Scandinavian Journal of Infectious Diseases, 2014; Early Online: 1–9
Original article
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Clinical presentations and outcomes of influenza infection among hematology/oncology patients from a single cancer center: pandemic and post-pandemic seasons Mustafa Saad1,2, Wail Hayajneh3, Sawsan Mubarak4, Ibraheem Yousef1, Hazem Awad5, Wafa Elbjeirami6 & Rawad Rihani5 From the 1Department of Medicine, King Hussein Cancer Center, Amman, Jordan, 2Department of Medical Administration, Prince Sultan Cardiac Center, Riyadh, KSA, 3Department of Pediatrics, Jordan University of Science and Technology, Irbid, Jordan, 4Infection Control Program, 5Department of Pediatrics, and 6Department of Pathology, King Hussein Cancer Center, Amman, Jordan
Abstract Background: Influenza can cause severe infection in hematology/oncology patients. The occurrence of the 2009 pandemic represented an opportunity to study the impact of influenza on such patients in pandemic and post-pandemic seasons. Methods: We retrospectively reviewed medical records of hematology/oncology patients who had laboratory-confirmed influenza infection during the 2009 pandemic and the first post-pandemic seasons. We assessed influenza-related outcomes in both seasons with emphasis on the development of pneumonia and mortality. We also analyzed factors associated with poor outcomes. Results: We included 350 patients; 207 were diagnosed in the pandemic and 143 in the post-pandemic seasons. Influenza severity was similar in both seasons with no significant differences in the development of pneumonia or death. Infection with the pH1N1 virus was associated with the development of pneumonia (24.7% vs 14.9%, p 0.029) but did not affect mortality. A multivariate analysis showed that initiation of antiviral treatment after 48 h, healthcare acquisition of influenza, and low albumin were independent risk factors for the development of pneumonia (p values 0.022, 0.003, and 0.0001, respectively). A log-rank test showed increased mortality in patients who received therapy 48 h after onset of symptoms (p 0.001). Conclusions: In hematology/oncology patients, influenza was as severe in the post-pandemic as in the pandemic season. Pneumonia developed more commonly in patients infected with pH1N1 virus. Healthcare acquisition of infection and low albumin were associated with the development of pneumonia. Delayed initiation of antiviral treatment was associated with both pneumonia and mortality.
Keywords: H1N1 influenza, 2009 pandemic, post-pandemic, hematology, oncology
Introduction The year 2009 was marked by the occurrence of the first influenza pandemic in the 21st century. The pandemic started with the reporting of the first series of infections with a novel swine-origin H1N1 influenza virus in April 2009, and was officially declared a pandemic by the World Health Organization (WHO) in June, 2009 [1]. The 2009 H1N1 pandemic (pH1N1) virus was the predominantly circulating influenza virus in the 2009/2010 season. The pandemic has affected people of all ages around the world with the highest rates being reported in children and young adults, and the overall case-fatality
rate was estimated to be 0.5% [2]. In August 2010, the WHO declared the pandemic to be over, marking the beginning of the first post-pandemic influenza season in the 21st century [3]. Hematology/oncology patients were classified among high-risk groups expected to have excess morbidity and mortality during the 2009 pandemic. Although prior studies have shed some light on the clinical presentations and outcomes of pandemic influenza in these patients, little is currently known about the risk factors for poor outcomes, rates of influenza-related complications, and the optimal timing and duration of antiviral therapy in this
Correspondence: Mustafa Saad MD, Department of Medical Administration, Prince Sultan Cardiac Center, PO Box 7897-A.55, Riyadh 11159, KSA. E-mail: [email protected] (Received 8 February 2014; accepted 24 June 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.943282
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vulnerable group. Furthermore, studies of influenza infection in cancer patients during post-pandemic seasons are lacking. This study was conducted to better understand the clinical presentations, complications, outcomes, and risk factors for poor outcomes of influenza infections in pandemic and post-pandemic seasons in hematology/oncology patients from a single cancer center in Jordan.
Materials and methods Scand J Infect Dis Downloaded from informahealthcare.com by University of Newcastle on 08/23/14 For personal use only.
Patients Microbiology data and infection control records at the King Hussein Cancer Center were searched for patients diagnosed as having influenza infection in the pandemic (2009/2010) and post-pandemic (2010/2011) seasons. We only included cases confirmed by positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) tests for any of the influenza viruses. Each patient was included once per season. We retrospectively reviewed medical records of patients and collected data on: demographics, underlying diseases, co-morbid conditions, immunosuppression, clinical presentations, radiological and laboratory investigations, treatments received, and outcomes. Patients were followed until they showed complete resolution of all signs and symptoms related to infection or death. For patients who survived, the median follow-up was 135 days (range 39–790) for the pandemic versus 120 days (range 20–385) for the post-pandemic seasons. The study protocol was approved by the institutional review board before the study was conducted; written informed consent was waived.
RT-PCR test The RT-PCR test was run on samples obtained by nasopharyngeal washes or swabs or bronchoalveolar lavage fluid from patients with clinical presentations compatible with influenza. Patients who presented between September 28 and October 17, 2009 had their samples tested for the pH1N1 virus by RT-PCR at the central laboratories of the Ministry of Health of Jordan. Kits were provided to the central laboratories through the WHO and followed the protocol from the US Centers for Disease Control and Prevention. As of October 18, 2009 and until the end of the post-pandemic season, all influenza infections were confirmed using a multiplex RT-PCR test (FTD FLU, Fast-Track Diagnostics, Luxembourg) that can detect influenza A, influenza B, and pH1N1 (swinelineage) viruses.
Definitions We applied similar definitions to those described in previous studies [4,5]. A case of influenza was defined as a patient with any hematology/oncology diagnosis (benign or malignant) who presented with an acute respiratory illness compatible with influenza, and infection was confirmed by a positive RT-PCR test. Infections were classified as community-acquired if symptoms developed before or within 48 h of admission, or healthcare-associated if the onset of symptoms was 48 h after hospitalization. Upper respiratory tract infection (URI) was defined as the onset of a combination of rhinorrhea, nasal congestion, sore throat, and cough, and a positive RT-PCR test on a nasopharyngeal wash or swab, with no radiological evidence of pneumonia. Pneumonia was defined as the presence of signs and symptoms of influenza with a positive RT-PCR test on a nasopharyngeal wash or bronchoalveolar lavage fluid, and new or changing pulmonary infiltrates seen on chest X-rays or CT scans. Gastrointestinal complaints included nausea, vomiting, diarrhea, and abdominal pain. Neurological complaints included headache, dizziness, seizures, confusion and, for infants, hypo-activity and irritability. Obesity was defined as a body mass index (BMI) of 30 in adults 18 years of age or older, or a BMI percentile of 95–100 in children between the ages of 1 and 18 years. Neutropenia was defined as an absolute neutrophil cell count of 500 cells/ml and severe lymphopenia was defined as an absolute lymphocyte cell count of 200 cells/ml. Concomitant antimicrobials included all antibiotics used while the patient was receiving antiviral treatment for influenza. A concurrent co-infection was considered when another organism (a bacterium, virus other than influenza, or fungus) was isolated within 14 days of influenza isolation by RT-PCR. Complete recovery was defined as the resolution of all signs and symptoms related to influenza regardless of viral shedding. In addition to complete recovery, other clinical outcomes that were followed included progression to pneumonia and mortality within 60 days of onset of symptoms. Immunodeficiency status was classified into none, mild, moderate, or severe. We applied the same criteria that were previously described by Chemaly et al. [5]. Statistical methods Univariate comparisons for categorical data were made using either chi-squared or Fisher’s exact tests. The Mann–Whitney test was used to compare continuous variables. A p value 0.05 (based on a two-tailed test) was considered statistically significant.
