It is hard to believe that 2022 (Chinese zodiac Year of the Tiger) has started. We begin the year, unfortunately, with COVID-19 still front and center of health care news. The Omicron variant has, as of this writing, spread to more than 110 countries, including here in the United States. This variant contains 30 mutations in the spike protein, which makes it highly transmissible and has been noted to be the most rapidly spreading of all the SARS-CoV-2 variants. The current COVID-19 vaccines provide some protection against this variant, although less than against the other variants. The risk for breakthrough infections and hospitalizations among those that are fully vaccinated is increased with the Omicron variant.

On a more promising note, ever since the US Food and Drug Administration granted emergency use authorization for the Pfizer/BioNTech vaccine for children aged 5 to 11 years, an estimated 20% of those in this age group (as of this writing) have received at least 1 dose of the vaccine. Let’s hope this trend continues.

This month’s January/February issue packs a number of must-read articles:

 features an excellent piece on harmful pharmaceutical excipients (eg, protein stabilizers, solvents, preservatives). We don’t think about this problem very often, but some of these agents can cause adverse reactions in certain patients.

 section offers a sobering look at the gun violence crisis, and particularly the dangers it presents for children in underserved areas. This includes commentary by Steven Selbst, MD, a member of the 

 explores the reasons behind the poor eating habits of adolescents. It also provides some practical recommendations for ways to improve their food choices.

Respiratory and Infections Diseases section

 discusses the crossover symptoms of COVID-19 and influenza, infections that everyone will be seeing in their practices. This piece was cowritten by Russell Libby, MD, also a member of the Contemporary Pediatrics® editorial board.

Thank you for providing outstanding care to your patients during these rapidly changing times. “Wishing you a Happy New Year! May it be filled with new adventures and good fortunes.” (Anonymous.)

Please stay safe and well. As always, I welcome your suggestions, comments, and questions.

Articles

Editor-in-chief Tina Q. Tan, MD, FAAP, FIDSA, FPIDS reflects on what 2022 may hold and shares her must-read articles from the January/February issue.

What might 2022 hold?

A 5-month-old girl with a large scalp infantile hemangioma (IH), present since 6 weeks of age, was evaluated in the emergency department for lethargy and pallor. Two days prior, the patient’s mother witnessed significant bleeding from the tumor that resolved spontaneously.

The patient had been on propranolol 2 mg/kg/day for 2 months, managed by an outside provider. On exam, a segmental, mixed-type IH measuring 112.5 cm

 was evident on the right temporoparietal and occipital scalp, with foci of ulceration and hemorrhagic crust.

Laboratory results showed that the patient’s hemoglobin was 5.7 g/dL. Her platelet count and coagulation studies were normal. Magnetic resonance imaging (MRI) of the brain and magnetic resonance angiography (MRA) of the head and neck revealed an intensely enhancing mass fed by numerous branches of the internal and external carotid and vertebral arteries. The tumor completely encased the right internal carotid artery and internal jugular vein without significant narrowing and infiltrated the right paraspinal muscles and parapharyngeal, carotid, retropharyngeal, and masticator spaces. No additional vascular anomalies were identified other than an aberrant right subclavian artery arising distal to the left subclavian, possibly a normal variant. Cardiology did not recommend routine monitoring based on this finding. There were no additional findings concerning for PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies).

The patient was transfused with 15 cc/kg of packed red blood cells. Propranolol was increased to 3 mg/ kg/day and prednisolone 1 mg/kg/ day was initiated. The lesion responded well to treatment and, after 1 month, had decreased in size with- out recurrent hemorrhage (Figure 1). Figure 2 depicts the lesion 6 months following hemorrhage and demonstrates further reduction in size.

Given the history and morphology of the patient’s tumor, IH was the most likely diagnosis. However, certain differential diagnoses may be considered in an infant with a similar lesion. Onset and natural history are the most important factors distinguishing IHs from other vascular anomalies of infancy (Table 1). Congenital hemangiomas are present at birth and appear as violaceous or pink vascular plaques or exophytic masses with peripheral pallor, typically on the head, neck, or limbs. They can be divided into rapidly involuting congenital hemangiomas (RICH), noninvoluting congenital hemangiomas (NICH), and partially involuting congenital hemangiomas (PICH) based on their clinical course. Because proliferation of these tumors occurs in utero, congenital hemangiomas are fully formed at birth and do not typically grow postnatally, unlike IHs, which characteristically undergo self-limited proliferation followed by spontaneous involution. Tufted angiomas (TAs) and kaposiform hemangioendotheliomas (KHE) are rare vascular tumors that fall under the same neoplastic spectrum and may clinically resemble IHs. TAs appear as indurated, dusky to red plaques or nodules with ill-defined borders, and KHEs present as purpuric subcutaneous masses. TAs and KHEs typically manifest in the first few years of life on the trunk or extremities and, in contrast to IHs, they rarely involve craniofacial areas and do not regress over time. Of note, KHE, and less commonly TA, can be complicated by Kasabach-Merritt phenomenon, which is a life-threatening condition characterized by consumption coagulopathy and thrombocytopenia. Vascular malformations are structural anomalies comprised of capillaries, arteries, veins, and/or lymphatic vessels. They may appear morphologically similar to deep IHs, but are commonly present at birth, grow proportionally with or more rapidly than the child, do not spontaneously regress and can progress in adulthood. We diagnosed this as a case of exceedingly rare, life- threatening hemorrhage from a large IH on the scalp.

