First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit.

BACKGROUND: Primary ciliary dyskinesia (PCD) is typically an autosomal recessive disease characterized by recurrent infections of the lower respiratory tract, frequent and severe otitis media, chronic rhinosinusitis, neonatal respiratory distress, and organ laterality defects. While severe lower respiratory tract infections and bronchiectasis are common in Inuit, PCD has not been recognized in this population. METHODS: We report a case series of seven Inuit patients with PCD identified by genetic testing in three Canadian PCD centers. RESULTS: Patients ranged from 4 to 59 years of age (at time of last evaluation) and originated in the Qikiqtaaluk region (Baffin Island, n = 5), Nunavut, or Nunavik (northern Quebec, n = 2), Canada. They had typical features of PCD, including neonatal respiratory distress (five patients), situs inversus totalis (four patients), bronchiectasis (four patients), chronic atelectasis (six patients), and chronic otitis media (six patients). Most had chronic rhinitis. Genetic evaluation demonstrated that all had homozygous pathogenic variants in DNAH11 at NM_001277115.1:c.4095+2C>A. CONCLUSIONS: The discovery of this homozygous DNAH11 variant in widely disparate parts of the Nunangat (Inuit homelands) suggests this is a founder mutation that may be widespread in Inuit. Thus, PCD may be an important cause of chronic lung, sinus, and middle ear disease in this population. Inuit with chronic lung disease, including bronchiectasis or laterality defects, should undergo genetic testing for PCD. Consideration of including PCD genetic analysis in routine newborn screening should be considered in Inuit regions.

Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4 years of age; however, a year later he transitioned to denosumab 1 mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62 mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83 µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7 pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10 days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1 mg/kg alternating every three months with IV ZA 0.025 mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.

Evaluation of TB elimination strategies in Canadian Inuit populations: Nunavut as a case study.

Tuberculosis (TB) continues to disproportionately affect Inuit populations in Canada with some communities having over 300 times higher rate of active TB than Canadian-born, non-Indigenous people. Inuit Tuberculosis Elimination Framework has set the goal of reducing active TB incidence by at least 50% by 2025, aiming to eliminate it by 2030. Whether these goals are achievable with available resources and treatment regimens currently in practice has not been evaluated. We developed an agent-based model of TB transmission to evaluate timelines and milestones attainable in Nunavut, Canada by including case findings, contact-tracing and testing, treatment of latent TB infection (LTBI), and the government investment on housing infrastructure to reduce the average household size. The model was calibrated to ten years of TB incidence data, and simulated for 20 years to project program outcomes. We found that, under a range of plausible scenarios with tracing and testing of 25%-100% of frequent contacts of detected active cases, the goal of 50% reduction in annual incidence by 2025 is not achievable. If active TB cases are identified rapidly within one week of becoming symptomatic, then the annual incidence would reduce below 100 per 100,000 population, with 50% reduction being met between 2025 and 2030. Eliminating TB from Inuit populations would require high rates of contact-tracing and would extend beyond 2030. The findings indicate that time-to-identification of active TB is a critical factor determining program effectiveness, suggesting that investment in resources for rapid case detection is fundamental to controlling TB.

Noninvasive ventilation of air transported infants with respiratory distress in the Canadian Arctic.

Objectives: Since 2016, use of nasal continuous positive airway pressure (nCPAP) in Nunavut for air transport in select patients has become common practice. This study examines the outcomes of patients transferred by air from the Qikiqtaaluk Region during air transport. We examined intubation rates, adverse events during transfer, and respiratory parameters at departure and upon arrival. Methods: This was a retrospective review from September 2016 to December 2019 including patients under 2 years of age transferred by air on nCPAP from the Qikiqtaaluk Region of Nunavut. Results: Data were collected for 40 transfers involving 34 unique patients. Six transfers were from remote communities in Nunavut to Iqaluit, and 33 transfers were from Iqaluit to CHEO. The primary outcome measure was whether the patient required intubation during transport, or urgent intubation upon arrival to CHEO. The median nCPAP setting during transport was 6 cm H2O (5-7 cm H2O) and at arrival to CHEO was 6 cm H2O (6-7 cm H2O). Six of the 33 (18.2%) patients required intubation during their hospital stay and five (15.2%) in a controlled ICU setting. There were no discernible adverse events that occurred during transport for 28 patients (84.5%). Four patients (12.1%) required a brief period of bag-mask ventilation and one patient had an episode of bradycardia. Conclusions: nCPAP on air transport is a safe and useful method for providing ventilatory support to infants and young children with respiratory distress.

