Comparative analysis of CRP as a biomarker of the inflammatory response intensity among common viral infections affecting the lungs: COVID-19 versus influenza A, influenza B and respiratory syncytial virus.

Severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) is associated with significant morbidity and mortality. C-reactive protein (CRP) is a useful inflammatory biomarker for patients admitted with an infection. This study aimed to compare CRP level as an indicator of inflammation severity between SARS-CoV-2 and common respiratory viral infections. A cross-sectional study of all adult patients hospitalized in the internal medicine department, geriatric department, or internal intensive care unit between 02/2012 and 06/2021 with laboratory-confirmed respiratory viral infection was performed. SARS-CoV-2, influenza A, influenza B, and respiratory syncytial virus (RSV) were studied. Patients with laboratory-confirmed concurrent viral or bacterial infections were excluded. Patients with malignancy were also excluded. Age, gender, comorbidities, and CRP level upon admission were compared between groups. Univariate and multivariable analyses were applied. Among 1124 patients, 18.2% had SARS­CoV­2, 48.3% influenza A, 18.9% RSV, and 14.6% influenza B. SARS­CoV­2 patients were significantly younger (median 69.4 vs. ≥ 76 years) and had lower Charlson score (median 3 vs. ≥ 4 in other groups) compared to patients with other viral pathogens. After adjustment for patients' age, gender and comorbidities, SARS­CoV­2 patients had a higher probability (OR = 1.84-2.02, p < 0.01) of having CRP values in the upper quartile (> 117 mg/L) compared to all other viral pathogens while between all others there was no significant difference. To conclude, a higher CRP level upon admission is approximately twice more common among SARS-CoV-2 patients compared to other widespread respiratory viruses which may demonstrate the higher intensity of inflammation caused by SARS-CoV-2.

Normoferremia in Patients with Acute Bacterial Infections-A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin.

Ferritin is an acute phase response protein, which may not rise as expected in acute bacterial infections. This could be due to the time required for its production or to a lack of response of ferritin to the bacterial inflammatory process. Medical records of hospitalized patients with acute hyper inflammation were retrieved and studied, looking closely at two acute phase proteins: C-reactive protein (CRP) and ferritin. The estimated time between symptom onset and the procurement of blood tests was also measured. 225 patients had a median ferritin level of 109.9 ng/mL [IQR 85.1, 131.7] and a median CRP level of 248.4 mg/L [IQR 221, 277.5]. An infectious inflammatory process was identified in 195 patients. Ferritin levels were relatively low in comparison with the CRP in each group, divided according to time from symptom onset until the procurement of blood tests. The discrepancy between high CRP and low ferritin suggests that these two acute phase response proteins utilize different pathways, resulting in a failure to increase ferritin concentrations in a documented state of hyperinflammation. A new entity of normoferremic inflammation accounts for a significant percentage of patients with acute bacterial infections, which enables bacteria to better survive the inflammation and serves as a new "inflammatory stamp".

Early signaling of bacteremia in patients who present to the department of emergency medicine with relatively low C-reactive protein (CRP) concentrations.

OBJECTIVES: Examiningthe usefulness of C-reactive protein velocity (CRPv) as an early biomarker for the presence of bacteraemia in patients presenting to the Department of Emergency Medicine with acute infection/inflammation and suspected bacteraemia. METHODS: A retrospective study examining a cohort of patients who presented to the E.R and in whom blood cultures were taken. CRPv was calculated as the difference in mg/hour/litter between two consecutive CRP tests performed within 12 h. RESULTS: 256 patients were included in the cohort. Using CRPv in patients who at first presented with a relatively low (17.9 ≤ mg/L 1stquartile) CRP concentration, we found an AUC of 0.808 ± 0.038 (p < 0.001) for the presence of positive versus negative blood cultures (what is AUC?). This was better than the AUC that was obtained when the WBC for the same purpose. CONCLUSIONS: CRPv may be a useful biomarker in the identification of patients with suspected bacteremiaand a low CRP-a challenging situation for clinicians who may underestimate the severity of illness in this patient group.