Cancer and pandemic/post-pandemic influenza Results
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Risk factors for the development of pneumonia were initially assessed using a univariate analysis. Then factors that were found to be significant in the univariate analysis were included in a multivariate regression analysis to identify independent risk factors for the development of pneumonia. A log-rank test was used to assess mortality in patients who received antiviral treatment within 48 h of the onset of symptoms versus those who did not. All statistical analyses were performed using the Statistical Package for the Social Sciences software, version 16.0 (SPSS Inc., Chicago, IL, USA).
Pandemic versus post-pandemic seasons A total of 350 patients with RT-PCR-confirmed influenza infection were included in the study; 207 were diagnosed in the pandemic and 143 were diagnosed in the post-pandemic 2010/2011 season. As shown in Table I, patients in the two seasons were similar with regard to age, gender, immunodeficiency status, underlying diseases, and presence of obesity. Patients in the post-pandemic season were more likely to have an active underlying disease at the time
Table I. Baseline characteristics of patients with influenza infections: pandemic (2009/2010) versus post-pandemic (2010/2011) seasons. Characteristic Total Age Median (years) Range (years) Age group, no. (%) 0–5 years 6–18 years 19–50 years 50 years Sex, no. (%) Male Female Type of influenza, no. (%) pH1N1 virus Influenza A (non-pandemic) Influenza B pH1N1 and influenza B Immunodeficiency status, no. (%) None Mild Moderate Severe Underlying disease (%) Hematological malignancy Solid tumor Benign hematology Status of underlying condition, no. (%) Active Remission HSCT recipient, no. (%) Allogeneic HSCT Autologous HSCT Obesity, no. (%) Co-morbid conditions, no. (%) Any condition Hypertension Diabetes mellitus Chronic airway diseases Chronic kidney disease Endocrine disorders Hyperlipidemia Cardiac diseases Neuropsychiatric disorders Other
3
Pandemic season
Post-pandemic season
207
143
13.0 0.8–75
16.5 0.67–79
NS
29 44 41 29
(20.3%) (30.8%) (28.7%) (20.3%)
NS
115 (55.6%) 92 (44.4%)
84 (58.7%) 59 (41.3%)
NS
174 5 26 2
(84.1%) (2.4%) (12.6%) (1.0%)
42 42 58 1
(29.4%) (29.4%) (40.6%) (0.7%)
72 39 56 40
(34.8%) (18.8%) (27.1%) (19.3%)
38 26 38 41
(26.6%) (18.2%) (26.6%) (28.7%)
40 84 56 27
(19.3%) (40.6%) (27.1%) (13.0%)
p value
0.0001
NS
NS 113 (54.6%) 71 (34.3%) 23 (11.1%)
89 (62.2%) 45 (31.5%) 9 (6.3%) 0.037
63 144 45 32 13 39/186 56 31 21 20 7 6 5 4 1 11
(30.4%) (69.6%) (21.7%) (15.5%) (6.3%) (21.0%) (27.1 %) (15.0%) (10.1%) (9.7%) (3.4%) (2.9%) (2.4%) (1.9%) (0.5%) (5.3%)
HSCT, hematopoietic stem cell transplant; NS, not significant.
59 84 29 13 16 32/135
(41.3%) (58.7%) (20.3%) (9.1%) (11.2%) (23.7%)
NS 0.024
62 20 15 13 6 11 6 5 8 11
(43.4%) (14.0%) (10.5%) (9.1%) (4.2%) (7.7%) (4.2%) (3.5%) (5.6%) (7.7%)
0.002 NS NS NS NS 0.04 NS NS 0.004 NS
NS
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of diagnosis (41.3% vs 30.4%, p 0.037) and to have co-morbid conditions (43.4% vs 27.1%, p 0.002). More patients in the pandemic season, on the other hand, had received allogeneic hematopoietic stem cell transplants (HSCTs) (15.5% vs 9.1%, p 0.024). Table I summarizes the baseline characteristics of patients in both seasons. During the pandemic season, pH1N1 was the most common circulating influenza virus, causing 84.1% of infections, followed by influenza B and thereafter influenza A viruses. In the post-pandemic season, all three viruses were circulating among patients, with a slight dominance of the influenza B virus, which caused 40.6% of cases. Three patients from both seasons had co-infections of the pH1N1 and influenza B viruses. Not only were the two seasons different in the types of circulating viruses, but onset, peak, and duration of the influenza seasons were also different (Figure 1). During the pandemic, the influenza season started earlier (week 39/2009), showed one large peak, and ended earlier (spanned over 13 weeks). In contrast, the post-pandemic season started later (week 47/2010), had two peaks, and lasted longer (spanned over 21 weeks). Patients in both seasons presented with influenza-like illnesses (Table II). Clinical manifestations in both seasons were similar except for fever (84.5% vs
70.6%, p 0.002) and sore throat (41.5% vs 21.0%, p 0.0001), which were more common during the pandemic season. Healthcare-associated infection was more frequently encountered in the postpandemic season (12.6% vs 6.3%, p 0.041). Duration of symptoms before hospitalization (median, 2 versus 1 day, p 0.014) and duration of hospital stay (median, 7 versus 5 days, p 0.014) were longer in the post-pandemic season. No differences were noted between the two seasons in the baseline laboratory abnormalities. Most of the patients received antiviral therapy, namely oseltamivir. Three patients, one with influenza B during the pandemic and two with pH1N1 in the post-pandemic seasons, died before the diagnosis was established and did not receive antiviral therapy. Other patients who did not receive antiviral treatment had mild presentations and recovered completely. Patients in both groups were managed similarly in terms of oseltamivir usage and duration, and the use of concomitant antimicrobials and adjunctive treatments. Mortality in both seasons was high, 10 and 12 deaths occurring in the pandemic and post-pandemic seasons. All other influenza-related outcomes and complications, including hospitalization, development of pneumonia, intensive care unit (ICU) admission,
60 pH1N1
Influenza A
Influenza B
50
Number of new cases
40
30
20
0
2010-44 2010-45 2010-46 2010-47 2010-48 2010-49 2010-50 2010-51 2010-52 2011-1 2011-2 2011-3 2011-4 2011-5 2011-6 2011-7 2011-8 2011-9 2011-10 2011-11 2011-12 2011-13 2011-14 2011-15 2011-16 2011-17 2011-18
10
2009-36 2009-37 2009-38 2009-39 2009-40 2009-41 2009-42 2009-43 2009-44 2009-45 2009-46 2009-47 2009-48 2009-49 2009-50 2009-51 2009-52 2010-1 2010-2 2010-3
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4
Week/Year Figure 1. Number of influenza cases by type and by week of diagnosis in the pandemic and the first post-pandemic seasons in hematology/ oncology patients.
Cancer and pandemic/post-pandemic influenza
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Table II. Clinical presentations, treatments, and outcomes of patients diagnosed with influenza: pandemic (2009/2010, n 207) versus post-pandemic (2010/2011, n 143) seasons.
