Confluence of RSV, COVID-19, and Influenza

• New hospitalizations for respiratory illnesses, especially influenza and COVID-19, continue to spike following the Thanksgiving holiday. Flu hospitalizations “remain at a decade high” and COVID-19 hospitalizations have increased 13.8% compared to last week. COVID-19 cases have increased 49.6% compared to last week.
• While RSV may have peaked in some areas, overall increases in hospitalizations from COVID-19 and flu in adult and pediatric populations continue to put additional strain on hospitals that are already at or above capacity. Such strain, especially with months of the respiratory season still ahead, may further constrain capacity to care for critically ill patients of all ages across the US.
• CDC is encouraging use of masks and COVID-19 and influenza vaccinations to help prevent spread of COVID-19, flu, and RSV during the holiday season.
• As of 12/7, vaccination of children for both COVID-19 and influenza remain very low. American Academy of Pediatrics analysis based on CDC data shows only 11% of children (compared to 10% last week, an increase of 1 percentage point) aged 6 months to 4 years old have received at least one dose of the COVID-19 vaccine.  
• As of 11/26, according to CDC, 42.5% of children (+4.6%) between the ages of 6 months and 17 years have been vaccinated for influenza for the 2022-2023 season, compared with 40.9% for the same week in 2021.
• There is an outbreak of Invasive Group A Streptococcus (iGAS) in the United Kingdom that has led to 15 pediatric deaths in recent weeks. CDC created an advisory page for possible increase in iGAS infections in the US where it outlines what actions parents, healthcare providers, and laboratorians should take if they suspect a child might be infected with Streptococcus A. Streptococcus A is typically treated with penicillin or amoxicillin.
• If Streptococcus A infections continue to spread globally, the penicillin class of antibiotics, which includes already disrupted amoxicillin formulations, may see greater disruptions in an already strained market.  

RSV

• Data shows that rates of RSV cases and hospitalizations may have peaked in some areas of the US. However, lack of comprehensive localized (smaller than state-level) data leaves gaps in national picture of when and where cases are peaking. Disclaimer: The following analysis is based on the limited available data for RSV.
• CDC National Respiratory and Enteric Virus Surveillance System (NREVSS) RSV laboratory test data show:
• RSV cases in HHS Region 8 (Montana, Wyoming, Utah, Colorado, North Dakota, and South Dakota) have likely peaked regionally. Cases in some states in the Region may not have peaked: state level data shows a continuous upward trend in 3-week averages for RSV PCR test positivity in Montana. State level data shows a downward trend in 3-week averages for RSV PCR test positivity in Wyoming. PCR test positivity for North Dakota and Colorado indicates cases in those states likely have peaked and are now trending downward. South Dakota’s PCR test positivity has shown an inconsistent (not continuous) upward trend; it is unclear if this indicates a peak in cases. Data for Utah is not available.  
• Cases in Region 10 (Washington, Oregon, Idaho, Alaska) may be peaking in some states, while others continue to rise. PCR test positivity for Idaho shows an upward trend in 3-week averages for RSV PCR test positivity that may be peaking or plateauing. PCR test positivity in Alaska shows a continuous upward trend in 3-week averages, indicating cases in the state may not have peaked. Oregon data shows a downward trend in cases in 3-week averages. Data from Washington state show a continuous downward trend in 3-week averages for RSV PCR test positivity.
• RSV-NET data for the week ending in 12/10 shows a continuing downward trend in positive RSV cases. The data from CDC’s RSV-NET* for the week ending 11/26 shows a decrease of RSV-related hospitalization rates in most demographics, including children ages 6 months to 4 years. The non-representative dataset shows declines in hospitalizations across race and ethnicities and age groups (data accounts for about 8% of the US and actual trends may be higher).
• Guidance for assessing and prioritizing bronchiolitis patient needs is available in resources such as East Tennessee’s Children’s Hospital’s Bronchiolitis Care Map and Spectrum Health’s Clinical Pathway: Pediatric Bronchiolitis, Inpatient.
• ASPR TRACIE released guidance on use of high flow nasal cannulas (HFNC) in pediatric patients, including the clinical pathways, decision support tools, and information on use of HFNC in non-intensive care unit settings and during patient transport.

