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Original article| Volume 15, 101059, May 01, 2022

Differences in inflammatory markers between coronavirus disease 2019 and sepsis in hospitalised patients

Open AccessPublished:May 08, 2022DOI:https://doi.org/10.1016/j.cegh.2022.101059
Differences in inflammatory markers between coronavirus disease 2019 and sepsis in hospitalised patients
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      Abstract

      Background

      Inflammatory markers are pivotal for the diagnosis of coronavirus disease 2019 (COVID-19) and sepsis. This study compared markers between hospitalised patients with COVID-19 and those with bacterial sepsis.

      Methods

      This retrospective single-centre cohort study included 50 patients with COVID-19 clinical stages II and III and 24 patients with bacterial sepsis. Both groups were treated according to the country's official standards. Leukocytes, C-reactive protein (CRP), ferritin, and D-dimer were registered at the time of patient's admission and 24, 48, and 72 h after initiating intrahospital treatment.

      Results

      Upon admission, marker levels were high, with a significant decrease at 72 h after antibiotic therapy in the sepsis group. The leukocyte count was higher in deceased patients with sepsis. The mean ferritin levels were 1105 mcg/dl for COVID-19 and 525 mcg/dL for sepsis. Higher ferritin levels in COVID-19 (P = 0.001) seemed to be a predictor of higher mortality. Upon admission, the median D-dimer level was 0.68 mg/L for COVID-19 and 3 mg/L for patients with sepsis, whether recovered or deceased. As D-dimer, procalcitonin levels were higher in patients with sepsis (P = 0.001). CRP levels were equally elevated in both entities but higher in deceased patients with COVID-19.

      Conclusion

      Ferritin was the main inflammatory marker for COVID-19, and leukocytes, procalcitonin, and D-dimer were the main markers of sepsis. Markers that were most affected in deceased patients were CRP for COVID-19 and leukocyte for sepsis. The therapeutic implications of these differences require further study.

      Keywords

      1. Introduction

      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and bacterial sepsis are infectious diseases that continue to be life-threatening medical conditions that challenge daily medical practice. Both show inflammation markers that can have prognostic value.
      • Marshall J.C.
      Sepsis definitions: a work in progress.
      Crit Care Clin. 2018; 34: 1-14
      , 
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      J Thromb Haemostasis. 2020; 18: 844-847
      , 
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395: 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      Three stages characterise the clinical presentations of coronavirus disease 2019 (COVID-19).
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Lancet. 2020; 395: 497-506https://doi.org/10.1016/S0140-6736(20)30183-5
      Stage I presents with fever, malaise, and cough. Stage II (pulmonary) presents with ground glass opacities in computed tomography (CT) scan, oxygen desaturation <94%, and biomarkers indicating inflammation (C-reactive protein [CRP], ferritin, and D-dimer), while stage III shows higher levels of inflammation with cytokine cascade, interleukin, and multiorgan failure.
