Article

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

According to the United States Transgender Survey, 39% of respondents reported experiencing serious psychological distress (based on the Kessler 6 Psychological Distress Scale) in the past 30 days compared with 5% in the general population.¹ Additionally, 40% of respondents attempted suicide in their lifetime, compared with 5% in the general population.¹ Almost half of respondents reported being sexually assaulted at some time in their life, and 10% reported being sexually assaulted in the past year.¹

Studies have also shown that veterans and active-duty service members experience worse mental health outcomes and are at increased risk for suicide than civilians and nonveterans.^2-5 About 1 in 4 active-duty service members meet the criteria for diagnosis of a mental illness.⁴ Service members were found to have higher rates of probable anxiety and posttraumatic stress disorder (PTSD) compared with the general population.^2,6 In 2018, veteran suicide deaths accounted for about 13% of all deaths by suicide in the US even though veterans only accounted for about 7% of the adult population in that year.^5,7 Also in 2018, about 17 veterans committed suicide per day.⁵ According to the Health Related Behaviors Survey of active-duty service members, about 18% reported thinking about attempting suicide some time in their lives compared with 4% of the general population.^2,3 Additionally, 5% of service members reported previous suicide attempts compared with 0.5% in the general population.^2,3 It is clear that transgender individuals, veterans, and service members have certain mental health outcomes that are worse than that of the general population.^1-7

Transgender individuals along with LGB (lesbian, gay, bisexual) individuals have long faced discrimination and unfair treatment in the military.^8-11 In the 1920s, the first written policies were established that banned gay men from serving in the military.⁹ The US Department of Defense (DoD) continued these policies until in 1993, the “Don’t Ask Don’t Tell” policy was established, which had the façade of being more inclusive for LGB individuals but forced LGB service members to hide their sexual identity and continued the anti-LGBTQ messages that previous policies had created.^8,10,11 In 2010, “Don’t Ask Don’t Tell” was repealed, which allowed LGB individuals to serve in the military without concealing their sexual orientation and without fear of discharge based on their sexual identity.¹¹ This repeal did not allow transgender individuals to serve their country as the DoD categorized transgender identity as a medical and mental health disorder.^8,11

In 2016, the ban on transgender individuals serving in the military was lifted, and service members could no longer be discharged or turned away from joining the military based on gender identity.^8,12 However, in 2018, this order was reversed. The new policy stated that new service members must meet requirements and standards of their sex assigned at birth, and individuals with a history of gender dysphoria or those who have received gender-affirming medical or surgical treatment were prohibited to serve in the military.^8,13 This policy did not apply to service members who joined before it took effect. Finally, in April 2021, the current policy took effect, permitting transgender individuals to openly serve in the military. The current policy states that service members cannot be discharged or denied reenlistment based on their gender identity and provides support to receive gender-affirming medical care.¹⁴ Although transgender individuals are now accepted in military service, there is still much progress needed to promote equity among transgender service members.

Methods

We conducted a systematic review of articles presenting data on mental health outcomes in transgender veterans and active-duty service members. The National Library of Medicine PubMed database was searched using the following search terms in various combinations: mental health outcomes, transgender, veterans, military, active duty, substance use, and sexual trauma. The literature search was performed in August 2021 and included articles published through July 31, 2021. Methodology, size, demographics, measures, and main findings were extracted from each article. All studies were eligible for inclusion regardless of sample size. Studies that examined the LGBTQ population without separating transgender individuals were excluded. Studies that examined mental health outcomes including, but not limited to, PTSD, depression, suicidality, anxiety, and substance use disorders (SUDs) in addition to sexual trauma were included. Studies that only examined physical health outcomes were excluded. Qualitative studies, case reports, and papers that did not present original data were excluded (Figure).

Results

Our search resulted in 86 publications. After excluding 65 articles that did not meet the inclusion criteria, 19 studies were included in this review. The Appendix shows the summary of findings from each study, including the study size and results. All studies were conducted in the United States. Most papers used a cross-sectional study design. Most of the studies focused on transgender veterans, but some included data on transgender active-duty service members.

We separated the findings into the following categories based on the variables measured: mental health, including depression, anxiety, PTSD, and serious mental illness; suicidality and self-harm; substance use; and military sexual trauma (MST). Many studies overlapped multiple categories.

Mental Health

Most of the studies included reported that transgender veterans have statistically significant worse mental health outcomes compared with cisgender veterans.^28-30 In addition, transgender active-duty service members were found to have worse mental health outcomes than cisgender active-duty service members.³¹ MST and discrimination were associated with worse mental health outcomes among transgender veterans.^32,33 One study showed a different result than others and found that transgender older adults with prior military service had higher psychological health-related quality of life and lower depressive symptoms than those without prior military service (P = .02 and .04, respectively).³⁴ Another study compared transgender veterans with active-duty service members and found that transgender veterans reported higher rates of depression (64.6% vs 30.9%; χ² = 11.68; P = .001) and anxiety (41.3% vs 18.2%; χ² = 6.54; P = .01) compared with transgender service members.³⁵

Suicidality and Self-harm

Eleven of the 19 studies included measured suicidality and/or self-harm as an outcome. Transgender veterans and active-duty service members were found to have higher odds of suicidality than their cisgender counterparts.^16,28,29,31 In addition, transgender veterans may die by suicide at a younger age than cisgender veterans.³⁶ Stigma and gender-related discrimination were found to be associated with suicidal ideation.^33,37-39 Transgender veterans were less likely than transgender nonveterans to report nonsuicidal self-injury (NSSI).⁴⁰

Substance Use

Two studies focused on substance use, while 5 other studies included substance use in their measures. One of these 2 studies that focused only on substance use outcomes found that transgender veterans were more likely than cisgender veterans to have any SUD (7.2% vs 3.9%; P < .001), in addition to specifically cannabis (3.4% vs 1.5%; P < .001), amphetamine (1.1% vs 0.3%; P < .001), and cocaine use disorders (1.5% vs 1.1%; P < .001).⁴¹

Another study reported that transgender veterans had lower odds of self-reported alcohol use but had greater odds of having alcohol-related diagnoses compared with cisgender veterans.⁴² Of the other studies, it was found that a higher percentage of transgender veterans were diagnosed with an SUD compared with transgender active-duty service members, and transgender veterans were more likely than cisgender veterans to be diagnosed with alcohol use disorder.^29,31 Additionally, rural transgender veterans had increased odds of tobacco use disorder compared with transgender veterans who lived in urban areas.⁴³

Military Sexual Trauma

Five of the studies included examined MST, defined as sexual assault or sexual harassment that is experienced during military service.⁴⁴ Studies found that 15% to 17% of transgender veterans experienced MST.^32,45 Transgender veterans were more likely to report MST than cisgender veterans.^28,29 MST was found to be consistently associated with depression and PTSD.^32,45 A high percentage (83.9%) of transgender active-duty service members reported experiencing sexual harassment and almost one-third experienced sexual assault.⁴⁶

Discussion

Outcomes examined in this review included MST, substance use, suicidality, and symptoms of depression, anxiety, and PTSD among transgender active-duty service members and veterans. To our knowledge, no other review on this topic exists. There is a review of the health and well-being of LGBTQ veterans and service members, but a majority of the included studies did not separate transgender individuals from LGB persons.¹⁷ This review of transgender individuals showed similar results to the review of LGBTQ individuals.¹⁷ This review also presented similar results to previous studies that indicated that transgender individuals in the general population have worse mental health outcomes compared with their cisgender counterparts, in addition to studies that showed that veterans and active-duty service members have worse mental health outcomes compared with civilians and nonveterans.^1-5 The population of focus in this review faced a unique set of challenges, being that they belonged to both of these subsets of the population, both of which experienced worse mental health outcomes, according to the literature.

Studies included in our review found that transgender veterans and service members have worse mental health outcomes than cisgender veterans and service members.^28-31 This outcome was predicted based on previous data collection among transgender individuals, veterans, and active-duty service members. One of the studies included found different results and concluded that prior military service was a protective factor against poorer mental health outcomes.³⁴ This could be, in part, due to veterans’ access to care through the US Department of Veterans Affairs (VA) system. It has been found that transgender veterans use VA services at higher rates than the general population of veterans and that barriers to care were found more for medical treatment than for mental health treatment.⁴⁷ One study found that almost 70% of transgender veterans who used VA services were satisfied with their mental health care.⁴⁸ In contrast, another study included in our review found that transgender veterans had worse mental health outcomes than transgender service members, possibly showing that even with access to care, the burden of stigma and discrimination worsens mental health over time.³¹ Although it has been shown that transgender veterans may feel comfortable disclosing their gender identity to their health care professional, many barriers to care have been identified, such as insensitivity and lack of knowledge about transgender care among clinicians.^49-51 With this information, it would be useful to ensure proper training for health care professionals on providing gender-affirming care.

Most of the studies also found that transgender veterans and service members had greater odds of suicidal thoughts and events than cisgender veterans and service members.^16,28,29,35 On the contrary, transgender veterans were less likely than transgender nonveterans to report NSSI, which could be for various reasons.⁴⁰ Transgender veterans may report less NSSI but experience it at similar rates, or veteran status may be a protective factor for NSSI.

Limitations

This review was limited due to the lack of data collected from transgender veterans and service members. The studies included did not allow for standardized comparisons and did not use identical measures. Some papers compared transgender veterans with transgender nonveterans, some transgender veterans and/or service members with cisgender veterans and/or service members, and some transgender veterans with transgender service members. There were some consistent results found across the studies, but some studies showed contradictory results or no significant differences within a certain category. It is difficult to compare such different study designs and various participant populations. Additional research is required to verify and replicate these results.

Conclusions

Although this review was limited due to the lack of consistent study designs in the literature examining the mental health of transgender veterans and active-duty service members, overall results showed that transgender veterans and service members experience worse mental health outcomes than their cisgender counterparts. With this knowledge and exploring the history of discrimination that this population has faced, improved systems must be put into place to better serve this population and improve health outcomes. Additional research is required to examine the effects of gender-affirming care on mental health among transgender veterans and service members.

According to the United States Transgender Survey, 39% of respondents reported experiencing serious psychological distress (based on the Kessler 6 Psychological Distress Scale) in the past 30 days compared with 5% in the general population.¹ Additionally, 40% of respondents attempted suicide in their lifetime, compared with 5% in the general population.¹ Almost half of respondents reported being sexually assaulted at some time in their life, and 10% reported being sexually assaulted in the past year.¹

Studies have also shown that veterans and active-duty service members experience worse mental health outcomes and are at increased risk for suicide than civilians and nonveterans.^2-5 About 1 in 4 active-duty service members meet the criteria for diagnosis of a mental illness.⁴ Service members were found to have higher rates of probable anxiety and posttraumatic stress disorder (PTSD) compared with the general population.^2,6 In 2018, veteran suicide deaths accounted for about 13% of all deaths by suicide in the US even though veterans only accounted for about 7% of the adult population in that year.^5,7 Also in 2018, about 17 veterans committed suicide per day.⁵ According to the Health Related Behaviors Survey of active-duty service members, about 18% reported thinking about attempting suicide some time in their lives compared with 4% of the general population.^2,3 Additionally, 5% of service members reported previous suicide attempts compared with 0.5% in the general population.^2,3 It is clear that transgender individuals, veterans, and service members have certain mental health outcomes that are worse than that of the general population.^1-7

Transgender individuals along with LGB (lesbian, gay, bisexual) individuals have long faced discrimination and unfair treatment in the military.^8-11 In the 1920s, the first written policies were established that banned gay men from serving in the military.⁹ The US Department of Defense (DoD) continued these policies until in 1993, the “Don’t Ask Don’t Tell” policy was established, which had the façade of being more inclusive for LGB individuals but forced LGB service members to hide their sexual identity and continued the anti-LGBTQ messages that previous policies had created.^8,10,11 In 2010, “Don’t Ask Don’t Tell” was repealed, which allowed LGB individuals to serve in the military without concealing their sexual orientation and without fear of discharge based on their sexual identity.¹¹ This repeal did not allow transgender individuals to serve their country as the DoD categorized transgender identity as a medical and mental health disorder.^8,11

In 2016, the ban on transgender individuals serving in the military was lifted, and service members could no longer be discharged or turned away from joining the military based on gender identity.^8,12 However, in 2018, this order was reversed. The new policy stated that new service members must meet requirements and standards of their sex assigned at birth, and individuals with a history of gender dysphoria or those who have received gender-affirming medical or surgical treatment were prohibited to serve in the military.^8,13 This policy did not apply to service members who joined before it took effect. Finally, in April 2021, the current policy took effect, permitting transgender individuals to openly serve in the military. The current policy states that service members cannot be discharged or denied reenlistment based on their gender identity and provides support to receive gender-affirming medical care.¹⁴ Although transgender individuals are now accepted in military service, there is still much progress needed to promote equity among transgender service members.

Methods

We conducted a systematic review of articles presenting data on mental health outcomes in transgender veterans and active-duty service members. The National Library of Medicine PubMed database was searched using the following search terms in various combinations: mental health outcomes, transgender, veterans, military, active duty, substance use, and sexual trauma. The literature search was performed in August 2021 and included articles published through July 31, 2021. Methodology, size, demographics, measures, and main findings were extracted from each article. All studies were eligible for inclusion regardless of sample size. Studies that examined the LGBTQ population without separating transgender individuals were excluded. Studies that examined mental health outcomes including, but not limited to, PTSD, depression, suicidality, anxiety, and substance use disorders (SUDs) in addition to sexual trauma were included. Studies that only examined physical health outcomes were excluded. Qualitative studies, case reports, and papers that did not present original data were excluded (Figure).

Results

Our search resulted in 86 publications. After excluding 65 articles that did not meet the inclusion criteria, 19 studies were included in this review. The Appendix shows the summary of findings from each study, including the study size and results. All studies were conducted in the United States. Most papers used a cross-sectional study design. Most of the studies focused on transgender veterans, but some included data on transgender active-duty service members.

We separated the findings into the following categories based on the variables measured: mental health, including depression, anxiety, PTSD, and serious mental illness; suicidality and self-harm; substance use; and military sexual trauma (MST). Many studies overlapped multiple categories.

