Tibialis Anterior Tendon Reconstruction Utilizing Split Tendon Turn-down: A Case Report and Technique Guide.

Tibialis anterior tendon (TAT) ruptures are rare, equating to less than 1% of all musculotendinous injuries. These injuries can be acute or atraumatic, with the latter often associated with chronic degenerative tendinopathy. Surgical repair is indicated when conservative measures fail in meeting functional demands. Direct end-to-end repair is the preferred method for TAT ruptures but may not be feasible with a large tendon defect. Various surgical techniques have been described to address this pathology, including allograft tendon interposition or extensor hallucis longus (EHL) transfer. The authors present a unique technique utilizing a minimal incision TAT turn-down with dermal matrix allograft augmentation, and, in addition, a case implementing this technique in a patient with a large insertional defect. The patient's postoperative course and outcomes were favorable, with improvements in pain, satisfaction, functional scores, and strength. The surgical technique offers versatility and can be adapted to different tendon defect sizes. It also allows for minimal-incision exposure, beneficial for patients with comorbidities or compromised skin integrity. In conclusion, the authors present a case report and surgical technique for the management of large-deficit, chronic TAT ruptures using split TAT turn-down. This technique provides a potential solution for cases where direct end-to-end repair is not feasible.Level of Evidence: Level V.

Parallax and Distortion in Fluoroscopy Units.

BACKGROUND: Parallax is an imaging phenomenon where an object appears to be at different positions when viewed from different angles. Distortion can occur secondary to internal fluoroscopic, or external environmental, factors. Fluoroscopy is a vital tool to assist surgeons intraoperatively. However, parallax and distortion can lead to inaccuracy, potentially leading to incorrect surgical decisions. The purpose of this study was to investigate the prevalence of parallax/distortion in large fluoroscopy units at a level-1 trauma center. METHODS: Two types of C-arm models were evaluated, including (1) round image intensifiers, and (2) flat plate detectors (FPD). A square plexiglass grid with embedded wire at ½-in intervals was created, with a round metal washer secured centrally. The grid was placed 16 in from the image intensifier. A metal ball bearing (BB) was secured to the center of the x-ray tube. Fluoroscopic images were obtained until the BB and washer were "center-center." A straight blade served as a fiducial marker to ensure there was no off-axis angulation. Standard anterior-posterior and lateral views were obtained. External factors were considered, tested, and limited. Images were printed and the patterns of parallax/distortion were identified. RESULTS: All 11/11 (100%) of fluoroscopy units had some degree of parallax and/or distortion. We noted 3 different patterns, including sigmoidal, converging, and diverging. The FPD units had less apparent distortion overall; however, two-thirds (66%) were off-axis in the x- and y-axes in relation to the fiducial marker. CONCLUSION: All fluoroscopy units had varying degrees and patterns of parallax/distortion. We noted less overall distortion in FPDs. However, some of these units may produce images that are off-axis. This research has important implications for improving the accuracy of intraoperative fluoroscopy. Musculoskeletal surgeons should understand the limitations of fluoroscopy and how to combat parallax distortion to improve surgical outcomes and reduce patient morbidity. LEVEL OF EVIDENCE: Level V.

Defining the Structures at Risk and an Anatomical Safe Zone for Percutaneous Antegrade Subtalar Joint Fixation With a Single Screw: A Cadaveric Study.

Percutaneous antegrade (anterior to posterior) fixation for subtalar joint (STJ) arthrodesis offers various intraoperative and biomechanical advantages. Currently, the entry point for percutaneous antegrade STJ screw fixation is not clearly described and variable. To our knowledge, there are no publications that evaluate anatomic structures at risk or define an anatomically safe entry point for this fixation. The aim of this investigation was to define an anatomically safe and reproducible entry point for percutaneous antegrade STJ arthrodesis fixation, while also describing anatomic structures at risk when undertaking this method of fixation. We hypothesized that percutaneous single screw antegrade STJ fixation would encroach upon named anatomic structures in more than one cadaveric specimen. Ten cadaver limbs were used in this investigation. A percutaneous guidewire was inserted 5 mm lateral to the tibialis anterior tendon. The midpoint of the talar neck served as the sagittal plane starting point, as seen on the lateral fluoroscopic view. A cannulated 6.5-mm headed screw was inserted antegrade through the STJ into the calcaneus. Each specimen was dissected to assess the distance from the screw to nearby anatomic structures and distance from the tibialis anterior tendon to named structures. Our hypothesis was found to be incorrect, as 0/10 screws invaded neurovascular or tendinous structures. The dorsalis pedis artery and deep peroneal nerve were on average 12.1 ± 2.79 mm and 12.2 ± 2.82 mm lateral to the screw, respectively. These findings are clinically relevant and ultimately allow us to define an anatomic safe starting point for percutaneous antegrade STJ single screw fixation.

Association Between Pronation External Rotation IV Fracture Pattern and Regional Bone Density.

