The burgeoning drug overdose epidemic in the United States led to more than 100,000 deaths in 2021, which were mostly related to opioid toxicity, according to the Centers for Disease Control and Prevention (CDC).¹ The majority of these deaths have been attributed to synthetic opioids such as fentanyl and its analogs, which caused more than 80% of opioid-related deaths in 2020 — an 18-fold increase since 2013.² While the short-acting opioid antagonist naloxone has become the standard treatment for suspected or known opioid overdose, certain situations may call for additional therapies, such as longer-acting opioid antagonists.
 
Adam Bisaga, MD, professor of psychiatry at the Columbia University Irving Medical Center in New York City, New York, and research scientist at the New York State Psychiatric Institute, discussed various clinical considerations in the treatment of opioid overdose. Among the topics of his research in the area of opioid use disorder (OUD), Dr Bisaga has investigated treatment outcomes associated with long-acting opioid antagonists. He has also been involved in various substance abuse training programs and public health projects on the local, national, and international levels.

Are there any notable updates in the field of opioid antagonists? What should clinicians know about the more recently introduced higher-dose formulations of naloxone?

Naloxone is a widely used, first-line opioid receptor antagonist medication for treating opioid overdose and is administered by medical professionals, first responders, and bystanders in the general public. Its safety and efficacy have been well established. Naloxone is currently available as an intranasal spray (2 or 4 mg) or injection (0.4 or 2 mg). In 2021, the US Food and Drug Administration (FDA) approved a higher strength (8 mg) intranasal spray and a 5-mg injection preparation.^3,4 Naloxone has historically only been available by prescription, but just recently, the FDA announced that some versions of the drug are safe for over-the-counter use.⁵
 
Most of the evidence for the effectiveness and safety of naloxone has come from work with prescription opioid or heroin users. One of the main problems that we are facing right now is how to best approach reversal of overdoses from “street drugs” containing highly potent synthetic opioids, such as nonpharmaceutical fentanyl and its analogs. It is not clear whether the current naloxone formulations are as effective for fentanyl as they have been proven to be for heroin and other opioids. This is because the effects on the body from a fentanyl overdose are different from heroin; in addition to the central decrease of the respiratory drive, fentanyl overdose can include a constriction of respiratory muscles and vocal cords — ie, “wooden chest syndrome” — which is not present during overdoses from other opioids.⁶ Naloxone has very limited to no effect on muscle constriction, which is primarily mediated via the adrenergic system rather than the opioidergic system. Anecdotal reports suggest that multiple doses of naloxone in succession are needed to revive individuals who overdose from fentanyl. The most important factor for reversing fentanyl overdoses is to deliver naloxone as soon as possible, as its onset of action on respiration is much shorter than for other opioids.
 
However, a problem arises when giving a higher initial naloxone dose, as it may cause precipitated withdrawal. Opioid withdrawal symptoms can show up as hyperalgesia, anxiety, nausea, hypertension, and tachycardia. This may develop gradually or suddenly, precipitated by administration of an opioid antagonist or partial agonist.⁷ One of the reasons precipitated withdrawal can be dangerous is that it includes an adrenergic surge, which can further constrict the laryngeal and chest wall muscles, thereby restricting respiration. Therefore, giving several smaller doses of naloxone may be actually safer in patients who are still breathing. If there is no breathing detected, then a higher initial dose would be necessary.

The American Heart Association (AHA) recommends, after initiation of CPR, the use of intranasal or intramuscular naloxone with repeat dosing as needed for acute life-threatening opioid overdose.⁸ Can you discuss naloxone dosing in specific settings to avoid acute opioid withdrawal? If there are concerns regarding concurrent stimulant overdose, what should clinicians be aware of? Can you discuss dose re-administration according to opioid type and duration of action?

A standard approach to an opioid overdose includes protection of the airways and administration of a standard naloxone dose, preferably a 0.4- to 0.8-mg intramuscular or intravenous (IM/IV) injection, or a 2-mg intranasal dose if injection is not available. Higher initial doses of 1- to 2-mg IM/IV should be given to patients with apnea or in cardiorespiratory arrest.⁹ A respiratory support — assisted breathing, with supplemental oxygen if available — is also recommended after naloxone is administered. The clinical response (ie, increase in respiratory rate and pupil dilation) should occur within 2 to 3 minutes following IM/IV administration, but if no response is seen during this time, higher (1- to 2-mg IM/IV, or 4- to 8-mg intranasal) repeated doses should be given at 2- to 3-minute intervals while ventilation and oxygenation are maintained.⁶
 
Naloxone only works for 1 to 2 hours after each dose, whereas it can take 8 to 12 hours for the toxic effects of fentanyl or methadone to start resolving. Therefore, a short-acting agent like naloxone needs to be re-administered several times, or given as an IV infusion, to successfully reverse and prevent the recurrence of the overdose. Redosing of naloxone should be guided by clinical parameters. The primary goal of naloxone administration is to restore ventilation to more than 10 respirations per minute and oxygenation above 92% rather than full alertness, as higher doses of naloxone can precipitate opioid withdrawal and may cause difficulty with controlling agitation. An acute lung injury with hypoxia, rales, and mouth frothing can be seen in rapid overdose reversals in patients with marked hypoventilation.¹⁰

Ideally, all individuals who were found overdosed on opioids would be brought in and observed in the hospital for at least 8 to 12 hours to determine if additional doses of an opioid antagonist medication might be needed. This is particularly important because many individuals have an overdose with multiple sedative or stimulant substances, which may cause unpredictable clinical outcomes. The possible synergistic toxic and lethal respiratory and cardiac effects of polysubstance overdose are best assessed and managed with close monitoring.

What is the clinical utility of long-acting opioid antagonists in acute opioid overdose?

Nalmefene is a long-acting opioid receptor antagonist. As compared with naloxone, nalmefene is more potent and approximately 4 times longer acting, which means it has a particular advantage for reversing overdoses from long-acting opioids such as fentanyl or methadone.¹¹
 
Since naloxone only works for 1 to 2 hours after each dose and the toxic effects of fentanyl or methadone can take 8 to 12 hours to start resolving, a short-acting agent like naloxone needs to be re-administered several times to successfully reverse and prevent the recurrence of the overdose. With nalmefene, however, only 1 dose can have the same effect as multiple consecutive doses of naloxone, which is important in the case of a patient who is revived and does not want to go to the hospital, as is often the case. Additionally, nalmefene is more effective at removing fentanyl from the opioid receptors of the brain as compared with naloxone, producing faster and more complete reversal of the overdose.¹²
 
One of the downsides to nalmefene is that if the dose is too high, the precipitated withdrawal that can follow may take longer to resolve than in situations where a short-acting medication like naloxone was used. However, considering how lethal fentanyl is, it appears that nalmefene might be a more effective intervention for fentanyl overdose. Although precipitated withdrawal symptoms are extremely unpleasant, they are not life threatening. The effectiveness and safety of nalmefene in the clinical setting of fentanyl overdose reversals has not been studied.

Can you review reversal of respiratory depression associated with partial opioid agonists such as buprenorphine?

Buprenorphine is a partial agonist at the opioid receptors, which means that the opioid effect it exerts is limited to approximately only 50% of the maximum effect that heroin or methadone can produce.¹³ Moreover, there is a “ceiling” on the respiratory depression buprenorphine may produce, even if very high doses are taken. Because of these properties, buprenorphine is considered to be relatively safe if taken in an overdose. The 2 exceptions are overdoses in the pediatric population or if buprenorphine is taken as a high-dose IV injection in combination with other agents that can reduce respiration, such benzodiazepines or alcohol.⁸
 
Because buprenorphine binds very strongly with the opioid receptor, naloxone has a limited effect to reverse buprenorphine-induced overdose, though it is usually administered in such cases. It is not clear if nalmefene might be more effective for reversal of buprenorphine overdose. Interestingly, buprenorphine can be used to reverse overdose from long-acting opioids such as fentanyl or methadone because it can out-compete those agents at the receptor site while having less opioidergic activity, therefore reducing the overall net opioid effect, such as respiratory depression.⁸ This approach, though effective in anecdotal reports, has not been formally tested.

What are remaining gaps in terms of clinician knowledge regarding the opioid overdose strategies?

The emergence of fentanyl contamination has been linked to a massive increase in the risk for overdose in individuals using “street” opioids and stimulants.⁶ Therefore, all medical practitioners should be familiar with strategies to prevent opioid overdose and provide them to all patients for the greatest public health impact. This primarily includes a prescription for naloxone with instructions on when and how to use it or a link to services providing mail-delivered naloxone and overdose education. In addition, these efforts should include information on harm-reduction interventions such as low-barrier treatment with buprenorphine, syringe exchange programs, services or take-home strips that can test the drug supply for fentanyl, and education on decreasing overdose risk in active drug users.

This Q&A was edited for clarity and length.

