key: cord-1004951-6tde42nw
authors: Gharamti, Amal A; Mei, Fei; Jankousky, Katherine C; Huang, Jin; Hyson, Peter; Chastain, Daniel B; Fan, Jiawei; Osae, Sharmon; Zhang, Wayne W; Montoya, José G; Erlandson, Kristine M; Scherger, Sias J; Franco-Paredes, Carlos; Henao-Martínez, Andrés F; Shapiro, Leland
title: Diagnostic utility of a Ferritin-to-Procalcitonin Ratio to differentiate patients with COVID-19 from those with Bacterial Pneumonia: A multicenter study
date: 2021-03-14
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab124
sha: 065dcefa636646d4eb1ce926ee472c621bf0bd37
doc_id: 1004951
cord_uid: 6tde42nw

BACKGROUND: There is an urgent need for accurate, rapid, inexpensive biomarkers that can differentiate COVID-19 from bacterial pneumonia. We assess the role of the ferritin-to-procalcitonin (F/P) ratio to classify pneumonia cases into those due to COVID-19 or due to bacterial pathogens. METHODS: This multicenter case-control study compared patients with either COVID-19 and bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded. The F/P in patients with COVID-19 or with bacterial pneumonia were compared. Receiver operating characteristic analysis determined the sensitivity and specificity of various cut-off F/P values for COVID-19 versus bacterial pneumonia. RESULTS: A total of 242 COVID-19 pneumonia cases and 34 bacterial pneumonia controls were included. Patients with COVID-19 pneumonia had a lower mean age (57.11 vs 64.4 years, p=0.02) and a higher BMI (30.74 vs 27.15 kg/m 2, p=0.02) compared to patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%, p=0.5) and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%, p=0.01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared to the F/P in bacterial pneumonia (802, p<0.001). An F/P ≥ 877 used to diagnose COVID-19 resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2%, and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥ 877 was associated with greater odds of identifying a COVID-19 case (OR: 11.27, CI: 4-31.2, p<0.001). CONCLUSION: An F/P ≥ 877 increases the likelihood of COVID-19 pneumonia compared to bacterial pneumonia.

The Coronavirus Disease 2019 (COVID- 19) was declared a global pandemic by the World Health Organization on March 11, 2020. 1 It is challenging to differentiate COVID-19 pneumonia from bacterial pneumonia at the time of clinical presentation. The clinical similarity between COVID-19 and bacterial pneumonia has resulted in concomitant use of antibiotics in up to 100% of COVID-19 patients. [2] [3] [4] In 4,267 COVID-19 patients in New York City, co-infections were diagnosed in 3.6% of patients (mostly bacterial), yet antibiotics were given in 71% of these patients. 5 This mismatch between true co-infection and clinically The clinical utility of other rapid antigen or molecular-based tests has not been established. 6 Thus, investigation of biomarkers has emerged as an important area of study in efforts to discriminate COVID-19 pneumonia from bacterial pneumonia.

Several laboratory markers have been studied for diagnosing COVID-19 and for assessing the severity of COVID-19 at the time of clinical presentation. We created the F/P index using a model-based approach to biomarker development. A scientific model is a simplified description of a phenomenon (disease) that represents the disease to learn about the mechanism of disease production (how it arises) and suggests treatments. 7, 8 A common example of this activity is the use of animal models to explore pathogenesis and therapy. In our model, we use simple components that include respiratory cells and the pathogen SARS-A c c e p t e d M a n u s c r i p t 5 CoV-2. The model specifies interactions between pathogen and respiratory cells derived from the literature. In this model, SARS-CoV-2 produces disease by virion replication and obligate cytolysis in the respiratory epithelium that results in respiratory dysfunction. The magnitude of virus replication and cytolysis reflects disease severity. There is also an associated inhibition of systemic inflammation caused by-products of viral replication. 9, 10 In contrast, in bacterial pneumonia, most organisms do not require intracellular replication and cytolysis and thus produce less respiratory cell destruction compared to SARS-CoV-2. PCT is a marker of systemic inflammation that is consistently higher in bacterial infections compared to viral infections. 11 This model focuses on significant differences in the mechanism of pathogen replication and host inflammation during infection, and we sought biomarkers that best represented these two model components. We restricted candidate biomarkers to those widely available, rapidly obtainable, and inexpensive. This model-based approach led us to focus on procalcitonin (PCT) and the iron-storage protein ferritin.

