“Infant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir - American Academy of Pediatrics” plus 1 more

Infant With SARS-CoV-2 Infection Causing Severe Lung Disease Treated With Remdesivir - American Academy of Pediatrics

Posted: 01 Sep 2020 12:00 AM PDT

During the coronavirus disease 2019 (COVID-19) pandemic, few children have been infected, and those affected have had a typically milder course than adults.^1–8 We describe an ex-premature infant who presented with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the fifth week of life. His clinical course differs from other reported pediatric cases showing only mild respiratory system involvement.^5,8 Severe respiratory distress developed in a short time frame, following severe airway compromise due to significant glottic swelling. Although his condition initially improved, severe acute respiratory distress syndrome (ARDS) developed at the time prophylactic steroids were given to prepare for extubation. High-frequency oscillatory ventilation, nitric oxide, and intermittent prone positioning were then required, and after the use of the antiviral agent remdesivir, he made a full recovery before being discharged from the hospital.

Case Report

The patient is a twin born at 32 + 6 weeks for maternal preeclampsia with a small atrial septal defect (<4 mm) and cleft palate. He was intubated at birth before weaning off respiratory support within a week. At 37 + 3 weeks' corrected gestational age, he developed respiratory distress at home and presented to the hospital. Of note, he had been in recent contact with both family members and asymptomatic health care workers, who subsequently developed symptoms and were confirmed to have SARS-CoV-2 infection.

In the emergency department, progressive hypoxia led to several failed attempts at intubation. Nasopharyngeal aspirate SARS-CoV-2 RNA polymerase chain reaction (PCR) result was positive (cycle threshold 20). Oxygenation and ventilation were maintained via laryngeal mask during transfer to a quaternary center for otolaryngological input. He was successfully intubated in theater via microlaryngobronchoscopy by using appropriate personal protective equipment for all personnel.⁹ Significant glottic swelling and copious airway secretions were noted (Fig 1).

FIGURE 1

Operative photographs of airway swelling. A, Glottis with grossly swollen vocal folds. B, Trachea with moderate inflammation and copious distal airway secretions.

Initial moderate ventilatory pressures and fraction of inspired oxygen of 0.6 were weaned over 3 days. An initial chest radiograph revealed mild bilateral ground-glass opacities (Fig 2). C-reactive protein was 42 mg/L, and the patient was lymphopenic (1.45 × 10⁹/L) with an otherwise normal blood picture (Fig 3). Serial tracheal aspirates, urine, and stool cultures excluded bacterial or fungal coinfection. A line-associated femoral arterial thrombus was treated with therapeutic anticoagulation.

FIGURE 2

Chest radiographs performed. A, Performed on day 2. B, Performed on day 5. C, Performed on day 6. Initially, only mild bilateral ground-glass opacities were present. Subsequent radiologic worsening is noted with progressive airspace opacification (day 5) and bilateral consolidation with predominant peripheral distribution, lung overinflation, and right basal pneumothorax (day 6).

FIGURE 3

Patient results. Shown are the laboratory values including SARS-CoV-2 RNA PCR results throughout admission. Remdesivir treatment was prescribed from day 7 to 17. Alb, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; Bili, bilirubin; CRP, C-reactive protein; Eos, eosinophils; Hb, hemoglobin; IFN-γ, interferon-γ; IL, interleukin; Lymph, lymphocytes; TNF-α, tumor necrosis factor α; WBC, white blood cell; -, no test performed.

After several days of laryngeal rest, ventilation parameters had improved and he was suitable for a trial of extubation. The multidisciplinary team decided to use usual prophylactic steroids to optimize laryngeal conditions for extubation, particularly considering the difficult intubation. Two prophylactic dexamethasone doses were given.

Before extubation, the patient deteriorated, developing fulminant ARDS with corresponding worsening of chest radiograph findings (Fig 2). He could no longer be managed with conventional ventilation and required high-frequency oscillatory ventilation, nitric oxide, prone ventilation, and inotropic support to maintain oxygenation and ventilation. Extracorporeal membrane oxygenation was considered but not required. Possible secondary bacterial infection was treated with broad-spectrum antibiotics and excluded by bronchoalveolar lavage by using strict personal protective equipment precautions.

Given the life-threatening deterioration, an urgent multidisciplinary meeting was held, followed by an innovative therapy review with the bioethics team and parents via video link.¹⁰ Because there was limited evidence for hyperinflammation (interleukin 6 <50 pg/mL; ferritin 411 μg/L), antiviral therapy was preferred to immunomodulation. A compassionate access application for remdesivir was agreed on and was granted.^11,12

An intravenous loading dose of 5 mg/kg remdesivir was given, followed by 1.25 mg/kg maintenance dose for 10 days. Interleukin 10 was raised (110 pg/mL) but normalized by day 5 of treatment. C-reactive protein peaked at 63 mg/L on day 6, ferritin 789 μg/L on day 9, and D-dimer 1143 μg/L on day 10. Initially positive SARS-CoV-2 RNA PCR tracheal aspirates became negative after 5 days of treatment with remdesivir, excluding an isolated positive result on day 10 of remdesivir. No drug toxicity was observed.

