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Correlation of ferritin with the duration of illness, disease severity, oxygenation status, ventilatory requirement, and lung fibrosis in COVID-19 pneumonia: A single-center experience of 1000 cases in tertiary care setting in India
*Corresponding author: Shital Patil, Department of Pulmonary Medicine, MIMSR Medical College, Venkatesh Chest Hospital, Latur, Maharashtra, India. drsvpatil1980@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Patil S, Dhumal U, Acharya A. Correlation of ferritin with the duration of illness, disease severity, oxygenation status, ventilatory requirement, and lung fibrosis in COVID-19 pneumonia: A single-center experience of 1000 cases in tertiary care setting in India. Adesh Univ J Med Sci Res 2022;4:86-93.
Abstract
Objective:
Robust data of ferritin are available as prognostic marker in bacterial infection and we have analyzed its usefulness in COVID-19 pneumonia in predicting severity of illness, response to treatment, and final outcome.
Materials and Methods:
A prospective and observational 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 Bi-level positive airway pressure (BIPAP)/Non invasive ventilation (NIV) and outcome as with or without lung fibrosis as per CT severity were key observations. Statistical analysis is done using Chi-square test.
Results:
In a study of 1000 COVID-19 pneumonia cases, age (<50 and >50 years) and gender (male vs. female) have significant association with ferritin (P < 0.00001) and (P < 0.010), respectively. CT severity score at entry point with ferritin level has significant correlation in severity score (P < 0.00001). Ferritin level has significant association with the duration of illness (P < 0.00001). Comorbidities have significant association with ferritin level (P < 0.00001). Ferritin level has significant association with oxygen saturation (P < 0.00001). BIPAP/NIV during hospitalization has significant association with ferritin level (P < 0.00001). Timing of BIPAP/NIV requirement in critical care setting has significant association with ferritin level (P < 0.00001). Follow-up ferritin titer during hospitalization as compared to entry point normal and abnormal ferritin has significant association in post-COVID lung fibrosis, respectively (P < 0.00001).
Conclusion:
Ferritin is easily available, and universally acceptable inflammatory marker in COVID-19 pandemic, documented very crucial role in predicting severity of illness and assessing response to treatment and follow-up ferritin titer during hospitalization, can be used as early predictor of post-COVID lung fibrosis.
Keywords
COVID-19 pneumonia
Ferritin
Oxygen saturation
Inflammatory marker
Post-COVID lung fibrosis
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 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 acute-phase reactant and role as marker of inflammation have been evolved over decades. Various inflammatory markers such as ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), interleukin (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 direct association with raised ferritin level, and indirectly, it will help in predicting ongoing inflammatory surge resulting in cytokine storm. Cytokine storm is most dreadful event in pathophysiology of COVID-19 pneumonia, and ultimately, it will lead to either direct cytokine-induced lung injury manifesting as 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 analysis found to be very crucial in this COVID-19 pneumonia, apart from routine inflammatory marker, its usefulness as marker of underlying immunosuppression.[9] In addition, it is useful in predicting severity of illness in patients suffering with comorbidity as diabetes mellitus and in geriatric cases and marker of increased morbidity in these cases.[10-12]
In the present study, we have utilized ferritin as basic marker in laboratory panel workup in all COVID patients and analyzed as core marker during follow-up in all admitted patients to assess response to therapy and predictor of post-COVID fibrosis as dismal outcome of this pandemic of pneumonia in tertiary care setting.
MATERIAL AND METHODS
Ethical approval
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/90-2020-2021; approval date July 4, 2020).
Data source
A prospective, observational, 12 weeks follow-up study conducted during July 2020–May 2021, in MIMSR Medical College, Latur, and Venkatesh Hospital, Latur, India, included 1000 COVID-19 cases confirmed with reverse transcription-polymerase chain reaction (RTPCR), to find out 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 critical care unit. A total of 1000 cases were enrolled in study after IRB approval and written informed consent of all included cases was taken at respective center of study in Venkatesh Hospital and MIMSR Medical College, Latur.
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 not willing to give consent, not able to perform ferritin, and not willing to remain in follow-up and cases died during hospitalization or before 12 weeks of discharge from hospital were excluded from the study.
Study design
Prospective, observational, 12 weeks follow up study.
