Biomarkers of Immunity: Immature Granulocytes

Optimal Takeaways

Immature granulocytes (IGs) are precursors of granulocyte white blood cells, i.e., eosinophils, basophils, and neutrophils, and reflect an early response to infection or inflammation. The level of IGs in circulation often increases proportionally to the severity of the condition. Higher levels are observed with sepsis, surgical infections, SIRS, hematological malignancy, and more severe pancreatitis, appendicitis, cholecystitis, and COVID-19. A low IG is likely associated with the absence of severe infection or inflammation and may be zero in healthy individuals.

Immature Granulocytes, Absolute

Standard Range: 0.0 - 0.10 k/cumm            

The ODX Range: 0 - 0.03 k/cumm       

Immature Granulocytes, Percentage

Standard Range: 0 - 1%

The ODX Range: 0 – 0.5 %        

High immature granulocytes (IGs) are associated with severe appendicitis (Turkes 2022), severe cholecystitis (Unal 2022), severe pancreatitis, surgical infections complications, systemic inflammatory response syndrome (SIRS), more severe COVID-19 (Georgakopoulou 2022), sepsis (Ayres 2019), higher neutrophil/lymphocyte ratios, ARDS (Choto 2022), hematological malignancy, glucocorticoids, chemotherapy, severe infection, and pregnancy (Roehrl 2011). Increased IGs may also be seen with neoplasia, tissue damage, hemolysis, seizures, metabolic abnormalities, and steroid use (Labcorp. CAP Today).

Higher levels are also associated with fatal versus nonfatal STEMI (Korkut 2022), acute inflammatory disease, tissue necrosis, acute transplant rejection, and higher SYNTAX scores related to acute coronary syndrome (Bedel 2020).

Low immature granulocytes are consistent with the absence of infection.

Overview

Granulocytes are white blood cell types that include eosinophils, basophils, and neutrophils, the most common granulocytes (Pagana 2022). Immature granulocytes (IGs) include promyelocytes, myelocytes, and metamyelocytes and are precursors to neutrophils, which play a critical role in fighting fungal and bacterial infections (Georgakopoulou 2022).

Increased production of immature white blood cells causes a “shift to the left” in WBC production, usually in response to infection or inflammation. Immature granulocyte measurement is more accurate for identifying infection than measuring band cells, which are more mature neutrophil precursors (Prabu 2020).

Most healthy individuals do not have IGs in circulation or maintain a level of 0.5% or 0.03 k/cumm or below, although 0-1% has been considered the standard range for IG% (Lipinski 2017).

A retrospective observational study of 200 suspected infection inpatients found that those with positive blood cultures had significantly higher IG counts and IG% (0.70 k/cumm and 4.86 IG%) than those with negative cultures (0.17 k/cumm and 1.58 IG%), respectively. An IG count above 0.3 k/cumm and IG% above 3% had a greater than 90% specificity for sepsis. Researchers suggest that lower IG counts of 0.03 k/cumm and IG% of 0.5% and above can be used as an initial screen for bacteremia (Senthilnayagam 2012).

Immature granulocyte production is stimulated by TNF-alpha and interleukin-1, inflammatory compounds that contribute to systemic inflammatory response syndrome (SIRS) (Lipinski 2017). Measuring IG can help differentiate between infective and non-infective SIRS within the first 48 hours of SIRS diagnosis (Nierhaus 2013).

Elevated IG counts, and percentages may help differentiate between noninfective inflammation and sepsis and help identify sepsis early, avoiding a critical delay in care (Bhansaly 2022). Generally, an IG% above 3% has been associated with sepsis, while an IG% below should rule out sepsis (Ayres 2019).

Immature granulocytes are earlier indicators of infection than band cells and can be significantly elevated in pancreatitis, sickle cell disease, liver abscess, COVID-19, and infective complications following cardiac surgery (Turkes 2022).

An elevation in immature granulocytes may reflect prolonged stimulation of the bone marrow accompanied by a prolonged innate immune response. This can aggravate inflammation further and contribute to acute respiratory distress syndrome (ARDS) and more severe infections such as COVID-19 (Choto 2022).

Measuring IGs may be more helpful in predicting the severity of acute pancreatitis than total WBCs or CRP. A cohort study of 77 acute pancreatitis (AP) patients found that IG% was significantly higher in those with severe versus mild or moderate AP. Results indicated that IG% above 0.6% had a sensitivity and specificity above 90% for predicting severe AP early in the disease (Lipinski 2017).

The immature granulocyte count may help predict more severe and complicated appendicitis. Immature granulocyte count and percentages were significantly higher in complicated versus uncomplicated appendicitis in a retrospective cross-sectional study of 99 acute appendicitis patients and 41 controls. Complicated appendicitis is characterized by increased post-op complications, delayed recovery, increased length of hospitalization, and increased cost of care. Subjects with complicated appendicitis had a median IG count of 0.03 10-3/uL (20%) versus 0.02 10-3/uL (10%) with simple appendicitis. Controls had a median IG of 0.01 10-3/uL (0-10%) (Turkes 2022).