      • Asrani P.
      • Hassan M.I.
      SARS-CoV-2 mediated lung inflammatory response in host: targeting the cytokine storm for therapeutic interventions.
      Mol Cell Biochem. 2021; 475: 675-687
      https://dx.doi.org/10.1007/s11010-020-03935-z
      The main markers of inflammatory responses are leukocytes, CRP, ferritin, interleukin-6, and D-dimer.
      • Zhang L.
      Response to uncertainties on the prognostic value of D-dimers in COVID-19 patients.
      J Thromb Haemostasis. 2020; 18: 2067-2068https://doi.org/10.1111/jth.14899
      ,
      • Lippi G.
      • Favaloro E.J.
      D-dimer is associated with severity of Coronavirus Disease 2019: a pooled Analysis.
      Tromb Haemost. 2020; 120: 876-878https://doi.org/10.1055/s-0040-1709650
      In the case of ferritin, values of 1000 mg/dL and above are associated with a poorer prognosis.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Lancet. 2020; 395: 1054-1062https://doi.org/10.1016/S0140-6736(20)30566-3
      On the other hand, sepsis syndrome stages are characterised by high temperature (>38.3 °C), hypothermia (T < 35.6 °C), tachycardia (>90 bpm), tachypnea (respiratory rate >20 rpm), and at least one of the following: mental disturbance, hypoxemia, lactate elevation, and oliguria (<30 mL or 0.4 mL/kg/h). Haemodynamic collapse occurred during this critical stage. This definition, which has been used since 1987 and was described by Bones in 1987,
      • Bone R.C.
      • Fisher Jr., C.J.
      • Clemmer T.P.
      • Slotman G.J.
      • Metz C.A.
      • Balk R.A.
      A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.
      N Engl J Med. 1987; 317: 653-658
      has undergone modifications over time. The Third International Consensus Definitions Task Force defined sepsis as ‘life-threatening organ dysfunction due to a dysregulated host response to infection’.
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      However, there is no consensus on the operational definition.
      Sepsis can be caused by bacteria, viruses, fungi, rickettsia, parasites, or protozoa. Likewise, the inflammatory cascade is significant and progressive unless treated. Biomarkers include elevated leukocytes, erythrocyte sedimentation rate (ESR), CRP, ferritin, D-dimer, procalcitonin, and interleukins (IL).
      • Carrillo Esper R.
      • Peña Pérez C.
      • Zepeda Mendoza A.D.
      • et al.
      Ferritina y síndrome hiperferritinémico. Su impacto en el enfermo grave; conceptos actuales.
      Rev Asoc Mex Med Crít Ter Intensiva. 2015; 29: 157-166
      Such elevation depends on the severity of the infection and the host's immune response. For example, less than 20% of patients with sepsis present with disseminated intravascular coagulation (DIC), and almost all have high D-dimer levels.
      As its etiological agents are different, the response of the white blood cell count and inflammatory markers in both groups of patients differ in their behaviour. Therefore, this study aimed to compare biomarker levels and outcomes between a group of patients with sepsis and COVID-19 at the time of admission and during the first 72 h of in-hospital treatment.

