Role of “Ferritin” in COVID-19 pneumonia: Sensitive marker of inflammation, predictor of mechanical ventilation, and early marker of post-COVID-lung fibrosis – A prospective, observational, and interventional study in a tertiary care setting in India

Shital Patil; Sham Toshniwal; Abhijit Acharya; Ganesh Narwade

doi:10.4103/mjmsr.mjmsr_19_22

ORIGINAL ARTICLE

Year : 2022 | Volume : 13 | Issue : 1 | Page : 28-34

Role of “Ferritin” in COVID-19 pneumonia: Sensitive marker of inflammation, predictor of mechanical ventilation, and early marker of post-COVID-lung fibrosis – A prospective, observational, and interventional study in a tertiary care setting in India

Shital Patil¹, Sham Toshniwal², Abhijit Acharya³, Ganesh Narwade⁴
¹ Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
² Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India
³ Department of Pathology, MIMSR Medical College, Latur, Maharashtra, India
⁴ MIMSR Medical College, Latur, Maharashtra, India

Date of Submission	28-Mar-2022
Date of Acceptance	28-Jun-2022
Date of Web Publication	02-Sep-2022

Correspondence Address:
Dr. Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/mjmsr.mjmsr_19_22

Abstract

Aims and Objectives: Robust data of ferritin are available as a prognostic marker in bacterial infection and we have analyzed its usefulness in coronavirus disease 2019 (COVID-19) pneumonia in predicting severity of illness, response to treatment, and final outcome. Materials and Methods: A multicentric, prospective, observational, and interventional study included 1000 COVID-19 cases confirmed with reverse transcription–polymerase chain reaction. All cases were assessed with lung involvement documented and categorized on high-resolution computed tomography (CT) thorax, oxygen saturation, inflammatory marker, ferritin at entry point, and follow-up during hospitalization. Age, gender, comorbidity and use of BIPAP (bilevel positive airway pressure)/NIV (non-invasive ventilation) /NIV, and outcome as with or without lung fibrosis as per CT severity were key observations. Statistical analysis was done using Chi-square test. Observations and Analysis: In a study of 1000 COVID-19 pneumonia cases, age (<50 and > 50 years) and gender (male versus female) had a significant association with ferritin (P < 0.00001 and P < 0.010, respectively). CT severity score at entry point with ferritin level had a significant correlation in severity score (P < 0.00001). Ferritin level had a significant association with duration of illness (P < 0.00001). Comorbidities had a significant association with ferritin level (P < 0.00001). Ferritin level had a significant association with oxygen saturation (P < 0.00001). BIPAP/NIV during hospitalization had a significant association with ferritin level (P < 0.00001). Timing of BIPAP/NIV requirement in critical care setting had a significant association with ferritin level (P < 0.00001). Follow-up ferritin titer during hospitalization as compared to entry point normal and abnormal ferritin had a significant association in post-COVID lung fibrosis, respectively (P < 0.00001). Conclusions: Ferritin has documented very crucial role in COVID-19 pneumonia in predicting severity of illness, progression of illness and requirement of mechanical ventilation, assessing response to treatment during hospitalization. Follow up ferritin titre during hospitalization and at discharge can be used as early predictor of post-covid lung fibrosis.

Keywords: COVID-19 pneumonia, ferritin, inflammatory marker, oxygen saturation, post-COVID lung fibrosis

How to cite this article:
Patil S, Toshniwal S, Acharya A, Narwade G. Role of “Ferritin” in COVID-19 pneumonia: Sensitive marker of inflammation, predictor of mechanical ventilation, and early marker of post-COVID-lung fibrosis – A prospective, observational, and interventional study in a tertiary care setting in India. Muller J Med Sci Res 2022;13:28-34

How to cite this URL:
Patil S, Toshniwal S, Acharya A, Narwade G. Role of “Ferritin” in COVID-19 pneumonia: Sensitive marker of inflammation, predictor of mechanical ventilation, and early marker of post-COVID-lung fibrosis – A prospective, observational, and interventional study in a tertiary care setting in India. Muller J Med Sci Res [serial online] 2022 [cited 2023 Mar 26];13:28-34. Available from: https://www.mjmsr.net/text.asp?2022/13/1/28/355293

Introduction

The current pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, originally emerged from China, has documented 274,628,461 confirmed cases and 5,358,978 deaths globally and 34,752,164 confirmed cases and 478,007 deaths in India.^[1] The International Federation of Clinical Chemistry and Laboratory Medicine Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management.^[2],[3]