Mental Health

Most of the studies included reported that transgender veterans have statistically significant worse mental health outcomes compared with cisgender veterans.^28-30 In addition, transgender active-duty service members were found to have worse mental health outcomes than cisgender active-duty service members.³¹ MST and discrimination were associated with worse mental health outcomes among transgender veterans.^32,33 One study showed a different result than others and found that transgender older adults with prior military service had higher psychological health-related quality of life and lower depressive symptoms than those without prior military service (P = .02 and .04, respectively).³⁴ Another study compared transgender veterans with active-duty service members and found that transgender veterans reported higher rates of depression (64.6% vs 30.9%; χ² = 11.68; P = .001) and anxiety (41.3% vs 18.2%; χ² = 6.54; P = .01) compared with transgender service members.³⁵

Suicidality and Self-harm

Eleven of the 19 studies included measured suicidality and/or self-harm as an outcome. Transgender veterans and active-duty service members were found to have higher odds of suicidality than their cisgender counterparts.^16,28,29,31 In addition, transgender veterans may die by suicide at a younger age than cisgender veterans.³⁶ Stigma and gender-related discrimination were found to be associated with suicidal ideation.^33,37-39 Transgender veterans were less likely than transgender nonveterans to report nonsuicidal self-injury (NSSI).⁴⁰

Substance Use

Two studies focused on substance use, while 5 other studies included substance use in their measures. One of these 2 studies that focused only on substance use outcomes found that transgender veterans were more likely than cisgender veterans to have any SUD (7.2% vs 3.9%; P < .001), in addition to specifically cannabis (3.4% vs 1.5%; P < .001), amphetamine (1.1% vs 0.3%; P < .001), and cocaine use disorders (1.5% vs 1.1%; P < .001).⁴¹

Another study reported that transgender veterans had lower odds of self-reported alcohol use but had greater odds of having alcohol-related diagnoses compared with cisgender veterans.⁴² Of the other studies, it was found that a higher percentage of transgender veterans were diagnosed with an SUD compared with transgender active-duty service members, and transgender veterans were more likely than cisgender veterans to be diagnosed with alcohol use disorder.^29,31 Additionally, rural transgender veterans had increased odds of tobacco use disorder compared with transgender veterans who lived in urban areas.⁴³

Military Sexual Trauma

Five of the studies included examined MST, defined as sexual assault or sexual harassment that is experienced during military service.⁴⁴ Studies found that 15% to 17% of transgender veterans experienced MST.^32,45 Transgender veterans were more likely to report MST than cisgender veterans.^28,29 MST was found to be consistently associated with depression and PTSD.^32,45 A high percentage (83.9%) of transgender active-duty service members reported experiencing sexual harassment and almost one-third experienced sexual assault.⁴⁶

Discussion

Outcomes examined in this review included MST, substance use, suicidality, and symptoms of depression, anxiety, and PTSD among transgender active-duty service members and veterans. To our knowledge, no other review on this topic exists. There is a review of the health and well-being of LGBTQ veterans and service members, but a majority of the included studies did not separate transgender individuals from LGB persons.¹⁷ This review of transgender individuals showed similar results to the review of LGBTQ individuals.¹⁷ This review also presented similar results to previous studies that indicated that transgender individuals in the general population have worse mental health outcomes compared with their cisgender counterparts, in addition to studies that showed that veterans and active-duty service members have worse mental health outcomes compared with civilians and nonveterans.^1-5 The population of focus in this review faced a unique set of challenges, being that they belonged to both of these subsets of the population, both of which experienced worse mental health outcomes, according to the literature.

Studies included in our review found that transgender veterans and service members have worse mental health outcomes than cisgender veterans and service members.^28-31 This outcome was predicted based on previous data collection among transgender individuals, veterans, and active-duty service members. One of the studies included found different results and concluded that prior military service was a protective factor against poorer mental health outcomes.³⁴ This could be, in part, due to veterans’ access to care through the US Department of Veterans Affairs (VA) system. It has been found that transgender veterans use VA services at higher rates than the general population of veterans and that barriers to care were found more for medical treatment than for mental health treatment.⁴⁷ One study found that almost 70% of transgender veterans who used VA services were satisfied with their mental health care.⁴⁸ In contrast, another study included in our review found that transgender veterans had worse mental health outcomes than transgender service members, possibly showing that even with access to care, the burden of stigma and discrimination worsens mental health over time.³¹ Although it has been shown that transgender veterans may feel comfortable disclosing their gender identity to their health care professional, many barriers to care have been identified, such as insensitivity and lack of knowledge about transgender care among clinicians.^49-51 With this information, it would be useful to ensure proper training for health care professionals on providing gender-affirming care.

Most of the studies also found that transgender veterans and service members had greater odds of suicidal thoughts and events than cisgender veterans and service members.^16,28,29,35 On the contrary, transgender veterans were less likely than transgender nonveterans to report NSSI, which could be for various reasons.⁴⁰ Transgender veterans may report less NSSI but experience it at similar rates, or veteran status may be a protective factor for NSSI.

Limitations

This review was limited due to the lack of data collected from transgender veterans and service members. The studies included did not allow for standardized comparisons and did not use identical measures. Some papers compared transgender veterans with transgender nonveterans, some transgender veterans and/or service members with cisgender veterans and/or service members, and some transgender veterans with transgender service members. There were some consistent results found across the studies, but some studies showed contradictory results or no significant differences within a certain category. It is difficult to compare such different study designs and various participant populations. Additional research is required to verify and replicate these results.

Conclusions

Although this review was limited due to the lack of consistent study designs in the literature examining the mental health of transgender veterans and active-duty service members, overall results showed that transgender veterans and service members experience worse mental health outcomes than their cisgender counterparts. With this knowledge and exploring the history of discrimination that this population has faced, improved systems must be put into place to better serve this population and improve health outcomes. Additional research is required to examine the effects of gender-affirming care on mental health among transgender veterans and service members.

According to the United States Transgender Survey, 39% of respondents reported experiencing serious psychological distress (based on the Kessler 6 Psychological Distress Scale) in the past 30 days compared with 5% in the general population.¹ Additionally, 40% of respondents attempted suicide in their lifetime, compared with 5% in the general population.¹ Almost half of respondents reported being sexually assaulted at some time in their life, and 10% reported being sexually assaulted in the past year.¹

Studies have also shown that veterans and active-duty service members experience worse mental health outcomes and are at increased risk for suicide than civilians and nonveterans.^2-5 About 1 in 4 active-duty service members meet the criteria for diagnosis of a mental illness.⁴ Service members were found to have higher rates of probable anxiety and posttraumatic stress disorder (PTSD) compared with the general population.^2,6 In 2018, veteran suicide deaths accounted for about 13% of all deaths by suicide in the US even though veterans only accounted for about 7% of the adult population in that year.^5,7 Also in 2018, about 17 veterans committed suicide per day.⁵ According to the Health Related Behaviors Survey of active-duty service members, about 18% reported thinking about attempting suicide some time in their lives compared with 4% of the general population.^2,3 Additionally, 5% of service members reported previous suicide attempts compared with 0.5% in the general population.^2,3 It is clear that transgender individuals, veterans, and service members have certain mental health outcomes that are worse than that of the general population.^1-7

Transgender individuals along with LGB (lesbian, gay, bisexual) individuals have long faced discrimination and unfair treatment in the military.^8-11 In the 1920s, the first written policies were established that banned gay men from serving in the military.⁹ The US Department of Defense (DoD) continued these policies until in 1993, the “Don’t Ask Don’t Tell” policy was established, which had the façade of being more inclusive for LGB individuals but forced LGB service members to hide their sexual identity and continued the anti-LGBTQ messages that previous policies had created.^8,10,11 In 2010, “Don’t Ask Don’t Tell” was repealed, which allowed LGB individuals to serve in the military without concealing their sexual orientation and without fear of discharge based on their sexual identity.¹¹ This repeal did not allow transgender individuals to serve their country as the DoD categorized transgender identity as a medical and mental health disorder.^8,11

In 2016, the ban on transgender individuals serving in the military was lifted, and service members could no longer be discharged or turned away from joining the military based on gender identity.^8,12 However, in 2018, this order was reversed. The new policy stated that new service members must meet requirements and standards of their sex assigned at birth, and individuals with a history of gender dysphoria or those who have received gender-affirming medical or surgical treatment were prohibited to serve in the military.^8,13 This policy did not apply to service members who joined before it took effect. Finally, in April 2021, the current policy took effect, permitting transgender individuals to openly serve in the military. The current policy states that service members cannot be discharged or denied reenlistment based on their gender identity and provides support to receive gender-affirming medical care.¹⁴ Although transgender individuals are now accepted in military service, there is still much progress needed to promote equity among transgender service members.

Methods

We conducted a systematic review of articles presenting data on mental health outcomes in transgender veterans and active-duty service members. The National Library of Medicine PubMed database was searched using the following search terms in various combinations: mental health outcomes, transgender, veterans, military, active duty, substance use, and sexual trauma. The literature search was performed in August 2021 and included articles published through July 31, 2021. Methodology, size, demographics, measures, and main findings were extracted from each article. All studies were eligible for inclusion regardless of sample size. Studies that examined the LGBTQ population without separating transgender individuals were excluded. Studies that examined mental health outcomes including, but not limited to, PTSD, depression, suicidality, anxiety, and substance use disorders (SUDs) in addition to sexual trauma were included. Studies that only examined physical health outcomes were excluded. Qualitative studies, case reports, and papers that did not present original data were excluded (Figure).

Results

Our search resulted in 86 publications. After excluding 65 articles that did not meet the inclusion criteria, 19 studies were included in this review. The Appendix shows the summary of findings from each study, including the study size and results. All studies were conducted in the United States. Most papers used a cross-sectional study design. Most of the studies focused on transgender veterans, but some included data on transgender active-duty service members.

We separated the findings into the following categories based on the variables measured: mental health, including depression, anxiety, PTSD, and serious mental illness; suicidality and self-harm; substance use; and military sexual trauma (MST). Many studies overlapped multiple categories.

Mental Health

Most of the studies included reported that transgender veterans have statistically significant worse mental health outcomes compared with cisgender veterans.^28-30 In addition, transgender active-duty service members were found to have worse mental health outcomes than cisgender active-duty service members.³¹ MST and discrimination were associated with worse mental health outcomes among transgender veterans.^32,33 One study showed a different result than others and found that transgender older adults with prior military service had higher psychological health-related quality of life and lower depressive symptoms than those without prior military service (P = .02 and .04, respectively).³⁴ Another study compared transgender veterans with active-duty service members and found that transgender veterans reported higher rates of depression (64.6% vs 30.9%; χ² = 11.68; P = .001) and anxiety (41.3% vs 18.2%; χ² = 6.54; P = .01) compared with transgender service members.³⁵

Suicidality and Self-harm

Eleven of the 19 studies included measured suicidality and/or self-harm as an outcome. Transgender veterans and active-duty service members were found to have higher odds of suicidality than their cisgender counterparts.^16,28,29,31 In addition, transgender veterans may die by suicide at a younger age than cisgender veterans.³⁶ Stigma and gender-related discrimination were found to be associated with suicidal ideation.^33,37-39 Transgender veterans were less likely than transgender nonveterans to report nonsuicidal self-injury (NSSI).⁴⁰

Substance Use

Two studies focused on substance use, while 5 other studies included substance use in their measures. One of these 2 studies that focused only on substance use outcomes found that transgender veterans were more likely than cisgender veterans to have any SUD (7.2% vs 3.9%; P < .001), in addition to specifically cannabis (3.4% vs 1.5%; P < .001), amphetamine (1.1% vs 0.3%; P < .001), and cocaine use disorders (1.5% vs 1.1%; P < .001).⁴¹

Another study reported that transgender veterans had lower odds of self-reported alcohol use but had greater odds of having alcohol-related diagnoses compared with cisgender veterans.⁴² Of the other studies, it was found that a higher percentage of transgender veterans were diagnosed with an SUD compared with transgender active-duty service members, and transgender veterans were more likely than cisgender veterans to be diagnosed with alcohol use disorder.^29,31 Additionally, rural transgender veterans had increased odds of tobacco use disorder compared with transgender veterans who lived in urban areas.⁴³

Military Sexual Trauma

Five of the studies included examined MST, defined as sexual assault or sexual harassment that is experienced during military service.⁴⁴ Studies found that 15% to 17% of transgender veterans experienced MST.^32,45 Transgender veterans were more likely to report MST than cisgender veterans.^28,29 MST was found to be consistently associated with depression and PTSD.^32,45 A high percentage (83.9%) of transgender active-duty service members reported experiencing sexual harassment and almost one-third experienced sexual assault.⁴⁶

Discussion

Outcomes examined in this review included MST, substance use, suicidality, and symptoms of depression, anxiety, and PTSD among transgender active-duty service members and veterans. To our knowledge, no other review on this topic exists. There is a review of the health and well-being of LGBTQ veterans and service members, but a majority of the included studies did not separate transgender individuals from LGB persons.¹⁷ This review of transgender individuals showed similar results to the review of LGBTQ individuals.¹⁷ This review also presented similar results to previous studies that indicated that transgender individuals in the general population have worse mental health outcomes compared with their cisgender counterparts, in addition to studies that showed that veterans and active-duty service members have worse mental health outcomes compared with civilians and nonveterans.^1-5 The population of focus in this review faced a unique set of challenges, being that they belonged to both of these subsets of the population, both of which experienced worse mental health outcomes, according to the literature.

Studies included in our review found that transgender veterans and service members have worse mental health outcomes than cisgender veterans and service members.^28-31 This outcome was predicted based on previous data collection among transgender individuals, veterans, and active-duty service members. One of the studies included found different results and concluded that prior military service was a protective factor against poorer mental health outcomes.³⁴ This could be, in part, due to veterans’ access to care through the US Department of Veterans Affairs (VA) system. It has been found that transgender veterans use VA services at higher rates than the general population of veterans and that barriers to care were found more for medical treatment than for mental health treatment.⁴⁷ One study found that almost 70% of transgender veterans who used VA services were satisfied with their mental health care.⁴⁸ In contrast, another study included in our review found that transgender veterans had worse mental health outcomes than transgender service members, possibly showing that even with access to care, the burden of stigma and discrimination worsens mental health over time.³¹ Although it has been shown that transgender veterans may feel comfortable disclosing their gender identity to their health care professional, many barriers to care have been identified, such as insensitivity and lack of knowledge about transgender care among clinicians.^49-51 With this information, it would be useful to ensure proper training for health care professionals on providing gender-affirming care.

Most of the studies also found that transgender veterans and service members had greater odds of suicidal thoughts and events than cisgender veterans and service members.^16,28,29,35 On the contrary, transgender veterans were less likely than transgender nonveterans to report NSSI, which could be for various reasons.⁴⁰ Transgender veterans may report less NSSI but experience it at similar rates, or veteran status may be a protective factor for NSSI.

