The disease outbreak of coronavirus disease -2019 (COVID-19) continues to affect a large swath of the global population 1. The Philippine records four hundred seventy-four thousand sixty-four (474, 064) confirmed COVID 19 cases after the Department of health (DOH) reported one thousand five hundred fourty one (1,541) additional cases last December 31 2020. The COVID 19 has recently highlighted the role of systemic hyperinflammation as a major cause of death1. A virally induced cytokine storm syndrome associated with a massive and overwhelming systemic inflammation, burdens a subgroup of patients with severe COVID 19 which lead to pulmonary inflammation and extensive lung damage2. The association between high ferritin levels and a more aggressive subset of these diseases may suggest a possible pathogenic role of this molecule as proposed by the concept of hyperferritinemic syndrome3. A hyperinflammatory environment has been a hallmark of COVID 19 infection and is thought to be a key mediator of mortality4. In this study, we were able to correlate the serum ferritin level and disease mortality in COVID19 pneumonia and predict in hospital mortality based on demographics and co morbidities.

We reviewed the records of all COVID 19 admitted patients from World Citi Medical Center, a Tertiary General Hospital with 150 bed capacity and ISO certifications for Quality Management System, Environmental Management System, and Health and Safety Management from April 2020 up to April 2021. A stastically significant sample size of seventy nine (79) patients in hospital admission was used in this study. A retrospective observational cohort study was conducted to patients presenting at the emergency department with COVID 19 confirmed pneumonia diagnosis. Serum ferritin levels was assayed using an electrochemilumenescence immunoassay with a Roche COBAS analyzer. Of all the COVID 19 positive patients, only hospitalized patients with a ferritin level available over admission were included in the analysis. Patients who had a ferritin level obtained within three days of admission were considered also as acceptable ferritin result. In patients with multiple ferritin levels obtained, the one closest to admission was used for the admission ferritin.

To summarize the demographic and clinical characteristics of the patients, descriptive statistic was used. Descriptive statistics were used to summarize the data in the form of frequency, percentage, mean and median ± interquartile range (IQR). Continuous variables were summarized as median (IQR) and categorical variables as absolute frequency. Summary statistics were performed for these data and grouping patients in survivors and non survivors in correlation to ferritin levels.  A 5% significance level was used to test the results. Statistical analyses were performed using SPSS version 27 (SPSS) and R software. P values were calculated from the z value obtained. Differences between those groups were evaluated using Mann Whitney U test for quantitative variables and fischer’s exact test for categorical variables. (Table 2).

Demographics and co morbidities for seventy nine (79) COVID 19 infections, who were admitted at World Citi Medical Center were included for analysis. Clinical characteristics are summarized in table 2 and ferritin results are presented in table 1.

Fourteen (17.7%) patients did not survive the thirty (30) days hospitalization. At the time of hospital admission, their baseline characteristics and differences were monitored in correlation with ferritin levels between patients who died and those who survived and discharged, including age 48 (19 - 65) vs 49 (24-64), with mean ferrin level for non survivor (FLNS) of 1399.10ng/ml vs among ferritin level of survivors (FLS) 1300.4 ng/ml respectively, OR 0.14; 95%( CI 3.87 to 26.77; p=0.9823), sex 71.40% vs 55.38% males, with mean FLNS of 1645.75ng/ml vs 823.5 FLS respectively, OR 1.29 95% (CI 1.4 to 1.8; p=0.0001), 28.57% vs 44.62 % females, with mean FLNS of 1069ng/ml vs 823.15ng/ml FLS respectively, OR 1.59 95% (2.2 to 3.5; p=<0.0001) and smokers 21.43% vs 23.08, with FLNS of 1523.5ng/ml vs 1489.6ng/ml FLS, OR 1.08 95% (CI 4.33 to 4.67 p=0.9132); non-smokers 78.57% vs 76.92%, with mean FLNS 823.5ng/ml vs 820.5 ng/ml FLS, OR 0.98 95% (CI 1.27 to 1.3 p=0.916) (table 2).

Specific comorbidities were also correlated to serum ferritin level. (Table 3), such as Hypertensive atherosclerotic cardiovascular disease (HASCVD) with mean ferritin level of 1187.78 ng/ml, five (5) patients out of eighteen (18) patients in this group did not survived with FLNS 1532.2ng/ml vs 623.5ng/ml FLS respectively with p value of <0.0001. Type 2 Diabetes mellitus with mean ferritin level of 1261.75 ng/ml, three (3) patients out of sixteen (16) patients did not survived with FLNS 1543ng/ml vs 1023.2 FLS with p value of <0.0001. Chronic Kidney Disease (with or without maintainance dialysis)with mean ferritin level of 1247.2 ng/ml, four (4) patients out of five (5) patients did not survived with FLNS of 1343.33ng/ml vs 1103ng/ml FLS respectively with p value of <0.0001. These top three co morbidities gave a significant impact to thirty (30) days in hospital mortality.

