We’ve Been Measuring the Wrong Thing — and the Lungs Have Been Signaling It All Along

Here is an uncomfortable but well-supported reality: for decades, respiratory disease has been managed primarily through episodic measurements of lung mechanics and structure, even though the underlying diseases are driven by biological and metabolic processes that evolve continuously.

As a result, nearly 500 million people worldwide living with chronic respiratory disease are typically diagnosed or stratified only after substantial and often irreversible lung injury has already occurred.

This gap is not due to a lack of clinical expertise or therapeutic effort.

It reflects a limitation in what we have chosen to measure.

The Core Limitation of Current Respiratory Diagnostics

Spirometry, imaging, and symptom-based assessment remain foundational tools in respiratory medicine. They are valuable, standardized, and clinically familiar.

However, they share a common constraint: They primarily detect functional or structural consequences of disease, rather than the biological processes driving disease progression.

Small-airways dysfunction, early fibrotic remodelling, inflammatory signalling, oxidative stress, and infection-related metabolic changes can all be active well before abnormalities become apparent on pulmonary function testing or imaging. By the time such changes are detected, disease trajectories are often already established.

This limitation has been widely acknowledged in conditions such as idiopathic pulmonary fibrosis, interstitial lung disease, lung cancer, and postoperative or ventilator-associated pneumonia.

A Complementary Approach: Molecular Measurement from Exhaled Breath

Exhaled human breath contains thousands of volatile organic compounds (VOCs) that originate from endogenous metabolic processes, host inflammatory responses, oxidative stress, and interactions with pathogens. Among these, carbonyl compounds (aldehydes and ketones) have been repeatedly associated with lung disease biology.

At Breath Diagnostics, our patented OneBreath platform enables a fundamentally different type of measurement:

• Carbonyl VOCs are selectively and covalently captured from exhaled breath using aminooxy chemistry.
• The captured compounds are chemically defined and quantitatively measured using high-resolution mass spectrometry.
• This approach yields molecular-level data that reflect ongoing biological processes in the lung, rather than downstream functional impairment.

Importantly, this is not a sensor or pattern-only approach.

The assay begins with specific chemical capture of defined analytes, followed by quantitative analysis. Statistical or machine-learning models may then be applied for classification or stratification, but they operate on measured molecular inputs rather than raw signal patterns.

Idiopathic Pulmonary Fibrosis: A Case Study

Idiopathic pulmonary fibrosis (IPF) illustrates why this molecular perspective matters.

IPF is characterized by:

• Heterogeneous disease trajectories
• Poor correlation between symptoms, imaging, and outcomes
• Reliance on forced vital capacity (FVC) decline as a surrogate endpoint, despite ongoing debate about its relationship to underlying biology

In a peer-reviewed proof-of-concept clinical study, exhaled breath carbonyl compounds captured using the microreactor process were evaluated in patients with IPF and connective-tissue–related ILD.

Key findings included:

• Breath carbonyl profiles differentiated IPF from CTD-ILD with a mean AUROC of approximately 0.88 in validation subsets.
• The same molecular data enabled classification of disease severity based on pulmonary function groupings (DLCO, FVC, FEV₁), with AUROCs ranging from approximately 0.82 to 0.90 depending on the endpoint.
• A subset of 11 carbonyl VOCs carried most of the discriminatory signal for diagnosis and severity classification.

These findings are significant not because they replace pulmonary function testing, but because they demonstrate that exhaled molecular signatures can be quantitatively linked to disease presence and functional impairment, offering insight into the biological processes underlying fibrosis.

The study was explicitly framed as proof-of-concept, and further longitudinal and prospective validation is required. Nonetheless, it provides strong evidence that breath-based molecular measurements can complement existing clinical tools in fibrotic lung disease.

Evidence Across Multiple Respiratory Conditions

Beyond IPF, the same microreactor-based carbonyl capture and analysis approach has been reported in peer-reviewed clinical studies involving:

• Lung cancer detection and discrimination from benign pulmonary disease, including early-stage disease
• Postoperative and ventilator-associated pneumonia, including diagnostic and predictive modeling
• COVID-19 and other infectious respiratory diseases
• Post-resection surveillance and normalization of disease-associated breath markers

Across these studies, a consistent observation emerges: specific carbonyl compounds in breath reflect disease-associated metabolic and inflammatory processes and can be measured non-invasively with molecular specificity.

These results do not imply universal early detection across all diseases or patient populations. They do, however, demonstrate that breath carbonyl analysis is a generalizable analytical platform capable of capturing biologically meaningful information across diverse respiratory pathologies.

Why This Matters for Drug Development and Clinical Trials

From a drug development perspective, respiratory trials frequently struggle with:

• Late patient enrollment
• Heterogeneous disease biology within enrollment criteria
• Endpoints that change slowly and variably

Quantitative breath-based molecular measurements offer a potential complement by enabling:

• Improved biological stratification prior to randomization
• Assessment of disease-associated metabolic activity alongside functional endpoints
• Earlier signals of biological response or non-response in some settings

In diseases such as IPF, where therapeutic mechanisms often target fibrotic or inflammatory pathways, molecular readouts related to oxidative stress and tissue injury may provide additional context to traditional physiologic measures.

Our OneBreath platform integrates seamlessly into standard clinical workflows and requires only a single exhaled breath sample from the patient.

Because the workflow is simple and the assay relies on single-use consumables, the platform supports a cost-effective deployment model appropriate for routine clinical settings

Regulatory Perspective: Why This Approach Is Interpretable

From a regulatory standpoint, this class of assay has several attributes that are well aligned with established diagnostic evaluation frameworks:

• Defined analytes with known chemical structures
• Quantitative outputs with internal standards and quality controls
• Provides independent, orthogonal molecular qualifiers alongside imaging and physiologic measurements, enabling greater confidence in identifying the underlying disease processes driving observed clinical findings.
• Clear traceability from sample to result

For this reason, the OneBreath technology is best described as a molecular diagnostic assay that uses breath as the sample matrix, rather than as a consumer breath test attempting to become diagnostic.

That distinction is critical for analytical validation, clinical validation, and regulatory review.

The Bottom Line

Respiratory diseases are driven by biology long before they are expressed as airflow limitation or radiographic change.

Our patented OneBreath platform enables direct measurement of disease-associated molecular products from exhaled breath, offering a non-invasive window into processes such as oxidative stress, inflammation, infection, and fibrosis.

The IPF study and related clinical work demonstrate that this approach is not theoretical. It has already shown the ability to classify disease presence and severity in real patient populations, using chemically specific and quantitative measurements.

This does not necessarily replace spirometry, imaging, or clinical judgment.

It complements them — by measuring what is happening, not only what has already happened.

The remaining question is not whether breath-based molecular diagnostics have clinical relevance.

It is how deliberately and rigorously they are integrated into respiratory medicine and drug development moving forward — a responsibility our team at Breath Diagnostics takes seriously as we work to translate this science into clinical practice.