Limitations

This review was limited due to the lack of data collected from transgender veterans and service members. The studies included did not allow for standardized comparisons and did not use identical measures. Some papers compared transgender veterans with transgender nonveterans, some transgender veterans and/or service members with cisgender veterans and/or service members, and some transgender veterans with transgender service members. There were some consistent results found across the studies, but some studies showed contradictory results or no significant differences within a certain category. It is difficult to compare such different study designs and various participant populations. Additional research is required to verify and replicate these results.

Conclusions

Although this review was limited due to the lack of consistent study designs in the literature examining the mental health of transgender veterans and active-duty service members, overall results showed that transgender veterans and service members experience worse mental health outcomes than their cisgender counterparts. With this knowledge and exploring the history of discrimination that this population has faced, improved systems must be put into place to better serve this population and improve health outcomes. Additional research is required to examine the effects of gender-affirming care on mental health among transgender veterans and service members.

Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.

Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.^1,2

As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.

Discussion 

Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.

The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).³ These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.^4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.^4-7

Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.^8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.

As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.

Conclusions

Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.

Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.

Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.^1,2

As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.

Discussion 

Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.

The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).³ These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.^4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.^4-7

Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.^8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.

As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.

Conclusions

Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.

Recent natural disasters, civil disorder, and the COVID-19 pandemic response created an unprecedented demand for the US National Guard and Reserve components as well as active-duty personnel to serve on homefront missions critical to our nation. At times, those serving in these capacities are front and center to the most tragic events confronting our nation, and they frequently encounter tremendous suffering.

Recognizing the potential for these missions to create psychological sequela for those who serve on them, the authority for the Veterans Health Administration (VHA) vet centers to provide readjustment counseling services was broadened on December 30, 2021. Vet centers are community-based counseling centers that have traditionally served combat veterans, and broadening services reflects a major change in mission. Revised VHA Directive 1500(2) specifies that those who “served on active duty in response to a national emergency or major disaster declared by the President” or “served on active duty in the National Guard of a State under orders of the chief executive of that State in response to a disaster or civil disorder in such State” may now receive therapy at vet centers.^1,2

As a result of this recent policy change, National Guard and active-duty Reserve service members now have parity with combat veterans to obtain therapy for symptoms arising as a result of their activation for service on homefront missions. As they seek care, we need to be ready so that these service members can obtain the best therapy services possible. Soldiers who served on homefront missions comprise a new cohort of service members now eligible for vet center therapy. Soldiers who served on homefront missions may present with issues that differ from those of combat veterans and veterans who have experienced military sexual trauma (MST), the populations treated by vet centers and other VHA mental health care clinics prior to this broadened authority. This article highlights some suggestions for service delivery to best meet the needs of this population.

Discussion 

Available evidence-based therapies to treat posttraumatic stress disorder (PTSD) are effective regardless of whether the trauma occurred in combat, on the homefront, or in a civilian setting. The vet centers and VHA mental health services already have staff trained to deliver these therapy modalities and, in this sense, are ready to provide trauma-focused therapy treatment to soldiers with PTSD who served on homefront missions.

The broadened authority for the vet centers to provide readjustment services is necessary, as it corrects for a critical gap in services, but the importance of ensuring adequate staffing to meet the expected increased demand for services cannot be underscored. According to clinical practice guidelines for the treatment of PTSD, developed by the US Department of Veterans Affairs (VA) and the US Department of Defense (DoD), the therapies with the strongest evidence-based backing are prolonged exposure-based therapy (PE), cognitive processing therapy (CPT), and eye movement and desensitization reprocessing (EMDR).³ These therapy modalities, based on findings from clinical trials, are predicated on seeing a client for a sufficient number of sessions. Attendance at these sessions is recommended at least weekly to ensure adequate intensity of service delivery.^4-7 According to the National Center for PTSD, PE typically involves 8 to 15 weekly or twice weekly sessions; CPT requires 8 to 14 or more weekly sessions, and EMDR is usually 4 to 12 weekly sessions.^4-7

Ensuring adequate staffing is critical to offer these therapies at least weekly as the efficacies of these therapies are otherwise not proven if return session visits are stretched out over multiple weeks or months. The most recent clinical research has demonstrated that PTSD recovery can be expedited and there are lower patient dropout rates when sessions are massed or compressed so that multiple sessions are administered over 1 week.^8-12 Providing these therapies in a massed format has shown to be as effective as when these therapies are provided weekly.

As the authority to treat soldiers serving on homefront missions is new, epidemiologic data do not yet exist to estimate the proportion of this population who will need treatment or present with PTSD, depression, anxiety, a substance use disorder, and/or comorbid conditions. Those with PTSD can benefit from PTSD evidence-based therapies already available for treatment. Others may benefit from treatments that are proven effective for their mental health diagnoses.

Conclusions

Now that National Guard and Reserve component soldiers who have responded to national and local emergencies are eligible for therapy, we need to be prepared to provide these services. In addition to addressing systemic staffing concerns, therapists need to be aware of the unique challenges faced by those who have served on homefront missions. These homefront missions have the potential to hit home for therapists.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

►Anish Bhatnagar, MD, Chief Medical Resident, Veterans Affairs Boston Healthcare System (VABHS) and Beth Israel Deaconess Medical Center (BIDMC): The patient noted erectile dysfunction starting 4 years ago, with accompanied decreased libido. However, until recently, he was able to achieve acceptable erectile capacity with medications. As part of his previous evaluations for erectile dysfunction, the patient had 2 total testosterone levels checked 6 months apart, both low at 150 ng/dL and 38.3 ng/dL (reference range, 220-892). The results of additional hormone studies are shown in the Table. Dr. Ananthakrishnan, can you help us interpret these laboratory results and tell us what tests you might order next?

►Sonia Ananthakrishnan, MD, Section of Endocrinology, Diabetes and Nutrition, Boston Medical Center (BMC) and Assistant Professor of Medicine, Boston University School of Medicine (BUSM): When patients present with signs of hypogonadism and an initial low morning testosterone levels, the next test should be a confirmatory repeat morning testosterone level as was done in this case. If this level is also low (for most assays < 300 ng/dL), further evaluation for primary vs secondary hypogonadism should be pursued with measurement of luteinizing hormone and follicle-stimulating hormone levels. Secondary hypogonadism should be suspected when these levels are low or inappropriately normal in the setting of a low testosterone level as in this patient. This patient does not appear to be on any medication or have reversible illnesses that we traditionally think of as possibly causing these hormone irregularities. Key examples include medications such as gonadotropin-releasing hormone analogs, glucocorticoids, and opioids, as well as conditions such as hyperprolactinemia, sleep apnea, diabetes mellitus, anorexia nervosa, or other chronic systemic illnesses, including cirrhosis or lung disease. In this setting, further evaluation of the patient’s anterior pituitary function should be undertaken. Initial screening tests showed mildly elevated prolactin and low normal thyroid-stimulating hormone levels, with a relatively normal free thyroxine. Given these abnormalities in the context of the patient’s total testosterone level < 150 ng/dL, magnetic resonance imaging (MRI) of the anterior pituitary is indicated, and what I would recommend next for evaluation of pituitary and/or hypothalamic tumor or infiltrative disease.¹

►Dr. Bhatnagar: An MRI of the brain showed a large 2.7-cm sellar mass, with suprasellar extension and mass effect on the optic chiasm and pituitary infundibulum, partial extension into the right sphenoid sinus, and invasion into the right cavernous sinus. These findings were consistent with a pituitary macroadenoma. The patient was subsequently evaluated by a neurosurgeon who felt that because of the extension and compression of the mass, the patient would benefit from surgical resection.

Given his lower urinary tract symptoms, a prostate-specific antigen level was checked and returned elevated at 11.5 ng/mL. In the setting of these abnormalities, the patient underwent MRI of the abdomen, which noted a new 5.6-cm enhancing mass in the upper pole of his solitary right kidney, highly concerning for new RCC. After a multidisciplinary discussion, urology scheduled the patient for partial right nephrectomy first, with plans for pituitary resection only if the patient had adequate recovery following the urologic procedure.

Dr. Rifkin, this patient went straight from imaging to presumed diagnosis to planned surgical intervention without a confirmatory biopsy. In a patient who already has chronic kidney disease stage 4, why would we not want to pursue biopsy prior to this invasive procedure on his solitary kidney? In addition, given his baseline advanced renal disease, why pursue partial nephrectomy to delay initiation of hemodialysis instead of total nephrectomy and beginning hemodialysis?

►Ian Rifkin, MBBCh, PhD, MSc, Chief, Renal Section, VABHS, Section of Nephrology, BMC, and Associate Professor of Medicine, BUSM: In most cases, imaging alone is used to make a presumptive diagnosis of benign vs malignant renal masses. In one study, RCC was identified by MRI with 85% sensitivity and 76% specificity.² However, as imaging and biopsy techniques have advanced, there are progressing discussions regarding the utility of biopsy. That being said, there are a number of situations in which patients currently undergo biopsy, particularly when there is diagnostic uncertainty.³ In this patient, with a history of RCC and imaging findings concerning for RCC, biopsy is unnecessary given the high clinical suspicion.

Regarding the choice of partial vs total nephrectomy, there are 2 important distinctions to be made. The first is that though it was previously felt that early initiation of dialysis improves survival, newer studies suggest that early initiation based off of glomerular filtration rate (GFR) offers no survival benefits compared to delayed initiation.⁴ Second, though there is less clinical data to support this, there is a signal toward the use of partial nephrectomy decreasing mortality compared to radical nephrectomy in management of RCC.⁵ In this patient, partial nephrectomy may not only increase rates of survival, but also delay initiation of dialysis.

►Dr. Bhatnagar: Prior to undergoing partial right nephrectomy, a morning cortisol level was found to be 5.8 μg/dL with an associated corticotropin (ACTH) level of 26 pg/mL. Dr. Ananthakrishnan, how would you interpret these laboratory results and what might you recommend prior to surgery?

►Dr. Bhatnagar: The patient was started on hydrocortisone and underwent a successful laparoscopic partial right nephrectomy. During the procedure, an estimated 2.5 L of blood was lost, with transfusion of 3 units of packed red blood cells. A surgical drain was left in the peritoneum. Postoperatively, he developed hypotension, requiring vasopressors and prolonged continuation of stress dosing of hydrocortisone. Over the next 4 days, the patient was weaned off vasopressors, and his creatinine level was noted to increase from a baseline of 1.8 mg/dL to 4.4 mg/dL.

Dr. Rifkin, how do you think about renal recovery in the patient postnephrectomy, and should we be concerned with the dramatic rise in his creatinine level?

►Dr. Rifkin: Removal of renal mass will result in an initial reduction of GFR proportional to the amount of functional renal tissue removed. However, in as early as 1 week, the residual nephrons begin to compensate through various mechanisms, such as modulation of efferent and afferent arterioles and renal tissue growth by hypertrophy and hyperplasia.⁷ In the acute setting, it may be difficult to distinguish an acute renal injury vs physiological GFR reduction postnephron loss, but often the initially elevated creatinine level may normalize/stabilize over time. Other markers of kidney function should concomitantly be monitored, including urine output, electrolyte/acid-base status, and urine sediment examination. In this patient, although his creatinine level may be elevated over the first few days, if his urine output remains robust and the urine sediment examination is normal, my concern for permanent kidney injury would be lessened.

►Dr. Rifkin: The most common cause of acute kidney injury in hospitalized patients is acute tubular necrosis (ATN).⁸ However, in this patient, who was recovering well postoperatively, was hemodynamically stable with a robust urine output, and in whom no apparent cause for ATN could be identified, other diagnoses were more likely. Considering the abrupt onset of oligo-anuria, the most likely diagnosis was urinary tract obstruction, particularly given the frank blood and blood clots that were present in the urine. Additional possibilities might be a late surgical complication or infection. Surgical complications could range from direct damage to the renal parenchyma to urinary leakage into the peritoneum from the site of anastomosis or tissue injury. Infections introduced either intraoperatively or developed postoperatively could also cause this sudden drop in urine output, though one would expect more systemic symptoms with this. Given that this patient has a surgical drain in place in the peritoneum, I would recommend testing the creatinine level in the peritoneal fluid drainage. If it is comparable to serum levels, this would argue against a urine leak, as we would expect the level to be significantly elevated in a leak. In addition, he should have imaging of the urinary tract followed by procedures to decompress the presumed obstructed urinary tract. These procedures might include either cystoscopy with ureteral stent placement or percutaneous nephrostomy, depending on the result of the imaging.

►Dr. Bhatnagar: The creatinine level obtained from the surgical drain was roughly equivalent to the serum creatinine, decreasing suspicion for a urine leak as the cause of his findings. Cystoscopy with ureteral stent placement was performed with subsequent increase in both urine output and concomitant decrease in serum creatinine.

Around this time, the patient also began to note blurry vision. Evaluation revealed difficulty with visual field confrontation in the right lower quadrant, right eye ptosis, right eye impaired adduction, absent abduction and impaired upgaze, but intact downgaze. Diplopia was present with gaze in all directions. His constellation of physical examination findings were concerning for a pathologic lesion partially involving cranial nerves II and III, with definitive involvement of cranial nerve VI, but sparing of cranial nerve IV. Repeat MRI of the brain showed hemorrhage into the sellar mass, with ongoing mass effect on the optic chiasm and extension into the sinuses (eAppendix). These findings were consistent with pituitary apoplexy. Dr. Ananthakrishnan, can you tell us more about pituitary apoplexy?

►Dr. Ananthakrishnan: Pituitary apoplexy is a clinical syndrome resulting from acute hemorrhage or infarction of the pituitary gland. It typically occurs in patients with preexisting pituitary adenomas and is characterized by the onset of headache, fever, vomiting, meningismus, decreased consciousness, and sometimes death. In addition, given the location of the pituitary gland within the sella, rapid changes in size can result in compression of cranial nerves III, IV, and VI, as well as the optic chiasm, resulting in ophthalmoplegia and visual disturbances as seen in this patient.⁹

There are a multitude of causes of pituitary apoplexy, including alterations in coagulopathy, pituitary stimulation (eg, dynamic pituitary hormone testing), and both acute increases and decreases in blood flow.¹⁰ This patient likely had an ischemic event due to changes in vascular perfusion, spurred by both his blood loss intraoperatively and ongoing hematuria. Management of pituitary apoplexy is dependent on the patient’s hemodynamics, mass effect symptoms, electrolyte balances, and hormone dysfunction. The decision for conservative management vs surgical intervention should be made in consultation with both neurosurgery and endocrinology. Once the patient is hemodynamically stable, the next step in evaluating this patient should be repeating his hormone studies.