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Characteristic Symptoms, no. (%) Fever Cough Runny nose Sore throat Sputum production Shortness of breath Myalgia/arthralgia Fatigue Gastrointestinal complaints Neurological complaints Duration of symptoms before hospitalization Median (range), days Acquisition of infection, no. (%) Healthcare-associated Community-acquired Infection type, no. (%) Upper respiratory tract infection Pneumonia Laboratory abnormalities on presentation, no. (%) Leukocytosis (WBC count 11 000/mm3) Neutropenia (ANC 500 cells/ml) Severe lymphopenia (ALC 200 cells/ml) Elevated creatinine ( 1.3 mg/dl) Decreased albumin ( 3.5 g/dl) Admission to the hospital, no. (%) Duration of hospital stay, median (range), days ICU admission, no. (%) Mechanical ventilation, no. (%)a Duration of ICU stay, median (range), days Antiviral treatment, no. (%) Oseltamivir None Duration of oseltamivir therapy, median (range), days Concomitant antimicrobial treatment, no. (%) Adjunctive treatment, no. (%) GCSF IVIG Concurrent co-infections, no. (%) Mortality, no. (%)
Pandemic season 175 180 134 86 43 40 43 37 48 44
(84.5%) (87.0%) (64.7%) (41.5%) (20.8%) (19.3%) (20.8%) (17.9%) (23.2%) (21.3%)
Post-pandemic season 101 124 80 30 38 25 30 27 28 29
(70.6%) (86.7%) (55.9%) (21.0%) (26.6%) (17.5%) (21.0%) (18.9%) (19.6%) (20.3%)
p value 0.002 NS NS 0.0001 NS NS NS NS NS NS
1.0 (1–21)
2.0 (1–14)
0.014
13 (6.3%) 194 (93.7%)
18 (12.6%) 125 (87.4%)
0.041
169 (81.6%) 38 (18.4 %)
108 (75.5%) 35 (24.5%)
NS
13/198 29/198 22/198 12/155 69/155 99 5.0 22 18 6.0
(6.6%) (14.6%) (11.1%) (7.7%) (44.5%) (47.8%) (1–72) (10.6%) (8.7%) (1–33)
8/134 28/134 12/134 15/111 41/111 72 7.0 23 17 4.0
(6.0%) (20.9%) (9.0%) (13.5%) (36.9%) (50.3%) (2–90) (16.1%) (11.9%) (1–77)
NS NS NS NS NS NS 0.014 NS NS NS
198 9 9.0 174
(95.7%) (4.3%) (1–17) (84.1%)
131 12 10 125
(91.6%) (8.4%) (1–12) (87.4%)
NS
22 2 12 10
(10.6%) (1.0%) (5.8%) (4.8%)
20 2 13 12
(14.0%) (1.4%) (9.1%) (8.4%)
NS NS NS NS
NS NS
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; GCSF, granulocyte colony stimulation factor; ICU, intensive care unit; IVIG, intravenous immunoglobulins; NS, not significant; WBC, white blood cell. aIncludes invasive and non-invasive ventilation.
use of mechanical ventilation, and concurrent co-infections were similar in both seasons. Table II compares the clinical presentations, treatments, and outcomes in both seasons. Pandemic H1N1 versus non-pandemic influenza viruses Pandemic H1N1 virus was the cause of influenza in 216 patients from both seasons, 3 patients had co-infections of pH1N1 and influenza B, and 131 patients developed influenza due to non-pandemic
viruses. Both groups were similar in their baseline characteristics including age, immunodeficiency status, underlying diseases, status of underlying conditions, receipt of HSCT, and presence of obesity and co-morbid conditions. Patients with pH1N1 infections were more likely to present with fever (85.8% vs 67.2%, p 0.0001), cough (89.5% vs 82.1%, p 0.047), sore throat (37.4% vs 26.9%, p 0.041), and shortness of breath (22.4% vs 11.9%, p 0.014). Other clinical manifestations were similar in both groups (data not shown). Laboratory abnormalities were similar in both groups except for decreased
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M. Saad et al.
albumin, which was more common in patients with pH1N1 infections (45.9% vs 32.3%, p 0.03). Patients with pH1N1 influenza were more likely to present earlier (median, 1 vs 2 days, p 0.026), develop pneumonia (24.7% vs 14.9%, p 0.029), be hospitalized (54.3% vs 39.6%, p 0.007), receive antiviral treatment (96.3% vs 91%, p 0.037), and have longer duration of oseltamivir therapy (median, 10 vs 5 days, p 0.0003). Acquisition of infection, duration of hospitalization, ICU admission, co-infections, and mortality rates were similar in both groups.
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Outcomes Seventy-three (20.9%) patients developed pneumonia. Compared with patients who only had URI, patients with pneumonia were older (median age, 44 vs 11 years, p 0.0001), had moderate to severe immunodeficiency (71.2% vs 44.4%, p 0.0001), had an active underlying disease (64.4% vs 27.1%, p 0.0001), were obese (36.4% vs 18.5%, p 0.017),
had co-morbid conditions (56.2% vs 27.8%, p 0.0001), and were more likely to develop healthcare-associated infections (30.1% vs 3.2%, p 0.0001). Pandemic H1N1 virus was isolated in the majority (74%) of patients with pneumonia. Underlying diseases were similar in patients with URI and pneumonia. Laboratory abnormalities occurred more commonly in patients with pneumonia, who tended to have neutropenia more frequently (28.8% vs 6.6%, p 0.0001), renal impairment (22.2% vs 5.6%, p 0.0001), and decreased albumin (77.7% vs 27.8%, p 0.0001). Furthermore, patients with pneumonia presented later (median, 2 vs 1 day, p 0.0005), and were less likely to receive antiviral therapy within 48 h of symptoms onset (45.0% vs 73.9%, p 0.0001). Multivariate logistic regression showed that delayed initiation of antiviral therapy, healthcare acquisition of infection, and low albumin were independent factors for the development of pneumonia (p values 0.022, 0.003, and 0.0001, respectively) (Table III).
Table III. Risk factors for the development of pneumonia in patients with PCR-confirmed influenza infections. Pneumonia Characteristic Age in years, median (range) Age group, no. (%) 0–5 years 6–18 years 19–50 years 50 years Type of influenza, no. (%) pH1N1 Non-pH1N1 Immunodeficiency status, no. (%) None–mild Moderate–severe Underlying disease, no. (%) Hematological malignancy Solid tumor Benign hematology Status of underlying condition, no. (%) Active Obesity, no. (%) Co-morbid conditions (any), no. (%) Acquisition of infection, no. (%) Healthcare-associated Duration of symptoms before hospitalization, median (range), days Treatment within 48 h of symptoms Laboratory abnormalities on presentation, no. (%) Leukocytosis (WBC count 11 000/mm3) Neutropenia (ANC 500 cells/ml) Severe lymphopenia (ALC 200 cells/ml) Elevated creatinine ( 1.3 mg/dl) Decreased albumin ( 3.5 g/dl)
Yes (n 73) 44 (0.67–79) 7 10 31 24
(9.7%) (13.9%) (43.1%) (33.3%)
No (n 277) 11 (0.75–75) 62 117 66 32
(22.4%) (42.2%) (23.8%) (11.6%)
Univariate Multivariate logistic regression analysis p value Odds ratio (95% CI) p value 0.0001
1.02 (1–1.04)
0.13
0.0001
–
–
54 (74.0%) 19 (26.0%)
165 (59.6%) 112(40.4%)
0.024
2.06 (0.76–5.57)
0.15
21 (28.8%) 52 (71.2%)
154 (55.6%) 123 (44.4%)
0.0001
1.59 (0.32–7.90)
0.82
46 (63.0%) 24 (32.9%) 3 (4.1%)
156 (56.3%) 92 (33.2%) 29 (10.5%)
NS
–
–
47 (64.4%) 24/66 (36.4%) 41 (56.2%)
75 (27.1%) 47/254 (18.5%) 77 (27.8%)
0.0001 0.017 0.0001
1.60 (0.64–3.85) 1.68 (0.64–4.44) 1.63 (0.65–10.77)
0.32 0.3 0.3
0.0001 0.0005
6.51 (1.51–28.00) 1.07 (0.83–1.22)
0.003 0.34
0.0001
3.00 (1.51–28)
0.022
NS 0.0001 NS 0.0001 0.0001
– 1.43 (0.36–1.43) – 2.11 (0.61–7.34) 4.46 (1.85–10.75)
22 (30.1%) 2.0 (1–21) 27/60 (45.0%) 7/73 21/73 17/73 16/72 56/72
(9.6%) (28.8%) (23.3%) (22.2%) (77.7%)
9 (3.2%) 1.0 (1–21) 198/268 (73.9%) 14/259 17/259 36/259 11/195 54/194
(5.4%) (6.6%) (13.9%) (5.6%) (27.8%)
– 0.61 – 0.24 0.0001
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CI, confidence intervals; ICU, intensive care unit; NS, not significant; pH1N1, pandemic H1N1; WBC, white blood cell; –, not included.