IHs are the most common vascular tumors in infants and become clinically apparent within the first days to months of life. Approximately half appear on the head and neck. They are classified by pattern: localized (focal), segmental (large lesions spanning a linear/geographic territory), or multifocal, as well as by type: superficial (bright red papule/plaque), deep (skin- colored to blue nodule), or mixed (both superficial and deep components). IHs classically undergo a proliferative phase, which is most rapid in the first several months and can last up to 1 year. This is followed by a gradual involution phase, with most involution occurring by 3 to 4 years of age. Thicker hemangiomas leave behind fibrofatty residue that may be amenable to excision, but scarring can be significant. American Academy of Pediatrics (AAP) guidelines exist to help pediatricians identify high-risk IH that require early treatment with propranolol.

 usually during the proliferative phase when demand surpasses blood supply to proliferating capillaries. Mild bleeding is common in ulcerated IH but is rarely clinically significant.

 Life-threatening hemorrhage is exceedingly rare, with only 5 other reported cases in the literature, 4 of which required transfusion (Table 2).

 Most occurred in large, bulky mixed-type IHs, known to have increased risk of ulceration, severe bleeding, and a prolonged proliferative phase.

 These IHs likely had numerous large or anomalous feeder vessels more readily damaged by minor trauma or ulceration. Imaging with arteriography may be helpful in further characterizing the extent of feeder vessels that supply these lesions and may aid in risk stratification for potential hemorrhage. In 1 case of a neck IH, arteriography demonstrated feeders from an aberrant collection of vessels from the thyrocervical trunk, subclavian, external carotid, and vertebral arteries.6 MRA of our patient’s IH demonstrated numerous feeders from the internal carotid, external carotid, and vertebral arteries. The lesion also extended into internal spaces and encased critical vessels. Theoretical complications include internal hemorrhage, serious infection, and massive stroke. The extent of the other reported IHs on imaging was not described, possibly due to inconsistent imaging prior to 2016 PHACE syndrome screening guidelines.

A subset of bulky mixed-type IHs are at a small but serious risk of hemorrhage and should counsel families accordingly. Imaging with MRI and MRA should be performed of large (> 5 cm), bulky, segmental, mixed-type IHs of the head and neck as soon as possible to characterize blood supply, anatomic boundaries, and complication risk.

 AAP guidelines help identify high-risk hemangiomas that require early treatment with propranolol.

 Life-threatening hemorrhage from IHs warrants further study to optimize risk stratification.

1. Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical practice guideline for the management of infantile hemangiomas. 

2019;143(1):e20183475. doi:10.1542/peds.2018-3475

2. Charny JW, Moon AT, Treat JR. Scalp infantile hemangioma complicated by life-threatening bleeding. 

2017;34(4):473-475. doi:10.1111/pde.13171

3. Yildirimcakar D, Demirsoy U, Azizoglu M, Corapcioglu F. Evaluation of clinical properties and treatment responses of infantile hemangioma. 

2020;19(12):1156-1165. doi:10.36849/JDD.2020.5009

4. Darrow DH, Greene AK, Mancini AJ, Nopper AJ. Diagnosis and management of infantile hemangioma. 

2015;136(4):e1060-1104. doi:10.1542/peds.2015-2485

5. Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicenter prospective study of ulcerated hemangiomas. 

2007;151(6):684-689.e1. doi:10.1016/j.jpeds.2007.04.055

6. Connelly EA, Viera M, Price C, Waner M. Segmental hemangioma of infancy complicated by life-threatening arterial bleed. 

2009;26(4):469-472. doi:10.1111/j.1525-1470.2009.00955.x

7. Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome: consensus-derived diagnosis and care recommendations. 

2016;178:24-33.e22. doi:10.1016/j.jpeds.2016.07.054

A 5-month-old girl with a large scalp infantile hemangioma (IH), present since 6 weeks of age, is evaluated in the emergency department for lethargy and pallor. 

Severe hemorrhage from infantile hemangioma

The United States Pharmacopeia (USP) defines pharmaceutical excipients as substances other than the active pharmaceutical ingredient that is intentionally included in an approved drug delivery system or finished drug product.

 There is a growing body of literature to suggest pharmaceutical excipients contained in commercially available and extemporaneously compounded medications may have adverse clinical effects on pediatric and adult patients. The US Food and Drug Administration (FDA) requires over-the-counter (OTC) products marketed under their respective drug monographs to contain only suitable inactive ingredients which are administered in safe amounts; however, it is entirely under the responsibility of the manufacturer to comply with these standards.