►Dr. Bhatnagar: An assessment of pituitary function was consistent with values obtained preoperatively. After multidisciplinary discussions, surgery was deferred, and hydrocortisone was reinitiated to reduce inflammation caused by bleeding into the mass. As the ophthalmoplegia improved, this was transitioned to dexamethasone.

Twelve days after admission, he was discharged to a subacute rehabilitation center, with improvement in his ophthalmoplegia and stabilization of his creatinine level and urine output.

Thiazolidinediones (TZDs), such as pioglitazone, appear to be protective against dementia whereas sulfonylureas appear to increase the risk, a new observational study in patients with type 2 diabetes suggests.

The data, obtained from nationwide electronic medical records from the Department of Veterans Affairs, yielded a 22% lower risk of dementia with TZD monotherapy and a 12% elevated risk with sulfonylurea monotherapy, compared with metformin monotherapy. The apparent protective effects of TZDs were greater among individuals with overweight or obesity.

“Our findings provide additional information to aid clinicians’ selection of [glucose-lowering medications] for patients with mild or moderate type 2 diabetes and [who] are at high risk of dementia,” Xin Tang and colleagues wrote in their article, published online in BMJ Open Diabetes Research & Care.

The results “add substantially to the literature concerning the effects of [glucose-lowering medications] on dementia where previous findings have been inconsistent. Studies with a follow-up time of less than 3 years have mainly reported null associations, while studies with longer a follow-up time typically yielded protective findings. With a mean follow-up time of 6.8 years, we had a sufficient duration to detect treatment differences,” the investigators wrote.

“Supplementing [a] sulfonylurea with either metformin or [a] TZD may partially offset its prodementia effects. These findings may help inform medication selection for elderly patients with T2D at high risk of dementia,” they added.
 

Randomized trials needed to determine cause and effect

Ivan Koychev, PhD, a senior clinical researcher in the department of psychiatry at the University of Oxford (England), told the UK Science Media Centre: “This is a large, well-conducted real-world data study that highlights the importance of checking whether already prescribed medications may be useful for preventing dementia.”

The findings regarding TZDs, also known as glitazones, are in line with existing literature suggesting dementia protection with other drugs prescribed for type 2 diabetes that weren’t examined in the current study, such as newer agents like glucagonlike peptide–1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. Koychev said.

“The main limitations of this study is that following the initial 2-year period the authors were interested in, the participants may have been prescribed one of the other type 2 diabetes drugs [GLP-1 agonists or SGLT2 inhibitors] that have been found to reduce dementia risk, thus potentially making the direct glitazone [TZD] effect more difficult to discern,” Dr. Koychev noted.

And, he pointed out that the study design limits attribution of causality. “It is also important to note that people with type 2 diabetes do run a higher risk of both dementia and cognitive deficits and that these medications are only prescribed in these patients, so all this data is from this patient group rather than the general population.”

James Connell, PhD, head of translational science at Alzheimer’s Research UK, agreed. “While this observational study found that those with type 2 diabetes taking thiazolidinedione had a lower dementia risk than those on the most common medication for type 2 diabetes, it only shows an association between taking the drug and dementia risk and not a causal relationship.

“Double-blind and placebo-controlled clinical trials are needed to see whether the drug [TDZ] could help lower dementia risk in people with and without diabetes. Anyone with any questions about what treatments they are receiving should speak to their doctor,” he told the UK Science Media Centre.
 

Opposite effects of sulfonylureas, TZDs versus metformin

The study authors analyzed 559,106 VA patients with type 2 diabetes who initiated glucose-lowering medication during 2001-2017 and took it for at least a year. They were aged 60 years or older and did not have dementia at baseline. Most were White (76.8%) and male (96.9%), two-thirds (63.1%) had obesity, and mean hemoglobin A1c was 6.8%.

Overall, 31,125 developed all-cause dementia. The incidence rate was 8.2 cases per 1,000 person-years, ranging from 6.2 cases per 1,000 person-years among those taking metformin monotherapy to 13.4 cases per 1,000 person-years in those taking both sulfonylurea and a TZD.

Compared with metformin monotherapy, the hazard ratio for all-cause dementia for sulfonylurea monotherapy was a significant 1.12. The increased risk was also seen for vascular dementia, with an HR of 1.14.

In contrast, TZD monotherapy was associated with a significantly lower risk for all-cause dementia (HR, 0.78), as well as for Alzheimer’s disease (HR, 0.89) and vascular dementia (HR, 0.43), compared with metformin monotherapy.

The combination of metformin and TZD also lowered the risk of all-cause dementia, while regimens including sulfonylureas raised the risks for all-cause and vascular dementia.

Most of the results didn’t change significantly when the drug exposure window was extended to 2 years.
 

Effects more pronounced in those with obesity

The protective 1-year effects of TZD monotherapy and of metformin plus TZD, compared with metformin alone, were more significant among participants aged 75 or younger and with a body mass index above 25 kg/m², compared with those who were older than 75 years and with normal BMIs, respectively.

On the other hand, the greater risk for dementia incurred with sulfonylureas was further increased among those with higher BMI.

This research was partially funded by grants from the National Human Genome Research Institute, the National Science Foundation, the National Institute of Diabetes and Digestive and Kidney Disease, and the National Heart, Lung, and Blood Institute. Dr. Koychev is chief investigator for a trial, sponsored by Oxford University and funded by Novo Nordisk, testing whether the GLP-1 agonist semaglutide reduces the risk for dementia in aging adults.

A version of this article first appeared on Medscape.com.

Thiazolidinediones (TZDs), such as pioglitazone, appear to be protective against dementia whereas sulfonylureas appear to increase the risk, a new observational study in patients with type 2 diabetes suggests.

The data, obtained from nationwide electronic medical records from the Department of Veterans Affairs, yielded a 22% lower risk of dementia with TZD monotherapy and a 12% elevated risk with sulfonylurea monotherapy, compared with metformin monotherapy. The apparent protective effects of TZDs were greater among individuals with overweight or obesity.

“Our findings provide additional information to aid clinicians’ selection of [glucose-lowering medications] for patients with mild or moderate type 2 diabetes and [who] are at high risk of dementia,” Xin Tang and colleagues wrote in their article, published online in BMJ Open Diabetes Research & Care.

The results “add substantially to the literature concerning the effects of [glucose-lowering medications] on dementia where previous findings have been inconsistent. Studies with a follow-up time of less than 3 years have mainly reported null associations, while studies with longer a follow-up time typically yielded protective findings. With a mean follow-up time of 6.8 years, we had a sufficient duration to detect treatment differences,” the investigators wrote.

“Supplementing [a] sulfonylurea with either metformin or [a] TZD may partially offset its prodementia effects. These findings may help inform medication selection for elderly patients with T2D at high risk of dementia,” they added.
 

Randomized trials needed to determine cause and effect

Ivan Koychev, PhD, a senior clinical researcher in the department of psychiatry at the University of Oxford (England), told the UK Science Media Centre: “This is a large, well-conducted real-world data study that highlights the importance of checking whether already prescribed medications may be useful for preventing dementia.”

The findings regarding TZDs, also known as glitazones, are in line with existing literature suggesting dementia protection with other drugs prescribed for type 2 diabetes that weren’t examined in the current study, such as newer agents like glucagonlike peptide–1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. Koychev said.

“The main limitations of this study is that following the initial 2-year period the authors were interested in, the participants may have been prescribed one of the other type 2 diabetes drugs [GLP-1 agonists or SGLT2 inhibitors] that have been found to reduce dementia risk, thus potentially making the direct glitazone [TZD] effect more difficult to discern,” Dr. Koychev noted.

And, he pointed out that the study design limits attribution of causality. “It is also important to note that people with type 2 diabetes do run a higher risk of both dementia and cognitive deficits and that these medications are only prescribed in these patients, so all this data is from this patient group rather than the general population.”

James Connell, PhD, head of translational science at Alzheimer’s Research UK, agreed. “While this observational study found that those with type 2 diabetes taking thiazolidinedione had a lower dementia risk than those on the most common medication for type 2 diabetes, it only shows an association between taking the drug and dementia risk and not a causal relationship.

“Double-blind and placebo-controlled clinical trials are needed to see whether the drug [TDZ] could help lower dementia risk in people with and without diabetes. Anyone with any questions about what treatments they are receiving should speak to their doctor,” he told the UK Science Media Centre.
 

Opposite effects of sulfonylureas, TZDs versus metformin

The study authors analyzed 559,106 VA patients with type 2 diabetes who initiated glucose-lowering medication during 2001-2017 and took it for at least a year. They were aged 60 years or older and did not have dementia at baseline. Most were White (76.8%) and male (96.9%), two-thirds (63.1%) had obesity, and mean hemoglobin A1c was 6.8%.

Overall, 31,125 developed all-cause dementia. The incidence rate was 8.2 cases per 1,000 person-years, ranging from 6.2 cases per 1,000 person-years among those taking metformin monotherapy to 13.4 cases per 1,000 person-years in those taking both sulfonylurea and a TZD.

Compared with metformin monotherapy, the hazard ratio for all-cause dementia for sulfonylurea monotherapy was a significant 1.12. The increased risk was also seen for vascular dementia, with an HR of 1.14.

In contrast, TZD monotherapy was associated with a significantly lower risk for all-cause dementia (HR, 0.78), as well as for Alzheimer’s disease (HR, 0.89) and vascular dementia (HR, 0.43), compared with metformin monotherapy.

The combination of metformin and TZD also lowered the risk of all-cause dementia, while regimens including sulfonylureas raised the risks for all-cause and vascular dementia.

Most of the results didn’t change significantly when the drug exposure window was extended to 2 years.
 

Effects more pronounced in those with obesity

The protective 1-year effects of TZD monotherapy and of metformin plus TZD, compared with metformin alone, were more significant among participants aged 75 or younger and with a body mass index above 25 kg/m², compared with those who were older than 75 years and with normal BMIs, respectively.

On the other hand, the greater risk for dementia incurred with sulfonylureas was further increased among those with higher BMI.

This research was partially funded by grants from the National Human Genome Research Institute, the National Science Foundation, the National Institute of Diabetes and Digestive and Kidney Disease, and the National Heart, Lung, and Blood Institute. Dr. Koychev is chief investigator for a trial, sponsored by Oxford University and funded by Novo Nordisk, testing whether the GLP-1 agonist semaglutide reduces the risk for dementia in aging adults.

A version of this article first appeared on Medscape.com.

Thiazolidinediones (TZDs), such as pioglitazone, appear to be protective against dementia whereas sulfonylureas appear to increase the risk, a new observational study in patients with type 2 diabetes suggests.

The data, obtained from nationwide electronic medical records from the Department of Veterans Affairs, yielded a 22% lower risk of dementia with TZD monotherapy and a 12% elevated risk with sulfonylurea monotherapy, compared with metformin monotherapy. The apparent protective effects of TZDs were greater among individuals with overweight or obesity.

“Our findings provide additional information to aid clinicians’ selection of [glucose-lowering medications] for patients with mild or moderate type 2 diabetes and [who] are at high risk of dementia,” Xin Tang and colleagues wrote in their article, published online in BMJ Open Diabetes Research & Care.

The results “add substantially to the literature concerning the effects of [glucose-lowering medications] on dementia where previous findings have been inconsistent. Studies with a follow-up time of less than 3 years have mainly reported null associations, while studies with longer a follow-up time typically yielded protective findings. With a mean follow-up time of 6.8 years, we had a sufficient duration to detect treatment differences,” the investigators wrote.

“Supplementing [a] sulfonylurea with either metformin or [a] TZD may partially offset its prodementia effects. These findings may help inform medication selection for elderly patients with T2D at high risk of dementia,” they added.
 

Randomized trials needed to determine cause and effect

Ivan Koychev, PhD, a senior clinical researcher in the department of psychiatry at the University of Oxford (England), told the UK Science Media Centre: “This is a large, well-conducted real-world data study that highlights the importance of checking whether already prescribed medications may be useful for preventing dementia.”

The findings regarding TZDs, also known as glitazones, are in line with existing literature suggesting dementia protection with other drugs prescribed for type 2 diabetes that weren’t examined in the current study, such as newer agents like glucagonlike peptide–1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, Dr. Koychev said.

“The main limitations of this study is that following the initial 2-year period the authors were interested in, the participants may have been prescribed one of the other type 2 diabetes drugs [GLP-1 agonists or SGLT2 inhibitors] that have been found to reduce dementia risk, thus potentially making the direct glitazone [TZD] effect more difficult to discern,” Dr. Koychev noted.

And, he pointed out that the study design limits attribution of causality. “It is also important to note that people with type 2 diabetes do run a higher risk of both dementia and cognitive deficits and that these medications are only prescribed in these patients, so all this data is from this patient group rather than the general population.”

James Connell, PhD, head of translational science at Alzheimer’s Research UK, agreed. “While this observational study found that those with type 2 diabetes taking thiazolidinedione had a lower dementia risk than those on the most common medication for type 2 diabetes, it only shows an association between taking the drug and dementia risk and not a causal relationship.

“Double-blind and placebo-controlled clinical trials are needed to see whether the drug [TDZ] could help lower dementia risk in people with and without diabetes. Anyone with any questions about what treatments they are receiving should speak to their doctor,” he told the UK Science Media Centre.
 

Opposite effects of sulfonylureas, TZDs versus metformin

The study authors analyzed 559,106 VA patients with type 2 diabetes who initiated glucose-lowering medication during 2001-2017 and took it for at least a year. They were aged 60 years or older and did not have dementia at baseline. Most were White (76.8%) and male (96.9%), two-thirds (63.1%) had obesity, and mean hemoglobin A1c was 6.8%.

Overall, 31,125 developed all-cause dementia. The incidence rate was 8.2 cases per 1,000 person-years, ranging from 6.2 cases per 1,000 person-years among those taking metformin monotherapy to 13.4 cases per 1,000 person-years in those taking both sulfonylurea and a TZD.

Compared with metformin monotherapy, the hazard ratio for all-cause dementia for sulfonylurea monotherapy was a significant 1.12. The increased risk was also seen for vascular dementia, with an HR of 1.14.

In contrast, TZD monotherapy was associated with a significantly lower risk for all-cause dementia (HR, 0.78), as well as for Alzheimer’s disease (HR, 0.89) and vascular dementia (HR, 0.43), compared with metformin monotherapy.

