Hypoalbuminemia in Severe COVID-19 Post Recovery Patients

Pandemic Coronavirus disease 2019 (COVID-19) is a contagious disease affecting more than 200 countries, territories and regions. Thousands of studies have dealt with all aspects of the disease but little is known about post recovery status of the patients. Here, we examined ESR, CRP and serum albumin biomarkers in severe and mild-moderate COVID-19 post recovery patients. In severe group patients, serum albumin had a strong negative correlation with both ESR and CRP (R 2 = -0.861), (R 2 = -0.711) respectively. Also, there was a positive correlation between ESR and CRP (R 2 =0.85) in the same group. However, there was no correlation among mild-moderate group patients in those biomarkers. In addition, no correlation recorded between severe and mild-moderate groups. This nding concludes the sustained elevation of ESR and CRP with decreased serum albumin level in severe COVID-19 post recovery patients.


Introduction
The outbreak of the coronavirus disease 2019 (COVID-19) is an infectious disease, with an etiological agent of a novel coronavirus, SARS-CoV-2, named for the similarity of its symptoms to those induced by the severe acute respiratory syndrome 1 . The disease appeared in late December 2019 in Wuhan, China 2 and within 3 months of its discovery, the disease spread rapidly worldwide 3,4 . Accordingly, on 11 th of March 2020, the World Health Organization (WHO) announced COVID-19 as a pandemic disease 5 .
Gastrointestinal symptoms such as diarrhea, nausea and vomiting have also been described, along with loss of the sense of taste and smell 8,9 . Since the initial outbreak, great efforts from scientists have taken place to understand the pathophysiology and progression of the disease 8,10,11 .
The clinical manifestations of COVID-19 infected patients are categorized as mild, moderate, severe, and critical 12 . The majority of affected patients (81%) suffer mild/moderate symptoms, whereas, severe and critical cases comprise 14% and 5% of infected cases, respectively 13 .
Several biological markers have been found to correlate with the severity of COVID-19, including high Creactive protein (CRP) level, high erythrocyte sedimentation rate (ESR) level and low level of serum albumin (hypoalbuminemia) 8,[14][15][16] . These biomarkers in parallel with the clinical symptoms can be used to interpret more con dently the likely progression and severity of the disease 17 . CRP is an exquisitely sensitive systemic marker for acute-phase response to in ammation, infection, and tissue damage 18 . It has been reported that CRP levels are positively related to the severity of COVID-19 19 . Another study illustrated a high ESR level in patients suffering severe COVID-19 symptoms when compared to nonsevere groups, due to an increase in in ammation in severely affected patients 14 . In addition, other studies considered the serum albumin level as a vital indicator in severe COVID-19 patients 16,20 .
Since the appearance of the disease, much research has been conducted on COVID-19 patients 8,10,11,17 . However, millions of people have recovered and limited follow-up studies have focused on the post recovery health status to check their biological markers 21 . Here, we studied the levels of ESR, CRP and serum albumin in severe COVID-19 post recovery patients and compared with a mild-moderate COVID-19 post recovery group.