 Due to the vast differences in metabolism and clearance of medications in various stages of development, it is difficult to assess precise harmful levels of pharmaceutical excipients and the extent to which they will impact patients. Pediatric pharmacokinetic and pharmacodynamic profiles can vary drastically, and with this variability ultimately comes variance in safety profiles. Many of these discoveries have been attributed to therapeutic misadventures, such as the discovery of the neonatal gasping syndrome when physicians started to use bacterial static saline flushes containing benzyl alcohol.

 In a 2019 study surveying 42,052 oral solid dosage forms from the Pillbox database, an American database regulated by the National Institutes of Health, medications were found on average to contain 8.8 inactive ingredients.

 Given the overall prevalence of potentially harmful pharmaceutical excipients in various medications, the potential risks posed to children remains a pertinent topic for discussion.

Ethanol is the second most commonly used solvent in oral liquid medications, preceded by water. Ethanol additionally has antimicrobial properties. Patients with impaired alcohol dehydrogenase enzyme systems, including children aged less than 6 years, patients with hepatic disease, and patients treated with disulfiram or metronidazole are at greatest risk of toxicity, as alcohol dehydrogenase activity is less than 20% of adult enzymatic activity in children under the age of 6 years. Prenatal exposure to ethanol may result in fetal alcohol syndrome. The FDA, American Academy of Pediatrics (AAP), and European Medicines Agency (EMA) have all published dose limits related to ethanol-containing medications; however, these standards are based on acute central nervous system (CNS) toxicity after single-dose administration.

 Although most are familiar with the signs and symptoms of ethanol intoxication and acute poisonings in adults, children may present with hypoglycemia, hypothermia, acidosis, tachycardia, seizures, and disorders of consciousness. These effects should be treated promptly with supportive care measures and the drug should be discontinued if possible. Very little is understood about the longterm effects of ethanol exposure in children; however, the clinical benefits of administering ethanol-containing medications may outweigh the potential risks. For this reason, administration of extemporaneously compounded buprenorphine sublingual drops (30% ethanol), phenobarbital elixir and oral solution (15% ethanol), and methadone oral solution (9.8% ethanol) in neonatal abstinence syndrome has remained controversial. Additional examples of medications containing ethanol include dexamethasone oral solution (30% ethanol), furosemide oral solution (11.5% ethanol), digoxin oral solution (10% ethanol), and many others. Alternative formulations or medications should be considered if possible, especially when the product contains more than 5% ethanol by volume.

Propylene glycol is a solvent used in many oral, topical, and intravenous medications and as a humectant in some topical medications. It is metabolized to lactaldehyde by alcohol dehydrogenase. Lactaldehyde is converted by aldehyde dehydrogenase to lactate, and accumulation may lead to an anion gap metabolic acidosis. Propylene glycol may additionally result in direct organ toxicity through an unknown mechanism, manifesting as CNS depression and seizures, cardiac arrhythmias, hypotension, respiratory depression, hemolysis, and acute kidney injury. Patients with impaired alcohol dehydrogenase systems, as discussed in the ethanol section above, and renal impairment are at greatest risk. This becomes most clinically relevant in patients receiving continuous infusions of medications containing propylene glycol as an excipient. Examples include esmolol (25% propylene glycol), lorazepam (80% propylene glycol), and phenobarbital (40% to 70% propylene glycol). Manifestations of toxicity should be treated promptly and the drug should be discontinued if possible. Propylene glycol can be removed by hemodialysis. Topical administration may result in contact dermatitis. Systemic toxicity has been reported rarely in patients with a damaged stratum corneum (eg, severe diaper rash, burns, toxic epidermolysis), including patients receiving silver sulfadiazine cream for burns. However, propylene glycol is highly water soluble and therefore not expected to be absorbed through the dermis in any appreciable amount. Routine, intermittent administration of oral, topical, and intravenous medications containing propylene glycol is generally considered safe. Clinicians should use caution and monitor lactate, comprehensive or basic metabolic panel, anion gap, serum osmolarity, pH, and neurologic, cardiovascular, and respiratory status in patients at risk for accumulation and systemic toxicity, particularly those on continuous infusions.

Benzalkonium chlorides (BAC) are cationic surfactants commonly used for their broad-spectrum antimicrobial properties in topical sanitizers, nasal sprays, ophthalmic solutions, and nebulized solutions.

 The mechanism of toxicity is not abundantly clear, but may be related to oxidative stress.

 BAC is generally considered safe and can be found in OTC nasal decongestant sprays, including sodium chloride and oxymetazoline. Nasal sprays containing less than 0.1% BAC have been found to be safe. Some data suggest it may damage the human nasal epithelia and/or cause exacerbation of rhinitis medicamentosa at higher concentrations. When used in ophthalmic preparations such as prednisolone acetate ophthalmic suspension (0.01% BAC), various OTC eye lubricants, and others, BAC may cause dry eye, trabecular meshwork degeneration, ocular inflammation, and mitotoxic effects.

