The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused the continuing coronavirus disease 2019 (COVID-19) pandemic poses a serious threat to health worldwide and the global economy (1). The outbreak of coronavirus originating in December, 2019 was termed SARS-CoV-2 by the World Health Organization (WHO) and the associated disease was named COVID-19(2). By the middle of February 2022, there were over 422 million confirmed cases of COVID-19 confirmed worldwide as per the WHO (3). Moreover, 5.8 million related deaths have occurred due to this disease. Since the time first case of COVID-19 identified in Saudi Arabia on March 2, 2020, the Saudi Ministry of Health has reported 734,389 cases by February 17, 2022, and this included 8,977 related deaths (4,5). Owing to the clinical course of COVD-19 as a subclinical infection, its long incubation period and convalescence, COVID-19 was declared as public health emergency at a global level by the WHO (6). There is a lack of defined treatment protocols for COVID-19, essentially warrants controlling of transmission (7,8). Yet, hospitalization is required in ~20% of symptomatic patients, with 2-5% of patients later requiring management in intensive care units (ICUs) with mechanical ventilation (9,10).

In individuals who are at an advanced age and who have comorbidities, the frequency of hospitalisation, ICU admission and mechanical breathing is markedly higher (11,12,13). Characteristic features of severe infection with COVID-19 include a hyper-inflammatory condition that involves augmented levels of inflammation markers, such as IL-6 and CRP, and increased levels of ferritin (14,15). Ferritin has proven to be the key iron storage protein. Inflammation or iron loading is known to induce the expression of ferritin. In the case of individuals with COVID-19, abnormalities in the concentration of ferritin are associated with the severity of the disease, the development of acute respiratory distress syndrome and mortality (9,14,16). It is well recognised that inflammation alters iron homeostasis. The most common changes include the augmented acquisition of iron, as well as retention inside macrophages and the decreased absorption of iron inside the intestine (17). This leads to a reduced concentration of iron in the circulation and low levels of iron available for erythropoiesis, a process that is required to generate haemoglobin (Hb). In combination with cytokine-mediated erythropoiesis inhibition, the reduced half-life of erythrocytes and diminished erythropoietin activity, this leads to the development of anaemia of inflammation (AI) (18). Low levels of iron and transferrin in the circulation and the diminished saturation of transferrin with iron have been proven to be the characteristic features of AI. However, the ferritin concentration remains at a normal or higher level. Due to this fact, AI differs from iron deficiency anaemia (IDA), which is defined by low ferritin levels, along with elevated transferrin levels (18,19).

Researchers have demonstrated a link between anaemia and worse clinical outcomes of patients with a number of illnesses, including infections and inflammatory diseases (20,21). Reduced levels of iron in the body and increased levels of tissue iron are linked to a reduced lung activity, as well as to severe inflammation of the pulmonary system (22). Anaemia has been proven to be a common manifestation in individuals infected with COVID-19. According to reports, >60% of cases of anaemic COVID-19 have been found to have considerably more adverse outcomes in comparison to COVID-19 cases that were not anaemic (23,24). The WHO has described anaemia as a condition with a Hb level <13 g/dl in males and 12 g/dl in females (25). It has been suggested that the levels of Hb and ferritin are associated with the COVID-19 severity, and that iron metabolism and anaemia affect the pathogenicity, prognosis and treatment of patients with COVID-19 (23,26). Therefore, the present study aimed to examine the association between IDA upon admission to hospital and the outcomes of patients with COVID-19 admitted to King Fahad Specialist Hospital, Tabuk, Kingdom of Saudi Arabia. The present study was conducted in an aim to assess the association between IDA and COVID-19 positivity, as well as severity.

It has been demonstrated that >90% of hospitalized patients with COVID-19 have exhibited reduced blood iron levels (28), and that 30% of patients still had iron insufficiency at 60 days following the onset of COVID-19(28). Mutations in the homeostatic iron regulator (HFE) gene have been reported to be associated with COVID-19 (29,30). The HFE gene encodes the hemochromatosis protein. This protein plays a crucial role in iron metabolism and homeostasis (31).

The present study examined the association between IDA and COVID-19. For this purpose, the data of 100 patients with COVID-19 from the King Fahad Specialist Hospital were collected. Of these 100 patients, 11% patients did not survive, and 61.0 and 39.0% of patients were admitted to the isolation unit and ICU, respectively. Moreover, cardiovascular disorders, diabetes and hypertension were the most prevalent comorbidities among these patients with COVID-19.

