Persistent fibroblast-related tissue activity in long COVID after moderate-to-severe acute COVID-19 assessed by [⁶⁸Ga]Ga-FAPI PET/CT, 2026, Hasan+

[Chandelier]

Persistent fibroblast-related tissue activity in long COVID after moderate-to-severe acute COVID-19 assessed by [⁶⁸Ga]Ga-FAPI PET/CT

Spoiler: Authors

Hasan, Ö.; Abidin, K.; Halil, Ö.; Didem, D.Z.; Burcu, Y.; Dilek, E.; Recai, E.; Baykal, T.; Orhan Önder, E.; Farise, Y.; Gonca, K.G.; Fikret, K.

Abstract​

Purpose​

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms. Fibroblast activation protein (FAP), expressed on activated fibroblasts during tissue remodeling, can be visualized with [⁶⁸Ga]Ga-FAPI PET/CT.
This study investigated lung and muscle fibroblastic activity in patients with post-acute sequelae of COVID-19 (PASC) following moderate-to-severe COVID-19 pneumonia more than two years after the acute infection, using [⁶⁸Ga]Ga-FAPI PET/CT.

Methods​

In this pilot prospective observational study, we enrolled patients with PASC following severe acute COVID-19 requiring high-flow nasal cannula or mechanical ventilation and age- and sex-matched controls without pulmonary pathology between September 2023 and February 2024.
PASC patients underwent high-resolution CT (HRCT), pulmonary function tests (PFTs), and [⁶⁸Ga]Ga-FAPI PET/CT.
SUVmax and SUVmean were measured for each lung lobe. HRCT abnormalities were scored using a semi-quantitative scale (0–20) and categorized as ground-glass opacities, reticulations, parenchymal bands, traction bronchiectasis, or subpleural cysts.
These findings were statistically compared and correlated with PET parameters, PFTs, and clinical symptoms.
In addition, [⁶⁸Ga]Ga-FAPI uptake in the paravertebral muscles was assessed at the level of the L3 vertebra.

Results​

Twenty patients with PASC and 10 control subjects were included (median ages: 64 and 58.5 years, respectively).
The mean interval between hospitalization for acute COVID-19 and study imaging was 25 ± 4.5 months. PASC patients exhibited significantly increased [⁶⁸Ga]Ga-FAPI uptake in the lungs compared with controls.
Lung [⁶⁸Ga]Ga-FAPI uptake was markedly increased in patients with traction bronchiectasis.
No correlations were observed between lung [⁶⁸Ga]Ga-FAPI SUVmax and PFTs or symptom burden.
However, lung [⁶⁸Ga]Ga-FAPI SUVmean demonstrated moderate inverse correlation with DLCO (r = -0.455, p = 0.044).
In addition, [⁶⁸Ga]Ga-FAPI SUVmax in muscle was significantly higher in PASC patients than in controls, with particularly elevated uptake observed in patients with a history of mechanical ventilation.

Conclusions​

[⁶⁸Ga]Ga-FAPI PET/CT demonstrated increased lung tracer uptake in patients with PASC more than two years after moderate to severe COVID-19, supporting persistent fibroblast-related tissue activity.
Limited associations between lung SUVmean and DLCO suggest a potential link between tracer uptake and functional impairment.
Increased muscle [⁶⁸Ga]Ga-FAPI uptake was also observed as an exploratory finding requiring further functional and histopathological validation.

Web | DOI | Revista Española de Medicina Nuclear e Imagen Molecular (English Edition) | Paywall

 

[V.R.T.]

Of possible interest- the variant of BTN2A1 found more in MECFS patients by Astrazeneca has an isoform that is highly expressed in fibroblasts

I plotted all available organs, specifically paying attention to the cerebellum and immune cell "tissues" (Whole Blood, Spleen, EBV-transformed lymphoblasts, cultured fibroblasts). While the two SPRY-containing isoforms (Q7KYR7-2 and Q7KYR7-5) had highest levels in the cerebellum, each was roughly matched by at least one immune tissue (fibroblasts and spleen, respectively). High expression in the arterial tissues matching cerebellar expression was also notable.