 Adverse effects have been demonstrated in concentrations as low as 0.0001%. Recommending short courses of BAC-containing nasal sprays or ophthalmic products is the ideal way to avoid these adverse effects. Examples of inhaled medications containing BAC include nonsterile, multidose 0.5% albuterol solutions; nonsterile, screw-cap, unit-dose 0.083% albuterol nebulizer solutions; and nonsterile, multidose metaproterenol solutions. Use of BAC-containing products has resulted in poor pulmonary outcomes including decline in forced expiratory volume 1 by 20% or more, increased risk of requiring additional respiratory support, and lower likelihood of stopping continuous albuterol in patients with asthma when compared to preparations without BAC.

 Albuterol preparations without BAC should be used preferentially as they are now available as 5-mg/mL multidose concentrate for continuous nebulization and 2.5 mg/3 mL-unit dose bullets.

Benzyl alcohol is a preservative used in medications for its antibacterial properties. Due to incomplete liver maturation, benzoic acid may not be converted to the renally excreted metabolite hippuric acid in infants and children. Large administrations in neonates may lead to elevated benzoic acid concentrations, metabolic acidosis, respiratory depression, and gasping syndrome. Gasping syndrome occurs when metabolic acidosis and respiratory depression progress to gasping respirations, renal failure, CNS depression, seizures, and hypotension. Due to these concerns and documented evidence of increased mortality in infants weighing less than 1250 g receiving intravascular catheter washes containing benzyl alcohol, benzyl alcohol is contraindicated in patients less than 3 years of age.

 The EMA has suggested doses greater than 100 to 200 mg/kg/24h are linked to neonatal gasping syndrome.

 A report published by the Centers for Disease Control and Prevention suggested a similar range of 99 to 405 mg/kg/24h may be linked to accumulation of benzyl alcohol in neonates. The FDA recommends the exclusion of benzyl alcohol from medications, intravenous fluids, and heparin washing solutions for newborns. Although benzyl alcohol is commonly found in oral formulations of cetirizine chewable tablets, diphenhydramine tablets, hydroxyurea tablets, montelukast chewable tablets, and olanzapine oral disintegrating tablets, these medications are typically used in older children with the developed metabolic capacity to process benzyl alcohol exposure and are therefore at less risk for toxicity. Benzyl alcohol has been found in some parenteral formulations of aminophylline, amiodarone, bumetanide, diazepam, furosemide, heparin, metoclopramide, midazolam, lorazepam, parenteral vitamin E, multidose vial pediatric trace elements (neonatal single-dose vials should be reserved for neonates), parenteral vitamin K, multivitamin infusion, and trimethoprim-sulfamethoxazole.

 Treatment of complications due to benzyl alcohol are predominately symptom focused (ie, reversal of metabolic acidosis with sodium bicarbonate, management of respiratory depression with increased respiratory support).

Ultimately, there is a paucity of safety data for several of the pharmaceutical excipients discussed. There is a great need for further investigation to evaluate the safety of pharmaceutical excipients. There is also a need for more transparency and improved labeling regarding excipient content of various medications. Clinicians should be mindful of pharmaceutical excipients in medications and monitor for signs and symptoms of toxicity.

Adverse effects of active medicines and pharmaceutical excipients can be characterized as a dose-dependent, immune-mediated (eg, anaphylaxis), or iatrogenic event. The ontogeny of pediatric organ systems has a direct influence on dose-dependent adverse events. Individuals with a history of polyethylene glycol hypersensitivity/anaphylaxis should avoid receiving mRNA COVID-19 vaccines and the commonly used laxative, polyethylene glycol electrolyte solution (eg, Miralax), due to its presence as an excipient and active medicine, respectively. 

- Carlton K.K. Lee, Pharm.D., MPH, FASHP, FPPAG, BCPPS, Pediatric Pharmacy Residency Program director, Johns Hopkins Children’s Center, Baltimore, Maryland

U. S. Pharmacopeia. Sheehan C. Novel excipients: updates on recent survey findings. November 13, 2019. Accessed November 14, 2021. 

https://www.usp.org/sites/default/files/usp/document/stakeholder-forum/2019-11-13-06-novel-excipients-update-on-recent-survey-findings-catherine-sheehan.pdf

United States Food and Drug Administration. Guidance for industry. Nonclinical studies for the safety evaluation of pharmaceutical excipients. Published May 2005. Accessed November 14, 2021. 

Pereira BMP, Tagkopoulos I. Benzalkonium chlorides: uses, regulatory status, and microbial resistance. 

. 2019;85(13):e00377-19. doi:10.1128/aem.00377-19

Reker D, Blum SM, Steiger C, et al. "Inactive" ingredients in oral medications. 

. 2019;11(483):eaau6753. doi:10.1126/scitranslmed.aau6753

United States Food and Drug Administration. Over-the-counter drug products intended for oral ingestion that contain alcohol. Final Rule. 21 Code of Federal Regulations (CFR) Part 328. 2020. Amended November 23, 2021. Accessed November 30, 2021. 