Disclosures

Adam Bisaga, MD, reported affiliations with Alkermes, plc.

References

1. Spencer MR, Miniño AM, Warner M. Drug overdose deaths in the United States, 2001-2021. NCHS Data Brief. 2022;(457):1-8. doi:10.15620/cdc:122556
 
2. Centers for Disease Control and Prevention. Synthetic opioid overdose data. Updated June 6, 2022. Accessed January 10, 2023. https://www.cdc.gov/drugoverdose/deaths/synthetic/index.html
 
3. FDA approves higher dosage of naloxone nasal spray to treat opioid overdose. News release. US Food and Drug Administration. May 11, 2021. Accessed January 20, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-higher-dosage-naloxone-nasal-spray-treat-opioid-overdose
 
4. FDA approves naloxone injection to counteract opioid overdoses. US Food and Drug Administration. October 18, 2021. Accessed January 20, 2023. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-naloxone-injection-counteract-opioid-overdoses
 
5. FDA announces preliminary assessment that certain naloxone products have the potential to be safe and effective for over-the-counter use. News release. US Food and Drug Administration. November 15, 2022. Accessed January 10, 2023. https://www.fda.gov/news-events/press-announcements/fda-announces-preliminary-assessment-certain-naloxone-products-have-potential-be-safe-and-effective  
 
6. Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2022;233:108019. doi:10.1016/j.pharmthera.2021.108019
 
7. Neale J, Strang J. Naloxone — does over-antagonism matter? Evidence of iatrogenic harm after emergency treatment of heroin/opioid overdose. Addiction. 2015;110(10):1644-52. doi:10.1111/add.13027
 
8. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-associated out-of-hospital cardiac arrest: distinctive clinical features and implications for health care and public responses: a scientific statement from the American Heart Association. Circulation. 2021;143(16):e836-e870. doi:10.1161/CIR.0000000000000958
 
9. Tylleskar I, Gjersing L, Bjørnsen LP, et al. Prehospital naloxone administration – what influences choice of dose and route of administration? BMC Emerg Med. 2020;20(1):71. doi:10.1186/s12873-020-00366-3
 
10. Jordan MR, Morrisonponce D. Naloxone. In: StatPearls. StatPearls Publishing; 2022.
 
11. Edinoff AN, Nix CA, Reed TD, et al. Pharmacologic and clinical considerations of nalmefene, a long duration opioid antagonist, in opioid overdose. Psychiatry Int. 2021;2(4):365-378. doi:10.3390/psychiatryint2040028
 
12. Krieter P, Gyaw S, Crystal R, Skolnick P. Fighting fire with fire: development of intranasal nalmefene to treat synthetic opioid overdose. J Pharmacol Exp Ther. 2019;371(2):409-415. doi:10.1124/jpet.118.256115
 
13. Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol. 2004;2(4):395-402. doi:10.2174/1570159043359477

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

To increase protection against currently circulating variants of the SARS-CoV-2 virus and associated complications, the US Food and Drug Administration (FDA) recently granted approval or emergency use authorization (EUA) for several updated COVID-19 vaccines. The 2023 to 2024 formula mRNA vaccines by Moderna and Pfizer-BioNTech were approved on September 11, 2023, for use in individuals aged 12 years and older and granted EUA for those aged 6 months to 11 years. The updated adjuvanted, protein-based COVID-19 vaccine by Novavax received EUA on October 3, 2023, for use in patients aged 12 years and older.¹ The COVID-19 vaccination can offer protection against the long-term effects of SARS-CoV-2 infection.²
 
Elie Saade, MD, MPH, is a researcher and director of infection control at University Hospitals in Cleveland, Ohio. Among other accomplishments in his clinical role, he has been honored for his work leading multidisciplinary teams in interventions aimed at reducing hospital-acquired infections. In this article, Dr Saade describes updates in the understanding and treatment of long COVID and the potential role of the updated COVID-19 vaccines in reducing the risk for related complications.

How has the understanding of long COVID changed since it was first recognized, and what are current perspectives on the underlying pathophysiology?

Since the recognition of long COVID, or postacute sequelae of SARS-CoV-2 infection (PASC), the understanding of its pathophysiology has evolved significantly. Initially, there was a lack of consensus on the definition and classification of long COVID. Many studies focused on individual symptoms rather than defined phenotypes. This approach was further complicated by a disproportionate inclusion of individuals with a history of severe acute COVID-19 illness, which may have skewed the understanding of the condition.
 
The initial focus was on the lingering effects of acute infection, with symptoms believed to be a continuation of acute COVID-19 pathology associated with the direct viral damage caused by SARS-CoV-2. However, as research progressed, a more complex picture emerged, and studies revealed a wide range of symptoms affecting multiple organ systems, indicating that the impact of the infection was systemic rather than localized to the respiratory system.³
 
Moreover, emerging evidence revealed that long COVID could affect individuals regardless of the severity of the initial infection; however, the severity and number of symptoms during acute illness are still considered risk factors for long COVID.⁴ The current perspectives on the underlying pathophysiology of long COVID suggest that it is a complex and multifaceted condition. The exact mechanisms are not yet fully understood, but several factors have been proposed. These include immune dysregulation, inflammatory states, vascular compromise through endothelial abnormality and thromboembolic events, microbiota disruption, dysfunctional neurologic signaling, and autoimmunity.³
 
Despite advancements, there are still significant gaps in understanding the specific pathophysiological mechanisms at play and the identification of risk factors predisposing certain individuals to PASC. The elucidation of these mechanisms is imperative for the formulation of targeted therapeutic interventions and prognostic assessments.

What are the current approaches to the diagnosis and management of patients with long COVID? What are some of the rehabilitation strategies that have shown efficacy with these patients?

The clinical management of long COVID is an intricate process that mirrors the condition’s complexity. Diagnoses are primarily clinical, relying on an extensive review of the patient’s medical history, symptoms, and overall function. The US Centers for Disease Control and Prevention (CDC) recommends a thorough evaluation process, emphasizing the need for a customized approach due to the diverse and multiorgan symptomatology of PASC.⁵
 
Similarly, the National Institute for Health and Care Excellence advises a structured assessment, underscoring the importance of a precise clinical case definition. Patients typically present with persistent symptoms following the resolution of acute COVID-19, which can last for more than 4 weeks and are not explained by an alternative diagnosis. The symptom profile can range broadly, with fatigue, shortness of breath, chest discomfort, cognitive issues, and more, all markedly affecting quality of life.⁶ Complementary diagnostic tools such as biomarkers and imaging studies play a supportive role in evaluating specific organ involvement and excluding alternative pathologic entities.⁷
 
Treatment for long COVID remains elusive, with no standard therapy due to its complex nature and varied subtypes. For physicians, it is crucial to adopt an interdisciplinary approach, integrating physical, cognitive, psychological, and social care components. Patient care strategies often involve symptomatic relief, functional rehabilitation, and psychological support.⁶ Treatment modalities are symptom-focused, employing methods such as cough alleviation for persistent coughs or cognitive therapy for concentration difficulties. Rehabilitation protocols aim to rebuild physical capacity and endurance gradually. Mental health interventions address the psychological ramifications of long COVID, employing therapies such as cognitive behavioral therapy.
 
Patient education is central to self-care, with emphasis on techniques for conserving energy and strategically pacing activities. Monitoring and regular follow-ups are essential to dynamically refine management plans in response to symptom evolution. Continual research feeds into this adaptive management model, with clinical trials and cohort studies enhancing the evidence base and informing regularly updated treatment guidelines. Hence, the management of long COVID is an individualized, evolving practice grounded in incremental scientific insight and patient-centered care principles.

What is the role of vaccines such as Spikevax in preventing severe COVID-19 disease and long-term COVID-related complications?

Vaccination against SARS-CoV-2 is essential for pandemic control and mitigating long-term health issues such as long COVID. Research indicates that vaccinated individuals have consistently lower odds of developing long COVID than those unvaccinated.⁸ The relationship between vaccination and long COVID symptoms appears to be significant for certain symptoms, particularly headaches and muscle pain, where vaccinated people experienced these symptoms less frequently than those who were unvaccinated.⁹
 
Overall, the data underscore the role of vaccines in reducing long COVID risk by preventing or lessening the severity of infections in breakthrough cases. Vaccines prime the immune system to recognize and fight the SARS-CoV-2 virus, which could potentially decrease the intensity of the acute phase immune response, enabling faster clearance of the virus and preventing or lessening organ damage, immune dysfunction, and exacerbation of pre-existing conditions.^3,10 Although vaccines were not explicitly designed to prevent long COVID, the evidence suggests a trend toward milder symptoms and reduced effect on patients’ quality of life in social, professional, and personal settings.¹⁰
 
From a public health perspective, widespread vaccination permits the collection of long-term data on immunity and the effectiveness of vaccines against emerging variants, which is essential for understanding and mitigating long-term complications. In summary, vaccination against COVID-19 is a foundational strategy in controlling the pandemic and its associated long-term health impacts, including long COVID. The ongoing research and surveillance continue to reinforce the importance of vaccines in public health strategy and individual protection against COVID-19.

