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Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index
Accepted Manuscript Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index Joumana Kmeid, MD, Jakapat Vanichanan, MD, Dimpy P. Shah, MD, MSPH, PhD, Firas El Chaer, MD, Jacques Azzi, MD, Ella Ariza Heredia, MD, Chitra Hosing, MD, Victor Mulanovich, MD, Roy F. Chemaly, MD, MPH PII:
S1083-8791(15)00742-9
DOI:
10.1016/j.bbmt.2015.11.015
Reference:
YBBMT 54047
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 12 October 2015 Accepted Date: 20 November 2015
Please cite this article as: Kmeid J, Vanichanan J, Shah DP, El Chaer F, Azzi J, Ariza Heredia E, Hosing C, Mulanovich V, Chemaly RF, Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.11.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index Joumana Kmeid1, MD, Jakapat Vanichanan1, MD, Dimpy P. Shah1, MD, MSPH, PhD, Firas El
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Chaer1, MD, Jacques Azzi1, MD, Ella Ariza Heredia1, MD, Chitra Hosing2, MD, Victor Mulanovich1, MD, Roy F. Chemaly1, MD, MPH
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Departments of 1Infectious Diseases, Infection Control, & Employee Health, and 2 Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center,
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Houston, TX
Corresponding author: Roy F. Chemaly, MD, MPH, Department of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA, 77030-4009; telephone: 713-
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745-1116; fax: 713-745-6839; e-mail: [email protected].
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Running title: Influenza in HCT recipients
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Financial Disclosures:
R.F.C. received research grants from GlaxoSmithKline. The remaining authors declare no competing financial interests.
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Abstract Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza
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vaccination and are susceptible to lower respiratory tract infection (LRI) and death. We determined clinical characteristics and outcomes of laboratory-confirmed influenza, including 2014/H3N2 infection, in 146 HCT recipients. An immunodeficiency scoring index (ISI) was applied to identify patients at high risk for LRI and death. Thirty three patients developed LRI
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(23%), and 7 died within 30 days of diagnosis (5%). Most patients received antiviral therapy (83%); however, only 18% received it within 48 hours of symptom onset. The incidence of LRI
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was significantly higher in the ISI high-risk group than in the low-risk group (P < 0.001). Receiving early antiviral therapy was associated with a substantial reduction in LRI for all ISI risk groups with the greatest risk reduction observed in the high-risk group. When compared to previous seasons, no significant differences in patient outcomes were observed during the
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2014/H3N2 season; however, antiviral therapy was more promptly initiated in the latter season. The ISI that was originally developed for respiratory syncytial virus may help identifying HCT recipients at risk for progression to LRI and mortality following influenza infection. These
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patients should be monitored more closely. Early initiation of antiviral therapy for influenza in
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HCT recipients, irrespective of the ISI risk group, may improve morbidity as well as mortality.
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Introduction The severity of influenza infection in the general population depends on vaccination uptake and the main circulating virus, among other factors. Some seasons, such as the 2009/H1N1 pandemic
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season, have had higher rates of hospitalizations (274,000 hospitalizations in the United States alone); however, the disease severity in that season was not significantly different from that in previous seasons.(1, 2) The severity of influenza infection also depends on the host immune
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status and its underlying risk factors. Multiple studies have shown that susceptible populations such as children, the elderly, pregnant women, solid organ transplant recipients, and
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hematopoietic cell transplant (HCT) recipients have a higher risk of developing severe disease and higher rates of complications such as hospitalizations, prolonged viral shedding, emergence of viral resistance, and mortality compared to the general population.(3-7)
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Influenza infection in HCT recipients has been increasingly recognized as a serious infection with severe implications.(8-10) In fact, it is one of the most common respiratory viral infections (influenza accounts for 30% of all respiratory viral infections) and it causes increased morbidity
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and mortality in this population. Up to 35% of these patients progress to lower respiratory tract infection (LRI) with subsequent high mortality.(10, 11) Previous studies have revealed various
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risk factors for influenza-associated LRI in HCT recipients, such as lymphocytopenia, nosocomial acquisition of the virus, older age, and preexisting lung disease.(12-14) Using these clinically available risk factors, an immunodeficiency scoring index (ISI) was developed in HCT recipients with respiratory syncytial virus (RSV) infections to help identify patients at higher risk for complications and those who would benefit the most from antiviral therapy.(15) As this
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scoring index was not based on virus-specific factors, it may be extrapolated to other respiratory viruses, such as influenza, in HCT recipients.
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In this study, we aimed to compare the clinical characteristics and outcomes of influenza
infection, including the pandemic 2009/H1N1, strains from the subsequent seasons, and the current 2014/H3N2 influenza strain in HCT recipients, especially in view of the reported
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decreased efficacy of the 2014-2015 influenza vaccine (the main circulating virus during the past season was influenza A/2014/H3N2, which was a drifted strain that was not included in the
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current vaccine.(16) We also applied the ISI to stratify HCT recipients according to their risk of severe influenza infection, to compare their probabilities for serious complications such as LRI
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and death.
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Materials and Methods We conducted a retrospective study and included all HCT recipients with laboratory-confirmed influenza infection from July 2009 to December 2013 at The University of Texas MD Anderson
waived the requirement for obtaining informed consent.
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Cancer Center in Houston, Texas. The Institutional Review Board approved the protocol and
We also examined the clinical characteristics and outcomes of patients with 2014/H3N2
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influenza A infections from November 2014 to December 2014 and compared those with the four previous seasons. We collected the following data from medical chart review: demographic
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information including age, sex, race, BMI, and smoking status; cancer type; type of HCT, time from HCT to influenza infection, type of conditioning regimen, use of myeloablative regimen within 100 days before the diagnosis of influenza infection; co-infections; use of immunosuppressive therapy within the month preceding the diagnosis of influenza A infection;
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and detailed information on clinical characteristics, laboratory test results, and radiologic characteristics upon presentation. Data about treatment and the outcomes, such as length of hospital stay, development of LRI, admission to intensive care unit, mechanical ventilation,
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Definitions
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oxygen supplementation, and death, were also recorded.
An influenza case was defined as any HCT recipient who developed acute respiratory illness and had influenza confirmed via viral culture, and/or a direct fluorescent antigen test. The Polymerase Chain Reaction (PCR) assay was only available and used during the 2014/ H3N2 influenza season. Upper respiratory tract infection (URI) was defined as the onset of any of the following symptoms: fever, cough, rhinorrhea, sore throat, earache, or nasal or sinus congestion with a normal or unchanged chest radiograph or chest computed tomography scan at the time of 5
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influenza virus infection confirmed via nasal wash. LRI was defined as the onset of any of the previous symptoms with chest imaging (chest radiograph or chest computed tomography scan) demonstrating new or worsening pulmonary infiltrates suggestive of viral infection at the time of
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influenza virus infection confirmed via any respiratory specimen including nasal wash, sputum, bronchoalveolar washing or lavage, or endotracheal tube aspirate. A nosocomial infection was defined as the onset of respiratory symptoms at least 48 hours after admission. Severe
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neutropenia was defined as an absolute neutrophil count of < 500 cells/ml, and severe
lymphocytopenia was defined as an absolute lymphocyte count of < 200 cells/ml. All-cause
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mortality was defined as death from any cause within 30 days of the diagnosis of influenza infection, and mortality was attributed to influenza if a persistent or progressive influenza infection with respiratory failure was present at the time of death. Antiviral therapy was considered to be early if it was started within 48 hours of diagnosis.
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Immunodeficiency Scoring Index
In a previous study,(15) we developed an ISI in HCT recipients with RSV infection, using
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variables related to the host such as age, low neutrophil and lymphocyte counts, the nature of the conditioning regimen used, time from transplantation, the presence of complications such as
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graft versus host disease (GVHD), and corticosteroid use (supplemental table). This scoring index allowed us to identify a group of allogeneic HCT recipients with RSV infection who were at higher risk for complications and who would benefit the most from aerosolized ribavirin therapy. We applied this ISI to our cohort of HCT recipients with influenza infection to predict their risk for LRI and/or death based on their immunodeficiency risk group. Statistical analyses
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After checking data for accuracy and consistency, we compared the clinical characteristics and outcomes of HCT recipients with influenza infections in the four previous seasons with those who were infected with the 2014/H3N2 strain during the current season using a chi-square test or
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Fisher’s exact test for categorical variables and Student’s t-test or Wilcoxon rank sum test for continuous variables. Using multivariable logistic regression modeling, we identified differences in characteristics between patients who presented with LRI and those who had only URI. We
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applied the previously developed ISI to the current cohort and stratified patients into three different risk groups on the basis of their overall immunodeficiency score (low risk [0-2],
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moderate risk [3-6], and high risk [7-12]). The probability of poor outcomes (LRI and death) between these three immunodeficiency risk groups, stratified by receiving early versus late antiviral therapy, was compared using Kaplan-Meier failure curves. A two-sided P value of 0.05 was considered statistically significant for all analyses using Stata version 13 (Statacorp, College
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Station, TX).