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Overall, mortality in both seasons was 6.3% and was higher in patients who developed pneumonia; of the 22 patients who died, 20 (90.9%) had pneumonia and 2 (9.1%) had URI, with mortality rates of 27.5% and 0.7%, respectively (p 0.0001) (data not shown). A log-rank test revealed increased mortality when treatment was started 48 h from symptoms onset (p 0.001) (Figure 2). Patients who had pneumonia and died developed progressive respiratory failure, while those with URI who died had progressive underlying malignant diseases; one died after withdrawal of care.
Discussion In the current study, we describe the clinical presentations and outcomes of influenza infections in a relatively large cohort of hematology/oncology patients who developed influenza during the 2009 pandemic and the first post-pandemic seasons. Our study was conducted in a single cancer center where screening for and management of influenza were consistent over both seasons, and followed locally adapted guidelines that were developed at the onset of the pandemic. There are several important findings that need to be highlighted. First, the severity of influenza was comparable in the pandemic and post-pandemic seasons. Indeed, in the post-pandemic season the rates of pneumonia (24.5% vs 18.4%) and mortality were higher (8.4% vs 4.8%) but the differences were not statistically
Cancer and pandemic/post-pandemic influenza
7
significant. Similarly, several studies on the general population showed increased rates of pneumonia and mortality in the post-pandemic season [6–10]. The reasons behind these findings are not well understood. Yet we and other investigators observed significant differences between the two seasons that could have contributed to the severity of influenza in the post-pandemic season. Patients in the postpandemic season presented later [8,10], were older [7,8,10,11], and were more likely to have co-morbid conditions [7,8]. Second, clinical presentations were similar in the pandemic and post-pandemic seasons except for fever and sore throat, which were more common in the pandemic season. Furthermore, patients infected with the pH1N1 versus non-pandemic viruses were more likely to present with fever, cough, sore throat, and shortness of breath. Several studies have reported certain clinical manifestations to be more common in pH1N1 versus seasonal and post-pandemic influenza [10,12–14]. Nonetheless, the majority of patients in these and other studies have presented with nonspecific influenza-like illnesses; this indicates that pandemic influenza cannot be differentiated from seasonal influenza in individual patients on clinical grounds alone and emphasizes the need to confirm the diagnosis by more objective tests. Third, while pH1N1 was the most common circulating virus in the pandemic season, representing 84.1% of infections, the post-pandemic season was characterized by the circulation of various influenza viruses. In particular, influenza B was more common
Figure 2. Log-rank test for patients who received antiviral treatment within 48 h of onset of symptoms versus those who did not (p 0.001).
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during the post-pandemic season than pH1N1 and non-pandemic influenza A viruses. This is different from reports on influenza in the first post-pandemic season in the general population [6,11,15], where pH1N1 was the cause of influenza in 67–98% of infections. The difference in the circulating viruses observed may partly be due to the fact that our cohort only included hematology/oncology patients and is the only study reported from our region. In our study, three patients had dual co-infections with pH1N1 and influenza B viruses; a finding reported previously by Calistri et al. [16]. Furthermore, dual co-infections with two seasonal influenza viruses have also been described [17,18]. Fourth, patients infected with the pH1N1 virus were more likely than patients subjected to nonpandemic strains to be admitted to the hospital and to develop pneumonia. But, in multivariate analysis, pH1N1 virus was not an independent risk factor for the development of pneumonia. Additionally, the type of influenza virus had no impact on influenzaassociated mortality. Similarly, Choi et al. and Chaves et al. [19,20] reported increased incidence of pneumonia following pH1N1 versus seasonal influenza, but pH1N1 had no impact on influenza-associated mortality. Fifth, our study showed three factors, namely delayed initiation of antiviral treatment, healthcare acquisition of infection, and low albumin, to be independent risk factors for the development of pneumonia. The effect of delayed antiviral treatment on the development of pneumonia has been described previously [4,5,19,21]. However, healthcare acquisition of influenza and low albumin seem to be unique to our study. Although these findings were reported by other investigators, they were not shown to be independent risk factors for the development of pneumonia [22,23]. Patients who have low albumin are usually malnourished and tend to be more ill and hence more susceptible to develop severe complications once infected. In particular, the ability of the body to synthesize essential proteins will be affected, which may include those produced by the immune system to defend against different infectious pathogens. In contrast to our study, Ljungman et al. [22], Choi et al. [19], and Chemaly et al. [5] reported older age, moderate to severe immunodeficiency, and lymphopenia as independent risk factors for the development of pneumonia. While the rationale behind the differences between our study and these studies is not apparent, their study populations were different from ours; they included older patients (median 38.3–42 vs 14.5 years), patients from different countries/ regions, and patients with either solid tumors or HSCT [5,19,22].