What is the role of booster shots in protecting against the risk for long COVID, and how does the durability of response vary across vaccine types and patient characteristics?

Booster shots enhance and prolong the protective effects of the initial COVID-19 vaccination series, potentially reducing the risk for infection and, by extension, long COVID. Boosters are particularly important in maintaining immunity against emerging variants of concern, which may partially evade the immune response induced by the original vaccine series. Booster shots may prevent severe disease and limit mild infection and transmission. By decreasing the likelihood of breakthrough infections, boosters may reduce the incidence of postacute sequelae associated with COVID-19. Moreover, boosting can increase neutralizing antibody levels and broaden the immune response, which might be critical for preventing the virus from establishing the conditions that lead to long COVID.^11,12
 
Durability of response to vaccines and boosters can vary based on vaccine technology. For instance, mRNA vaccines such as Moderna’s Spikevax have shown increased antibody durability and enhanced long-term immune protection upon boosting.¹² In a study, participants who received an mRNA vaccine booster dose reported fewer symptoms at 6 months after infection compared with those who were unvaccinated or had only received the primary series. Additionally, those who received the booster vaccination had higher health-related quality of life (HRQOL) scores compared with the unvaccinated and primed groups. The study concluded that booster vaccination with an mRNA vaccine was associated with a reduced risk for long COVID symptoms and improved HRQOL.¹³ Emerging research continues to guide recommendations on booster intervals and populations at greater need for boosters. These recommendations evolve as more data become available on vaccine performance in diverse demographic groups and against new variants.

What does the available evidence suggest about the ideal dosing schedule of booster shots to optimize antibody levels against SARS-CoV-2?

The ideal dosing schedule for COVID-19 booster shots is subject to ongoing research and debate, with evidence evolving as new variants of the virus emerge and more data on vaccine durability become available. The goal of optimizing antibody levels against SARS-CoV-2 is to ensure sustained immunity and to minimize the risk for breakthrough infections and severe disease. Evidence indicates that antibody levels diminish post-primary vaccination, yet boosters significantly bolster these titers.¹⁴
 
The timing of booster shots has varied across different countries and with different vaccine platforms, but emerging consensus indicates that a booster shot is often administered around 6 months after the completion of the initial vaccine series, with adjustments being made for different population groups and vaccine types. For mRNA vaccines, such as Pfizer-BioNTech and Moderna, booster doses are recommended based on evidence showing increased immunity post-booster, which is considered robust for several months thereafter. A study that evaluated the effectiveness of mRNA-1273 and BNT162b2 booster vaccinations against SARS-CoV-2 under various schedules, using a model considering antibody waning, infection probability, and timing to breakthrough infections, found that delaying boosters past 2 years significantly increases infection risk, closely resembling the risk without boosters.¹⁵ Thus, annual or more frequent boosters may be necessary for effective risk mitigation.
 
Guidance from the CDC and World Health Organization (WHO) incorporates various factors, including age, health status, and virus strains in circulation, to inform booster recommendations. For certain immunocompromised individuals and older adults, the dosing schedule may be adjusted to earlier or additional doses to maintain optimal protection.¹⁶ Further research is needed to determine the best timing for subsequent booster doses, especially in the context of new variants and long-term immune response monitoring. The longevity of protection from boosters and the potential need for variant-specific boosters are key areas of investigation.

Are there any differences in recommendations for booster shots based on the specific COVID-19 vaccine a person initially received? How should individuals decide which booster to receive if multiple options are available?

Guidance for COVID-19 booster vaccinations is tailored according to the initial vaccine regimen and may adapt with emerging data on SARS-CoV-2 variants. For the youngest demographic aged 6 months to 4 years, unvaccinated children should receive 2 or 3 homologous doses of the updated 2023 to 2024 formula mRNA vaccine, with the exact number based on whether they receive the Moderna or Pfizer-BioNTech vaccine. Those who have started but not completed the original vaccine series should receive 1 or 2 additional doses of the updated vaccine to complete the series, while those who have completed the initial series need only 1 booster dose of the updated vaccine. An 8-week interval between the first and second mRNA COVID-19 vaccine for non-immunocompromised individuals aged 6 months to 4 years might be used. For children aged 5 to 11 years old, a single updated dose of the 2023 to 2024 formula mRNA vaccine is advised, independent of their prior vaccination history.¹⁶
 
Unvaccinated individuals aged 12 years and older are recommended to get either 1 dose of the updated mRNA vaccine or a 2-dose regimen of the updated Novavax vaccine. Those who have previously received any original COVID-19 vaccines, including monovalent, bivalent, or Janssen vaccines, should receive 1 updated dose of any COVID-19 vaccine currently available. This recommendation simplifies the booster schedule across different previous vaccination statuses for these age groups. In those aged 12 years to 64 years who are not immunocompromised, an extended 8-week interval between the first and second doses of mRNA and Novavax COVID-19 vaccines is considered beneficial for reducing the risk for myocarditis and pericarditis, which remains a rare but documented side effect of these vaccines that is particularly noted in males aged 12 to 39 years. However, for the immunocompromised, those over 65, and others needing rapid protection due to high risk, the standard interval is maintained.¹⁶
 
It is important for individuals to consult with healthcare providers for advice tailored to their personal health circumstances and the most current public health guidance. This is most important for people who are moderately or severely immunocompromised, as the vaccine guidance may differ substantially from those who are not immunocompromised.

As we approach the winter months, what unique challenges and strategies should clinicians consider to extend the vaccination season, ensuring that people continue to receive COVID-19 vaccines throughout November, December, and January? What is the role of public health campaigns in promoting vaccination during the winter season and how effective are they?

As the winter months approach, clinicians face the challenge of ensuring the continuation of COVID-19 vaccinations amid potential surges in respiratory infections such as influenza and respiratory syncytial virus (RSV), which may complicate the clinical picture. Clinicians should consider the coadministration of COVID-19 vaccines with the seasonal flu vaccine, as endorsed by the CDC, to reduce visits and increase vaccination rates. Education efforts should emphasize the enhanced risk for respiratory illnesses during winter and the benefits of vaccination. Expanding vaccine availability in clinics, hospitals, and community settings and extending hours to accommodate different schedules can improve vaccine access. Staying informed about the prevalence of SARS-CoV-2 variants allows clinicians to better advise their patients on the need for booster doses. Furthermore, identifying and reaching out to populations with lower vaccination rates with tailored messaging and resources can address gaps in vaccination coverage.
 
Public health campaigns play a critical role in promoting COVID-19 vaccination during the winter by raising awareness. Campaigns can inform the public about the increased risks of COVID-19 during the winter months when people are more likely to be indoors. Active efforts to correct misinformation can help improve vaccine acceptance. Sharing data on vaccine effectiveness in preventing severe disease, hospitalization, and death can encourage uptake. Campaigns should use a mix of traditional media, social media, and community outreach to reach diverse audiences.
 
In practice, public health campaigns, when combined with easy access to vaccines and robust education efforts, have been effective in increasing vaccination rates during the winter season. Campaigns that are culturally sensitive, easy to understand, and address specific concerns or barriers to vaccination can be more effective. Involving community leaders, health care providers, and other trusted figures can enhance the impact of these campaigns. However, their success also depends on factors such as vaccine supply, public perception of vaccine necessity, and the prevalence of competing health priorities.

Can you provide insights into the latest research on the potential long-term effects of COVID-19 on various organ systems? How should clinicians be prepared to address these complications?

Proactive management and ongoing research are critical for understanding the full impact of COVID-19 and providing the best care for those with long-term effects. The long-term effects of COVID-19 can affect multiple organ systems^2,3:
 
Respiratory system: Symptoms such as dyspnea and cough have been documented. It may be a good idea to follow up with pulmonary function tests and imaging for management and surveillance.

Cardiovascular system: There have been reports of cardiac impairment, myocardial inflammation, and postural orthostatic tachycardia syndrome post-COVID-19. Clinicians should maintain a high index of suspicion for these conditions in patients with corresponding symptoms.

Neurologic system: Neurologic manifestations, such as headaches, brain fog, changes in smell or taste, and dizziness, are under investigation. Cognitive assessments and neurologic support might be necessary for some patients.

Renal system: Adverse kidney outcomes have been observed during COVID-19, and the long-term effects of this organ damage are unknown.

Gastrointestinal system: COVID-19 may cause diarrhea. Gastroenterologists should be vigilant about these potential outcomes in recovered patients.

Endocrine system: There is emerging evidence linking COVID-19 with new-onset diabetes and potential disruptions to other hormonal pathways.