An elevation in IG% differentiated the severity of acute cholecystitis (AC) in a retrospective study of 528 AC patients. Those with severe AC had a mean IG% of 2.6% versus 1.3% with moderate AC and 0.4% with mild AC. It is essential to identify and treat severe AC as it can be associated with perforation, abscess, gangrene, and a mortality rate that can exceed 10%. Elevations in neutrophil/lymphocyte count and CRP also helped identify severe AC (Unal 2022).

A significantly higher percentage of immature granulocytes was observed in individuals who did not survive an ST-segmented elevation myocardial infarction (STEMI) in a retrospective study of 146 STEMI inpatients. The mean IG% in non-survivors was 1.12% versus 0.5% in STEMI survivors. Those with IG% of 0.6 or above also had significantly higher WBCs, neutrophils, glucose, BUN, creatinine, and mortality rates. Although elevated IG% identified systemic inflammation, CRP levels in the two groups were not significantly different but were elevated at 37.62 mg/dL in non-survivors and 21.22 mg/dL in survivors (Korkut 2022).

A cross-sectional study of 78 acute coronary syndrome patients found that those with the highest SYNTAX scores (above 22) had significantly higher IG counts and IG%, i.e., 0.08 versus 0.07 10-3/mm-3 and 0.7 versus 0.44%, respectively. Those with the highest IGs and SYNTAX scores also had significantly higher WBCs, neutrophils, glucose, CRP, troponin, and mortality (Bedel 2020).

References

Ayres, Laura S et al. “Immature granulocytes index as early marker of sepsis.” International journal of laboratory hematology vol. 41,3 (2019): 392-396. doi:10.1111/ijlh.12990 Bedel, Cihan et al. “Usefulness of Immature Granulocytes to Predict High Coronary SYNTAX Score in Acute Coronary Syndrome; a Cross-sectional Study.” Archives of academic emergency medicine vol. 8,1 e73. 15 Sep. 2020

Bhansaly, Prabhav et al. “Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.” Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine vol. 26,2 (2022): 216-223. doi:10.5005/jp-journals-10071-23920

Choto, Tanaka Arthur et al. “Excessive neutrophil recruitment promotes typical T-helper 17 responses in Coronavirus disease 2019 patients.” PloS one vol. 17,8 e0273186. 18 Aug. 2022, doi:10.1371/journal.pone.0273186

Georgakopoulou, Vasiliki Epameinondas et al. “Immature granulocytes: Innovative biomarker for SARS‑CoV‑2 infection.” Molecular medicine reports vol. 26,1 (2022): 217. doi:10.3892/mmr.2022.12733

Korkut, Mustafa et al. “Usefulness of Immature Granulocytes as A Prognostic Factor in ST-Elevation Myocardial Infarction.” Brazilian journal of cardiovascular surgery vol. 37,6 893-899. 1 Dec. 2022, doi:10.21470/1678-9741-2021-0088

Labcorp. CAP Today August 2010, Q&A Section. http://www.captodayonline.com/Archives/0810/0808_QA.html

Lipinski, Michał, and Grażyna Rydzewska. “Immature granulocytes predict severe acute pancreatitis independently of systemic inflammatory response syndrome.” Przeglad gastroenterologiczny vol. 12,2 (2017): 140-144. doi:10.5114/pg.2017.68116

Nierhaus, Axel et al. “Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis--a prospective, observational study.” BMC immunology vol. 14 8. 12 Feb. 2013, doi:10.1186/1471-2172-14-8

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Prabu, Natesh R, and Vijaya P Patil. “Is Immature Granulocyte Count a Potential Prognostic Marker for Upper Gastrointestinal Tract Bleeding? A New Road to Explore.” Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine vol. 24,9 (2020): 750-752. doi:10.5005/jp-journals-10071-23606

Roehrl, Michael H A et al. “Age-dependent reference ranges for automated assessment of immature granulocytes and clinical significance in an outpatient setting.” Archives of pathology & laboratory medicine vol. 135,4 (2011): 471-7. doi:10.5858/2010-0258-OA.1

Senthilnayagam, Balamurugan et al. “Automated measurement of immature granulocytes: performance characteristics and utility in routine clinical practice.” Pathology research international vol. 2012 (2012): 483670. doi:10.1155/2012/483670

Turkes, Gulsum Feyza et al. “Predictive value of immature granulocyte in the diagnosis of acute complicated appendicitis.” PloS one vol. 17,12 e0279316. 21 Dec. 2022, doi:10.1371/journal.pone.0279316

Unal, Yılmaz et al. “An effective and reliable marker in gradıng the severity of acute cholecystitis: Increased immature granulocyte percentage.” Turkish journal of trauma & emergency surgery : TJTES vol. 28,12 (2022): 1716-1722. doi:10.14744/tjtes.2021.86322