Background

The Egyptian coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is part of a worldwide pandemic. On February 14, 2020, it was confirmed that the virus had invaded Egypt (Saied et al. 2021). At the time this article was written, SARS-CoV-2 had infected nearly 515,667 in Egypt and killed around 24,624 (Africa CDC 2022). Egypt’s low COVID-19 prevalence does not represent reality and might be attributed to various variables (Perlman and Netland 2009).

Although the number of people currently diagnosed with COVID-19 has dramatically multiplied, the link between comorbidity and COVID-19 remains unclear (Albadawy et al. 2021). Worldwide, COVID-19-related mortality has been linked in the literature to various factors; however, most data comes from high-income countries (Jassat et al. 2021). Race, ethnicity, and poverty were linked to an elevated risk of mortality in COVID-19 cases (Sze et al. 2020; Ranzani et al. 2021; Williamson et al. 2020).

Egypt is at the top of the list of nations where the hepatitis C virus (HCV) is prevalent, estimated to be 8–10 million people, with genotype 4 dominating (Waked et al. 2014; Centers for Disease Control Prevention 2012). Since 2007, HCV treatment has been one of Egypt’s top national goals. The Egyptian National Committee for the Control of Viral Hepatitis has taken all appropriate action to provide direct-acting antivirals (DAAs) to HCV patients (Omran et al. 2018).

The cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2(ACE2) (Ni et al. 2020). Hyperinflammation (“Cytokine storm”), hypercoagulability (microthrombosis in the pulmonary circulation), and the resulting severe hypoxemia (impaired oxygen absorption ) are the three pathologic processes that contribute to multi-organ failure and poor outcomes in COVID-19 (Abdelzaher et al. 2021). The role of ACE-2 in liver disease is especially important because numerous lines of evidence suggest that, like other organs, the renin-angiotensin system (RAS) is involved in the control of hepatic inflammation, tissue remodeling, and fibrosis after liver injury (Abbas et al. 2011; Mak et al. 2015). ACE-2 plays a protective function in lung disease similar to that observed in liver disease (Oarhe et al. 2015; Skurk et al. 2001). Anti-hepatic C virus medications could prevent COVID-19 by modulating RAS, according to the theory (Negm 2022).

A modern iteration of Occam’s razor deduces that “the simplest explanation is usually correct and entities should not be multiplied without necessity.” The simplest explanation is that COVID-19 has a single mechanism that is shared by both predicted and unexpected features (Czick et al. 2020). Although early reports of COVID-19 cases highlighted hepatic manifestation, the mechanism of liver impairment remains unclear (Ronderos et al. 2021).

To the best of our knowledge, data do not provide specific information regarding the prevalence and impact of viral hepatitis, specifically, HCV in COVID-19 patients, and its relation to the severity and outcome is still a dilemma (Ronderos et al. 2021; Zhang et al. 2020; Wang et al. 2020; Kulkarni et al. 2020). Thus, this study aimed to assess the prevalence of chronic hepatitis C as a risk factor among COVID-19 patients and to investigate the impact of it and the prior exposure to different HCV management protocols on the clinical characteristics and outcome of COVID-19 hospitalized patients.

Methods

Study design and setting

This retrospective cohort study included ICU-admitted confirmed severe and critical COVID-19 cases from May 30, 2020, to May 30, 2022, at Zagazig University Hospitals Isolation ICUs. Zagazig University Hospitals are Egyptian tertiary care teaching hospitals that receive patients from the East Delta, Suez Canal, and Sinai governorates. Thirty beds in 2 isolation ICUs (15 in each one) were available at the time of data collection.