Result And Discussion
COVID-19 infected patients can be assessed clinically by using quantitative measurements of numerous biomarkers such as, ESR, CRP, and serum albumin. Monitoring those biomarkers play a key role in checking pathological development and helping prognosis and outcomes of the disease 22 .
In this study, all cases were identi ed by RT-PCR and categorized into two groups (Mild-moderate and severe COVID-19 post recovery groups). ESR, CRP, and serum albumin were measured in both groups, and we found that albumin had a strong negative correlation with ESR (R 2 = -0.861) and CRP (R 2 = -0.711) in the severe COVID-19 post recovery group ( Table 1).
The hypoalbuminemia was seen predominantly in severe COVID-19 cases compared with mild cases 23 . However, no study has been conducted yet for evaluating the levels of albumin and its effect on the health of COVID-19 post recovery patients. In our study, we found a persistent hypoalbuminemia in severe COVID-19 post recovery patients.
Although the mechanisms for hypoalbuminemia in COVID-19 have not been studied thoroughly 24 , albumin is a major serum protein produced by hepatic cells 24,25 and has a critical role in human health.
Hypoalbuminemia is considered a sinister clinical sign in COVID-19 viral infection, that may be due to the release of the major acute-phase cytokines into the blood vessels during the cytokine storm, 16 or due to the increase of vascular permeability which allows the albumin to diffuse into the extravascular space 26 .
Reduction in albumin synthesis may also be due to anorexia that is caused by the viral infection 16 .
In the present study we found that ESR increased in all severe COVID-19 post recovery patients. Similar results were found by Pu, et al., 27  Our study revealed a high concentration of CRP in severe COVID-19 post recovery patients. A signi cant negative correlation was also found between albumin level and the in ammatory indicator, CRP (R 2 = -711) ( Table 1). Studies have determined a signi cant increase of CRP concentration in severe COVID-19 patients [30][31][32] . However, our data is the rst study related to the COVID-19 post recovery patients. CRP is produced by the liver as a nonspeci c immune protein and it is considered as a signal of systemic in ammation 33 CRP level in serum also can be affected with the level of other serum proteins which are produced by liver cells 34,35 .
Ponti et al. 36 found the severity of COVID-19 is positively correlated with ESR and CRP, while no study on both biomarkers after the recovery of COVID-19 patients has been recorded yet. Our data has revealed a positive correlation between ESR and CRP (R 2 =0.85) in severe COVID-19 post recovery patients. Elevation of in ammatory biomarkers can be considered as a parameter for COVID-19 infection and its severity 37 .
In the mild-moderate COVID-19 post recovery group, data showed non-signi cant positive correlation between ESR and CRP (0.6149). In addition, there was neither correlation between CRP and albumin (-0.3277) nor between ESR and albumin (-0.0504) ( Table 1) Our study seems to be the rst attempt to observe those biological markers in COVID-19 post recovery patients.
In Table 1 data analyses showed no correlation between mild-moderate and severe groups in COVID-19 post recovery patients when both groups compared in terms of ESR, CRP and serum albumin markers.
A study showed a signi cant difference in ESR, CRP and serum albumin between mild and severe COVID-19 patients. However, the difference between moderate and severe groups was observed only in ESR. In conclusion we found a prolonged increase of ESR, CRP and decrease of serum albumin in severe COVID-19 post recovery patients. We also discovered a strong negative correlation of albumin with both ESR and CRP in the group. Therefore replacing albumin and ESR/CRP de-escalation is vitally recommended for the physician to avoid further consequences to COVID-19 post recovery patients.

COVID-19 Severity Category
The criteria for severity of COVID-19 were de ned according to the diagnosis and treatment protocol for novel coronavirus pneumonia (Version 7) as mild, moderate and severe 42 . Mild cases -the patient shows mild clinical symptoms with no sign of pneumonia on imaging; moderate cases -the patient shows fever and respiratory symptoms with radiological ndings of pneumonia; severe cases -cases have any of the following criteria, respiratory distress (≧30 breaths/min), oxygen saturation ≤93% at rest, arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ≦300 mmHg (l mmHg = 0.133 kPa).
Based on the above criteria patients were divided into two groups; 23 mild-moderate cases and 23 severe cases. Within 2-4 weeks of post recovery, blood samples were collected from each participant.

Biological marker Test
Biological marker tests including CRP and serum albumin were assessed for mild/moderate and severe groups using an automated multiparametric analyzer (cobas c111, Roche Diagnostics, Germany) and ESR were tested by Westergren method 43 .

Statistical Analysis
Pearson correlation and polynomial regressions were employed to understand the relationship between ESR, SRP and serum albumin biomarkers.

Declarations Con ict of interests: No
Author contribution: KMA and AMA have performed lab work, HMT and HMR have contributed in the writing. GF has analyzed the data.