FERRITIN LEVELS IN COVID-19: A REVIEW

Affiliation:

Faculty of Pharmacy, Ziauddin University, Karachi, Pakistan

Corresponding Author Email:

[email protected]

ABSTRACT:

The corona virus illness 2019 (COVID-19) is a global issue from the day it was first diagnosed in Wuhan, China in December, 2019. Cytokine storm together with higher levels of inflammatory cytokines is associated with death in individuals severely affected with COVID-19 virus. The clinical and laboratory indicators in cases of severe infection are still required to be evaluated in order to appraise the seriousness or death in the severe case. Ferritin is an intracellular protein that accumulate iron as well as possesses serious role in inflammatory diseases like infection, cancer, or neurodegeneration. According to some reports ferritin is found to be an independent risk factor for seriousness of illness in COVID-19 positive individuals. In different studies the ferritin levels have been evaluated in severely ill and patients admitted in intensive care unit (ICU) due to COVID-19.

KEYWORDS: COVID-19; Virus, Ferritin; Hyperferritinemia; Infections

INTRODUCTION:

In December 2019 there was an occurrence of pneumonia in the city of Wuhan, Hubei province, China. Its etiology was not known. The health authorities of China, urgently investigated this in order to recognize this outbreak as well as methods to control this disease. The precautions taken included segregation of patients having this disease, deep observation of other people who has been in contact with the patient, collecting patients’ data clinically and epidemiologically and establishment of methods that can help in diagnosis and cure.

Chinese scientific scholars found a novel Corona Virus (CoV) from infected people in the city of Wuhan, by 7th January 2020. The DNA sequencing of the 2019 novel Corona Virus (2019-nCoV) became the reason for fast establishment of Point-Of-Care Real-Time (RT-PCR) diagnostic tests specifically for 2019 novel Corona Virus, which was based on full genome sequence data on the Global Initiative on Sharing All Influenza Data [GISAID] platform. By this time cases of 2019 novel coronavirus were not only limited to the city of Wuhan, but had also been reported in other countries of the world. 9 export cases of this viral infection were found in the United States of America, Thailand, Japan, Korea, Singapore and Vietnam. Travelling by air was highly probable cause in spreading of this infection.

The reported cases of novel Corona Virus in health care personals, especially those who were involved in the care of infected patients showed that this infection transmitted from person to person and thus chances of spreading was high for this infection. By January 23rd 2020, a sum of 835 cases of 2019 novel Corona Virus infection had been identified in China, among which 23 had lost their lives while 93% were admitted in hospitals (Wang et al., 2020a).

The 2019 novel Corona Virus, is a beta Corona Virus belonging to group 2B and 70 %similar to Severe Acute Respiratory Syndrome Corona Virus in genetic sequencing. The 2019 novel Corona Virus differs from both Middle East Respiratory Syndrome Corona Virus and Severe Acute Respiratory Syndrome Corona Virus. It is the 7th member of the family that causes similar human infection. It is believed to have originated from Chinese horseshoe bats that are natural source of Severe Acute Respiratory Syndrome Corona Virus and can transmit from person to person (Song et al., 2020)

The 2019 novel Corona Virus is closely similar to the bat Corona Viruses and it is thought that it is originated from bats but still investigations are ongoing. According to the recent findings it has been suggested that it is transmitted to humans from wild animals that were marketed illegally in the Huanan Seafood Wholesale Market.

Huang and his associates primarily documented 41 cases of 2019 novel Corona Virus–Infected Pneumonia (NCIP), among which many patients were known to be exposed to Huanan Seafood Wholesale Market. The clinical indications from patients included fever, dry cough, shortness of breath, muscular pain, fatigue, usual or lower leukocyte counts and pneumonia confirmed by radiographic test.

Irregular function of organs (like shock, Acute Respiratory Distress Syndrome, Acute Heart Injury and Acute Kidney Dysfunction) and death was also reported in extreme cases. Chen and his associates also documented reports for 99 cases of 2019 Novel Corona Virus Infected Pneumonia (NCIP) from similar hospital and accordingly concluded that the 2019 novel Corona Virus infection, was more likely to be found within groups of people who were in close contact and it affected elderly more especially those with comorbidities and resulted in Acute Respiratory Distress Syndrome.

The distinction in clinical features between severe and mild cases were not documented, however case reports showed person to person transmission of novel Corona Virus Infected Pneumonia (Wang et al., 2020b).

World Health Organization confirmed the COVID-19 as a pandemic on 11th March 2020. The confirmed cases were found to be 30 675 675 including 954 417 deaths by 20th September 2020. Patients having comorbidities like elevated blood glucose levels, heart diseases, respiratory problems as well as cancer are more likely to have serious problems and chances of death. This worldwide calamity needs united struggles of every person to combat it (Cheng et al., 2020).

Findings reveal that in seriously ill patients hyper inflammation was found and it involved increased serum C-reactive Protein (CRP), procalcitonin (PCT), D-dimer as well as hyperferritinemia. These indications proposed a possible essential part of a cytokine chain in pathophysiology of COVID-19. Lab biomarkers to predict the serious illness by COVID-19 are important as resource provision must be wisely planned in the perspective of respiratory treatment. Huang and co-workers performed a systematic analysis as well as meta-analysis to examine the relationship between various biomarkers involving serum C-reactive protein, procalcitonin, D-dimer together with serum ferritin with the seriousness of illness (Huang et al., 2020).

