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Reference: Agnello et al. Monocyte distribution width (MDW) as a screening tool for early detecting sepsis: a systematic review and meta-analysis. Clinical Chemistry and Laboratory Medicine 2022; 60(5):786-792 Clin Chem Lab Med. 2022

Date: February 21, 2025

Guest Skeptic: Dr. Aaron Skolnik is an Assistant Professor of Emergency Medicine at the Mayo Clinic Alix School of Medicine and Vice Chair of Critical Care Medicine at Mayo Clinic Arizona.  He is board-certified in Emergency Medicine, Medical Toxicology, Addiction Medicine, Internal Medicine-Critical Care, and Neurocritical Care.  Aaron is a full-time multidisciplinary intensivist.  He is the Medical Director of Respiratory Care for Mayo Clinic Arizona and enjoys serving as medical student clerkship director for critical care.

Case: A 62-year-old male presents to the Emergency Department (ED) with fever, confusion, and shortness of breath. His symptoms began two days ago, starting with generalized malaise and chills, followed by progressive dyspnea and mental status changes. The patient also reports decreased urine output over the past day. He has a history of Type 2 diabetes mellitus, hypertension, and chronic kidney disease (stage 3). His home medications include metformin, lisinopril, and amlodipine, though he hasn’t taken his antihypertensives for the last two days. He is tachycardic, tachypneic, and febrile with a BP of 92/58, and an oxygen saturation of 91% on room air. Physical examination reveals diffuse crackles bilaterally and chest x-ray shows bilateral infiltrates consistent with pneumonia. His WBC is elevated at 23,000 with a left shift. Lactate is 3.8 mmol/L and blood cultures are pending.

Background: Rapid and accurate diagnosis of sepsis is critical, as early intervention can significantly reduce patient mortality. However, diagnosing sepsis early remains challenging because it presents with nonspecific symptoms. New biomarkers, such as procalcitonin and lactate, offer some utility but are not sufficiently reliable on their own​​.

Recently, monocyte distribution width (MDW) has emerged as a promising biomarker in this diagnostic challenge. MDW, an indicator of variability in monocyte size, can be rapidly assessed as part of an automated complete blood count differential and may flag potential sepsis early in patients. This parameter has the advantage of being available very quickly without additional blood draws, which could be helpful in the fast-paced ED setting. Current evidence suggests MDW could be used alongside existing clinical criteria to help screen for sepsis risk and guide further assessment and treatment, even in patients where sepsis is not immediately suspected​​.

Clinical Question: What is the diagnostic accuracy of monocyte distribution width for early detection of sepsis?

Reference: Agnello et al. Monocyte distribution width (MDW) as a screening tool for early detecting sepsis: a systematic review and meta-analysis. Clinical Chemistry and Laboratory Medicine 2022; 60(5):786-792 Clin Chem Lab Med. 2022

  • Population: Adults admitted to various clinical settings, particularly the ED, intensive care unit (ICU), and one infectious diseases unit (I don’t have one of those Ken – do you?).
    • Excluded: Pediatric patients, COVID-19 patients, non-diagnostic studies (ie studies evaluating only the prognostic role of MDW), non-English studies and case reports and reviews.
  • Intervention: Monocyte distribution width (MDW)
  • Comparison: Sepsis-2 and Sepsis-3 diagnostic criteria. Sepsis-2 is based on systemic inflammatory response syndrome (SIRS) markers, while Sepsis-3 relies on organ dysfunction as assessed by the sequential organ failure assessment (SOFA) score​.
  • Outcome: Diagnostic accuracy of MDW for early sepsis detection, measured by pooled sensitivity, specificity, and likelihood ratios​.
  • Type of Study: Systematic review and meta-analysis for diagnostic accuracy

Authors’ Conclusions: “MDW represents a reliable biomarker for sepsis screening”.

Quality Checklist for Systematic Review Diagnostic Studies:

  1. The diagnostic question is clinically relevant with an established criterion standard. Yes
  2. The search for studies was detailed and exhaustive. No
  3. The methodological quality of primary studies were assessed for common forms of diagnostic research bias. No
  4. The assessment of studies were reproducible. No
  5. There was low heterogeneity for estimates of sensitivity or specificity. No
  6.  The summary diagnostic accuracy is sufficiently precise to improve upon existing clinical decision-making models. Unsure
  7. Funding and COIs: No research funding was declared and the authors reported no conflicts of interest.

Results: Ten studies were included in the SRMA with 9,475 patients.  There were 1,370 diagnosed with sepsis (742 using Sepsis-2 criteria and 628 with Sepsis-3).

Key Result: MDW showed reasonable diagnostic accuracy for detecting sepsis early but with wide confidence intervals and high heterogeneity.

  • Diagnostic Accuracy:
    • Sepsis 2: Pooled sensitivity and specificity of 78.9% and 77.7% (I29% and 99.3%)
    • Sepsis 3: Pooled sensitivity and specificity of 83.8% and 70.4% (I2 7% and 93.6%)
    • Sepsis 2: The positive LR for Sepsis-2 was 3.533, negative LR was 0.271
    • Sepsis-3, the positive LR was 2.833, negative LR was 0.230​.
    • Assuming a prevalence of 15% the PPV is ~34.2% and the NPV ~96.2%
    • Area under the curve (AUC) ranging from 0.625 to 0.964 across studies​.

1) Quality of Primary Studies: All ten studies were retrospective or prospective observational studies. These lack the randomization of experimental designs, so they are more susceptible to confounding factors. These are variables related to both the test result and the disease status, which may affect the observed association between test accuracy and outcomes, leading to biased results​.