      2. Patients and methods

      2.1 Sample collection

      A comparative analytical study was carried out at the Hospital General del Sur in the city of Choluteca, Honduras. Patients older than 18 years were recruited between 26 January and 2 March 2021.
      The first group consisted of 50 patients with COVID-19, 62% of whom (n = 31) were diagnosed by real-time polymerase chain reaction (RT–PCR) using nasopharyngeal swabs, and 38% (n = 19) were diagnosed by combining clinical, imaging, and inflammatory marker criteria and antigen for SARS-CoV-2 using nasopharyngeal swabs or IgM antibodies. The presence of a positive test for COVID-19 was the inclusion criterion for this group.
      The second group consisted of 24 patients with sepsis with negative COVID-19 test results and standard evidence for sepsis of any aetiology. Eleven (46%) patients had cultures that supported the diagnosis of bacterial sepsis. In the other 13 cases, bacterial sepsis was diagnosed by combining clinical, imaging, and laboratory criteria (positive Gram tests and inflammatory markers).
      Demographic, clinical, and laboratory data were also collected at the same intervals. Pneumonia was documented using chest radiography or CT tomography, as available. Data were extracted from the clinical files and were anonymised.

      2.2 Laboratory data

      For both groups, inflammatory markers were registered at the time of patient's admission and 24, 48, and 72 h after initiating intrahospital treatment (Table 1). The inflammatory markers included leukocytes, CRP, ferritin, and D-dimer. Owing to resource shortages, there was no access to IL-6 testing.
      Table 1Demographic and clinical characteristics of patients with COVID-19.
      VariableCOVID-19 (n = 50)Sepsis (n = 24)OR95% CIP-value
      N%n%
      Age (years)
       <302428.3
       31–401122312.5
       41–50714416.7
       51–601020520.8
       61–701428312.5
       71–8024520.8
       >814828.3
       Mean54.756.40.7
      Sex
       Male3060416.77.52.2–25.20
       Female20402083.3
      Days from onset of symptoms
       1–3918937.5
       4–616321458.3
       7–9153014.2
       10–1271400
       >123600
       Mean6.254.290.001
      Comorbidities
       Diabetes mellitus14281666.70.190.06–0.550.002
       High blood pressure1020729.20.60.19–1.860.38
       Obesity714005.940.6–181.90.13*
      Oxygen saturation at admission (%)
       <501200
       61–702400
       71–803600
       81–92316200
       >933624100
       Mean85.7596.170
      Chest X-ray
       Normal510937.50.000*
       Pneumonia2040520.8
       Not done25501041.7
      Chest CT score (%)
       <2524
       26–501428
       51–751020
       >75612
       Mean51.75
      Chest CT score (maximum 25 points)
       <524
       6–10714
       11–151734
       16–20612
       21–2512
       Mean13
      Severity of disease
       Mild12
       Moderate3366
       Severe1632
      CURB-65***
       014281354.2
       12040729.2
       21326312.5
       32400
       41200
       Mean1.120.570.014
      Outcome
       Recovered3923
       Deceased11221 (4.3%)6.36**0.82–291.10.107*
      28562291.70.110.02–0.540.002
      *Yates correction, **Fisher's exact test.
      ***CURB-65 mortality risk prediction: 0 or 1 points (1.5%), 2 points (9.2%), and ≥3 points (22%). According to this score 68% of patients with COVID-19 and 83.4% patients with sepsis had a mortality risk of 1.5%; 26% patients with COVID-19 and 12.5% patients with sepsis had a mortality risk of 9.2%, while 6% of patients with COVID-19 had 22% risk of mortality. No patient with sepsis had this high risk.

      2.3 Severity score and inflammatory markers

      The CURB-65 pneumonia severity score calculator
      • Lim W.S.
      • van der Eerden M.M.
      • Laing R.
      • et al.
      Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study.
      Thorax. 2003; 58: 377-382https://doi.org/10.1136/thorax.58.5.377
      was used to classify mortality risk upon admission in both groups.
      • Carriel J.
      • Muñoz-Jaramillo R.
      • Bolaños-Ladinez O.
      • Heredia-Villacreses F.
      • Menéndez-Sanchón J.
      • Martin-Delgado J.
      CURB 65 as a predictor of 30 days mortality in patients hospitalized with COVID-19 in Ecuador: COVID-19-EC study.
      Rev Clin Esp. 2021; 222: 37-41https://doi.org/10.1016/j.rceng.2020.10.006
      The CURB-65 stands for confusion, blood urea nitrogen (BUN) > 7 mmol/L, respiratory rate ≥30, systolic blood pressure (SBP) < 90 mmHg, diastolic BP (DBP) ≤ 60 mmHg, and age ≥65. This score was previously used as risk stratification and prediction tool for community-acquired pneumonia. The total score was 5, and each risk factor contributed to 1 point and could be used to predict mortality as follows: 0 or 1 point (1.5% mortality), 2 points (9.2% mortality), and 3–5 points (22% mortality).

      2.4 Statistical analysis

      Data were analysed using Statistical Package for the Social Sciences (SPSS) version 2 statistical software,
      • IBM Corp. Released
      IBM SPSS Statistics for Windows, Version 27.0.
      IBM Corp, Armonk, NY2020
      and categorical or binary data were reported as frequencies and percentages. Continuous variables were described as mean ± standard deviation or median (interquartile range [IQR], as appropriate). Differences between study groups were evaluated using the Mann–Whitney U test, Yates correction, and Fisher's exact test. Odds ratios (ORs) and 95% confidence intervals were calculated, and a P-value of less than 0.05 was considered statistically significant.

