Pattern of liver injury during acute COVID-19 had been addressed enormously, meanwhile, the long-term impact of COVID-19 on the hepatic functions is still unclear. In the current study, Liver function tests showed statistically significant variations in COVID-19 survivors than individuals without history of COVID-19 exposure. ALT, AST, GGT, and ALP were significantly elevated in COVID-19 survivors. On the other hand, although normal values of serum albumin, we noticed statistically significant reduction of serum albumin in COVID-19 survivors. Interestingly, serum bilirubin showed non-significant difference between the study groups.

Ya-Wen et al. [10] found elevated levels of ALT, GGT and ALP along with reduced serum albumin in COVID-19 survivors for a period of 14 days after discharge but with gradual normalization of these parameters within two months. In our study, we found a persistent elevation of ALT, AST, GGT, and ALP for 3 month after resolved COVID-19. The former study reported dropout of the majority of COVID-19 survivors during the follow-up period.

Fan et al. [11] studied disruption of liver function in COVID-19 patients and reported reversible mild to moderate elevation of hepatic aminotransferases without concomitant elevation of serum total bilirubin. Also, Xu et al. [12] reported a non-elevated serum bilirubin in COVID-19 patients, despite the abundant expression of ACE2 in the hepatic vascular endothelium, cholangiocytes rather than the hepatocytes. They attributed these findings to the overwhelming systemic inflammatory response rather than direct viral invasion. However, the precise pathogenesis of liver injury in COVID-19 patients is still controversial. Multiple theories were postulated to explain the pathogenesis of hepatic changes such as ACE2-mediated direct hepatocyte viral invasion, disrupted immune homeostasis, systemic inflammatory response, concurrent hypotension, pneumonia-associated hypoxia, cytokine storm with a surge of the pro-inflammatory cytokines, and drug-induced hepatotoxicity [13, 14]. In addition, Xu et al. [15] reported moderate micro-vesicular steatosis, lobular and portal tract inflammatory infiltrates with significant reduction of CD4 and CD8 cells in liver biopsies of COVID-19 patients. Also, Tian et al. [16] found mild sinusoidal dilatation, focal macro-vesicular steatosis without reliable evidence of bile duct damage. Moreover, Zsuzsanna et al. [17] attributed these alterations to the lymphocytic endothelitis with hepatocyte necrosis induced by direct vial invasion and immune cell hyper-activation.

In our study, COVID-19 survivors experienced mild but significant elevated serum lipase and amylase than healthy counterparts. This finding may be explained by the copious expression of ACE2 receptors within the pancreatic tissue. In agreement with Furong et al. [18] and Fan et al. [19] who considered SARS-COV-2 as a potential viral cause of pancreatitis through direct cytopathic effect as well as the systemic inflammatory response, disrupted immune system with cytokine surge, and potential drug-induced pancreatitis.

In our study, BUN, serum creatinine, and urine albumin creatinine ratio were significantly elevated along with relatively reduced eGFR in COVID-19 survivors than others without a history of COVID-19. In accordance with Xu-Wei et al. [20] who carried out a case-series study for 12 patients with COVID-19 and reported significantly elevated serum creatinine, BUN, and micro-albuminuria during COVID-19 illness with partial improvement over a period more than 1 month after recovery. These findings were explained by Zou X et al. [21] who reported high expression of ACE2 in the apical membrane of the epithelial cells at the proximal renal tubules.

We found significantly reduced lymphocyte count percentage in COVID-19 survivors than non-COVID-19 exposed peers. Lowered lymphocytic count is a common association and sequence of various coronavirus infection. Wong et al. [22] reported reduced lymphocyte count in the majority of patients with SARS-CoV. Furthermore, the lymphocytic count was inversely correlated with severity of COVID-19 [23]. The direct invasion and lysis of lymphocytes by SARS-CoV-2 via ACE2 receptors located on their surface, enhanced lymphocyte apoptosis triggered by the systemic inflammatory response with pro-inflammatory cytokines surge and lymphoid organs atrophy were hypothesized to explain the lowered lymphocytic count during and after COVID-19 [24].

On the other hand, Holshue et al. [25] studied the first case of COVID-19 in the United States and reported rapid reversal of reduced lymphocytic count after 2 weeks of acute illness. On contrary, COVID-19 survivors in the current study showed persistently lowered lymphocytic count for more than 3 months after recovery.

Our results revealed persistent higher levels of inflammatory markers such as ESR, CRP, D-dimer, and ferritin in COVID-19 survivors denoting residual systemic inflammatory response. Despite different study design, our results are consistent with Sandra et al. [26] who conducted meta-analysis of the long-term effects of COVID-19. They found residual elevation of CRP, D-dimer, and ferritin associating post-COVID-19 related symptoms despite the heterogeneity of their data.

Our results agreed with Mandal et al. [27] who carried out a follow-up observational study for COVID-19 survivors during a period of 4 to 6 weeks after discharge. They found persistent elevated inflammatory markers such as D-dimer and CRP. Also, Sonnweber et al. [28] found persistent high ferritin levels among COVID-19 survivors 2 months after the onset of COVID-19.

In the current study, systolic blood pressure was significantly elevated in COVID-19 survivors. COVID-19 pandemic may increase fear, anxiety, socio-economic burdens, mental disorders, and decrease physical activity. Therefore, it can potentially compromise blood pressure control [29].

We strived to detect the pathological clinical and biochemical residue after COVID-19 recovery in our locality. Our strength points were the relatively longer follow-up period after the negative RT-PCR test of SARS-CoV-2. Strictly, the case group included COVID-19 survivors with a history of mild to moderate illness. We tried to avoid confounders such as severe COVID-19 illness as well as a history of acute or chronic morbidities after recovery till enrolment time. We faced many limitations such as the lack of documented data of COVID-19 survivors before and during the acute stage of illness, we relied on the detailed medical history of participants. However honestly, we cannot guarantee full trust in participants’ story. Moreover, the scarcity of similar trials due to novelty of SARS-CoV-2 and the single-centre study represented major limitations. In this study, we tried to detect the significant differences between COVID-19 survivors who are expected to be definitely healthy after pre-specified convalescence period versus healthy subjects without COVID-19 exposure. Multi-centre trials with larger-scale, multiple ethnicities, longer follow-up period and invasive tools may help more advanced research in the future.

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