COVID-19 pneumonia is heterogeneous disease with variable effect on lung parenchyma, airways, and vasculature, leading to long-term effects on lung functions. Although lung is the primary target organ involvement in COVID-19, many patients were shown pulmonary and extrapulmonary manifestations of diseases variably during the first and second wave, which occurred as resultant pathophysiological effects of immune activation pathway and direct virus-induced lung damage. In COVID-19 pneumonia, pathophysiology constitutes different pathways such as immune activation, inflammatory, thrombogenic, and direct viral affection to lungs and extrapulmonary tissues.^[4],[5]

Ferritin is highly ubiquitous iron-binding protein first isolated in 1937 from horse spleen; since then, its isolation methodology and role as an acute phase reactant and role as a marker of inflammation have been evolved over decades. Various inflammatory markers such as ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), interleukin-6 (IL-6), and D-dimer have been evaluated in this pandemic and now robust data are available regarding its usefulness in analyzing severity, decision-making in critical cases, assessing response to interventions, and predicting outcome. Cytokine syndrome is defined as “A group of conditions sharing same pathological mechanisms with different etiologies, causing massive release of pro-inflammatory cytokines resulting into aberrant activation of immune and coagulation systems.”^[6] Cytokine storms have a direct association with raised ferritin level and indirectly it will help in predicting ongoing inflammatory surge, resulting in cytokine storm. cytokine storm is the most dreadful event in the pathophysiology of COVID-19 pneumonia and ultimately it will lead to either direct cytokine-induced lung injury manifesting as acute lung injury/acute respiratory distress syndrome (ALI/ARDS) or extrapulmonary systemic secondary hemophagocytic lymphohistiocytosis.^[7] Studies have documented significantly raised ferritin with other inflammatory markers in COVID-19 pneumonia^[8] and now COVID-19 has been included in conditions causing hyperferritinemia.^[7]

Ferritin is considered as marker of inflammation before this covid-19 pandemic, and now its usefulness has been documented as marker of underlying immunosuppression.^[9] Also, it is useful in predicting severity of illness and marker of increased morbidity in geriatric cases, and cases with underlying comorbidities like diabetes mellitus.^{[10],[11],[12]}

In the present study, we have utilized ferritin as a basic marker in laboratory panel workup in all COVID-19 patients and analyzed as a core marker during follow-up in all admitted patients to assess the response to therapy and predictor of post-COVID fibrosis as dismal outcome of this pandemic of pneumonia in a tertiary care setting.

Materials and Methods

A multicentric, prospective, observational, and interventional study, conducted during July 2020 to May 2021, in MIMSR Medical College and Venkatesh Hospital, Latur, India, included 1000 COVID-19 cases confirmed with reverse transcription–polymerase chain reaction (RT-PCR), to find out the role of ferritin in predicting severity of illness, assessing response to therapy, and outcome as post-COVID fibrosis in diagnosed COVID-19 pneumonia cases admitted in a critical care unit. A total of 1000 cases were enrolled in the study after IRB approval and written informed consent of the patient.

Inclusion criteria

COVID-19 patients, confirmed with RT-PCR, above the age of 18 years, hospitalized in the study centers, including those with comorbidities and irrespective of severity and oxygen saturation, were included in the study.

Exclusion criteria

Those who were not willing to give consent, not able to perform D-dimer, and not willing to remain in follow-up were excluded from the study.

All study cases were undergone following assessment before enrolling in the study:

COVID-19 RT-PCR test performed in all cases; if first test results were negative and radiological features clearly documenting pneumonia, we repeated RT-PCR test and enrolled all cases with positive COVID-19 RT-PCR test
High-resolution computed tomography (CT) thorax to assess the severity of lung involvement and categorized as mild if score <7, moderated if score 8–15, and severe if score >15 or 15–25
Clinical assessment: Vital parameters such as heart rate, respiratory rate, blood pressure, and documentation of respiratory adventitious sounds
Laboratory parameters: Hemoglobin, renal functions, blood sugar level, liver functions, electrocardiography
Viral inflammatory markers such as CRP, ferritin, LDH, IL-6 assessed at entry point, and repeated whenever required during the course of illness. Normal and abnormal parameter readings were considered as per the pathological laboratory standard.
Entry point ferritin titer was utilized as assessment tool of severity of illness with clinical parameters
If ferritin analysis was normal at entry point, then ferritin titer was repeated on day of discharge from hospital or done during hospitalization if clinical course deteriorates
If ferritin analysis was abnormal at entry point, we repeated on every 72 h as follow-up to assess severity, progression of illness, and also titer level utilized to assess response to medical treatment.