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Results From 2009 to 2014, a total of 146 laboratory-confirmed influenza A infections were diagnosed in HCT recipients at our institution, including 23 patients who had influenza A (H3N2 strain)
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during the 2014-2015 season. The median age was 52 years, and 77 (53%) were males (Table 1). The majority of the patients were non-Hispanic whites (60%) who had an allogeneic HCT (64%) and were in remission (79%). All except 3 patients had community-acquired infection with the
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median time from symptom onset to presentation was 2 days (range: 1-21 days).
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Fever and cough were the most common symptoms for all patients, irrespective of the seasons (Figure 1). Most influenza infections (119 [82%]) were diagnosed at the URI stage, and 6 of these cases (5%) progressed from URI to LRI. A total of 33 (23%) patients developed LRI within 30 days, with a median time from the onset of symptoms to LRI of 4 days (range: 0-30 days), and 7 patients (5%) died within 30 days of influenza diagnosis, including 6 influenza-
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associated deaths. Two of the 6 patients who died with influenza were diagnosed with URI at presentation and progressed to LRI and respiratory failure, and the remaining 4 presented with LRI and respiratory failure later on. Overall, 62 (42%) patients were admitted to the hospital, 12
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(8%) required intensive care unit admission, and 7 (5%) required mechanical ventilation. The
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median length of hospital stay was 7 days (range: 1-74 days). The majority of our patients (83%) received antiviral therapy; however, only 26 patients (18%) started antiviral therapy within 48 hours of symptom onset. When compared to patients with influenza infection beyond day 30 of HCT, 6 (4%) patients developed influenza infection within 30 days of HCT and had higher rates of LRI (50% vs. 21%, P = 0.129) and mortality (17% vs. 4%, P = 0.259), although not statistically significant. In addition, no difference in outcomes was observed for patients who developed influenza infection before or after 100 days of HCT. 8
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Bronchoalveolar lavage (BAL) was performed in 18 out of 33 (55%) patients with LRI and influenza was recovered in 14 (78%) while the remaining 4 BAL samples showed no growth. In addition, 5 out of the 18 patients (28%) with influenza recovered from BAL had other
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respiratory co-pathogens including Klebsiella pneumoniae, Stenotrophomonas maltophilia,
Methicillin Resistant Staphylococcus aureus, Mycobacterium avium, Aspergillus niger, and Curvularia species. Using a multivariable logistic regression modeling, we identified differences
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in characteristics between patients who presented with LRI and patients who presented with URI and never progressed to LRI. Odds ratio and 95% confidence interval are provided as measures
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of strength of association and precision, respectively (Table 2). When compared to the URI group, patients who presented with LRI were more likely to be black (adjusted odds ratio [AOR] 5.87; 95% confidence interval [CI] 1.22-28.34; P=0.027), irrespective of the influenza season (Table 2). They were also more likely to have a longer interval between symptom onset and
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seeking medical care (AOR 1.89; 95% CI 1.3-2.75; P=0.001), to have severe lymphocytopenia (AOR 12.24; 95% CI 2.4-62.3; P=0.003), to have elevated creatinine levels (AOR 5.19; 95% CI 1.29-20.96; P=0.021), and to be hypoxic at diagnosis when compared to the URI group (AOR
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7.09; 95% CI 1.35-37.32; P=0.021). Other factors, including age, sex, donor relationship, HCT cell source, time from transplant to influenza infection, underlying malignancy, cancer status at
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the time of diagnosis, corticosteroid use in the 30 days prior to influenza diagnosis, smoking status, BMI, severe neutropenia, and respiratory coinfections in the 30 days preceding the influenza diagnosis, were not associated with the site of influenza infection at presentation (Table 2). Multivariable modeling was not conducted for death owing to small numbers. We also compared patients’ clinical characteristics and outcomes from the current 2014/H3N2 season with those from the previous seasons. We identified few differences in
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patients’ characteristics, including more males, patients with Hispanic ethnicity, more smokers and a lower median BMI in the 2014/H3N2 group compared to previous seasons. Outcomes were similar between the 2014/H3N2 season and previous seasons, including all-cause mortality
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at day 30 (5% vs. 4%), LRI rates (24% vs. 17%), hospital admission rates (40% vs. 57%), and median length of hospital stay (7 days vs. 5 days). Interestingly, more patients (83%) with
influenza infections during the 2014/H3N2 season started antiviral therapy within 48 hours of
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diagnosis, compared to only 15% during previous seasons (P < 0.001).
Of the 146 HCT recipients with influenza infections, 25 (17%) patients did not receive
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any antiviral therapy; 2 of those cases progressed to LRI, but none of the patients died. None of the 33 patients with LRI had received antiviral therapy within 48 hours of symptom onset of their symptoms, primarily owing to delays in seeking medical care (27 [82%] presented with LRI) and, to a lesser extent, owing to delays in diagnosis and treatment (6 [18%] presented with URI
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and did not receive antiviral therapy at the URI stage).
After risk stratifying patients on the basis of their ISI scores, we observed a significantly higher probability of LRI in HCT recipients in the high-risk category than in the low-risk group
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(45% versus 17%), (P = 0.035) (Table 3). Kaplan-Meier failure curves also showed a significantly higher incidence of LRI in the high-risk group than in the low-risk group (P <0.001)
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(Figure 2). Receiving early antiviral therapy for influenza infection was associated with a substantial risk reduction in LRI for all risk groups; however, the greatest risk reduction was observed in the high-risk group. Despite small numbers, a reduction in the number of deaths was observed for patients receiving early antiviral therapy compared to those receiving it more than 48 hours after symptom onset, especially in the high-risk group of HCT recipients who had the highest difference in mortality (Table 3).
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Discussion Clinically relevant conclusions can be drawn from this cohort of HCT recipients with laboratory-confirmed influenza infection from different influenza seasons. The use of the ISI as a
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prognostic tool helps identify HCT recipients with influenza infections who are at higher risk of progression to LRI and/ or mortality that may need hospital admission and/or closer observation. Regardless, all HCT recipients diagnosed with influenza infection should receive adequate
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antiviral therapy as early as possible and within 48 hours from symptom onset preferably.
Despite some significant differences in clinical characteristics between the 2014/H3N2 influenza
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season and previous seasons (such as sex, race, BMI, and smoking status), the clinical outcomes were the same during all the studied seasons regardless of the circulating strain, probably owing to the good potency and/or the prompt initiation of the neuraminidase inhibitors in this patient population.
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We found that severe lymphocytopenia was significantly associated with LRI presentation in HCT recipients with influenza infection, probably because of faster disease progression. Previous studies have found that one of the most significant risk factors for
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progression to LRI is severe lymphocytopenia.(10, 11, 17) We also observed that elevated creatinine levels were significantly associated with LRI but not less so with URI. Patients with
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kidney disorders are considered to be at high risk for influenza-associated complications.(18) In the current study, another significant factor associated with higher LRI presentation was a delay in seeking medical care after the onset of symptoms. Furthermore, none of the patients in whom URI progressed to LRI had received antiviral therapy within 48 hours (early antiviral therapy) of symptom onset, which adds to the evidence that early diagnosis and treatment may prevent progression to LRI in HCT recipients. Hence, seeking medical care early on during the winter
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season and increased promptness in diagnosing these respiratory viral infections should be reinforced to clinical providers and patients alike. It is imperative to raise awareness among HCT recipients, especially those in the high-risk group, to be proactive in seeking medical attention as
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soon as they develop minimal symptoms such as cough or fever or develop any flu-like illness. In addition, empiric antiviral therapy may be initiated, in high risk patients in particular, while the diagnostic results are pending, as this will reduce the time from onset of symptoms to
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initiation of therapy.