      3. Results

      In 50 patients with COVID-19, diagnosis was made by RT-PCR (n = 31, 62%), rapid IgM (n = 10, 20%), and rapid antigen tests using swab (n = 9, 18%). Most patients in this group were men (OR = 7.5), with an average age of 54.7 years, and 56% had comorbidities, especially diabetes (OR, 0.19; P = 0.002) and obesity (OR 5.94, P 0.38). Sixty-six percent of patients had a moderate clinical presentation of the disease according to the CURB-65 score (Table 1).
      In patients with sepsis, 13 (54%) had urinary tract infections, and 9 (21%) had criteria for bacterial pneumonia. In the other cases, there was previous treatment with antibiotics or logistic limitations in performing the test on time (Table 1). The mean number of days of symptoms from onset until admission was 6.25 days in the COVID-19 group and 4.29 days in the sepsis group (P 0.001). Oxygen saturation was lower in patients with COVID-19. Comorbidities were more frequent in patients with sepsis (Table 1).
      Differences in inflammatory markers were found in the blood counts (Table 2). There was a higher total leukocyte count upon admission in patients with sepsis than in patients with severe COVID-19, but at 72 h of hospitalisation, the count was levelled in both groups, with a marked decrease in the count in the sepsis group after antibiotic treatment was initiated. In the COVID-19 group, the lymphocyte count was lower upon admission and at 72 h, while the mean number of neutrophils was higher in the sepsis group upon admission and at 72 h.
      Table 2Comparison of blood counts between patients with COVID-19 and sepsis.
      Blood countsCOVID-19SepsisP-value
      N%n%
      Leukocytes (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/mL)
      Upon admission
       <4500714.01
       >110001734.019
       Mean981115,9760.000
      72 h
       <450012814.2
       >110001616937.5
       Mean10,94310,7240.860
      Neutrophils' (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/mL)
      Upon admission
       <200024
       >7500244820
       Mean812012,8720.000
      72 h
       <2000
       >75001938.0937.5
       Mean (Q25%, 75%)7480 (5,200, 10,701)6835 (5,225, 9010)0.263*
      Range (IQR)2349–21,250 (5501)2250–20,350 (18,100)
      Lymphocytes (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/mL)
      Upon admission
      <10002856.0729.2
      >450036.01770.8
      Median (Q25%, 75%)849 (517, 1367)1346 (925, 1935)0.001*
      Range (IQR)146–8191 (850)650–4140 (1010)
      72 h
      <10002040.028.3
      >450000
      Mean115418770.000
      *Mann–Whitney U.
      Other inflammatory markers were also different between the groups (Table 3). Ferritin levels were higher upon admission and at 72 h in the COVID-19 group. D-dimer levels were higher in the sepsis group upon admission and at 72 h, while CRP levels showed a similar reduction in both groups after 72 h of treatment. In contrast, procalcitonin levels were higher in patients with sepsis upon admission and at 72 h.
      Table 3Comparison of other inflammatory markers between patients with COVID-19 and sepsis.
      COVID-19SepsisP
      N%n%
      CRP (mg/L)
      Upon admission
       <6612.02
       >1501020.06
       Median (Q25%, 75%)48 (12, 96)48 (12, 196)0.956*
      Range (IQR)0–34(84)0–196 (154)
      72 h
       <61428.0520.8
       >15012.014.2
       Median (Q25%, 75%)12 (6, 24)22 (8.5, 49.5)0.109*
       Range (IQR)0–192 (18)0–192 (41)
      Ferritin (mcg/L)
      Upon admission
       <3381020.0150
       >20007141
       Mean11055250.001*
      72 h
       <33648.011
       20,00036.0
       Mean10884640.000*
      D-dimer (mg/L)
      Upon admission
       0.51836.03
       >31020.011
       Median (Q25%, 75%)0.68 (0.28, 2.62)3 (1.89, 7.13)0.000*
       Range (IQR)0.0–10.0 (2.34)0.36–10.0 (5.24
      72 h
       <0.51224.0312.5
       >3816.01041.7