Mental health: The impact on mental health includes depression, anxiety, and post-traumatic stress disorder, necessitating psychological or psychiatric intervention for some patients.
 
The dynamic nature of the pandemic requires that clinicians remain vigilant and adaptable to new findings and treatment protocols. Clinicians should be prepared to address the complications of long COVID by collaborating across specialties to manage the multifaceted needs of patients with long COVID. Establishing or utilizing post-COVID care clinics to provide integrated support for patients with persistent symptoms can also be helpful. Clinicians should inform patients of the potential for long-term effects and the importance of follow-up care; provide access to physical therapy, occupational therapy, and other rehabilitation services to aid recovery; and keep abreast of emerging data and research on long COVID to inform clinical practice. Moreover, supporting and participating in longitudinal studies that track patient outcomes over time may help in understanding the full spectrum of long COVID. This will allow for the utilization of the latest evidence to guide treatment decisions while also considering individual patient contexts.

This Q&A was edited for clarity and length.

Disclosures

Elie Saade, MD, MPH, reported affiliations with the American Hospital Association; the Centers for Disease Control and Prevention; Envision Pharma Group; Johnson & Johnson, Inc; Protein Sciences Corporation; and Sanofi Pasteur.

References

1. Regan JJ, Moulia DL, Link-Gelles R, et al. Use of updated COVID-19 vaccines 2023-2024 formula for persons aged ≥6 months: Recommendations of the Advisory Committee on Immunization Practices – United States, September 2023. MMWR Morb Mortal Wkly Rep. 2023;72(42):1140-1146. doi:10.15585/mmwr.mm7242e1
 
2. Long COVID or post-COVID conditions. US Centers for Disease Control and Prevention. Updated July 20, 2023. Accessed November 15, 2023. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
 
3. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146. doi:10.1038/s41579-022-00846-2
 
4. Marjenberg Z, Leng S, Tascini C, et al. Risk of long COVID main symptoms after SARS-CoV-2 infection: a systematic review and meta-analysis. Sci Rep. 2023;13(1):15332. doi:10.1038/s41598-023-42321-9
 
5. Post-COVID conditions: information for healthcare providers. Centers for Disease Control and Prevention. Updated September 11, 2023. Accessed November 15, 2023. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html
 
6. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. Updated March 11, 2022. Accessed November 15, 2023. https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742
 
7. Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto HC, Pelosi P, Rocco PRM. Laboratory biomarkers for diagnosis and prognosis in COVID-19. Front Immunol. 2022;13:857573. doi:10.3389/fimmu.2022.857573
 
8. Brannock MD, Chew RF, Preiss AJ, et al. Long COVID risk and pre-COVID vaccination in an EHR-based cohort study from the RECOVER program. Nat Commun. 2023;14(1):2914. doi:10.1038/s41467-023-38388-7
 
9. Babicki M, Kapusta J, Pieniawska-Śmiech K, et al. Do COVID-19 vaccinations affect the most common post-COVID symptoms? Initial data from the STOP-COVID Register-12-month follow-up. Viruses. 2023;15(6):1370. doi:10.3390/v15061370
 
10. Tran VT, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with long covid: target trial emulation based on ComPaRe e-cohort. BMJ Med. 2023;2(1):e000229. doi:10.1136/bmjmed-2022-000229
 
11. Moderna COVID-19 booster may protect against variants. National Institutes of Health. Published November 2, 2021. Accessed November 16, 2023. https://www.nih.gov/news-events/nih-research-matters/moderna-covid-19-booster-may-protect-against-variants
 
12. Ailsworth SM, Keshavarz B, Richards NE, et al. Enhanced SARS-CoV-2 IgG durability following COVID-19 mRNA booster vaccination and comparison of BNT162b2 with mRNA-1273. Ann Allergy Asthma Immunol. 2023;130(1):67-73. doi:10.1016/j.anai.2022.10.003
 
13. Di Fusco M, Sun X, Moran MM, et al. Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron. J Patient Rep Outcomes. 2023;7(1):77. doi:10.1186/s41687-023-00616-5
 
14. Chenchula S, Karunakaran P, Sharma S, Chavan M. Current evidence on efficacy of COVID-19 booster dose vaccination against the Omicron variant: a systematic review. J Med Virol. 2022;94(7):2969-2976. doi:10.1002/jmv.27697
 
15. Townsend JP, Hassler HB, Dornburg A. Infection by SARS-CoV-2 with alternate frequencies of mRNA vaccine boosting. J Med Virol. 2023;95(2):e28461. doi:10.1002/jmv.28461
 
16. US Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines in the United States. Updated November 3, 2023. Accessed November 15, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR played no role in this content’s production. 

Between 0.23% to 0.5% of children and adolescents have severe, uncontrolled asthma, which is typically defined as persistent or recurring asthmatic symptoms or acute asthma attacks that are insufficiently controlled by maximal standard treatment such as inhaled corticosteroid (ICS) therapy, long-acting beta-2 agonists (LABA), leukotriene receptor antagonists (LTRA), and other therapies.¹ As the prevalence of asthma has grown globally over the last several decades,² asthma in children similarly has become more prevalent, with considerable negative effects on a range of physical, social, and emotional outcomes, as well as quality of life. Of particular concern, while mortality due to severe asthma has decreased across patient groups aged older than 15, the mortality rate in children has not decreased similarly.³ Furthermore, there are persistent disparities in the prevalence of asthma in the United States across racial, sex, geographic, and age factors. In particular, asthma attacks and presentation for emergency care are more common in children aged 12 to 17 and in racial and ethnic groups other than non-Hispanic White and Asian Americans.⁴ The considerable expenses spent on health care utilization among asthma patients may also be unequally distributed; school-aged children with asthma are more likely to come from underserved or disadvantaged populations and poorer families and have more chronic comorbidities than their peers without asthma.⁵
 
Treatment options for addressing treatment-resistant, allergic-type severe asthma have advanced in recent years, as research has begun to uncover the pathological processes, known as endotypes, that underlie asthma phenotypes. In children, the most common endotype, T2-high, features excessive activity of T-helper 2 (T2) lymphocytes. These lymphocytes predominantly secrete cytokines interleukin (IL)-4, IL-5, IL-9, and IL-13, which cause airway inflammation.^6,7 Immunoglobulin E (IgE)-mediated inflammation further aggravates this hypersensitivity reaction in some patients with T2-high asthma.
 
Our improved understanding of these pathological processes now allows clinicians to tailor treatment decisions and monitor outcomes in allergic asthma in young patients based on disease endotype. The potential for personalized medical care brought about by these advances has been exemplified by the development of a range of biologic drugs and their approval as add-on therapies for severe asthma. Omalizumab was the first biologic approved for patients aged 12 and older with moderate to severe persistent asthma in 2003.⁸ In subsequent years, 4 other biologics for treatment-resistant asthma received approval: mepolizumab in 2015,⁹ benralizumab in 2017,¹⁰ dupilumab in 2018,¹¹ and tezepelumab in 2021¹²; 2 of these biologics later received expanded approved for the treatment of asthma in patients aged 6 and older: omalizumab in 2016¹³ and dupilumab in 2021.¹⁴
 
The mechanism of action among these biologics varies, reflecting our increasingly nuanced understanding of asthma endotypes. Omalizumab causes IgE blockade, whereas mepolizumab and benralizumab are both IL-5 blockers. Dupilumab inhibits signaling of both IL-4 and IL-13; tezepelumab differs by targeting the thymic stromal lymphopoietin (TSLP), an airway epithelial cytokine, and has demonstrated benefit in both the T2-high and T2-low asthma subtypes.¹⁵
 
While the advent of biologics for severe asthma has dramatically expanded treatment options, we still have much to learn regarding how to optimize and personalize pediatric asthma treatment. For example, treatment selection requires consideration of patient age, asthma phenotype, moderate vs severe disease status, therapeutic goals, symptom triggers, side effect risks, patient preferences, and relevant comorbidities (eg, atopic dermatitis).⁷ However, in pediatric patients, outcomes research to guide and prioritize these considerations is still in its early stages. Early reports indicate that these biologic therapies are generally well tolerated, with a low rate of adverse effects requiring discontinuation.⁶ However, conclusions such as these are extrapolated in part from literature on adult patients.
 
Long-term outcome studies focused on children are needed, particularly in children aged younger than 12, children of lower socioeconomic status, and children from racial and ethnic minorities. Future studies are also needed to identify novel predictive biomarkers and help clinicians determine the optimal choice for patients who are eligible for multiple treatment options.¹⁶ Such research will help clarify the appropriate durations of treatment with biologics for severe allergic asthma.
 
Meyer Kattan, MD, professor of pediatrics at Columbia University Irving Medical Center, New York, and director of the Pediatric Pulmonary Division at New York-Presbyterian/Morgan Stanley Children’s Hospital, has a multi-decade record of performing research on asthma in children funded by the National Institutes of Health. In this article, Dr Kattan discusses state-of-the-art treatments for severe allergic asthma in children and future directions for research.