Sixth, the overall mortality rate in our cohort was 6.3%. This rate is high compared with the mortality from pandemic influenza in the general population, which was reported to be 0.5% [2]. In contrast, mortality rates in hematology/oncology patients with pH1N1 infection were reported at a wide range of estimates (0–22%) in different studies [5,22,24–28]. In our study, almost all patients who died had pneumonia with progressive respiratory failure. Our data, in agreement with other reports [5,8,19], show that delayed initiation of antiviral treatment is an important risk factor for poor outcome in patients with influenza infections. Our study has several limitations inherent to its design. First, this is a retrospective study with data collection from laboratory reports and medical records. This carries the potential for incomplete recording of data and/or variation of data entry according to the healthcare provider. Second, data on vaccination of patients were not available to study the impact of immunization on the epidemiology of influenza. Third, during the first 3 weeks of the pandemic, only RT-PCR tests that detect pH1N1 were used. So, we could have missed non-pandemic influenza cases during that period and this could have affected our results. Finally, no data on viral shedding or resistance were available to study their impact on influenza outcomes. In conclusion, our study on hematology/oncology patients demonstrates that the first post-pandemic season was similar in severity to the 2009 pandemic season. Patients infected with the pH1N1 virus were more likely to present with pneumonia. Delayed initiation of antiviral treatment, healthcare acquisition of infection, and low albumin were independent risk factors for the development of pneumonia. Mortality significantly increased in patients who received antiviral therapy 48 h after symptoms onset. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] New influenza A (H1N1) virus: global epidemiological situation, June 2009. Releve epidemiologique hebdomadaire/ Section d’hygiene du Secretariat de la Societe des Nations Weekly epidemiological record/Health Section of the Secretariat of the League of Nations 2009;84:249–57. [2] Writing Committee of the WHOCoCAoPI, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362:1708–19. [3] World Health Organization declares post-pandemic phase. Euro Surveill 2010;15(32). Available from: URL: http:// www.eurosurveillance.org/ViewArticle.aspx?ArticleId 19636
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[4] Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis 2004;39:1300–6. [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;118:4627–33. [6] Athanasiou M, Baka A, Andreopoulou A, Spala G, Karageorgou K, Kostopoulos L, et al. Influenza surveillance during the post-pandemic influenza 2010/11 season in Greece, 04 October 2010 to 22 May 2011. Euro Surveill 2011;16(44). [7] Lehners N, Geis S, Eisenbach C, Neben K, Schnitzler P. Changes in severity of influenza A(H1N1)pdm09 infection from pandemic to first postpandemic season, Germany. Emerg Infect Dis 2013;19:748–55. [8] Martin-Loeches I, Diaz E, Vidaur L, Torres A, Laborda C, Granada R, et al. Pandemic and post-pandemic influenza A (H1N1) infection in critically ill patients. Crit Care 2011; 15:R286. [9] Rodriguez A, Martin-Loeches I, Bonastre J, Olaechea P, Alvarez-Lerma F, Zaragoza R, et al. First influenza season after the 2009 pandemic influenza: report of the first 300 ICU admissions in Spain. Med Intensiva 2011;35:208–16. [10] Viasus D, Cordero E, Rodriguez-Bano J, Oteo JA, Fernandez-Navarro A, Ortega L, et al. Changes in epidemiology, clinical features and severity of influenza A (H1N1) 2009 pneumonia in the first post-pandemic influenza season. Clin Microbiol Infect 2012;18:E55–62. [11] Bolotin S, Pebody R, White PJ, McMenamin J, Perera L, Nguyen-Van-Tam JS, et al. A new sentinel surveillance system for severe influenza in England shows a shift in age distribution of hospitalised cases in the post-pandemic period. PLoS One 2012;7:e30279. [12] Minnema BJ, Patel M, Rotstein C, Mazzulli T, Hota S, Cole EH, et al. Comparison of hospitalized solid organ transplant recipients and nonimmunocompromised patients with pandemic H1N1 infection: a retrospective cohort study. Transplantation 2011;92:230–4. [13] Gordon A, Saborio S, Videa E, Lopez R, Kuan G, Balmaseda A, et al. Clinical attack rate and presentation of pandemic H1N1 influenza versus seasonal influenza A and B in a pediatric cohort in Nicaragua. Clin Infect Dis 2010; 50:1462–7. [14] Belongia EA, Irving SA, Waring SC, Coleman LA, Meece JK, Vandermause M, et al. Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008–2009 (H1N1), and 2007–2008 (H3N2) infections. JAMA 2010;304:1091–8. [15] De Florentiis D, Parodi V, Orsi A, Rossi A, Altomonte F, Canepa P, et al. Impact of influenza during the postpandemic season: epidemiological picture from syndromic and virological surveillance. J Prev Med Hyg 2011;52:134–6. [16] Calistri A, Salata C, Cosentino M, Asnicar S, Franchin E, Cusinato R, et al. Report of two cases of influenza virus
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A/H1N1v and B co-infection during the 2010/2011 epidemics in the Italian Veneto Region. Virol J 2011;8:502. [17] Ju L, Jiang L, Yang J, Shi Q, Jiang Q, Shen H, et al. Co-infection with influenza A/H1N1 and A/H3N2 viruses in a patient with influenza-like illness during the winter/spring of 2008 in Shanghai, China. J Med Virol 2010;82: 1299–305. [18] Falchi A, Arena C, Andreoletti L, Jacques J, Leveque N, Blanchon T, et al. Dual infections by influenza A/H3N2 and B viruses and by influenza A/H3N2 and A/H1N1 viruses during winter 2007, Corsica Island, France. J Clin Virol 2008;41:148–51. [19] 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;117:5050–6. [20] Chaves SS, Aragon D, Bennett N, Cooper T, D’Mello T, Farley M, et al. Patients hospitalized with laboratoryconfirmed influenza during the 2010–2011 influenza season: exploring disease severity by virus type and subtype. J Infect Dis 2013;208:1305–14. [21] Jain S, Benoit SR, Skarbinski J, Bramley AM, Finelli L, Pandemic Influenza AVHIT. Influenza-associated pneumonia among hospitalized patients with 2009 pandemic influenza A (H1N1) virus – United States, 2009. Clin Infect Dis 2012;54:1221–9. [22] 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;96:1231–5. [23] Siau C, Tee A, Au V, Raghuram J, Oh HM, Fock KM, et al. Influenza A H1N1 (2009): clinical spectrum of disease among adult patients admitted to a regional hospital in Singapore. Singapore Med J 2011;52:475–80. [24] Caselli D, Carraro F, Castagnola E, Ziino O, Frenos S, Milano GM, et al. Morbidity of pandemic H1N1 influenza in children with cancer. Pediatr Blood Cancer 2010;55: 226–8. [25] Cost C, Brock E, Adams-Huet B, Siegel JD, Ardura MI. 2009 pandemic influenza A (H1N1) virus infection in pediatric oncology and hematopoietic stem cell transplantation patients. Pediatr Blood Cancer 2011;56:127–33. [26] Rihani R, Hayajneh W, Sultan I, Ghatasheh L, Abdel-Rahman F, Hussein N, et al. Infections with the 2009 H1N1 influenza virus among hematopoietic SCT recipients: a single center experience. Bone Marrow Transplant 2011; 46:1430–6. [27] Souza TM, Salluh JI, Bozza FA, Mesquita M, Soares M, Motta FC, et al. H1N1pdm influenza infection in hospitalized cancer patients: clinical evolution and viral analysis. PLoS One 2010;5:e14158. [28] Espinosa-Aguilar L, Green JS, Forrest GN, Ball ED, Maziarz RT, Strasfeld L, et al. Novel H1N1 influenza in hematopoietic stem cell transplantation recipients: two centers’ experiences. Biol Blood Marrow Transplant 2011; 17:566–73.
Original article
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Clinical presentations and outcomes of influenza infection among hematology/oncology patients from a single cancer center: pandemic and post-pandemic seasons Mustafa Saad1,2, Wail Hayajneh3, Sawsan Mubarak4, Ibraheem Yousef1, Hazem Awad5, Wafa Elbjeirami6 & Rawad Rihani5 From the 1Department of Medicine, King Hussein Cancer Center, Amman, Jordan, 2Department of Medical Administration, Prince Sultan Cardiac Center, Riyadh, KSA, 3Department of Pediatrics, Jordan University of Science and Technology, Irbid, Jordan, 4Infection Control Program, 5Department of Pediatrics, and 6Department of Pathology, King Hussein Cancer Center, Amman, Jordan
Abstract Background: Influenza can cause severe infection in hematology/oncology patients. The occurrence of the 2009 pandemic represented an opportunity to study the impact of influenza on such patients in pandemic and post-pandemic seasons. Methods: We retrospectively reviewed medical records of hematology/oncology patients who had laboratory-confirmed influenza infection during the 2009 pandemic and the first post-pandemic seasons. We assessed influenza-related outcomes in both seasons with emphasis on the development of pneumonia and mortality. We also analyzed factors associated with poor outcomes. Results: We included 350 patients; 207 were diagnosed in the pandemic and 143 in the post-pandemic seasons. Influenza severity was similar in both seasons with no significant differences in the development of pneumonia or death. Infection with the pH1N1 virus was associated with the development of pneumonia (24.7% vs 14.9%, p 0.029) but did not affect mortality. A multivariate analysis showed that initiation of antiviral treatment after 48 h, healthcare acquisition of influenza, and low albumin were independent risk factors for the development of pneumonia (p values 0.022, 0.003, and 0.0001, respectively). A log-rank test showed increased mortality in patients who received therapy 48 h after onset of symptoms (p 0.001). Conclusions: In hematology/oncology patients, influenza was as severe in the post-pandemic as in the pandemic season. Pneumonia developed more commonly in patients infected with pH1N1 virus. Healthcare acquisition of infection and low albumin were associated with the development of pneumonia. Delayed initiation of antiviral treatment was associated with both pneumonia and mortality.
