Pharmacology Consult

Preventing and treating flu in immunocompromised patients: 2019-2020 update

Selena Warminski, PharmD
Selena Warminski
Leah Molloy, PharmD
Leah Molloy

Influenza remains an important threat to public health, and people with impaired immune systems are at particularly high risk for severe disease and complications. One comparative analysis showed that severely immunocompromised patients with influenza experienced significantly more hospitalizations, ICU admissions and mechanical ventilation than nonimmunocompromised patients. However, clinical signs and symptoms may be pronounced on initial presentation, underscoring the importance of seeking early medical attention. Additionally, antiviral resistance is more common and the mean viral shedding time was longer among immunocompromised patients (19 days compared with 6.4 days in healthy people).

Vaccination

Vaccination remains the most important and effective prevention strategy to reduce influenza burden in both the healthy population and immunocompromised patients. The 2018-2019 influenza season was marked by two waves in influenza A: first a predominance of H1N1 from October through mid-February, followed by H3N2 from February through May. Although the 2018-2019 and 2019-2020 vaccines include both H1N1 and H3N2 strains, the specific components chosen for the 2019-2020 vaccine are different. The decision on which H3N2 component would be included in the new vaccine was delayed until March to get a better match against circulating strains. As a result, influenza manufacturing and delivery will be delayed by a number weeks for the 2019-2020 flu season, shortening the window of time for patients to be immunized and increasing the importance of prompt vaccinations once available. As always, live vaccines, like the nasal spray influenza vaccine, are widely avoided for immunocompromised patients. If a household contact of a hematopoietic stem cell transplant recipient or someone living with severe combined immunodeficiency receives a live influenza vaccine, close contact should be avoided for 7 days following immunization to avoid transmission from shedding of the influenza virus through the nasal secretions.

Treatment

It is recommended to promptly initiate antiviral therapy in patients who are immunocompromised to minimize viral shedding and hospital and ICU admission. Neuraminidase inhibitors (oseltamivir, peramivir and zanamivir) have long been the mainstays of treatment. Initial studies of oseltamivir focused on previously healthy people, and dosing recommendations for immunocompromised patients are not well established. In one opinion article, higher doses and longer duration of therapy of oseltamivir are recommended (Table). The higher dose is suggested to overcome higher viral load and uncertain absorption, and the extended duration of therapy is recommended due to the prolonged viral shedding in immunocompromised patients. Although data remain limited for the immunocompromised population, one study of critically ill patients with serious influenza infection found no additional benefit when 150 mg was used instead of 75 mg, which was of particular interest during a shortage of oseltamivir. Also, antiviral resistance has been reported among immunocompromised patients who received treatment for longer than the standard 5 days. As such, until more evidence is available to draw strong conclusions, the risks and benefits of different antiviral doses and durations should be carefully evaluated in the clinical setting. Additionally, the term immunocompromised can be applied to people with varying degrees of impairment. For example, the recommendation for high-dose oseltamivir was made specifically for patients with hematologic malignancies, and worsened clinical courses are best described among severely immunocompromised patients. As such, certain precautions and recommendations may be of greater relevance and potential benefit to different subsets of patients.

Table. Neuraminidase inhibitors for influenza treatment  among previously healthy and immunocompromised patients

Unlike the neuraminidase inhibitors that prevent release of formed virus, the novel antiviral baloxavir marboxil blocks an earlier step in viral replication by inhibiting the cap-dependent endonuclease enzyme involved in mRNA synthesis. Baloxavir gained initial FDA approval in October 2018 after the phase 3 CAPSTONE-1 trial, in which baloxavir reduced viral load more than oseltamivir or placebo on the first day of treatment, with symptom improvement similar to oseltamivir among otherwise healthy patients. More than 80% of patients in that study were infected with an H3N2 strain of influenza. Since then, the CAPSTONE-2 trial drew similar conclusions among patients with risk factors for complicated disease, although the most common risk factors were being aged 65 years or older and having chronic lung disease, but not impaired immune function. More recently, the phase 3 BLOCKSTONE trial identified a potential role for baloxavir in the prevention of influenza among household contacts of infected people. Combination therapy with baloxavir and oseltamivir has shown synergistic activity with improved survival in animal models, suggesting another possible area for future research, along with clarifying the ideal dose and duration of both novel and existing flu treatments for patients with cancer.

Influenza remains an important threat to public health, and immunocompromised patients are a diverse and vulnerable population. Prevention and treatment of influenza among these individuals requires careful and individualized consideration along with continued research to optimize antiviral selection and dosage.