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Overall, we observed lower rates of LRI and complications in our HCT recipients than in cohorts from previous studies. Out of 146 HCT recipients with influenza infection, only 18% of our patients presented to the hospital with LRI, including a few (7%) who were hypoxic upon diagnosis, whereas in other studies, the frequency of LRI attributed to influenza infection in HCT
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recipients ranged from 7% up to 80%.(17, 19, 20) (21) We also observed relatively lower rates of overall 30-day mortality (5%) and influenza-related 30-day mortality (4%) than the rates reported in previous studies in which influenza-associated mortality in HCT patients reached
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9.3% and all-cause mortality was 12.4%.(14)
The clinical variables used in the aforementioned ISI reflect the immune status of the host
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in the HCT population. The vulnerability of the patients as indicated by the ISI would predispose them not only to RSV (15) but also to other respiratory viruses in general, including the influenza virus and its complications. The application of this scoring index to our cohort of HCT recipients with influenza infection aided in identifying patients at high risk for complications after influenza infections and it can be used as a prognostic tool to anticipate the probability of LRI and/or mortality at day 30. The current study also compared the most recent 2014/H3N2
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influenza season with previous influenza seasons, including the pandemic 2009/H1N1 influenza season, in HCT recipients. According to Centers for Disease Control, the predominance of influenza A (H3N2) viruses circulating this season drifted from the component of the available
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vaccine, which resulted in reduced vaccine effectiveness and a high number of patients with documented influenza infection in the community (98,680) and in our institution.(22) In our
cohort, we observed low rates of LRI (17%), progression from URI to LRI (0 cases) and 30-day
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mortality (only one death, and it was attributed to influenza) for the most recent 2014/H3N2 influenza season, which were not significantly different compared to previous seasons. Early
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antiviral therapy was much more aggressively implemented during the recent 2014/H3N2 influenza season than in the previous seasons. The mild course of 2014/H3N2 influenza infection in most of our cases may reflect the fact that the majority of our patients (15% in the group of previous influenza seasons and 83% in the 2014/H3N2 influenza season) received oseltamivir
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treatment as a result of high physician awareness of the possible consequences of this infection in the HCT population. This may suggest that despite the virulent strain circulating this season as indicated by the high rates of influenza-associated hospitalizations among adults 65 years and
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older (258 cases per 100,000 population)(22) and a non-protective vaccine, the outcomes in HCT recipients were not as severe as expected, probably because of the use of early and adequate
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antiviral therapy.
This study had some limitations, such as the retrospective nature of the data collection,
the small sample to assess risk factors for mortality, and the small sample of patients with 2014/H3N2 infections, which precluded multivariable modeling. Other limitations included the use of different methods for diagnosing influenza infection; in the recent season, PCR was used, whereas direct immunofluorescent assays and/or viral cultures on respiratory specimens were
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used in the previous seasons. Furthermore, the ISI was developed in HCT recipients with RSV infections and has not been validated yet; however, it was developed for the same patient population and was successful in risk stratifying these patients with influenza infection.
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In summary, the ISI can successfully stratify HCT recipients into risk groups for
progression to LRI and death. Early initiation of antiviral therapy had a positive impact on this infection and its complications in all HCT recipients. Finally, despite differences in the
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characteristics of patients infected by the H3N2 influenza strain, the outcomes were similar,
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probably owing to quick intervention with antiviral therapy.
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Acknowledgements We thank Ms. Markeda Wade, Department of Scientific Publications at the University of Texas
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MD Anderson Cancer Center, for her editorial support. This study was supported by the NIH/NCI under award number P30CA016672 and used the Cancer Center Support Grant
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resources.
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1. (CDC) CfDCaP. Update: Influenza Activity- United States, 2009-10 season. In., 2010: 901-908. 2. Shrestha SS, Swerdlow DL, Borse RH, Prabhu VS, Finelli L, Atkins CY et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis 2011;52 Suppl 1:S75-82. 3. Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009;361(20):1935-1944. 4. Shah DP, El Taoum KK, Shah JN, Vigil KJ, Adachi JA, Granwehr BP et al. Characteristics and outcomes of pandemic 2009/H1N1 versus seasonal influenza in children with cancer. Pediatr Infect Dis J 2012;31(4):373-378. 5. Chemaly RF, Vigil KJ, Saad M, Vilar-Compte D, Cornejo-Juarez P, Perez-Jimenez C et al. A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes. Cancer 2012;118(18):4627-4633. 6. Minnema BJ, Husain S, Mazzulli T, Hosseini-Mogaddam SM, Patel M, Brandwein J et al. Clinical characteristics and outcome associated with pandemic (2009) H1N1 influenza infection in patients with hematologic malignancies: a retrospective cohort study. Leuk Lymphoma 2013;54(6):1250-1255. 7. Matias G, Taylor R, Haguinet F, Schuck-Paim C, Lustig R, Shinde V. Estimates of mortality attributable to influenza and RSV in the United States during 1997-2009 by influenza type or subtype, age, cause of death, and risk status. Influenza Other Respir Viruses 2014;8(5):507-515. 8. Martino R, Porras RP, Rabella N, Williams JV, Rámila E, Margall N et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005;11(10):781-796. 9. Ljungman P, Ward KN, Crooks BN, Parker A, Martino R, Shaw PJ et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2001;28(5):479-484. 10. 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(9):1300-1306. 11. Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ 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(5):278-287. 12. Protheroe RE, Kirkland KE, Pearce RM, Kaminaris K, Bloor A, Potter MN et al. The clinical features and outcome of 2009 H1N1 influenza infection in allo-SCT patients: a British Society of Blood and Marrow Transplantation study. Bone Marrow Transplant 2012;47(1):88-94. 13. Ljungman P, de la Camara R, Perez-Bercoff L, Abecasis M, Nieto Campuzano JB, Cannata-Ortiz MJ et al. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients. Haematologica 2011;96(8):1231-1235. 14. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood 2011;117(19):5050-5056. 15. Shah DP, Ghantoji SS, Ariza-Heredia EJ, Shah JN, El Taoum KK, Shah PK et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood 2014;123(21):3263-3268. 16. Prevention CfDCa. CDC: Flu Activity Expands; Severity Similar to Past H3N2 Seasons. 2015 [cited 2015 january 5 2015]; Available from: http://www.cdc.gov/flu/news/flu-activity-expands.htm
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Table 1. Clinical Characteristics and Outcomes of Influenza Infections in 146 HCT Recipients (N [%]). Total Characteristic N=146 (range, %) 52 (14 -80)
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Age, y Median (range) Sex
77 (53)
Female
69 (47)
Race
Black
17 (12)
Hispanic
34 (23)
Other
Donor relationship
8 (5)
50 (34)
Matched Unrelated
34 (23)
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Matched Related
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HCT cell source
87 (60)
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Non-Hispanic white
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Male
Mismatched
10 (7)
Autologous
52 (36)
Peripheral Marrow Cord
111 (76) 29 (20) 2 (1)
Time from HCT to infection Median [range]
398 (2–7140)
Acute GVHD
11 (8)
Chronic GVHD
27 (18) 19
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Underlying malignancy 69 (47)
Lymphoma
29 (20)
Other
48 (33)
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Leukemia
Cancer status at the time of infection
Active/Relapse Myeloablative conditioning regimen (past 100 days)
31 (21)
17 (12)
46 (32)
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Corticosteroids within 30 days of diagnosis
115 (79)
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Remission
Smoking history
103 (71)
Former
32 (22)
Current
11 (8)
27 (15–63)
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BMI, kg/m2 Median (range)
Never
BMI categories (WHO classification)
5 (3)
Normal: 18.5–24.99
39 (27)
Overweight: 25–29.99
51 (35)
Obese: ≥30
50 (34)
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Underweight: <18.5
Time from symptoms onset to presentation Median (range), d
2 (0–21)
URI
119 (82)
Infection site at diagnosis
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LRI
27 (18)
Leukocytosis (WBC >11,000/mm)
8 (5)
Neutropenia (ANC <500 cells/mL)
10 (7)
Lymphocytopenia (ALC <200 cells/mL)
11 (8)
23 (16)
Decreased albumin (<3.5 g/dL)
37 (25)
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Elevated creatinine (>1.3 mg/dL)
Hypoxia at diagnosis
10 (7)
22 (15)
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Co-infections (within 1 month of diagnosis) Respiratory co-pathogens Outcomes Progression from URI to LRI
16 (11)
6/119 (5) 33 (23)
Admission to the hospital Length of stay
62 (42)
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Overall LRI
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Median (range), d
ICU admission
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Laboratory abnormalities at presentation:
7 (1 – 74)
On admission
3 (2)
Later
9 (6)
Mechanical ventilation
7 (5)
Oxygen supplement
22 (15)
Antiviral therapy Anytime during the episode Within 48 hours of symptoms onset
121 (83) 26 (18)
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Within 48 hours of diagnosis
38 (26)
All-cause mortality
7 (5)
Influenza-related death
6 (4)
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Death within 30 days from date of diagnosis
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Abbreviations: d, days; HCT, hematopoietic cell transplant; BMI, body mass index; WHO, World Health Organization; y, years.; LRI, lower respiratory tract infection; URI, upper respiratory tract infection; GVHD, graft versus host disease; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; ICU, intensive care unit.
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Table 2. Differences in Characteristics Between Patients Presenting with LRI and Patients
LRI at Resolved at URI diagnosis n (%) n (%)
Risk factors Number of patients
Unadjusted Odds Ratio (95% CI) -
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Presenting with URI.
