It is worth to mention that till now there are no data on the safety, tolerability, or even effectiveness of the influenza vaccines in the patients with mild COVID-19 or even with those who have recovered from COVID-19. Therefore, the safety and efficacy of vaccinating persons have not been documented yet . So, this study was carried out to investigate the probable effect of Tamiflu which listed as the main drug in the treatment protocol.
Our biochemical findings showed significant increases in the serum toxicity markers of both liver and kidneys (ALT, AST, ALP, GGT, indirect bilirubin, urea, creatinine, uric acid and Na+), which were accompanied by decreases in the levels of serum total protein, albumin and K+ ions of G2 (The therapeutic dose) and G4 (long-term prophylactic dose). On the other hand, neither the liver’s nor kidneys’ serum functions were affected by Tamiflu in G3 (short-term prophylactic dose); except the serum albumin level which was significantly decreased compared with the control group. Al-Rikabi  and  reported significant increases of hepatic and renal serum markers in the rats that treated with Tamiflu (1 mg/kg/6 weeks), with significant increase in serum ALP, direct bilirubin and uric acid, and significant decrease in ALT activity and indirect bilirubin. Also, the results by El-Sayed and Al-Kahtani  showed significant elevations in AST and ALT activities in male and female rats that dosed with Tamiflu (2.2 mg/kg/5 days); the same dose caused oxidative stress and acute toxicity in both genders. Akanji et al.  reported that the increase in the serum enzymes as ALT, AST, ALP, GGT might be due to permeability alterations in the plasma membrane leading to enzyme leakage from liver tissues into the blood stream, leads to hepatocellular functions impairment (such as pyknosis/necrosis).
Significant increases in the liver enzymes markers in G2 and G4 imply a loss of cellular membrane integrity. Aminotransferases catalyse the interconversion of AAs and oxoacids by transferring amino groups in protein metabolism and gluconeogenesis. ALP is a potent anti-inflammatory mediator, protects tissues from damage/injury. Also, it plays an integral role in metabolism and biosynthesis of energy macromolecules within the liver, and breaks down proteins and catalyses the removing of phosphoric esters. AST, ALT and GGT are the most important indicators of hepatocellular injury/necrosis, inflammation and metabolic disorders .
The main cause of hyperbilirubinemia could be due to rise an indirect serum bilirubin (unconjugated bilirubin), which may result from poor conjugation, or decreased liver uptake of an indirect bilirubin or/and rapid synthesis (haemolysis) in drug induced liver injury . Moreover, elevation of serum indirect bilirubin in G2 and G4 may be due to free fatty acids which displace indirect bilirubin from its attachment to plasma albumin . Hypoproteinemia can also be caused by liver impairment, which reduces the synthesis of plasma proteins like albumin (hypoalbuminemia) . Other previous studies indicated that the protein depletion referred to impairment in the secretory function of the liver arising probably from hepatocellular injury , or increased catabolism . Hyperlipidemia is a well-known risk factor for fatty liver infiltration, which can lead to liver failure. Hypercholesterolemia has been linked to an increase in the production of oxygen free radicals, which has been linked to negative effects on organ tissues such as blood vessels, liver and kidney . All of the aforementioned alterations represent either an increase or a decrease in a certain parameter(s) investigated in this study.
Xenobiotics caused oxidative stress, which is shown histologically. The results of the present study showed foamy/cytoplasmic vacuolization. The latter alteration was explained by Santucci et al.  due to accumulations of the neutral lipids. The latter cause the foamy appearance of the cells, originate at the ER, accumulate in it and pinched off the ER membrane into the cytosol. Abdel-Ghaffar  mentioned that the accumulation of the lipid droplets was a prominent alteration observed ultrastructurally in transverse sections of the testes of Tamiflu-administrated rats.
Also, mononucleated cells infiltration (Küpffer cells/LGC/histiocytes) and haemorrhage (dilatation of PoV/congested BS) were seen in the present study which indicate chronic inflammation. The previous observations agreed with those observed by Michael and Cynthia . The authors explained that mononucleated and Küpffer cells activation and others promoting due to tissue damage. While Farrag et al.  explained that the drug caused the changes should be listed among “drugs-induced liver injury”. The latter type of drugs defined as “drug-induced critical alterations of hepatocytes that trigger the immune systems of susceptible hosts to infiltrate their livers and assault/damage hepatocytes, which leads to liver injury”. Kupffer cells, which are found in the normal liver, play an important role in both hepatic immunological homeostasis and the immunopathology of liver disorders. In response to acute/chronic inflammation, Kupffer cells generate high levels of proinflammatory cytokines and activation of these cells is a critical factor of peroxynitrite production and the severity of liver damage . Moreover, the creation of neoantigens by medicines or their metabolites interacting with host proteins, such as albumin, could be the starting point for initiation of other immune cells, particularly cytotoxic T cells, resulting in liver injury. Hepatic toxicity caused by drugs might be dose/time-dependent or caused by a drug immune response mechanism . In the present study, the liver injury attributable to Tamiflu shows that immuno-allergic factors, resulting from high dose or long duration of treatment, may have caused the liver damage. On the same manner, a previous study reported that OP had a hepatotoxic impact in rats given orally a therapeutic dose of one mg/kg.BW for various periods .
Also, as seen in G2 and G4, the nuclear alterations (pyknosis/karyorrhexis/karyolysis) in hepatocytes may be attributed to interference with DNA and protein synthesis in response to Tamiflu-toxic effects.