Our model predicts the ratio of circulating ferritin level (ng/ml) and PCT (ng/ml), called the ferritin/procalcitonin ratio (F/P), would be higher in COVID-19 pneumonia than in bacterial pneumonia. Statistical analyses were performed using STATA software, version 12.1 (StataCorp, College Station, Texas, USA). Continuous variables were summarized using means (± standard deviations) or medians (± interquartile ranges). Frequencies (percent) were used to describe categorical variables. Dichotomous outcomes were compared using chi-square analysis. The Fisher exact test was used to compare nominal independent variables, and a ttest or Mann-Whitney U test was employed for interval independent variables. Co-linear variables or variables with missing significant data were excluded. We excluded from analysis 102 cases with COVID-19 and bacterial pneumonia co-infections. We compared F/P A c c e p t e d M a n u s c r i p t 8 in patients diagnosed with COVID-19 to F/P in patients with bacterial pneumonia using a logistic regression controlling for age, sex, BMI, DM, HTN, and cohort site. A receiver operating characteristic (ROC) curve that compared true positive rates (sensitivity) to falsepositive rates (1-specificity) for various F/P values. The optimal F/P value that separated patients with COVID-19 pneumonia from patients with bacterial pneumonia was determined.

Statistical significance was set at the 0.05 alpha level.

We analyzed F/P in the UCHealth cohort and separately analyzed F/P in the other two hospitals combined. An ROC curve was constructed for F/P in UCHealth patients and separately in the two hospital cohorts combined, and areas under the ROC curves calculated.

The corresponding author had full access to data in the study and had final responsibility for the decision to submit the manuscript for publication. The datasets used in the current study are available from the corresponding author on a reasonable request.

Clinical characteristics and laboratory data in the three participating sites There was no predominant type of bacteria.

The median ferritin level was significantly higher in the COVID-19 pneumonia group compared to the bacterial pneumonia group. Patients with bacterial pneumonia had a significantly higher median procalcitonin level compared to patients with COVID-19 pneumonia. The median F/P was significantly higher in patients with COVID-19 (Table 2 and Figure 1B) . Table 3 ).

In this retrospective multicenter study, an F/P cut-off point of ≥ 877 generated a sensitivity of 85% and a specificity of 56% to differentiate COVID-19 pneumonia from bacterial pneumonia. We found similar F/P performance in patients from UCHealth and the validation cohort, suggesting the diagnostic value of the F/P generalizes to other patient populations.

The F/P may have substantial clinical applicability. Circulating ferritin and procalcitonin levels can be easily obtained on admission blood testing, with results available within minutes to a few hours and providing real-time information on whether patients are more likely to have COVID-19 compared to bacterial pneumonia. This information may guide antimicrobial administration, patient isolation until the diagnosis of COVID-19 is confirmed, and specific treatment considerations. Unnecessary antimicrobial therapy and associated harms may be reduced. The prevalence of bacterial co-infections among patients with COVID-19 in our study was 15.4%, and we excluded these patients from this report. In a large cohort of 1705 COVID-19 patients, the prevalence of community-onset bacterial coinfections was only 3.5%. Despite the low rate of bacterial co-infections, the rate of empiric antimicrobial use was 56.6%. 12 In another cohort of 4,267 COVID-19 patients in New York City, co-infections were diagnosed in 3.6% of the cases. 5 The larger percentage of co-infected patients in our study in the total patient group reflects patient population variability. The disproportionately high rate of antimicrobial use in COVID-19 patients despite the low A c c e p t e d M a n u s c r i p t 12 prevalence of co-infections is uniformly reported across studies. 13 We realize the sensitivity of F/P in our cohort is low to accurately rule out SARS-CoV-2 infection. We believe this tool is complementary to clinical judgement and other laboratory tests that help in the distinction between COVID-19 and bacterial infection. Its utility might be best in low-resource settings or in situations where the results of the PCR are delayed. It is also best used in settings where the PCR is falsely negative and the clinical suspicion for COVID-19 is high. Although not addressed in this report, we are evaluating F/P for use in discerning co-infected patients from patients infected with COVID-19 alone.