P value
Adjusted Odds Ratio (95% CI)
P value
-
-
-
0.52
-
-
0.23
-
-
113
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≤ 40 years
32 (84)
6 (16)
>40 years
81 (79)
21 (21)
Female
52 (85)
9 (15)
1.00
Male
61 (77)
18 (23)
1.7 (0.71–4.12)
Non-Hispanic white
67 (80)
17 (20)
1.00
Black
10 (67)
5 (33)
1.97 (0.59–6.53)
0.26
5.87 (1.22–28.34)
0.027
Hispanic
31 (94)
2 (6)
0.25 (0.06–1.17)
0.07
0.31 (0.04–2.36)
0.26
Other
5 (63)
3 (38) 2.36 (0.51–10.89)
0.26
3.38 (0.52–21.98)
0.203
-
-
-
-
1.38 (0.51–3.74)
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Race
43 (91)
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Matched Related
1.00
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Sex
Donor relationship
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Age
4 (9)
1.00
1.00
Matched Unrelated
23 (70)
10 (30) 4.67 (1.32–16.56)
0.017
Mismatched
6 (60)
4 (40) 7.17 (1.41–36.5)
0.018
Autologous
41 (82)
9 (18)
2.36 (0.67–8.26)
0.179
1.00
0.644
1.28 (0.45–3.58)
-
HCT cell source Peripheral Marrow
88 (83) 23 (79)
18 (17)
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Cord
0
6 (21)
-
Time from HCT to infection
399 (2– 7140)
345 (7– 4825)
1.00 (0.99–1.00)
GVHD at the time of infection None
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2 (100)
0.882
-
-
-
-
19 (18)
26 (76)
8 (24)
Leukemia
53 (80)
13 (20)
1.00
Lymphoma
20 (71)
8 (29)
1.63 (0.59–4.52)
0.347
Other
40 (87)
6 (13)
0.61 (0.21–1.75)
0.359
-
-
0.208
-
-
0.674
-
-
-
-
Active/Relapse
92 (83)
19 (17)
1.00
21 (72)
8 (28)
1.84 (0.71–4.78)
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Corticosteroids in past 30 days
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Remission
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Cancer status at the time of infection
1.41 (0.55–3.59)
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Underlying malignancy:
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87 (82)
Yes
0.472
No
80 (82)
18 (18)
1.00
Yes
33 (79)
9 (21)
1.21 (0.49–2.97)
81 (84)
16 (16)
1.00
Never
24 (75)
8 (25)
1.69 (0.64–4.42)
0.287
Former
8 (73)
3 (27)
1.9 (0.45–7.94)
0.38
Smoking status
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Current BMI, kg/m2
1.00
Underweight: <18.5
4 (80)
Normal: 18.5–24.99
29 (76)
1.24 (0.12 – 9 (24) 12.57)
Overweight: 25–29.99
40 (80)
10 (20) 1 (0.1 – 9.96)
Obese: ≥30
39 (85)
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0.855
1.00
7 (15)
0.72 (0.07- 7.41)
2 (0 – 7) 3 (1 – 21)
1.54 (1.19–1.99)
0.781
-
-
0.001
1.89 (1.3–2.75)
0.001
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Time from symptoms to presentation
1 (20)
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Laboratory abnormalities 5 (71)
2 (29) 1.66 (0.3–9.08)
0.55
-
-
Neutropenia
5 (50)
5 (50) 4.73 (1.26–17.73)
0.02
-
-
Lymphocytopenia
6 (55)
5 (45)
3.9 (1.09–13.93)
0.03
Elevated creatinine
12 (60)
8 (40)
3.37 (1.21– 9.35)
0.02
Decreased albumin
21 (62)
13 (38)
4.5 (1.77 – 11.48)
0.002
No
109 (83)
22 (17)
1.00
Yes
4 (44)
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Antiviral therapy within 48 h of symptom onset
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Hypoxia at diagnosis
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Leukocytosis
5 (56) 6.19 (1.54–24.92)
No
87 (76)
27 (24)
Yes
26 (100)
0
No
106 (83)
21 (17) 1.00
-
12.24 (2.4–62.3)
0.003
5.19 (1.29–20.96)
0.021
-
-
1.00 0.01
7.09 (1.35–37.32)
0.021
-
-
-
Respiratory coinfections 1.00
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Yes
7 (54)
6 (46) 4.33 (1.32–14.17)
Past seasons
94 (80)
23 (20)
1.00
2014/H3N2 season
19 (83)
4 (17)
0.86 (0.27–2.77)
0.016
3.4 (0.72–16.09)
0.123
0.801
-
-
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Influenza seasons:
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Abbreviations: d, days; HCT, hematopoietic cell transplant; BMI, body mass index; WHO, World Health Organization; y, years.; LRI, lower respiratory tract infection; URI, upper respiratory tract infection; GVHD, graft versus host disease; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; ICU, intensive care unit
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Table 3. Incidence of LRI and influenza-associated death stratified by ISI risk groups and antiviral therapy (N=142) Total
Antiviral Therapy
Risk groups as defined by the ISI
N
LRI
Influenza -related Death
78
13 (17)
2 (3)
13
0
48
13 (27)
2 (4)
53
15 (28)
2 (4)
9
0
38
13 (34)
2 (5)
11
5 (45)
2 (18)
3
0
7
5 (71)
2 (29)
n
LRI/Death
n
LRI
Death
Moderate-risk (ISI of 3 to 6) High-risk
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(ISI of 7 to 12)
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Low-risk (ISI of 0 to 2)
(after 48 hours of symptom onset)
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(within 48 hours of symptom onset)
Late
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Early
Note: Data required for generating ISI were missing in 4 patients.
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Abbreviations: LRI, lower respiratory tract infection; ISI immunodeficiency scoring index
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Figure legends:
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Figure 1. Symptom Profile for Patients with Influenza Infection. Figure 2. Kaplan-Meier Failure Curves for LRI incidence, stratified by ISI risk groups and early
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antiviral therapy.
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2014 season
EP
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Previous season
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100 90 80 70 60 50 40 30 20 10 0
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Fig 1. Symptom Profile for Patients with Influenza Infections
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LRI incidence, stratified by ISI risk groups and antiviral therapy
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LRI incidence (%) 25 50 75 0
P < 0.001
0
15
30
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100
Figure 2. Kaplan-Meier Failure Curves for LRI incidence, stratified by ISI risk groups and early antiviral therapy.
45
60
75
90
Time from onset of symptoms to LRI Low risk / early antiviral therapy
Moderate risk / early antiviral therapy
Moderate risk / late antiviral therapy High risk / late antiviral therapy
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High risk / early antiviral therapy
Low risk / late antiviral therapy
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Supplemental Table. Development of the ISI-RSV for patients presenting with RSV infections (N = 237). No. (%)
ANC <500/µL
11 (5)
7 (64)
2
ALC <200/µL
35 (15)
11 (31)
3
Age ≥40 years Myeloablative conditioning regimen GVHD (acute or chronic)
154 (65)
28 (18)
98 (41)
17 (17)
149 (63)
19 (13)
117 (49)
17 (15)
21 (9)
5 (24)
7
Corticosteroids† Recent† or preengraftment allo-HSCT
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6
>2.5
3
>2.5
3
2.0-2.5
2
<2.0
1
<2.0
1
<2.0
1
<2.0
1
Maximum possible overall score‡
12
Low risk: 0-2 score, moderate risk 3-6 score, high risk 7-12 score ISI-RSV indicates immunodeficiency scoring index for RSV; AHR adjusted hazard ratio; LRTI, lower respiratory tract infection; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; CI, confidence interval; and GVHD, graft-versus-host disease. *Adjusted for year of RSV diagnosis and ribavirin-based therapy at the URTI stage to identify the independent effect of each immunodeficiency indicator on progression to LRTI. † Within the prior 30 days. ‡ The overall score equals the sum of the scores for the immunodeficiency indicators present at the time of diagnosis of RSV infection. For example, for a patient with an ANC less than 500/µL (ISI-RSV score, 3) and acute graft-versus-host disease (ISI-RSV score, 1), the total ISI-RSV score would be 4, and the patient would be stratified into the moderaterisk group.
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AHR* (95% CI) 4.1 (1.4-11.6) 2.6 (1.02-6.4) 2.5 (1.1-5.6) 1.2 (0.6-2.3) 1.0 (0.5-2.2) 0.89 (0.4-1.8) 0.68 (0.2-2.3)
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4
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1
Weighi ng criteri a
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Patients 237 (N, %)
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Criteri a
Progression to LRTI 37 (n, %)
Assig ned weig hts (scor e)
This research was originally published in Blood Online. Shah DP, Ghantoji SS, Ariza-Heredia EJ, et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood. 2014;123(21):3263-3268.
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Early antiviral therapy reduces influenza-associated complications.
•
ISI is a prognostic tool to identify patients at higher risk of progression to LRI.
•
2014 influenza had similar outcomes in HCT recipient compared to previous seasons.