The combination of metformin and TZD also lowered the risk of all-cause dementia, while regimens including sulfonylureas raised the risks for all-cause and vascular dementia.

Most of the results didn’t change significantly when the drug exposure window was extended to 2 years.
 

Effects more pronounced in those with obesity

The protective 1-year effects of TZD monotherapy and of metformin plus TZD, compared with metformin alone, were more significant among participants aged 75 or younger and with a body mass index above 25 kg/m², compared with those who were older than 75 years and with normal BMIs, respectively.

On the other hand, the greater risk for dementia incurred with sulfonylureas was further increased among those with higher BMI.

This research was partially funded by grants from the National Human Genome Research Institute, the National Science Foundation, the National Institute of Diabetes and Digestive and Kidney Disease, and the National Heart, Lung, and Blood Institute. Dr. Koychev is chief investigator for a trial, sponsored by Oxford University and funded by Novo Nordisk, testing whether the GLP-1 agonist semaglutide reduces the risk for dementia in aging adults.

A version of this article first appeared on Medscape.com.

In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.¹ While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.² When I read of these ambitious projects, I recalled 2 prescient memories from my youth.

The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”

The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”

Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.³

Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.⁴

Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.⁵ Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.⁵ These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.

LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.

The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.⁶ Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.⁷

This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.⁸ Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.¹⁰ Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.¹⁰

These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.⁹ It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.

In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.¹ While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.² When I read of these ambitious projects, I recalled 2 prescient memories from my youth.

The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”

The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”

Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.³

Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.⁴

Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.⁵ Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.⁵ These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.

LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.

The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.⁶ Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.⁷

This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.⁸ Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.¹⁰ Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.¹⁰

These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.⁹ It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.

In 2019 the Defense Advanced Research Projects Agency invested $27 million in the Focused Pharma program to develop new, more efficacious, rapid-acting drugs, including hallucinogens.¹ While Focused Pharma does not include human studies, the Veterans Health Administration’s (VHA) newly launched psychedelics program research does include clinical trials.² When I read of these ambitious projects, I recalled 2 prescient memories from my youth.

The first memory was of a dinner table conversation between my father, then chief of pediatrics at a military hospital, and one of my older brothers, a burgeoning hippie. My father mentioned that the military was doing research on lysergic acid diethylamide (LSD), and my brother asked whether he could bring some home for my brother to try. My father looked up from the dinner table with incredulity and in an ironic monotone replied, “No you would not qualify for the research, you are not in the Army.”

The second was about 10 years later, when I visited the state psychiatric hospital where my father directed the adolescent ward. I saw a group of young adults watching test patterns on an old-fashioned television set. When I asked my father what was wrong with them, he shook his head and said, “Too much LSD.”

Albert Hoffman was a Sandoz chemist when in 1938 he serendipitously developed LSD while working on a fungus that grew on grain. LSD’s psychoactive properties were not discovered until 1943. About a decade later, as the Cold War chilled international relations, the Central Intelligence Agency (CIA) began conducting experiments on military personnel in the MKUltra program using LSD, electroshock, hypnosis, and other techniques to develop a mind control program before its rivals did.³

Beginning in the 1950s, the US government collaborated with pharmaceutical companies and research universities to develop LSD as part of a campaign of psychological warfare. Though planned to be used against enemies, the program instead exploited US service members to develop hallucinogens as a form of chemical warfare that could render enemy troops mentally incapacitated. That psychiatrists, who then (as now) led much of this research, raised a host of ethical concerns about dual roles, disclosure, and duty.⁴

Government investigations and academic studies have shown that even soldiers who volunteered for the research were not given adequate information about the nature of the experiments and the potential adverse effects, such as persisting flashbacks. The military’s research on LSD ended in 1963, not because of the unethical aspects of the research, but because the effects of LSD were so unpredictable that the drug could not be effectively weaponized. Like Tuskegee and other research abuses of the time, when the MKUltra program was exposed, there were congressional investigations.⁵ Later studies found that many of the active-duty research subjects experienced a plethora of lasting and serious psychiatric symptoms. VHA practitioners had to put back together many of these broken service members. This program was rife with violations of research ethics and human rights, and those abuses tainted the field of hallucinogenic research in US Department of Defense (DoD) and VHA circles for decades.⁵ These research abuses, in part, have led to hallucinogens being categorized as Schedule I controlled substances, effectively blocking federal funding for research until recently.

LSD, Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), and 3,4-methylenedioxy-methamphetamine (MDMA), popularly known as psychedelics, are again receiving attention. However, the current investigations into psychedelics are vastly different—scientifically and ethically. The most important difference is that the context and leadership of these studies is not national security—it is health care.

The goal of this new wave of psychedelic research is not mind control or brain alteration, but liberation of the mind from cycles of rumination and trauma and empowerment to change patterns of self-destruction to affirmation of life. The impetus for this research is not international espionage but to find better treatments for chronic posttraumatic stress disorder, severe substance use disorders, and treatment-resistant depression that contribute to unquantifiable mental pain, psychosocial dysfunction, and an epidemic of suicide among military service members and veterans.⁶ Though we have some effective treatments for these often combat-inflicted maladies—primarily evidence-based psychotherapies—yet these treatments are not tolerable or safe, fast-acting, or long-lasting enough to succor each and every troubled soul. The success of ketamine, a dissociative drug, in relieving the most distressing service-connected psychiatric diagnoses has provided a proof of concept to reinvigorate the moribund hallucinogenic research idea.⁷

This dark chapter in US military research is a cautionary tale. The often quoted and more often ignored advice of the Spanish American philosopher George Santayana, “Those who cannot remember the past are condemned to repeat it,” should serve as the guiding principle of the new hallucinogenic research.⁸ Human subjects’ protections have exponentially improved since the days of the secret LSD project even for active-duty personnel. The Common Rule governs that all research participants are given adequate information that includes whatever is known about the risks and benefits of the research.¹⁰ Participants must provide full and free informed consent to enroll in these clinical trials, a consent that encompasses the right to withdraw from the research at any time without jeopardizing their careers, benefits, or ongoing health care.¹⁰

These rules, though, can be bent, broken, avoided, or worked around. Only the moral integrity of study personnel, administrators, oversight agencies, research compliance officers, and most important, principal investigators can assure that the rules are upheld and the rights they guarantee are respected.⁹ It would be a tragic shame if the promised hope for the relief of psychic pain went unrealized due to media hype, shared desperation of clinicians and patients, and conflicts of interests that today are more likely to come from profit-driven pharmaceutical companies than national security agencies. And for all of us in federal practice, remembering the sordid past forays with LSD can redeem the present research so future service members and veterans and the clinicians who care for them have better balms to heal the wounds of war.

A 13-YEAR-OLD GIRL presented to the clinic with a 1-year history of a slow-growing mass on the third toe of her right foot. As a soccer player, she experienced associated pain when kicking the ball or when wearing tight-fitting shoes. The lesion was otherwise asymptomatic. She denied any overt trauma to the area and indicated that the mass had enlarged over the previous year.

On exam, there was a nontender 8 × 8-mm firm nodule underneath the nail with associated nail dystrophy (FIGURE 1). The toe had full mobility, sensation was intact, and capillary refill time was < 2 seconds.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A plain radiograph of the patient’s foot showed continuity with the bony cortex and medullary space, confirming the diagnosis of subungual exostosis (FIGURE 2).¹ An exostosis, or osteochondroma, is a form of benign bone tumor in which trabecular bone overgrows its normal border in a nodular pattern. When this occurs under the nail bed, it is called subungual exostosis.² Exostosis represents 10% to 15% of all benign bone tumors, making it the most common benign bone tumor.³ Generally, the age of occurrence is 10 to 15 years.³

Repetitive trauma can be a culprit. Up to 8% of exostoses occur in the foot, with the most commonly affected area being the distal medial portion of the big toe.^3,4 Repetitive trauma and infection are potential risk factors.^3,4 The affected toe may be painful, but that is not always the case.⁴ Typically, lesions are solitary; however, multiple lesions can occur.⁴

Most pediatric foot lesions are benign and involve soft tissue

Benign soft-tissue masses make up the overwhelming majority of pediatric foot lesions, accounting for 61% to 87% of all foot lesions.³ Malignancies such as chondrosarcoma can occur and can be difficult to diagnose. Rapid growth, family history, size > 5 cm, heterogenous appearance on magnetic resonance imaging, and poorly defined margins are a few characteristics that should increase suspicion for possible malignancy.⁵

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity.

The differential diagnosis for a growth on the toe similar to the one our patient had would include pyogenic granuloma, acral fibromyxoma, periungual fibroma, and verruca vulgaris.

Pyogenic granulomas are benign vascular lesions that occur in patients of all ages. They tend to be dome-shaped and flesh-toned to violaceous red, and they are usually found on the head, neck, and extremities—­especially fingers.⁶ They are associated with trauma and are classically tender with a propensity to bleed.⁶

Acral fibromyxoma is a benign, slow-growing, predominately painless, firm mass with an affinity for the great toe; the affected area includes the nail in 50% of cases.⁷ A radiograph may show bony erosion or scalloping due to mass effect; however, there will be no continuity with the bony matrix. (Such continuity would suggest exostosis.)

Periungual fibromas are benign soft-tissue masses, which are pink to red and firm, and emerge from underneath the nails, potentially resulting in dystrophy.⁸ They can bleed and cause pain, and are strongly associated with tuberous sclerosis.⁵

Continue to: Verruca vulgaris

Verruca vulgaris, the common wart, can also manifest in the subungual region as a firm, generally painless mass. It is the most common neoplasm of the hand and fingers.⁶ Tiny black dots that correspond to thrombosed capillaries are key to identifying this lesion.

Surgical excision when patient reaches maturity

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity. Surgery at this point is associated with decreased recurrence rates.^3,4 That said, excision may need to be performed sooner if the lesion is painful and leading to deformity.³

Our patient’s persistent pain prompted us to recommend surgical excision. She underwent a third digit exostectomy, which she tolerated without any issues. The patient was fitted with a postoperative shoe that she wore until her 2-week follow-up appointment, when her sutures were removed. The patient’s activity level progressed as tolerated. She regained full function and returned to playing soccer, without any pain, 3 months after her surgery.

A 13-YEAR-OLD GIRL presented to the clinic with a 1-year history of a slow-growing mass on the third toe of her right foot. As a soccer player, she experienced associated pain when kicking the ball or when wearing tight-fitting shoes. The lesion was otherwise asymptomatic. She denied any overt trauma to the area and indicated that the mass had enlarged over the previous year.

On exam, there was a nontender 8 × 8-mm firm nodule underneath the nail with associated nail dystrophy (FIGURE 1). The toe had full mobility, sensation was intact, and capillary refill time was < 2 seconds.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A plain radiograph of the patient’s foot showed continuity with the bony cortex and medullary space, confirming the diagnosis of subungual exostosis (FIGURE 2).¹ An exostosis, or osteochondroma, is a form of benign bone tumor in which trabecular bone overgrows its normal border in a nodular pattern. When this occurs under the nail bed, it is called subungual exostosis.² Exostosis represents 10% to 15% of all benign bone tumors, making it the most common benign bone tumor.³ Generally, the age of occurrence is 10 to 15 years.³

Repetitive trauma can be a culprit. Up to 8% of exostoses occur in the foot, with the most commonly affected area being the distal medial portion of the big toe.^3,4 Repetitive trauma and infection are potential risk factors.^3,4 The affected toe may be painful, but that is not always the case.⁴ Typically, lesions are solitary; however, multiple lesions can occur.⁴

Most pediatric foot lesions are benign and involve soft tissue

Benign soft-tissue masses make up the overwhelming majority of pediatric foot lesions, accounting for 61% to 87% of all foot lesions.³ Malignancies such as chondrosarcoma can occur and can be difficult to diagnose. Rapid growth, family history, size > 5 cm, heterogenous appearance on magnetic resonance imaging, and poorly defined margins are a few characteristics that should increase suspicion for possible malignancy.⁵

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity.

The differential diagnosis for a growth on the toe similar to the one our patient had would include pyogenic granuloma, acral fibromyxoma, periungual fibroma, and verruca vulgaris.

Pyogenic granulomas are benign vascular lesions that occur in patients of all ages. They tend to be dome-shaped and flesh-toned to violaceous red, and they are usually found on the head, neck, and extremities—­especially fingers.⁶ They are associated with trauma and are classically tender with a propensity to bleed.⁶

Acral fibromyxoma is a benign, slow-growing, predominately painless, firm mass with an affinity for the great toe; the affected area includes the nail in 50% of cases.⁷ A radiograph may show bony erosion or scalloping due to mass effect; however, there will be no continuity with the bony matrix. (Such continuity would suggest exostosis.)

Periungual fibromas are benign soft-tissue masses, which are pink to red and firm, and emerge from underneath the nails, potentially resulting in dystrophy.⁸ They can bleed and cause pain, and are strongly associated with tuberous sclerosis.⁵

Continue to: Verruca vulgaris

Verruca vulgaris, the common wart, can also manifest in the subungual region as a firm, generally painless mass. It is the most common neoplasm of the hand and fingers.⁶ Tiny black dots that correspond to thrombosed capillaries are key to identifying this lesion.

Surgical excision when patient reaches maturity

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity. Surgery at this point is associated with decreased recurrence rates.^3,4 That said, excision may need to be performed sooner if the lesion is painful and leading to deformity.³

Our patient’s persistent pain prompted us to recommend surgical excision. She underwent a third digit exostectomy, which she tolerated without any issues. The patient was fitted with a postoperative shoe that she wore until her 2-week follow-up appointment, when her sutures were removed. The patient’s activity level progressed as tolerated. She regained full function and returned to playing soccer, without any pain, 3 months after her surgery.

A 13-YEAR-OLD GIRL presented to the clinic with a 1-year history of a slow-growing mass on the third toe of her right foot. As a soccer player, she experienced associated pain when kicking the ball or when wearing tight-fitting shoes. The lesion was otherwise asymptomatic. She denied any overt trauma to the area and indicated that the mass had enlarged over the previous year.