Disclosures: Molloy and Warminski report no relevant financial disclosures.

Selena Warminski, PharmD
Selena Warminski
Leah Molloy, PharmD
Leah Molloy

Influenza remains an important threat to public health, and people with impaired immune systems are at particularly high risk for severe disease and complications. One comparative analysis showed that severely immunocompromised patients with influenza experienced significantly more hospitalizations, ICU admissions and mechanical ventilation than nonimmunocompromised patients. However, clinical signs and symptoms may be pronounced on initial presentation, underscoring the importance of seeking early medical attention. Additionally, antiviral resistance is more common and the mean viral shedding time was longer among immunocompromised patients (19 days compared with 6.4 days in healthy people).

Vaccination

Vaccination remains the most important and effective prevention strategy to reduce influenza burden in both the healthy population and immunocompromised patients. The 2018-2019 influenza season was marked by two waves in influenza A: first a predominance of H1N1 from October through mid-February, followed by H3N2 from February through May. Although the 2018-2019 and 2019-2020 vaccines include both H1N1 and H3N2 strains, the specific components chosen for the 2019-2020 vaccine are different. The decision on which H3N2 component would be included in the new vaccine was delayed until March to get a better match against circulating strains. As a result, influenza manufacturing and delivery will be delayed by a number weeks for the 2019-2020 flu season, shortening the window of time for patients to be immunized and increasing the importance of prompt vaccinations once available. As always, live vaccines, like the nasal spray influenza vaccine, are widely avoided for immunocompromised patients. If a household contact of a hematopoietic stem cell transplant recipient or someone living with severe combined immunodeficiency receives a live influenza vaccine, close contact should be avoided for 7 days following immunization to avoid transmission from shedding of the influenza virus through the nasal secretions.

Treatment

It is recommended to promptly initiate antiviral therapy in patients who are immunocompromised to minimize viral shedding and hospital and ICU admission. Neuraminidase inhibitors (oseltamivir, peramivir and zanamivir) have long been the mainstays of treatment. Initial studies of oseltamivir focused on previously healthy people, and dosing recommendations for immunocompromised patients are not well established. In one opinion article, higher doses and longer duration of therapy of oseltamivir are recommended (Table). The higher dose is suggested to overcome higher viral load and uncertain absorption, and the extended duration of therapy is recommended due to the prolonged viral shedding in immunocompromised patients. Although data remain limited for the immunocompromised population, one study of critically ill patients with serious influenza infection found no additional benefit when 150 mg was used instead of 75 mg, which was of particular interest during a shortage of oseltamivir. Also, antiviral resistance has been reported among immunocompromised patients who received treatment for longer than the standard 5 days. As such, until more evidence is available to draw strong conclusions, the risks and benefits of different antiviral doses and durations should be carefully evaluated in the clinical setting. Additionally, the term immunocompromised can be applied to people with varying degrees of impairment. For example, the recommendation for high-dose oseltamivir was made specifically for patients with hematologic malignancies, and worsened clinical courses are best described among severely immunocompromised patients. As such, certain precautions and recommendations may be of greater relevance and potential benefit to different subsets of patients.

Table. Neuraminidase inhibitors for influenza treatment  among previously healthy and immunocompromised patients
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Unlike the neuraminidase inhibitors that prevent release of formed virus, the novel antiviral baloxavir marboxil blocks an earlier step in viral replication by inhibiting the cap-dependent endonuclease enzyme involved in mRNA synthesis. Baloxavir gained initial FDA approval in October 2018 after the phase 3 CAPSTONE-1 trial, in which baloxavir reduced viral load more than oseltamivir or placebo on the first day of treatment, with symptom improvement similar to oseltamivir among otherwise healthy patients. More than 80% of patients in that study were infected with an H3N2 strain of influenza. Since then, the CAPSTONE-2 trial drew similar conclusions among patients with risk factors for complicated disease, although the most common risk factors were being aged 65 years or older and having chronic lung disease, but not impaired immune function. More recently, the phase 3 BLOCKSTONE trial identified a potential role for baloxavir in the prevention of influenza among household contacts of infected people. Combination therapy with baloxavir and oseltamivir has shown synergistic activity with improved survival in animal models, suggesting another possible area for future research, along with clarifying the ideal dose and duration of both novel and existing flu treatments for patients with cancer.

Influenza remains an important threat to public health, and immunocompromised patients are a diverse and vulnerable population. Prevention and treatment of influenza among these individuals requires careful and individualized consideration along with continued research to optimize antiviral selection and dosage.

Disclosures: Molloy and Warminski report no relevant financial disclosures.