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•
S1083-8791(15)00742-9
DOI:
10.1016/j.bbmt.2015.11.015
Reference:
YBBMT 54047
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 12 October 2015 Accepted Date: 20 November 2015
Please cite this article as: Kmeid J, Vanichanan J, Shah DP, El Chaer F, Azzi J, Ariza Heredia E, Hosing C, Mulanovich V, Chemaly RF, Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.11.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index Joumana Kmeid1, MD, Jakapat Vanichanan1, MD, Dimpy P. Shah1, MD, MSPH, PhD, Firas El
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Chaer1, MD, Jacques Azzi1, MD, Ella Ariza Heredia1, MD, Chitra Hosing2, MD, Victor Mulanovich1, MD, Roy F. Chemaly1, MD, MPH
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Departments of 1Infectious Diseases, Infection Control, & Employee Health, and 2 Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center,
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Houston, TX
Corresponding author: Roy F. Chemaly, MD, MPH, Department of Infectious Diseases, Infection Control, and Employee Health, Unit 402, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA, 77030-4009; telephone: 713-
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745-1116; fax: 713-745-6839; e-mail: [email protected].
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Running title: Influenza in HCT recipients
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Financial Disclosures:
R.F.C. received research grants from GlaxoSmithKline. The remaining authors declare no competing financial interests.
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Abstract Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza
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vaccination and are susceptible to lower respiratory tract infection (LRI) and death. We determined clinical characteristics and outcomes of laboratory-confirmed influenza, including 2014/H3N2 infection, in 146 HCT recipients. An immunodeficiency scoring index (ISI) was applied to identify patients at high risk for LRI and death. Thirty three patients developed LRI
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(23%), and 7 died within 30 days of diagnosis (5%). Most patients received antiviral therapy (83%); however, only 18% received it within 48 hours of symptom onset. The incidence of LRI
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was significantly higher in the ISI high-risk group than in the low-risk group (P < 0.001). Receiving early antiviral therapy was associated with a substantial reduction in LRI for all ISI risk groups with the greatest risk reduction observed in the high-risk group. When compared to previous seasons, no significant differences in patient outcomes were observed during the
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2014/H3N2 season; however, antiviral therapy was more promptly initiated in the latter season. The ISI that was originally developed for respiratory syncytial virus may help identifying HCT recipients at risk for progression to LRI and mortality following influenza infection. These
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patients should be monitored more closely. Early initiation of antiviral therapy for influenza in
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HCT recipients, irrespective of the ISI risk group, may improve morbidity as well as mortality.
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Introduction The severity of influenza infection in the general population depends on vaccination uptake and the main circulating virus, among other factors. Some seasons, such as the 2009/H1N1 pandemic
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season, have had higher rates of hospitalizations (274,000 hospitalizations in the United States alone); however, the disease severity in that season was not significantly different from that in previous seasons.(1, 2) The severity of influenza infection also depends on the host immune
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status and its underlying risk factors. Multiple studies have shown that susceptible populations such as children, the elderly, pregnant women, solid organ transplant recipients, and
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hematopoietic cell transplant (HCT) recipients have a higher risk of developing severe disease and higher rates of complications such as hospitalizations, prolonged viral shedding, emergence of viral resistance, and mortality compared to the general population.(3-7)
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Influenza infection in HCT recipients has been increasingly recognized as a serious infection with severe implications.(8-10) In fact, it is one of the most common respiratory viral infections (influenza accounts for 30% of all respiratory viral infections) and it causes increased morbidity
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and mortality in this population. Up to 35% of these patients progress to lower respiratory tract infection (LRI) with subsequent high mortality.(10, 11) Previous studies have revealed various
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risk factors for influenza-associated LRI in HCT recipients, such as lymphocytopenia, nosocomial acquisition of the virus, older age, and preexisting lung disease.(12-14) Using these clinically available risk factors, an immunodeficiency scoring index (ISI) was developed in HCT recipients with respiratory syncytial virus (RSV) infections to help identify patients at higher risk for complications and those who would benefit the most from antiviral therapy.(15) As this
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scoring index was not based on virus-specific factors, it may be extrapolated to other respiratory viruses, such as influenza, in HCT recipients.
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In this study, we aimed to compare the clinical characteristics and outcomes of influenza
infection, including the pandemic 2009/H1N1, strains from the subsequent seasons, and the current 2014/H3N2 influenza strain in HCT recipients, especially in view of the reported
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decreased efficacy of the 2014-2015 influenza vaccine (the main circulating virus during the past season was influenza A/2014/H3N2, which was a drifted strain that was not included in the
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current vaccine.(16) We also applied the ISI to stratify HCT recipients according to their risk of severe influenza infection, to compare their probabilities for serious complications such as LRI
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and death.
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Materials and Methods We conducted a retrospective study and included all HCT recipients with laboratory-confirmed influenza infection from July 2009 to December 2013 at The University of Texas MD Anderson
waived the requirement for obtaining informed consent.
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Cancer Center in Houston, Texas. The Institutional Review Board approved the protocol and
We also examined the clinical characteristics and outcomes of patients with 2014/H3N2
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influenza A infections from November 2014 to December 2014 and compared those with the four previous seasons. We collected the following data from medical chart review: demographic
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information including age, sex, race, BMI, and smoking status; cancer type; type of HCT, time from HCT to influenza infection, type of conditioning regimen, use of myeloablative regimen within 100 days before the diagnosis of influenza infection; co-infections; use of immunosuppressive therapy within the month preceding the diagnosis of influenza A infection;
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and detailed information on clinical characteristics, laboratory test results, and radiologic characteristics upon presentation. Data about treatment and the outcomes, such as length of hospital stay, development of LRI, admission to intensive care unit, mechanical ventilation,
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Definitions
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oxygen supplementation, and death, were also recorded.
An influenza case was defined as any HCT recipient who developed acute respiratory illness and had influenza confirmed via viral culture, and/or a direct fluorescent antigen test. The Polymerase Chain Reaction (PCR) assay was only available and used during the 2014/ H3N2 influenza season. Upper respiratory tract infection (URI) was defined as the onset of any of the following symptoms: fever, cough, rhinorrhea, sore throat, earache, or nasal or sinus congestion with a normal or unchanged chest radiograph or chest computed tomography scan at the time of 5
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influenza virus infection confirmed via nasal wash. LRI was defined as the onset of any of the previous symptoms with chest imaging (chest radiograph or chest computed tomography scan) demonstrating new or worsening pulmonary infiltrates suggestive of viral infection at the time of
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influenza virus infection confirmed via any respiratory specimen including nasal wash, sputum, bronchoalveolar washing or lavage, or endotracheal tube aspirate. A nosocomial infection was defined as the onset of respiratory symptoms at least 48 hours after admission. Severe
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neutropenia was defined as an absolute neutrophil count of < 500 cells/ml, and severe
lymphocytopenia was defined as an absolute lymphocyte count of < 200 cells/ml. All-cause
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mortality was defined as death from any cause within 30 days of the diagnosis of influenza infection, and mortality was attributed to influenza if a persistent or progressive influenza infection with respiratory failure was present at the time of death. Antiviral therapy was considered to be early if it was started within 48 hours of diagnosis.
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Immunodeficiency Scoring Index
In a previous study,(15) we developed an ISI in HCT recipients with RSV infection, using
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variables related to the host such as age, low neutrophil and lymphocyte counts, the nature of the conditioning regimen used, time from transplantation, the presence of complications such as
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graft versus host disease (GVHD), and corticosteroid use (supplemental table). This scoring index allowed us to identify a group of allogeneic HCT recipients with RSV infection who were at higher risk for complications and who would benefit the most from aerosolized ribavirin therapy. We applied this ISI to our cohort of HCT recipients with influenza infection to predict their risk for LRI and/or death based on their immunodeficiency risk group. Statistical analyses
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After checking data for accuracy and consistency, we compared the clinical characteristics and outcomes of HCT recipients with influenza infections in the four previous seasons with those who were infected with the 2014/H3N2 strain during the current season using a chi-square test or
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Fisher’s exact test for categorical variables and Student’s t-test or Wilcoxon rank sum test for continuous variables. Using multivariable logistic regression modeling, we identified differences in characteristics between patients who presented with LRI and those who had only URI. We
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applied the previously developed ISI to the current cohort and stratified patients into three different risk groups on the basis of their overall immunodeficiency score (low risk [0-2],
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moderate risk [3-6], and high risk [7-12]). The probability of poor outcomes (LRI and death) between these three immunodeficiency risk groups, stratified by receiving early versus late antiviral therapy, was compared using Kaplan-Meier failure curves. A two-sided P value of 0.05 was considered statistically significant for all analyses using Stata version 13 (Statacorp, College
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Station, TX).
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Results From 2009 to 2014, a total of 146 laboratory-confirmed influenza A infections were diagnosed in HCT recipients at our institution, including 23 patients who had influenza A (H3N2 strain)
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during the 2014-2015 season. The median age was 52 years, and 77 (53%) were males (Table 1). The majority of the patients were non-Hispanic whites (60%) who had an allogeneic HCT (64%) and were in remission (79%). All except 3 patients had community-acquired infection with the
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median time from symptom onset to presentation was 2 days (range: 1-21 days).