       Median (Q25%, 75%)0.78 (0.44, 2.03)1.0 (0.72, 4)0.86*
       Range (IQR)0.0–10.0 (1.59)0–10 (3.28)
      Procalcitonin (ng/mL)
      Upon admission
       <0.53162.0729.2
       >524.0625.0
       Median (Q25%, 75%)0.20 (0.19, 0.66)1.51 (0.37, 8.0)0.003*
       Range (IQR)0.0–92.0 (0.47)0.0–100 (3.37)
      72 h
       <0.52652.0833.3
       >512.0416.7
       Median (Q25%, 75%)0.26 (0.18, 0.46)1.0 (0.35, 3.75)0.004*
       Range (IQR)0.0–590.0–100 (2.48)
      *Mann–Whitney U.
      In patients with COVID-19 treated with tocilizumab when available or indicated, the mean ferritin level was 1105 mcg/L upon admission and 1089 mcg/L at 72 h. In patients not treated with tocilizumab, the mean levels were 1725 and 1074 mcg/L upon admission and at 72 h, respectively. Remdesivir was prescribed more often in patients with mild-to-moderate clinical presentations (n = 18), and tocilizumab was mostly prescribed in critical patients (n = 30). No significant differences were seen between the two subgroups at 72 h.
      The mean ferritin levels in COVID-19 survivors were 983 mcg/L upon admission and 1427 mcg/L in the deceased. Upon admission, D-dimer mean levels did not vary significantly in COVID-19 survivors compared with the deceased (3.8 mg/L vs. 2.59 mg/L). A total of 11/50 patients died in the COVID-19 group and 1/24 in the sepsis group (OR 6.36, 95% CI 0.82–291.1, P = 0.107). According to the CURB-65 score, the mortality risk was higher in COVID-19 (Table 1): 26% patients with COVID-19 and 12.5% patients with sepsis had a mortality risk of 9.2%, while 6% of patients with COVID-19 had 22% risk of mortality. No patient with sepsis had this high risk.
      Table 4 shows differences in inflammatory markers between recovered and deceased patients in both groups. White cell counts were higher in deceased patients with sepsis, whereas CRP and ferritin levels were higher in deceased patients with COVID-19. D-dimer was higher in patients with sepsis, whether recovered or diseased. Procalcitonin levels were higher in patients with sepsis. Only one patient with sepsis died, but his procalcitonin levels were normal.
      Table 4Inflammatory markers upon admission and outcome of patients.
      Inflammatory markers admissionOutcome
      Recovered (n = 62)Deceased (n = 12)
      COVID-19 (n = 39)Sepsis (n = 23)COVID-19 (n = 11)Sepsis (n = 1)
      Leukocytes (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/ml)
       Mean939114,86911,83631,200
       Median875014,70012,50031,200
       Standard deviation4693766760340
       DistributionNormalNormalNormalNormal
      Neutrophils (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/mL)
       Mean766411,70310,32525,272
       Median696312,07010,62525,272
       Standard deviation4315623855770
       DistributionNormalNormalNormalNormal
      Lymphocytes (10
      • Seymour C.W.
      • Liu V.X.
      • Iwashyna T.J.
      • et al.
      Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3).
      JAMA. 2016; 315: 762-774https://doi.org/10.1001/jama.2016.0288
      μ/mL)
       Mean1317144811383774
       Median89214206483774
       Standard deviation161067515730
       DistributionNot normalNormalNot normalNormal
      CRP (C-reactive protein) mg/mL
       Mean78.571.5492.2724
       Median4848.05424
       Standard deviation94.975.3565.90
       DistributionNot normalNot normalNot normalNormal
      Ferritin (mcg/L)
       Mean1022336.41427401
       Median954265.01713401
       Standard Deviation653218.758140
       DistributionNormalNormalNormalNormal
      D-dimer (mg/L)
       Mean2.024.402.593.5
       Median0.722.700.653.5
       Standard deviation2.963.823.770
       Normal distributionNot normalNormalNot normalNormal
      Procalcitonin (ng/mL)
       Mean2.9418.961.510.25
       Median0.300.770.390.25
       Standard deviation14.8536.482.880
       DistributionNot normalNot normalNot normalNormal