A subset of children with severe, persistent allergic asthma do not achieve adequate disease control with inhaled corticosteroids. Among those over 6 years of age, treatment options have changed considerably over the past several years and now include biologic therapies. Would you give an overview of how this new era of biologic therapies evolved in the past several years?

Asthma is a heterogeneous disease characterized by chronic inflammation. Over the last 3 decades, we have usually treated it with ICS, but not every patient responds to this therapy. The question is, what is different about those who respond to steroids and those who do not?
 
In this regard, with an improved understanding of cellular mechanisms and transcriptional factors within the cell, we have been able to study cellular pathways and cytokines that were making the inflammation worse. That is, we gained insights into what type of cell receptor is being activated, or what pathways are being activated by a certain receptor in a certain individual. For example, the majority of patients with severe asthma are T2-high, which is characterized by eosinophils in the blood.
 
What we learned is that although the clinical presentation of asthma — the phenotype — may be similar across many patients, we needed to target particular cellular and molecular pathways, which we call endotypes. The current biologics were developed to counteract the effects of these inflammatory mediators within a pathway such as T2. Furthermore, each biologic has been developed to target a different part of a given pathway.
 
To date, 5 biologics have been approved for the treatment of moderate to severe asthma in children. Of those, 3 are approved for children aged 6 years and older: omalizumab, mepolizumab, and dupilumab. The other 2, benralizumab and tezepelumab, are approved for children aged 12 years and older. Again, each biologic affects different signaling pathways within the inflammatory cascade.

In deciding when and whether to initiate biologic therapy in this patient group, what factors or considerations do you prioritize for optimal outcomes?

The first thing to prioritize is the patient’s history, which is more important than anything else. As I mentioned, we are considering a patient who is not responding to therapy, but via looking into their history we ask the question, why are they not responding to therapy? Is it because they are not taking the medicine properly? Is it because they are not taking the medicine at all? We really have to ask the right questions and sometimes do a little detective work. For example, you may be able to check the patient’s refills via the electronic health record and see whether they have actually been filling their medication. Also, you can easily determine whether the patient’s inhalation technique is correct during a visit. I had a patient who showed me his inhaler and showed me how he took it, but when I asked him what the number was on the readout of how many puffs were left, it was 0. We really have to rule out that sort of problem.
 
But supposing you have established that the patient really has failed to respond to high-dose steroid therapy, you do not want to keep increasing the steroid dose if they are not responding, especially in children, even though inhaled steroids are generally safe. So that patient may be a candidate for a biologic, especially if their asthma is allergic-type. But how do we know that they have allergic asthma? We look for comorbidities, such as eczema and allergic rhinitis, that may suggest atopy; we look for a high blood eosinophil count, which is a marker of allergy; and we test exhaled nitric oxide (FeNO), which is an indicator of allergic inflammation. If the patient confirms that they feel the medication they are using is not working, even at the right doses, then they may be an excellent candidate for biologics.
 
A caveat is that we have to confirm the diagnosis of asthma; it is possible that a patient who does not respond to high-dose steroids actually does not have asthma. A very common missed diagnosis is vocal cord dysfunction, such as exercise induced laryngeal obstruction (EILO).¹⁷ Respiratory noises in a child with EILO may sound like asthma, but they are actually from the upper airway. Other conditions in children that may produce respiratory symptoms like chronic cough, but are not really asthma, include cystic fibrosis, primary ciliary dyskinesia, and perhaps reflux.¹⁸ Thus, make sure the patient is taking the medicine correctly, and make sure you have the right diagnosis. Given those confirmations, if the patient is not responding well to medication, a biologic may be indicated.

How do you select among the options for biologic therapy in this patient population?

Treatment selection is driven by the patient’s clinical and endotype characteristics, and also according to the specific indications for each agent, because each biologic targets a different pathway. The unique properties of each biologic make them especially appealing for precision medicine. The relevant biomarkers need to be evaluated: usually blood eosinophils, skin prick testing, and serum IgE. As mentioned earlier, we can measure the degree of inflammation in the airways with FeNO, which tells us in a nonspecific manner that there is some allergic type of inflammation.
 
As an example of treatment considerations for these patients, omalizumab is a biologic that has been available for over a decade, and there is a lot of experience with it in children. It is an anti-IgE biologic, so the patient must have a somewhat elevated IgE for this drug to be indicated,¹⁹ although it should not be too high because then the needed dose probably would be too high for it to be recommended. Regardless, omalizumab has a good track record in those children and it has been shown that, in many of these patients, we do not even have to give that medication all year long.²⁰ This is particularly true for patients whose symptoms are induced by viruses, which often starts occurring in autumn between September and January. So if that therapy starts in August, right before the viral season and before the patients start school, it is very effective. An interesting question this raises is, why does an anti-allergy drug help viral-induced exacerbations? This could be because people who are allergic have a diminished interferon response to the virus,²¹ and there is some evidence that omalizumab affects the interferon response.^22,23

Again, that is just 1 type of patient, and there are limitations to using omalizumab. Omalizumab is dosed for asthma according to an algorithm based on weight and serum IgE level,¹⁹ so a patient who is obese and has an excessively high IgE probably is not eligible for omalizumab.
 
Dupilumab, in addition to being a very good asthma medication, happens to be excellent for eczema and is actually approved for the treatment of eczema in children aged as young as 6 months old.²⁴ In a child with both eczema and asthma, dupilumab can be used to treat both at once. Patients with a somewhat elevated eosinophil count — an absolute count of at least 150 or 200 — are eligible for this biologic. Mepolizumab is also an excellent biologic; it can be given once a month,²⁵ whereas dupilumab has to be given every 2 weeks. It also depends on what is acceptable to the patient. Eligibility and dosing for tezepelumab, on the other hand, do not depend on a high eosinophil count.²⁶ Hence, if a patient aged 12 or older is not doing well on ICS and does not have a high eosinophil count, that may be a treatment option.
 
These drugs all work well in the right patient, and you have to decide which is best for that particular patient based on their history and lab values.

Historically, medical treatment of children has sometimes been driven by evidence from trials that were carried out mainly in adults. For the treatment of severe allergic asthma in children, what evidence base now exists from studies carried out with patients aged younger than 18? What population-specific research is still needed to maximize safety and help predict treatment responses?

As a condition of drug approval, the US Food and Drug Administration (FDA) typically requires studies of new drugs to be conducted in patients aged 12 and older. Accordingly, those studies do include children aged between 12 and 17 as participants, but often in very small numbers. Therefore, there is less data in children for many drugs; historically, a lot of drugs that we use in children have not been approved for children. But having said that, there are studies in children with these biologics. First of all, there are studies in children with omalizumab,²⁷ and there has been plenty of real-life clinical experience in using omalizumab in children over the years. To summarize that research and experience: it has a good safety profile and it has been effective.²⁸
 
With the newer biologics, there is not as much real-life experience yet, but studies likewise have been conducted in children.²⁹ Furthermore, some of that research has been conducted in minority populations, including Black and Hispanic populations.³⁰ However, we do need more data, and there certainly is not as much data in children as there is in adults. In dupilumab, there have been studies in children aged as young as 6 months for eczema, but not for asthma.
 
Still, as a result of studying the effects of a given drug in multiple diseases, more and more data are accumulating specific to children. These drugs seem to be quite safe, demonstrate very few side effects, and may have a steroid-sparing effect.¹³ The most common side effects with all these biologics are allergic reactions such as hives. With dupilumab, another side effect is conjunctivitis, which is treatable but can be severe.³¹ Anaphylaxis is mentioned in the package inserts, but that is very rare.³²

What future therapeutic pathways and outstanding questions are on your mind regarding severe allergic asthma in children?

There are certainly other mediators that could be future targets in asthma. Tezepelumab was a good example of a biologic that targets a different cytokine, TLSP. That made it a bit different from the other currently approved biologics. As a potential example for the future, IL-6 has been associated with asthma³³; there are anti-IL-6 drugs available for rheumatic diseases.³⁴ Perhaps some of those agents, or new agents derived from those, could be helpful for asthma.
 
In the meantime, an important question is, do any of these biologics help prevent asthma? Some children at high risk for asthma wheeze; not all children who wheeze end up with asthma, but if a patient wheezes, has a family history of asthma, and also has eczema, that is a high-risk child. Can we prevent asthma with these biologics? In fact, there is an ongoing study posing this question, a trial of omalizumab in young children (aged 2 to 3) who have not yet been diagnosed with asthma but are at high risk.³⁵
 
Another important question is, do you have to give these biologic therapies year-round? Or can young patients take a treatment holiday, similarly to how we pause inhaled steroids in the summer for many children? As mentioned earlier, we showed (at least with omalizumab) that we do not have to give it all the time. Rather, we can administer it for 4 months starting just before and continuing through the viral season, which cuts the cost considerably. However, with the other biologics, we do not yet know whether it is okay to pause them during the summer; we need to learn the answer to that question.