Participants and case definition

The study enrolled all adult patients (≥ 18 years) with laboratory-confirmed SARS-CoV-2 infection and radiological evidence of pneumonia. The microbiological diagnosis of SARS-CoV-2 infection was defined by real-time polymerase chain reaction of a nasal-pharyngeal swab specimen. Patients with incomplete or missing clinical and laboratory data at baseline were excluded from the study. Ward cases (mild to moderate cases) were excluded because they were asked to continue their care at home shortly after admission to the investigated university and discharged against medical advice with missed data. Patients who received vaccinations were also not included.

According to Chinese guidelines for COVID-19 management; severe COVID-19 was categorized as the presence of radiographic evidence of ˃ 50% lung infiltrate plus one of the following: respiratory rate of 30 breaths or more per minute; oxygen saturation (SaO2) < 94% with breathing ambient air at rest; or ARDS, which is defined as the ratio of arterial oxygen partial pressure (PaO2) to a fraction of inspired oxygen (FiO2) (PaO2: FiO2) of ≤ 300 mmHg. Critical COVID-19 was categorized as respiratory failure requiring ventilator support, either invasive or non-invasive, septic shock, and/or any organ dysfunction that requires ICU-supportive treatment (Lin and Li 2020).

Data collection

Historical, clinical, laboratory, and radiological data were obtained retrospectively by team members from patients’ records. Requirements for antiviral, anticoagulants, steroids, antibiotics, as well as other anti-COVID-19 measures, were administered in the ICU on the basis of indication and patient situation guided by the Ministry of Health (MOH). Patients were discharged from critical care according to the MOH recommendations. Patient mortality was the primary outcome. Morbidity parameters such as ICU length of stay (LOS) and ventilator days (non-invasive or invasive) were recorded.

Patients were then classified into those with chronic liver disease (CLD) and those without CLD. We reviewed medical charts and laboratory parameters (HCV antibody) to obtain the HCV infection status and its management protocols. Any history of receiving HCV treatment (Ribavirin and Interferon), (Daclatasvir and Sofosbuvir), or (Daclatasvir and Sofosbuvir plus Ribavirin) was recorded after confirmation by related documentation. The prevalence of chronic hepatitis C COVID-19 patients was estimated.

Statistical analysis

Statistical analysis was conducted using the Statistical Package for the Social Sciences (SPSS) software version 27 (IBM SPSS Statistics for Windows, Version 27 2020). Kolmogorov–Smirnov and Levene tests were used to determine the distribution characteristics of variables and variance homogeneity. Descriptive statistics were generated for all variables. Comparison between survived and dead patients was performed using the appropriate tests of significance. Student’s t test was used to analyze continuous normally distributed variables. The Mann–Whitney U test was used to analyze continuous not normally distributed variables. The chi-squared test and Fisher’s exact test were used to analyze qualitative variables as appropriate. All factors that were significantly associated with the outcome were run in a binary logistic regression model to determine the independent predictors of death. Survival analysis was done using the Kaplan–Meier diagram and log-rank test. The level of statistical significance was set at p < 0.05.

Results

The study cohort distribution is summarized in a flowchart (Fig. 1). Of 2106 enrolled confirmed cases with COVID-19, 99 (4.7%) cases with CLD were included during the study period, and 96 of the 99 cases were cirrhotic. A total of 69 patients (3.3%) were categorized as HCV-positive. Among the positive HCV cases, 49 patients (71%) received anti-hepatitis C viral medications, whereas the remaining 20 (29%) did not. Of those who received treatment, 31 patients (63.3%) survived. Fourteen cases (70%) of those who didn’t receive treatment died.

Fig. 1
figure 1

Flow chart of investigated cohort

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The mortality rate for the study cohort was 24.3% (Fig. 2). Some comorbidities were associated with death; diabetes mellitus, hypertension, ischemic heart disease, hepatic diseases, malignancy, chronic kidney disease, and organ transplantation (Table 1). The length of ICU stay was significantly longer in survivors with median (11) days versus (8) days in the mortality group (Table 1, Fig. 3).

