Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study, 2022

[SNT Gatchaman]

Nebivolol: an effective option against long-lasting dyspnoea following COVID-19 pneumonia - a pivotal double-blind, cross-over controlled study
Dal Negro RW, Turco P, Povero M

Background: Pulmonary microvascular occlusions can aggravate SARS-CoV-2 pneumonia and result in a variable decrease in capillary blood volume (Vc). Dyspnoea may persist for several weeks after hospital discharge in many patients who have "radiologically recovered" from COVID-19 pneumonia. Dyspnoea is frequently "unexplained" in these cases because abnormalities in lung vasculature are understudied. Furthermore, even when they are identified, therapeutic options are still lacking in clinical practice, with nitric oxide (NO) supplementation being used only for severe respiratory failure in the hospital setting. Nebivolol is the only selective β1 adrenoceptor antagonist capable of inducing nitric oxide-mediated vasodilation by stimulating endothelial NO synthase viaβ3 agonism. The purpose of this study was to compare the effect of nebivolol versus placebo in patients who had low Vc and complained of dyspnoea for several weeks after COVID-19 pneumonia.

Methods: Patients of both genders, aged ≥18 years, non-smokers, who had a CT scan that revealed no COVID-related parenchymal lesions but still complaining of dyspnoea 12-16 weeks after hospital discharge, were recruited. Spirometrical volumes, blood haemoglobin, SpO2, simultaneous diffusing capacity for carbon monoxide (CO) and NO (DLCO and DLNO, respectively), DLNO/DLCO ratio, Vc and exhaled NO (eNO) were measured together with their dyspnoea score (DS), heart frequency (HF), and blood arterial pressure (BAP). Data were collected before and one week after both placebo (P) and nebivolol (N) (2.5 mg od) double-blind cross-over administered at a two-week interval. Data were statistically compared, and p<0.05 assumed as statistically significant.

Results: Eight patients (3 males) were investigated. In baseline, their mean DS was 2.5±0.6 SD, despite the normality of lung volumes. DLCO and DLNO mean values were lower than predicted, while mean DLNO/DLCO ratio was higher. Mean Vc proved substantially reduced. Placebo did not modify any variable (all p=ns) while N improved DLco and Vc significantly (+8.5%, p<0.04 and +17.7%, p<0.003, respectively). eNO also was significantly increased (+17.6%, p<0.002). Only N lowered the dyspnoea score (-76%, p<0.001). Systolic and diastolic BAP were slightly lowered (-7.5%, p<0.02 and -5.1%, p<0.04, respectively), together with HF (-16.8%, p<0.03).

Conclusions: The simultaneous assessment of DLNO, DLCO, DLNO/DLCO ratio, and Vc confirmed that long-lasting dyspnoea is related to hidden abnormalities in the lung capillary vasculature. These abnormalities can persist even after the complete resolution of parenchymal lesions regardless of the normality of lung volumes. Nebivolol, but not placebo, improves DS and Vc significantly. The mechanism suggested is the NO-mediated vasodilation via the β3 adrenoceptor stimulation of endothelial NO synthase. This hypothesis is supported by the substantial increase of eNO only assessed after nebivolol. As the nebivolol tolerability in these post-COVID normotensive patients was very good, the therapeutic use of nebivolol against residual and symptomatic signs of long-COVID can be suggested in out-patients.

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[MeSci]

Interesting. I take 2.5 mg Nebivolol daily myself, having researched anti-hypertensives some years back when I was still capable of researching,

It's the only anti-hypertensive I've tried that doesn't have side-effects for me. It doesn't always/often reduce the systolic pressure all that well, but I've taken it for over 8 years and I tolerate it well.

 

[SNT Gatchaman]

Looking at patients who were hospitalised with Covid-related pneumonia. Discharged and deemed "recovered", despite ongoing dyspnoea (which the authors address). "Recovered" appears to be defined as resolution of radiologically demonstrable lung changes, eg on CT. (I hope findings relating to those in this paper ward off any "Functional Pulmonary Disorder" nonsense).

Dyspnoea is in fact complained by a considerable proportion of patients for several weeks after their "apparent recovery" from COVID-19 pneumonia. Unfortunately, though dyspnoea can affect daily activities persistently in these subjects, its underlying causes still are poorly investigated in clinical practice.

The crucial pathogenetic events [in COVID pneumonia] occurring in the lung are high local concentration of cytokines, chemokines and IgM-mediated immunocomplexes that induce a tremendous recruitment of inflammatory cells; diffuse damage at alveolar level; microvascular thrombosis and capillary occlusion at variable extent; activation of platelets and tissue factors further causing coagulation and micro-thrombosis.

Recently, the simultaneous assessment of DLCO and DLNO proved suitable and reliable for investigating the underlying causes of long-lasting dyspnoea in out-patients defined "recovered" from COVID-19 pneumonia, being the reduction of capillary blood flow assessed in these cases strictly related to their dyspnoea score, regardless of their normal lung volumes.