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Fever and cough were the most common symptoms for all patients, irrespective of the seasons (Figure 1). Most influenza infections (119 [82%]) were diagnosed at the URI stage, and 6 of these cases (5%) progressed from URI to LRI. A total of 33 (23%) patients developed LRI within 30 days, with a median time from the onset of symptoms to LRI of 4 days (range: 0-30 days), and 7 patients (5%) died within 30 days of influenza diagnosis, including 6 influenza-
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associated deaths. Two of the 6 patients who died with influenza were diagnosed with URI at presentation and progressed to LRI and respiratory failure, and the remaining 4 presented with LRI and respiratory failure later on. Overall, 62 (42%) patients were admitted to the hospital, 12
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(8%) required intensive care unit admission, and 7 (5%) required mechanical ventilation. The
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median length of hospital stay was 7 days (range: 1-74 days). The majority of our patients (83%) received antiviral therapy; however, only 26 patients (18%) started antiviral therapy within 48 hours of symptom onset. When compared to patients with influenza infection beyond day 30 of HCT, 6 (4%) patients developed influenza infection within 30 days of HCT and had higher rates of LRI (50% vs. 21%, P = 0.129) and mortality (17% vs. 4%, P = 0.259), although not statistically significant. In addition, no difference in outcomes was observed for patients who developed influenza infection before or after 100 days of HCT. 8
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Bronchoalveolar lavage (BAL) was performed in 18 out of 33 (55%) patients with LRI and influenza was recovered in 14 (78%) while the remaining 4 BAL samples showed no growth. In addition, 5 out of the 18 patients (28%) with influenza recovered from BAL had other
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respiratory co-pathogens including Klebsiella pneumoniae, Stenotrophomonas maltophilia,
Methicillin Resistant Staphylococcus aureus, Mycobacterium avium, Aspergillus niger, and Curvularia species. Using a multivariable logistic regression modeling, we identified differences
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in characteristics between patients who presented with LRI and patients who presented with URI and never progressed to LRI. Odds ratio and 95% confidence interval are provided as measures
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of strength of association and precision, respectively (Table 2). When compared to the URI group, patients who presented with LRI were more likely to be black (adjusted odds ratio [AOR] 5.87; 95% confidence interval [CI] 1.22-28.34; P=0.027), irrespective of the influenza season (Table 2). They were also more likely to have a longer interval between symptom onset and
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seeking medical care (AOR 1.89; 95% CI 1.3-2.75; P=0.001), to have severe lymphocytopenia (AOR 12.24; 95% CI 2.4-62.3; P=0.003), to have elevated creatinine levels (AOR 5.19; 95% CI 1.29-20.96; P=0.021), and to be hypoxic at diagnosis when compared to the URI group (AOR
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7.09; 95% CI 1.35-37.32; P=0.021). Other factors, including age, sex, donor relationship, HCT cell source, time from transplant to influenza infection, underlying malignancy, cancer status at
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the time of diagnosis, corticosteroid use in the 30 days prior to influenza diagnosis, smoking status, BMI, severe neutropenia, and respiratory coinfections in the 30 days preceding the influenza diagnosis, were not associated with the site of influenza infection at presentation (Table 2). Multivariable modeling was not conducted for death owing to small numbers. We also compared patients’ clinical characteristics and outcomes from the current 2014/H3N2 season with those from the previous seasons. We identified few differences in
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patients’ characteristics, including more males, patients with Hispanic ethnicity, more smokers and a lower median BMI in the 2014/H3N2 group compared to previous seasons. Outcomes were similar between the 2014/H3N2 season and previous seasons, including all-cause mortality
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at day 30 (5% vs. 4%), LRI rates (24% vs. 17%), hospital admission rates (40% vs. 57%), and median length of hospital stay (7 days vs. 5 days). Interestingly, more patients (83%) with
influenza infections during the 2014/H3N2 season started antiviral therapy within 48 hours of
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diagnosis, compared to only 15% during previous seasons (P < 0.001).
Of the 146 HCT recipients with influenza infections, 25 (17%) patients did not receive
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any antiviral therapy; 2 of those cases progressed to LRI, but none of the patients died. None of the 33 patients with LRI had received antiviral therapy within 48 hours of symptom onset of their symptoms, primarily owing to delays in seeking medical care (27 [82%] presented with LRI) and, to a lesser extent, owing to delays in diagnosis and treatment (6 [18%] presented with URI
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and did not receive antiviral therapy at the URI stage).
After risk stratifying patients on the basis of their ISI scores, we observed a significantly higher probability of LRI in HCT recipients in the high-risk category than in the low-risk group
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(45% versus 17%), (P = 0.035) (Table 3). Kaplan-Meier failure curves also showed a significantly higher incidence of LRI in the high-risk group than in the low-risk group (P <0.001)
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(Figure 2). Receiving early antiviral therapy for influenza infection was associated with a substantial risk reduction in LRI for all risk groups; however, the greatest risk reduction was observed in the high-risk group. Despite small numbers, a reduction in the number of deaths was observed for patients receiving early antiviral therapy compared to those receiving it more than 48 hours after symptom onset, especially in the high-risk group of HCT recipients who had the highest difference in mortality (Table 3).
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Discussion Clinically relevant conclusions can be drawn from this cohort of HCT recipients with laboratory-confirmed influenza infection from different influenza seasons. The use of the ISI as a
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prognostic tool helps identify HCT recipients with influenza infections who are at higher risk of progression to LRI and/ or mortality that may need hospital admission and/or closer observation. Regardless, all HCT recipients diagnosed with influenza infection should receive adequate
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antiviral therapy as early as possible and within 48 hours from symptom onset preferably.
Despite some significant differences in clinical characteristics between the 2014/H3N2 influenza
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season and previous seasons (such as sex, race, BMI, and smoking status), the clinical outcomes were the same during all the studied seasons regardless of the circulating strain, probably owing to the good potency and/or the prompt initiation of the neuraminidase inhibitors in this patient population.
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We found that severe lymphocytopenia was significantly associated with LRI presentation in HCT recipients with influenza infection, probably because of faster disease progression. Previous studies have found that one of the most significant risk factors for
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progression to LRI is severe lymphocytopenia.(10, 11, 17) We also observed that elevated creatinine levels were significantly associated with LRI but not less so with URI. Patients with
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kidney disorders are considered to be at high risk for influenza-associated complications.(18) In the current study, another significant factor associated with higher LRI presentation was a delay in seeking medical care after the onset of symptoms. Furthermore, none of the patients in whom URI progressed to LRI had received antiviral therapy within 48 hours (early antiviral therapy) of symptom onset, which adds to the evidence that early diagnosis and treatment may prevent progression to LRI in HCT recipients. Hence, seeking medical care early on during the winter
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season and increased promptness in diagnosing these respiratory viral infections should be reinforced to clinical providers and patients alike. It is imperative to raise awareness among HCT recipients, especially those in the high-risk group, to be proactive in seeking medical attention as
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soon as they develop minimal symptoms such as cough or fever or develop any flu-like illness. In addition, empiric antiviral therapy may be initiated, in high risk patients in particular, while the diagnostic results are pending, as this will reduce the time from onset of symptoms to
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initiation of therapy.
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Overall, we observed lower rates of LRI and complications in our HCT recipients than in cohorts from previous studies. Out of 146 HCT recipients with influenza infection, only 18% of our patients presented to the hospital with LRI, including a few (7%) who were hypoxic upon diagnosis, whereas in other studies, the frequency of LRI attributed to influenza infection in HCT
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recipients ranged from 7% up to 80%.(17, 19, 20) (21) We also observed relatively lower rates of overall 30-day mortality (5%) and influenza-related 30-day mortality (4%) than the rates reported in previous studies in which influenza-associated mortality in HCT patients reached
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9.3% and all-cause mortality was 12.4%.(14)
The clinical variables used in the aforementioned ISI reflect the immune status of the host
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in the HCT population. The vulnerability of the patients as indicated by the ISI would predispose them not only to RSV (15) but also to other respiratory viruses in general, including the influenza virus and its complications. The application of this scoring index to our cohort of HCT recipients with influenza infection aided in identifying patients at high risk for complications after influenza infections and it can be used as a prognostic tool to anticipate the probability of LRI and/or mortality at day 30. The current study also compared the most recent 2014/H3N2
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influenza season with previous influenza seasons, including the pandemic 2009/H1N1 influenza season, in HCT recipients. According to Centers for Disease Control, the predominance of influenza A (H3N2) viruses circulating this season drifted from the component of the available
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vaccine, which resulted in reduced vaccine effectiveness and a high number of patients with documented influenza infection in the community (98,680) and in our institution.(22) In our
cohort, we observed low rates of LRI (17%), progression from URI to LRI (0 cases) and 30-day
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mortality (only one death, and it was attributed to influenza) for the most recent 2014/H3N2 influenza season, which were not significantly different compared to previous seasons. Early
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antiviral therapy was much more aggressively implemented during the recent 2014/H3N2 influenza season than in the previous seasons. The mild course of 2014/H3N2 influenza infection in most of our cases may reflect the fact that the majority of our patients (15% in the group of previous influenza seasons and 83% in the 2014/H3N2 influenza season) received oseltamivir
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treatment as a result of high physician awareness of the possible consequences of this infection in the HCT population. This may suggest that despite the virulent strain circulating this season as indicated by the high rates of influenza-associated hospitalizations among adults 65 years and
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older (258 cases per 100,000 population)(22) and a non-protective vaccine, the outcomes in HCT recipients were not as severe as expected, probably because of the use of early and adequate
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antiviral therapy.