Keywords: H1N1 influenza, 2009 pandemic, post-pandemic, hematology, oncology
Introduction The year 2009 was marked by the occurrence of the first influenza pandemic in the 21st century. The pandemic started with the reporting of the first series of infections with a novel swine-origin H1N1 influenza virus in April 2009, and was officially declared a pandemic by the World Health Organization (WHO) in June, 2009 [1]. The 2009 H1N1 pandemic (pH1N1) virus was the predominantly circulating influenza virus in the 2009/2010 season. The pandemic has affected people of all ages around the world with the highest rates being reported in children and young adults, and the overall case-fatality
rate was estimated to be 0.5% [2]. In August 2010, the WHO declared the pandemic to be over, marking the beginning of the first post-pandemic influenza season in the 21st century [3]. Hematology/oncology patients were classified among high-risk groups expected to have excess morbidity and mortality during the 2009 pandemic. Although prior studies have shed some light on the clinical presentations and outcomes of pandemic influenza in these patients, little is currently known about the risk factors for poor outcomes, rates of influenza-related complications, and the optimal timing and duration of antiviral therapy in this
Correspondence: Mustafa Saad MD, Department of Medical Administration, Prince Sultan Cardiac Center, PO Box 7897-A.55, Riyadh 11159, KSA. E-mail: [email protected] (Received 8 February 2014; accepted 24 June 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.943282
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vulnerable group. Furthermore, studies of influenza infection in cancer patients during post-pandemic seasons are lacking. This study was conducted to better understand the clinical presentations, complications, outcomes, and risk factors for poor outcomes of influenza infections in pandemic and post-pandemic seasons in hematology/oncology patients from a single cancer center in Jordan.
Materials and methods Scand J Infect Dis Downloaded from informahealthcare.com by University of Newcastle on 08/23/14 For personal use only.
Patients Microbiology data and infection control records at the King Hussein Cancer Center were searched for patients diagnosed as having influenza infection in the pandemic (2009/2010) and post-pandemic (2010/2011) seasons. We only included cases confirmed by positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) tests for any of the influenza viruses. Each patient was included once per season. We retrospectively reviewed medical records of patients and collected data on: demographics, underlying diseases, co-morbid conditions, immunosuppression, clinical presentations, radiological and laboratory investigations, treatments received, and outcomes. Patients were followed until they showed complete resolution of all signs and symptoms related to infection or death. For patients who survived, the median follow-up was 135 days (range 39–790) for the pandemic versus 120 days (range 20–385) for the post-pandemic seasons. The study protocol was approved by the institutional review board before the study was conducted; written informed consent was waived.
RT-PCR test The RT-PCR test was run on samples obtained by nasopharyngeal washes or swabs or bronchoalveolar lavage fluid from patients with clinical presentations compatible with influenza. Patients who presented between September 28 and October 17, 2009 had their samples tested for the pH1N1 virus by RT-PCR at the central laboratories of the Ministry of Health of Jordan. Kits were provided to the central laboratories through the WHO and followed the protocol from the US Centers for Disease Control and Prevention. As of October 18, 2009 and until the end of the post-pandemic season, all influenza infections were confirmed using a multiplex RT-PCR test (FTD FLU, Fast-Track Diagnostics, Luxembourg) that can detect influenza A, influenza B, and pH1N1 (swinelineage) viruses.
Definitions We applied similar definitions to those described in previous studies [4,5]. A case of influenza was defined as a patient with any hematology/oncology diagnosis (benign or malignant) who presented with an acute respiratory illness compatible with influenza, and infection was confirmed by a positive RT-PCR test. Infections were classified as community-acquired if symptoms developed before or within 48 h of admission, or healthcare-associated if the onset of symptoms was 48 h after hospitalization. Upper respiratory tract infection (URI) was defined as the onset of a combination of rhinorrhea, nasal congestion, sore throat, and cough, and a positive RT-PCR test on a nasopharyngeal wash or swab, with no radiological evidence of pneumonia. Pneumonia was defined as the presence of signs and symptoms of influenza with a positive RT-PCR test on a nasopharyngeal wash or bronchoalveolar lavage fluid, and new or changing pulmonary infiltrates seen on chest X-rays or CT scans. Gastrointestinal complaints included nausea, vomiting, diarrhea, and abdominal pain. Neurological complaints included headache, dizziness, seizures, confusion and, for infants, hypo-activity and irritability. Obesity was defined as a body mass index (BMI) of 30 in adults 18 years of age or older, or a BMI percentile of 95–100 in children between the ages of 1 and 18 years. Neutropenia was defined as an absolute neutrophil cell count of 500 cells/ml and severe lymphopenia was defined as an absolute lymphocyte cell count of 200 cells/ml. Concomitant antimicrobials included all antibiotics used while the patient was receiving antiviral treatment for influenza. A concurrent co-infection was considered when another organism (a bacterium, virus other than influenza, or fungus) was isolated within 14 days of influenza isolation by RT-PCR. Complete recovery was defined as the resolution of all signs and symptoms related to influenza regardless of viral shedding. In addition to complete recovery, other clinical outcomes that were followed included progression to pneumonia and mortality within 60 days of onset of symptoms. Immunodeficiency status was classified into none, mild, moderate, or severe. We applied the same criteria that were previously described by Chemaly et al. [5]. Statistical methods Univariate comparisons for categorical data were made using either chi-squared or Fisher’s exact tests. The Mann–Whitney test was used to compare continuous variables. A p value 0.05 (based on a two-tailed test) was considered statistically significant.
Cancer and pandemic/post-pandemic influenza Results
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Risk factors for the development of pneumonia were initially assessed using a univariate analysis. Then factors that were found to be significant in the univariate analysis were included in a multivariate regression analysis to identify independent risk factors for the development of pneumonia. A log-rank test was used to assess mortality in patients who received antiviral treatment within 48 h of the onset of symptoms versus those who did not. All statistical analyses were performed using the Statistical Package for the Social Sciences software, version 16.0 (SPSS Inc., Chicago, IL, USA).
