Core Areas of Contribution

Sepsis & Hyperinflammation

In the pivotal 2022 paper “Chasing the Ghost: Hyperinflammation Does Not Cause Sepsis,” Dr. Shapiro and collaborators attacked the “cytokine storm” paradigm — highlighting the unappreciated facts that decades of anti-inflammatory trials failed, cytokine levels in sepsis are insufficient to cause damage, and the paradigm persists despite contradictory evidence (ResearchGate, Frontiers). Their work calls for abandoning this inadequate theory and redirecting efforts toward a more coherent framework of sepsis pathogenesis.

COVID-19 Diagnostics & Treatment Analysis

Building on the sepsis work, Dr. Shapiro has critically examined COVID-19 treatment strategies. He co-authored studies on empiric therapies in 2020, including questioning IL-6 blockade (Frontiers). Dr. Shapiro and colleagues published a detailed analysis of the premature acceptance of Interleukin-1 blockade as a COVID-19 treatment. Bold predictions offered in this paper are proving correct. Their analyses cautioned that anti-inflammatory approaches for COVID-19 were “destined to fail” (som.cuanschutz.edu).

Notably, in 2021, Dr. Shapiro led the development of a practical diagnostic tool using the ferritin-to-procalcitonin (F/P) ratio to distinguish COVID-19 pneumonia from bacterial pneumonia — showing that a F/P threshold provided significant diagnostic accuracy (PMC). A theoretical approach to constructing this biomarker tool represents an approach designed to circumvent the looming reproducibility crisis generated by the indiscriminate combination of big data and superfast computer analyses.

Underlying Philosophy

Dr. Shapiro’s work is unified by a thorough reassessment of the role of hyperinflammation in infectious diseases. He convincingly argues that the “cytokine storm” model is conceptually flawed and therapeutically unproductive — an unexorcisable ghost that hinders progress. His contributions push the field toward a novel paradigm that explains disease without resorting to inconsistent or paradoxical inflammatory concepts.

Selected Notable Publications

Peer-reviewed work supported by the Foundation

  1. 01

    Chasing the Ghost: Hyperinflammation Does Not Cause Sepsis

    Shapiro L, et al. · Frontiers in Pharmacology, 2022

    A pivotal paper that dismantled the "cytokine storm" paradigm — demonstrating that decades of anti-inflammatory trials failed and calling for abandoning this unfalsifiable theory.

  2. 02

    A Theory-Based Ferritin-Procalcitonin Ratio Differentiates COVID-19 Pneumonia vs Bacterial Pneumonia

    Gharamti AA, Scherger SJ, Shapiro L, et al. · Open Forum Infectious Diseases, 2021

    Development of a practical diagnostic tool using the ferritin-to-procalcitonin (F/P) ratio to distinguish COVID-19 pneumonia from bacterial pneumonia — showing that an F/P threshold ≥ 1250 significantly improved diagnostic accuracy.

  3. 03

    Anakinra authorized to treat severe COVID-19; Sepsis breakthrough or time to reflect?

    Shapiro L, Scherger S, Franco-Paredes C, Henao-Martínez AF · Clinical Microbiology and Infection, 2023

    Exploring the weak case for IL-1 blockade in COVID-19 treatment, building on the sepsis work to examine COVID-19 treatment strategies.

  4. 04

    Proinflammatory cytokines levels in sepsis and healthy volunteers, and TNF-alpha associated sepsis mortality: A systematic review and meta-analysis

    Shapiro L, et al. · Cytokine, 2020

    Meta-analysis showing elevated TNF-α levels in sepsis but highlighting that anti-TNF therapies have not improved mortality.

  5. 05

    Circulating TNFα Levels in Rheumatoid Arthritis Versus Sepsis: A Systematic Review

    Shapiro L, et al. · Rheumatology International, 2021

    Compares TNF-α levels in rheumatoid arthritis and sepsis to evaluate implications for anti-TNF therapy.

  6. 06

    Adjunct corticosteroids for non-HIV infected patients with severe Pneumocystis jirovecii pneumonia

    Shapiro L, et al. · Respirology, 2019

    Study finding that adjunctive corticosteroid therapy was associated with lower mortality in non-HIV Pneumocystis jirovecii pneumonia.

  7. 07

    Glucocorticoids as a risk factor for infection and adverse outcomes in non-HIV and non-transplant patients with cryptococcal meningitis

    Shapiro L, et al. · Medical Mycology, 2019

    Shows prior glucocorticoid exposure worsens outcomes in non-HIV cryptococcal meningitis.

  8. 08

    Diabetes Mellitus Type 2 as a Risk Factor and Outcome Modifier for Cryptococcosis in HIV Negative, Non-transplant Patients, a Propensity Score Match Analysis

    Shapiro L, et al. · Open Forum Infectious Diseases, 2019

    Type 2 diabetes increases incidence and severity of cryptococcosis in non-HIV, non-transplant patients.

  9. 09

    Rethinking interleukin-6 blockade for treatment of COVID-19

    Shapiro L, et al. · Medical Hypotheses, 2020

    Reviews IL-6 inhibitors in COVID-19 and their potential downsides due to IL-6's dual roles.

  10. 10

    Previous corticosteroid exposure associates with increased Pneumocystis jirovecii pneumonia mortality among HIV-negative patients

    Shapiro L, et al. · Respirology, 2020

    A global research network with a follow-up multicenter case-control study demonstrating that prior corticosteroid use significantly increases mortality in HIV-negative PJP patients.

Next Steps

A radically new theoretical framework, currently under construction.

Dr. Shapiro’s team is currently completing a new theoretical framework for infectious disease that may replace decades of failed research and entrenched inconsistencies that plague current inflammation-based concepts. If validated, the paradigm shift they are working on could redefine clinical practice and redirect scientific research.

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