      4. Discussion

      Upon admission, the leukocyte count, procalcitonin, and D-dimer levels were higher in the sepsis group than in the COVID-19 group, with leukocytes decreasing at 72 h after antibiotic treatment in the sepsis group. Ferritin levels were higher at 72 h in patients with COVID-19. CRP levels were high in both groups and decreased after treatment. Upon admission and at 72 h, lymphocytes were lower in the COVID-19 group, and neutrophils were higher in the sepsis group.
      Upon admission, higher leukocyte counts in patients with sepsis than in patients with severe COVID-19 have already been reported in the medical literature.
      • Terpos E.
      • Ntanasis-Stathopoulos I.
      • Elalamy I.
      • et al.
      Hematological findings and complications of COVID-19.
      Am J Hematol. 2020; 95: 834-847https://doi.org/10.1002/ajh.25829
      ,
      • Aird W.C.
      The hematologic system as a marker of organ dysfunction in sepsis.
      Mayo Clin Proc. 2003; 78: 869-881https://doi.org/10.4065/78.7.869
      The use of pulmonary tomography has improved the diagnosis of pneumonia in COVID-19. In our study, an average lung involvement of 52% was found. It is recommended to perform a tomographic study in patients with sepsis and suspected pneumonia with a normal chest X-ray.
      • Castillo A.F.
      • Basaes N.D.
      • Huete G.A.
      Radiology in the COVID-19 Pandemic: current role, recommendations for structured reporting and experience of our Department.
      Rev Chil Radiol. 2020; 26: 88-89https://doi.org/10.4067/S0717-93082020000300088
      COVID-19 in its advanced stages and bacterial sepsis both cause changes in the white blood cell count. In patients with severe COVID-19 disease, the white cell count is slightly elevated at the expense of neutrophils with a marked decrease in the cluster of differentiation (CD)4 and CD8 lymphocytes because they express angiotensin-converting enzyme-2 (ACE2) receptors on their surface, which converts them into SARS-CoV-2 target cells.
      • Terpos E.
      • Ntanasis-Stathopoulos I.
      • Elalamy I.
      • et al.
      Hematological findings and complications of COVID-19.
      Am J Hematol. 2020; 95: 834-847https://doi.org/10.1002/ajh.25829
      ,
      • Aird W.C.
      The hematologic system as a marker of organ dysfunction in sepsis.
      Mayo Clin Proc. 2003; 78: 869-881https://doi.org/10.4065/78.7.869
      On the other hand, cytokine storms in COVID-19 can lead to lymphocyte apoptosis and lymphoid organ atrophy.
      • Asrani P.
      • Hassan M.I.
      SARS-CoV-2 mediated lung inflammatory response in host: targeting the cytokine storm for therapeutic interventions.
      Mol Cell Biochem. 2021; 475: 675-687
      https://dx.doi.org/10.1007/s11010-020-03935-z
      Unlike COVID-19, leukocytosis in sepsis is more frequent due to neutrophilia; however, neutropenia may occasionally be observed, especially in the paediatric population.
      • Lee J.A.
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      • Tuminski W.
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      Best pharmaceuticals for children act—pediatric trials network steering committee. Effectiveness of granulocyte colony-stimulating factor in hospitalized infants with neutropenia.
      Am J Perinatol. 2017; 34: 458-464https://doi.org/10.1055/s-0036-1593349
      CRP was a biomarker that showed a reduction in both groups after treatment initiation. This marker is an acute phase reactant secreted by the liver during inflammation and favours the phagocytosis of microorganisms, with high levels correlating with severe bacterial pneumonia or COVID-19.
      • Wang L.
      C-reactive protein levels in the early stage of COVID-19.
      Med Maladies Infect. 2020; 50: 332-334https://doi.org/10.1016/j.medmal.2020.03.007
      Elevated CRP is considered sensitive but not specific for the diagnosis of sepsis;
      • Pradhan S.
      • Ghimire A.
      • Bhattarai B.
      • et al.
      The role of C-reactive protein as a diagnostic predictor of sepsis in a multidisciplinary Intensive Care Unit of a tertiary care center in Nepal.
      Indian J Crit Care Med. 2016; 20: 417-420https://doi.org/10.4103/0972-5229.186226
      however, a CRP level >100 mg/L on the third day of intensive care unit (ICU) admission is associated with higher mortality.
      • Devran Ö.
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      C-reactive protein as a predictor of mortality in patients affected with severe sepsis in intensive care unit.
      Multidiscip Respir Med. 2012; 7https://doi.org/10.1186/2049-6958-7-47