Hepatic fibrosis was shown in the branches of the hepatic portal veins and the central veins that exhibited markedly thickened endothelial walls. According to Amin et al. , fibrosis initiated by parenchymal cell destruction due to multiple injurious agents, and followed by inflammation, the latter activates resting hepatic stellate cells.
Tissue injury might result in a high plasma urea level. A high uric acid level is most commonly caused by inefficient uric acid elimination by the kidneys. Urate crystals can form when uric acid builds up, causing kidney injury . So, the elevations in the levels of serum renal toxicity markers (such urea and uric acid) at G2 and G4 might be attributed to impairment/obstruction of protein and nucleic acid catabolism (an indication of the nephrotoxicity of Tamiflu), as it adversely affected the tubular and glomerular function of the rats . On the other hand, creatinine is not reabsorbed; instead, it rises as a result of a lower glomerular filtration rate, which is used to detect renal impairment . When the kidneys fail, the balance of fluid and electrolytes is disrupted, resulting in an imbalance of specific electrolytes. Hypokalemia can also affect the kidneys' ability to concentrate urine, leading to excessive urination and thirst (polyuria and polydipsia, respectively). Also, it can cause several alterations in kidney function, including impaired tubular transport and the development of chronic tubulointerstitial dysfunction . The ability of the kidneys to maintain water homeostasis is known to be affected by chronic renal disease, and thus the risk of both hypo- and hypernatremia, with water changes resulting to cellular swelling or shrinking, can increase as the disease progresses . In this study, the elevated serum creatinine concentration and electrolytes such as Na+, as well as the reduction in concentration of serum K+ indicate tubular dysfunction . Kang et al.  concluded that hypernatremia does occur when there is loss of body fluids containing less Na+ than plasma. Nduka  reported that Na+ increase is suspected to be due to the inability of the kidneys to excrete adequate Na+ ion from the tubular fluid. These might explain the excess of Na+ ion levels in the Tamiflu-administrated rats (G2&4). Earlier researches [11, 42, 43] reported that renal impairment in the highest-dose group (761 mg/kg) of Tamiflu was accompanied by increased water intake, increased leukocyte count and increased bilirubin, urea, creatinine, and urine volume. Also, the same researchers found that the renal histological examination of their studies revealed degenerating/regenerating changes in the renal tubular epithelia, basement membranes and Bowman capsules; vacuolization in the renal tubular epithelia; and mineralization of tubules of renal medulla, as seen in our study. Glomerular dilation, degeneration of the epithelial cells lining the renal tubules, infiltration of inflammatory cells, hyperemia of medullary and cortical parts infiltrates were evident especially in G2 and G4 treated with Tamiflu. In previous studies in rats, experimental hyperuricemia, hyperuricemia and hypercreatininemia have also been associated with the development of mild renal disease, characterized by mild proteinuria, changes in renal blood vessels, glomerular damage, tubulointerstitial fibrosis, stimulation of inflammatory mediators and glomerulosclerosis [40, 44].
We know that OP is hydrolysed by hepatic carboxylesterases to oseltamivir carboxylate (its active metabolite), that excreted by the kidneys through glomerular filtration and renal tubular secretion . Farrely  reported that repetitive doses/long-term use of Tamiflu caused the kidneys to become unable to hydrolyse the oseltamivir/Tamiflu sufficiently. So, its active metabolite forms excessive quantities of ph− will accumulate, leading to mineralization of the kidneys. This may explain the obtained results of this work. According to Basile et al. , the damage of the four major structures of the kidney (the tubules; the glomeruli; the interstitium; and the intrarenal blood vessels) is the major reason resulted in acute kidney injury.
In addition, the biochemical and histopathological alterations observed in the present study were in parallel with the molecular findings. The production of reactive oxygen species (ROS) by Tamiflu toxic metabolism or the consequent mitochondrial damage might cause direct or indirect oxidative DNA damage. Our results of hepatic DNA electrophoresis demonstrated that the oral administration of Tamiflu significantly induced necrosis, especially in G2 and G4 (therapeutic and long-term prophylactic doses) at three bp location (600, 400 and 200 bp), which increased gradually depending on the doses accumulation (dose-dependent) as well as long duration (time-dependent). While the integrity of hepatic DNA in G3 (short-term prophylactic dose) gave necrotic hepatic DNA smears at two bp location (600, and 400 bp) only. In addition, renal DNA integrity in G2 and G4 (the therapeutic and long-term prophylactic doses) gave necrotic DNA smears at two bp location (200 and 600) and three bp location (600, 400 and 200 bp), respectively. On the other hand, renal DNA integrity of G3 at 200, 400 and 600 bp location did not show any significant change compared to the control group. Thus, the effect of the examined drug on the integrity of DNA in the liver samples was higher than in the kidney’s samples. The optical density gradually increased depending on the doses accumulation as well as long duration. El-Ganzuri et al.  and Abdel-Ghaffar  reported that the therapeutic dose, short-term and long-term prophylactic doses gave necrotic DNA smears, but the intensity of such dose was both time- and dose-dependent.
Finally, the reasons that lead to hepatoxicity and nephrotoxicity due to Tamiflu administration should be adequately focused and addressed. In general, increased vigilance during pre-clinical drug/vaccines development and clinical trials, serum hepatic/renal enzymes monitoring with particular medications and the potential finding of both diagnostic/prognostic biomarkers are all ways to prevent drug hepato- or/and renal toxicities.