2) PRISMA: They used the 2020 PRISMA guidelines, which cover all types of SRMAs. However, the PRISMA-DTA 2018 focuses specifically on diagnostic test accuracy reviews. This later guideline includes specific items like the clinical role of the index test (Item D1) and definitions for data extraction on target conditions, index tests, and reference standards. This is critical in DTA as it allows readers to understand the clinical context and diagnostic accuracy metrics uniquely associated with DTA studies​. Both versions address the risk of bias, but PRISMA-DTA 2018 goes further. It requires methods for assessing concerns unique to diagnostic testing that can bias test accuracy interpretations​.

3) Types of Bias in Diagnostic Studies

  • Selection Bias: Observational diagnostic studies may suffer from selection bias because the population being tested is often not randomly selected but rather chosen based on specific characteristics, symptoms, or clinician referrals. This can lead to a sample that doesn’t represent the general population, which affects the study’s external validity​​.
  • Verification Bias: Also known as “work-up bias,” this occurs when not all patients receive the same reference standard (usually a definitive test that confirms diagnosis), often because it’s invasive or costly. For example, patients with a positive initial test might undergo a more thorough evaluation than those with a negative test. This can skew sensitivity and specificity estimates since the true status of some patients remains unknown​.
  • Incorporation Bias: In some observational diagnostic studies, the index test itself is included in determining the disease status. This artificially inflates test performance because the test is “incorporated” into the reference standard rather than assessed independently​.
  • Copper Standard Bias: In diagnostic accuracy studies, a “copper standard” bias occurs when an imperfect test is used as a reference instead of an ideal “gold standard.” This leads to misclassification of disease status, influencing the perceived accuracy of the diagnostic test being studied. The copper standard is less reliable, often resulting in biased estimates of sensitivity and specificity—frequently inflating sensitivity and decreasing specificity or vice versa, depending on the test’s direction of error​​​. This bias underscores the importance of selecting a highly accurate reference standard whenever possible to ensure that diagnostic tests are evaluated against reliable criteria​​.

4) GIGO “Garbage-In, Garbage-Out“: We have discussed the concept of GIGO before on the SGEM. This is a principle from information science, which holds that the quality of output is directly dependent on the quality of the input. In the context of SRMAs, this means that the reliability and validity of the conclusions are heavily influenced by the quality of the studies included. If a review or meta-analysis incorporates studies with poor methodological quality, biases, or inconsistent definitions, the pooled results and overall findings may also be flawed, potentially leading to misleading clinical or scientific recommendations. This diagnostic accuracy study was limited to observational studies with multiple potential biases, significant heterogeneity and pooled metrics that lacked reliability, increasing our skepticism of the point estimates and lowering our confidence in the clinical utility of the findings.

5) Better than Gestalt? This one is for Dr. Justin Morgenstern from First10EM. In the case you provided it was clear that the person was sick, had pneumonia, needed fluid, antibiotics and needed to be admitted to the hospital. I’m not sure if having an MDW would have changed my management in any way. We see this with other diagnostic tests like BNP or pro-BNP for diagnosing congestive heart failure (CHF). It is usually obvious when someone does or does not have severe CHF exacerbation. What clinicians need help for is in the indeterminant cases, and will that have a net patient-oriented impact of benefit?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The authors concluded: “MDW represents a reliable biomarker for sepsis screening”. We would have a friendly amendment that says MDW represents a potentially reliable biomarker for sepsis screening.

SGEM Bottom Line: While MDW shows promise as a sepsis biomarker, it is premature to incorporate it into routine clinical practice.

Case Resolution: You quickly initiate broad-spectrum antibiotics (e.g., piperacillin-tazobactam and vancomycin), provide intravenous fluid resuscitation and admit him to the ICU due to hemodynamic instability and risk of septic shock.

Dr. Aaron Skolnik

Clinical Application: Physicians should approach the use of MDW as a sepsis biomarker with skepticism. The study suggests some potential utility for early identification of sepsis, but limitations such as moderate sensitivity and specificity, heterogeneity across studies, and the lack of external validation in diverse real-world settings indicate that MDW should not yet replace established diagnostic workflows. Its clinical utility is uncertain without robust validation demonstrating a consistent benefit in improving patient-oriented outcomes.

What Do I Tell the Patient? You have severe pneumonia and need to be admitted to the ICU. We are giving you a couple of types of antibiotics plus some IV fluids.

Keener Kontest: Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next episode.

Other FOAMed: We have covered the topic of sepsis many times on the SGEM.

  • SGEM#69: Cry Me A River (Early Goal-Directed Therapy) ProCESS Trial
  • SGEM#90: Hunting High and Low (Best MAP for Sepsis Patients)
  • SGEM#92: ARISE Up, ARISE Up (EGDT vs. Usual Care for Sepsis)
  • SGEM#113: EGDT – ProMISe(s) ProMISe(s)
  • SGEM#168: HYPRESS – Doesn’t Got the Power
  • SGEM#174: Don’t Believe the Hype – Vitamin C Cocktail for Sepsis
  • SGEM Xtra: Petition to Retire the Surviving Sepsis Campaign Guidelines
  • SGEM Xtra: Say What You Need to Say…but Don’t Say “Sepsis Screening”
  • SGEM#346: Sepsis – You Were Always on My Mind
  • SGEM#371: All My LOVIT, Vitamin C Won’t Work for You

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.