HHS Public Access Author manuscript Author Manuscript
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01. Published in final edited form as: Biol Blood Marrow Transplant. 2016 March ; 22(3): 542–548. doi:10.1016/j.bbmt.2015.11.015.
Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index
Author Manuscript
Joumana Kmeid, MD1, Jakapat Vanichanan, MD1, Dimpy P. Shah, MD, MSPH, PhD1, Firas El Chaer, MD1, Jacques Azzi, MD1, Ella Ariza Heredia, MD1, Chitra Hosing, MD2, Victor Mulanovich, MD1, and Roy F. Chemaly, MD, MPH1 1Department
of Infectious Diseases, Infection Control, & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 2Department
of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Abstract
Author Manuscript
Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza 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 (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 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 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 patients should be monitored more closely. Early initiation of antiviral therapy for influenza in HCT recipients, irrespective of the ISI risk group, may improve morbidity as well as mortality.
Author Manuscript
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: 713-745-1116; fax: 713-745-6839; [email protected]. Financial Disclosures: R.F.C. received research grants from GlaxoSmithKline. The remaining authors declare no competing financial interests. Publisher's Disclaimer: 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 citable 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.
Kmeid et al.
Page 2
Author Manuscript
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 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 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 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)
Author Manuscript Author Manuscript
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 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 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 scoring index was not based on virusspecific factors, it may be extrapolated to other respiratory viruses, such as influenza, in HCT recipients. 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 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 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 and death.
Materials and Methods Author Manuscript
We conducted a retrospective study and included all HCT recipients with laboratoryconfirmed influenza infection from July 2009 to December 2013 at The University of Texas MD Anderson Cancer Center in Houston, Texas. The Institutional Review Board approved the protocol and waived the requirement for obtaining informed consent. We also examined the clinical characteristics and outcomes of patients with 2014/H3N2 influenza A infections from November 2014 to December 2014 and compared those with the
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 3
Author Manuscript
four previous seasons. We collected the following data from medical chart review: demographic 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; coinfections; use of immunosuppressive therapy within the month preceding the diagnosis of influenza A infection; 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, oxygen supplementation, and death, were also recorded. Definitions
Author Manuscript Author Manuscript
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 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 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 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 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. Immunodeficiency Scoring Index
Author Manuscript
In a previous study,(15) we developed an ISI in HCT recipients with RSV infection, using 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 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 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 Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 4
Author Manuscript
those who were infected with the 2014/H3N2 strain during the current season using a chisquare test or 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 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], 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 Station, TX).
Results Author Manuscript
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) 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 median time from symptom onset to presentation was 2 days (range: 1–21 days).
Author Manuscript Author Manuscript
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-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 (8%) required intensive care unit admission, and 7 (5%) required mechanical ventilation. The 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. 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 respiratory co-pathogens including Klebsiella pneumoniae, Stenotrophomonas maltophilia, Methicillin Resistant Staphylococcus aureus, Mycobacterium avium, Aspergillus niger, and Curvularia species. Using a multivariable logistic regression
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 5
Author Manuscript Author Manuscript
modeling, we identified differences 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 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 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 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 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.
Author Manuscript
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 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 allcause mortality 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 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 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 and did not receive antiviral therapy at the URI stage).
Author Manuscript
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 (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
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01. Published in final edited form as: Biol Blood Marrow Transplant. 2016 March ; 22(3): 542–548. doi:10.1016/j.bbmt.2015.11.015.
Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index
Author Manuscript
Joumana Kmeid, MD1, Jakapat Vanichanan, MD1, Dimpy P. Shah, MD, MSPH, PhD1, Firas El Chaer, MD1, Jacques Azzi, MD1, Ella Ariza Heredia, MD1, Chitra Hosing, MD2, Victor Mulanovich, MD1, and Roy F. Chemaly, MD, MPH1 1Department
of Infectious Diseases, Infection Control, & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 2Department
of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Abstract
Author Manuscript
Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza 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 (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 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 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 patients should be monitored more closely. Early initiation of antiviral therapy for influenza in HCT recipients, irrespective of the ISI risk group, may improve morbidity as well as mortality.
Author Manuscript
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: 713-745-1116; fax: 713-745-6839; [email protected]. Financial Disclosures: R.F.C. received research grants from GlaxoSmithKline. The remaining authors declare no competing financial interests. Publisher's Disclaimer: 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 citable 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.
Kmeid et al.
Page 2
Author Manuscript
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 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 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 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)
Author Manuscript Author Manuscript
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 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 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 scoring index was not based on virusspecific factors, it may be extrapolated to other respiratory viruses, such as influenza, in HCT recipients. 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 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 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 and death.
Materials and Methods Author Manuscript
We conducted a retrospective study and included all HCT recipients with laboratoryconfirmed influenza infection from July 2009 to December 2013 at The University of Texas MD Anderson Cancer Center in Houston, Texas. The Institutional Review Board approved the protocol and waived the requirement for obtaining informed consent. We also examined the clinical characteristics and outcomes of patients with 2014/H3N2 influenza A infections from November 2014 to December 2014 and compared those with the
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 3
Author Manuscript
four previous seasons. We collected the following data from medical chart review: demographic 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; coinfections; use of immunosuppressive therapy within the month preceding the diagnosis of influenza A infection; 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, oxygen supplementation, and death, were also recorded. Definitions
Author Manuscript Author Manuscript
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 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 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 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 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. Immunodeficiency Scoring Index
Author Manuscript
In a previous study,(15) we developed an ISI in HCT recipients with RSV infection, using 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 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 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 Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 4
Author Manuscript
those who were infected with the 2014/H3N2 strain during the current season using a chisquare test or 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 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], 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 Station, TX).
Results Author Manuscript
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) 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 median time from symptom onset to presentation was 2 days (range: 1–21 days).
Author Manuscript Author Manuscript
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-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 (8%) required intensive care unit admission, and 7 (5%) required mechanical ventilation. The 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. 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 respiratory co-pathogens including Klebsiella pneumoniae, Stenotrophomonas maltophilia, Methicillin Resistant Staphylococcus aureus, Mycobacterium avium, Aspergillus niger, and Curvularia species. Using a multivariable logistic regression
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2017 March 01.
Kmeid et al.
Page 5
Author Manuscript Author Manuscript
modeling, we identified differences 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 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 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 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 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.
Author Manuscript
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 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 allcause mortality 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 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 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 and did not receive antiviral therapy at the URI stage).
Author Manuscript
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 (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