All study cases were undergone following assessment before enrolling in study
COVID-19 RT-PCR test was performed on nasopharyngeal samples collected with all standard institutional infection control policies, if the first test results were negative and radiological features clearly documenting pneumonia, we have repeated RT-PCR test and enrolled all cases with positive COVID-19 RT-PCR test. High-resolution computed tomography HRCT Thorax was done in all cases to assess severity of lung involvement as per COVID-19 Reporting and Data System (CO-RADS)[13] and categorized as Mild if score <7, moderate if score 8-15 and severe if score >15 or 15-25. We have performed clinical assessment and routine biochemistry analysis with hematological workup including viral inflammatory markers such as CRP, Ferritin, LDH, IL-6 titers in all study cases. 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 utilized to assess response to medical treatment. Follow-up HRCT thorax was done after twelve weeks of discharge from hospital for analysis of post covid lung fibrosis in selected cases with abnormal ferritin titer at discharge and required BIPAP/ NIV during hospitalization and cases required oxygen supplementation at home [Figure 1].
- Flow of the study.
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: Value 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 2-to-4-fold change as per gender.
Statistical analysis
The statistical analysis was done using Chi-square test in R-3.4 software. Significant values of c2 were seen from probability table for different degree of freedom required. P value was considered significant if it was below 0.05 and highly significant in case if it was <0.001.
RESULTS: COVARIATES
In the present study, 1000 COVID-19 pneumonia cases confirmed by COVID-19 RT-PCR, males were 650/1000 and females were 350/1000, age >50 was 600 cases, and age <50 was 400 cases.
Significant association in ferritin and COVID-19 pneumonia has been documented with variables such as age, gender, diabetes mellitus, ischemic heart disease (IHD), hypertension, chronic obstructive pulmonary disease (COPD), and obesity (P < 0.00001) [Table 1].
| COVID-19 RT-PCR positive (n=1000) | Ferritin level normal (n=320) | Ferritin level abnormal (n=680) | Chi2 test value and P value |
|---|---|---|---|
| Age>50 years (n=600) | 140 | 460 | χ2=51.77 |
| Age<50 years (n=400) | 180 | 220 | P<0.00001 |
| Male gender (n=650) | 190 | 460 | χ2=6.5 |
| Female gender (n=350) | 130 | 220 | P<0.010 |
| Diabetes mellitus (n=600) | 150 | 450 | χ2=33.77 |
| Without diabetes (n=400) | 170 | 230 | P<0.00001 |
| Hypertension (n=210) | 160 | 50 | χ2=238.55 |
| Without hypertension (n=790) | 160 | 630 | P<0.00001 |
| COPD (n=150) | 100 | 50 | χ2=97.46 |
| Without COPD (n=850) | 220 | 630 | P<0.00001 |
| IHD (n=200) | 110 | 90 | χ2=60.77 |
| Without IHD (n=800) | 210 | 590 | P<0.00001 |
| Obesity (n=160) | 20 | 140 | χ2=33.28 |
| Without obesity (n=840) | 300 | 540 | P<0.00001 |
IHD: Ischemic heart disease, COPD: Chronic obstructive pulmonary disease
RESULTS: CORE OBSERVATIONS
Computed tomography (CT) severity score at entry point has significant correlation with ferritin level (P < 0.00001) [Table 2]. Ferritin level has significant association with the duration of illness (Doi) (P < 0.00001) [Table 3]. Ferritin level has significant association with oxygen saturation in COVID-19 pneumonia cases (P < 0.00001) [Table 4]. BIPAP/ NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with ferritin level (P < 0.00001) [Table 5]. Timing of BIPAP/NIV requirement during course of COVID-19 pneumonia in critical care setting has significant association with ferritin level (P < 0.00001) [Table 6]. Follow-up ferritin titer during hospitalization as compared to entry point abnormal ferritin has significant association in post-COVID lung fibrosis (P < 0.00001), that is, ferritin at entry point to 4-fold raised cases in the presence or absence of pulmonary fibrosis was 40/170 and 360/110 cases, respectively (P < 0.00001) [Table 7]. Follow-up ferritin titer during hospitalization as compared to entry point normal ferritin has significant association in post-COVID lung fibrosis (P < 0.00001), that is, ferritin at entry point to 4-fold raised cases in the presence or absence of pulmonary fibrosis was 5/35 and 115/165 cases, respectively (P < 0.00001) [Table 8].