The highest troponin was 138 ng/L. There were no clinical or echocardiographic signs of myocarditis. An echocardiogram on day 7 of illness revealed only a small patent foramen ovale with left-to-right shunt, mild dilation left side structures, and mild mitral regurgitation.

Ventilatory and inotropic support were weaned, and extubation was successful on day 18 of illness (Fig 4). He has been discharged from the hospital.

FIGURE 4

Events and treatments during patient admission. This figure depicts respiratory support requirements, treatment with antiviral and antibacterial agents, and other significant medications. LMA, laryngeal mask airway; PC, pressure control; PS, pressure support; PSV, pressure support ventilation; SIMV, synchronized intermittent mandatory ventilation.

Discussion

We describe the clinical course of an infant with SARS-CoV-2 infection causing severe airway inflammation and ARDS who improved after treatment with the novel antiviral remdesivir.

SARS-CoV-2 Infection in Infants and Neonates

No clear explanation has been found as to the different severities of SARS-CoV-2 infection in children and adults.¹³ A low proportion of those infected have been children, and even fewer have been young infants.^{1,7,8,14–17} In a large Chinese series of 2143 pediatric patients, researchers found <6% of SARS-CoV-2 infected children developed hypoxia, and <1% progressed to ARDS.⁴ A Spanish group reported only 4 of 41 SARS-CoV-2 infected children (9.7%) required support beyond nasal prongs, and only a single patient was intubated.⁶ In an early study reporting infection epidemiology in New York, researchers reported fewer than 1% of admissions were children, and none required intensive care.¹⁸

Airway Manifestation in This Infant

Cellular composition of airway epithelium is similar between children and adults, and new research indicates little difference in the transcription of genes associated with SARS-CoV-2 infection in airway epithelium between children and adults.¹⁹ In a large systematic review of upper airway symptoms observed during the COVID-19 pandemic, researchers did not report stridor and airway compromise as features of SARS-CoV-2 infection.²⁰

Previous studies comparing ARDS in adults and children indicate different phenotypical disease courses.²¹ This child was on the transition of neonatal²² to pediatric ARDS²³ at 2.2 kg and 37 weeks' corrected gestational age; however, after secondary lung deterioration, all age-specific ARDS definitions were fulfilled. His treatment response interestingly mapped adult ARDS by improving with prone ventilation but only moderately with nitric oxide.

Use of Corticosteroids

Large-scale systematic reviews have revealed benefit in reducing postextubation stridor and some reduction in reintubation rates especially in those with high-risk airways or airway abnormalties.^24–27 In early literature, researchers recommend against the use of corticosteroids for treatment of SARS-CoV-2 infection unless for other indications because of concerns about blunting the inflammatory response to viral infection and previous studies of similar viral infections suggesting impaired viral clearance and increased mortality.^28,29 Because of the severity of glottic swelling seen at presentation and the extreme difficulty intubating the child, the highest risk was felt to be from airway swelling, so corticosteroids were administered in preparation for extubation.

Given the adult phenotype severe pneumonitis with initial improvement and then deterioration in SARS-CoV-2 infection, it is unclear if this patient followed the adult pattern of delayed severe disease transition described by Gattinoni et al³⁰ or if administration of steroids altered his disease course.

Radiologic Findings

Ground-glass opacification with a bilateral peripheral distribution is the most common finding in COVID-19 and is mainly based on computed tomography experience in adults.³¹ Other findings, such as septal thickening and bronchiectasis may appear later on with disease progression, although pneumothorax is uncommon, but is described in later stages.³¹ Similar but milder changes are described in children,³¹ but computed tomographic scanning is reserved for specific indications (eg, immunocompromised patients, atypical presentations).³² Chest radiographs may be completely unremarkable in less severe cases. The parenchymal findings seen in our patient's radiographs are particularly prominent considering the age of the child but are consistent with the common description in the literature of ground-glass opacification and consolidation.

Cardiac Involvement

In adults, a history of cardiovascular disease has been associated with higher morbidity and mortality from SARS-CoV-2 infection, particularly in elderly patients.³³ In total, 20% to 30% of patients with severe infection developed infection-related myocarditis and acute ischemic myocardial injury during ARDS, characterized by elevated troponin.³⁴ This patient's troponin was mildly elevated throughout the illness, peaking at 138 ng/L on day 10; however, no clinical signs of myocarditis or cardiac failure were apparent. Echocardiography during this admission revealed no residual atrial septal defect. Although there was some left-to-right shunting via a patent foramen ovale, it was felt his cardiac anatomy did not play a role in the severity of his illness or his susceptibility to infection.