Fig. 2
figure 2

Outcome of the COVID-19 patients

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Table 1 Characteristics and outcomes of COVID-19 patients in the study cohort
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Fig. 3
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Length of stay of the COVID-19 patients according to outcome

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59.8% of cases (1260 cases) were supported by noninvasive mechanical ventilation, where 39.7% of them (500 cases) died. The median noninvasive ventilator duration was 14 days. 24.12% of cases (508 cases) were supported by invasive mechanical ventilation, and 99.21% of them (504 cases) died. The median invasive ventilator duration was 5 days. Mechanical ventilation was significantly associated with death (Table 1).

A regression analysis model was used to determine the predictors of death in the investigated COVID-19 patients. Patient age was a significant predictor of death with an OR (95% CI) = 8.07 (2.05–21.09). The severity of COVID-19 at admission also was a significant predictor with OR (95% CI) = 6.17 (2.26–10.21). Regarding comorbidities, hepatic diseases, malignancy, and chronic kidney disease were significant risk factors for death in the study of COVID-19 patients [OR (95% CI) = 2.78 (1.29–5.98), 2.72 (1.14–6.46), and 3.79 (1.39–10.36) respectively]. Also, invasive mechanical ventilator was a predictor for mortality in the study cohort (Table 2).

Table 2 Binary logistic regression analysis of the outcome of the COVID-19 patients with significantly related independent variables
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Regarding the COVID-19 patients being studied with hepatic diseases, the mortality rate was 54.5% (Table 3). The mortality rate was 46.4%, and 73.3% between HCV and Non-HCV patients, respectively (Fig. 4). A statistically significant association was between outcome and some variables. The length of stay was significantly longer in survivors (median = 15 days) than in dead patients (median = 9 days) (Table 3, Fig. 5).

Table 3 Characteristics and outcomes of COVID-19 patients with chronic liver disease
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Fig. 4
figure 4

Outcome of the COVID-19 patients with chronic liver diseases

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Fig. 5
figure 5

Length of stay of the COVID-19 patients with chronic liver disease according to outcome

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71.7% of hepatic cases (71 cases) were supported by noninvasive mechanical ventilation, and 76.1% of them (54 cases) died. The median noninvasive ventilator duration was (14) days and longer in surviving cases (22 days). Of the cases, 54.5% (54 cases) were supported by invasive mechanical ventilation, and 100% of them (54 cases) died. The median invasive ventilator duration was 2 days. Mechanical ventilation was significantly associated with death. All invasively ventilated hepatic patients had poor outcomes (Table 3).

Among the study COVID-19 patients with hepatic diseases, HCV patients had better outcomes than non-HCV patients as 82.2% of the survivors had HCV (Table 3). Patients who presented for admission with signs of hepatic encephalopathy were significantly associated with mortality. Table 3 shows a significant correlation between the degree of cirrhosis and the outcome. Decreased serum albumin level and platelet count and elevated both conjugated bilirubin and liver enzymes [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], as baseline laboratory data at admission, were associated with mortality (Table 3).

Among the COVID-19 patients being studied with chronic liver diseases, there was a statistically significant association between outcome and treatment of hepatitis C. Non-treatable hepatitis C patients had a poor outcome as 43.8% of the deceased patients had not received hepatitis C management. Alternatively, triple antiviral therapy was associated with a better outcome as 40.5% of surviving patients had received triple therapy alone and 5.4% had received ribavirin and interferon ( patients who received triple therapy were more 4.77 times more likely to survive than other therapies ) (Table 4).