Differentiating between bacterial and viral infections by estimated CRP velocity.

PURPOSE: Differentiating between acute viral and bacterial infection is challenging due to the similarity in symptom presentation. Blood tests can assist in the diagnosis, but they reflect the immediate status and fail to consider the dynamics of an inflammatory response with time since symptom onset. We applied estimated C-reactive protein (CRP) velocity (eCRPv), as derived from the admission CRP level divided by time from symptom onset, in order to better distinguish between viral and bacterial infections. METHODS: This cross-sectional study included patients admitted to the emergency department with a confirmed viral (n = 83) or bacterial (n = 181) infection. eCRPv was defined as the ratio between the absolute CRP level upon admission to time from symptom onset (in hours). Absolute CRP and eCRPv values were compared between the 3 groups. RESULTS: Bacterial patients presented with higher CRP levels (133 mg/L) upon admission compared to viral patients (23.31 mg/L) (P < 0.001). Their median value of eCRPv velocity was 4 times higher compared to the viral patients (1.1 mg/L/h compared 0.25 mg/L/h, P < 0.001). Moreover, in intermediate values of CRP (100-150 mg/L) upon admission, in which the differential diagnosis is controversial, high eCRPv is indicative of bacterial infection, eCRPv >4 mg/L/h represents only bacterial patients. CONCLUSIONS: During an acute febrile illness, the eCRPv value can be used for rapid differentiation between bacterial and viral infection, especially in patients with high CRP values. This capability can potentially expedite the provision of appropriate therapeutic management. Further research and validation may open new applications of the kinetics of inflammation for rapid diagnosis of an infectious vs. a viral source of fever.

C-Reactive Protein Velocity (CRPv) as a New Biomarker for the Early Detection of Acute Infection/Inflammation.

C-reactive protein (CRP) is considered a biomarker of infection/inflammation. It is a commonly used tool for early detection of infection in the emergency room or as a point-of-care test and especially for differentiating between bacterial and viral infections, affecting decisions of admission and initiation of antibiotic treatments. As C-reactive protein is part of a dynamic and continuous inflammatory process, a single CRP measurement, especially at low concentrations, may erroneously lead to a wrong classification of an infection as viral over bacterial and delay appropriate antibiotic treatment. In the present review, we introduce the concept of C-reactive protein dynamics, measuring the velocity of C-reactive protein elevation, as a tool to increase this biomarker's diagnostic ability. We review the studies that helped define new metrics such as estimated C-reactive protein velocity (velocity of C-reactive protein elevation from symptoms' onset to first C-reactive protein measurement) and the measured C-reactive protein velocity (velocity between sequential C-reactive protein measurements) and the use of these metrics in different clinical scenarios. We also discuss future research directions for this novel metric.

Candida albicans evades NK cell elimination via binding of Agglutinin-Like Sequence proteins to the checkpoint receptor TIGIT.

Candida albicans is the most common fungal pathogen and a prevalent cause of deadly bloodstream infections. Better understanding of the immune response against it, and the ways by which it evades immunity, are crucial for developing new therapeutics against it. Natural Killer (NK) cells are innate lymphocytes best known for their role against viruses and tumors. In recent years it became clear that NK cells also play an important role in anti-fungal immunity. Here we show that while NK cells recognize and eliminate C. albicans, the fungal cells inhibit NK cells by manipulating the immune checkpoint receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) in both humans and mice. We identify the responsible fungal ligands as members of the Als (Agglutinin-Like Sequences) protein family. Furthermore, we show that blocking this interaction using immunotherapy with a TIGIT-blocking antibody can re-establish anti-Candida immunity and serve as a potential therapeutic tool.

Age-Dependent Biomarkers for Prediction of In-Hospital Mortality in COVID-19 Patients.