 

[DMissa]

Of possible interest- the variant of BTN2A1 found more in MECFS patients by Astrazeneca has an isoform that is highly expressed in fibroblasts

this is part of the reason the grant i just submitted will do side by side experiments on t cells and fibroblasts

 

[SNT Gatchaman]

See also 68GaFAPI PET/CT reveals increased pulmonary fibroblast activation protein expression in long COVID patients after ICU discharge (2025) —

Increased pulmonary FAP expression was observed in PASC, (TBR 0.79 ± 0.23) compared to controls (TBR 0.40 ± 0.13, P < 0.001). Increased FAP expression was also observed in the paravertebral muscles (PASC: TBR 1.17 and controls TBR 1.00, P = 0.03).

 

[SNT Gatchaman]

Selected quotes from introduction —

Fibroblast activation protein (FAP) is a cell surface serine protease that is selectively expressed on activated fibroblasts involved in tissue remodeling and fibrosis. ⁶⁸Galabeled FAP inhibitors (FAPI) have emerged as promising molecular imaging probes, enabling noninvasive visualization of fibrotic activity in various cancers.

In addition to pulmonary involvement, extrapulmonary manifestations of PASC, including myalgia, muscle weakness, and fatigue, are increasingly recognized [20-22].

Our threads for 20-22 are —

[20] Muscle abnormalities worsen after post-exertional malaise in long COVID (2024)

[21] Low Cardiorespiratory Fitness Post-COVID-19: A Narrative Review (2022)

[22] Plasma metabolomics reveals disrupted response and recovery following maximal exercise in myalgic encephalomyelitis/chronic fatigue syndrome (2023)

In this study, we aimed to assess persistent fibroblastic activity in the lungs and paravertebral muscles of patients with PASC using [⁶⁸Ga]Ga-FAPI PET/CT, approximately two years after the acute phase. By comparing PASC patients with age- and sex-matched controls, we sought to explore the potential of [⁶⁸Ga]Ga-FAPI imaging in detecting ongoing tissue remodeling.

 

[SNT Gatchaman]

Selected quotes from methods —

We conducted a pilot, prospective, single-center observational study involving patients with a history of moderate-to-severe COVID-19 pneumonia who required high-flow nasal cannula (HFNC) oxygen therapy or mechanical ventilation (MV) and who experienced persistent respiratory symptoms, including dyspnea, cough, or fatigue.

Interesting focus where fatigue is grouped as a respiratory symptom. Usually it's a neurological (or psychological) symptom.

Age- and sex-matched control subjects consisted of patients with histopathologically confirmed glioblastoma who had previously undergone [⁶⁸Ga]Ga-FAPI PET/CT as part of a previously published study conducted at our institution. None of the controls had known pulmonary disease, thoracic malignancy, pulmonary metastases, active pulmonary infection, thoracic surgery, or thoracic radiotherapy.

PFT parameters included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁); the FEV₁/FVC ratio was also calculated. Results were expressed as percentages of predicted values. The diffusion capacity of the lung for carbon monoxide (DLCO) was measured using the single-breath technique. […] All tests were conducted by the American Thoracic Society and European Respiratory Society guidelines [23,24].

A low-dose CT scan […] was performed for attenuation correction and anatomical localization. […] PET/CT images were interpreted by a nuclear medicine physician […] who was blinded to clinical symptoms and pulmonary function data. However, complete blinding to cohort assignment was not always possible, as postsurgical cranial findings in some control subjects could potentially be recognized on CT images.

For quantitative analysis, 2 cm spherical regions of interest (ROIs) were manually placed on axial PET images of each of the five lung lobes. The SUVmax and SUVmean for each lobe were recorded, and the mean of the five values was calculated to represent overall lung parenchymal uptake.

Since increased paravertebral muscle uptake was visually observed in PASC patients, we decided to quantitatively measure [⁶⁸Ga]Ga-FAPI SUVmax in the paravertebral muscle. SUVmax of the paravertebral muscles was measured bilaterally at the level of the L3 vertebra using 2 cm spherical ROIs. The average SUVmax values from both sides were recorded to represent paravertebral muscle uptake.