Table 4 Outcomes of the COVID-19 patients with HCV
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A regression analysis model was used to determine the predictors of death in the investigated COVID-19 patients with hepatic disease. The severity of COVID-19 at admission was a significant predictor for death with OR (95% CI) = 4.77 (1.79–7.92). Hepatic encephalopathy was also a significant predictor for death with OR (95% CI) = 7.35 (3.28–16.5). Regarding laboratory findings, high ALT, high AST, high total bilirubin, and high direct bilirubin were significant risk factors for death [OR (95% CI) = 1.69 (1.01–2.99), 1.99 (1.05–3.76), 2.32 (1.13–4.75) and 3.19 (1.14–8.98) respectively]. Also, invasive mechanical ventilator 6.92 (1.38–14.63) and Grade C liver cirrhosis 2.28 (1.01–5.12) were predictors for mortality, while HCV and treated HCV had better outcomes when compared with other hepatic cases (OR = 0.56 and 0.37 respectively) (Table 5).

Table 5 Binary logistic regression analysis of the outcome of the COVID-19 patients who had chronic liver disease with significantly related independent variables
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Survival analysis using the Kaplan–Meier method was used to determine the relation between treatment and survival in the investigated COVID-19 patients with hepatic disease. There was a statistically significant increase in median survival among cases who received HCV treatment compared to non-treated cases. In addition, there was a statistically significant increase in median survival among cases that received triple therapy either alone or associated with other drugs compared to other treatment types (Table 6, Fig. 6). Table 7 shows a significant increase in the survival rate among Child A and C-treated cases compared to non-treated cases.

Table 6 Median Survival of COVID-19 patients with HCV
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Fig. 6
figure 6

Kaplan–Meir survival of HCV cases according to HCV treatment

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Table 7 Outcomes of the COVID-19 patients with chronic liver disease according to treatment and Child−Pugh classification
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Discussion

Egypt has the highest HCV prevalence in the world (Kouyoumjian et al. 2018). In September 2018, the Egyptian government released the “100 Million Healthy Lives” campaign with a fruitful nationwide HCV screening and treatment program (Blagosklonny 2020). To the best of our knowledge, this is the first study in Egypt focusing on the analysis of the prevalence, characteristics, and outcomes of chronic liver disease patients among a large cohort of severe and critical COVID-19 patients throughout a considerable time (24 months) in a large Egyptian tertiary care hospital, as well as, the effect of different types of anti-hepatitis C therapy on the outcome.

The mean age of the current study ICU patients was (54.9 ± 14.1). Evidence suggests that the protective counterbalancing arms of RAS are diminished in the elderly, making them more sensitive to the harmful effects of the ACE axis (Czick et al. 2020). Aging is linked not only with severe illness but also mortality (Waked et al. 2020; Onder et al. 2020).

The median ICU length of stay ranged from 6 to 12 days in China, compared with 4 to 19 days in other countries (Rees et al. 2020). The median length of ICU stay in the current study was 8 days. This could be due to differences in the admission and discharge criteria. Furthermore, many Egyptian caregivers gained more expertise and proficiency in managing the condition at home upon patients’ request and for their psychological pleasure, which impacted the results between close centers.

Although males had higher levels of RAS than premenopausal females, the male-to-female ratio suggests a higher incidence of males with the same outcome (Czick et al. 2020). In this study, the percentage of males was (57.5%) with an equal survival rate as females. Another Egyptian study showed no significant association between male gender and disease severity (Ramadan et al. 2020). Males were nearly 2.5 times more likely to die from COVID-19 in another study (Jin et al. 2020).

In a meta-analysis of 24 observational studies including 10,150 patients, ICU mortality rates ranged from 0 to 84% (Armstrong et al. 2020). Although nearly one-quarter of our COVID-19 patients died, the mortality rate in our cohort (24.3%) was lower than that reported in previous large cohorts (Grasselli et al. 2020a; Richards-Belle et al. 2020). This could be due to differences in ICU admission criteria, a less-stressed healthcare system in a university hospital setting, and the ability to maintain typical management standards. Another Egyptian study found a 24.4% total ICU/hospital death rate, which is substantially similar to our findings (Nassar et al. 2021).