INTRODUCTION: Throughout the musculoskeletal system, fracture patterns and subsequent healing rely partly on bone density. In the foot and ankle, bone density has been shown to play a role in supination and external rotation fracture patterns. Adding to previous research, this investigation examines the association between bone density and trimalleolar versus trimalleolar equivalent fracture patterns following pronation and external rotation injuries using computed tomography (CT)-derived Hounsfield units (HU). METHODS: A retrospective chart review was conducted among patients without a history of fracture or osteoporosis who sustained a PER IV fracture. Demographic data were collected. Fractures were separated between PER IV equivalent and fracture groups. CT-derived HU was assessed at the distal tibia and fibula. Density was compared between PER IV equivalent and fracture groups and among posterior malleolar fracture patterns. RESULTS: Seventy-five patients met the selection criteria, with 17 comprising the equivalent group and 58 in the fracture group. There were 38 type 1, 9 type 2, and 11 type 3 posterior malleolus fractures. The ankle bone density of the PER fracture equivalent group (331.98 ± 65.71HU) was greater than the PER fracture group (281.61 ± 76.99HU; P = .008). A statistically significant difference in tibial bone densities among equivalent and all PER fracture types (P = .01) with the equivalent group (331.98 ± 65.71HU) maintaining a greater tibial bone density than the type 2 posterior malleolus fracture group (252.35 ± 57.33HU; P = .009). CONCLUSION: Higher bone density was associated with PER IV equivalent fractures; however, there was no density difference among posterior malleolus fracture types. When presented with PER IV fractures, consider fixation that addresses a lower bone density. LEVEL OF EVIDENCE: III.

The Aggressive Open Anterior Ankle Cheilectomy as Joint Salvage for Anterior Ankle Impingement Syndrome and Arthritis.

Anterior ankle impingement syndrome can frequently present in athletes and post-traumatic patients who have osteophytes contributing to limited dorsiflexion and pain. Surgical treatment options include arthroscopy, open arthrotomy, arthrodesis, and total implant arthroplasty. For many, joint-sparing arthroscopy or arthrotomy yield satisfactory results if significant debridement is performed. If debridement is not aggressive, patients may not obtain the desired improvement. In cases where a larger amount of bone must be removed, or the patient does not have an anatomic appearing talar neck due to osteophytic changes, we have found that an open approach is necessary to achieve good results. To the best of our knowledge, no such technique has been previously published detailing a standard approach to open ankle arthrotomy. Our technique is coined the "Aggressive Open Anterior Ankle Cheilectomy" and involves a systematic 3-step approach. First, the tibial osteophytes are resected with an osteotome; second, the ankle gutters are addressed, and all hypertrophic bones removed; and third, an anatomic talar neck is fashioned. We herein describe our surgical technique and case examples.Level of Evidence: 5.

Loose Body Versus Trochlear Biopsy Matrix-Induced Autologous Chondrocyte Implantation (MACI) MOCART Scores and IKDC Reported Outcomes in Pediatric Patients.

BACKGROUND: Matrix-induced autologous chondrocyte implantation (MACI) has shown promising results in the treatment of osteochondral lesions of the knee. A recent study showed similar viability comparing chondrocytes harvested from the intercondylar notch compared to those harvested from osteochondral loose bodies. However, there is limited evidence assessing how these different biopsies perform clinically. The goal of this study was to compare both radiographic and patient-reported outcomes in patients with patellar and femoral osteochondral lesions treated with MACI using either a standard intercondylar notch biopsy or an osteochondral loose body biopsy. METHODS: A retrospective study was performed on all pediatric autologous chondrocyte implantation procedures performed from 2014 to 2017 at a single institution. Patients were divided into 2 groups: one group had cartilage derived from a standard intercondylar notch biopsy (n=9) and the other group had cartilage derived from an osteochondral loose body found within the ipsilateral knee (n=10). At a minimum of 1-year postimplantation, magnetic resonance imagings of the operative knee were performed and the Magnetic Resonance Observation of Cartilage Repair Tissue Knee Score (MOCART 2.0) knee score was used to assess the integrity and quality of the cartilage repair tissue. Interclass correlation coefficients were calculated between the 2 groups. International Knee Documentation Committee (IKDC) outcome scores were determined at a minimum 2 years post-implantation. RESULTS: The interclass correlation coefficient between three independent examiners for the MOCART scoring was excellent at 0.94. With regards to the MOCART score, the loose body group had an insignificant 17-point lower median score at 63 [interquartile range (IQR): 58 to 89] compared to the intercondylar group at 80 (IQR: 65 to 90) ( P =0.15). There was no difference in IKDC scores with the loose body group having a median score of 82 (IQR: 65 to 95) and the intercondylar group having a median score of 84 (IQR: 53 to 99) ( P =0.90). CONCLUSION: These results demonstrate that osteochondral loose bodies can be used as viable harvest site in MACI procedures with no difference in functional and radiographic outcomes at 2 years postimplantation. This may limit both short and long-term donor site morbidity. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Functional Outcomes and Complications Associated With Total Talus Arthroplasty: A Systematic Review.