Methodology of Ferritin titer assessment

Principle: Sandwich immunoluminometric assay.

Interpretation of results with reference values

Male: 14–250 ng/ml
Female: age <45 years old 6-160 ng/ml and age ≥45 years old 5–200 ng/ml
Results may differ between laboratories due to variations in population and test method. Each laboratory should establish its own reference range.

Interpretation of results

Negative: Values with in normal limit as per gender
Positive: Values above reference range as per gender
Significant: Two-fold raised value as per gender
Highly significant: Four-fold raised as per gender
Follow-up significance: Values raised or decreased in two-to-four-fold change as per gender.

The statistical analysis was done using Chi-squared test. Significant values of χ² were seen from probability table for different degrees of freedom required. P value was considered significant if it was below 0.05 and highly significant in case if it was <0.001.

Observations and analysis

In study of 1000 COVID-19 pneumonia cases confirmed by COVID 19 RT PCR, males were 65% (650/1000) and females were 35% (350/1000), and age >50 were 60% (600/1000) cases and age <50 were 40% (400/1000).

CT severity score at entry point had a significant correlation with ferritin level (P < 0.00001) [Table 1].

Table 1: Correlation of computed tomography severity (at entry point) and ferritin in coronavirus disease 2019 cases (n=1000)

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Ferritin level had a significant association with duration of illness (DOI) (P < 0.00001) [Table 2].

Table 2: Duration of illness at entry point during hospitalization and ferritin level in coronavirus disease 2019 pneumonia cases (n=1000)

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A significant association in ferritin and COVID-19 pneumonia had been documented with variables such as age, gender, diabetes mellitus, IHD, hypertension, COPD, and obesity (P < 0.00001) [Table 3].

Table 3: Other variables and ferritin level in coronavirus disease 2019 pneumonia cases (n=1000)

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Ferritin level had a significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001) [Table 4].

Table 4: Oxygen saturation at entry point and ferritin level in coronavirus disease 2019 pneumonia cases (n=1000)

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BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting had a significant association with ferritin level (P < 0.00001) [Table 5].

Table 5: Correlation of bilevel positive airway pressure use with ferritin level in coronavirus disease 2019 pneumonia cases (n=1000)

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Timing of BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting had a significant association with ferritin level (P < 0.00001) [Table 6].

Table 6: Bilevel positive airway pressure/noninvasive ventilation initiation time at entry point and ferritin level coronavirus disease 2019 pneumonia cases (n=600)

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Follow-up ferritin titer during hospitalization as compared to entry point abnormal ferritin had a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 7].

Table 7: Abnormal ferritin level at entry point (n=680) and follow-up and its correlation with post-COVID lung fibrosis

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Follow-up ferritin titer during hospitalization as compared to entry point normal ferritin had a significant association in post-COVID lung fibrosis (P < 0.00001) [Table 8].

Table 8: Normal ferritin level (n=320) at entry point and follow-up and its correlation with post-COVID lung fibrosis

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Discussion

Correlation of computed tomography severity (at entry point) and ferritin in COVID-19 cases

In the present study, CT severity score at entry point has a significant correlation with ferritin level In present study of 1000 COVID-19 pneumonia cases, CT severity score at entry point has documented significant correlation with ferritin level i.e., score <8, 8-15 and >15 documented normal and abnormal ferritin level in 190/110, 90/210 and 40/360 cases respectively [P<0.00001]. We have documented that, as CT severity increases, inflammatory marker ferritin also increases; a significant number of mild cases were also having abnormal ferritin level. Similarly, Various Zhou et al., Komurcuoglu et al., Dahan et al., Quirit et al., Alroomi et al., Del Valle et al., Huang et al., Montecino-Rodriguez et al., Dhont et al., and Wu et al.^{[4],[13],[14],[15],[16],[17],[18],[19],[20],[21]} have analyzed the role of ferritin as a “severity predictor” in their study. We have observed CT severity as the best visual marker of severity of COVID-19 pneumonia, which can be correlated with inflammatory markers such as ferritin, CRP, IL-6 LDH, D-dimer, lymphopenia, and lymphocyte–platelet ratio, and it will help in triaging cases in casualty and help in targeting interventions in indoor units accordingly to have a successful treatment outcome. Fox et al.^[22] documented in autopsy series in New Orleans regarding high ferritin level in cases with advanced pneumonia showing necrosis and hyaline membrane formation on histopathology of lung specimens.