Pandemic versus post-pandemic seasons A total of 350 patients with RT-PCR-confirmed influenza infection were included in the study; 207 were diagnosed in the pandemic and 143 were diagnosed in the post-pandemic 2010/2011 season. As shown in Table I, patients in the two seasons were similar with regard to age, gender, immunodeficiency status, underlying diseases, and presence of obesity. Patients in the post-pandemic season were more likely to have an active underlying disease at the time
Table I. Baseline characteristics of patients with influenza infections: pandemic (2009/2010) versus post-pandemic (2010/2011) seasons. Characteristic Total Age Median (years) Range (years) Age group, no. (%) 0–5 years 6–18 years 19–50 years 50 years Sex, no. (%) Male Female Type of influenza, no. (%) pH1N1 virus Influenza A (non-pandemic) Influenza B pH1N1 and influenza B Immunodeficiency status, no. (%) None Mild Moderate Severe Underlying disease (%) Hematological malignancy Solid tumor Benign hematology Status of underlying condition, no. (%) Active Remission HSCT recipient, no. (%) Allogeneic HSCT Autologous HSCT Obesity, no. (%) Co-morbid conditions, no. (%) Any condition Hypertension Diabetes mellitus Chronic airway diseases Chronic kidney disease Endocrine disorders Hyperlipidemia Cardiac diseases Neuropsychiatric disorders Other
3
Pandemic season
Post-pandemic season
207
143
13.0 0.8–75
16.5 0.67–79
NS
29 44 41 29
(20.3%) (30.8%) (28.7%) (20.3%)
NS
115 (55.6%) 92 (44.4%)
84 (58.7%) 59 (41.3%)
NS
174 5 26 2
(84.1%) (2.4%) (12.6%) (1.0%)
42 42 58 1
(29.4%) (29.4%) (40.6%) (0.7%)
72 39 56 40
(34.8%) (18.8%) (27.1%) (19.3%)
38 26 38 41
(26.6%) (18.2%) (26.6%) (28.7%)
40 84 56 27
(19.3%) (40.6%) (27.1%) (13.0%)
p value
0.0001
NS
NS 113 (54.6%) 71 (34.3%) 23 (11.1%)
89 (62.2%) 45 (31.5%) 9 (6.3%) 0.037
63 144 45 32 13 39/186 56 31 21 20 7 6 5 4 1 11
(30.4%) (69.6%) (21.7%) (15.5%) (6.3%) (21.0%) (27.1 %) (15.0%) (10.1%) (9.7%) (3.4%) (2.9%) (2.4%) (1.9%) (0.5%) (5.3%)
HSCT, hematopoietic stem cell transplant; NS, not significant.
59 84 29 13 16 32/135
(41.3%) (58.7%) (20.3%) (9.1%) (11.2%) (23.7%)
NS 0.024
62 20 15 13 6 11 6 5 8 11
(43.4%) (14.0%) (10.5%) (9.1%) (4.2%) (7.7%) (4.2%) (3.5%) (5.6%) (7.7%)
0.002 NS NS NS NS 0.04 NS NS 0.004 NS
NS
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of diagnosis (41.3% vs 30.4%, p 0.037) and to have co-morbid conditions (43.4% vs 27.1%, p 0.002). More patients in the pandemic season, on the other hand, had received allogeneic hematopoietic stem cell transplants (HSCTs) (15.5% vs 9.1%, p 0.024). Table I summarizes the baseline characteristics of patients in both seasons. During the pandemic season, pH1N1 was the most common circulating influenza virus, causing 84.1% of infections, followed by influenza B and thereafter influenza A viruses. In the post-pandemic season, all three viruses were circulating among patients, with a slight dominance of the influenza B virus, which caused 40.6% of cases. Three patients from both seasons had co-infections of the pH1N1 and influenza B viruses. Not only were the two seasons different in the types of circulating viruses, but onset, peak, and duration of the influenza seasons were also different (Figure 1). During the pandemic, the influenza season started earlier (week 39/2009), showed one large peak, and ended earlier (spanned over 13 weeks). In contrast, the post-pandemic season started later (week 47/2010), had two peaks, and lasted longer (spanned over 21 weeks). Patients in both seasons presented with influenza-like illnesses (Table II). Clinical manifestations in both seasons were similar except for fever (84.5% vs
70.6%, p 0.002) and sore throat (41.5% vs 21.0%, p 0.0001), which were more common during the pandemic season. Healthcare-associated infection was more frequently encountered in the postpandemic season (12.6% vs 6.3%, p 0.041). Duration of symptoms before hospitalization (median, 2 versus 1 day, p 0.014) and duration of hospital stay (median, 7 versus 5 days, p 0.014) were longer in the post-pandemic season. No differences were noted between the two seasons in the baseline laboratory abnormalities. Most of the patients received antiviral therapy, namely oseltamivir. Three patients, one with influenza B during the pandemic and two with pH1N1 in the post-pandemic seasons, died before the diagnosis was established and did not receive antiviral therapy. Other patients who did not receive antiviral treatment had mild presentations and recovered completely. Patients in both groups were managed similarly in terms of oseltamivir usage and duration, and the use of concomitant antimicrobials and adjunctive treatments. Mortality in both seasons was high, 10 and 12 deaths occurring in the pandemic and post-pandemic seasons. All other influenza-related outcomes and complications, including hospitalization, development of pneumonia, intensive care unit (ICU) admission,
60 pH1N1
Influenza A
Influenza B
50
Number of new cases
40
30
20
0
2010-44 2010-45 2010-46 2010-47 2010-48 2010-49 2010-50 2010-51 2010-52 2011-1 2011-2 2011-3 2011-4 2011-5 2011-6 2011-7 2011-8 2011-9 2011-10 2011-11 2011-12 2011-13 2011-14 2011-15 2011-16 2011-17 2011-18
10
2009-36 2009-37 2009-38 2009-39 2009-40 2009-41 2009-42 2009-43 2009-44 2009-45 2009-46 2009-47 2009-48 2009-49 2009-50 2009-51 2009-52 2010-1 2010-2 2010-3
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Week/Year Figure 1. Number of influenza cases by type and by week of diagnosis in the pandemic and the first post-pandemic seasons in hematology/ oncology patients.
Cancer and pandemic/post-pandemic influenza
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Table II. Clinical presentations, treatments, and outcomes of patients diagnosed with influenza: pandemic (2009/2010, n 207) versus post-pandemic (2010/2011, n 143) seasons.
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Characteristic Symptoms, no. (%) Fever Cough Runny nose Sore throat Sputum production Shortness of breath Myalgia/arthralgia Fatigue Gastrointestinal complaints Neurological complaints Duration of symptoms before hospitalization Median (range), days Acquisition of infection, no. (%) Healthcare-associated Community-acquired Infection type, no. (%) Upper respiratory tract infection Pneumonia Laboratory abnormalities on presentation, no. (%) Leukocytosis (WBC count 11 000/mm3) Neutropenia (ANC 500 cells/ml) Severe lymphopenia (ALC 200 cells/ml) Elevated creatinine ( 1.3 mg/dl) Decreased albumin ( 3.5 g/dl) Admission to the hospital, no. (%) Duration of hospital stay, median (range), days ICU admission, no. (%) Mechanical ventilation, no. (%)a Duration of ICU stay, median (range), days Antiviral treatment, no. (%) Oseltamivir None Duration of oseltamivir therapy, median (range), days Concomitant antimicrobial treatment, no. (%) Adjunctive treatment, no. (%) GCSF IVIG Concurrent co-infections, no. (%) Mortality, no. (%)
Pandemic season 175 180 134 86 43 40 43 37 48 44
(84.5%) (87.0%) (64.7%) (41.5%) (20.8%) (19.3%) (20.8%) (17.9%) (23.2%) (21.3%)
Post-pandemic season 101 124 80 30 38 25 30 27 28 29
(70.6%) (86.7%) (55.9%) (21.0%) (26.6%) (17.5%) (21.0%) (18.9%) (19.6%) (20.3%)
p value 0.002 NS NS 0.0001 NS NS NS NS NS NS
1.0 (1–21)
2.0 (1–14)
0.014
13 (6.3%) 194 (93.7%)
18 (12.6%) 125 (87.4%)
0.041
169 (81.6%) 38 (18.4 %)
108 (75.5%) 35 (24.5%)
NS
13/198 29/198 22/198 12/155 69/155 99 5.0 22 18 6.0
(6.6%) (14.6%) (11.1%) (7.7%) (44.5%) (47.8%) (1–72) (10.6%) (8.7%) (1–33)
8/134 28/134 12/134 15/111 41/111 72 7.0 23 17 4.0
(6.0%) (20.9%) (9.0%) (13.5%) (36.9%) (50.3%) (2–90) (16.1%) (11.9%) (1–77)
NS NS NS NS NS NS 0.014 NS NS NS
198 9 9.0 174
(95.7%) (4.3%) (1–17) (84.1%)
131 12 10 125
(91.6%) (8.4%) (1–12) (87.4%)
NS
22 2 12 10
(10.6%) (1.0%) (5.8%) (4.8%)
20 2 13 12
(14.0%) (1.4%) (9.1%) (8.4%)
NS NS NS NS
NS NS
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; GCSF, granulocyte colony stimulation factor; ICU, intensive care unit; IVIG, intravenous immunoglobulins; NS, not significant; WBC, white blood cell. aIncludes invasive and non-invasive ventilation.
