Clinical trial NCT05445531: Low-field Magnetic Resonance Imaging in Pediatric Post Covid-19
Official title: Low-field Magnetic Resonance Imaging to Assess Changes in Pulmonary Function Parameters in Confirmed Pediatric SARS-CoV-2 Infection
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: COVID-19
COVID-19 Respiratory Infection
Long COVID
Keywords: COVID-19
Long COVID
post COVID
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
First posted: 2022-07-06
Enrollment: 111
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: SARS-CoV-2 (Severe acute respiratory syndrome coronavirus type 2) is a new coronavirus and identified causative agent of COVID-19 disease. These viruses predominantly cause mild colds, but can sometimes cause severe pneumonia and pulmonary skeletal changes. By low-field gastric magnetic resonance imaging (NF-MRI), only a small number of structural, scarring changes were seen in a preliminary study of pediatric and adolescent patients with past SARS-CoV-2 infection. In contrast, however, extensive changes in ventilation and blood flow function of the lungs were seen.

The long-term consequences and spontaneous progression of these changes on imaging are completely unclear. The aim of this study is to assess the course of these functional lung changes in pediatric and adolescent patients and to validate them with other standard clinical procedures.

Detailed description: SARS-CoV-2 (Severe acute respiratory syndrome coronavirus type 2) is a new coronavirus and identified causative agent of COVID-19 disease. They predominantly cause mild colds but can sometimes cause severe pneumonia and pulmonary skeletal disease. While the molecular basis for the changes in lung tissue or multi-organ involvement have been described, the age-specific long-term consequences, especially in children and adolescents, remain largely unexplained and misunderstood today.

Early publications from the primarily affected Chinese provinces described rather mild, partly asymptomatic courses in children. This is consistent with the observation that the risk of severe COVID-19 disease increases steeply from the age of 70 years, and is also determined by the severity of obesity as well as other risk factors. Developmental expression of tissue factors may be one reason for the relative protection of younger patients from severe courses of the disease.

However, it is now becoming increasingly clear that some individuals with milder initial symptoms of COVID-19 may suffer from variable and persistent symptoms for many months after initial infection - this includes children. A modern low-field MRI is located in Erlangen, Germany. This technique has already been used to demonstrate persistent damage to lung tissue in adult patients after COVID-19. The device with a field strength of 0.55 Tesla (T) currently has the world's largest aperture (and is thus particularly suitable for patients with claustrophobia, among other things), a very quiet operating noise, and lower energy absorption in the tissue due to the weaker magnetic field than MRI scanners with 1.5T or 3T. This allows MRI imaging in a very broad pediatric population without the need for sedation.

To date, no structural changes were revealed by means of this MRI technique - however, large defects in the area of ventilation and blood flow function of the lung are apparent in specific functional sequences. The aim of this study is to assess the course of these functional lung changes in pediatric and adolescent patients and to validate them with other standard clinical procedures.

Eligibility criteria: Control arm:

Inclusion Criteria:

* Proof of SARS-CoV-2 infection and at least 2/3 times complete vaccination before infection (at least 14 days) (complete vaccination status according to German recommendations)
* Long Covid criteria not met according to AWMF S1 guideline

Exclusion Criteria:

* Acute SARS-CoV-2 infection and need for isolation
* Necessary quarantine
* Pregnancy, lactation
* Indication of acute infection
* Known pleural or pericardial effusion
* Critical condition (need for respiratory support, ventilation, oxygen administration, shock, symptomatic heart failure)
* Marked thoracic deformities
* Previous lung surgery
* Injuries that do not allow for physical stress testing
* Refusal of MRI imaging
* General contraindications to MRI examinations (e.g., electrical implants such as pacemakers or perfusion pumps, etc.)
* History, clinical, or other suspicion of pulmonary disease
* Current respiratory infection/symptomatology
* Pain leading to respiratory limitation
* Inhaled therapy (e.g., steroids or beta-mimetics)
* Immunosuppression
* Any condition that may lead to respiratory limitation (e.g., pain disorder)
* Obesity (\>97% of age percentile)

Recovered arm:

Inclusion Criteria:

* Positive SARS-CoV-2 infection confirmed by PCR
* Long Covid criteria not met according to AWMF S1 guideline

Exclusion Criteria:

* Acute SARS-CoV-2 infection and need for isolation
* Necessary quarantine
* Pregnancy, lactation
* Indication of acute infection
* Known pleural or pericardial effusion
* Critical condition (need for respiratory support, ventilation, oxygen administration, shock, symptomatic heart failure)
* Marked thoracic deformities
* Previous lung surgery
* Injuries that do not allow for physical stress testing
* Refusal of MRI imaging
* General contraindications to MRI examinations (e.g., electrical implants such as pacemakers or perfusion pumps, etc.)

Long Covid arm:

Inclusion Criteria:

* Positive SARS-CoV-2 infection confirmed by PCR
* Long Covid criteria according to AWMF S1 guideline fulfilled

Exclusion Criteria:

* Acute SARS-CoV-2 infection and need for isolation
* Necessary quarantine
* Pregnancy, lactation
* Indication of acute infection
* Known pleural or pericardial effusion
* Critical condition (need for respiratory support, ventilation, oxygen administration, shock, symptomatic heart failure)
* Marked thoracic deformities
* Previous lung surgery
* Injuries that do not allow for physical stress testing
* Refusal of MRI imaging
* General contraindications to MRI examinations (e.g., electrical implants such as pacemakers or perfusion pumps, etc.)