Background: Several biomarkers and models have been proposed to predict in-hospital mortality among COVID-19 patients. However, these studies have not examined the association in sub-populations. The present study aimed to identify the association between the two most common inflammatory biomarkers in the emergency department and in-hospital mortality in subgroups of patients. Methods: A historical cohort study of adult patients who were admitted to acute-care hospital between March and December 2020 and had a diagnosis of COVID-19 infection. Data on age, sex, Charlson comorbidity index, white blood cell (WBC) count, C-reactive protein (CRP), and in-hospital mortality were collected. Discrimination ability of each biomarker was observed and the CHAID method was used to identify the association in subgroups of patients. Results: Overall, 762 patients (median age 70.9 years, 59.7% males) were included in the study. Of them, 25.1% died during hospitalization. In-hospital mortality was associated with higher CRP (median 138 mg/L vs. 85 mg/L, p < 0.001), higher WBC count (median 8.5 vs. 6.6 K/µL, p < 0.001), and higher neutrophil-to-lymphocyte ratio (NLR) (median 9.2 vs. 5.4, p < 0.001). The area under the ROC curve was similar among all biomarkers (WBC 0.643, NLR 0.677, CRP 0.646, p > 0.1 for all comparisons). The CHAID method revealed that WBC count was associated with in-hospital mortality in patients aged 43.1−66.0 years (<11 K/µL: 10.1% vs. 11+ K/µL: 27.9%), NLR in patients aged 66.1−80 years (≤8: 15.7%, >8: 43.3%), and CRP in patients aged 80.1+ years (≤47 mg/L: 18.8%, 47.1−149 mg/L: 43.1%, and 149.1+: 71.7% mortality). Conclusions: WBC, NLR, and CRP present similar discrimination abilities. However, each biomarker should be considered as a predictor for in-hospital mortality in different age groups.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

C-reactive protein velocity discriminates between acute viral and bacterial infections in patients who present with relatively low CRP concentrations.

BACKGROUND: To assess the utility of C-reactive protein (CRP) velocity to discriminate between patients with acute viral and bacterial infections who presented with relatively low CRP concentrations and were suspected of having a bacterial infection. METHODS: We analyzed a retrospective cohort of patients with acute infections who presented to the emergency department (ED) with a relatively low first CRP measurement (CRP1) ≤ 31.9 mg/L and received antibiotics shortly after. We then calculated C-reactive protein velocity (CRPv), milligram per liter per hour, for each patient based on CRP1 and the second CRP value (CRP2) measured within the first 24 h since admission. Finally, we compared CRPv between patients with bacterial and viral infections. RESULTS: We have presently analyzed 74 patients with acute bacterial infections and 62 patients with acute viral infections at the mean age of 80 and 66 years respectively, 68 male and 68 female. CRP1 did not differ between both groups of patients (16.2 ± 8.6 and 14.8 ± 8.5 for patients with viral and bacterial infections respectively, p value = 0.336). However, the CRP2 was significantly different between the groups (30.2 ± 21.9 and 75.6 ± 51.3 for patients with viral and bacterial infections respectively, p-value < 0.001) and especially the CRPv was much higher in patients with acute bacterial infections compared to patients with acute viral infections (0.9 ± 1.2 and 4.4 ± 2.7 respectively, p-value < 0.001). CONCLUSION: CRPv and CRP2 are useful biomarkers that can discriminate significantly between patients who present with acute bacterial and viral infections, and relatively low CRP concentration upon admission who were suspected of having a bacterial infection.

Impact of tolerance to fluconazole on treatment response in Candida albicans bloodstream infection.