| CT severity | Normal ferritin (n=320) | Abnormal ferritin level (n=680) |
Analysis |
|---|---|---|---|
| <8 score (n=300) | 190 | 110 | χ2=224.87, P<0.00001 |
| 9–15 (n=300) | 90 | 210 | |
| >15 (n=400) | 40 | 360 |
| Doi | Normal ferritin (n=320) | Abnormal ferritin (n=680) | Analysis |
|---|---|---|---|
| <7 days (n=340) | 30 | 310 | χ2=185.65 |
| 8–15 days (n=460) | 160 | 300 | P<0.00001 |
| >15 days (n=200) | 130 | 70 |
Doi: Duration of illness
| Oxygen saturation | Normal ferritin level (n=320) | Abnormal ferritin level (n=680) | Analysis |
|---|---|---|---|
| >90% (n=210) | 110 | 100 | χ2=60.37 P<0.00001 |
| 75–90% (n=490) | 150 | 340 | |
| <75% (n=300) | 60 | 240 |
| BIPAP/NIV | Normal ferritin (n=320) | Abnormal ferritin level (n=680) | Analysis |
|---|---|---|---|
| BIPAP/NIV required (n=600) |
155 | 445 | χ2=26.21, P<0.00001 |
| BIPAP/NIV not required (n=400) |
165 | 235 |
| BIPAP used (n=600) with duration of illness | Abnormal ferritin level (n=290) | Four-fold raised ferritin level (n=310) | Analysis |
|---|---|---|---|
| Entry point<1 days (n=180) | 110 | 70 | χ2=31.30, |
| 3–7 days (n=310) | 150 | 160 | P<0.00001 |
| After 7 days (n=110) | 30 | 80 |
| Post-COVID pneumonia fibrosis | Ferritin titer increased/abnormal at entry point (n=400) | Ferritin titer 4-fold increased during follow-up (n=280) | Analysis |
|---|---|---|---|
| Pulmonary fibrosis present (n=210) | 40 | 170 | χ2=198.45, P<0.00001 |
| Pulmonary fibrosis absent (n=470) | 360 | 110 |
| Post-COVID pneumonia fibrosis | Ferritin normal at entry point and remained less than 4-fold (n=120) | Ferritin titer 4-fold increased during follow-up (n=200) | Analysis |
|---|---|---|---|
| Pulmonary fibrosis present (n=40) | 5 | 35 | χ2=12.19, P<0.00048 |
| Pulmonary fibrosis absent (n=280) | 115 | 165 |
DISCUSSION
Correlation of CT severity (at entry point) and ferritin in COVID-19 cases
In the present study, CT severity score at entry point with ferritin level has significant correlation in COVID-19 pneumonia cases, score <8, 8–15, and >15 documented normal and abnormal ferritin level as in 190/110, 90/210, and 40/360, respectively, of total 1000 study cases (P < 0.00001). We have documented that, as CT severity increases, inflammatory marker ferritin also increases, significant number of mild cases was also having abnormal ferritin level. Similarly, various authors[4,14-22] have analyzed role of ferritin as “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 successful treatment outcome. Fox et al.[23] 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.
Doi at entry point during hospitalization and ferritin level in COVID-19 pneumonia cases (n=1000)
In the present study, ferritin level has 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 and 14 days of illness were having abnormal or raised ferritin level. Rational for observation is not known, may be 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 similar observation in their studies.[4,17,21,22] Raised ferritin after the 2nd 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 management of these cases by assessing follow-up titers. Authors[9,17,24] have mentioned 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 has 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 has very well correlation with requirement of BIPAP/ NIV, high-flow nasal cannula oxygen supplementation, and invasive mechanical ventilation in ICU setting. Rational for this, high ferritin and its strong association with extreme inflammatory burden and these patients have propensity to land in to hyperkinetic cytokine stimulation syndrome. Numerous authors [4,16,17,18,22,25-27] have documented similar observation in their studies.