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-328

European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Information for the package leaflet regarding ethanol used as an excipient in medicinal products for human use. Updated September 28, 2018. Accessed November 30, 2021. 

https://www.ema.europa.eu/en/documents/scientific-guideline/information-package-leaflet-regarding-ethanol-used-excipient-medicinal-products-human-use_en.pdf

Meyers, RS, Thackray, J, Matson, KL, et al. Key potentially inappropriate drugs in pediatrics: The KIDs List. 

. 2020;25(3):175-191. doi:10.5863/1551-6776-25.3.175

Kwon D, Lim Y, Kwon J, et al. Evaluation of pulmonary toxicity of benzalkonium chloride and triethylene glycol mixtures using in vitro and in vivo systems. 

. 2019;34(5):561-572. doi:10.1002/tox.22722

Datta S, Baudouin C, and Brignole-Baudouin F, Denoyer A, Cortopassi GA. The eye drop preservative benzalkonium chloride potently induces mitochondrial dysfunction and preferentially affects LHON mutant cells. 

. 2017;58(4):2406-2412. doi:10.1167/iovs.16-20903

Prabhakaran S, Abu-Hasan M, Hendeles L. Benzalkonium chloride: a bronchoconstricting preservative in continuous albuterol nebulizer solutions. 

. 2017;37(5):607-610. doi:10.1002/phar.1929

Pertzborn M, Prabhakaran S, Abu-Hasan M, et al. Continuous albuterol with benzalkonium in children hospitalized with severe asthma. 

. 2020;145(4):e20190107. doi:10.1542/peds.2019-0107

Valeur KS, Holst H, Allegaert K. Excipients in neonatal medicinal products: never prescribed, commonly administered. 

2018; 32(4):251-258. doi:10.1007/s40290-018-0243-9

European Medicines Agency- Science Medicines Health. Committee for Human Medicinal Products Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use (2017). Accessed November 4, 2021. 

https://www.ema.europa.eu/en/documents/scientific-guideline

National Institutes of Health. Arginase deficiency. Genetic and Rare Diseases Information Center. Accessed November 12, 2021. 

https://rarediseases.info.nih.gov/diseases/5840/arginase-deficiency

Durk MR, Jones NS, Liu J, et al. Understanding the effect of hydroxypropyl‐β‐cyclodextrin on fenebrutinib absorption in an itraconazole-fenebrutinib drug-drug interaction study. 

. 2020;108(6):1224-1232. doi:10.1002/cpt.1943

Rouaz K, Chiclana-Rodríguez B, Nardi-Ricart A, et al. Excipients in the paediatric population: a review. 

. 2021;13(3):387. doi:10.3390/pharmaceutics13030387

Johnson K, Maple B, Brion L. Neonatal jaundice. In: McInerny TK, Adam HM, Campbell DE, DeWitt TG, Foy JM, Karnat DM, eds. 

American Academy of Pediatrics Textbook of Pediatric Care.

Sellaturay P, Nasser S, Ewan P. Polyethylene glycol-induced systemic allergic reactions (anaphylaxis). 

. 2021;9(2):670-675. doi:10.1016/j.jaip.2020.09.029

Sellaturay P, Nasser S, Islam S, et al. Polyethylene glycol (PEG) is a cause of anaphylaxis to the Pfizer/BioNTech mRNA COVID-19 vaccine. 

. 2021;5(6)1:861-863. doi:10.1111/cea.13874

McSweeney M, Mohan M, Commins S, Lai SK. Anaphylaxis to Pfizer/BioNTech mRNA COVID-19 vaccine in a patient with clinically confirmed PEG allergy. 

https://www.frontiersin.org/articles/10.3389/falgy.2021.715844/full

Kriegel C, Festag M, Kishore RSK, Roethlisberger D, Schmitt G. Pediatric safety of polysorbates in drug formulations. 

. 2019;7(1):1. doi:10.3390/children7010001

. 2019;136(02):218-221. doi:10.32440/ar.2019.136.02.rev17

Bayraktar Ekincioglu A, Demirkan K. Awareness of healthcare professionals about sorbitol-related diarrhea in pediatrics. 

Journal of Medical and Surgical Intensive Care Medicine

. 2017;8(1):14-18. doi:10.5152/dcbybd.2017.1454

Evidence suggests some pharmaceutical excipients in medications may have adverse effects on pediatric patients. Here’s what you should know.

Harmful excipients for pediatric patients

It is hard to believe that in the fall of 2019, the No. 1 winter viral threat to the health of our communities was influenza. Based on its quasi-predictable genetic markers, we urgently promoted vaccination, stocked up on Clinical Laboratory Improvement Amendments–waived test kits, and prescribed antiviral medications for patients and their families to protect our communities and reduce the potential for spread. Most of us were not prepared for what was coming and how it would dwarf the severity and impact of a viral pandemic that had been the historic standard by which we measured suffering.