BACKGROUND: Treatment of Candida albicans bloodstream infection with fluconazole is associated with significant mortality despite in vitro susceptibility to the drug. OBJECTIVES: We sought to determine whether tolerance to fluconazole is predictive of treatment failure. METHODS: We reviewed patients with monomicrobial C albicans bloodstream infection who received primary monotherapy with fluconazole. Tolerance to fluconazole, defined as the fraction of growth above the MIC, was quantified using the disc diffusion assay and digital image analyses. Survival analyses were performed with host and treatment factors as predictive variables. RESULTS: Among 44 patients included in the study, all-cause mortality was 29.5% at 30 days and 43.1% at 12 weeks. Forty-one isolates (93%) were susceptible to fluconazole (MIC50, 0.5 mg/L). Fluconazole tolerance was strongly associated with death for patients treated with fluconazole within 24 h of candidemia onset (33.3% vs 0%; p = .007), but not among patients whose treatment was started later. MIC did not correlate with survival, regardless of treatment delay. A Cox regression model including time to treatment, tolerance to fluconazole, fluconazole exposure and Pitt bacteraemia score provided good prediction of treatment outcome (area under the receiver-operator curve, 0.82). CONCLUSIONS: In patients with C albicans bloodstream infection, tolerance testing was predictive of fluconazole efficacy if the drug was started early. Further study is required to validate the utility of this metric to guide treatment choices.

The superiority of 72 h leukocyte descent over CRP for mortality prediction in patients with sepsis.

BACKGROUND: Detection of an eventful course in the early days of sepsis treatment is clinically relevant. The white blood cell count (WBCC) and C-reactive protein (CRP) are used in daily practice to monitor the intensity of the inflammatory response associated with sepsis. It is not entirely clear which of the two might better discriminate the outcomes of patients with sepsis. METHODS: 30-day mortality was assessed in a cohort of patients who were hospitalized with sepsis in the departments of Internal Medicine in a tertiary medical center. Admission and 72-hour time points were analyzed to discriminate between patients with increased versus decreased 30 days mortality risk. RESULTS: The study included 195 patients. Higher 72 h CRP, WBCC, neutrophil counts and neutrophils to lymphocyte ratio were associated with increased mortality (p < 0.02). Baseline WBCC and CRP failed to discriminate between patients who died and those who survived (AUC = 0.551, 0.479). In multivariate analysis of the 72 h tests, higher WBCC count (OR = 1.12, 95%CI 1.05-1.20, p = 0.001), was associated with increased mortality whereas CRP was not (OR = 1.004, 95%CI 0.998-1.01, p = 0.146). CONCLUSION: Patients who presented a 72-hour leukocyte descent had a better outcome and in this regard, WBCC was superior to 72-hour CRP in predicting 30 days mortality.

A second C-reactive protein (CRP) test to detect inflammatory burst in patients with acute bacterial infections presenting with a first relatively low CRP.

A first C-reactive protein (CRP) test, as often performed by clinicians during the presentation of patients with an acute bacterial infection, might be misleading. The aim of our study was to explore the dynamic between a second CRP test taken within 12 hours from admission CRP test in a cohort of patients diagnosed with acute bacterial infection in comparison to CRP in a control group of apparently healthy individuals.This was a historical cohort study comprised of all patients admitted to the Sourasky Tel-Aviv Medical Center, Israel, between July 2007 and March 2016. The study cohort included adult patients who were diagnosed as having an infection, assumed to be of bacterial etiology (cellulitis and erysipelas, pneumonia, cholecystitis, pyelonephritis, or septicemia), who had a CRP test during the first 6 hours of hospital admission (baseline CRP), and a successive CRP test up to 12 hours from the first one (recurrent CRP). The control group was of healthy subjects who attended our medical center for a routine annual check-up.The study included 950 patients. Baseline CRP ranged from 0.04 to 454 mg/L. The median CRP velocity was 0.53 mg/L/h. Patients were grouped by baseline CRP into 4 groups (CRP < 10, 10-74.9, 75-199.9, ≥200). There was an increase in median CRP velocity between the first (0.48 mg/L/h) and the second (0.93 mg/L/h) groups, which then was decreased in the next 2 groups (0.46 and -2.58 mg/L/h, respectively). In 45 of 103 (44%) patients of the group of baseline CRP concentration less than 10 mg/dL with bacterial diagnosis, there was a complete overlap with CRP values of apparently healthy individuals during their routine annual checkup.A first single low CRP result cannot exclude the presence of a significant bacterial infection. Patients with acute bacterial infection might present with a relatively low CRP value that at times correspond to normal limit CRP concentrations. A second test, obtained within 12 hours of admission, might serve as an important tool to identify patient with an evolving inflammatory burst commonly seen during acute bacterial infection.

