other tests like cytokine assays, can provide more specific information about which proteins may be active in inflammatory pathways, these tests can take one to two days to process, and COVID-19 patients' conditions can worsen before the results are received. CRP tests can therefore serve as a practical addition to standard protocols for assessing the anticipated clinical trajectories of COVID-19 patients.
 
Dr Kim added, "Because of our findings, we changed our guidelines at the Brigham to mandate CRP tracking every day for the first three days of hospitalization so that we could try to identify vulnerable patients and keep a close eye on their inflammation."
 
The study team also stressed the importance of putting findings into practice as early as possible amid the current uptick of positive cases.
 
The research findings from a study population of 100 Brigham patients also provide insight into the underlying mechanisms at play in COVID-19 infections. In particular, an increase in a cytokine called IL-6 during the first 24-48 hours was correlated to CRP levels and the progression of the disease.
 
Although CRP is associated with IL-6, CRP can reflect other inflammatory pathways besides IL-6, so targeting other inflammatory cytokines or pathways besides IL-6 could be considered.
 
Dr Kin added, "Even if you gave immunomodulatory drugs, which reduce rising inflammation, as early as Day 3 which is pretty early for a clinical trial that may already be too late. But here we have some evidence that a rise in inflammation directly drives respiratory failure, which implies that the immunomodulatory drugs might be able to prevent respiratory failure if given very, very early as early as hospital Day 1 and 2."
 
Dr Kim ultimately, hopes that the findings will help front-line workers better understand the volatility of COVID-19 patients' conditions.
 
He commented, "Doctors' and nurses' clinical instincts about COVID-19 are not fully developed because the disease is still so new. But when we showed these results to frontline doctors and nurses at the Brigham, they felt like it matched what they intuitively saw in the spring. It's always nice to hear that what you do in the lab reflects what goes on in the real world, too."
 
The study team also pointed out that recent studies have suggested that acute respiratory distress syndrome (ARDS) related to COVID-19 is not more inflammatory than ARDS unrelated to COVID-19, with similar levels for plasma IL-6 in COVID-19 and non-COVID-19 ARDS. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30366-0/fulltext
 
https://pubmed.ncbi.nlm.nih.gov/32602883/
 
However, it is clear from this study and others that severe COVID-19 is more inflammatory than milder COVID-19. This study highlights that the dynamic nature of the inflammation in COVID-19 is key and directly associated to physiological parameters. The key limitations of this work are its single-center and retrospective design. Future prospective studies could study a wider range of cytokines and chemokines along with the interaction of CRP rise and immunomodulatory treatment.
 
In conclusion, the study team suggests that closely tracking the levels of CRP in the hyper-acute phase of admission for COVID-19 patients is a valuable tool to stratify the risk that a patient will have progressive hypoxemic respiratory failure requiring intubation. This metric is feasible for frontline clinicians in the emergency department observation units or medical floor inpatient wards. Second, longitudinal CRP profile may distinguish unique phenotypes of patients with critical illness from COVID-19. Finally, these findings suggest that clinical trials of IL-6 receptor monoclonal antibodies should pay particular attention to intervention in the first 48 hours of the hospital course.
 
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