This Q&A was edited for clarity and length.

References

1. Votto M, De Filippo M, Licari A, Marseglia A, De Amici M, Marseglia GL. Biological therapies in children and adolescents with severe uncontrolled asthma: a practical review. Biologics. 2021;15:133-142. doi:10.2147/BTT.S252574
 
2. Masoli M, Fabian D, Holt S, Beasley R, Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59(5):469-478. doi:10.1111/j.1398-9995.2004.00526.x
 
3. Pennington E, Yaqoob ZJ, Al-Kindi SG, Zein J. Trends in asthma mortality in the United States: 1999 to 2015. Am J Respir Crit Care Med. 2019;199(12):1575-1577. doi:10.1164/rccm.201810-1844LE
 
4. Pate CA, Zahran HS, Qin X, Johnson C, Hummelman E, Malilay J. Asthma surveillance — United States, 2006–2018. MMWR Surveill Summ. 2021;70(5):1-32. doi:10.15585/mmwr.ss7005a1
 
5. Sullivan PW, Ghushchyan V, Navaratnam P, et al. The national cost of asthma among school-aged children in the United States. Ann Allergy Asthma Immunol. 2017;119(3):246-252.e1. doi:10.1016/j.anai.2017.07.002
 
6. Perikleous EP, Steiropoulos P, Nena E, Paraskakis E. Biologic therapies in pediatric asthma. J Pers Med. 2022;12(6):999. doi:10.3390/jpm12060999
 
7. Saco T, Ugalde IC, Cardet JC, Casale TB. Strategies for choosing a biologic for your patient with allergy or asthma. Ann Allergy Asthma Immunol. 2021;127(6):627-637. doi:10.1016/j.anai.2021.09.009
 
8. FDA Drug Safety Communication: FDA approves label changes for asthma drug Xolair (omalizumab), including describing slightly higher risk of heart and brain adverse events. US Food and Drug Administration. Published September 26, 2014. Updated February 26, 2018. Accessed January 29, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-label-changes-asthma-drug-xolair-omalizumab-including
 
9. Ullmann N, Peri F, Florio O, et al. Severe pediatric asthma therapy: mepolizumab. Front Pediatr. 2022;10:920066. doi:10.3389/fped.2022.920066
 
10. Fasenra (benralizumab) receives US FDA approval for severe eosinophilic asthma. News release. AstraZeneca. November 14, 2017. Accessed January 29, 2023. https://www.astrazeneca.com/media-centre/press-releases/2017/fasenra-benralizumab-receives-us-fda-approval-for-severe-uncontrolled-eosinophilic-asthma-14112017.html
 
11. FDA approves asthma indication for Dupixent^® (dupilumab). News release. Regeneron. October 19, 2018. Accessed January 29, 2023. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-asthma-indication-dupixentr-dupilumab/
 
12. Tezspire (tezepelumab) approved in the US for severe asthma. News release. AstraZeneca. December 17, 2021. Accessed January 4, 2023. https://www.astrazeneca.com/media-centre/press-releases/2021/tezspire-tezepelumab-approved-in-the-us-for-severe-asthma.html
 
13. Chipps BE, Lanier B, Milgrom H, et al. Omalizumab in children with uncontrolled allergic asthma: review of clinical trial and real-world experience. J Allergy Clin Immunol. 2017;139(5):1431-1444. doi:10.1016/j.jaci.2017.03.002
 
14. FDA expands approval of Dupixent^® (dupilumab) to include children aged 6 to 11 years with moderate-to-severe asthma. News release. Sanofi. October 20, 2021. Accessed January 29, 2023. https://www.sanofi.com/en/media-room/press-releases/2021/2021-10-20-21-30-00-2317854
 
15. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386(2):157-171. doi:10.1056/NEJMra2032506
 
16. Tenero L, Piacentini G. New opportunities with biologic treatments in pediatric allergic and respiratory diseases. Pediatr Allergy Immunol. 2022;33(S27):8-10. doi:10.1111/pai.13617
 
17. Hull JH, Godbout K, Boulet LP. Exercise-associated dyspnea and stridor: thinking beyond asthma. J Allergy Clin Immunol Pract. 2020;8(7):2202-2208. doi:10.1016/j.jaip.2020.01.057
 
18. Weinberger M, Fischer A. Differential diagnosis of chronic cough in children. Allergy Asthma Proc. 2014;35(2):95-103. doi:10.2500/aap.2014.35.3711
 
19. XOLAIR^®. Prescribing information. Genentech. Accessed January 28, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pdf
 
20. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476-1485. doi:10.1016/j.jaci.2015.09.008
 
21. Edwards MR, Regamey N, Vareille M, et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol. 2013;6(4):797-806. doi:10.1038/mi.2012.118
 
22. Cardet JC, Casale TB. New insights into the utility of omalizumab. J Allergy Clin Immunol. 2019;143(3):923-926.e1. doi:10.1016/j.jaci.2019.01.016
 
23. López-Abente J, Benito-Villalvilla C, Jaumont X, Pfister P, Tassinari P, Palomares O. Omalizumab restores the ability of human plasmacytoid dendritic cells to induce Foxp3+Tregs. Eur Respir J. 2021;57(1):2000751. doi:10.1183/13993003.00751-2020
 
24. Dupixent^®. Prescribing information. Sanofi. Accessed January 29, 2023. https://www.regeneron.com/downloads/dupixent_fpi.pdf
 
25. Nucala. Prescribing information. GlaxoSmithKline. Accessed January 29, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761122s000lbl.pdf
 
26. Tezspire. Prescribing information. AstraZeneca. Accessed January 29, 2023. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/e306dc06-d580-4457-b15f-9f28545ad63a/e306dc06-d580-4457-b15f-9f28545ad63a_viewable_rendition__v.pdf
 
27. Henriksen DP, Bodtger U, Sidenius K, et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020;16(1):49. doi:10.1186/s13223-020-00442-0
 
28. Agache I, Beltran J, Akdis C, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI guidelines – recommendations on the use of biologicals in severe asthma. Allergy. 2020;75(5):1023-1042. doi:10.1111/all.14221
 
29. Bacharier LB, Jackson DJ. Biologics in the treatment of asthma in children and adolescents. J Allergy Clin Immunol. 2023;S0091-6749(23)00006-4. doi:10.1016/j.jaci.2023.01.002
 
30. Kelly RS, Weiss ST. Biologic therapies for asthma in underserved populations. Lancet. 2022;400(10351):471-473. doi:10.1016/S0140-6736(22)01383-6
 
31. Fukuda K, Kishimoto T, Sumi T, Yamashiro K, Ebihara N. Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye. Allergol Int. 2022;S1323-8930(22)00120-4. doi:10.1016/j.alit.2022.09.005
 
32. Jackson K, Bahna SL. Hypersensitivity and adverse reactions to biologics for asthma and allergic diseases. Expert Rev Clin Immunol. 2020;16(3):311-319. doi:10.1080/1744666X.2020.1724089
 
33. Raita Y, Zhu Z, Camargo CA, et al. Relationship of soluble interleukin-6 receptors with asthma: a Mendelian randomization study. Front Med (Lausanne). 2021;8:665057. doi:10.3389/fmed.2021.665057
 
34. Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting interleukin-6 signaling in clinic. Immunity. 2019;50(4):1007-1023. doi:10.1016/j.immuni.2019.03.026
 
35. Phipatanakul W, Mauger DT, Guilbert TW, et al. Preventing asthma in high risk kids (PARK) with omalizumab: design, rationale, methods, lessons learned and adaptation. Contemp Clin Trials. 2021;100:106228. doi:10.1016/j.cct.2020.106228

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Phyllis Tien, MD, is a professor of medicine in the Division of Infectious Diseases at the University of California, San Francisco, and a staff physician at the San Francisco Veterans Affairs Health Care System. Dr Tien serves as chair of the Inter-CFAR Collaboration on HIV Research in Women and is currently a member of the National Institutes of Health COVID-19 Treatment Guidelines panel.

In one study, experts compared different booster vaccines by measuring neutralizing antibody responses, seroresponse, and binding antibody responses against multiple variants, all of which served as biomarkers for efficacy.¹ Can you explain how those data translate to preventing COVID-19 infection in the general public?

Neutralizing antibodies, seroresponse, and binding antibodies can be considered as surrogate markers of whether a vaccine is effective in preventing severe disease, hospitalization, and death. It would be incredibly difficult to perform a large-scale randomized controlled trial (RCT) to determine true vaccine efficacy by use of clinical outcomes. This is especially true when the virus keeps mutating into different variants against which some vaccines may be less effective. Instead, to compare vaccines, like a booster bivalent dose with a booster monovalent dose, we have to rely on assessing their effects on neutralizing antibodies, binding antibodies, and seroresponse.
 
