Severe Features of Systemic Juvenile Idiopathic Arthritis in Patients with Congenital Heart Disease.

OBJECTIVE: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). METHODS: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. RESULTS: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy but all of the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n=5), rash (n=5), and arthritis (n=4) developed after surgical intervention in all of the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n=5), elevated IL-18 levels (n=5), baseline eosinophilia prior to initiation of biologic disease modifying anti-rheumatic drugs (bDMARDs) (n=4), and positivity for HLA-DRB1*15:01 alleles (n=4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. CONCLUSION: We identified an association between CHD and severe forms of sJIA. While these findings will need to be confirmed in larger, multi-center cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD.

Identification of Irpex and Rhodotorula on surveillance bronchoscopy in a pediatric lung transplant recipient: A case report and review of literature of these atypical fungal organisms.

BACKGROUND: Invasive fungal disease (IFD) is a frequent complication in pediatric lung transplant recipients, occurring in up to 12% of patients in the first year. Risk factors for infection include impaired lung defenses and intense immunosuppressive regimens. While most IFD occurs from Aspergillus, other fungal conidia are continuously inhaled, and infections with fungi on a spectrum of human pathogenicity can occur. CASE REPORT: We report a case of a 17-year-old lung transplant recipient in whom Irpex lacteus and Rhodotorula species were identified during surveillance bronchoscopy. She was asymptomatic and deemed to be colonized by Irpex lacteus and Rhodotorula species following transplant. 2 years after transplantation, she developed a fever, respiratory symptoms, abnormal lung imaging, and histological evidence of acute and chronic bronchitis on transbronchial biopsy. After developing symptoms concerning for a pulmonary infection and graft dysfunction, she was treated for a presumed IFD. Unfortunately, further diagnostic testing could not be performed at this time given her tenuous clinical status. Despite the initiation of antifungal therapy, her graft function continued to decline resulting in a second lung transplantation. CONCLUSIONS: This case raises the concern for IFD in lung transplant recipients from Irpex species. Further investigation is needed to understand the pathogenicity of this organism, reduce the incidence and mortality of IFD in lung transplant recipients, and refine the approach to diagnosis and manage the colonization and isolation of rare, atypical fungal pathogens in immunocompromised hosts.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

A pneumonectomy model to study flow-induced pulmonary hypertension and compensatory lung growth.

In newborns, developmental disorders such as congenital diaphragmatic hernia (CDH) and specific types of congenital heart disease (CHD) can lead to defective alveolarization, pulmonary hypoplasia, and pulmonary arterial hypertension (PAH). Therapeutic options for these patients are limited, emphasizing the need for new animal models representative of disease conditions. In most adult mammals, compensatory lung growth (CLG) occurs after pneumonectomy; however, the underlying relationship between CLG and flow-induced pulmonary hypertension (PH) is not fully understood. We propose a murine model that involves the simultaneous removal of the left lung and right caval lobe (extended pneumonectomy), which results in reduced CLG and exacerbated reproducible PH. Extended pneumonectomy in mice is a promising animal model to study the cellular response and molecular mechanisms contributing to flow-induced PH, with the potential to identify new treatments for patients with CDH or PAH-CHD.

Development of a Screening Algorithm for Lung Disease in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Lung disease (LD) is an increasingly recognized complication of systemic juvenile idiopathic arthritis (sJIA). As there are no currently available guidelines for pulmonary screening in sJIA, we sought to develop such an algorithm at our institution. METHODS: A multidisciplinary workgroup was convened, including members representing rheumatology, pulmonary, stem cell transplantation, and patient families. The workgroup leaders drafted an initial algorithm based on published literature and experience at our center. A modified Delphi approach was used to achieve agreement through three rounds of anonymous, asynchronous voting and a consensus meeting. Statements approved by the workgroup were rated as appropriate with moderate or high levels of consensus. These statements were organized into the final approved screening algorithm for LD in sJIA. RESULTS: The workgroup ultimately rated 20 statements as appropriate with a moderate or high level of consensus. The approved algorithm recommends pulmonary screening for newly diagnosed patients with sJIA with clinical features that the workgroup agreed may confer increased risk for LD. These "red flag features" include baseline characteristics (young age of sJIA onset, human leukocyte antigen type, trisomy 21), high disease activity (macrophage activation syndrome [MAS], sJIA-related ICU admission, elevated MAS biomarkers), respiratory symptoms or abnormal pulmonary examination findings, and features of drug hypersensitivity-like reactions (eosinophilia, atypical rash, anaphylaxis). The workgroup achieved consensus on the recommended pulmonary work-up and monitoring guidelines. CONCLUSION: We developed a pulmonary screening algorithm for sJIA-LD through a multidisciplinary consensus-building process, which will be revised as our understanding of sJIA-LD continues to evolve.

Presentation of an H-type tracheoesophageal fistula in an adolescent male with cystic fibrosis: A case report and review of literature.

Congenital TEFs without esophageal atresia are rare but may occur more frequently than previously documented in literature. Careful history is required to suspect the diagnoses, as most patients will present with coughing associated with solid or liquids, recurrent unexplained pulmonary infections and complaints with eating. Some patients may show signs of chronic airway changes from recurrent aspiration pneumonia at the time of presentation. Diagnosis is challenging, with multiple imaging modalities including x ray, CT scan and esophogram able to identify a fistula. Surgery is required to improve quality of life and prevent chronic airway changes, and most cases repaired have no complications.