      As explained, ferritin levels were higher in the COVID-19 group. Ferritin is an acute-phase reactant nonspecifically elevated in acute and chronic inflammatory processes, such as chronic kidney disease, rheumatoid arthritis, and autoimmune diseases. Ferritin is elevated during the COVID-19 cytokine storm and may be a predictor of mortality in these cases.
      • Carubbi F.
      • Salvati L.
      • Alunno A.
      • et al.
      Ferritin is associated with the severity of lung involvement but not with worse prognosis in patients with COVID-19: data from two Italian COVID-19 units.
      Sci Rep. 2021; 11https://doi.org/10.1038/s41598-021-83831-8
      Although it is less used to make the diagnosis and estimate the prognosis of mortality in sepsis. A study showed an association between low levels of iron and transferrin and high levels of serum ferritin in patients with sepsis. The much higher serum ferritin levels in patients with COVID-19 in our study reinforce the hypothesis that this disease can be considered a hyperferritinemic syndrome.
      • Missano Florido M.
      • Assunção M.
      • Mazza B.
      • et al.
      Evaluation of iron, transferrin and ferritin serum levels in patients with severe sepsis and septic shock.
      Crit Care. 2012; 16: 424https://doi.org/10.1186/cc11031
      ,
      • Carrillo E.R.
      • Peña P.C.
      • Zepeda M.A.
      • Meza M.J.
      • Maldonado R.N.
      • et al.
      Ferritina y síndrome hiperferritinémico: su impacto en el enfermo grave; conceptos actuales.
      Rev Asoc Mex Med Crít Ter Intensiv. 2015; 29: 157-166
      In inflammation, serum ferritin rises in the blood by at least 25% and values greater than 3000 ng/L have exponentially higher mortality.
      • Carrillo E.R.
      • Peña P.C.
      • Zepeda M.A.
      • Meza M.J.
      • Maldonado R.N.
      • et al.
      Ferritina y síndrome hiperferritinémico: su impacto en el enfermo grave; conceptos actuales.
      Rev Asoc Mex Med Crít Ter Intensiv. 2015; 29: 157-166
      D-dimer levels were higher in the sepsis group than in the control group at 72 h. This marker is a fibrin degradation product during thrombotic diseases; however, it can also be elevated in malignant diseases, chronic liver diseases, inflammatory processes, and infections. A study found elevated D-dimer levels in patients with COVID-19 pneumonia and community-acquired bacterial pneumonia, with the highest levels in COVID-19 pneumonia.
      • Yu B.
      • Li X.
      • Chen J.
      • et al.
      Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis.
      J Thromb Thrombolysis. 2020; 50: 548-557https://doi.org/10.1007/s11239-020-02171-y
      This elevation was associated with critical viral disease and was even higher in deceased patients.
      • He X.
      • Yao F.
      • Chen J.
      • et al.
      The poor prognosis and influencing factors of high D-dimer levels for COVID-19 patients.
      Sci Rep. 2021; (1830): 11https://doi.org/10.1038/s41598-021-81300-w
      Another study, including multivariate analysis to determine whether several biomarkers, such as CRP, procalcitonin, and D-dimer, were markers of mortality in patients with sepsis, showed that the only biomarker with a linear relationship with mortality was D-dimer.
      • Rodelo J.R.
      • De la Rosa G.
      • Valencia M.L.
      • et al.
      D-dimer is a significant prognostic factor in patients with suspected infection and sepsis.
      Am J Emerg Med. 2012; 30: 1991-1999https://doi.org/10.1016/j.ajem.2012.04.033
      COVID-19 can produce a coagulopathy similar to that of sepsis. However, unlike the DIC seen in sepsis, prolonged prothrombin and partial thromboplastin times, decreased antithrombin activity, and thrombocytopenia are less common in COVID-19.
      • Iba T.
      • Levy J.H.
      • Levi M.
      • Thachil J.
      Coagulopathy in COVID-19.
      J Thromb Haemostasis. 2020; 18: 2103-2109https://doi.org/10.1111/jth.14975
      This could explain why D-dimer values were higher in patients with sepsis upon admission and at 72 h.
      Procalcitonin levels were higher in the sepsis group upon admission and at 72 h. It is a precursor to the hormone calcitonin, and elevated levels have been correlated with the severity of COVID-19 or bacterial coinfection in these patients.
      • Hu R.
      • Han C.
      • Pei S.
      • Yin M.
      • Chen X.
      Procalcitonin levels in COVID-19 patients.
      Int J Antimicrob Agents. 2020; 56: 106051https://doi.org/10.1016/j.ijantimicag.2020.106051