Impact of non-pharmaceutical interventions and vaccination on COVID-19 outbreaks in Nunavut, Canada: a Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Nunavut, the northernmost Arctic territory of Canada, experienced three community outbreaks of the coronavirus disease 2019 (COVID-19) from early November 2020 to mid-June 2021. We sought to investigate how non-pharmaceutical interventions (NPIs) and vaccination affected the course of these outbreaks. METHODS: We used an agent-based model of disease transmission to simulate COVID-19 outbreaks in Nunavut. The model encapsulated demographics and household structure of the population, the effect of NPIs, and daily number of vaccine doses administered. We fitted the model to inferred, back-calculated infections from incidence data reported from October 2020 to June 2021. We then compared the fit of the scenario based on case count data with several counterfactual scenarios without the effect of NPIs, without vaccination, and with a hypothetical accelerated vaccination program whereby 98% of the vaccine supply was administered to eligible individuals. RESULTS: We found that, without a territory-wide lockdown during the first COVID-19 outbreak in November 2020, the peak of infections would have been 4.7 times higher with a total of 5,404 (95% CrI: 5,015-5,798) infections before the start of vaccination on January 6, 2021. Without effective NPIs, we estimated a total of 4,290 (95% CrI: 3,880-4,708) infections during the second outbreak under the pace of vaccination administered in Nunavut. In a hypothetical accelerated vaccine rollout, the total infections during the second Nunavut outbreak would have been 58% lower, to 1,812 (95% CrI: 1,593-2,039) infections. Vaccination was estimated to have the largest impact during the outbreak in April 2021, averting 15,196 (95% CrI: 14,798-15,591) infections if the disease had spread through Nunavut communities. Accelerated vaccination would have further reduced the total infections to 243 (95% CrI: 222-265) even in the absence of NPIs. CONCLUSIONS: NPIs have been essential in mitigating pandemic outbreaks in this large, geographically distanced and remote territory. While vaccination has the greatest impact to prevent infection and severe outcomes, public health implementation of NPIs play an essential role in the short term before attaining high levels of immunity in the population.

Effectiveness and cost-effectiveness of RSV infant and maternal immunization programs: A case study of Nunavik, Canada.

BACKGROUND: Despite passive immunization with palivizumab to select high-risk children under two years of age, the health and economic burden of respiratory syncytial virus (RSV) remains substantial. We evaluated the effectiveness and cost-effectiveness of immunization programs with new generations of RSV prophylactics, including long-acting monoclonal antibodies (LAMA) and maternal vaccines, in terms of reducing hospitalizations in Nunavik, a Canadian Arctic region. METHODS: We developed an agent-based model of RSV transmission and parameterized it with the demographics and burden of RSV in Nunavik, Québec. We compared various immunization strategies, taking into account the costs associated with program delivery and calculating the incremental cost-effectiveness ratio (ICER) using quality-adjusted life-years (QALYs) gained as a measure of effectiveness. Scenario analyses included immunization with palivizumab and LAMA for infants under one year of age, and maternal vaccination in mild, moderate, and severe RSV seasons. Data were analysed from November 1, 2019 to May 1, 2021. FINDINGS: We found that a Nunavik pilot program with palivizumab which included healthy full-term infants aged 0-2 months in addition to those considered high-risk for complicated RSV disease is not cost-effective, compared to offering palivizumab only to preterm/chronically ill infants under 1 year of age. Using LAMA as prophylaxis produces ICER values of CAD $39,414/QALY (95% Credible Interval [CrI]: $39,314-$40,017) in a mild season (moderately cost-effective) and CAD $5,255/QALY (95% CrI: $5,222-$5,307) in a moderate season (highly cost-effective). LAMA was a dominant (cost-saving with negative incremental costs and positive incremental effects) strategy in a severe RSV season. Maternal vaccination combined with immunization of preterm/chronically ill infants 3-11 months was also a dominant (cost-saving) strategy in all seasons. INTERPRETATION: The switch from palivizumab in RSV immunization programs to new prophylactics would lead to significant savings, with LAMA being an effective strategy without compromising benefits in terms of reducing hospitalizations.

Nasal CPAP on paediatric air transport in the Canadian Arctic: A case series.

AIMS: Paediatric transport in remote regions of Canada represents a huge challenge given the acuity of the patients, immense distances, weather and lack of road infrastructure. Transport of patients in the Baffin region of Nunavut is completed entirely by air transport. Two very common paediatric transports are in regards to lower respiratory tract infections and premature deliveries in small rural communities north of Iqaluit. Recently, the advent of noninvasive ventilation has been introduced to the region. METHOD: We report five cases of long-distance air transport of paediatric patients in respiratory distress using nasal continuous positive airway pressure (nCPAP). Two cases involve lower respiratory tract infections, and three cases involve neonates (two premature infants and one term infant). RESULTS: Overall, these cases highlight effective and safe use of noninvasive ventilation in air transport of patients in respiratory distress and demonstrate how this modality can improve patient transport in rural and remote regions.

Invasive Fusariosis: A Single Pediatric Center 15-Year Experience.

Invasive fungal infection (IFI) is an important cause of mortality in immunocompromised children, particularly after hematopoietic stem cell transplantation. We describe 5 cases of Fusarium IFI in immunocompromised children seen at our institution over a 15-year period. A summary of all published pediatric cases of invasive Fusarium infection is presented. A focus on antifungal management challenges in these patients will be discussed.