Special Report
Influenza in Severely Immunocompromised Patients
By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA, Editor of Infectious Disease Alert
SYNOPSIS: Influenza virus infection in severely immunocompromised patients is associated with reduced initial symptoms, but increased risk of severe outcomes. Treatment options with good supportive evidence are limited.
SOURCES: Memoli MJ, et al. The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts. Clin Infect Dis 2014; 8:214-24.
Ison MG. Influenza prevention and treatment in transplant recipients and immunocompromised hosts. Influenza Other Respir Viruses 2013;7:Suppl 3:60-6.
Prevention
The optimal approach to influenza is prevention but there are problems related to the immunogenicity of influenza vaccines in immunosuppressed transplant recipients, as indicated by Ison et al. There is a consensus that influenza vaccination does not lead to organ transplant rejection. Serological response to vaccination is, however, diminished in transplant patients when compared to non-immunocompromised individuals.
Very recent IDSA guidelines currently state the following regarding influenza vaccination.1 "Annual vaccination with inactivated influenza vaccine (IIV) is recommended for immunocompromised patients aged >6 months, except for patients very unlikely to respondsuch as those receiving intensive chemotherapy or those who have received anti-B-cell antibodies within 6 months." Allogeneic and autologous HSCT recipients should receive a single dose beginning 6 months after transplantation, but, in the context of a community outbreak of influenza, the first dose should be given at 4 months. Children 6 months to 8 years of age receiving IIV for the first time should receive 2 doses. A "double-dose" influenza vaccine has improved immunogenicity in the elderly, but whether it has similar benefit in immunocompromised patients, including transplant recipients, is not yet known.
Household members >6 months of age should be vaccinated with IIV. Live attenuated vaccine (LAIV) should not be given to members of the household of a hematopoietic stem cell recipient transplanted within the previous 2 months or with graft vs. host disease, or if the patient has severe combined immunodeficiency. If a household member receives LAIV, he or she should avoid contact with the patient for 7 days.
Clinical Manifestations
Memoli and colleagues prospectively evaluated 32 severely immunocompromised and 54 non-immunocompromised adults with influenza virus infection in order to assess any differences in their clinical manifestations and course. Influenza vaccination had been received in the previous year in 59% and 25%, respectively. Nineteen (59.4%) of the immunocompromised patients had undergone hematopoietic stem cell transplantation (HSCT).
A dry cough was present in approximately three-fourths of the immunocompromised patients, as was coryza while 85.2% were febrile, 70.4% complained of headache, and 40.7% of myalgia. Many symptoms were less prevalent in the immunocompromised than in the nonimmunocompromised cohort. These included dry cough, chills, sweats, myalgia, and shortness of breath. All the immunocompromised patients were hospitalized and 6 (18%) required intensive care, including mechanical ventilation, while none of the nonimmunocompromised patients required intensive care, although 16 (29.6%) were hospitalized. One (3%) patient, who was immunocompromised, died.
The mean durations of viral shedding were 19.0 days and 6.4 days in immunocompromised and non-immunocompromised patients, respectively. Persistent shedding was often associated with a lack of symptoms. New chest radiographic abnormalities, often in the absence of physical findings, were present significantly more immunocompromised patients, although many of the comparator group did not undergo lung imaging. Two thirds of the viruses detected were A (H1N1)pdm09. Neuraminidase resistance occurred during neuraminidase inhibitor therapy in 3 cases. One H3N2 virus developed a novel mutation, while 2 A(H1N1)pdm09 viruses developed H275Y mutations. There was no difference in proinflammatory cytokine levels in nasal washes and serum between the two groups.
Treatment
Studies suggest that treatment of infection due to susceptible influenza virus with oseltamivir is associated with improved outcomes. The data in severely immunocompromised hosts is limited, but more is available regarding hospitalized and critically ill patients in general. For instance, a recent retrospective analysis found evidence of survival benefit in critically ill patients infected with A(H1N1)pdm09 when oseltamivir administration was initiated as late as 5 days after symptom onset.2
There is limited data in immunodeficient patients with use of nebulized zanamivir. An intravenous form of zanamivir remains investigational, but non-randomized data suggests it is effective in the treatment of influenza A viruses with an H275Y associated with resistance to oseltamivir. This mutation is also associated with reduced susceptibility to peramivir, which is also under investigation as a parenterally administered agent.
Administration of intravenous peramivir produced clinical responses similar to that of oseltamivir in a randomized trial in hospitalized patients with influenza virus infection.3 Lanamivir, a neuraminidase inhibitor active against oseltamivir-resistant influenza virus and which is administered as a single dose by inhalation, is in a Phase 3 trial. Favipravir (formerly T-705), which inhibits RNA-dependent RNA polymerase, is active against a spectrum of RNA viruses and is being evaluated in a Phase 3 trial in patients with uncomplicated influenza. In a very underpowered randomized trial, there was no difference in the duration of symptoms of patients infected with A(H1N1)pdm09 treated with either oseltamivir alone or together with zanamivir.4 A retrospective analysis of critically ill patients requiring mechanical ventilation with A(H1N1)pdm09 infection concluded that a 3-drug combination of oseltamivir, amantadine, and ribavirin "was comparable to that of oseltamivir monotherapy."5
Administration of hyperimmune globulin derived from convalescent plasma of patients who had survived A(H1N1)pdm09 infection to patients with infection with this virus was associated with modestly improved survival.6 A number of monoclonal antibodies are also under development.
DAS181 is a sialidase that cleaves terminal sialic acid residues on respiratory epithelial cells that are necessary for binding of influenza viruses. Administered by inhalation, it has in vivo activity against influenza A, including A(H1N1)pdm09, influenza B, and parainfluenza viruses types 1-3. Its administration was associated with reduced viral load in a Phase 2 trial.7
As the result of evidence suggesting that the lung injury in influenza virus pneumonia results from the inflammatory response, corticosteroids have been suggested as an adjunctive therapy, but available evidence does not suggest resulting benefit.
A number of additional anti-inflamatory molecules are under investigation.
Extracorporeal membrane oxygenation (ECMO) is increasingly being used as salvage therapy. A systematic review and meta-analysis of the use of ECMO in patients with acute lung injury in association with A(H1N1)pdm09 infection could only conclude that it is "feasible and effective," but that it is usually prolonged for > 7 days and the mortality remains high.8 The conclusion that it is effective can be questioned since all included studies were only observational.
References
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Rubin LG, et al. 2013 IDSA Clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014; 58:e44-e100.
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Louie JK, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012; 55:1198-204.
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Ison MG, et al. Intravenous peramivir for treatment of influenza in hospitalized patients. Antivir Ther 2013;Aug 28. doi:10.3851/IMP2680.
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Escuret V, et al. Oseltamivir-zanamivir bitherapy compared to oseltamivir monotherapy in the treatment of pandemic 2009 influenza A(H1N1) virus infections. Antiviral Res 2012; 96:130-7.
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Kim WY, et al. Korean Society of Critical Care Medicine H1N1 Collaborative. Triple-combination antiviral drug for pandemic H1N1 influenza virus infection in critically ill patients on mechanical ventilation. Antimicrob Agents Chemother 2011; 55:5703-9.
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Hung IF, et al. Hyperimmune IV immunoglobulin treatment: A multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 2013;144:464-73.
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Moss RB, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis 2012; 206:1844-51.
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Zangrillo A, et al. Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: A systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO. Crit Care 2013;17(1):R30.