Primary outcomes:
measure: Functional lung assessment (LF-MRI)
timeFrame: Baseline compared to 6 months
Secondary outcomes:
measure: Morphologic lung assessment (LF-MRI)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (VO2)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (VO2max)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (VT2)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (VCO2)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (HR)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (HRR)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (Breath rate at VAT)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (BRR)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (VE)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (O2Pulse)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (HRV)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (Borg Scale)
timeFrame: Baseline compared to 6 months
measure: Cardiological functional diagnostics (BGA)
timeFrame: Baseline compared to 6 months
measure: Nailfold capillaroscopy (capillaries)
timeFrame: Baseline compared to 6 months
measure: Nailfold capillaroscopy (first row)
timeFrame: Baseline compared to 6 months
measure: Nailfold capillaroscopy (morphology)
timeFrame: Baseline compared to 6 months
measure: Blood sample (antibodies)
timeFrame: Baseline compared to 6 months
measure: Blood sample (auto antibodies)
timeFrame: Baseline compared to 6 months
measure: Blood sample (RT-DC)
timeFrame: Baseline compared to 6 months
measure: Blood sample (Blood count)
timeFrame: Baseline compared to 6 months
measure: Blood sample (IL-6)
timeFrame: Baseline compared to 6 months
measure: Blood sample (CrP)
timeFrame: Baseline compared to 6 months
measure: Blood sample (Calpro)
timeFrame: Baseline compared to 6 months
measure: Blood sample (Coagulation)
timeFrame: Baseline compared to 6 months
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Hospital Erlangen
state: Bavaria
Study officials:
affiliation: University Hospital Erlangen
name: Ferdinand Knieling, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sajuthi SP, DeFord P, Li Y, Jackson ND, Montgomery MT, Everman JL, Rios CL, Pruesse E, Nolin JD, Plender EG, Wechsler ME, Mak ACY, Eng C, Salazar S, Medina V, Wohlford EM, Huntsman S, Nickerson DA, Germer S, Zody MC, Abecasis G, Kang HM, Rice KM, Kumar R, Oh S, Rodriguez-Santana J, Burchard EG, Seibold MA. Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. Nat Commun. 2020 Oct 12;11(1):5139. doi: 10.1038/s41467-020-18781-2.
citation: Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, Feldman J, Muus C, Wadsworth MH 2nd, Kazer SW, Hughes TK, Doran B, Gatter GJ, Vukovic M, Taliaferro F, Mead BE, Guo Z, Wang JP, Gras D, Plaisant M, Ansari M, Angelidis I, Adler H, Sucre JMS, Taylor CJ, Lin B, Waghray A, Mitsialis V, Dwyer DF, Buchheit KM, Boyce JA, Barrett NA, Laidlaw TM, Carroll SL, Colonna L, Tkachev V, Peterson CW, Yu A, Zheng HB, Gideon HP, Winchell CG, Lin PL, Bingle CD, Snapper SB, Kropski JA, Theis FJ, Schiller HB, Zaragosi LE, Barbry P, Leslie A, Kiem HP, Flynn JL, Fortune SM, Berger B, Finberg RW, Kean LS, Garber M, Schmidt AG, Lingwood D, Shalek AK, Ordovas-Montanes J; HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org; HCA Lung Biological Network. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell. 2020 May 28;181(5):1016-1035.e19. doi: 10.1016/j.cell.2020.04.035. Epub 2020 Apr 27.
citation: Huang J, Hume AJ, Abo KM, Werder RB, Villacorta-Martin C, Alysandratos KD, Beermann ML, Simone-Roach C, Lindstrom-Vautrin J, Olejnik J, Suder EL, Bullitt E, Hinds A, Sharma A, Bosmann M, Wang R, Hawkins F, Burks EJ, Saeed M, Wilson AA, Muhlberger E, Kotton DN. SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response. Cell Stem Cell. 2020 Dec 3;27(6):962-973.e7. doi: 10.1016/j.stem.2020.09.013. Epub 2020 Sep 18.
citation: Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, Zheng M, Sundaram B, Banoth B, Malireddi RKS, Schreiner P, Neale G, Vogel P, Webby R, Jonsson CB, Kanneganti TD. Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell. 2021 Jan 7;184(1):149-168.e17. doi: 10.1016/j.cell.2020.11.025. Epub 2020 Nov 19.
citation: Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, Zhang W, Wang Y, Bao S, Li Y, Wu C, Liu H, Liu D, Shao J, Peng X, Yang Y, Liu Z, Xiang Y, Zhang F, Silva RM, Pinkerton KE, Shen K, Xiao H, Xu S, Wong GWK; Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 Infection in Children. N Engl J Med. 2020 Apr 23;382(17):1663-1665. doi: 10.1056/NEJMc2005073. Epub 2020 Mar 18. No abstract available.
citation: Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021 Jan;27(1):28-33. doi: 10.1038/s41591-020-01202-8. Epub 2021 Jan 13.
citation: Schuler BA, Habermann AC, Plosa EJ, Taylor CJ, Jetter C, Negretti NM, Kapp ME, Benjamin JT, Gulleman P, Nichols DS, Braunstein LZ, Hackett A, Koval M, Guttentag SH, Blackwell TS, Webber SA, Banovich NE; Vanderbilt COVID-19 Consortium Cohort; Human Cell Atlas Biological Network; Kropski JA, Sucre JM. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. J Clin Invest. 2021 Jan 4;131(1):e140766. doi: 10.1172/JCI140766.
citation: Heiss R, Grodzki DM, Horger W, Uder M, Nagel AM, Bickelhaupt S. High-performance low field MRI enables visualization of persistent pulmonary damage after COVID-19. Magn Reson Imaging. 2021 Feb;76:49-51. doi: 10.1016/j.mri.2020.11.004. Epub 2020 Nov 18.
citation: Shelmerdine SC, Lovrenski J, Caro-Dominguez P, Toso S; Collaborators of the European Society of Paediatric Radiology Cardiothoracic Imaging Taskforce. Coronavirus disease 2019 (COVID-19) in children: a systematic review of imaging findings. Pediatr Radiol. 2020 Aug;50(9):1217-1230. doi: 10.1007/s00247-020-04726-w. Epub 2020 Jun 18.
citation: Duan YN, Zhu YQ, Tang LL, Qin J. CT features of novel coronavirus pneumonia (COVID-19) in children. Eur Radiol. 2020 Aug;30(8):4427-4433. doi: 10.1007/s00330-020-06860-3. Epub 2020 Apr 14.
citation: Steinberger S, Lin B, Bernheim A, Chung M, Gao Y, Xie Z, Zhao T, Xia J, Mei X, Little BP. CT Features of Coronavirus Disease (COVID-19) in 30 Pediatric Patients. AJR Am J Roentgenol. 2020 Dec;215(6):1303-1311. doi: 10.2214/AJR.20.23145. Epub 2020 May 22.