Out-patients aged ≥18 years previously defined “recovered” for COVID-19 pneumonia, but still complaining dyspnoea for 12-16 weeks after discharge were investigated

This was a double-blind cross-over study. All lung function parameters, together with the [Dyspnoa Score], [Heart Rate], [Systolic BP], [Diastolic BP] were collected before and after nebivolol 2.5 mg od, and before and after undistinguishable placebo, both randomly administered for one week, with a two-week interval in between.

 

[SNT Gatchaman]

Results seem quite impressive. Pre/post-P = placebo. Pre/post-N = nebivolol.
Mean +/- SD

HF = heart rate (frequency)
DLco = Lung diffusing capacity to carbon monoxide
DLno = Lung diffusing capacity to nitric oxide
Vc = Lung capillary volume
eNO = exhaled nitric oxide

 

[SNT Gatchaman]

The original hypothesis of the present study was the assumption that nebivolol, due to its peculiar mechanism of action, would provide an interesting opportunity for intervention against the COVID-induced alterations of lung capillary bed and related persisting dyspnoea, otherwise therapeutically “orphan”. On the other hand, nebivolol is the only selective β1 adrenoceptor antagonist that is capable to induce nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via β3 agonism and endothelium-dependent vasodilation mediated via the Larginine/NO pathway.

The vasodilatory mechanism of action strongly differentiates nebivolol from all other vasodilatory β-blockers (such as labetalol and carvedilol) that act via α1-receptor antagonism.

It was also documented that nebivolol is capable to provide anti-thrombotic, anti-platelet and anti-aggregation activity associated to its enhanced NO bioactivity. In particular, while endothelial-derived NO acts as a major vasodilator, cyclic guanosine monophosphate (cGMP) and protein kinase (PKG), that are its downstream effectors, are also provided with peculiar vasodilatative, anti-proliferative, anti-coagulant, and anti-inflammatory effects on pulmonary vasculature.

This therapeutic effect, assessed experimentally after a low dose (2.5 mg od) administered for a short period (one week) empirically decided, is supported by the basic pharmacology of nebivolol and confirms the original hypothesis of the study. In particular, the significant increase of the exhaled NO release at pulmonary level (eNO) assessed after nebivolol further confirms the therapeutic mechanism of action of this molecule at pulmonary level.

Moreover, it should be emphasized that the efficacy of nebivolol on pulmonary capillary blood volume proved strictly correlated to the drop in patients’ dyspnoea score. This outcome further confirms the relationship existing between the documented pulmonary capillary alterations and the persistence of dyspnoea, even in the absence of lung volume limitations in this kind of patients.

 

[RedFox]

This is the first completed blinded LC treatment trial I recall seeing. We're turning a corner here. 75% reduction in shortness of breath score? Wow.

8 people is too small to be "pivotal." But I believe it's a valuable study. We need a larger trial ASAP. With these impressive results, getting funding should be easy.

This raises interesting questions. Could other vasodilators help? Should people with LC and shortness of breath avoid vasoconstrictors like excessive caffeine?

 

[Trish]

I wonder whether this drug affects capillary blood flow in other parts of the body, eg in the brain, and possibly helping with Long Covid brain fog etc.

 

[SNT Gatchaman]

I wonder whether this drug affects capillary blood flow in other parts of the body, eg in the brain, and possibly helping with Long Covid brain fog etc.

We've had a few signals of microvascular impairment in LC, eg the HypXe MRI lung perfusion studies, the retinal microcirculation and sublingual capillary rarefaction. I hope some of those accessible body regions are amenable to testing whether this might have more widespread effect. Perhaps PET studies for the brain to complement functional tests?

 

[belbyr]

Does/could this apply at all to ME/CFS and/or POTS at all?

 

[RedFox]

I doubt it. It's for treating shortness of breath.

 

[SNT Gatchaman]

Does/could this apply at all to ME/CFS and/or POTS at all?

Only if something similar were happening as part of those diseases, eg part of downstream effects. Even if that were the case, I don't know if the mechanism of action of this drug could have helpful effects in non-pulmonary capillaries.

Investigators looking at LC are often coming from a "non-ME" angle - sometimes even completely oblivious to its existence. There's often biased thinking that COVID is a respiratory virus so ongoing symptoms may be assumed to relate to lung damage, esp if the symptom is breathlessness. The heart gets similar attention (eg a focus on myocarditis). However, while blinkered, this allows researchers that are thinking purely from a biological perspective to sidestep BPS and make observations. It's possible those observations may inform more widely, but maybe not.

A small point that I found interesting. Following standard bacterial pneumonia we typically see some radiological evidence for weeks and often there is minor scarring or pleural thickening years later, although it may be subtle. Covid pneumonia in these cases (viral, although secondary bacterial infections do occur, particularly if ventilated) had no residual abnormality. These patients weren't ventilated but did have significant changes acutely.

All patients suffered from COVID pneumonia originally affecting ≥50% of their lung volume (CT documented) and during their hospitalization they received high flow oxygen. At recruitment, patients had to provide a CT scan performed in the previous two weeks and showing the absence of any residual COVID-related parenchymal lesions.

This reinforces to me the idea that the pulmonary capillaries may be "ground zero". They're hard to see with imaging, but note the early thinking behind acute CT lung findings described here.