Виремия и интерлейкин 6

[chuka_lis]

Испанцы задались выяснить,  что первично, а что вторично в патологии ковида, связанной с выбросом сильного иммунного медиатора- интерлейкина 6 (ассоциированного с цитокиновым штормом и его проявлениями на уровне тканей и органов, и тп). Согласно их данным (последовательных замеров титров вируса и уровней медиатора у 57 больных), к увеличению ИЛ6 приводит виремия. Виремия наступает сравнительно скоро после заражения, когда она достигает определенного уровня (1.3 log10 copies/m) начинает расти ИЛ6 ( IL6>30 pg/ml). Если вирус продолжает персистировать, ИЛ6 продолжают расти до 10 дней.
Так что мониторинг титров вируса у госпитализированных был бы хорошим маркером предсказания тяжести болезни
One of the most feared complications of the disease caused by the coronavirus SARS-CoV-2 (COVID-19), is the development of an Acute Respiratory Distress Syndrome (ARDS), which can affect 15.6-31% of patients [1]. Siddiqui and Mehra [2] proposed that ARDS is part of the final stage of the disease, in which clinical features are mainly the consequence of the host hyperinflammatory response and a cytokine storm; whereas the stage I (early infection) is mainly caused by viral replication and the early immune response
Since the outbreak of the COVID-19 pandemic, many efforts have been made to find early risk factors and biomarkers able to predict the evolution towards the cytokine storm. In this sense, older age, obesity and comorbidities such as hypertension, diabetes and coronary heart disease have been associated with higher risk of death [3,4]. On the other hand, increased levels of C reactive protein (CRP), lactate dehydrogenase (LDH) and D-dimer, among others, have been shown to be related to the development of ARDS and mortality [3,5,6].
In this context, Interleukin 6 (IL6) has been described as one of the most useful biomarkers [7]. In a previous work, we showed that IL6 could be a severity biomarker but also a guide to select COVID-19 patients who could benefit from treatment with tocilizumab, an inhibitor of the IL6 receptor [8]. Another important biomarker is the presence of SARS-CoV-2 RNA in peripheral blood (viremia), which has been associated with disease severity and a hyperinflammatory state [9,10]. Saji et al.[11] showed that the combination of SpO2/FiO2, IL6 and the presence of SARS-CoV-2 viremia at admission had the highest accuracy to predict fatal outcomes. Bermejo et al. [12] and Myhre et al.[13] found that the presence of SARS-CoV-2 viremia at admission correlated with increased levels of IL6, CRP and ferritin. In addition, a proteomic analysis showed that the expression of viral response and interferon/monocytic pathway proteins such as IL6 and one of its regulators, the Nicotinamide phosporibosyl transferase (NAMPT), were upregulated in patients with quantifiable SARS-CoV-2 viremia at admission, compared to those with undetectable viremia [14].
In a previous study of our group, we found that viremia was associated with Intensive Care Unit (ICU) admission and in-hospital death, and it was a better biomarker than IL6 [10]. In this regard, since SARS-CoV-2 infection is involved in triggering IL6 expression, viremia as an indicator of the systemic viral shedding, could be related with the IL6 response and be useful as an early biomarker (phase of viral response). Nevertheless, the factors determining an IL6 increase in COVID-19 patients have not been well established yet and the association over time between SARS-CoV-2 viremia and IL6, has not been assessed in a prospective cohort with serial samples.
Considering our previous results, the aim of this study was to evaluate the relationship between the presence of SARS-CoV-2 viremia and the time evolution and IL6 levels in a prospective cohort of COVID-19 hospitalized patients.Methods Secondary analysis from a prospective cohort including COVID-19 hospitalized patients from Hospital Universitario La Princesa between November 2020 and January 2021. Serial plasma samples were collected from admission until discharge. Viral load was quantified by Real-Time Polymerase Chain Reaction and IL6 levels with an enzyme immunoassay. To represent the evolution over time of both variables we used the graphic command twoway of Stata.
Results A total of 57 patients were recruited, with median age of 63 years (IQR [53-81]), 61.4% male and 68.4% caucasian.
Most patients who progressed to a severe disease started this evolution 7 to 14 days after the symptoms onset. In addition, patients with a more benign course were discharged at the end of the first week after admission. For clinical consistency, we decided to analyze only the samples corresponding to the first two weeks of hospitalization, a maximum of 5 samples per patient. Thus, IL6 levels were measured in 228 samples, with a median of 3.6 pg/ml (IQR 0-21 pg/ml). Baseline clinical characteristics of patients depending on IL6 status are shown in table 1. SARS-CoV-2 viremia was determined in 234 samples, with the highest percentage of positive viremia (36.8%) at admission (visit 1).
The average serum levels of IL6 and SARS-CoV-2 viral load were moderately but significantly correlated
The peak of viremia appeared shortly after symptom onset in patients with persistent viremia (more than 1 sample with >1.3 log10 copies/ml) and also in those with at least one IL6>30 pg/ml, followed by a progressive increase in IL6 around 10 days later.
The peak of viremia appeared early, at the first days after symptom onset (day 3 to 5), and quickly decreased. On the other hand, the highest levels of IL6 were found at day 20.In the persistent viremia group, viral load showed a peak around day 4, whereas IL6 had a two-phase increase: one at the first days from symptom onset and then a subsequent progressive increase after day 5. Regarding non-persistent viremia the increase of IL6 was slow from symptom onset until day 20. The median of the average levels of IL6 were 3.6 pg/ml (IQR 1.0-9.2 pg/ml) in the non-persistent viremia group and 21.4 pg/ml (IQR 12.3-44.9) in patients with persistent viremia (p<0.001).The median of the average IL6 concentration was significantly higher in males (11.3 pg/ml [IQR 3.3-27.5] than in females (2.5 pg/ml [IQR 0.7-9.2 pg/ml]; p=0.005).However, predicting curves for IL6 and viral load were substantially different depending on sex (Figure 3A). In males, curves had a fast increase in viral load with a peak around day 2 from symptom onset and a later rise in IL6 levels until day 20, while women showed a small increase in viral load and IL6 between day 2 and 7 approximately.
Persistent viremia in the first week of hospitalization was associated with higher levels of IL6. Both IL6 and SARS-CoV-2 viral load were higher in males, with a quicker increase with age.
In our previous work [10], we described that the presence of relevant SARS-CoV-2 viremia was associated with higher risk of death and ICU admission. Furthermore, viremia was the most useful biomarker for these outcomes, being superior to IL6, lymphopenia and LDH. In the present study, we show that the SARS-CoV-2 viremia appears early in the course of the disease, standing out as a relevant, simple and early biomarker.
Conclusions In those patients with worse outcomes, an early peak of SARS-CoV-2 viral load precedes an increase in IL6 levels. Monitoring SARS-CoV-2 viral load during the first week after symptom onset may be helpful to predict disease severity in COVID-19 patients.