HRCT scans were acquired using the same PET/CT scanner. […] Current HRCT scans were performed on all PASC patients, while acute-phase HRCT images were retrieved from their medical records. HRCT at diagnosis and on the current scan were evaluated using a semiquantitative scoring system, where each of the five pulmonary lobes (three on the right, two on the left) was rated from 0 to 4 based on the extent of involvement: […]. Residual parenchymal abnormalities, such as GGOs [Ground Glass Opacities], reticulations, parenchymal bands, traction bronchiectasis, and subpleural cysts, were categorized.

I've clipped out the technical parameters but the HRCT [High Resolution CT] protocol is not as high resolution as we would typically do for lung evaluation, but is probably fine for this purpose (eg slice thickness of 3 mm vs 0.6 mm).

 

[SNT Gatchaman]

Selected quotes from results —

The study included 20 patients with PASC (10 male, 10 female) and 10 control patients (five male, five female) with extrapulmonary malignancies. The mean time following the acute phase of COVID-19 admission to the study visit was 25 ± 4.5 months. The median age was 64 years (range: 38–83) in the PASC group and 58.5 years (range: 42–71) in the control group.

Residual HRCT abnormalities were shown in all patients except one at follow-up. Residual score did not correlate with lung [⁶⁸Ga]Ga-FAPI SUVmax (r = 0.238, p = 0.311). GGOs were observed in 11 patients (55%), reticulations in 18 patients (90%), traction bronchiectasis in 6 patients (30%), and subpleural cysts in 3 patients (15%). Among the residual HRCT findings, only traction bronchiectasis was significantly associated with higher lung [⁶⁸Ga]Ga-FAPI uptake.

Most PASC patients (who had been hospitalised on high-flow O2 or intubated) had lung abnormalities on CT, but one just had some parenchymal bands and one was normal.

Lung [⁶⁸Ga]Ga-FAPI uptake was also significantly higher in patients who required MV during the acute phase

The paravertebral muscle [⁶⁸Ga]Ga-FAPI SUVmax was significantly higher in PASC patients compared to controls (median: 6.35 vs. 3.65; p < 0.001). Among the PASC group, those who received MV during the acute phase also exhibited higher paravertebral muscle [⁶⁸Ga]Ga-FAPI SUVmax (median: 7.60, IQR: 6.30-8.30) compared to those managed with HFNC (median: 5.80, IQR: 3.10-10.90) (p = 0.042).

 

[SNT Gatchaman]

Selected quotes from discussion —

FAPI uptake observed in this study suggests persistent fibroblast-related tissue activity in patients with PASC. An important finding of the present study was the lack of consistent correlations between lung [⁶⁸Ga]Ga-FAPI uptake and clinical or functional parameters.

Because DLCO is a sensitive indicator of diffuse alveolar-capillary dysfunction, the observed association with SUVmean may suggest that diffuse lung [⁶⁸Ga]Ga-FAPI activity is more closely related to impaired gas exchange than focal uptake measures such as SUVmax.

Overall, lung [⁶⁸Ga]Ga-FAPI PET/CT should currently be regarded primarily as a biological imaging biomarker reflecting fibroinflammatory activity rather than a direct surrogate of symptom burden or functional impairment in PASC.

Increased muscle [⁶⁸Ga]Ga-FAPI uptake was observed in patients with PASC, particularly in those who required MV during the acute phase. These findings should be interpreted cautiously […] Although increased uptake may reflect fibroblast-related remodeling activity, alternative explanations, including prolonged immobilization, deconditioning, critical illness myopathy, ventilator-associated muscle injury, systemic inflammation, or cancer-related sarcopenia in controls, should also be considered.

(but)

Collectively, these observations suggest that molecular imaging may help further investigate musculoskeletal abnormalities associated with PASC.

Some of the listed limitations —

The absence of a matched post-COVID cohort without persistent symptoms also limits the interpretation of symptom-specific associations. Finally, there is currently no standardized method for quantifying lung [⁶⁸Ga]Ga-FAPI uptake, and skeletal muscle analysis was exploratory without dedicated functional assessments.