Updated Interim Recommendations: Special Considerations for Clinicians Regarding 2009 H1N1 Influenza in Severely Immunosuppressed Patients

December 16, 2009, 11:30 AM ET

Epidemiology

Immunosuppression can result from a variety of clinical conditions, and the severity of immunosuppression may vary with the severity of the condition. Immunosuppression may also result from immunosuppressive treatments, the extent of which may depend on factors such as dosage or synergistic medication combinations. Some common conditions and treatments associated with immunodeficiency are shown in the tables below. These interim recommendations refer to patients who are severely immunosuppressed as a result of receiving treatment for malignancies; or as a result of receiving treatment related to solid organ or hematopoietic stem cell transplants; or as a result of autoimmune conditions and treatment. Such patients may be at high risk of influenza-related complications such as more severe illness and hospitalization. These recommendations may be updated as further information becomes available. In addition to this guidance, there are documents available for caregivers of adult and adolescent HIV-infected patients as well as for patients with rheumatological diseases.

Patients with severe immunosuppression from the following conditions or treatments may be at high risk for influenza-related complications.

Some Conditions and Treatment that Suppress the Immune System*

• Hematopoietic stem cell transplant recipient receiving anti-rejection medication
• Solid organ transplant recipient receiving anti-rejection medication
• Congenital immunodeficiency disorder
• Chemotherapy for cancer
• Autoimmune conditions and treatments
• Chronic corticosteroid use

* HIV and Rheumatologic conditions are included in other guidance

Patients with conditions that confer some degree of immunosuppression, e.g., asplenia, may not necessarily have increased risk for influenza-associated complications, but may be at high risk for secondary invasive infection with encapsulated bacteria (e.g., pneumococcal disease).

Patients who use short courses of treatments that weaken the immune system for mild, common ailments (e.g., corticosteroid use for poison ivy), are likely NOT at increased risk of complications from influenza unless they also have other high-risk conditions for influenza complications such as asthma, chronic obstructive pulmonary disease, diabetes, heart disease, pregnancy, cancer, etc.

Clinical Issues

While some severely immunosuppressed patients may develop typical signs and symptoms of influenza, fever may not always be present¹. Therefore, clinicians should suspect influenza in any severely immunosuppressed patient with acute respiratory symptoms, with or without fever, and initiate empiric antiviral treatment as soon as possible and send respiratory specimens for real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) (see Influenza diagnostic testing and Antiviral treatment sections below). Appropriate infection control including isolation should be implemented for any suspected patient as soon as possible even before testing results are available.

Although the type and severity of immune dysfunction that correlates with increased risk of influenza-associated complications is not well defined, transplant patients with significant lymphodepletion (i.e., lymphopenia due to immunosuppression for recent hematopoietic stem cell transplant) or lymphocyte dysfunction have had serious complications of influenza virus infection, prolonged viral shedding, and have acquired resistance to antiviral medications². Sporadic cases of oseltamivir-resistant 2009 H1N1 influenza virus infection have been reported; some of these cases were in severely immunosuppressed patients in whom resistance emerged during treatment for symptomatic illness and who experienced prolonged viral shedding³. Therefore, some experts have recommended that immunosuppressed patients with 2009 H1N1 influenza virus infection should strictly adhere to recommended personal protective equipment and infection control measures until symptoms have resolved and there are serial respiratory specimens that test negative for 2009 H1N1 viral RNA by rRT-PCR ^{4, 5}.

Influenza Vaccination and Prevention

Although influenza vaccination is the best way to prevent influenza, influenza vaccination may be poorly immunogenic in severely immunosuppressed patients⁶. Therefore, antiviral chemoprophylaxis of influenza can be considered for severely immunosuppressed patients⁷. Immunosuppressed persons aged 6 months and older are recommended to receive both inactivated seasonal influenza vaccine and inactivated 2009 H1N1 monovalent influenza vaccine. In addition, persons aged 6 months and older who are household contacts of severely immunosuppressed persons are recommended for annual inactivated seasonal influenza vaccination. Further details regarding reasons for vaccinating these groups can be found in the 2009 H1N1 Vaccination Recommendations.

Influenza Diagnostic Testing

Any severely immunosuppressed patient who is ill with suspected influenza should be started on empiric antiviral treatment as soon as possible without waiting for influenza testing to be conducted or influenza testing results. Confirmatory influenza diagnostic testing for 2009 H1N1 influenza with rRT-PCR should be considered for severely immunosuppressed patients with suspected influenza because results will inform decisions regarding clinical care and infection control. Additional influenza testing of respiratory specimens of severely immunosuppressed patients by rRT-PCR is recommended by some experts for determination of prolonged viral shedding. Guidelines for influenza testing in solid organ or hematopoietic stem cell transplant donors with suspected influenza are available^{8, 9}. Recommendations on the use of influenza diagnostic tests for the 2009-2010 influenza season are available.

Antiviral Treatment

Antiviral therapy with a neuraminidase inhibitor(oseltamivir, zanamivir) should be initiated empiricallyas early as possible for severely immunosuppressed patients with suspected influenza. Although efficacy of early antiviral treatment (<48 hours from illness onset) of previously healthy persons with uncomplicated influenza has been demonstrated in randomized clinical trials, observational studies indicate that initiation of oseltamivir treatment after 48 hours of onset in hospitalized patients with seasonal influenza or 2009 H1N1 is associated with survival benefit compared to no treatment^{10, 11, 12, 13}. Although there are no prospective data available for neuraminidase inhibitor treatment of immunosuppressed patients with influenza, initiation of therapy beyond 48 hours after symptom onset should be considered.

