key: cord-0960458-nsqvyget
authors: Feld, Jonathan; Tremblay, Douglas; Thibaud, Santiago; Kessler, Alaina; Naymagon, Leonard
title: Ferritin levels in patients with COVID‐19: A poor predictor of mortality and hemophagocytic lymphohistiocytosis
date: 2020-08-13
journal: Int J Lab Hematol
DOI: 10.1111/ijlh.13309
sha: a8bad6840640cf5f09169f74aaa22a2b37935213
doc_id: 960458
cord_uid: nsqvyget

INTRODUCTION: A hyperinflammatory environment has been a hallmark of COVID‐19 infection and is thought to be a key mediator of morbidity. Elevated ferritin has been observed in many patients with COVID‐19. Several retrospective studies have shown ferritin levels can be correlated and predictive of poor outcomes in COVID‐19, though a rigorous analysis has been lacking. METHODS: A retrospective analysis of 942 adult COVID‐19 patients admitted in March 2020 at a large New York City health system with available ferritin levels. RESULTS: The primary outcome, all‐cause mortality, was observed in 265 (28.1%) patients. Patients who died had a significantly higher median admission and maximum ferritin levels than those who did not. However, death was poorly predicted by admission and maximum ferritin levels on receiver operator curve (ROC) analysis, with AUCs of 0.677 and 0.638, respectively. AUCs increased when the cohort was limited to progressively younger patients. Ferritin levels were minimally better at predicting our secondary outcomes. These included mechanical ventilation, observed in 280 (29.7%) patients with an ROC yielding an area under the curve (AUC) of 0.769, and new renal replacement therapy, observed in 80 (8.5%) of patients with an ROC yielding an AUC of 0.787. We also performed a subset analysis on 22 patients with ferritins >20 000 ng/mL. None of the patients met HLH‐2004 diagnostic criteria. Fifteen (68.2%) of these patients had suspected or confirmed bacterial infections. CONCLUSIONS: Though many patients with COVID‐19 present with hyperferritinemia, elevated ferritin levels are not accurate predictors of outcomes and do not appear to be indicative of hemophagocytic lymphohistiocytosis.

The disease outbreak of coronavirus-19 continues to affect a large swath of the global population. However, while the first details of the disease were initially reported in December 2019, there is still much unknown about its pathophysiology. 1 The virus responsible, severe acute respiratory coronavirus 2 (SARS-CoV-2), has been shown to cause a constellation of symptoms affecting multiple organ systems. 2 One of the earlier and more dramatic findings has been the association of an acute inflammatory syndrome ("cytokine storm") associated with COVID-19, with certain extreme patients having a clinical picture consistent with secondary hemophagocytic lymphohistiocytosis. 3, 4 Ferritin, the major intracellular iron storage protein, is an acute phase reactant elevated in many inflammatory conditions, including acute infections. 5 Extremely high ferritin levels are the hallmark of hyperferritinemic syndromes, an umbrella term for macrophage activation syndrome, catastrophic antiphospholipid syndrome, adult onset Still's disease, and septic shock. 6, 7 In general, highly elevated ferritin levels portend poor prognoses in hospitalized patients. 8 There are multiple studies correlating elevated ferritin levels and other pro-inflammatory markers in COVID-19 with poor outcomes. [9] [10] [11] [12] [13] [14] [15] Current efforts in treating COVID-19 include trialing various anti-inflammatory biologic agents to inhibit this robust immune response. [16] [17] [18] [19] However, the utility of ferritin to predict outcomes has not yet been established. 20 We report here on a large retrospective analysis of patients admitted for COVID-19, evaluating the predictive value of presentation and maximum ferritin values. In patients with the highest ferritin values, we looked to see if patients met HLH criteria and how they responded to different anti-inflammatory treatments.

This study was approved by the Program for Protection of Human Subjects of the Icahn School of Medicine at Mount Sinai. We reviewed the records of all laboratory-confirmed COVID-19 patients across a large multi-hospital New York City health system from March 1 to April 1, 2020. COVID-19-positive patients were identified based on a positive reverse-transcriptase polymerase chain reaction SARS-CoV-2 assay of a specimen obtained from a nasopharyngeal swab. Serum ferritin levels were assayed using an electrochemiluminescence immunoassay with a Roche COBAS analyzer system. All included sites used the same means of ferritin measurement. Of all the COVID-19-positive patients, only hospitalized patients with a ferritin level available over admission were included in the analysis.

were considered to also have a presentation ferritin. If multiple ferritin levels were obtained, then the one closest to admission was used for the admission ferritin, and the highest ferritin over the admission was chosen as the maximum ferritin.