IDA is a condition characterized by a reduced concentration of iron. Reduced iron levels may result in the diminished generation of RBCs that transport oxygen to tissues of the body (32). In general, IDA occurs due to inadequate consumption and the absorption of iron and/or loss of this metal due to bleeding (33). Even though the mechanisms through which anaemia augments the susceptibility of an individual to developing infectious disorders remain unclear, and these may involve a number of other factors, such as immunity. IDA affects the health of an individual. In the present study, 23 patients suffered from IDA, indicating an association of IDA with the highest severity of the condition. After analysing the data, it was found that the patients with IDA had greater susceptibility for admission to the ICU in comparison to patients with COVID-19 who did not have IDA. Moreover, the patients with IDA had a longer period of hospitalization. Similarly, a decreased number of patients with IDA were discharged from the hospital without any complications. These results indicated that IDA needs to be considered and treated, particularly in patients suffering from infectious disorders, such as COVID-19.

According to the study conducted by Lechuga et al (34), long-term COVID-19 is linked to a number of persistent haematological changes, including changes in RBC composition, anaemia, lymphocytopenia and higher concentrations of inflammatory markers, such as IL-6, D-dimer and ferritin (34). Lechuga et al (34) also suggested that the haematological changes associated with long COVID-19 may have implications for the diagnosis, monitoring, and therapy of patients with this disease. Furthermore, Mertens and Peñalvo (35) reported that countries where malnutrition is common and may serve as a driving factor for causing the mortality of patients infected with SARS-CoV-2. Their study reported a moderate positive association between COVID-19 severity and anaemia. They concluded that there was an association between anaemia and an increased risk of developing severe COVID-19(35). Anaemic patients have reduced concentrations of haemoglobin, which transports oxygen to different parts of the body (35). This oxygen transportation is disrupted when the haemoglobin level is low. This usually results in hypoxia, leading to multiple organ dysfunction, including the organs of the respiratory system. This scenario increases the severity of COVID-19, as regards symptoms and outcomes (36). The iron deficiency can result in IDA and increase susceptibility to infection via the suppression of the immune response against pathogens (33,37). The association between iron and infections is not yet fully understood however, and requires further investigations. Previous research has reported that iron deficiency predisposes individuals to infections (38), and studies have also proposed the protective effects of iron (38,39). Therefore, the most efficient strategy to prevent COVID-19 is the maintenance of iron homeostasis (38).

In the present study, the number of patients with a history of stroke was greater in the IDA group in comparison to the non-IDA patients. This result is consistent with the findings of a previous study (40). Chang et al (41) investigated the link between stroke and IDA. IDA has been reported to augment the risk of ischemic stroke as it disrupts the transport of oxygen to different tissues via the reduction of haemoglobin (41). In IDA, the secretion of erythropoietin increases the number of RBCs. This secretion stimulates the formation of platelets, leading to thrombocytosis and thrombus formation (42).

In the present study, the results also revealed that the number of patients exhibiting increased blood pressure was also considerably greater in the IDA group as compared with the non-IDA group. This is in line with the study by Savarese et al (43), which reported that a deficiency of iron is common in patients with cardiovascular disease (43), and the study by Lanser et al (44), which also reported an association of anaemia with cardiovascular disease.

The results of the present study also demonstrated that the patients with IDA had reduced rates of cough as compared with non-IDA COVID-19 patients. The potential association between serum iron and COVID-19 severity was previously investigated by Zhao et al (45). They reported that the insufficiency of iron may be one of the factors causing cough in the majority of individuals infected with COVID-19. The result in the present study is in contrast with that in the study by Zhao et al (45). The reduced rates of cough among the patients with IDA observed in the present study may be due to the rapid delivery of medical care given to patients at the hospital. Nevertheless, these results are substantially in agreement with those of Zhao et al (45), namely that the decreased concentration of serum iron was an independent risk factor for COVID-19.

The present study also demonstrated that IDA was associated with a longer period of hospitalization and with a greater number of complications, eventually necessitating admission into ICUs. Herein, the number of patients with IDA discharged without complications was lower than that of non-IDA patients discharged without complications. It is therefore highly recommended that anaemic patients should be instructed to strongly adhere to the precautionary measures to prevent the infections. Moreover, physicians should closely monitor anaemic patients to avoid adverse outcomes due to COVID-19. Anaemia may be considered one of the factors in the development of risk stratification models for COVID-19 in the future.

The present study had certain limitations, which should be mentioned. The present study was a single-centre study with a limited sample size. The association between IDA and COVID-19 needs to be further be investigated in multicentre, larger-scales studies to verify the findings presented herein.

In conclusion, the present study demonstrated significant associations between IDA and longer periods of hospitalization, and a greater incidence of complications in hospitalised patients with SARS-COV-2. However, the results should be interpreted with caution, given the retrospective nature of the study and the constraints on data collection. Considering the notable effect of IDA on different aspects of COVID-19 revealed in the present study, screening tests need to be carried out to identify patients with IDA followed by the treatment of IDA to improve patient outcomes. IDA can be treated through blood transfusions, the administration of iron supplements or other strategies. Moreover, different measures need to be taken to prevent and treat cases with IDA against viral infection.