There is limited data available on serum ferritin levels in swine H1N1 and avian H5N1 infected patients to tell whether this ratio can be applied to this other viral infection 14 . A recent study 15 showed that hyperferritinemia is associated with poor outcomes in influenza A infection. Since lung injury in influenza is mediated by cytolysis -in a similar manner as with SARS-CoV-2-we hypothesize the ratio may have some utility in Influenza pneumonia as well.

observations in the closely related virus SARS-CoV, where prodigious viral replication within human primary ciliated respiratory epithelial cells caused cytopathy and cell shedding from tissues. 16 Ferritin was chosen as the marker for cytolysis during viral infection. Ferritin stores iron within cells and protects cell components from iron-induced free radical generation. 17 Circulating ferritin is often mischaracterized as an acute-phase reactant and likely originates from cell injury or cytolysis. Observations supporting this concept include the absence of a mechanism for cell secretion of ferritin. 18 Serum ferritin levels are unaffected by elevated plasma levels of acute-phase inducing cytokines tumor necrosis factor-alpha (TNF) or Interleukin-6 (IL-6) in healthy volunteers. In contrast, there is a correlation between serum ferritin levels and circulating cell-free DNA (cfDNA) in A c c e p t e d M a n u s c r i p t 13 hemodialysis patients. 19 Since cell-free DNA is a cytolysis footprint, this report indicates that cytolysis is mirrored by elevated ferritin. 20 This study has several limitations. Proper use of F/P requires obtaining ferritin and PCT simultaneously as soon as possible after clinical presentation. However, our data included the first available levels of ferritin and PCT, and these levels were often not obtained simultaneously or immediately after initial presentation. The diagnostic characteristics of F/P may improve with the use of early and simultaneous acquisition of ferritin and PCT. Another limitation is the low specificity of this metric in either including or excluding bacterial pneumonia. Therefore, it might not be helpful in the decision-making of initiating or withholding antibiotics. Our study is likely underpowered to detect differences between COVID-19 pneumonia cases and bacterial pneumonia controls since we included only controls with microbiologic documentation of a bacterial infection, whereas most cases of community-acquired pneumonia do not have a positive bacterial culture. Additionally, without a matching strategy due to the relatively small number of patients, the sample size might be underpowered, limiting the reliability of the results presented. Our total patient cohort from all 3 hospitals included only 34 patients with bacterial pneumonia, and more bacterial pneumonia may provide a more accurate estimate of the utility of F/P. The F/P ratio is also dichotomized using ROC inflection points, and this dichotomization likely led to decreased statistical power. The retrospective study design makes it susceptible to several biases, and the applicability of F/P to other patient populations is uncertain. Due to limitations of available data, we were unable to assess F/P association with important M a n u s c r i p t 15 outcomes like mortality, ICU stay, and mechanical ventilation. Although we adjusted for several confounders, there may be confounders unaccounted for in our analysis. Furthermore, F/P overlap occurred at low values for F/P (Fig 1) , and our model predicts this is likely due to COVID-19 patients with mild disease. Low F/P in COVID-19 likely associates with smaller amounts of cytolysis and increased inflammation, a combination associated with a bacterial infection. It may therefore be difficult to separate mild COVID-19 cases from cases of bacterial pneumonia. If our model accurately reflects disease mechanism, serial calculation of F/P could be used as a tool to quantify the severity of infection over time and may predict clinical outcomes like mortality. This report introduces this novel index, and it is our belief F/P will perform better when ferritin and PCT are obtained as soon as possible after hospital presentation.

In summary, the novel F/P may assist with the early identification of COVID-19 patients. It is best used in combination with clinical judgment and other laboratory tools, where it could assist in the decision-making to withhold antibiotics in non-critical cases till the results of PCR and other laboratory markers and cultures are out. Further studies should evaluate its potential to quantify COVID-19 severity and prognosis. M a n u s c r i p t M a n u s c r i p t

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We acknowledge the support of the University of Colorado medical students who contributed significantly to the chart abstraction. 

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