The potential benefit of a second C-reactive protein measurement in patients with gram-negative bacteraemia presenting to the emergency medicine department.

BACKGROUND: Low C-reactive protein in acute bacterial infections could convey the erroneous impression of a mild infection. We focussed on gram-negative bacteraemia, a phenomenon frequently seen at the emergency room. METHODS: Of 2200 patients with gram-negative bacteraemia, 460 patients with first C-reactive protein <30 mg/L and 460 patients with C-reactive protein >187 mg/L were reviewed. Following exclusions, we finally investigated 229 and 289 patients with low and high C-reactive protein concentrations, respectively. RESULTS: The cohort was divided into low and high C-reactive protein groups. Median first C-reactive protein was 13.6 and 219.9 mg/L, respectively (interquartile range 6.4-21.6 and 195-270.1). Compared to patients with first high C-reactive protein, patients with first low C-reactive protein concentrations had a significant five-fold higher C-reactive protein level with their second test. CONCLUSIONS: Patients with gram-negative bacteraemia can present with C-reactive protein within the range of apparently healthy individuals. A second C-reactive protein might help to avoid an erroneous decision regarding the severity of the infection.

Pilonidal Sinus Disease: A 10-Year Review Reveals Occupational Risk Factors and the Superiority of the Minimal Surgery Trephine Technique.

OBJECTIVES: To identify military occupational risk factors for pilonidal sinus disease (PSD) and to compare an Army Clinic minimal surgery with techniques used at public hospitals. METHODS: Review of a historical cohort of soldiers (3,407 with PSD) to determine PSD risk factors in military personnel and comparison of postoperative sick leave days between surgical techniques. RESULTS: Male and female officers had a lower PSD incidence, whereas male combatants and female drivers were at higher risk compared to administrative personnel. The minimal surgery technique used at the Army Clinic was associated with an average 13 less postoperative sick leave days per patient, as compared to the surgical techniques including wide excision used at public hospitals. Compared to healthy soldiers, the relative risk for PSD recurrence was 7.87 in all males and 9.54 in male combatants. CONCLUSIONS: Male combatants and female drivers are at higher risk for PSD, whereas officers and administrative personnel are at lower risk. Compared with surgical techniques used at public hospitals, the Army Clinic exclusive use of the Gips minimal surgery technique is associated with fewer sick leave days. Prior surgery for PSD is a positive predictor of recurrence, and these patients warrant secondary prevention.

Attrition due to orthopedic reasons during combat training: rates, types of injuries, and comparison between infantry and noninfantry units.

PURPOSE: The purpose of this study is to identify the prevalence and types of orthopedic injuries in infantry and noninfantry units responsible for attrition from combat training. METHODS: 18,651 soldiers consecutively recruited to combat units (5 infantry and 4 noninfantry units) were included in this study. All recruited soldiers underwent and successfully passed a meticulous medical selection process. In all units, the soldiers participated in a suited fitness program that included marching, running, and strength training. Data were collected directly from attrite soldiers' files and detailed lists provided by the units' medical clinics. RESULTS: Out of 18,651 recruits, 641 (3.44%) attrite because of medical reasons. The leading cause of attrition was orthopedic diagnoses, and their overall rate was 43% (274 out of 641). Overuse injuries accounted for 90% of all orthopedic injuries. Low-back and lower extremity injuries accounted for 71.5% of all orthopedic injuries. There was high similarity in orthopedic injuries types and rates between infantry and noninfantry units. CONCLUSION: On the basis of our results, we recommend a multidisciplinary intense effort including physicians, physical training officers, physiotherapists, and commanders to significantly reduce overuse injuries, especially in the low-back and lower extremity regions.