Clinicians should be aware that severely immunosuppressed persons with influenza may experience prolonged influenza viral replication; those with significant lymphopenia will typically shed for longer than 5 days even with antiviral treatment². Therefore, some experts have recommended consideration of longer duration of neuraminidase inhibitor treatment (e.g. 10 days versus standard 5 days). Infection control precautions should be maintained for as long as such patients have evidence of prolonged influenza viral shedding as detected by rRT-PCR and/or remain symptomatic – whichever is longer. Sporadic cases of oseltamivir resistant 2009 H1N1 virus have been reported in severely immunosuppressed patients who were treated with oseltamivir. This oseltamivir resistance is associated with an H275Y mutation in viral neuraminidase. Patients with suspected or confirmed oseltamivir-resistant 2009 H1N1 influenza virus who require antiviral treatment should receive zanamivir. If orally inhaled zanamivir is contraindicated or not tolerated, then IV zanamivir is available for compassionate use from its manufacturer via an emergency Investigational New Drug (IND) application to the FDA. Patients with highly suspected or documented oseltamivir resistance should not be treated with peramivir because clinical isolates expressing the oseltamivir resistance-associated substitution H275Y in neuraminidase have demonstrated reduced in-vitro susceptibility to peramivir, although the clinical significance of this is currently unknown. Development of resistance to other antiviral medications during treatment is also possible. Such antiviral resistance would be associated with different mutations and can only be detected by robust screening assays that are not specific for the H275Y mutation. Clinicians managing 2009 H1N1 hospitalized patients who have not improved clinically and who have persistent laboratory-confirmed viral shedding may wish to consult infectious disease specialists, their state health department or CDC for questions about antiviral resistance, additional testing and antiviral treatment.

Optimal therapy for severely immunosuppressed patients with oseltamivir-resistant 2009 H1N1 influenza virus has not been defined. Some severely immunosuppressed patients with 2009 H1N1 have been treated with a combination of IV zanamivir and aerosolized ribavirin^{3, 14} therapy, or IV zanamivir monotherapy¹⁵. Clinicians should note that orally inhaled zanamivir may not be tolerated by critically ill patients with lower respiratory tract disease. Clinicians should be aware that intravenous antiviral medications are available, IV peramivir¹⁶ through an Emergency Use Authorization; and IV zanamivir¹⁵ through an Emergency Investigational New Drug Application) for treatment of critically ill 2009 H1N1 patients or for hospitalized patients who cannot tolerate orally inhaled zanamivir or oral oseltamivir when treatment is indicated. Critically ill immunosuppressed patients are particularly susceptible to secondary bacterial and fungal infections that can cause pneumonia and disseminated infection, including sepsis, and should be empirically treated with antibiotics based on clinical judgment.

References

1. Peck AJ, Englund JA, Kuypers J et al. Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection. Blood. 2007 Sep 1;110(5):1681-8.
2. Khanna N, Steffen I, Studt JD et al. Outcome of influenza infections in outpatients after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2009 Apr;11(2):100-5.
3. CDC. Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in Two Immunosuppressed Patients --- Seattle, Washington, 2009. MMWR, 2009. 58(32);893-896.
4. Gooskens J et al. Prolonged Influenza Virus Infection during Lymphocytopenia and Frequent Detection of Drug-Resistant Viruses. The Journal of Infectious Diseases 2009; 199:1435– 41
5. Lee N, Chan PK, et al. Viral Loads and Duration of Viral Shedding in Adult Patients Hospitalized with Influenza. J Infect Dis. 2009; 200:492-500.
6. Hodges GR, Davis JW, Lewis HD, et al. Response to influenza A vaccine among high-risk patients. South Med J 1979;72:29-32.
7. ASBMT Guidelines
8. Danziger-Isakov LA, Husain S, Mooney ML, Hannan MM; for the ISHLT Infectious Diseases Council. The Novel 2009 H1N1 Influenza Virus Pandemic: Unique Considerations for Programs in Cardiothoracic Transplantation. J Heart Lung Transplant. 2009 Oct 21. [Epub ahead of print]
9. Kumar D, Morris MI, Kotton CN et al. Guidance on Novel Influenza A/H1N1 in Solid Organ Transplant Recipients. American Journal of Transplantation 2009; 9: 1–8.
10. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324.
11. Hanshaoworakul W, Simmerman JM, Narueponjirakul U, et al. Severe human influenza infections in Thailand: oseltamivir treatment and risk factors for fatal outcome. PLoS One 2009;4(6):e6051.
12. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009;361:1935-1944.
13. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-1887.
14. Chan-Tack KM, Murray JS, Birnkrant DB. Use of ribavirin to treat influenza. N Engl J Med. 2009 Oct 2;361(17):1713-4.
15. Kidd IM, Down J, Nastouli E, Shulman R, Grant PR, Howell DC, Singer M. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009 Sep 19;374(9694):1036.
16. Birnkrant D, Cox E. The Emergency Use Authorization of Peramivir for Treatment of 2009 H1N1 Influenza. N Engl J Med. 2009 Nov 3. [Epub ahead of print]