Duration of illness at entry point during hospitalization and ferritin level in COVID-19 pneumonia cases (n = 1000)

In the present study, ferritin level had a significant association with DOI in COVID-19 pneumonia cases, DOI <7 days, 8-15 days, and >15 days of onset of symptoms documented normal and abnormal ferritin levels in 30/310, 160/300, and 130/70 cases, respectively (P < 0.00001). Although ferritin is raised in COVID-19 pneumonia, we have documented that proportionate number of cases with DOI <1 week or 7 days and many cases with DOI >2 weeks or 15 days were having normal ferritin level, while pneumonia cases between 7-14 days of illness were having abnormal or raised ferritin level. Rational for observation is not known, maybe inflammatory response pattern is different, and we have correlated ferritin pattern with other inflammatory markers such as CRP, IL-6, and LDH and documented that these two markers raised parallel to ferritin. Various authors have mentioned a similar observation in their studies.^{[4],[16],[20],[21]} Raised ferritin after the second week of illness may indicate worsening of COVID-19 pneumonia or secondary bacterial infection which can be confirmed with procalcitonin and it will help clinician to formulate antibiotics policy accordingly and indirectly guiding in the management of these cases by assessing follow-up titers. Abbaspour et al., Alroomi et al., and Meloni et al.^{[9],[16],[23]} have mentioned a similar observation in their studies.

Correlation of BIPAP use with ferritin level in COVID-19 pneumonia cases (n = 1000)

In the present study, BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting had a significant association with ferritin level; cases received BIPAP/NIV during hospitalization were documented normal and abnormal ferritin level in 155/445 and 165/235 cases, respectively (P < 0.00001). We have observed that ferritin level had a very well correlation with requirement of BIPAP/NIV, high-flow nasal cannula oxygen supplementation, and invasive mechanical ventilation in ICU setting. Rational for this correlation is that high ferritin is associated with exaggerated inflammatory burden and majority of these cases were having propensity to land in hyperkinetic cytokine stimulation syndrome. Numerous Zhou et al., Quirit et al., Alroomi et al., Del Valle et al., Montecino-Rodriguez et al., Wu et al., Zhou et al., and Rasyid et al.^{[4],[15],[16],[17],[19],[21],[24],[25]} have documented a similar observation in their studies.

Correlation of oxygen saturation at entry point and ferritin level in COVID-19 pneumonia cases (n = 1000)

In present study, ferritin level has significant association with oxygen saturation i.e., cases with oxygen saturation >90%, 75-90%, and <75% observed as normal and abnormal ferritin level in 110/100, 150/340 and 60/240 cases respectively [P<0.00001]. We observed that, as oxygen saturation drops at entry point, ferritin level increases in significant number of COVID-19 cases. Rational for similar correlation may be hypoxia-inflammatory burden pathway go hand-in-hand and worsening of oxygenation is indicator of advanced pneumonia with inflammatory surge. Zhou et al., Komurcuoglu et al., Alroomi et al., Del Valle et al., Montecino-Rodriguez et al., Wu et al., Rasyid et al., and Sarfaraz et al.^{[4],[13],[16],[17],[19],[20],[21],[25],[26]} have mentioned similar findings collaborating with our study. We have also observed that raised ferritin level will help in predicting severity of illness as many of these cases are having low oxygen saturation requiring interventions in intensive care units.

Correlation of BIPAP/NIV initiation time at entry point and ferritin level COVID-19 pneumonia cases (n = 600)

In the present study, timing of BIPAP/NIV requirement during the course of COVID-19 pneumonia in critical care setting had a significant association with ferritin level; cases received BIPAP/NIV at entry point <1 day, 3-7 days, and after 7 days of hospitalization were documented significance in four-fold raised ferritin level in 110/70, 150/160, and 30/80 cases, respectively (P < 0.00001). We observed that early initiation of BIPAP/NIV in cases with oxygen saturation less than 89% at room air were having beneficial effect in controlling systemic immune inflammatory syndrome which can be measured by ferritin level in follow up. Rational for this observation is improvement in oxygenation and lung compliance after use of BIPAP/NIV. Also, plausible mechanism is accelerated surge of hypoxia inducible transcription factor (HITF) resulted from ongoing hypoxia, which is important trigger for rise in inflammatory burden and concurrent lung parenchymal necrosis. Similarly, Zhou et al., Alroomi et al., Del Valle et al., Montecino-Rodriguez et al., Wu et al., and Rasyid et al.^{[4],[16],[17],[19],[21],[25]} have mentioned a similar observation in their study.

