Managing Influenza in Patients with Hematologic Malignancies
By Jerome Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.This article originally appeared in the January 2011 issue of Clinical Oncology Alert. It was edited by William B. Ershler, MD, and peer reviewed by V.R. Veerapalli, MD. Dr. Ershler is Director, Institute for Advanced Studies in Aging, Washington, DC; Member, INOVA Fairfax Cancer Center, Fairfax, VA, and Dr. Veerapalli is Staff Clinician, INOVA Fairfax Cancer Center, Fairfax, VA. Drs. Ershler and Veerapalli report no financial relationships relevant to this field of study.
A 74-year retired veterinarian presents to the emergency department (ED) with shortness of breath. He was recently diagnosed with diffuse large-cell lymphoma with prominent abdominal lymphadenopathy and positive bone marrow and has been treated with two cycles of R-CHOP. He has tolerated the chemotherapy well, without nausea, vomiting, or significant cytopenia after either cycle. The third cycle was scheduled to begin in five days. Shortness of breath developed progressively over the prior two days and has been associated with cough, low-grade fever, headache, and increasing fatigue. He lives with his wife, who is well. His past medical history is significant for hypertension and hyperlipidemia, both controlled with medication. He does not currently smoke, although he has a 40 pack/year history, having quit approximately 10 years ago. He drinks moderately (1-2 cocktails/evening).
In the ED, physical examination revealed a mildly dyspneic man. Blood pressure was 128/78, pulse was 94 and regular, and respiratory rate was 18/min. O2 saturation was 90% on room air. There were rales at the right base, heard posteriorly. The abdomen did not reveal palpable mass, tenderness, or organomegaly. The extremities were free of edema, and there was no clubbing or cyanosis. Oxygen was administered at 2L/min by nasal prong, and the O2 saturation rose to 96%. A chest X-ray revealed haziness in the right middle lobe, consistent with an interstitial pneumonia. Complete blood count revealed a white count of 11.3K/cu mm, with 88% neutrophils, hemoglobin was 10.4 g/dL, and the platelet count was 140K/cu mm. Blood and urine cultures were obtained. A nasopharyngeal swab was positive for influenza (and this was later confirmed to be seasonal H1N1 influenza). The patient was admitted to the hospital for treatment.
As with influenza occurring in healthy adults, its occurrence in patients with malignancy typically is heralded by upper respiratory symptoms, headache, and fever. However, these systemic symptoms, including fever, myalgia, and fatigue, may be reduced, or completely absent, in patients who are immunologically compromised. For example, among hematopoietic cell transplant (HCT) recipients, in whom this has been studied prospectively,1 most patients were afebrile and lacked systemic symptoms. It is possible that the cytokine response associated with acute influenza infection may be decreased in these patients, either because of their disease or the treatment thereof. Furthermore, the symptomatic phase typically lasts for 1 to 2 weeks in immunocompromised patients, although viral shedding may be prolonged beyond that.2
For most immunologically competent adults who are diagnosed with influenza, the symptoms, though often dramatic, are usually self-limited. However, when influenza progresses to a lower respiratory infection, the outcome can be devastating for both immune-competent and immune-deficient patients. The progression from upper- to lower-tract disease occurs after a median of one week in patients with hematologic malignancies,2 presenting clinically and radiographically as viral pneumonia. One significant risk factor for progression to lower-tract disease is profound lymphopenia.2,3 The impacts of corticosteroids and/or rituximab on influenza severity and outcome are conflicting, with no randomized trials assessing these effects. It is possible that steroids prolong viral shedding, but this might be balanced by a reduction in the inflammatory cytokine response. The effect of corticosteroids and immunomodulating drugs on the progression of influenza infection is an important but under-studied clinical-research domain. There have been very few studies that have evaluated the outcome of influenza disease relative to the underlying immunosuppression or pre-existing conditions, although a recent meta-analysis found an average case-fatality rate of 17%, with a range of 0% to 33% among HCT recipients infected with seasonal influenza.4
Certainly, influenza pneumonia may be complicated by bacterial or fungal co-infection, and this would seem more likely in immunologically compromised patients. In such patients, diagnostic vigilance must be high and the threshold for the addition of antibiotic and/or antifungal medicine low.
There are treatments for influenza of proven, albeit modest benefit. Once again, these agents have not been adequately studied in randomized trials specifically in patients undergoing chemotherapy or other forms of cancer treatment. Antiviral susceptibilities of circulating influenza strains must be continually evaluated. Due to documented resistance to M2 inhibitors exhibited by 2009 H1N1 strains, amantadine and rimantidine probably should still not be used as single agents to treat or prevent influenza A. There are two 2 neuraminidase inhibitors (zanamivir and oseltamivir) that are currently approved for the treatment of influenza. These compounds are licensed for inhaled (zanamivir) and oral (oseltamivir) use, with intravenous agents now available only under special circumstances (i.e., under Emergency Use Authorization through the U.S. Centers for Disease Control and Prevention).
Redelman-Sidi and colleagues5 provided some insight on the effects of optimal management of influenza during the recent H1N1 pandemic (2009). Among 45 influenza-confirmed cancer patients treated at Memorial Sloan Kettering Cancer Center, progression to lower respiratory tract disease occurred in 27%. In that cohort, 37% of patients were hospitalized for an average of 7 days (range, 3-15 days), and one person required admission to the intensive-care unit care without mechanical ventilation. Almost all patients were treated with oseltamivir. This is in contrast to a number of other reports in which, even with optimal therapy, death rates in patients with lower respiratory influenza among cancer patients were high.6
Although there is little evidence derived from sufficiently powered, randomized clinical trials, it is prudent to be aggressive in the management of immune-compromised patients with proven influenza pneumonia. Treatment should be initiated promptly, and should probably continue to the point of clinical resolution and beyond if there is still shedding of the virus.7
With all of this in mind, I would concur with hospitalization for the patient described above. His symptoms are of reasonably short duration, but as mentioned above, in patients receiving chemotherapy, steroids, and rituximab, the infection might be of longer duration than would have been predicted based upon the appearance of his symptoms. That stated, I would suggest a pulmonary-medicine consultation for bronchoscopy and lavage (to rule out concurrent bacterial or fungal infection). I would probably start the patient on oseltamivir and then consult with an infectious-disease specialist to determine whether a higher dose of this drug, combina-tion antiviral drugs, or procurement of an intravenous agent (such as peramivir) would provide a better chance for successful outcome. High-level supportive care is likely to be essential. And, of course, the third cycle of R-CHOP will need to be delayed until there is complete resolution of infection.
1. Peck AJ, et al. Respiratory virus infection among hematopoietic cell transplant recipients: Evidence for asymptomatic parainfluenza virus infection. Blood. 2007;110:1681-1688.
2. Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: Risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39:1300-1306.
3. Chemaly RF, et al. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: A retrospective study at a major cancer center. Medicine (Baltimore). 2006;85:278-287.
4. Kunisaki KM, Janoff EN. Influenza in immunosuppressed populations: A review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis. 2009;9:493-504.
5. Redelman-Sidi G, et al. 2009 H1N1 influenza infection in cancer patients and hematopoietic stem cell transplant recipients. J Infect. 2010;60:257-263.
6. Hajjar LA, Mauad T, Galas FR, et al. Severe novel influenza A (H1N1) infection in cancer patients. Ann Oncol. 2010;21:2333-2341.
7. Casper C, Englund J, Boeckh M. How I treat influenza in patients with hematologic malignancies. Blood. 2010;115:1331-1342.