Comorbidities are extensively proven to be key contributors to serious presentation and death in COVID-19 patients, allowing clinicians to construct risk stratification of COVID-19 patients as early as possible. The most prevalent chronic diseases in our cohort that also constituted risk factors for mortality were ischemic heart disease, hypertension, and diabetes mellitus. These findings are similar to those of a meta-analysis study by Emami et al. (Emami et al. 2020) and Ghweil et al. (Ghweil et al. 2020). Diabetes was shown to be a preexisting comorbidity in 33.8% of COVID-19 patients in a case study of 5700 hospitalized patients (Richardson et al. 2020). In an Italian case study, 49% of 1591 COVID-19 patients admitted to the ICU were hypertensive, and 21% had cardiovascular diseases (Grasselli et al. 2020b). CLD, malignancy, chronic kidney disease, organ transplantation, and neuropsychiatric symptoms at presentation were also associated with mortality in the current study. All exhibited a fingerprint of RAS imbalance, suggesting that RAS is a common offender (Czick et al. 2020).

Patients with CLD had greater rates of mortality than those without liver disease in a study of 2780 patients with COVID-19 (including 250 patients with CLD) (Singh and Khan 2020). The outcomes of adult patients with COVID-19 who were discharged from acute and post-acute care in France were investigated, including mechanical ventilation needs and day 30 mortality. COVID-19 mortality risk was not increased in patients with mild hepatic disease, compensated cirrhosis, acquired immunodepression syndrome, or organ transplantation, including liver transplantation. COVID-19-related mortality was higher in patients with alcohol abuse disorders, decompensated cirrhosis, and hepatocellular carcinoma, but the need for mechanical ventilation was less likely. The findings show that medical effort limitations may be linked to increased mortality in French residents with liver disease or an alcohol abuse disorder (Mallet et al. 2021).

The following are the study’s key findings for our cohort: CLD was found to be present in 4.7% (99 patients) of COVID-19 patients. Approximately 3.3% (69 patients) had HCV-positive serology, and 2.3% (49 patients) received antiviral therapy. CLD was found to be a risk factor for mortality, and HCV patients had better outcomes than non-HCV patients. The stage of cirrhosis was associated with the outcome, where grade C liver cirrhosis was a predictor of mortality. In addition, there was a statistically significant correlation between hepatitis C virus treatment and outcome; nevertheless, analyses showed that individuals who received triple DAA medication had a better prognosis. Survival was observed between double DAA therapies as well but was not considered in the statistics. We found no advantage in terms of outcome from the old-fashioned antiviral treatment, including ribavirin and interferon. The explanation could be the specificity of these medications (DAAs) in protecting by a unique mechanism or the close proximity of delivery, which is why we propose the use of DAAs in prophylactic techniques to combat the pandemic together with current vaccination.

Another study attempted to evaluate the possible reciprocal effect of COVID-19 and pre-existing cirrhosis, which reported results comparable to those of the current study. This includes 332 COVID-19 patients hospitalized at three Italian hospitals during the pandemic, as well as two large cohorts of HCV patients from real-world antiviral treatment studies (pangenotypic sofosbuvir/velpatasvir combination). Cirrhosis was associated with higher mortality, with metabolic cirrhosis accounting for most deaths. They concluded that the very low prevalence of COVID-19 in HCV cohorts suggests that HCV antibodies may have a protective effect (Mangia et al. 2020). The claim that only possessing hepatitis C antibodies is sufficient to explain and understand the observation is in conflict with our findings and with other interesting findings that identified hepatitis C as a significant predictor of in-hospital death (Ronderos et al. 2021; Cerbu et al. 2021). A history of hepatitis C infection accentuates SARS-CoV-2 viral virulence and raises the probability of a cumulative mortality risk to any other clinical or laboratory characteristics. The underlying processes might be connected to HCV extrahepatic effects, which would boost the ACE-2/TMPRSS mechanisms of the SARSCoV-2 virus, resulting in endothelial dysfunction (Ronderos et al. 2021). Another retrospective cohort analysis was performed to assess the risk of liver damage and all-cause mortality. When comparing the proportion of severe COVID-19 cases in the active and non-active HCV infection groups, the study found a statistically significant higher prevalence in the active HCV group. These findings suggest that active HCV patients with COVID-19 should be closely monitored and treated to avoid health deterioration and fatal outcomes (Cerbu et al. 2021).

