Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.

The effect of omalizumab on ventilation and perfusion in adults with allergic asthma.

Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.