Local and systemic responses to SARS-CoV-2 infection in children and adults.

It is not fully understood why COVID-19 is typically milder in children1-3. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children

Demographics, smoking history and SSc subtype and serology.

<p>NA- not assessed/available</p><p>lcSSc- limited cutaneous systemic sclerosis</p><p>dcSSc- diffuse cutaneous systemic sclerosis</p><p>SSc/PPM- Systemic sclerosis and polymyositis overlap</p><p>ACA- anticentromere antibody</p><p>SCL-70- anti-SCL 70 antibody</p><p>RNA Pol- anti-RNA polymerase III antibody</p><p>* SCL-70 not assessed</p><p>Demographics, smoking history and SSc subtype and serology.</p

Pulmonary function testing and Computed Tomography findings.

<p>*Total lung capacity, in all other cases FVC and TLC were similar</p><p>NSIP- non-specific interstitial pneumonia</p><p>UIP- usual interstitial pneumonia</p><p>Fib nos- fibrosis not otherwise specified</p><p>EMPHY- emphysema</p><p>NA- not assessed/available</p><p>Pulmonary function testing and Computed Tomography findings.</p

Computed Tomography showing (A) a left upper lobe lung mass with UIP basilar predominant fibrosis and (B) a left lower lobe consolidation (lung cancer) with NSIP.

<p>Computed Tomography showing (A) a left upper lobe lung mass with UIP basilar predominant fibrosis and (B) a left lower lobe consolidation (lung cancer) with NSIP.</p

Tumor characteristics and prognosis.

<p>NA- not assessed/available</p><p>WT: wild type</p><p>Tumor characteristics and prognosis.</p

Sections from the tumor of one of the patients with hematoxylin and eosin staining shows infiltrating tumor glands with acinar, lepidic and focal papillary features with surrounding areas of dense fibrosis and scattered chronic inflammation (A).

<p>These tumor cells stain positive with TTF-1 (B).</p

Left Heart Parameters by COPD Severity.

<p>LV; left ventricular, LA; left atrial.</p><p>*ANOVA comparing mild, moderate, moderately severe.</p

Comparison of Diastolic Function.

<p>BMI; body mass index, FVC; forced vital capacity, FEV1; forced expiratory volume in one second, Ratio; FEV1/FVC ratio, TLC; total lung capacity, RV; residual volume, DLCO; diffusion capacity of carbon monoxide, O2; oxygen.</p

Right Heart Parameters by COPD Severity.

<p>RV; right ventricular, TR; tricuspid regurgitant jet peak velocity, PASP; pulmonary artery systolic pressure, TAPSE; tricuspid annular plane systolic excursion.</p><p>*ANOVA comparing mild, moderate, moderately severe.</p