Influenza

• Influenza-associated pediatric deaths rose to 21 (+7) for 2022-2023 flu season as of the week ending 12/03.
  • Percent of deaths with high risk underlying medical condition with an option of a breakdown of medical conditions
  • Bacterial co-infection
  • Days onset to death
  • 75.1% of pediatric deaths have an onset up to 7 days
  • 40% of deaths occur in emergency departments, a 20% increase from typical years
  • 15% of patients suffered with bacterial co-infection, which was group A streptococcus
  • 44.4% had a high-risk condition, out of which neurologic and endocrine disorders
• The CDC influenza-associated pediatric mortality dashboard started reporting additional metrics in addition to gender, age group, and location of death, which are:
• The analysis of old and new metrics suggests that:
• HHS Region 10 (Alaska, Idaho, Oregon, Washington State) has the highest rate of pediatric mortality (0.7; rate is calculated as number of deaths reported per 100,000 inhabitants age 17 or younger).
• The 2022-2023 influenza season is the most severe in terms of hospitalizations for the time of year in 13 years. According to CDC, “the cumulative hospitalization rate… is higher than the rate observed in week 47 during every previous season since 2010-2011.”
• The number of influenza-related hospital admissions reported to HHS Protect system increased during week 48 as compared to the previous week.
• CDC estimates that this season, there have been 13 – 27 million influenza infections, 6.1- 13 million medical visits, 120,000 – 260,000 hospitalizations and 7,300 – 21,000 influenza-related deaths between October 1 and December 3, 2022. For comparison, CDC estimates that there were 9 million influenza infections, 4 million medical visits, 100,000 hospitalizations, and 5,000 during the entire 2021-2022 season. In other words, there have been up to 2.6 times more flu-related hospitalizations this season so far compared to the entirety of last year.
• Influenza-like illnesses (ILI) levels are very high across the United States for the week ending in 12/03. Forty-six states, New York City, Puerto Rico and the District of Columbia are experiencing high to very-high levels of ILI. Twelve of the jurisdictions are reporting ILI activity level 13, the highest possible. Those jurisdictions are: Colorado, Connecticut, District of Columbia, Kentucky, Nebraska, New Jersey, New Mexico, Ohio, Tennessee, Virginia, Washington, and New York City.
• The ILI activity level denotes the intensity of the ILI activity and not the geographic spread. Thus, an entire state might display as high due to a reporting entity reporting surge capacity to the point that the jurisdiction does not have the available resources to compensate.
• Very high ILI activity, levels 11-13, indicates that flu activity is 12-20 standard deviations present above the mean, indicating that the area’s infrastructure, workforce, and supply chain capacities might not be able to accommodate local needs without additional assistance.
• The test positivity rate decreased very slightly (-0.3 percentage points) between the week ending 11/26 (25.1%) and the week ending 12/03 (24.8%).  While there is a decrease since the prior week, which accounted for a spike in activity due to the Thanksgiving holidays, the influenza confirmed cases and influenza-related hospital admissions continue to rise.
• For the week ending in 12/03, the 0-4 age group experienced the highest rates (17.1%) of outpatient visits for influenza-like illnesses.
• Age groups 25-49 years, 50-64 years, and 65+ saw a percentage increase in positivity rates from the previous reported week with age 25-49 years experiencing the largest percentage point increase of 0.8.
• Aggregated data of all age groups demonstrates that the youngest populations are disproportionately contracting respiratory illnesses.

Source: CDC Outpatient Respiratory Illness Activity Map. Accessed: December 14, 2022.