According to our results, consistent with previously published studies related to this paper, ferritin is associated with in hospital mortality as it is higher at the baseline admission of non-survivor patients and maintains significance after multivariable adjustment. With ferritin level of 1437.07ng/ml, poor clinical outcome and possible in hospital mortality was considered. (Table 1). We also observed that demographics and co morbidities of patients in this study were significant to predict thirty (30) days in hospital mortality. Further sub-analysis of co morbidities, HASCVD, Type 2 Diabetes Mellitus, Chronic kidney disease, Liver disease, Chronic Obstructive Pulmonary Disease and Cerebrovascular disease showed poor outcome which were directly related to ferritin levels with p value of <0.0001. (Table 3).

At present, the pathophysiology, disease evolution, diagnosis and prognosis of patients with COVID 19 pneumonia are still unclear. In one study Dahan, et al,7 they concluded that elevated ferritin levels were shown to correlate with disease severity in 39 patients from Israel with confirmed COVID 19 infection. Severe patients had significantly higher level of ferritin (2817.6ng/ml) compared to non-severe patient (708.6ng/ml) p=0.02. In another released study of Moudhi et al,11 they concluded that elevated ferritin level >1000 were found to be an independent predictor of in hospital mortality. In one study of Zhoe et al,9 with 20 COVID -`19 patients, it was found that individuals with severe and very severe COVID-19 exhibited increase serum ferritin level, being serum ferritin the very severe COVID 19 group significantly higher than in the severe COVID -19 group (1006.16 ng/ml (IQR: 408.265-1988.25) vs 291.13ng/ml (IQR:102.1-648.42), respectively). In our study, we focused more on mortality outcomes to prognosticate patient during their admissions based on the ferritin levels. In this study, we were able to correlate the ferritin mean levels of survivors to non survivors (Table 1). At ferritin level of 1437.07 ng/ml, the prognosis of in hospital mortality may be predicted. Ferritin levels and prognostication of in hospital mortality may differ based on the co - morbidities at the time of admission (Table 3). Hypertensive Atherosclerosis Cardiovascular disease, Chronic kidney disease and Type 2 Diabetes Mellitus were the top three diseases that affect the mortality of the patient. Among other diseases listed in this table (Table 3), these three mentioned diseases got the higher levels of ferritin aside from acute coronary syndrome and cerebrovascular disease. In light of this data, we postulated that ferritin levels can be used as prognostic factor for in-hospital mortality. In plasma, ferritin circulates as apoferritin, a non-iron containing molecule. The plasma level generally reflects overall iron storage, with 1ng of ferritin per ml indicating approximately 10mg of total iron stores5. Due to its crucial role in cellular iron hemostasis, it is not surprising that ferritin synthesis is tightly regulated6. It has been well established that elevated serum ferritin levels may suggest not only the presence of an iron overload state but is also a marker for inflammatory, autoimmune, infectious or malignant conditions.7. The pathogenicity of the novel SARSCoV-2 and its effects on the immune system has yet not been completely understood. However, some studies with evidence suggest that severe progressive COVID-19 disease is associated with uncontrolled inflammation and massive cytokine release 7. It is also associated with immunological abnormalities, including cytokine storm and hyperferritinemia. 8. In agreement with this, another study revealed that in patients who died by COVID -19, ferritin levels were high upon hospital admission and throughout the hospital stay10. From these collected data, we postulated that ferritin level on the day of admission, can be used as prognostic marker of hospital mortality of COVID 19 pneumonia. .12

This study has demonstrated that elevated ferritin levels were shown to correlate with 30 day in hospital mortality among seventy-nine (79) patients admitted at World Citi Medical Center. Ferritin is readily available, measurable, cost effective and reliable test that could be very useful in establishing the risk of hospital mortality and guiding therapeutic decision in patient with COVID 19 infection. Patients who have medical comorbidities such as Hypertensive Cardiovascular disease, Type 2 Diabetes Mellitus, and chronic kidney disease have shown significant evidence for possible in hospital mortality. .131415

More studies with higher populations will be needed to support the use of ferritin levels as marker for 30 days in hospital mortality for COVID 19 pneumonia. A larger multicenter cohort study from various hospitals of the country would help to further validate the findings of our study, however, with the evidence we have, serum ferritin levels could be implemented in the prognostic evaluation of in hospital mortality for COVID 19 pneumonia. Further studies are needed to evaluate if high values of serum ferritin in patient with COVID 19 pneumonia could be related to other comorbidities and optimum timing of ferritin analysis could improve outcomes. It would be useful to have an exact value of serum ferritin levels in our institution rather than repeated values of >1000 would be helpful. .1617

The study is limited by data from single center with moderate to critically ill COVID 19 pneumonia which may introduce a selection bias and inflate the mortality. Hence result from this study may help in the risk stratification and management of similar moderate to critically ill pneumonia only. COVID-19 pneumonia is a complex and not yet well established disease and it should be mentioned that other factors could influence final outcome. 1819