COVID-19’s global impact has touched every aspect of our lives and precipitated a redesign of health care as we knew it. The morbidity and mortality seen in the senior and chronically ill populations have not been seen in children, although, as of this writing, hospitalizations for children have been spiking across the United States. It is hard to estimate the incidence and severity from reported data, and the variants and availability of vaccines make it even more so. Before Omicron, 0.1% to 1.8% of children with COVID-19 needed hospitalization, whereas 0.5% to more than 10% of adults (increasing with age) were hospitalized. Less than 0.03% of infected children died; for adults, that rate was about 1% and significantly higher in those over age 65 years. The fatality rate for children is dwarfed by that caused by unintentional accidents.

Hospitalization for influenza and COVID-19 in children has been most notable with specific underlying conditions. A retrospective analysis of 315 laboratory tests confirmed SARS-CoV-2, and 1402 laboratory tests confirmed cases of influenza A and B showed a significant increase in hospitalization for COVID-19 in children who had a neurologic diagnosis with global development delay or seizures (20% vs 8%). COVID-19 and seasonal influenza had similar rates of hospitalization, intensive care unit admission, mechanical ventilation, and duration of ventilator support.

As we became obsessively careful with sanitizers, masks, social distancing, and quarantines, we came to recognize that COVID-19 is very different from influenza. COVID-19 is more contagious and more significant in short- and long-term morbidity yet more variable in its manifestation from asymptomatic to rapidly fatal. Symptoms can be nearly identical and only testing can differentiate, but the overlap seems to stop there, with COVID-19 adding a more diverse menu of symptoms and complications. The Table lists some similarities and differences in symptoms, complications, and the diagnosis and treatment of influenza and COVID-19.

Most pediatricians used a fever and fatigue threshold for testing for influenza, but COVID-19 testing is done for anyone, even those with no symptoms. Incidence and outcomes are all local, and following local epidemiological reports is essential for helping to differentiate what is affecting communities, but with COVID-19, vaccination rates, infection precautions such as masks, and social determinants of health can have a disproportionate impact.

We often overlook some of the complicating features that are so infrequent with influenza in kids but can be devastating. A major difference between influenza and COVID-19 is the expectation that, with influenza, once the illness has subsided, the impact of that infectious agent is over, with the secondary infection or organ damage as separate residua. COVID-19, on the other hand, has the potential to directly incite the immune system and can have lingering effects that are disabling and potentially fatal.

When discussing COVID-19 infection with families, pediatricians will often include a caution for the infrequent possibility for multisystem inflammatory syndrome in children (MIS-C), but probably the most common and actionable concern is cardiac, especially for adolescent athletes. (Of note: Since June 2020, there have also been several reported cases of MIS in adults

). We have come to recognize that myocarditis, pericarditis, and rhythm abnormalities are common to both influenza and COVID-19 yet more common, lingering, and possibly more subtle with COVID-19. The immediate focus on COVID-19 has made it more of a concern and promulgated a set of recommendations for screening patients with specific symptoms and a severity-related algorithm and staged return to sports for adolescent athletes. Although the cardiac problems can be associated with influenza or COVID-19 infection, COVID-19 has the added etiologies of MIS-C and an adverse effect of the vaccine, especially in adolescent male patients.

Both the influenza and the COVID-19 messenger RNA vaccines have seen associated with Guillain-Barre syndrome, but not at the frequency seen with actual infection. The incidence after vaccination is rare enough and the public and individual health benefit large enough to recommend vaccination against both.

Certainly, there are so many other areas of overlap, especially as we see new formulations of vaccines that can adapt and generalize antigens that may provide better specificity and immunocompetence. However, for now we continue to deal with a hit-or-miss influenza vaccine and viral mutations that can reduce vaccine effectiveness and, unfortunately, feed the reluctant and refusers with self-justification. The elevation of COVID-19 and its identity as a pandemic magnifies the reality of both our vulnerability and our potential to effectively respond with the development of vaccines and treatments.

1. Accident statistics. Stanford Children’s Health. Accessed January 10, 2021. 

https://www.stanfordchildrens.org/en/topic/default?id=accident-statistics-90-P02853


2. Song X, Delaney M, Shah RK, Campos JM, Wessel DL, DeBiasi RL. Comparison of clinical features of COVID-19 vs seasonal influenza A and B in US children. 

. 2020;3(9):e2020495. doi:10.1001/jamanetworkopen.2020.20495

3. Multisystem inflammatory syndrome in adults (MIS-A). Centers for Disease Control and Prevention. November 13, 2020. Accessed January 10, 2022. 

4. Guillain-Barré syndrome and vaccines. Centers for Disease Control and Prevention. Updated August 25, 2021. Accessed annuary 7, 2021. 

https://www.cdc.gov/vaccinesafety/concerns/guillain-barre-syndrome.html

5. Pilarowski G, Lebel P, Sunshine S, et al. Performance characteristics of a rapid severe acute respiratory syndrome coronavirus 2 antigen detection assay at a public plaza testing site in San Francisco. 