COVID-19  

• On 12/09, CDC expanded the eligibility for the updated COVID-19 bivalent vaccines to include children ages 6 months through 5 years.
• The Commonwealth Health Foundation study published on 12/13 found that from December 2020 through November 2022 the COVID-19 vaccination programs prevented more than 18.5 million additional hospitalizations and a 3.2 million additional deaths.
• National-level data shows a slight decrease (compared to the prior week) in new hospital admissions of pediatric patients with confirmed COVID-19. New admissions of elderly patients also decreased since the week ending in 12/03. However, new admissions of patients with confirmed COVID-19 have shown a continuous upward trend overall that began in late October. While there is a decrease since the prior week, which accounted for a spike in activity due to the Thanksgiving holidays, the COVID-19 confirmed cases and new hospital admissions continue to rise. As of 12/10, compared to the average admissions for the week ending 12/03:
• People ages 0-17: -5.0% new admissions per 100,000
• People ages 70+:  -5.8% new admissions per 100,000
• If the upward trend of COVID-19 hospitalizations, not accounting for spikes that might be attributed to holidays, continues into the respiratory season, healthcare institutions might end up dealing with compounded crisis conditions and surge, putting further strain on healthcare infrastructure and workforce of these multiple populations.
• The COVID-19 public health emergency (PHE) provides a variety of federal, state, and local flexibilities in regulation and funding support for the response to RSV and flu. If the COVID-19 PHE is not renewed before its expiration mid-January 2023, between 5.3 and 14.2 million Medicaid enrollees could lose their coverage between January and April 2023.
• Federal funding for COVID-19 vaccines might run out as early as in January 2023, at which point COVID-19 vaccines and therapeutics will become available only via the commercial market. 
• According to an analysis from the Kaiser Family Foundation, “private insurers will be required to take on more of the cost of vaccines (including paying for the doses themselves once the federal supply runs out), which could have a small upward effect on premiums.”
• Implications for how these changes may affect vaccine availability and out-of-pocket costs to patients will become clearer as the commercial cost of vaccines and mechanisms for distribution and purchasing are defined.

Health Equity Concerns

• Some reporting suggests pediatric patient transport, which is already constrained due to staffing, availability of hospital beds that are staffed to receive a patient, and specific supplies needed to transport a child, is especially challenging for rural areas. Ability for rural areas to move patients, especially across state lines, may be limited.
• Children’s hospitals around the nation are experiencing long emergency room wait times, and many hospitals are being forced to consider a choice between turning away patients or stretching staff further, This type of conflict is occurring more frequently in areas with fewer resources and fewer hospitals/physicians. This leaves those already underserved, more vulnerable as hospitals battle increasing admissions.
• Children with underlying conditions, especially obesity and diabetes, are more likely to experience severe COVID-19 and hospitalization. According to data from CDC’s COVID-19 Associated Hospitalization Surveillance Network (COVID-NET), during the 2021-2022 Omicron surge (December 2021 – February 2022): 70% of hospitalized children had an underlying medical condition, 19% were admitted to an intensive care unit, and children with diabetes and obesity were more likely to experience severe COVID-19.
• For the limited areas tracked by CDC’s RSV-NET* for the week ending 12/10, hospitalization rates for all races and ethnicities have fallen compared to the previous week.
• RSV-NET data shows a continued downward trend in reported RSV-associated hospitalizations. 

Potential Threats for Pediatric Medical Surge

Several challenges are unique to managing pediatric medical surges, particularly for the healthcare workforce and supply chain. For one, pediatric hospitals require more intensive nursing resources to treat and monitor patients, especially in intensive care and neonatal intensive care units.
 
Additionally, pediatric supply chains can also be more vulnerable to supply chain disruptions, as some critical products have only one supplier or manufacturer capable of producing the necessary pediatric-specific equipment and supplies.