Other important observation in this study

Correlation of abnormal ferritin level at entry point (n = 680) and follow-up and its correlation with post-COVID lung fibrosis

In the present study, follow-up ferritin titer during hospitalization as compared to entry point abnormal ferritin had a significant association in post-COVID lung fibrosis (P < 0.00001), i.e., comparison ferritin titre at entry point abnormal to four-fold raised titres cases in presence or absence of pulmonary fibrosis were 40/170 and 360/110 cases respectively. The elevated levels of ferritin might be linked to the overproduction of inflammatory cytokines in severe patients with COVID-19. Cytokines fight against the microbes but when the immune system becomes hyperactive, it can damage lung tissue. Thus, ferritin production is induced by inflammatory cytokines and by tissue destruction in patients with COVID-19 and resultant outcome is lung fibrosis. Various authors have documented similar observation in their studies^{[17],[16],[20],[21],[27],[28],[29],[30]} and mentioned that raised titers during hospitalization and follow-up were having ongoing lung inflammation and can predict future lung fibrosis. Our findings are in accordance with documentations by Zhou et al, Ruan et al, Lin et al. and Gandini O et al,^{[4],[8],[31],[32]} documented that raised titers during hospitalization and follow up were having ongoing lung inflammation and can predict future lung fibrosis.

Correlation of normal ferritin level (n = 320) at entry point and follow-up and its correlation with post-COVID lung fibrosis

In the present study, follow-up ferritin titer during hospitalization as compared to entry point normal ferritin had a significant association in post-COVID lung fibrosis (P < 0.00001), i.e., comparison ferritin titre at entry point normal to four-fold raised titres cases in presence or absence of pulmonary fibrosis were 5/35 and 115/165 cases respectively. In this study, a small fraction of nonsevere patients developed into severe cases in the first 2 weeks after symptom onset. Therefore, health-care institutions should also pay close attention to the mild patients, identify progressors early, and provide appropriate treatment to reduce mortality. We have documented the role of LDH, ferritin, CRP, and lymphocytes count in COVID-19 cases for prognostic prediction, and persistent abnormality in these markers indicates state of unstoppable inflammation resulting in necrosis and resultant fibrosis due to increased fibromyxoid stroma and organized consolidations, which is ultimate sequelae of ARDS either due to COVID-19. Various authors have mentioned a similar observation in their studies.^{[4],[33],[34],[35],[36],[37],[38]}

Correlation of other variables and ferritin level in COVID-19 pneumonia cases

In the present study, age of patients, i.e., <50 years and >50 years, had a significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.00001). we have also documented that gender of the included cases had a significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.010). Similarly, various authors in their studies^{[4],[11],[14],[15],[16],[17],[19],[20],[21],[25],[26],[27]} have documented an important role of ferritin in predicting severity in geriatric cases.

In the present study, comorbidity as diabetes mellitus, COPD, hypertension, IHD, and obesity had a significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.00001). Numerous authors have documented a similar observation.^{[4],[11],[14],[15],[16],[17],[18],[19],[21],[25],[26]}

Conclusions

Ferritin is an easily available, sensitive, reliable, cost-effective, and universally acceptable inflammatory marker in COVID-19 pneumonia. Ferritin has a very crucial role in COVID-19 pneumonia in predicting severity of illness; especially, follow-up titers have a significant role in step-up or step-down interventions in critical care setting. Correlating ferritin with variables such as DOI, oxygenation status, and timing of BIPAP/NIV has an important role in predicting outcome.

Ferritin titer has significant associations in predicting progression of pneumonia, as proportionate number of pneumonia cases with mild variety on CT thorax with normal initial ferritin titer have progressed to critical course and we have documented follow up titers has played crucial role in this setting which can be correlated with other inflammatory markers and guided to target interventions accordingly in intensive care units. Ferritin follow-up titer can help in predicting progression of COVID-19 pneumonia and need of aggressive interventions, and indicates more inflammatory lung parenchymal damage which is precursor of underlying lung fibrosis as long-term outcome.

Research quality and ethics statement

This study was approved by the Institutional Review Board/Ethics Committee at Venkatesh Hospital and Critical Care Center, Latur, India and MIMSR Medical college, Latur, India (Approval #VCC/16-2020-2021; Approval date July 14, 2020). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the Observational studies, STROBE Guidelines, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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