Total talus arthroplasty (TTA) is a motion sparing procedure which can be utilized in specific and unique cases of talar necrosis and/or collapse. Literature on TTA is limited and predominantly composed of case studies or case reports. The purpose of this publication is to compile a systematic review of functional outcomes and complications associated with TTA. A search of current literature on TTA with >1-year follow-up was performed. Studies that described talar body implants or talonavicular implants were excluded. Twenty articles met inclusion criteria, which represented 161 TTAs. The average follow-up was 37.35 months (9-60 months). The indication for a TTA was predominately avascular necrosis of the talus, comprising 75.78% (122/161) of cases. The overall complication rate was 9.32% (15/161), with wound healing complications (5/161), replacement or implantation of a tibial component (4/161), and medial malleolus fracture (3/161) being the most common. One patient required proximal amputation due to residual pain and deformity. Functionally, American Orthopedic Foot and Ankle Score increased from 27.93 preoperative to 81.99 postoperative and Japanese Society for Surgery of the Foot Score increased from 43.2 preoperative to 89.34 postoperative. Visual analog scale pain score decreased from 6.44 to 2.60. Total ankle range of motion increased from 36.60° to 46.74°. Ankle plantarflexion increased by 3.45° and ankle dorsiflexion increased by 6.69°. Overall, available literature on TTA appears to be in favor of the procedure when indicated.Levels of Evidence: 4.

Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae.

The diagnosis of postacute sequelae of coronavirus disease 2019 (PASC) poses an ongoing medical challenge. To identify biomarkers associated with PASC we analyzed plasma samples collected from PASC and coronavirus disease 2019 patients to quantify viral antigens and inflammatory markers. We detect severe acute respiratory syndrome coronavirus 2 spike predominantly in PASC patients up to 12 months after diagnosis.

Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection.

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.

Switchable assembly and function of antibody complexes in vivo using a small molecule.

The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies.

Limited TCR repertoire and ENTPD1 dysregulation mark late-stage COVID-19.

T cell exhaustion and dysfunction are hallmarks of severe COVID-19. To gain insights into the pathways underlying these alterations, we performed a comprehensive transcriptome analysis of peripheral-blood-mononuclear-cells (PBMCs), spleen, lung, kidney, liver, and heart obtained at autopsy from COVID-19 patients and matched controls, using the nCounter CAR-T-Characterization panel. We found substantial gene alterations in COVID-19-impacted organs, especially the lung where altered TCR repertoires are noted. Reduced TCR repertoires are also observed in PBMCs of severe COVID-19 patients. ENTPD1/CD39, an ectoenzyme defining exhausted T-cells, is upregulated in the lung, liver, spleen, and PBMCs of severe COVID-19 patients where expression positively correlates with markers of vasculopathy. Heightened ENTPD1/CD39 is paralleled by elevations in STAT-3 and HIF-1α transcription factors; and by markedly reduced CD39-antisense-RNA, a long-noncoding-RNA negatively regulating ENTPD1/CD39 at the post-transcriptional level. Limited TCR repertoire and aberrant regulation of ENTPD1/CD39 could have permissive roles in COVID-19 progression and indicate potential therapeutic targets to reverse disease.

Type I, II, and III Interferon Signatures Correspond to Coronavirus Disease 2019 Severity.

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.

Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury.

INTRODUCTION: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI. METHODS: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography-mass spectrometry. RESULTS: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). CONCLUSION: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19-associated AKI.

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.

Profound Treg perturbations correlate with COVID-19 severity.

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

Protein and Polysaccharide-Based Electroactive and Conductive Materials for Biomedical Applications.

Electrically responsive biomaterials are an important and emerging technology in the fields of biomedical and material sciences. A great deal of research explores the integral role of electrical conduction in normal and diseased cell biology, and material scientists are focusing an even greater amount of attention on natural and hybrid materials as sources of biomaterials which can mimic the properties of cells. This review establishes a summary of those efforts for the latter group, detailing the current materials, theories, methods, and applications of electrically conductive biomaterials fabricated from protein polymers and polysaccharides. These materials can be used to improve human life through novel drug delivery, tissue regeneration, and biosensing technologies. The immediate goal of this review is to establish fabrication methods for protein and polysaccharide-based materials that are biocompatible and feature modular electrical properties. Ideally, these materials will be inexpensive to make with salable production strategies, in addition to being both renewable and biocompatible.

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

Profound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from activated endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant dysfunction of the endothelium and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. On lung autopsy specimens from COVID-19 patients, we found a prothrombotic endothelial signature as evidenced by increased von Willebrand Factor and loss of anticoagulant proteins. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed profound endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Moreover, our findings provide novel rationale for current trials of Tie2 activating therapy with AKB-9778 in severe COVID-19 disease.

Type I, II, and III interferon signatures correspond to COVID-19 disease severity.

We analyzed the plasma levels of interferons and cytokines, and the expression of interferon-stimulated genes in peripheral blood mononuclear cells in COVID-19 patients with different disease severity. Mild patients exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients. These results highlight the importance of type I and III interferon responses during the early phase of infection in controlling COVID-19 progression.

Innate lymphoid cells and disease tolerance in SARS-CoV-2 infection.

Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. This study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis, and the percentage of amphiregulin-producing ILCs was higher in females than in males. These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance accounts for increased COVID-19 severity with age and in males.