On exam, there was a nontender 8 × 8-mm firm nodule underneath the nail with associated nail dystrophy (FIGURE 1). The toe had full mobility, sensation was intact, and capillary refill time was < 2 seconds.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A plain radiograph of the patient’s foot showed continuity with the bony cortex and medullary space, confirming the diagnosis of subungual exostosis (FIGURE 2).¹ An exostosis, or osteochondroma, is a form of benign bone tumor in which trabecular bone overgrows its normal border in a nodular pattern. When this occurs under the nail bed, it is called subungual exostosis.² Exostosis represents 10% to 15% of all benign bone tumors, making it the most common benign bone tumor.³ Generally, the age of occurrence is 10 to 15 years.³

Repetitive trauma can be a culprit. Up to 8% of exostoses occur in the foot, with the most commonly affected area being the distal medial portion of the big toe.^3,4 Repetitive trauma and infection are potential risk factors.^3,4 The affected toe may be painful, but that is not always the case.⁴ Typically, lesions are solitary; however, multiple lesions can occur.⁴

Most pediatric foot lesions are benign and involve soft tissue

Benign soft-tissue masses make up the overwhelming majority of pediatric foot lesions, accounting for 61% to 87% of all foot lesions.³ Malignancies such as chondrosarcoma can occur and can be difficult to diagnose. Rapid growth, family history, size > 5 cm, heterogenous appearance on magnetic resonance imaging, and poorly defined margins are a few characteristics that should increase suspicion for possible malignancy.⁵

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity.

The differential diagnosis for a growth on the toe similar to the one our patient had would include pyogenic granuloma, acral fibromyxoma, periungual fibroma, and verruca vulgaris.

Pyogenic granulomas are benign vascular lesions that occur in patients of all ages. They tend to be dome-shaped and flesh-toned to violaceous red, and they are usually found on the head, neck, and extremities—­especially fingers.⁶ They are associated with trauma and are classically tender with a propensity to bleed.⁶

Acral fibromyxoma is a benign, slow-growing, predominately painless, firm mass with an affinity for the great toe; the affected area includes the nail in 50% of cases.⁷ A radiograph may show bony erosion or scalloping due to mass effect; however, there will be no continuity with the bony matrix. (Such continuity would suggest exostosis.)

Periungual fibromas are benign soft-tissue masses, which are pink to red and firm, and emerge from underneath the nails, potentially resulting in dystrophy.⁸ They can bleed and cause pain, and are strongly associated with tuberous sclerosis.⁵

Continue to: Verruca vulgaris

Verruca vulgaris, the common wart, can also manifest in the subungual region as a firm, generally painless mass. It is the most common neoplasm of the hand and fingers.⁶ Tiny black dots that correspond to thrombosed capillaries are key to identifying this lesion.

Surgical excision when patient reaches maturity

The definitive treatment for subungual exostosis is surgical excision, preferably once the patient has reached skeletal maturity. Surgery at this point is associated with decreased recurrence rates.^3,4 That said, excision may need to be performed sooner if the lesion is painful and leading to deformity.³

Our patient’s persistent pain prompted us to recommend surgical excision. She underwent a third digit exostectomy, which she tolerated without any issues. The patient was fitted with a postoperative shoe that she wore until her 2-week follow-up appointment, when her sutures were removed. The patient’s activity level progressed as tolerated. She regained full function and returned to playing soccer, without any pain, 3 months after her surgery.

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Small-molecule drugs such as aspirin, albuterol, atorvastatin, and lisinopril are the backbone of disease management in family medicine.¹ However, large-molecule biological drugs such as monoclonal antibodies (MAbs) are increasingly prescribed to treat common conditions. In the past decade, MAbs comprised 20% of all drug approvals by the US Food and Drug Administration (FDA), and today they represent more than half of drugs currently in development.² Fifteen MAbs have been approved by the FDA over the past decade for asthma, atopic dermatitis (AD), hyperlipidemia, osteoporosis, and migraine prevention.³ This review details what makes MAbs unique and what you should know about them.

The uniqueness of monoclonal antibodies

MAbs are biologics, but not all biologics are MAbs—eg, adalimumab (Humira) is a MAb, but etanercept (Enbrel) is not. MAbs are therapeutic proteins made possible by hybridoma technology used to create an antibody with single specificity.^4-6 Monoclonal antibodies differ from small-molecule drugs in structure, dosing, route of administration, manufacturing, metabolism, drug interactions, and elimination (TABLE 1^7-9).

MAbs can be classified as naked, “without any drug or radioactive material attached to them,” or conjugated, “joined to a chemotherapy drug, radioactive isotope, or toxin.”¹⁰ MAbs work in several ways, including competitively inhibiting ligand-­receptor binding, receptor blockade, or cell elimination from indirect immune system activities such as antibody-dependent cell-­mediated cytotoxicity.^11,12

Monoclonal antibody uses in family medicine

Asthma

Several MAbs have been approved for use in severe asthma, including but not limited to: omalizumab (Xolair),¹³ mepolizumab (Nucala),^9,14 and dupilumab (Dupixent).¹⁵All 3 agents can be self-administered subcutaneously (SC), depending on the clinician’s assessment. The Global Initiative for Asthma (GINA) guidelines recommend that, prior to considering MAb therapy for a patient who has asthma, clinicians should assess the patient’s inhaler technique and adherence, treat comorbidities such as gastroesophageal reflux disease, and modify triggering factors such as smoking or allergen exposure.¹⁶ In patients with severe asthma still uncontrolled after receiving high-dose inhaled corticosteroids (ICSs) or the lowest possible dose of oral corticosteroid (OCS), GINA recommends assessing for type 2 airway inflammation: blood eosinophils ≥ 150/μL, sputum eosinophils ≥ 2%, or evidence of allergen stimulation.¹⁶ If these factors are present, consider prescribing anti-immunoglobulin E (anti-IgE) (omalizumab), anti-interleukin-5 (anti-IL-5) (mepolizumab), or anti-IL-4/anti-IL-13 (dupilumab).¹⁶

Omalizumab is a humanized MAb that prevents IgE antibodies from binding to mast cells and basophils, thereby reducing inflammatory mediators.¹³ A systematic review found that, compared with placebo, omalizumab used in patients with inadequately controlled moderate-to-severe asthma led to significantly fewer asthma exacerbations (absolute risk reduction [ARR], 16% vs 26%; odds ratio [OR] = 0.55; 95% CI, 0.42-0.60; number needed to treat [NNT] = 10) and fewer hospitalizations (ARR, 0.5% vs 3%; OR = 0.16; 95% CI, 0.06-0.42; NNT = 40).¹³

Significantly more patients in the omalizumab group were able to withdraw from, or reduce, the dose of ICS. GINA recommends omalizumab for patients with positive skin sensitization, total serum IgE ≥ 30 IU/mL, weight within 30 kg to 150 kg, history of childhood asthma and recent exacerbations, and blood eosinophils ≥ 260/mcL.¹⁶ Omalizumab is also approved for use in chronic spontaneous urticaria and nasal polyps.

Mepolizumab is a humanized MAb that inhibits IL-5, effectively blocking the growth, differentiation, recruitment, activation, and survival of eosinophils.¹⁴ Mepolizumab was studied in patients with frequent exacerbations while already taking high-dose ICSs. The mean rate of clinically consequential exacerbations was significantly reduced with mepolizumab compared with placebo (0.83 vs 1.74; P < .001).¹⁷ This translates to about 1 less moderate-to-severe asthma exacerbation per year per person.

Continue to: Another trial found that...

Before considering a monoclonal antibody for asthma, assess the patient’s inhaler technique and adherence, treat comorbidities, and modify triggering factors.

Another trial found that mepolizumab reduced total OCS doses in patients with severe asthma by 50% without increasing exacerbations or worsening asthma control.¹⁸ All 3 anti-IL-5 drugs—including not only mepolizumab, but also benralizumab (Fasenra) and reslizumab (Cinqair)—appear to yield similar improvements. A 2017 systematic review found all anti-IL-5 treatments reduced rates of clinically significant asthma exacerbations (treatment with OCS for ≥ 3 days) by roughly 50% in patients with severe eosinophilic asthma and a history of ≥ 2 exacerbations in the past year.¹⁴ Mepolizumab, according to GINA, is preferred for patients with blood eosinophils ≥ 300/μL and severe exacerbations, nasal polyposis, adult-onset asthma, and maintenance OCS at baseline.¹⁶ Mepolizumab is also approved for use in eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and rhinosinusitis with nasal polyps.

Dupilumab is a humanized MAb that inhibits IL-4 and IL-13, which influence multiple cell types involved in inflammation (eg, mast cells, eosinophils) and inflammatory mediators (histamine, leukotrienes, cytokines).¹⁵ In a recent study of patients with uncontrolled asthma, dupilumab 200 mg every 2 weeks compared with placebo showed a modest reduction in the annualized rate of severe asthma exacerbations (0.46 exacerbations vs 0.87, respectively). Dupilumab was effective in patients with blood eosinophil counts ≥ 150/μL but was ineffective in patients with eosinophil counts < 150/μL.¹⁵

For patients ≥ 12 years old with severe eosinophilic asthma, GINA recommends using dupilumab as add-on therapy for an initial trial of 4 months at doses of 200 or 300 mg SC every 2 weeks, with preference for 300 mg SC every 2 weeks for OCS-dependent asthma. Dupilumab is approved for use in AD and chronic rhinosinusitis with nasal polyposis. If a biologic agent is not successful after a 4-month trial, consider a 6- to 12-month trial. If efficacy is still minimal, consider switching to an alternative biologic therapy approved for asthma.¹⁶

  ❯ Asthma: Test your skills

Subjective findings: A 19-year-old man presents to your clinic. He has a history of nasal polyps and allergic asthma. At age 18, he was given a diagnosis of severe persistent asthma. He has shortness of breath during waking hours 4 times per week, and treats each of these episodes with albuterol. He also wakes up about twice a week with shortness of breath and has some limitations in normal activities. He reports missing his prescribed fluticasone/salmeterol 500/50 μg, 1 inhalation bid, only once each month. In the last year, he has had 2 exacerbations requiring oral steroids.

Medications: Albuterol 90 μg, 1-2 inhalations, q6h prn; fluticasone/salmeterol 500/50 μg, 1 inhalation bid; tiotropium 1.25 μg, 2 puffs/d; montelukast 10 mg every morning; prednisone 10 mg/d.

Continue to: Objective data

Objective data: Patient is in no apparent distress and afebrile, and oxygen saturation on room air is 97%. Ht, 70 inches; wt, 75 kg. Labs: IgE, 15 IU/mL; serum eosinophils, 315/μL.

Which MAb would be appropriate for this patient? Given that the patient has a blood eosinophil level ≥ 300/μL and severe exacerbations, adult-onset asthma, nasal polyposis, and maintenance OCS at baseline, it would be reasonable to initiate mepolizumab 100 mg SC every 4 weeks, or dupilumab 600 mg once, then 300 mg SC every 2 weeks. Both agents can be self-administered.

Atopic dermatitis

Two MAbs—dupilumab and tralokinumab (Adbry; inhibits IL-13)—are approved for treatment of AD in adults that is uncontrolled with conventional therapy.^15,19 Dupilumab is also approved for children ≥ 6 months old.²⁰ Both MAbs are dosed at 600 mg SC, followed by 300 mg every 2 weeks. Dupilumab was compared with placebo in adult patients who had moderate-to-severe AD inadequately controlled on topical corticosteroids (TCSs), to determine the proportion of patients in each group achieving improvement of either 0 or 1 points or ≥ 2 points in the 5-point Investigator Global Assessment (IGA) score from baseline to 16 weeks.²¹ Thirty-seven percent of patients receiving dupilumab 300 mg SC weekly and 38% of patients receiving dupilumab 300 mg SC every 2 weeks achieved the primary outcome, compared with 10% of those receiving placebo (P < .001).²¹ Similar IGA scores were reported when dupilumab was combined with TCS, compared with placebo.²²

In atopic dermatitis, MAbs, unlike other systemic agents, do not require frequent monitoring of factors such as blood pressure and kidney or liver function.

It would be reasonable to consider dupilumab or tralokinumab in patients with: cutaneous atrophy or ­hypothalamic-­pituitary-adrenal axis suppression with TCS, concerns of malignancy with topical calcineurin inhibitors, or problems with the alternative systemic therapies (cyclosporine-induced hypertension, nephrotoxicity, or immunosuppression; azathioprine-induced malignancy; or methotrexate-induced bone marrow suppression, renal impairment, hepatotoxicity, pneumonitis, or gastrointestinal toxicity).²³

A distinct advantage of MAbs over other systemic agents in the management of AD is that MAbs do not require frequent monitoring of blood pressure, renal or liver function, complete blood count with differential, electrolytes, or uric acid. Additionally, MAbs have fewer black box warnings and adverse reactions when compared with other systemic agents. For dupilumab, the main adverse reactions (that occurred with > 10% frequency in trials) were injection site reactions and upper respiratory tract infections.¹⁵ Antidrug antibody development occurred in 4.2%.¹⁵ Tralokinumab had > 20% incidence of upper respiratory tract infections.¹⁹

Continue to: Hyperlipidemia

Hyperlipidemia

Three MAbs are approved for use in hyperlipidemia: the angiopoietin-like protein 3 ­(ANGPTL3) inhibitor evinacumab (Evkeeza)²⁴ and 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, evolocumab (Repatha)²⁵ and alirocumab (Praluent).²⁶

ANGPTL3 inhibitors block ­ANGPTL3 and reduce endothelial lipase and lipoprotein lipase activity, which in turn decreases low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol ­(HDL-C), and triglyceride formation. PCSK9 inhibitors prevent PCSK9 from binding to LDL receptors, thereby maintaining the number of active LDL receptors and increasing LDL-C removal.

Evinacumab is indicated for homozygous familial hypercholesterolemia and is administered intravenously every 4 weeks. Evinacumab has not been evaluated for effects on cardiovascular morbidity and mortality.

Evolocumab 140 mg SC every 2 weeks or 420 mg SC monthly has been studied in patients on statin therapy with LDL-C ≥ 70 mg/dL. Patients on evolocumab experienced significantly less of the composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization compared with placebo (9.8% vs 11.3%; hazard ratio [HR] = 0.85; 95% CI, 0.79-0.92; NNT = 67.²⁷

Alirocumab 75 mg SC every 2 weeks has also been studied in patients receiving statin therapy with LDL-C ≥ 70 mg/dL. Patients taking alirocumab experienced significantly less of the composite endpoint of death from coronary heart disease, nonfatal MI, ischemic stroke, or hospitalization for unstable angina compared with placebo (9.5% vs 11.1%; HR = 0.85; 95% CI, 0.78-0.93; NNT = 63).²⁸

Continue to: According to the 2018...

