Microcirculatory impairment and increased arterial stiffness in pediatric Long COVID patients, 2026, Boever et al.

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Microcirculatory impairment and increased arterial stiffness in pediatric Long COVID patients

Spoiler: Authors

Boever, Julie; Jakob, André; Paetzold, Clara; Gomes, Delphina; Birzele, Lena T; Baalmann, Katrin; Haas, Nikolaus A; Nussbaum, Claudia

PURPOSE
The exact pathogenesis of Long COVID remains unclear. Microvascular and endothelial dysfunction, established contributors to SARS-CoV-2-related conditions, appear to play a role in pediatric Long COVID.

METHODS
At the Childrens University Hospital of LMU Munich, we conducted a comparative cohort study including pediatric Long COVID patients. Microcirculation was assessed using sublingual sidestream dark field (SDF) imaging, analyzing the microvascular flow index (MFI), the total vessel density (TVD), and the proportion of perfused vessels (PPV). Endothelial function and arterial stiffness were evaluated using peripheral arterial tonometry (EndoPAT), measuring reactive hyperemia index (RHI) and augmentation index (AIx@75).

RESULTS
We analyzed 37 pediatric Long COVID patients (13.5 ± 2.6 years; 22 females) with persisting symptoms (> 4 weeks) and 46 healthy controls (12.4 ± 4.8 years; 21 females). Patients exhibited significant microcirculatory alterations, with reduced MFI (2.59 [IQR, 2.38–2.75] vs. 2.83 [IQR, 2.69–2.96]; p = .003), TVD (16.12 [IQR, 15.24–17.86] mm/mm2 vs. 19.38 [IQR, 17.58–20.57] mm/mm2; p < .001), and PPV (13.58 [IQR, 12.72–14.89]% vs. 17.67 [IQR, 16.60–19.32]%; p < .001). Microcirculatory changes varied with clinical phenotype and were most pronounced in patients presenting with dyspnea.We analyzed 37 pediatric Long COVID patients (13.5 ± 2.6 years; 22 females) with persisting symptoms (> 4 weeks) and 46 healthy controls (12.4 ± 4.8 years; 21 females). Patients exhibited significant microcirculatory alterations, with reduced MFI (2.59 [IQR, 2.38–2.75] vs. 2.83 [IQR, 2.69–2.96]; p = .003), TVD (16.12 [IQR, 15.24–17.86] mm/mm2 vs. 19.38 [IQR, 17.58–20.57] mm/mm2; p < .001), and PPV (13.58 [IQR, 12.72–14.89]% vs. 17.67 [IQR, 16.60–19.32]%; p < .001). Microcirculatory changes varied with clinical phenotype and were most pronounced in patients presenting with dyspnea.

CONCLUSION
We demonstrate measurable vascular alterations in pediatric Long COVID, including microvessel reduction and increased arterial stiffness. Our findings support a role of vascular changes in Long COVID and highlight the importance of integrating cardiovascular monitoring and follow-up into the management of affected children.

WHAT IS KNOWN
• Microvascular and endothelial dysfunction appear to play a role in SARS-CoV-2-related diseases.

• Adults with Long COVID show persistent capillary rarefaction and endothelial impairment supporting a vascular mechanism underlying ongoing symptoms.

WHAT IS NEW
• Pediatric Long COVID is likewise associated with significant microvascular damage and furthermore with increased arterial stiffness.

• Children with dyspnea exhibit a distinct vascular phenotype characterized by marked capillary loss, indicating a potential microvascular origin of persistent respiratory symptoms.

Web | DOI | PDF | European Journal of Pediatrics | Open Access

 

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Limitations —

First, the major limitation is the small study population caused by the rarity of diagnosed Long COVID cases in pediatric patients.

Second, the control group consists of historical controls recruited prior to the COVID-19 pandemic […] the use of historical controls may introduce temporal confounding and secular trends related to changes in environmental factors, health behaviors, or examination conditions over time. Sensitivity analyses […] as well as comparison with a small subgroup of contemporaneously examined controls, yielded consistent results.

Third, the study may be subject to survivor bias and referral bias, as participants were recruited from our specialized Long COVID clinic. […] In addition, the study population consisted predominantly of adolescents […] limiting the generalizability of the findings to younger children.

Physical activity levels and cardiorespiratory fitness were not quantitatively assessed […] Reduced physical activity and exercise intolerance […] may independently impair endothelial function and increase arterial stiffness, which should be considered when interpreting the findings.

Lastly, it would be of great interest to compare microvascular function and arterial stiffness in children with Long COVID to those who […] did not develop persistent symptoms […] remains unclear whether the observed microvascular alterations are specifically associated with Long COVID or represent a general consequence of SARS-CoV-2 infection.