. 2021;223(7):1139-1144. doi:10.1093/infdis/jiaa802

6. Interim guidance for antigen testing for SARS-CoV-2. Centers for Disease Control and Prevention. Update September 6, 2021. Accessed Jan 10, 2022. 2021.


https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html



7. Interim guidelines for COVID-19 antibody testing. Updated September 6, 2021. Accessed January 10, 2022. 

https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html

As respiratory viruses and COVID-19 variants lurk seemingly everywhere, here’s how best to detect and differentiate.

Crossover symptoms of COVID-19 and influenza

Obesity has increased in many segments of the population over recent decades, including children and adolescents. The COVID-19 pandemic has accelerated that trend, bringing to light changing patterns in eating habits, disparities in access to healthy food, decreased activity, and increased risk of poor health outcomes.

Historically, food was transformed for improved palatability, as well as preservation and storage.

 Foods have been processed to make them more appealing for both convenience and taste. Since the 1970s, ultraprocessed foods have been available in most of the world and over the past 20 years have become a major source of calories, comprising an average of 3 out of 5 calories consumed daily

). Ultraprocessed foods are easy to manufacture, which reduces industrial costs for companies.

 Food corporations have focused on advertising and marketing of these products to improve sales, but eating more ultraprocessed foods leads to a decline in dietary content of important vitamins, minerals, protein, and fiber.

Increased consumption of ultraprocessed foods has paralleled an increase in obesity, now involving low- and middle-income countries as well, contributing to a global health crisis.

 Children are an especially vulnerable population because they have higher nutritional needs for healthy growth, and critical nutrients are often absent from a diet of mostly ultraprocessed foods.

 The number of ready-to-eat meals consumed has significantly increased as well in the United States (Table 1).

 Adequate nutrition is necessary to support the immune system and prevent infection.

 Eating a diet low in nutritional value increases risk of malnutrition and rates of chronic diseases.

The NOVA classification system, developed by investigators at the University of Sao Paulo in Brazil, separates food into 4 categories based on their constitution and alteration. Foods with significant processing classically have been viewed as detrimental to overall health with promotion of weight gain and risk of chronic disease; however, there has been some discussion of the pitfalls that come with the classification system.

 Some foods are processed to add nutrients, such as iron-fortified cereal.

 Processing also may be important to ensure the safety of foods consumed.

Nevertheless, ultraprocessed foods are generally of low nutritional quality with high-energy density and are associated with the development of chronic noncommunicable diseases with long-term effects on health. Consumption of ultraprocessed foods is associated with a high glycemic response and reduced satiety, which may contribute to overeating.

 Noncommunicable chronic diseases, including cardiovascular disease and metabolic syndrome, account for 70% of deaths worldwide.

 foods consumed whole without major alterations or changes. These include fresh or frozen fruits, vegetables, meats, or legumes with minimal processing. The food itself is not changed and is considered a whole food.

 food items used in cooking to add flavor and taste or that are part of unprocessed foods. These include table salt, sugar, oil, and other substances extracted from unprocessed foods.

 foods taken from nature and altered with added substances, often sugar or salt, to create more stable and appealing foods. This includes canned fruits and vegetables, simple breads, and cheeses.

 foods with a combination of several ingredients creating a packaged food or meal that is sustainable, convenient, and appetizing. In addition to added culinary ingredients (sugar, salt, and oils), ultraprocessed foods also include nonculinary products such as high fructose corn syrup and artificial sweeteners.

 Added sugars, saturated fats, emulsifiers, and preservatives can extend the shelf life for months to years.

 Added sugars include brown sugar, cane sugar, confectioner’s sugar, granulated sugar, syrups, and honey. These foods tend to promote inflammation.

 The 2015-2020 Dietary Guidelines for Americans recommended limited intake of added sugars with a goal that sugars be less than 10% of total calories consumed.

Recent research into the dietary habits of adolescents around the world has focused on exposure to ultraprocessed foods. The National Health and Nutrition Examination Survey reviewed 10 cycles of 24-hour dietary recall to understand what children and adolescents were eating daily. They reviewed 2 different time periods, 1999-2000 and 2017-2018 to look at dietary eating habits.

 They found that consumption of ultraprocessed foods increased as children got older, with the highest percentages of daily intake occurring in adolescents.

Adolescence is a crucial time for emotional, mental, and physical development as individuals gain autonomy and independence. Several factors influence eating habits of adolescents, including their physical surroundings and social environment, self-awareness of food preferences and nutritional needs, and their exposure to the digital world of social media and advertisements.

 Adolescents believe the definition of healthy includes a balanced diet, consistent physical activity, and maintenance of a healthy body weight, but they sometimes struggle with how to characterize energy-dense and processed food.

 Food marketing targeted at children and adolescents through television and social media has been linked with a preference for those ultraprocessed foods that tend to be unhealthy.

 In 2009, $1.8 billion was spent on marketing to adolescents of ultraprocessed foods such as sugary carbonated beverages, snack foods, cookies, potato chips, and cakes.