According to the 2018 AHA Cholesterol Guidelines, PCSK9 inhibitors are indicated for patients receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe) with LDL-C ≥ 70 mg/dL, if they have had multiple atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk conditions (eg, heterozygous familial hypercholesterolemia, history of coronary artery bypass grafting or percutaneous coronary intervention, hypertension, estimated glomerular filtration rate of 15 to 59 mL/min/1.73m²).²⁹ For patients without prior ASCVD events or high-risk conditions who are receiving maximally tolerated LDL-C-lowering therapy (statin and ezetimibe), PCSK9 inhibitors are indicated if the LDL-C remains ≥ 100 mg/dL.

Osteoporosis

The 2 MAbs approved for use in osteoporosis are the receptor activator of nuclear factor kB ligand (RANKL) inhibitor denosumab (Prolia)³⁰ and the sclerostin inhibitor romosozumab (Evenity).³¹

Denosumab prevents RANKL from binding to the RANK receptor, thereby inhibiting osteoclast formation and decreasing bone resorption. Denosumab is approved for use in women and men who are at high risk of osteoporotic fracture, including those taking OCSs, men receiving androgen deprivation therapy for prostate cancer, and women receiving adjuvant aromatase inhibitor therapy for breast cancer.

In a 3-year randomized trial, denosumab 60 mg SC every 6 months was compared with placebo in postmenopausal women with T-scores < –2.5, but not < –4.0 at the lumbar spine or total hip. Denosumab significantly reduced new radiographic vertebral fractures (2.3% vs 7.2%; risk ratio [RR] = 0.32; 95% CI, 0.26-0.41; NNT = 21), hip fracture (0.7% vs 1.2%), and nonvertebral fracture (6.5% vs 8.0%).³² Denosumab carries an increased risk of multiple vertebral fractures following discontinuation, skin infections, dermatologic reactions, and severe bone, joint, and muscle pain.

Romosozumab inhibits sclerostin, thereby increasing bone formation and, to a lesser degree, decreasing bone resorption. Romosozumab is approved for use in postmenopausal women at high risk for fracture (ie, those with a history of osteoporotic fracture or multiple risk factors for fracture) or in patients who have not benefited from or are intolerant of other therapies. In one study, postmenopausal women with a T-score of –2.5 to –3.5 at the total hip or femoral neck were randomly assigned to receive either romosozumab 210 mg SC or placebo for 12 months, then each group was switched to denosumab 60 mg SC for 12 months. After the first year, prior to initiating denosumab, patients taking romosozumab experienced significantly fewer new vertebral fractures than patients taking placebo (0.5% vs 1.8%; RR = 0.27; 95% CI, 0.16-0.47; NNT = 77); however, there was no significant difference between the 2 groups with nonvertebral fractures (HR = 0.75; 95% CI, 0.53-1.05).³³

Continue to: In another study...

In another study, romosozumab 210 mg SC was compared with alendronate 70 mg weekly, followed by alendronate 70 mg weekly in both groups. Over the first 12 months, patients treated with romosozumab saw a significant reduction in the incidence of new vertebral fractures (4% vs 6.3%; RR = 0.63, P < .003; NNT = 44). Patients treated with romosozumab with alendronate added for another 12 months also saw a significant reduction in new incidence of vertebral fractures (6.2% vs 11.9%; RR = 0.52; P < .001; NNT = 18).³⁴ There was a higher risk of cardiovascular events among patients receiving romosozumab compared with those treated with alendronate, so romosozumab should not be used in individuals who have had an MI or stroke within the previous year.³⁴ Denosumab and romosozumab offer an advantage over some bisphosphonates in that they require less frequent dosing and can be used in patients with renal impairment (creatinine clearance < 35 mL/min, in which zoledronic acid is contraindicated and alendronate is not recommended; < 30 mL/min, in which risedronate and ibandronate are not recommended).

Migraine prevention

Four calcitonin gene-related peptide (CGRP) antagonists have been approved for migraine prevention: erenumab (Aimovig),³⁵ eptinezumab (Vyepti),³⁶ fremanezumab (Ajovy),³⁷ and galcanezumab (Emgality).³⁸ CGRP is released at areas in and around the brain, causing vasodilation and inflammation that is thought to be the major causative factor for migraine headaches.³⁹

Erenumab, fremanezumab, and galcanezumab are all available in subcutaneous autoinjectors (or syringe with fremanezumab). Eptinezumab is an intravenous (IV) infusion given every 3 months.

Erenumab is available in both 70-mg and 140-mg dosing options. Fremanezumab can be given as 225 mg monthly or 675 mg quarterly. Galcanezumab has an initial loading dose of 240 mg followed by 120 mg given monthly. Erenumab targets the CGRP receptor; the others target the CGRP ligand. Eptinezumab has 100% bioavailability and reaches maximum serum concentration sooner than the other antagonists (due to its route of administration), but it must be given in an infusion center. Few insurers approve the use of eptinezumab unless a trial of least 1 of the monthly injectables has failed.

There are no head-to-head studies of the medications in this class. Additionally, differing study designs, definitions, statistical analyses, endpoints, and responder-rate calculations make it challenging to compare them directly against one another. At the very least, all of the CGRP MAbs have efficacy comparable to conventional preventive migraine medications such as propranolol, amitriptyline, and topiramate.⁴⁰

Continue to: The most commonly reported adverse...

The most commonly reported adverse effect for all 4 CGRPs is injection site reaction, which was highest with the quarterly fremanezumab dose (45%).³⁷ Constipation was most notable with the 140-mg dose of erenumab (3%)³⁵; with the other CGRP MAbs it is comparable to that seen with placebo (< 1%).

Erenumab-induced hypertension has been identified in 61 cases reported through the FDA Adverse Event Reporting System (FAERS) as of 2021.⁴¹ This was not reported during MAb development programs, nor was it noted during clinical trials. Blood pressure elevation was seen within 1 week of injection in nearly 50% of the cases, and nearly one-third had pre-existing hypertension.⁴¹ Due to these findings, the erenumab prescribing information was updated to include hypertension in its warnings and precautions. It is possible that hypertension could be a class effect, although trial data and posthoc studies have yet to bear that out. Since erenumab was the first CGRP antagonist brought to market (May 2018 vs September 2018 for fremanezumab and galcanezumab), it may have accumulated more FAERS reports. Nearly all studies exclude patients with older age, uncontrolled hypertension, and unstable cardiovascular disease, which could impact data.⁴¹

Overall, this class of medications is very well tolerated, easy to use (again, excluding eptinezumab), and maintains a low adverse effect profile, giving added value compared with conventional preventive migraine medications.

The American Headache Society recommends a preventive oral therapy for at least 3 months before trying an alternative medication. After treatment failure with at least 2 oral agents, CGRP MAbs are recommended.⁴² CGRP antagonists offer convenient dosing, bypass gastrointestinal metabolism (which is useful in patients with nausea/vomiting), and have fewer adverse effects than traditional oral medications.

Worth noting. Several newer oral agents have been recently approved for migraine prevention, including atogepant (Qulipta) and rimegepant (Nurtec), which are also CGRP antagonists. Rimegepant is approved for both acute migraine treatment and prevention.

Continue to: Migraine

❯ Migraine: Test your skills

Subjective findings: A 25-year-old woman presents to your clinic for management of episodic migraines with aura. Her baseline average migraine frequency is 9 headache days/month. Her migraines are becoming more frequent despite treatment. She fears IV medication use and avoids hospitals.

History: Hypertension, irritable bowel syndrome with constipation (IBS-C), and depression. The patient is not pregnant or trying to get pregnant.

Medications: Current medications (for previous 4 months) include propranolol 40 mg at bedtime, linaclotide 145 μg/d, citalopram 20 mg/d, and sumatriptan 50 mg prn. Past medications include venlafaxine 150 mg po bid for 5 months.

What would be appropriate for this patient? This patient meets the criteria for using a CGRP antagonist because she has tried 2 preventive treatments for more than 60 to 90 days. Erenumab is not the best option, given the patient’s history of hypertension and IBS-C. The patient fears hospitals and IV medications, making eptinezumab a less-than-ideal choice. Depending on her insurance, fremanezumab or galcanezumab would be good options at this time.

CGRP antagonists have not been studied or evaluated in pregnancy, but if this patient becomes pregnant, a first-line agent for prevention would be propranolol, and a second-line agent would be a tricyclic antidepressant, memantine, or verapamil. Avoid ergotamines and antiepileptics (topiramate or valproate) in pregnancy.^43,44

Continue to: The challenges associated with MAbs

MAbs can be expensive (TABLE 2),⁴⁵ some prohibitively so. On a population scale, biologics account for around 40% of prescription drug spending and may cost 22 times more than small-molecule drugs.⁴⁶ Estimates in 2016 showed that MAbs comprise $90.2 billion (43%) of the biologic market.⁴⁶

MAbs also require prior authorization forms to be submitted. Prior authorization criteria vary by state and by insurance plan. In my (ES) experience, submitting letters of medical necessity justifying the need for therapy or expertise in the disease states for which the MAb is being prescribed help your patient get the medication they need.

Expect to see additional MAbs approved in the future. If the costs come down, adoption of these agents into practice will likely increase.

CORRESPONDENCE
Evelyn Sbar, MD, Texas Tech University Health Sciences Center, 1400 South Coulter Street, Suite 5100, Amarillo, TX 79106; [email protected]

Many years ago, I had a patient I’ll call “Hannah,” who was well into her 80s and always came into the office with her daughter. She was a heavy smoker and had hypertension and type 2 diabetes.

At each visit, I would ask her if she still smoked and if she was interested in talking about quitting. At every visit, she would say that she was still smoking and didn’t want to quit. My response was always something along the lines of: “When you’re ready, we can talk more. But I think it is the most important thing you can do to improve your health.” From there, we would discuss any concerns she or her daughter had.

It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

A few years shy of her 100th birthday, Hannah told me she had quit smoking. I was amazed and asked her why, after all these years, she’d done it.

“I quit,” she said, “because I was tired of you nagging me, sonny!” And we both had a good laugh about that.

Hannah’s story reminds me that, as family physicians, we often have an impact on our patients in ways we don’t see in the short term. It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

It is these relationships that we can draw upon when counseling our patients with type 2 diabetes to address lifestyle issues such as exercise and a healthy diet. In this issue, McMullan et al¹ provide us with a rather hopeful review of the evidence in support of lifestyle changes. For our patients with type 2 diabetes, lifestyle changes can decrease A1C levels by 0.5% (with environmental changes related to diet)² and 0.7% (with moderate aerobic exercise).³ This is comparable to what is reported for the starting doses of most medications.⁴ In fact, a meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients.⁵ (Caveat: The result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used.)

And yet, we often focus more on the various medications we can prescribe, with professional guidelines pointing the way.

Continue to: The National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence,⁶ American Diabetes Association,⁷ American College of Physicians,⁸ and American Academy of Family Physicians⁸ have followed the accumulating evidence that various medications improve outcomes—especially in patients at high risk or with established atherosclerotic cardiovascular disease. They have endorsed a stepwise pharmacologic approach beginning with metformin and recommend assessing each patient’s comorbidities to guide whether to add a sodium glucose co-transporter 2 (SGLT2) inhibitor or another agent. Where the groups diverge is what that second agent should be (glucagon-like peptide 1 receptor agonist, SGLT2 inhibitor, or dipeptidyl peptidase-4 inhibitor).

But what about lifestyle? Each organization’s guidelines address lifestyle changes as a foundation for managing patients with type 2 diabetes. But is that call loud enough? Do we heed it well enough?

Implementing lifestyle changes in office practice can be time consuming. Many clinicians lack adequate training or experience to gain any traction with it. Also, there is skepticism about success and sustainability.

I believe change starts when we recognize that while we have a priority list for each patient encounter, so do our patients. But they may not share that list with us unless we open the door by asking questions, such as:

• Of all the things you have heard about caring for your diabetes, what would you like to work on?
• What are you currently doing and what prevents you from meeting your goals?
• How would you like me to help you?

From there, we can start small and build on successes over time. We can go the distance with our patients. In the case of Hannah, I had the honor of caring for her until she died at age 104.

Many years ago, I had a patient I’ll call “Hannah,” who was well into her 80s and always came into the office with her daughter. She was a heavy smoker and had hypertension and type 2 diabetes.

At each visit, I would ask her if she still smoked and if she was interested in talking about quitting. At every visit, she would say that she was still smoking and didn’t want to quit. My response was always something along the lines of: “When you’re ready, we can talk more. But I think it is the most important thing you can do to improve your health.” From there, we would discuss any concerns she or her daughter had.

It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

A few years shy of her 100th birthday, Hannah told me she had quit smoking. I was amazed and asked her why, after all these years, she’d done it.

“I quit,” she said, “because I was tired of you nagging me, sonny!” And we both had a good laugh about that.

Hannah’s story reminds me that, as family physicians, we often have an impact on our patients in ways we don’t see in the short term. It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

It is these relationships that we can draw upon when counseling our patients with type 2 diabetes to address lifestyle issues such as exercise and a healthy diet. In this issue, McMullan et al¹ provide us with a rather hopeful review of the evidence in support of lifestyle changes. For our patients with type 2 diabetes, lifestyle changes can decrease A1C levels by 0.5% (with environmental changes related to diet)² and 0.7% (with moderate aerobic exercise).³ This is comparable to what is reported for the starting doses of most medications.⁴ In fact, a meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients.⁵ (Caveat: The result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used.)

And yet, we often focus more on the various medications we can prescribe, with professional guidelines pointing the way.

Continue to: The National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence,⁶ American Diabetes Association,⁷ American College of Physicians,⁸ and American Academy of Family Physicians⁸ have followed the accumulating evidence that various medications improve outcomes—especially in patients at high risk or with established atherosclerotic cardiovascular disease. They have endorsed a stepwise pharmacologic approach beginning with metformin and recommend assessing each patient’s comorbidities to guide whether to add a sodium glucose co-transporter 2 (SGLT2) inhibitor or another agent. Where the groups diverge is what that second agent should be (glucagon-like peptide 1 receptor agonist, SGLT2 inhibitor, or dipeptidyl peptidase-4 inhibitor).

But what about lifestyle? Each organization’s guidelines address lifestyle changes as a foundation for managing patients with type 2 diabetes. But is that call loud enough? Do we heed it well enough?

Implementing lifestyle changes in office practice can be time consuming. Many clinicians lack adequate training or experience to gain any traction with it. Also, there is skepticism about success and sustainability.