Product Availability

• Amoxicillin
• Amoxicillin remains in short supply.
• The majority of amoxicillin production facilities are located overseas. Domestic amoxicillin capacity is limited by staffing and active pharmaceutical ingredients (API) constraints, as well as reduction of capacity due to low demand in recent years.
• The lack of guaranteed demand prior to the respiratory season is driving a lack of surge capacity. Manufacturers of amoxicillin and other antibiotics typically determine production amounts prior to respiratory season based on the amount ordered. Manufacturers typically do not manufacture additional product beyond what is ordered because profit margins for the product are small; it would be a major risk to overproduce and not sell additional product. Contracts that guarantee demand (between manufacturers and government, distributors, and/or providers) may help mitigate shortages for future respiratory seasons.
• As of 12/8, multiple forms of amoxicillin remain on the FDA and ASHP drug shortage lists. This includes tablets, capsules, and powder for suspension. Providers and patients continue to experience impacts.
• The American Academy of Pediatrics reported on alternative therapies during the shortage.
• Tamiflu (oseltamivir)
• Tamiflu and its generic oseltamivir remain in high demand.  As of 11/29, both the oral suspension and capsule formulations of oseltamivir remain on the ASHP shortages list. Oseltamivir is not currently on the FDA shortage list.
• Other alternative influenza antivirals include Xofluza, Rimantadine, Zanamivir. There are no reported shortages for these drugs. 
• Updated as of 12/5: FDA’s list of available antiviral medications for the 2022-2023 influenza season. 
• FDA notes that while certain variations of Tamiflu are unavailable, there are no reported shortages (as of 12/7) among many companies.
• Many over-the-counter pediatric pain relievers (ibuprofen and acetaminophen) are experiencing spot shortages locally. With the exception of ibuprofen oral suspension (prescription only), which is on the ASHP Shortages list, these products are not yet on the ASHP or FDA Drug Shortage lists.
• The shortages of pediatric pain relievers as well as influenza and other respiratory illness medications will have compounding impacts on the surge in hospitalizations. If parents and caregivers cannot find medication for their sick children, their condition may worsen, and the parents will have no choice but to bring their children to the pediatric hospital or emergency room where we continue to see long wait times for access to healthcare. It is critical to continue mitigating supply chain disruptions around the pediatric drug shortage before hospitalization rates increase further.
• ASHP’s current drug shortages list includes the following drugs that could negatively impact treatment of RSV and other respiratory illnesses:
• As of 12/12: 0.9% Sodium Chloride Small Volume Bags (< 150 mL) of various sizes from six different companies have been added. There are a multitude of reasons for the shortage including increased demand, manufacturing delays, and labor shortages. A number of the companies have supplies on allocation as they work through this shortage while Fresenius Kabi expects a release date of mid-to-late December.
• As of 12/9: 0.9% Sodium Chloride Large Volume Bags of various sizes from five different companies have been added. The majority of companies stated that the reason for the shortage was due to an increase in demand. Additionally, a majority of the companies have product on allocation to their customers while Fresenius Kabi estimates a release date of mid-to-late December for the 250, 500, and 1000 mL bags.
• As of 11/30: Ibuprofen Oral Suspension (Prescription Products Only) from Teva has been added. While no reason for the shortage has been provided, we can assume it is due to or exacerbated by the surge of respiratory illnesses impacting the nation. There has been no estimated resupply date.
• While not listed on the ASHP and FDA Drug Shortage lists, other over-the-counter pediatric pain relievers (ibuprofen and acetaminophen) are experiencing spot shortages.
• As of 12/2: Oseltamivir Oral Suspension and Capsules of various sizes from 10 different companies have been added. While no reasons for the shortage was provided by the companies themselves, we can assume it was due to the increase in demand from the recent surge in respiratory illnesses. It is important to note that some formulations of the product are listed as “available.” The sizes/formulations that are in shortage will either release in late December 2022, are on allocation right now, or the company cannot estimate a release date.
• As of 12/6: 0.9% sodium chloride vials of various sizes from Fresenius Kabi and Pfizer have been added. The shortage is likely caused by increased demand, related to the application of sodium chloride for respiratory therapy. Pfizer has 0.9% sodium chloride 10 mL vials on backorder and the company estimates a release date of May 2023. Fresenius Kabi has 0.9% sodium chloride 10 and 20  mL vials on backorder and the company estimates a release date of mid- to late-December 2022.
• As of 12/6: 23.4% Sodium chloride injection of various formulations from Fresenius Kabi and Pfizer have been added. Both Fresenius Kabi and Pfizer have said the shortage is due to an increase in demand. Expected resupply dates are from mid-December 2022 to January 2023.
• As of 11/28: Ceftazidime Injection (and its generic name Tazicef) from Pfizer, Sagent, and BBraun have been added. The shortage is due to increased demand, likely due to the fact that ceftazidime is used to treat a wide variety of bacterial infections and providers could be prescribing this drug as a remedy to respiratory symptoms.
• As of 11/29: Rocuronium injection, used during tracheal intubation, is in shortage from several manufacturers due to increased demand and manufacturing delays. Estimated resupply dates vary based on manufacturer. 
• FDA’s drug shortage database lists the following updates regarding drugs that may be related to treating respiratory illness:
• Reverified on 12/2: Amoxicillin oral powder for suspension is available for current customers from Hikma pharmaceuticals. As of 12/6 most of the amoxicillin oral powder product for suspension from Sandoz is unavailable while some has limited availability. Additionally, as of 12/6, products from Aurobindo and Teva are on allocation.
• Reverified on 12/6: albuterol sulfate, a bronchodilator for oral inhalation, manufactured by Akorn Pharmaceuticals, remains unavailable and is estimated to be back in stock by Q2 2023. A 5 mL version from Nephron Pharmaceuticals is available.
• FDA’s medical device shortage database lists the following updates regarding medical devices that may be related to treating respiratory illness:
• As of 10/31: two ventilation-related products are on  the FDA medical device shortage list – JOH (Tube Tracheostomy And Tube Cuff) and BTO (Tube, Tracheostomy (with and without Connector).
• Definitions for product shortage vary by organization. Healthcare Ready sources data from multiple organizations that maintain drug shortage lists, including:
• American Society of Health-System Pharmacists (ASHP), which defines a drug shortage as “a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent.”
• US Food and Drug Administration (FDA), which defines a drug shortage as “a situation where the total supply of all versions of the approved product available at the user level will not meet the current demand, and a registered alternative manufacturer will not meet the current and/or projected demands for the potentially medically necessary use(s) at the user level.”
• On 11/22, the FDA issued an emergency use authorization (EUA) for the Lucira COVID-19 and influenza multiplex test for use in a point-of-care (POC) setting. This will expand the testing kit pool as well as reduce the strain on the testing kit supply chain as two tests are combined into one.