The World Health Organization has recommended reducing advertisements targeted toward children and developing a nutritional criterion for advertising.

 Governing bodies have encouraged a reduction of targeted marking of ultraprocessed foods to children and adolescents. The Better Business Bureau’s voluntary Child Food and Beverage Initiative in 2006 promoted reduced marketing. Seventeen large corporations agreed to advertise only healthy foods to children but in the end only a few companies actually reduced their marketing.

Other governing policy changes such as a soda tax has led to a decreased consumption of soft drinks.

 The National Student Lunch Program has been modified to reduce total calories and to increase fruits and vegetables. These changes have led to a slight decrease in ultraprocessed foods available at schools, however there is still a lot left to do to improve the health of children and adolescents.

The COVID-19 pandemic disrupted dietary habits with the transition from work and school to home for many families. The pandemic heightened the consumption of ultraprocessed foods as schools closed and access to food changed.

 In the early months of the pandemic, more meals were cooked and prepared at home to allow for social distancing and infrequent trips to restaurants and stores. However, this also meant that foods with longer shelf lives and sustainability, such as high-calorie snacks and nonperishable goods, were purchased more often.

 With the economic burden of the pandemic, families attempted to cope with food insecurity by purchasing foods with long shelf lives and low cost to ensure there would be food in the house.

The environment in which food was consumed in the home also has been altered during the pandemic. Adolescents reported eating more snacks rather than daily structured meals, and a study of 24-hour diet recall in several countries found increased intake of ultraprocessed foods during the COVID-19 pandemic’s first year.

 Additionally, sleeping patterns were disrupted, and there was an increase in screen time for both school and leisure, especially in low-income families.

 Given these extra stressors and isolation, adolescents reported an increase in “comfort food” consumption, which also contributed to excess weight gain.

Increased weight gain associated with the pandemic has been documented around the world.

 Previously, weight gain trends were known to occur during summer months when children did not have a regular school schedule with structured physical activity and all meals were consumed at home. During the COVID-19 pandemic, similar trends were seen with weight gain when many children were no longer regularly attending school. A disproportionate burden was seen among low-income households.

The COVID-19 pandemic not only exacerbated racial and ethnic disparities present in the United States with higher rates of COVID-19 infection and severe outcomes in Hispanic and non-Hispanic Black children, but it also disproportionally affected food access in these communities.

 Previously, the National School Health Program benefited children of low-income households, allowing access to predictable meals throughout the week. There were attempts to expand the summer lunch program during the COVID-19 pandemic to provide food to families, however, due to a lack of resources, the efforts proved difficult to implement.

Food deserts are areas in low-income neighborhoods with limited food resources, particularly for healthy and fresh foods such as fruits, vegetables, and whole grains. There is a larger presence of fast-food restaurants and convenience stores offering predominantly ultraprocessed foods.

 Food insecurity is defined as limited or uncertain access to food that is nutritionally adequate due to lack of money or ways to acquire food.

 Households with less financial stability and fewer resources often are those with higher rates of obesity.

 Children living in poverty also are experiencing higher rates of infection and severe disease during the COVID-19 pandemic.

During the COVID-19 pandemic, food insecurity increased and families purchased ultraprocessed foods more often due to lower cost and the foods’ longer shelf life.

 Decisions about the most cost-effective methods to provide food were influenced by lower costs for higher-calorie foods.

 During lockdown with social distancing, acquiring foods became even more difficult for families with food insecurity, and most families experienced a further reduction in income, only exacerbating the problem.

 Food insecurity rates in families tripled 6 weeks after the lockdown and overall food insecurity rates increased by approximately 20% in the United States and contributed to poor quality of diet.

 Children are often aware of their family’s food insecurity despite parental attempts to shelter them of that fact.

For clinicians, engaging with both parents and adolescents during visits creates an environment of shared decision-making, and motivational interviewing can lead to the most success for implementing dietary changes. Potential engaging questions that lead to action are included in Table 2. Utilizing a multidisciplinary approach, including access to behavioral psychologists and dietitians to help with decision-making and meal planning, also can be helpful.

Screening for social determinants of health with a focus on food security is becoming a common practice in pediatrician offices due to the frequency of visits, even if they are virtual. Whereas education is important, it alone does not have the desired impact on food insecurity. Recognition of social stressors associated with poverty is important due to its disruption of development and contribution to chronic disease. Addressing the “hunger vital sign” to screen for food insecurity can be done at all visits, both in person and virtual.

 Normalization and recognition of the struggle that families face, especially during the COVID-19 pandemic, can help families be more willing to discuss options for assistance.

 Primary care providers should be prepared to discuss social determinants of health in addition to having knowledge about weight concerns and obesity. Providing resources to families and ensuring adequate follow-up are crucial to promote long-term health.

 Active and passive referrals for food resources can be done by providing information for food shelters or giving foods directly to families at the visit.

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Disruptions to routines and economic troubles have affected the diets of families. Here’s how to foster better nutrition.

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