The primary outcome was all-cause mortality, with secondary outcomes including the need for renal replacement therapy (RRT) and for invasive mechanical ventilation (intubation). These outcomes were determined based on study investigator's review of the electronic health record (EHR).

We calculated the descriptive statistics used in this study, including percentages and frequencies, along with their 95% confidence intervals for categorical variables. For continuous variables, we used median and interquartile ranges (IQR). Comparison of independent medians and distributions were carried out via the Mann-Whitney U test.

The specificities and sensitivities of admission and maximum ferritin levels for each outcome of interest across all ferritin cutoffs were calculated. These specificity and sensitivity values were used to generate a receiver operator curve (ROC). We calculated the area under the curve (AUC) for the resultant ROC to evaluate the performance and accuracy of admission and maximum ferritins in predicting each outcome of interest. Youden's J statistic was used to determine the optimum cutoff values of admission ferritins in the prediction of each outcome of interest. The median presentation and maximum ferritins were significantly different in patients who did and did not survive COVID-19

(P < .0001). As detailed in Table S1 in the supplementary data, of the 265 patients who did not survive, the median presentation ferritin was 915 ng/mL and median maximum ferritin was 1648 ng/mL. For the 677 patients who survived, the median presentation ferritin was 634 ng/mL and median maximum ferritin was 928 ng/mL.

The ROCs for presentation and maximum ferritin in predicting allcause mortality are shown in Figure 1A ,B, respectively. The AUC for The ROCs for presentation and maximum ferritin in predicting the need for mechanical ventilation are shown in Figure 2A ,B, respectively. The AUC for presentation ferritin was 0.681, with an optimal cutoff of 619 ng/mL in predicting the need for mechani- The ROCs for presentation and maximum ferritin in predicting the need for new RRT are shown in Figure 3A ,B, respectively. The As ferritin values can increase with age ("inflammaging"), we evaluated the ROCs for maximum ferritin in predicting death at several age cutoffs, as seen in Figure 

The clinical characteristics and outcomes of the patients with the highest maximum ferritin values (>20 000 ng/mL) are detailed in AUCs > 0.7 and NPVs > 0.95 for both presentation and maximum ferritins, but this was not seen for our other outcomes of interest.

Though higher median ferritin levels were seen in those patients who died than those who survived, the test remains a poor clinical predictor overall.

Ferritin has been proposed to be a useful marker in predicting patient outcomes in those with COVID-19. There are multiple publications showing that higher ferritin levels, along with other pro-inflammatory markers, including CRP and IL-6, are correlated with worse outcomes and may even help predict these outcomes. [9] [10] [11] [12] [13] [14] [15] Several of these studies have limitations, including small sample populations, lack of clarity as to when during the admission the laboratories of impact were drawn, weak statistical analysis, and poor comparator arms. Notably, the one study that conducted an ROC for ferritin was only used to predict mild vs critically ill patients. It gov) and sarilumab (n = 14), the IL-6 inhibitor siltuximab (n = 2), the interleukin-1 (IL-1) receptor antagonist anakinra (n = 13), the interferon gamma inhibitor emapalumab (n = 1), and etoposide (n = 1).

There are a number of trials involving different corticosteroids and nonsteroidal anti-inflammatory agents as well. Several retrospective reports from Italy and China on the positive clinical impact of tocilizumab and consequent reduction in inflammatory markers have been published. [17] [18] [19] Sample sizes in the studies ranged from 21 to 100 patients, and oxygen requirements varied from mild oxygen supplementation to ventilation, depending on the study. The ferritin levels reported in the two Italian studies ranged from 1000 to 4000 ng/ mL. 17, 18 In our cohort of patients with ferritin levels >20 000 ng/mL, the use of tocilizumab did not appear to affect mortality, albeit in a small sample size of 10 patients.

Our study has a number of potential limitations, mostly deriving from its retrospective nature. Less than half of the patients in our original data set had a ferritin value recorded, which was required to be included in this study. These missing patients could have been less sick and/or incidentally found to have COVID-19, and therefore not had a ferritin drawn, perhaps enriching our cohort in patients with poorer outcomes. Furthermore, there are different practice patterns among the different hospitals across our health system. We only In conclusion, our retrospective study of over 900 patients admitted with COVID-19 shows that though higher ferritin levels are associated with all-cause mortality. However, ferritin cannot reliably predict several important outcomes, including death. Furthermore, though HLH has been commonly reported in association with COVID-19, we were unable to find any patient who met diagnostic criteria among our patients with the highest ferritin values.

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Additional supporting information may be found online in the Supporting Information section. How to cite this article

The authors would like to thank everyone who assisted in reviewing the EHR and inputted data for this project.

The authors have no competing interests. Leonard Naymagon https://orcid.org/0000-0002-6312-1307