There are no standardized correlations between antibody titer cutoffs and clinical outcomes because laboratories use different assays or ways to measure antibody titers. Within the context of an RCT, however, being able to compare antibody titers between groups can be informative and helps us to put these numbers into perspective in terms of vaccine effectiveness.

Several cohort studies have demonstrated that COVID-19 immunity decreases with time after immunization.^2-4 How does the administration of either a monovalent or a bivalent vaccine affect the durability of protection received by COVID-19 vaccination?

It is difficult to address the durability of vaccine response given the rapidly emerging immune-evasive variants. The results of cohort studies indicate that booster vaccine doses are associated with a reduced risk for COVID-19 infection, hospitalization, and death. In that sense, booster vaccine doses extend the durability of protection.

Is there a perceived benefit to administering a booster dose of the bivalent COVID-19 vaccine in patients who have already received multiple doses of a monovalent COVID-19 vaccine?

The bivalent Omicron-containing booster vaccine study presented in the New England Journal of Medicine suggests that, by use of neutralizing antibodies and binding antibodies as an endpoint, there is a benefit to using the bivalent mRNA-1273.214 vaccine over the monovalent mRNA-1273 vaccine in terms of raising antibody titers.¹
 
Participants in the study had received a primary vaccine series and a monovalent mRNA-1273 COVID-19 booster. Thus, we are seeing higher immune antibody responses in people given the bivalent booster vaccine, even in patients who had previously received a booster dose of the monovalent mRNA-1273 COVID-19 vaccine.

Can you elaborate on the effectiveness of COVID-19 vaccination in preventing various clinical outcomes, such as COVID-19 reinfection, hospitalization, or death?

The Centers for Disease Control and Prevention (CDC) COVID data tracker suggests that hospitalizations and deaths are lower now than earlier in the pandemic.⁵ Large cohort studies, notably the Veterans Affairs study³ and a study from North Carolina,⁴ confirm that COVID-19 vaccination, including booster doses, is contributing to the decline in new cases of severe COVID-19.
 
The greatest decreases are in hospitalization and death. When using a database for a cohort study, it is easier to assess whether a patient has been hospitalized or has died. Those hard endpoints are showing that COVID-19 vaccines are effective. With COVID-19 infection and reinfection, the data can be more difficult to quantify. A patient may have completed an antigen test at home, whereas someone else who is sicker may get tested at a facility. It is also possible that patients who have received a booster vaccine dose are more likely to be tested for COVID-19 infection. With so many confounders, we may not see the effect of vaccination on COVID-19 infection that we would prefer.

In another study, the neutralizing antibody response of the bivalent V-01D-351 booster was shown to be durable for at least 90 days after administration.⁶ Given these and other supporting data on the durability of boosters for maintaining immunity against COVID-19, how do you counsel patients on the need for repeat vaccinations, especially those who may have already received a monovalent booster dose?

Currently, the CDC is recommending a bivalent booster dose 2 months after the last dose of COVID-19 vaccine.⁷ When booster doses were first recommended, patients were asked to wait 5 months after the previous COVID-19 vaccination. Some patients are confused because the recommendations are changing. This is not uncommon in a pandemic because recommendations change as new information about the virus emerges, such as new variants that appear to be more immune-evasive. These are considerations that contribute to why the interval has been shortened. I tell my patients that the purpose of booster doses is to prevent hospitalization and death from COVID-19.
 
The frequency of vaccination may also be related to the type of vaccine that we are using — for example, an mRNA or a subunit protein vaccine. Some of our traditional subunit vaccines do not need to be repeated frequently only because of the durability of response. However, it takes time to develop the “right” type of vaccine that can elicit a longer durable response.

Some patients experience breakthrough COVID-19 infection as well as reinfection. Can you elaborate on the need for booster vaccination in this subset of patients as well as provide some insight into the timing (ie, when patients should follow up with their health care provider to receive the booster)?

I receive this question a lot, especially because so many patients were infected with the Omicron variant in the summer of 2022. Natural infection does lead to a nice immune response and has a synergistic effect with the bivalent COVID-19 vaccine.¹ In the study comparing the bivalent booster with the monovalent booster, vaccination with the bivalent booster led to an increase in neutralizing antibodies even in study participants with prior SARS-CoV-2 infection, and neutralizing antibody levels appeared to be higher in participants who had a previous SARS-CoV-2 infection than in those who had not been infected with SARS-CoV-2.¹
 
The CDC states that you could consider delaying your primary or booster vaccine dose by 3 months from the onset of your symptoms or a positive test result if you are asymptomatic.⁸ With the recommendation for people to receive the bivalent booster 2 months from the previous vaccine dose, a good general rule for when to get the COVID-19 vaccine booster seems to be 2 to 3 months after infection.

This Q&A was edited for clarity and length.

Disclosures

Phyllis Tien, MD, reported affiliations with Merck & Co, Inc.

References

1. Chalkias S, Harper C, Vrbicky K, et al. A bivalent Omicron-containing booster vaccine against COVID-19. N Engl J Med. 2022;387:1279-1291. doi:10.1056/NEJMoa2208343
 
2. Berec L, Smid M, Pribylova L, et al. Protection provided by vaccination, booster doses and previous infection against COVID-19 infection, hospitalisation or death over time in Czechia. PLOS One. 2022;17(7):e0270801. doi:10.1371/journal.pone.0270801
 
3. Kelly JD, Leonard S, Hoggatt KJ, et al. Incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines. JAMA. 2022;328(14):1427-1437. doi:10.1001/jama.2022.17985
 
4. Lin D-Y, Gu Y, Xu Y, et al. Association of primary and booster vaccination and prior infection with SARS-CoV-2 infection and severe COVID-19 outcomes. JAMA. 2022;328(14):1415-1426. doi:10.1001/jama.2022.17876
 
5. COVID data tracker. Centers for Disease Control and Prevention. Updated November 10, 2022. Accessed November 13, 2022. https://covid.cdc.gov/covid-data-tracker/#datatracker-home
 
6. Zhang Z, He Q, Zhao W, et al. A heterologous V-01 or variant-matched bivalent V-01D-351 booster following primary series of inactivated vaccine enhances the neutralizing capacity against SARS-CoV-2 Delta and Omicron strains. J Clin Med. 2022;11(14):4164. doi:10.3390/jcm11144164
 
7. Stay up to date with COVID-19 vaccines including boosters. Centers for Disease Control and Prevention. Updated November 1, 2022. Accessed November 13, 2022. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html
 
8. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Centers for Disease Control and Prevention. Updated October 19, 2022. Accessed November 14, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#infection

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

What bleeding patterns do you see when women who are ultimately diagnosed with uterine fibroids present at the clinic with abnormal menstrual bleeding?

The most common symptom of uterine fibroids is heavy menstrual bleeding. In a recent survey, approximately 60% of women diagnosed with uterine fibroids reported heavy menstrual bleeding.¹ Typically, the patient will say, “I’m bleeding heavily,” but when you go into more detail, the bleeding can take different forms. Some will say that they still have regular bleeding, more or less at the same time every month, but instead of what they consider normal, their bleeding is now much heavier. I’ve had women describe it as “hemorrhaging” or “soiling my clothes,” and others can quantify it by the number of tampons or sanitary pads that they use.

Over the years, clinician-scientists have tried to measure the normal range of menstrual bleeding. There is wide variation among women [in both the duration of menstruation and the amount of blood loss]. Up to 7 days of bleeding is within the normal range, and the total amount of blood loss is approximately 80 mL, which is roughly approximately 6 large spoonfuls. Anything greater than that is considered heavy bleeding.²  
 
Women with fibroids may have different bleeding patterns. Some women report prolonged duration of bleeding (37%), bleeding between periods (33%), frequent periods (28%), and/or irregular/unpredictable periods (36%); however, others even report light menstrual bleeding (11%), absent periods (14%), infrequent periods (17%), and/or shortened duration of menstrual bleeding (13%).¹ These women may say, “I had my period. I know this was my period, and then it stopped. But a few days later, I had another period.” They tend to have bleeding on and off throughout the month or sometimes during the whole month. If you quantify the total amount of all the bleedings, it can be quite a lot, and that is why many of these patients end up with anemia; one study reported that 35% of women with heavy or very heavy menstrual bleeding were anemic.³ These women are losing too much blood and too much iron, and their bodies cannot keep up. They often have anemia-related symptoms: fatigue, tiredness, headache, and lack of energy, among others. The normal hemoglobin level of a woman is typically between 12 and 16 g/dL. I have seen women living with one-quarter of that, 3 or 4 g/dL, which was remarkable. If a woman loses a lot of blood, then organs are going to start to suffer. Untreated iron-deficiency anemia can lead to  cardiac problems, such as arrhythmias and even heart failure, and those complications can have major health consequences.⁴

What are the challenges with diagnosing uterine fibroids?