 

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AIx@75 Augmentation index normalized to a heart rate of 75 bpm
MFI Microvascular flow index
OCT Optical coherence tomography
PAT Peripheral arterial tonometry
PPV Proportion of perfused vessels
RHI Reactive hyperemia index
TVD Total vessel density

Long COVID patients and healthy controls were examined using the same SDF imaging system and the same EndoPAT device under identical conditions.

Children with serological evidence of a SARS-CoV-2 infection and a diagnosis of Long COVID according to NICE criteria, presenting with persisting symptoms for more than 4 weeks after confirmed infection, were eligible

we used a control group that had been evaluated prior to the pandemic between February 2018 and April 2019 […] consisted of healthy children with a standardized clinical workup including uneventful clinical examination and no history of infectious diseases within the past 3 weeks

The sublingual microcirculation was visualized using a handheld video microscope with sidestream dark field (SDF) imaging technology. This microscope camera has an outer ring of greenlight-emitting diodes in the absorption maximum of hemoglobin (wavelength 530 nm) resulting in dark appearing vessels. The light penetrates the tissue and is reflected from deeper layers, enabling the transillumination of superficial layers.

Using the Automated Vascular Analysis program, we assessed total vessel density (TVD; mm/mm 2 ), microvascular flow index (MFI; 0 = no flow, 1 = intermittent, 2 = sluggish, 3 = continuous flow), proportion of perfused vessels (PPV; %), and vessel diameter distribution (%).

Small vessels were defined as vessels with a diameter < 10 μm, medium vessels from ≥ 10 to < 25 μm, and large vessels ≥ 25 μm.

 

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The plethysmography EndoPAT device was used to evaluate endothelial function and arterial stiffness by measurement of the reactive hyperemia index (RHI) and the augmentation index normalized to a heart rate of 75 beats per minute (AIx@75, %), respectively. The feasibility and reproducibility of this method in adolescents have been demonstrated previously.

The examination consisted of 5 min baseline measurement pre-occlusion, 5 min arterial occlusion, and 5 min post-occlusion. Arterial occlusion was induced by inflating a blood pressure cuff placed around the upper arm to 60 mmHg above systolic pressure (max. 200 mmHg). Deflating the cuff leads to reactive hyperemia by arterial vasodilatation, which reflects local bioavailability of endothelial NO and represents a surrogate for endothelial function. The contralateral arm served as control to account for non-specific changes in vascular tone.

 

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We recruited 37 (22 female) patients with Long COVID at a mean of 206 ± 167 days following a positive SARSCoV-2 test result. For the control group, we utilized data from 46 healthy children (21 female), who were part of a cohort examined in 2018.

So patients were 59% female, controls 46% female.

The most frequently reported symptoms included headache (25 patients, 68%), reduced endurance (20 patients, 54%), fatigue (16 patients, 43%), and dyspnea (14 patients, 38%). Laboratory findings of the Long COVID cohort at the time of investigation are […] no significant abnormalities were detected, and in particular, inflammatory markers were not elevated.

Long COVID patients differed significantly in microcirculatory parameters compared to healthy children, including significantly reduced MFI and TVD throughout the examined vessels, which in combination resulted in a generally lower PPV. […] remained highly significant when adjusting for known confounders such as age, BMI, blood pressure, and sex.

our microcirculatory measurements revealed redistributed vessels in Long COVID patients with small-vessel rarefication, i.e., capillaries. […] medium-sized vessels and large vessels displayed a relative increase.

we observed a significantly increased augmentation index (AIx@75) as a measure of arterial stiffness

To ensure that differences between the treatment group and the historic controls were not driven by time-related effects, we compared the historic control values with contemporary controls measured using the same protocol.

 

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we visualized clinical and experimental data together in a correlation matrix […] Notably, the symptom of dyspnea exhibited a divergent pattern compared to the other symptoms, showing an inverse correlation with small-vessel density and PPV small vessels. […] when we stratified data from the Long COVID group by the presence of major symptom, patients with dyspnea demonstrated a further reduction in density of small vessels and an additional reduction in capillary density.

Microvascular flow patterns and arterial stiffness, however, showed no significant differences related to the presence of dyspnea. Similarly, other symptoms, including headache, reduced endurance, fatigue, and dizziness, did not exhibit a significant impact on these vascular parameters.

PCA scatterplot […] indicating that Long COVID patients exhibit distinct microcirculatory phenotypes. PC1 was primarily driven by the PPV small (16.7%) and the TVD small (15.5%), while PC2 was mostly influenced by the MFI (38%).

when including only patients with dyspnea as a symptom in the PCA alongside controls […] finding suggests that dyspnea is associated with a more distinct microcirculatory phenotype […] potentially reflecting consistent and specific pathophysiological changes within this subgroup.

 

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