Correlation of oxygen saturation at entry point and ferritin level in COVID-19 pneumonia cases (n=1000)
In the present study, ferritin level has significant association with oxygen saturation in COVID-19 pneumonia cases; 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. Probable mechanism for correlation of hypoxia or low oxygen saturation and increase in inflammatory markers such as ferritin and CRP is underlying lung parenchymal inflammation secondary to pneumonia resulting into inflammatory burden and hypoxia go hand-in-hand in these cases. Authors[4,14,17,18,20,21,22,26,27] 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 course of COVID-19 pneumonia in critical care setting has 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 4-fold raised ferritin level in 110/70, 150/160, and 30/80 cases, respectively (P < 0.00001). We have observed that early initiation of BIPAP/ NIV those meeting criteria of oxygenation, as oxygen saturation less than 89% at room air during hospitalization was having beneficial effect in controlling systemic immune inflammatory syndrome which can be measured by ferritin level in follow-up, may be because of improvement in oxygenation and lung compliance after the use of BIPAP/NIV; as hypoxia is important trigger for rise in inflammatory burden by means of hypoxiainducible transcription factor. Similarly, authors [4,17,18,20,22,26] have mentioned 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 has significant association in post-COVID lung fibrosis (P < 0.00001). 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[8,17,21,28-32] and mentioned that raised titers during hospitalization and follow-up were having ongoing lung inflammation and can predict future lung fibrosis. We have also observed that raised ferritin at entry point is indicator of poor radiological outcome and many of these cases were having lung fibrosis and radiological sequelae in post-COVID care setting recovered in intensive care units or history of mechanical ventilation during hospitalization, and findings are in correlation with studies by various authors.[4,8,33,34]
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 has significant association in post-COVID lung fibrosis (P < 0.00001). In this study, a small fraction of non-severe 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 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 are ultimate sequelae of ARDS either due to COVID-19. Various authors have mentioned similar observation in their studies.[4,22,31,32,35-39]
Correlation of other variables and ferritin level in COVID-19 pneumonia cases
In the present study, age of patient, that is, <50 years and >50 years, has significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.00001). We have also documented that gender of included cases has significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.010). Similarly, various authors in their studies[4,12,15-19,21,23-27,32] have documented important role of ferritin in predicting severity in geriatric cases.
In the present study, comorbidity as diabetes mellitus, COPD, hypertension, IHD, and obesity has significant association in COVID-19 cases with normal and abnormal ferritin level (P < 0.00001). Numerous authors have documented similar observation.[4,12,15-19,21,23-27,32]
CONCLUSION
Ferritin is easily available, sensitive, reliable, cost-effective, and universally acceptable inflammatory marker in COVID-19 pneumonia. Ferritin has very crucial role in COVID-19 pneumonia in predicting severity of illness, especially follow-up titers have 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 important role in predicting outcome.
Ferritin titer has significant associations with predicting progression of pneumonia, as proportionate number of pneumonia cases with mild variety on CT thorax and normal initial ferritin has progressed to critical course and we have documented that follow-up titers have played crucial role with other inflammatory markers, and many times in the 2nd week of illness rising titers indicates nosocomial bacterial infection and targeting treatment accordingly. Ferritin titer can help in predicting final radiological outcome as post-COVID lung fibrosis, especially follow-up high titers in cases requiring aggressive interventions during hospitalization have higher chances of post-COVID lung fibrosis.
Limitations of the study
Our study is having enough sample size and analyzed role of ferritin at entry point and follow-up during 12 weeks period and association with post-COVID-19 lung fibrosis is documented. Limitations of this study are multivariate analysis which will help in finer details associated with ferritin level and oxygenations status, severity of illness, ventilatory support requirement, and post-COVID lung fibrosis are not done. The second limitation is other confounding factors leading to abnormal ferritin level and its effect on COVID-19 severity parameters were not possible. The third limitation is association of ferritin titer with other modes of intensive care treatments as high-flow nasal cannula and invasive mechanical ventilatory support is not assessed differently and cases predominantly on BIPAP/NIV were considered as ventilatory support, probably because majority of COVID-19 cases receiving high-flow nasal cannula were shifted to BIPAP/NIV and/or mechanical ventilation in intensive care units.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest
There are no conflicts of interest.
Financial support and sponsorship
Nil.
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