 

BIOCHEMICAL PARAMETERS:

ELEVATED FERRITIN LEVELS:

Huang and co-workers conducted the data based study and found that in ten studies increased ferritin level was reported in patients who lost their lives due to COVID-19 and also in patients that were severely affected by COVID-19. They also noticed that increased serum ferritin levels were related with Acute Respiratory distress Syndrome, death as well as serious illness of COVID-19. Hence, the existence of secondary hemophagocytic lymphohistiocytosis (sHLH) in COVID-19 patients can be hypothesized. It is a state of increased inflammation characterized by a cytokine storm, which leads to multiple organ damage. The condition is known to be activated by infections caused by the virus (Huang et al., 2020).

Ferritin is known to be a major mediator of irregular immune system particularly in severe hyperferritinemia through direct immune-suppression as well as pro-inflammatory effects that contribute in creating cytokine storm. Increased serum ferritin levels are noticed in diabetic patients. Also diabetic patients are most likely to have severe complications due to COVID-19. Vargas and co-workers briefly reviewed proofs in order to support their idea that levels of ferritin can be a key factor that influences COVID-19 severity.

One study based on a sample size of twenty patients of COVID-19 revealed that patients affected severely by COVID-19 showed higher levels of serum ferritin. Also, the group of people that were affected very severely by COVID-19 had marked increase in serum ferritin in comparison to group that were less severely affected by COVID-19.

An additional study showed that the individuals who did not survive due to COVID-19 had higher levels of ferritin at the time they were admitted in the hospital as well as during the time they stayed in the hospital. In addition, it was found that from day 17 of hospitalization the median values of serum ferritin levels in these individuals go beyond the upper limit, showing that levels of ferritin were elevated continuously. Lab results of individuals affected severely by COVID-19, commonly revealed cytokine storm including higher inflammatory markers, involving ferritin, which is related with serious condition. Iron chelators can help to reduce levels of ferritin. Deferoxamine may possibly be an appropriate option because of its safety as well as approval by Food and Drug Administration for clinical use. Non pharmacological management such as reduced intake of iron containing food can be applied, as it showed modification in levels of serum ferritin (Vargas-Vargas and Cortés-Rojo, 2020).

Gao et al reviewed a study that included 141 patients infected by COVID-19. The high levels of serum ferritin (more than 500 microgram per liter) was indicated in individuals severely affected by COVID-19 at the time they were admitted in hospitals while the individuals having mild illness had shown regular mean serum ferritin levels (303 ± 224 microgram per milliliter). In addition, individuals with severe disease as well as patients of Intensive Care Unit showed elevated levels of ferritin in comparison to individuals that had mild illness. One of the studies reported elevated mean serum ferritin levels in individuals having moderate to severe illness in comparison with individuals suffering from mild illness. Wu and co-workers noted marked increased in serum ferritin levels in individuals having Acute Respiratory Distress Syndrome in comparison with individuals having no comorbidities. Plasma therapy, high-volume hemofiltration and desferrioxamine can be considered to reduce ferritin levels in individuals having COVID-19. These strategies at present are utilized to treat sepsis as well as macrophage activation syndrome (Gao et al., 2021).

Deng and his associates, evaluated hyperferritinemia as an expecting element of death in individuals admitted in hospital due to COVID-19. They collected data of 100 COVID-19 positive patients that were admitted in hospital. They divided these individuals into three groups according to the guidelines given to detect and treat 2019 novel Corona Virus Infected Pneumonia. The group classified as Moderate exhibited fever as well as respiratory indications like dry cough together with chest X-Ray indicating pneumonia. The severe group was classified on the basis of fulfilling the parameters such as shortness of breath, respiration rate greater than or equal to thirty times per minute; oxygen saturation measured by pulse oximeter less than 93% at rest; partial pressure of arterial oxygen to fraction of inspired oxygen ratio less than or equals to 300 mmHg. Critical group was described by parameters such as, respiratory failure as well as need for mechanical ventilation, shock as well as other organ damage that required Intensive Unit Care. Severe as well as critical individuals were kept in Intensive Care Unit for treatment. The results of the study reported that levels of ferritin in critical individuals were markedly elevated in comparison to moderate as well as severe individuals. Moreover, the median concentration of ferritin was markedly increased in mortality group in comparison to survival group. In addition, the ferritin levels in critically ill patients was 2.3 to 4.6 times higher in comparison to patients who were moderately affected. The group containing increased ferritin levels were found to have higher death rate. The study reported higher ferritin levels in COVID-19 positive patients. Although elevated ferritin level is related with death rate, ferritin is not considered a depending factor to predict in-hospital death in individuals who are COVID-19 positive in Intensive Care Unit (Deng et al., 2021).

Table 1:

Clinical characteristics and Laboratory results in patients with COVID-19:

Characteristics Total (n =100) Moderate (n =17) Severe (n =40) Critical (n =43) Reference
Laboratory results

on admission:

 

 

Ferritin (µg/L)

 

1023.80

(434.45-1821.38)

 

370.70

(89.90–756.00)

 

855.75

(434.4-1687.2)

 

1715.8

(965.6-2429.2)

 

 15-150

(Deng et al., 2021)

Cao and his co-workers assessed the capability of ferritin to induce liver injury as well as enhance severity of illness on hospital admission and the tool to predict consequences in order to arrange management for successive medical practice. They conducted a study on total 147 COVID-19 positive patients. Ferritin levels were indicated in 79 patients were included in the study. They found that the severity of disease in the group that had increased ferritin concentration was markedly increased in comparison to normal group. Also, the individuals having increased ferritin concentration had greater rate of liver injury in comparison to those individuals who presented normal concentration of ferritin. The study also indicated value of ferritin for diagnosis of patients at the time of hospital admission (Cao et al., 2021).

CONCLUSION:

Based on various studies it is concluded that ferritin level is likely to predict mortality and severity of illness. Moreover, it is a valuable detector in COVID-19 and together with other clinical parameters and chemical biomarkers it can be helpful in designing treatment strategies.

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