Remdesivir

Remdesivir (GS-5734) is a nucleotide analogue with broad-spectrum antiviral activity against several RNA viruses developed after the emergence of Ebola by Gilead Sciences, Inc. It is a 1′-cyano-substituted adenosine nucleotide analogue prodrug. In animal models, remdesivir has demonstrated in vitro and in vivo activity against other coronavirus strains (severe acute respiratory syndrome coronavirus 1 and Middle East respiratory syndrome coronavirus) by inhibiting replication.³⁵ Before the COVID-19 pandemic, it has been used in the treatment of Ebola.^28,36 There is a report of a neonate infected with Ebola-infected being treated with remdesivir and surviving.³⁷ In vitro studies of remdesivir have demonstrated effective SARS-CoV-2 inhibition.¹¹ Early use in humans with SARS-CoV-2 has been promising.³⁸ Currently, there are 2 phase 3 trials being conducted to investigate the efficacy and safety of remdesivir in moderate COVID-19 in adults and children >12 years, weighing >40 kg (www.clinicaltrials.gov; identifier NCT04292730) and severe COVID-19 infection in adults (www.clinicaltrials.gov; identifier NCT04257656). To date, there are no published reports of children with COVID-19 treated with remdesivir. It is not possible in a single case report to determine the contribution of remdesivir to clinical recovery; however, it is noteworthy that it was well tolerated.

Compassionate Access

In view of this patient's disease severity, off-label remdesivir use was proposed. Our institution developed and published³⁹ a bespoke decision-making bioethics framework for such situations, involving children and their families.⁴⁰ The case was discussed at an urgent multidisciplinary team including intensive care, infectious diseases, virology, pharmacy, the bioethics team, and the parents. This process includes a mandatory second opinion from another institution. A successful compassionate access application was made for remdesivir.⁴¹

Acknowledgments

We thank the following colleagues for their input with the case study: Garth Dixon, Caroline Dalton, Kimberly Gilmore, Mark Gilchrist, Joe Standing, Louis Granjean, Delane Shingadia, Nele Alders, Karyn Moshal, Judith Breuer, members of the Great Ormond Street Hospital ethics committee, and Gilead Sciences, Inc, for access to medication to treat the child.

Phage therapy is effective against the superbug Acinetobacter baumannii - Massive Science

Posted: 05 Feb 2021 12:00 AM PST

The US residential power supply system is messed up at all times, but Texas's power supply is particularly problematic right now. And worse, it's about to be crushing financially for millions of families impacted by winter weather, especially the families that are poor, or elderly, or not white (or all three).

Because many states have deregulated their power markets, a lot of people get their power through retail energy suppliers. These companies are, essentially, energy arbitrage firms. They spend a lot of time and money analyzing weather and usage and production to decide how much power to buy for their customers, and how much to charge for that power. They usually make sure that their costs are significantly below the rate they offer customers — that's how they make money. Except for when something unexpected happens, like an extreme weather event.

Right now, for a lot of reasons, energy providers don't have access to a lot of power to purchase, and the massive winter demand coupled with huge supply problems are causing the wholesale price of power to skyrocket from $50 per megawatt-hour to over $9,000 per megawatt-hour.

But these retail energy suppliers still need to make money, so how do they make up this ginormous deficit? They charge people more for the power! They might be able to legally add a surcharge to your bill in some areas, or they might adjust rates next year. The easiest thing to do, though, is just charge people more - and the consumers they can charge more are the consumers with variable-rate plans (VRP).

There can be a lot of good reasons to choose a variable rate plan, but there are also a lot of bad reasons to choose (or be assigned) a VRP. Sometimes a VRP is all that's available to a consumer (they have bad credit, they can't afford to put a deposit down for a contract with a fixed rate), or it's assigned to a consumer. Much like credit card companies, if you miss a payment, energy suppliers can put you in the metaphorical penalty box by charging you interest on your overdue balance while also raising your rates - penalty plans are often variable rate plans.

Sometimes people end up with a VRP because of an information asymmetry — for example, when an elderly person signs up for a bad plan because it was incorrectly recommended or the first option offered, or when someone with limited English proficiency or literacy deficits doesn't understand their options.

After the 2014 polar vortex, households on VRPs experienced astronomical bills. In some areas, the cost of electricity jumped to $2 per kWh. For context, the average cost of residential electricity was $0.125 per kWh in 2014. In Chicago, one 72-year-old man reported that his monthly bill jumped from $81 to over $300.

That's why marginalized people are likely to be extra financially burdened by this storm. They are more likely than average to be on VRPs.

This winter weather is bad news for everyone - people are dying, people don't have power in frigid conditions. This weather crisis has the potential to be financially disastrous for families, on top of the costs of repairs from weather damage. Help these families by donating to charities that assist with paying heating and electric bills, demanding accountability from lawmakers and energy regulators, and taking steps to stop climate change so these storms don't get worse every year.

If you have power right now, you can help these households by trying not to use your power. Rationing is effective against blackouts, but it also helps drive down demand, and thus cost.

Severe Acute Respiratory Syndrome