      In bacterial sepsis, procalcitonin levels increase 6–12 h after the onset of infection and fall by 50% at 24 h with adequate antibiotic therapy. In addition, procalcitonin levels are not affected by anti-inflammatory drugs. In our study, procalcitonin levels were higher in patients with sepsis than in patients with COVID-19 with a secondary bacterial infection. Procalcitonin is a useful biomarker for differentiating bacterial infections from viral infections, with high sensitivity and specificity. High levels of this marker predict the severity of sepsis and correlate with the severity of inflammation.
      • Han J.
      • Gatheral T.
      • Williams C.
      Procalcitonin for patient stratification and identification of bacterial co-infection in COVID-19.
      Clin Med. 2020; 20: e47https://doi.org/10.7861/clinmed.let.20.3.3
      ,
      • Wacker C.
      • Prkno A.
      • Brunkhorst F.M.
      • Schlattmann P.
      Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis.
      Lancet Infect Dis. 2013; 13: 426-435https://doi.org/10.1016/s1473-3099(12)70323-7
      According to the CURB-65 score, the mortality risk in this study was higher in COVID-19. To date, this score has served as a predictor of complications in patients with pneumonia. Recently, Elmoheen et al. reported that CURB-65 outperformed pneumonia severity index in predicting 30-day mortality and critical care intervention in a multiethnic population from Qatar (2021).
      • Elmoheen A.
      • Abdelhafez I.
      • Awad W.
      • et al.
      External validation and recalibration of the CURB-65 and PSI for predicting 30-day mortality and critical care intervention in multiethnic patients with COVID-19.
      Int J Infect Dis. 2021; (S1201-9712) (21): 660-663https://doi.org/10.1016/j.ijid.2021.08.027
      Besides the CURB-65 score, it could be studied if including procalcitonin, D-dimer, and ferritin could help predict sepsis's inflammatory and coagulation states. Additionally, other scores, such as sequential organ failure assessment (SOFA), could be used for further evaluation of patients in the intensive care setting.
      • Ferreira F.L.
      • Bota D.P.
      • Bross A.
      • Mélot C.
      • Vincent J.L.
      Serial evaluation of the SOFA score to predict outcome in critically ill patients.
      JAMA. 2001; 286 (10): 1754-1758https://doi.org/10.1001/jama.286.14.1754
      Although more studies have been conducted on this approach, ferritin, procalcitonin, and D-dimer should be included in the laboratory panel in sepsis. Ferritin could indicate a hyperinflammatory process, and the D-dimer level in the context of sepsis should be interpreted based on the patient's profile and should be treated with anticoagulants if indicated. Procalcitonin could be considered as a reactant that increases in non-COVID sepsis.
      This study was limited by the sample size, but the results obtained in this comparative study between patients with COVID-19 and sepsis suggest that the approach to a patient with sepsis might need a change, pointing to the importance of the role of the hypercoagulable state, a condition that could increase the risk of death in these patients due to thromboembolic complications. More studies are needed to revisit anticoagulation and anti-inflammatory therapies for sepsis.
      In this study, patients with COVID-19 presented with higher levels of ferritin, and patients with sepsis presented with higher leukocytes, procalcitonin, and D-dimer levels. At baseline, CRP levels were higher in deceased patients with COVID-19, and leukocytes were higher in deceased patients with sepsis. This should be further evaluated to determine its therapeutic implications.

      Funding

      This work was supported by the Hospital General del Sur (Secretary of Health of Honduras) and the Universidad Tecnológica Centroamericana (UNITEC, Honduras) .

      Ethical approval

      This study was approved by the Research Ethics Committee of Universidad Tecnológica Centroamericana. Patient data were extracted from the files and were anonymised.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this study.

      Acknowledgements

      We thank the staff and COVID-19 Committee at the Hospital General del Sur, Choluteca.

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      Article Info

      Publication History

      Published online: May 08, 2022
      Accepted: May 1, 2022
      Received in revised form: April 24, 2022
      Received: January 11, 2022

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      DOI: https://doi.org/10.1016/j.cegh.2022.101059

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      © 2022 The Author(s). Published by Elsevier B.V. on behalf of INDIACLEN.

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