This is a very important topic. There is a lack of awareness of uterine fibroids, and there are some cultural and social barriers.^5,6 Undiagnosed fibroids are a major issue because of the additional symptoms caused by the heavy bleeding. Many women normalize their heavy bleeding because it is a subjective assessment.^5,7 In interviews with 60 women diagnosed with uterine fibroids, 37% reported they did not seek an immediate diagnosis despite experiencing severe symptoms.⁵ Women are often told by their relatives that this [heavy or abnormal bleeding] is part of being a woman and that they should expect it and get used to it. Then, the person keeps bleeding heavily and may develop severe anemia. They have absolutely no energy and are tired all the time, but they do not know why. Sometimes they go through this for years until finally they read an article or someone encourages them to get this bleeding checked out.
 
So, there is a lot of this “normalization” and a lot of stigma.⁵ Sometimes a woman knows that she is bleeding heavily and even that she has fibroids, but she does not seek help.⁷ Some women believe that hysterectomy is the only treatment option, and if she does not want a hysterectomy, she does not seek help. It is important to increase awareness [about uterine fibroids and newer treatment options].⁶

How do you determine whether to pursue surgical vs nonsurgical treatment for uterine fibroids?

After we confirm the diagnosis with the appropriate pelvic examination and either transvaginal or transabdominal ultrasound, we start exploring treatment options. I start by talking with the patient about medical vs surgical treatment options or watchful waiting with monitoring. I always feel my job is to give the patient a lot of accurate medical information with the options and let her choose because I believe that the patient knows her situation, needs, and reproductive plans the best. We discuss all of that, but in the end, the final decision is hers. For women who would like to become pregnant, obviously a hysterectomy is not a viable option.
 
Until recently, the medical treatment options were very limited; thus, we tended to go to surgery quite quickly. The US Food and Drug Administration (FDA) approved the first oral treatment for [heavy menstrual bleeding associated with] fibroids, Oriahnn^TM (elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules), just months ago.⁸ I was an investigator for the ELARIS UF-2 clinical trials. Even though I’m a surgeon, I strongly believe in trying medical treatment first. If we can avoid surgery altogether, that’s better.

What were the main findings that led to the FDA approval of elagolix with hormonal add-back therapy?

We conducted 2 large phase 3 studies (funded by AbbVie; Elaris UF-1 and Elaris UF-2, ClinicalTrials.gov Identifiers: NCT02654054 and NCT02691494), which included a total of 790 patients.⁹ About 68% of those were African American; I was very pleased with that because fibroids are more common in women of color, including African American women and Hispanic women.⁶ These were randomized, placebo-controlled studies. Patients received elagolix, with or without hormonal add-back therapy (estradiol, and norethindrone acetate), or placebo every day for 6 months, and we evaluated the bleeding and the size of the fibroid in addition to other assessments, including safety and quality of life. The results were published in January 2020 in the New England Journal of Medicine.
 
Elagolix with hormonal add-back therapy successfully controlled bleeding in approximately 75% of women, which is fantastic. We never had anything even close to that before. At the end of the 6 months, compared with baseline, bleeding was decreased by approximately 90%.⁹ After 6 months, we did an extension study (Elaris UF-EXTEND) for an additional 6 months, and the percentage of women with successfully controlled bleeding rose to nearly 90%.¹⁰ For safety, elagolix with hormonal add-back therapy was very well tolerated. There was slight increase in the number of women who had hot flushes compared with placebo. Those patients said the hot flushes were very mild, and they did not discontinue the study. The remainder of the side effects were similar between the treatment arms.⁹

How will the FDA approval of elagolix with hormonal add-back therapy affect the treatment landscape?

Previously, we had few medical treatment options with oral administration; most of them have not been thoroughly evaluated in well-designed clinical studies nor are they approved by the FDA for the treatment of fibroids. Most of these off-label strategies use the progestin hormone. These treatments make the lining of the uterus thinner and, in some cases, help decrease the bleeding temporarily.¹¹ They usually fail after a few months and might not even work from the beginning. Also, they do nothing for the fibroid itself and sometimes even make the fibroid grow. I’m very excited now that elagolix with hormonal add-back therapy has gone through the appropriate studies and secured FDA approval.
 
Oriahnn has very different active ingredients. It uses elagolix, which works centrally on the pituitary gland. It inhibits ovulation and the production of estrogen and progesterone in the ovary; these hormones are responsible for the growth of the fibroid. Thus, with this treatment, the fibroid gradually becomes inactive, and it can no longer make the uterine lining bleed more.⁹
 
However, when we inhibit ovulation, women sometimes have some side effects that are similar to the changes that happen when women go through menopause. With elagolix alone, you will have side effects such as hot flushes, night sweats, and vaginal dryness. For extended treatment periods, the bone also starts to lose some of its strength due to decreased bone mineral density, which estrogen helps maintain. Thus, to obtain the benefit of elagolix and alleviate the side effects, the team advising AbbVie, the company that produces elagolix, including myself, decided to add a small amount of estradiol and norethindrone acetate into the tablet. This allows you to decrease and control the bleeding while limiting the side effects.⁹
 
It is very encouraging, and I’m already using Oriahnn in my practice. I believe that Oriahnn should be the first-line treatment for women who have fibroids and heavy menstrual bleeding (unless the patient for some reason prefers another treatment option).

Are there other medical treatment options being developed?

I’ve been working in the fibroid field during the past 20 years or so — my entire professional career. I have been saying in many venues that women should have multiple options. I am very glad that more attention is being given to fibroid treatment options.
 
I’m aware of 2 other medications that are still going through their clinical research evaluations and do not yet have FDA approval. The first is called relugolix (funded by Myovant; ClinicalTrials.gov Identifier: NCT03049735). Phase 3 studies have been completed, and the results were also very encouraging; my understanding is that they will seek FDA approval soon. The other medication is linzagolix (funded by ObsEva; ClinicalTrials.gov Identifier: NCT03070951). Phase 3 studies are being completed, and it seems very effective as well. Hopefully in the near future, there will be several medical treatment options available for our patients.

Have there been any recent advances in the surgical treatment of uterine fibroids?

Robotic myomectomy is probably the newest development on the surgical side. In robotic myomectomy, which is very similar to laparoscopic or minimally invasive surgery, the robot gives us more flexibility, and the suturing is easier. We do encourage surgeons to use minimally invasive techniques with more cases where they might have done open myomectomy before.
 
The Q&A was edited for clarity and length.

Disclosure

Ayman Al-Hendy, MD, PhD, disclosed the following relationships: AbbVie: Consultant/Advisory Board; Allergan: Consultant/Advisory Board; Bayer: Consultant/Advisory Board; MD Stem Cells: Consultant/Advisory Board; Myovant: Consultant/Advisory Board.

References

1. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: An international internet-based survey of 21,746 women. BMC Womens Health. 2012;12:6. doi:10.1186/1472-6874-12-6
2. Reed BG, Carr BR. The normal menstrual cycle and the control of ovulation. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/pubmed/25905282. Accessed September 26, 2020.
3. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: Findings from a cross-sectional survey analysis. Int J Womens Health. 2017;9:403-411. doi:10.2147/IJWH.S133212
4. National Heart, Lung, and Blood Institute. Iron-deficiency anemia. https://www.nhlbi.nih.gov/health-topics/iron-deficiency-anemia. Accessed September 26, 2020.
5. Ghant MS, Sengoba KS, Vogelzang R, Lawson AK, Marsh EE. An altered perception of normal: understanding causes for treatment delay in women with symptomatic uterine fibroids. J Women’s Heal. 2016;25(8):846-852. doi:10.1089/jwh.2015.5531
6. Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: burden and unmet medical need. Semin Reprod Med. 2017;35(6):473-480. doi:10.1055/s-0037-1607264
7. Bernardi LA, Ghant MS, Andrade C, Recht H, Marsh EE. The association between subjective assessment of menstrual bleeding and measures of iron deficiency anemia in premenopausal African-American women: across-sectional study. BMC Womens Health. 2016;16(1):50. doi:10.1186/s12905-016-0329-z
8. U.S. Food and Drug Administration. FDA approves new option to treat heavy menstrual bleeding associated with fibroids in women. https://www.fda.gov/news-events/press-announcements/fda-approves-new-option-treat-heavy-menstrual-bleeding-associated-fibroids-women. Accessed September 26, 2020.
9. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382(4):328-340. doi:10.1056/NEJMoa1904351
10. Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135(6):1313-1326. doi:10.1097/AOG.0000000000003869
11. Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G. Uterine fibroids: an update on current and emerging medical treatment options. Ther Clin Risk Manag. 2019;15:157-178. doi:10.2147/TCRM.S147318
 
Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.