Nassar et al. investigated the characteristics, risk factors, and outcomes of critically ill COVID-19 pneumonia patients admitted to Cairo University Hospitals in Egypt and found that patients with chronic liver disease patients had the lowest incidence of all comorbidities, with zero mortality (Nassar et al. 2021). Ain-Shams University Isolation Hospital showed a low rate of CLD patient ward admission and zero percent ICU admission in a retrospective analysis that identified risk factors for patients needing ICU admission during their stay (Fouad et al. 2021). Other supporting evidence was discovered in numerous Egyptian institutions (Khamiss et al. 2021; Omran et al. 2021; Hafez et al. 2021). A multicenter retrospective Egyptian study evaluated the impact of cirrhosis on the outcome of COVID-19, stating that even though cirrhotic patients were more likely to experience severe COVID-19 and death, only decompensated patients exhibited cirrhotic mortality (Afify et al. 2021).

Indirect findings from a SARS epidemiological investigation revealed that the hepatitis B virus (HBV) infection was a risk factor for ARDS progression (Peiris et al. 2003). The absence of hepatitis B as a risk factor in the current study cannot exclude the possibility that with the wide spread of vaccination, its incidence in the community declined. HBV infection was found in 2.1% of SARS-CoV-2 patients from China, indicating a higher local prevalence of HBV (Guan et al. 2020). Ronderos D et al. discussed the incidence of hepatitis C between COVID-19 patients in their locality with a similar explanation. The incidence of history of HCV infection in their study was on the higher side (4.1%) (Ronderos et al. 2021) than that reported in the literature, where HCV infection was found in less than 0.1% of COVID-19 patients in a sizable study of 5700 hospitalized patients (Richardson et al. 2020). In the community where the study cohort was drawn from (Bronx, New York), there is a higher prevalence of injection drug abuse, which has been linked to a higher incidence of HCV, which could explain the higher HCV prevalence in their cohort (Des Jarlais et al. 2018).

Postulated mechanisms

Our finding; the value of anti-hepatitis C medications in COVID-19 protection, was explained and supported by 3 mechanisms proposed and widely debated (Negm 2022).

Our study has certain limitations. Although there is a significant prevalence of HCV among elderly individuals living in rural areas in Sharkia governorate and other areas served by the university (Emam et al. 2015; el Gohary et al. 1995), our cohort may not be representative of hepatic patients with COVID-19 admitted to all Egyptian ICUs. According to our university’s experience, non-critical patients who were admitted to the hospital or who were stable and discharged from the ICU preferred to stay back home to complete their management, therefore ward cases were excluded. Viral variant identification was not available at our institution. Unfortunately, HCV PCR was not performed, and we defined HCV status based on an antibody test for confirmation of positivity. Finally, the multivariate analysis may be limited by the included variables, and the impact of unmeasured confounders cannot be ruled out.

Conclusions

In this report, we demonstrated that chronic liver disease, chronic kidney disease, and malignancy were significant risk factors for death among COVID-19 patients. The Egyptian mass management of chronic hepatitis C may explain the favorable outcome of COVID-19 among these patients. Invasive mechanical ventilation and advanced liver cirrhosis were predictors of mortality. Further Egyptian and international multicenter studies are required to confirm or deny our results. Understanding the mechanisms may aid in better characterizing the disease and discovering novel therapeutic strategies. Intervention studies are needed to demonstrate the efficacy of DAAs as COVID-19 prophylactics. We will observe and monitor if our results, with existing immunization, will help Egypt’s herd immunity build more rapidly.