key: cord-0771520-avftrz5b
authors: Mendes-Filho, S. P.; Martins, F. S.; Giroldi, P. J.; Melo, R. H.; Oliveira, E. L.; Santos, A. B.; Medeiros, D. C.; Basano, S. A.; Lopes, J. A.; Chaves, Y. O.; Pinheiro, R. S.; Camargo, L. M.; Zuliani, J. P.; Nogueira, P. A.
title: Home Care Follow up determine the point of inversion of IL-6 levels in relation to C-Reactive Protein as the cytokine storm marker in COVID-19
date: 2022-03-23
journal: nan
DOI: 10.1101/2022.03.21.22270828
sha: 63cee32675ba8bbd682477f6b107396543c9a4bb
doc_id: 771520
cord_uid: avftrz5b

The IL-6 has been used for the characterization of the cytokine storm induced by SARS-CoV-2, but so far, no one has found out when and in whom the cytokine storm develops. Our study demonstrates how early and longitudinal clinical-based monitoring and dosing of five markers (C-reactive protein, IL-6, fibrinogen, ferritin and D-dimer) helped to identify who had developed the cytokine storm. The peak of IL-6 in pg/mL proportionally higher than the peak of CRP in mg/L was sufficient to define the timing of the evolution of cytokine storm syndrome. The administration of antibiotic therapy, anticoagulant therapy and pulse therapy resolved the infection and prevented the progressive deterioration of the lung function of the patients with potential for development of severe COVID-19.

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The copyright holder for this this version posted March 23, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. In the present study, we will demonstrate how the early and longitudinal 104 monitoring clinical-based practice, as well as quantifying 5 markers (CRP, IL-6, 105 fibrinogen, ferritin, D-dimer) daily has served to reduce the rates of mortality due is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint 6 resolved the infection and prevented the progressive deterioration of lung injury. 114 To this end the observation of CRP and IL-6 kinetics levels can be markers to 115 distinguish the timing of the cytokine storm in patients with a more severe form of 116 COVID-19 in relation that one that presented COVID-19 with endothelial injury 117 determining the therapy to be conduct. The principal goal was the early identification of cases followed by a severity 127 analysis and follow-up based on daily monitoring of clinical-laboratory parameters 128 to assess the patient's vulnerability potential. This follow-up was carried out by 129 the HMCS and consisted of a nursing team responsible for blood sample 130 collection, monitoring of vital signs and medicine administration when necessary, 131 and a medical remote health team that, when necessary, included a physical visit. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint 8 these data come from medical and laboratory assistance that took place between 161 2020 and 2021 and medical records were available anonymously encoded. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint

The YELLOW PATIENT group showed CRP elevations, and the use of 232 antibiotics decreased continuously these levels until the baseline ( Figure 1A ). In 233 these patients, IL-6 levels behaved more timidly and decreased synchronously 234 with CRP levels ( Figure 1B ). Fibrinogen levels did not exceed the limit of 437 235 mg/dL despite the mild increase in IL-6 levels ( Figure 1C ) and, therefore, the use 236 of enoxaparin was not necessary. Without increased in fibrinogen levels, there 237 was no thrombus formation and, therefore, the D-dimer, a predictor of fibrinolysis, 238 did not increase ( Figure 1D ). Figure 1E shows the ferritin curve in women. The 239 variation showed that some female patients demonstrated iron metabolism 240 disorder, requiring treatment according to the initial protocol. Antibiotic treatment 241 led to decreased CRP and IL-6 levels. Figure 1F demonstrated the ferritin levels 242 in men. In most of the male patients, ferritin levels were much higher than in 243 women in the first examination, which is probably due to the eating habits of men.

Similarly, the treatment of iron metabolism and control of metabolic syndromes 245 resulted in optimal results, with the decrease of ferritin levels and the reduction 246 of CRP and IL-6 levels concomitantly. These patients had mild to moderate 247 clinical symptoms, anosmia, cough, fever, and chest discomfort, and they did not 248 require the oxygen support. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint 12 CRP levels were below 25 mg/L, with the venous antibiotic therapy there was a 257 gradual decrease in IL-6 to normal levels ( Figure 2B ). In Figure 2C it is possible 258 to observe how increased fibrinogen was used within this protocol as the standard Between sixth-eighth day of illness, in patients with the most severe symptoms, 276 IL-6 levels increased earlier than those of CRP levels, and the peak of IL-6 in 277 pg/mL is proportionally higher than the peak of CRP in mg/L (see thick green 278 arrow, Figure 3B ). This abrupt increase characterizes the cytokine storm, which is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint of these markers to normal levels. In Figure 3D , the first increase in D-dimer levels 293 occurred a few days after the peak of fibrinogen levels, around the eighth to tenth 294 day. The new increase in D-dimer occurred on the thirteenth day, which was after 295 the second peak of fibrinogen levels that was observed between the eighth to the 296 tenth day ( Figure 3C ). In Figure 3E , the increase in ferritin levels in female 297 patients shows that these patients have had the disease for some days, and from 298 the sixth day, there is an exponential increase and the patient's improvement 299 response is translated into the decrease in the curve. Figure 3F showed the 300 increase in ferritin levels in male patients, with an expected upward and 301 progressive curve as can be seen in infections, but around the sixth to seventh 302 day there is a greater than 80% increase in relation to the previous day, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint kinetics levels allowed us to distinguish the timing of the cytokine storm in patients 307 with a more severe form of COVID-19 in relation that one that presented COVID- 308 19 with endothelial injury. Although the units of CRP and IL-6 are different, at the 309 beginning of the disease the kinetics of CRP and IL-6 levels in these two groups 310 of patients are similar, though with the peak IL-6 in pg/mL being higher than the 311 peak of CRP in mg/L ( Figures 4A and B) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint This fact makes us appreciate the importance of ferritin as an optimal marker of 484 a cytokine storm, especially in those with an initial increase due to metabolic 485 syndrome, and that without prior treatment against absorption/uptake, this would 486 interfere with its reliability.

Our study also has some significant limitations. The drawbacks of the work were 488 that, for some patients there are not all data of five markers daily, despite our 489 efforts to perform the monitoring and dosing of five markers every day. That is 490 due some patients did not present in the LEPAC or they were not found in their 491 residences.

The home care follow-up was completely effective regardless of a first is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The line represents the mean of data and gray area the standard deviation. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint similar, though with the peak of CRP in mg/L being higher than the peak IL-6 in 599 pg/mL. The thick lines represent the mean of data and dashed lines the standard is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint 27 dose of enoxaparin was increased to 2 mg/kg/day since fibrinogen rose again 624 after a few days even after 1 mg/kg/day of enoxaparin for more than 48 hours.

The line represents the mean of data. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 23, 2022. ; https://doi.org/10.1101/2022.03.21.22270828 doi: medRxiv preprint

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