Treatments for RSV

A monoclonal antibody therapy called palivizumab is available as a precautionary measure to prevent severe RSV illness in certain infants and children at high risk for severe disease during the normal respiratory season. It cannot cure or treat children who are already suffering from severe cases of RSV; it is a preventative treatment.

• On 11/17, AAP updated its guidance: Given the known efficacy of palivizumab along with the unpredictable surge capability of RSV, AAP recommends programmatic consideration of providing more than five consecutive doses of palivizumab depending on the duration of the current RSV surge in a particular region of the country.
• Palivizumab is sold under the brand name Synagis, and is marketed by Sobi in the United States. Sobi purchased US rights to Synagis from AstraZeneca in 2018. Before COVID-19, physicians prescribed Palivizumab more frequently as a preventative measure, yet, this treatment strategy slowed during the pandemic.
• AAP says that it recommends Palivizumab in eligible infants in regions that are experiencing high rates of RSV and that it will release updated guidance as they monitor the seasonal trends.

Workforce Shortages
Workforce shortages continue to impact access to care in hospitals around the country. Resident physicians, doctors, hospitals staff are advocating for increased federal support.
 
Ongoing workforce shortages may threaten the ability of facilities to establish a predictable quality of care for patients. Because pediatrics is a specialty practice, there may be additional strain on the workforce with pediatric care experience. Reports indicate that pediatricians are requesting increased federal support as they deal with RSV, COVID-19, and influenza treatment in unison. Physicians state that they can only successfully handle this “tripledemic” with the assistance of a federal emergency declaration and dissemination of support. The Administration for Strategic Preparedness and Response (ASPR), Technical Resources, Assistance Center, and Information Exchange (TRACIE) team has a staffing resources section on their pediatric surge response resources page, which can be found here.
 
Hospitals and other healthcare facilities may need to increase surveillance for respiratory illnesses among staff to reduce the spread and the potential for staff being out sick. Practitioners’ mental health should also be considered and protected. Additional training and support for practitioners that are not used to caring for acute pediatric cases for prolonged periods should be provided whenever possible.