This study had some limitations, such as the retrospective nature of the data collection,
the small sample to assess risk factors for mortality, and the small sample of patients with 2014/H3N2 infections, which precluded multivariable modeling. Other limitations included the use of different methods for diagnosing influenza infection; in the recent season, PCR was used, whereas direct immunofluorescent assays and/or viral cultures on respiratory specimens were
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used in the previous seasons. Furthermore, the ISI was developed in HCT recipients with RSV infections and has not been validated yet; however, it was developed for the same patient population and was successful in risk stratifying these patients with influenza infection.
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In summary, the ISI can successfully stratify HCT recipients into risk groups for
progression to LRI and death. Early initiation of antiviral therapy had a positive impact on this infection and its complications in all HCT recipients. Finally, despite differences in the
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characteristics of patients infected by the H3N2 influenza strain, the outcomes were similar,
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probably owing to quick intervention with antiviral therapy.
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Acknowledgements We thank Ms. Markeda Wade, Department of Scientific Publications at the University of Texas
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MD Anderson Cancer Center, for her editorial support. This study was supported by the NIH/NCI under award number P30CA016672 and used the Cancer Center Support Grant
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resources.
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References
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1. (CDC) CfDCaP. Update: Influenza Activity- United States, 2009-10 season. In., 2010: 901-908. 2. Shrestha SS, Swerdlow DL, Borse RH, Prabhu VS, Finelli L, Atkins CY et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis 2011;52 Suppl 1:S75-82. 3. Jain S, Kamimoto L, Bramley AM, Schmitz AM, Benoit SR, Louie J et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009;361(20):1935-1944. 4. Shah DP, El Taoum KK, Shah JN, Vigil KJ, Adachi JA, Granwehr BP et al. Characteristics and outcomes of pandemic 2009/H1N1 versus seasonal influenza in children with cancer. Pediatr Infect Dis J 2012;31(4):373-378. 5. Chemaly RF, Vigil KJ, Saad M, Vilar-Compte D, Cornejo-Juarez P, Perez-Jimenez C et al. A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: early therapy improves outcomes. Cancer 2012;118(18):4627-4633. 6. Minnema BJ, Husain S, Mazzulli T, Hosseini-Mogaddam SM, Patel M, Brandwein J et al. Clinical characteristics and outcome associated with pandemic (2009) H1N1 influenza infection in patients with hematologic malignancies: a retrospective cohort study. Leuk Lymphoma 2013;54(6):1250-1255. 7. Matias G, Taylor R, Haguinet F, Schuck-Paim C, Lustig R, Shinde V. Estimates of mortality attributable to influenza and RSV in the United States during 1997-2009 by influenza type or subtype, age, cause of death, and risk status. Influenza Other Respir Viruses 2014;8(5):507-515. 8. Martino R, Porras RP, Rabella N, Williams JV, Rámila E, Margall N et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005;11(10):781-796. 9. Ljungman P, Ward KN, Crooks BN, Parker A, Martino R, Shaw PJ et al. Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2001;28(5):479-484. 10. 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(9):1300-1306. 11. Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ 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(5):278-287. 12. Protheroe RE, Kirkland KE, Pearce RM, Kaminaris K, Bloor A, Potter MN et al. The clinical features and outcome of 2009 H1N1 influenza infection in allo-SCT patients: a British Society of Blood and Marrow Transplantation study. Bone Marrow Transplant 2012;47(1):88-94. 13. Ljungman P, de la Camara R, Perez-Bercoff L, Abecasis M, Nieto Campuzano JB, Cannata-Ortiz MJ et al. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients. Haematologica 2011;96(8):1231-1235. 14. Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M. Differences in clinical outcomes after 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood 2011;117(19):5050-5056. 15. Shah DP, Ghantoji SS, Ariza-Heredia EJ, Shah JN, El Taoum KK, Shah PK et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood 2014;123(21):3263-3268. 16. Prevention CfDCa. CDC: Flu Activity Expands; Severity Similar to Past H3N2 Seasons. 2015 [cited 2015 january 5 2015]; Available from: http://www.cdc.gov/flu/news/flu-activity-expands.htm
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17. Ljungman P. Respiratory virus infections in stem cell transplant patients: the European experience. Biol Blood Marrow Transplant 2001;7 Suppl:5S-7S. 18. Prevention CfDCa. People at high risk of developing Flu-related complications. 2015 [cited 2015 May 12]; Available from: http://www.cdc.gov/flu/about/disease/high_risk.htm 19. Hassan IA, Chopra R, Swindell R, Mutton KJ. Respiratory viral infections after bone marrow/peripheral stem-cell transplantation: the Christie hospital experience. Bone Marrow Transplant 2003;32(1):73-77. 20. Whimbey E, Elting LS, Couch RB, Lo W, Williams L, Champlin RE et al. Influenza A virus infections among hospitalized adult bone marrow transplant recipients. Bone Marrow Transplant 1994;13(4):437440. 21. Shah DP, Ghantoji SS, Mulanovich VE, Ariza-Heredia EJ, Chemaly RF. Management of respiratory viral infections in hematopoietic cell transplant recipients. Am J Blood Res 2012;2(4):203-218. 22. CDC. Update: Influenza Activity — United States, September 28, 2014–February 21, 2015. In. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6408a2.htm, 2015.
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Table 1. Clinical Characteristics and Outcomes of Influenza Infections in 146 HCT Recipients (N [%]). Total Characteristic N=146 (range, %) 52 (14 -80)
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Age, y Median (range) Sex
77 (53)
Female
69 (47)
Race
Black
17 (12)
Hispanic
34 (23)
Other
Donor relationship
8 (5)
50 (34)
Matched Unrelated
34 (23)
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Matched Related
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HCT cell source
87 (60)
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Non-Hispanic white
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Male
Mismatched
10 (7)
Autologous
52 (36)
Peripheral Marrow Cord
111 (76) 29 (20) 2 (1)
Time from HCT to infection Median [range]
398 (2–7140)
Acute GVHD
11 (8)
Chronic GVHD
27 (18) 19
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Underlying malignancy 69 (47)
Lymphoma
29 (20)
Other
48 (33)
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Leukemia
Cancer status at the time of infection
Active/Relapse Myeloablative conditioning regimen (past 100 days)
31 (21)
17 (12)
46 (32)
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Corticosteroids within 30 days of diagnosis
115 (79)
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Remission
Smoking history
103 (71)
Former
32 (22)
Current
11 (8)
27 (15–63)
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BMI, kg/m2 Median (range)
Never
BMI categories (WHO classification)
5 (3)
Normal: 18.5–24.99
39 (27)
Overweight: 25–29.99
51 (35)
Obese: ≥30
50 (34)
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Underweight: <18.5
Time from symptoms onset to presentation Median (range), d
2 (0–21)
URI
119 (82)
Infection site at diagnosis
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LRI
27 (18)
Leukocytosis (WBC >11,000/mm)
8 (5)
Neutropenia (ANC <500 cells/mL)
10 (7)
Lymphocytopenia (ALC <200 cells/mL)
11 (8)
23 (16)
Decreased albumin (<3.5 g/dL)
37 (25)
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Elevated creatinine (>1.3 mg/dL)
Hypoxia at diagnosis
10 (7)
22 (15)
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Co-infections (within 1 month of diagnosis) Respiratory co-pathogens Outcomes Progression from URI to LRI
16 (11)
6/119 (5) 33 (23)
Admission to the hospital Length of stay
62 (42)
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Overall LRI
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Median (range), d
ICU admission
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Laboratory abnormalities at presentation:
7 (1 – 74)
On admission
3 (2)
Later
9 (6)
Mechanical ventilation
7 (5)
Oxygen supplement
22 (15)
Antiviral therapy Anytime during the episode Within 48 hours of symptoms onset
121 (83) 26 (18)
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Within 48 hours of diagnosis
38 (26)
All-cause mortality
7 (5)
Influenza-related death
6 (4)
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Death within 30 days from date of diagnosis
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Abbreviations: d, days; HCT, hematopoietic cell transplant; BMI, body mass index; WHO, World Health Organization; y, years.; LRI, lower respiratory tract infection; URI, upper respiratory tract infection; GVHD, graft versus host disease; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; ICU, intensive care unit.
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Table 2. Differences in Characteristics Between Patients Presenting with LRI and Patients
LRI at Resolved at URI diagnosis n (%) n (%)
Risk factors Number of patients
Unadjusted Odds Ratio (95% CI) -
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Presenting with URI.