I believe change starts when we recognize that while we have a priority list for each patient encounter, so do our patients. But they may not share that list with us unless we open the door by asking questions, such as:

• Of all the things you have heard about caring for your diabetes, what would you like to work on?
• What are you currently doing and what prevents you from meeting your goals?
• How would you like me to help you?

From there, we can start small and build on successes over time. We can go the distance with our patients. In the case of Hannah, I had the honor of caring for her until she died at age 104.

Many years ago, I had a patient I’ll call “Hannah,” who was well into her 80s and always came into the office with her daughter. She was a heavy smoker and had hypertension and type 2 diabetes.

At each visit, I would ask her if she still smoked and if she was interested in talking about quitting. At every visit, she would say that she was still smoking and didn’t want to quit. My response was always something along the lines of: “When you’re ready, we can talk more. But I think it is the most important thing you can do to improve your health.” From there, we would discuss any concerns she or her daughter had.

It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

A few years shy of her 100th birthday, Hannah told me she had quit smoking. I was amazed and asked her why, after all these years, she’d done it.

“I quit,” she said, “because I was tired of you nagging me, sonny!” And we both had a good laugh about that.

Hannah’s story reminds me that, as family physicians, we often have an impact on our patients in ways we don’t see in the short term. It is our longitudinal relationships with patients that allow us to plant seeds and reap the benefits over time.

It is these relationships that we can draw upon when counseling our patients with type 2 diabetes to address lifestyle issues such as exercise and a healthy diet. In this issue, McMullan et al¹ provide us with a rather hopeful review of the evidence in support of lifestyle changes. For our patients with type 2 diabetes, lifestyle changes can decrease A1C levels by 0.5% (with environmental changes related to diet)² and 0.7% (with moderate aerobic exercise).³ This is comparable to what is reported for the starting doses of most medications.⁴ In fact, a meta-analysis showed that a low-carbohydrate diet induced remission at 6 months in 32% of patients.⁵ (Caveat: The result was not controlled for weight loss as a possible confounding factor and an A1C cutoff of 6.5% was used.)

And yet, we often focus more on the various medications we can prescribe, with professional guidelines pointing the way.

Continue to: The National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence,⁶ American Diabetes Association,⁷ American College of Physicians,⁸ and American Academy of Family Physicians⁸ have followed the accumulating evidence that various medications improve outcomes—especially in patients at high risk or with established atherosclerotic cardiovascular disease. They have endorsed a stepwise pharmacologic approach beginning with metformin and recommend assessing each patient’s comorbidities to guide whether to add a sodium glucose co-transporter 2 (SGLT2) inhibitor or another agent. Where the groups diverge is what that second agent should be (glucagon-like peptide 1 receptor agonist, SGLT2 inhibitor, or dipeptidyl peptidase-4 inhibitor).

But what about lifestyle? Each organization’s guidelines address lifestyle changes as a foundation for managing patients with type 2 diabetes. But is that call loud enough? Do we heed it well enough?

Implementing lifestyle changes in office practice can be time consuming. Many clinicians lack adequate training or experience to gain any traction with it. Also, there is skepticism about success and sustainability.

I believe change starts when we recognize that while we have a priority list for each patient encounter, so do our patients. But they may not share that list with us unless we open the door by asking questions, such as:

• Of all the things you have heard about caring for your diabetes, what would you like to work on?
• What are you currently doing and what prevents you from meeting your goals?
• How would you like me to help you?

From there, we can start small and build on successes over time. We can go the distance with our patients. In the case of Hannah, I had the honor of caring for her until she died at age 104.

In the 2020-2021 influenza season, there was practically no influenza circulating in the United States. This decline from seasonal expectations, described in a previous Practice Alert, was probably due to the interventions aimed at limiting the spread of ­COVID-19: masking, social distancing, working from home, and cancellation of large, crowded events.¹ In 2021-2022 influenza returned, but only in moderation.

The Centers for Disease Control and Prevention (CDC) estimates there were between 82,000 to 170,000 hospitalizations and 5000 to 14,000 deaths attributed to influenza.² In addition, US virologic surveillance indicates that 98.6% of specimens tested positive for influenza A.² While the vaccine’s effectiveness in 2021-2022 was far below what was desired, it still prevented a great deal of flu morbidity and mortality and reduced acute respiratory illness due to influenza A(H3N2) virus by 35% (TABLE 1).³ All vaccines for the upcoming flu season are quadrivalent, containing 2 influenza A antigens and 2 influenza B antigens (TABLES 2⁴ and 3⁵).

Vaccine effectiveness in older adults (≥ 65 years) has been very low. TABLE 4⁶ shows vaccine effectiveness in the elderly for 10 influenza seasons between 2011 and 2020.⁶ In nearly half of those seasons, the estimated vaccine effectiveness was possibly nil. All influenza vaccines licensed for use in the United States are approved for use in those ≥ 65 years of age, except live attenuated influenza vaccine (LAIV).

Three products were developed to address the issue of low vaccine effectiveness in the elderly. The Advisory Committee on Immunization Practices (ACIP) has not expressed a preference for any specific vaccine for this age group. The high-dose qudrivalent vaccine (HD-IIV4), Fluzone, contains 4 times the antigen level of the standard-dose vaccines (SD-IIV4)—60 μg vs 15 μg. Fluzone was initially approved in 2014 as a trivalent vaccine and was approved as a quadrivalent vaccine in 2019. The adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad, was also inititally approved as a trivalent vaccine in 2015 and as quadrivalent in 2021. Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. Recombinant quadrivalent influenza vaccine (RIV4), Flublok, is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. It contains 3 times the antigen level as SD-IIV4 vaccines.

All 3 of these vaccines (HD-IIV4, aIIV4, and RIV4) have been compared with SD-IIV4 for effectiveness in the elderly and have yielded better outcomes. However, direct comparisons among the 3 vaccines have not shown robust evidence of superiority, and ACIP is unwilling to preferentially recommend one of them at this time. At its June 2022 meeting, ACIP voted to recommend any of these 3 options over the SD-IIV 4 options for those ≥ 65 years of age, with the caveat that if only an SD-IIV4 option is available it should be administered in preference to delaying vaccination.

One other vaccine change for the upcoming season involves the cell culture–based quadrivalent inactivated influenza vaccine (ccIIV4), Flucelvax, which is now approved for those ages ≥ 6 months. It previously was approved only for ages ≥ 2 years. All unadjuvanted SD-IIV4 vaccines as well as ccIIV4 are now approved for everyone ≥ 6 months of age. LAIV continues to be approved for ages 2 through 49 years. The only influenza vaccine products that contain thimerosal are those in multidose vials (TABLE 2⁴).

Promote vaccination and infection-control practices. ACIP continues to recommend influenza vaccine for all those ages ≥ 6 months, with 2 doses for those < 9 years old not previously vaccinated with an influenza vaccine. In addition to encouraging and offering influenza vaccine to patients and staff, we can minimize the spread of influenza in the community by robust infection-control practices in the clinical setting: masking and isolation of patients with respiratory symptoms, encouraging those with symptoms to stay at home and mask when around family members, advising frequent hand washing and respiratory hygiene, and using pre- and post-exposure chemoprophylaxis as appropriate. All recommendations regarding influenza for 2022-2023 can be found on the CDC website.⁴

In the 2020-2021 influenza season, there was practically no influenza circulating in the United States. This decline from seasonal expectations, described in a previous Practice Alert, was probably due to the interventions aimed at limiting the spread of ­COVID-19: masking, social distancing, working from home, and cancellation of large, crowded events.¹ In 2021-2022 influenza returned, but only in moderation.

The Centers for Disease Control and Prevention (CDC) estimates there were between 82,000 to 170,000 hospitalizations and 5000 to 14,000 deaths attributed to influenza.² In addition, US virologic surveillance indicates that 98.6% of specimens tested positive for influenza A.² While the vaccine’s effectiveness in 2021-2022 was far below what was desired, it still prevented a great deal of flu morbidity and mortality and reduced acute respiratory illness due to influenza A(H3N2) virus by 35% (TABLE 1).³ All vaccines for the upcoming flu season are quadrivalent, containing 2 influenza A antigens and 2 influenza B antigens (TABLES 2⁴ and 3⁵).

Vaccine effectiveness in older adults (≥ 65 years) has been very low. TABLE 4⁶ shows vaccine effectiveness in the elderly for 10 influenza seasons between 2011 and 2020.⁶ In nearly half of those seasons, the estimated vaccine effectiveness was possibly nil. All influenza vaccines licensed for use in the United States are approved for use in those ≥ 65 years of age, except live attenuated influenza vaccine (LAIV).

Three products were developed to address the issue of low vaccine effectiveness in the elderly. The Advisory Committee on Immunization Practices (ACIP) has not expressed a preference for any specific vaccine for this age group. The high-dose qudrivalent vaccine (HD-IIV4), Fluzone, contains 4 times the antigen level of the standard-dose vaccines (SD-IIV4)—60 μg vs 15 μg. Fluzone was initially approved in 2014 as a trivalent vaccine and was approved as a quadrivalent vaccine in 2019. The adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad, was also inititally approved as a trivalent vaccine in 2015 and as quadrivalent in 2021. Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. Recombinant quadrivalent influenza vaccine (RIV4), Flublok, is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. It contains 3 times the antigen level as SD-IIV4 vaccines.

All 3 of these vaccines (HD-IIV4, aIIV4, and RIV4) have been compared with SD-IIV4 for effectiveness in the elderly and have yielded better outcomes. However, direct comparisons among the 3 vaccines have not shown robust evidence of superiority, and ACIP is unwilling to preferentially recommend one of them at this time. At its June 2022 meeting, ACIP voted to recommend any of these 3 options over the SD-IIV 4 options for those ≥ 65 years of age, with the caveat that if only an SD-IIV4 option is available it should be administered in preference to delaying vaccination.

One other vaccine change for the upcoming season involves the cell culture–based quadrivalent inactivated influenza vaccine (ccIIV4), Flucelvax, which is now approved for those ages ≥ 6 months. It previously was approved only for ages ≥ 2 years. All unadjuvanted SD-IIV4 vaccines as well as ccIIV4 are now approved for everyone ≥ 6 months of age. LAIV continues to be approved for ages 2 through 49 years. The only influenza vaccine products that contain thimerosal are those in multidose vials (TABLE 2⁴).

Promote vaccination and infection-control practices. ACIP continues to recommend influenza vaccine for all those ages ≥ 6 months, with 2 doses for those < 9 years old not previously vaccinated with an influenza vaccine. In addition to encouraging and offering influenza vaccine to patients and staff, we can minimize the spread of influenza in the community by robust infection-control practices in the clinical setting: masking and isolation of patients with respiratory symptoms, encouraging those with symptoms to stay at home and mask when around family members, advising frequent hand washing and respiratory hygiene, and using pre- and post-exposure chemoprophylaxis as appropriate. All recommendations regarding influenza for 2022-2023 can be found on the CDC website.⁴

In the 2020-2021 influenza season, there was practically no influenza circulating in the United States. This decline from seasonal expectations, described in a previous Practice Alert, was probably due to the interventions aimed at limiting the spread of ­COVID-19: masking, social distancing, working from home, and cancellation of large, crowded events.¹ In 2021-2022 influenza returned, but only in moderation.

The Centers for Disease Control and Prevention (CDC) estimates there were between 82,000 to 170,000 hospitalizations and 5000 to 14,000 deaths attributed to influenza.² In addition, US virologic surveillance indicates that 98.6% of specimens tested positive for influenza A.² While the vaccine’s effectiveness in 2021-2022 was far below what was desired, it still prevented a great deal of flu morbidity and mortality and reduced acute respiratory illness due to influenza A(H3N2) virus by 35% (TABLE 1).³ All vaccines for the upcoming flu season are quadrivalent, containing 2 influenza A antigens and 2 influenza B antigens (TABLES 2⁴ and 3⁵).

Vaccine effectiveness in older adults (≥ 65 years) has been very low. TABLE 4⁶ shows vaccine effectiveness in the elderly for 10 influenza seasons between 2011 and 2020.⁶ In nearly half of those seasons, the estimated vaccine effectiveness was possibly nil. All influenza vaccines licensed for use in the United States are approved for use in those ≥ 65 years of age, except live attenuated influenza vaccine (LAIV).

Three products were developed to address the issue of low vaccine effectiveness in the elderly. The Advisory Committee on Immunization Practices (ACIP) has not expressed a preference for any specific vaccine for this age group. The high-dose qudrivalent vaccine (HD-IIV4), Fluzone, contains 4 times the antigen level of the standard-dose vaccines (SD-IIV4)—60 μg vs 15 μg. Fluzone was initially approved in 2014 as a trivalent vaccine and was approved as a quadrivalent vaccine in 2019. The adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad, was also inititally approved as a trivalent vaccine in 2015 and as quadrivalent in 2021. Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. Recombinant quadrivalent influenza vaccine (RIV4), Flublok, is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. It contains 3 times the antigen level as SD-IIV4 vaccines.

All 3 of these vaccines (HD-IIV4, aIIV4, and RIV4) have been compared with SD-IIV4 for effectiveness in the elderly and have yielded better outcomes. However, direct comparisons among the 3 vaccines have not shown robust evidence of superiority, and ACIP is unwilling to preferentially recommend one of them at this time. At its June 2022 meeting, ACIP voted to recommend any of these 3 options over the SD-IIV 4 options for those ≥ 65 years of age, with the caveat that if only an SD-IIV4 option is available it should be administered in preference to delaying vaccination.

One other vaccine change for the upcoming season involves the cell culture–based quadrivalent inactivated influenza vaccine (ccIIV4), Flucelvax, which is now approved for those ages ≥ 6 months. It previously was approved only for ages ≥ 2 years. All unadjuvanted SD-IIV4 vaccines as well as ccIIV4 are now approved for everyone ≥ 6 months of age. LAIV continues to be approved for ages 2 through 49 years. The only influenza vaccine products that contain thimerosal are those in multidose vials (TABLE 2⁴).

Promote vaccination and infection-control practices. ACIP continues to recommend influenza vaccine for all those ages ≥ 6 months, with 2 doses for those < 9 years old not previously vaccinated with an influenza vaccine. In addition to encouraging and offering influenza vaccine to patients and staff, we can minimize the spread of influenza in the community by robust infection-control practices in the clinical setting: masking and isolation of patients with respiratory symptoms, encouraging those with symptoms to stay at home and mask when around family members, advising frequent hand washing and respiratory hygiene, and using pre- and post-exposure chemoprophylaxis as appropriate. All recommendations regarding influenza for 2022-2023 can be found on the CDC website.⁴