P value
Adjusted Odds Ratio (95% CI)
P value
-
-
-
0.52
-
-
0.23
-
-
113
27
≤ 40 years
32 (84)
6 (16)
>40 years
81 (79)
21 (21)
Female
52 (85)
9 (15)
1.00
Male
61 (77)
18 (23)
1.7 (0.71–4.12)
Non-Hispanic white
67 (80)
17 (20)
1.00
Black
10 (67)
5 (33)
1.97 (0.59–6.53)
0.26
5.87 (1.22–28.34)
0.027
Hispanic
31 (94)
2 (6)
0.25 (0.06–1.17)
0.07
0.31 (0.04–2.36)
0.26
Other
5 (63)
3 (38) 2.36 (0.51–10.89)
0.26
3.38 (0.52–21.98)
0.203
-
-
-
-
1.38 (0.51–3.74)
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Race
43 (91)
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Matched Related
1.00
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Sex
Donor relationship
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Age
4 (9)
1.00
1.00
Matched Unrelated
23 (70)
10 (30) 4.67 (1.32–16.56)
0.017
Mismatched
6 (60)
4 (40) 7.17 (1.41–36.5)
0.018
Autologous
41 (82)
9 (18)
2.36 (0.67–8.26)
0.179
1.00
0.644
1.28 (0.45–3.58)
-
HCT cell source Peripheral Marrow
88 (83) 23 (79)
18 (17)
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Cord
0
6 (21)
-
Time from HCT to infection
399 (2– 7140)
345 (7– 4825)
1.00 (0.99–1.00)
GVHD at the time of infection None
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2 (100)
0.882
-
-
-
-
19 (18)
26 (76)
8 (24)
Leukemia
53 (80)
13 (20)
1.00
Lymphoma
20 (71)
8 (29)
1.63 (0.59–4.52)
0.347
Other
40 (87)
6 (13)
0.61 (0.21–1.75)
0.359
-
-
0.208
-
-
0.674
-
-
-
-
Active/Relapse
92 (83)
19 (17)
1.00
21 (72)
8 (28)
1.84 (0.71–4.78)
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Corticosteroids in past 30 days
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Remission
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Cancer status at the time of infection
1.41 (0.55–3.59)
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Underlying malignancy:
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87 (82)
Yes
0.472
No
80 (82)
18 (18)
1.00
Yes
33 (79)
9 (21)
1.21 (0.49–2.97)
81 (84)
16 (16)
1.00
Never
24 (75)
8 (25)
1.69 (0.64–4.42)
0.287
Former
8 (73)
3 (27)
1.9 (0.45–7.94)
0.38
Smoking status
24
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Current BMI, kg/m2
1.00
Underweight: <18.5
4 (80)
Normal: 18.5–24.99
29 (76)
1.24 (0.12 – 9 (24) 12.57)
Overweight: 25–29.99
40 (80)
10 (20) 1 (0.1 – 9.96)
Obese: ≥30
39 (85)
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0.855
1.00
7 (15)
0.72 (0.07- 7.41)
2 (0 – 7) 3 (1 – 21)
1.54 (1.19–1.99)
0.781
-
-
0.001
1.89 (1.3–2.75)
0.001
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Time from symptoms to presentation
1 (20)
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Laboratory abnormalities 5 (71)
2 (29) 1.66 (0.3–9.08)
0.55
-
-
Neutropenia
5 (50)
5 (50) 4.73 (1.26–17.73)
0.02
-
-
Lymphocytopenia
6 (55)
5 (45)
3.9 (1.09–13.93)
0.03
Elevated creatinine
12 (60)
8 (40)
3.37 (1.21– 9.35)
0.02
Decreased albumin
21 (62)
13 (38)
4.5 (1.77 – 11.48)
0.002
No
109 (83)
22 (17)
1.00
Yes
4 (44)
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Antiviral therapy within 48 h of symptom onset
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Hypoxia at diagnosis
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Leukocytosis
5 (56) 6.19 (1.54–24.92)
No
87 (76)
27 (24)
Yes
26 (100)
0
No
106 (83)
21 (17) 1.00
-
12.24 (2.4–62.3)
0.003
5.19 (1.29–20.96)
0.021
-
-
1.00 0.01
7.09 (1.35–37.32)
0.021
-
-
-
Respiratory coinfections 1.00
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Yes
7 (54)
6 (46) 4.33 (1.32–14.17)
Past seasons
94 (80)
23 (20)
1.00
2014/H3N2 season
19 (83)
4 (17)
0.86 (0.27–2.77)
0.016
3.4 (0.72–16.09)
0.123
0.801
-
-
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Influenza seasons:
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Abbreviations: d, days; HCT, hematopoietic cell transplant; BMI, body mass index; WHO, World Health Organization; y, years.; LRI, lower respiratory tract infection; URI, upper respiratory tract infection; GVHD, graft versus host disease; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; ICU, intensive care unit
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Table 3. Incidence of LRI and influenza-associated death stratified by ISI risk groups and antiviral therapy (N=142) Total
Antiviral Therapy
Risk groups as defined by the ISI
N
LRI
Influenza -related Death
78
13 (17)
2 (3)
13
0
48
13 (27)
2 (4)
53
15 (28)
2 (4)
9
0
38
13 (34)
2 (5)
11
5 (45)
2 (18)
3
0
7
5 (71)
2 (29)
n
LRI/Death
n
LRI
Death
Moderate-risk (ISI of 3 to 6) High-risk
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(ISI of 7 to 12)
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Low-risk (ISI of 0 to 2)
(after 48 hours of symptom onset)
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(within 48 hours of symptom onset)
Late
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Early
Note: Data required for generating ISI were missing in 4 patients.
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Abbreviations: LRI, lower respiratory tract infection; ISI immunodeficiency scoring index
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Figure legends:
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Figure 1. Symptom Profile for Patients with Influenza Infection. Figure 2. Kaplan-Meier Failure Curves for LRI incidence, stratified by ISI risk groups and early
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antiviral therapy.
28
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2014 season
EP
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Previous season
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100 90 80 70 60 50 40 30 20 10 0
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Fig 1. Symptom Profile for Patients with Influenza Infections
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LRI incidence, stratified by ISI risk groups and antiviral therapy
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LRI incidence (%) 25 50 75 0
P < 0.001
0
15
30
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100
Figure 2. Kaplan-Meier Failure Curves for LRI incidence, stratified by ISI risk groups and early antiviral therapy.
45
60
75
90
Time from onset of symptoms to LRI Low risk / early antiviral therapy
Moderate risk / early antiviral therapy
Moderate risk / late antiviral therapy High risk / late antiviral therapy
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High risk / early antiviral therapy
Low risk / late antiviral therapy
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Supplemental Table. Development of the ISI-RSV for patients presenting with RSV infections (N = 237). No. (%)
ANC <500/µL
11 (5)
7 (64)
2
ALC <200/µL
35 (15)
11 (31)
3
Age ≥40 years Myeloablative conditioning regimen GVHD (acute or chronic)
154 (65)
28 (18)
98 (41)
17 (17)
149 (63)
19 (13)
117 (49)
17 (15)
21 (9)
5 (24)
7
Corticosteroids† Recent† or preengraftment allo-HSCT
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6
>2.5
3
>2.5
3
2.0-2.5
2
<2.0
1
<2.0
1
<2.0
1
<2.0
1
Maximum possible overall score‡
12
Low risk: 0-2 score, moderate risk 3-6 score, high risk 7-12 score ISI-RSV indicates immunodeficiency scoring index for RSV; AHR adjusted hazard ratio; LRTI, lower respiratory tract infection; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; CI, confidence interval; and GVHD, graft-versus-host disease. *Adjusted for year of RSV diagnosis and ribavirin-based therapy at the URTI stage to identify the independent effect of each immunodeficiency indicator on progression to LRTI. † Within the prior 30 days. ‡ The overall score equals the sum of the scores for the immunodeficiency indicators present at the time of diagnosis of RSV infection. For example, for a patient with an ANC less than 500/µL (ISI-RSV score, 3) and acute graft-versus-host disease (ISI-RSV score, 1), the total ISI-RSV score would be 4, and the patient would be stratified into the moderaterisk group.
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AHR* (95% CI) 4.1 (1.4-11.6) 2.6 (1.02-6.4) 2.5 (1.1-5.6) 1.2 (0.6-2.3) 1.0 (0.5-2.2) 0.89 (0.4-1.8) 0.68 (0.2-2.3)
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4
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1
Weighi ng criteri a
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Patients 237 (N, %)
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Criteri a
Progression to LRTI 37 (n, %)
Assig ned weig hts (scor e)
This research was originally published in Blood Online. Shah DP, Ghantoji SS, Ariza-Heredia EJ, et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood. 2014;123(21):3263-3268.
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Early antiviral therapy reduces influenza-associated complications.
•
ISI is a prognostic tool to identify patients at higher risk of progression to LRI.
•
2014 influenza had similar outcomes in HCT recipient compared to previous seasons.
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•