use of mechanical ventilation, and concurrent co-infections were similar in both seasons. Table II compares the clinical presentations, treatments, and outcomes in both seasons. Pandemic H1N1 versus non-pandemic influenza viruses Pandemic H1N1 virus was the cause of influenza in 216 patients from both seasons, 3 patients had co-infections of pH1N1 and influenza B, and 131 patients developed influenza due to non-pandemic
viruses. Both groups were similar in their baseline characteristics including age, immunodeficiency status, underlying diseases, status of underlying conditions, receipt of HSCT, and presence of obesity and co-morbid conditions. Patients with pH1N1 infections were more likely to present with fever (85.8% vs 67.2%, p 0.0001), cough (89.5% vs 82.1%, p 0.047), sore throat (37.4% vs 26.9%, p 0.041), and shortness of breath (22.4% vs 11.9%, p 0.014). Other clinical manifestations were similar in both groups (data not shown). Laboratory abnormalities were similar in both groups except for decreased
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albumin, which was more common in patients with pH1N1 infections (45.9% vs 32.3%, p 0.03). Patients with pH1N1 influenza were more likely to present earlier (median, 1 vs 2 days, p 0.026), develop pneumonia (24.7% vs 14.9%, p 0.029), be hospitalized (54.3% vs 39.6%, p 0.007), receive antiviral treatment (96.3% vs 91%, p 0.037), and have longer duration of oseltamivir therapy (median, 10 vs 5 days, p 0.0003). Acquisition of infection, duration of hospitalization, ICU admission, co-infections, and mortality rates were similar in both groups.
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Outcomes Seventy-three (20.9%) patients developed pneumonia. Compared with patients who only had URI, patients with pneumonia were older (median age, 44 vs 11 years, p 0.0001), had moderate to severe immunodeficiency (71.2% vs 44.4%, p 0.0001), had an active underlying disease (64.4% vs 27.1%, p 0.0001), were obese (36.4% vs 18.5%, p 0.017),
had co-morbid conditions (56.2% vs 27.8%, p 0.0001), and were more likely to develop healthcare-associated infections (30.1% vs 3.2%, p 0.0001). Pandemic H1N1 virus was isolated in the majority (74%) of patients with pneumonia. Underlying diseases were similar in patients with URI and pneumonia. Laboratory abnormalities occurred more commonly in patients with pneumonia, who tended to have neutropenia more frequently (28.8% vs 6.6%, p 0.0001), renal impairment (22.2% vs 5.6%, p 0.0001), and decreased albumin (77.7% vs 27.8%, p 0.0001). Furthermore, patients with pneumonia presented later (median, 2 vs 1 day, p 0.0005), and were less likely to receive antiviral therapy within 48 h of symptoms onset (45.0% vs 73.9%, p 0.0001). Multivariate logistic regression showed that delayed initiation of antiviral therapy, healthcare acquisition of infection, and low albumin were independent factors for the development of pneumonia (p values 0.022, 0.003, and 0.0001, respectively) (Table III).
Table III. Risk factors for the development of pneumonia in patients with PCR-confirmed influenza infections. Pneumonia Characteristic Age in years, median (range) Age group, no. (%) 0–5 years 6–18 years 19–50 years 50 years Type of influenza, no. (%) pH1N1 Non-pH1N1 Immunodeficiency status, no. (%) None–mild Moderate–severe Underlying disease, no. (%) Hematological malignancy Solid tumor Benign hematology Status of underlying condition, no. (%) Active Obesity, no. (%) Co-morbid conditions (any), no. (%) Acquisition of infection, no. (%) Healthcare-associated Duration of symptoms before hospitalization, median (range), days Treatment within 48 h of symptoms Laboratory abnormalities on presentation, no. (%) Leukocytosis (WBC count 11 000/mm3) Neutropenia (ANC 500 cells/ml) Severe lymphopenia (ALC 200 cells/ml) Elevated creatinine ( 1.3 mg/dl) Decreased albumin ( 3.5 g/dl)
Yes (n 73) 44 (0.67–79) 7 10 31 24
(9.7%) (13.9%) (43.1%) (33.3%)
No (n 277) 11 (0.75–75) 62 117 66 32
(22.4%) (42.2%) (23.8%) (11.6%)
Univariate Multivariate logistic regression analysis p value Odds ratio (95% CI) p value 0.0001
1.02 (1–1.04)
0.13
0.0001
–
–
54 (74.0%) 19 (26.0%)
165 (59.6%) 112(40.4%)
0.024
2.06 (0.76–5.57)
0.15
21 (28.8%) 52 (71.2%)
154 (55.6%) 123 (44.4%)
0.0001
1.59 (0.32–7.90)
0.82
46 (63.0%) 24 (32.9%) 3 (4.1%)
156 (56.3%) 92 (33.2%) 29 (10.5%)
NS
–
–
47 (64.4%) 24/66 (36.4%) 41 (56.2%)
75 (27.1%) 47/254 (18.5%) 77 (27.8%)
0.0001 0.017 0.0001
1.60 (0.64–3.85) 1.68 (0.64–4.44) 1.63 (0.65–10.77)
0.32 0.3 0.3
0.0001 0.0005
6.51 (1.51–28.00) 1.07 (0.83–1.22)
0.003 0.34
0.0001
3.00 (1.51–28)
0.022
NS 0.0001 NS 0.0001 0.0001
– 1.43 (0.36–1.43) – 2.11 (0.61–7.34) 4.46 (1.85–10.75)
22 (30.1%) 2.0 (1–21) 27/60 (45.0%) 7/73 21/73 17/73 16/72 56/72
(9.6%) (28.8%) (23.3%) (22.2%) (77.7%)
9 (3.2%) 1.0 (1–21) 198/268 (73.9%) 14/259 17/259 36/259 11/195 54/194
(5.4%) (6.6%) (13.9%) (5.6%) (27.8%)
– 0.61 – 0.24 0.0001
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CI, confidence intervals; ICU, intensive care unit; NS, not significant; pH1N1, pandemic H1N1; WBC, white blood cell; –, not included.
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Overall, mortality in both seasons was 6.3% and was higher in patients who developed pneumonia; of the 22 patients who died, 20 (90.9%) had pneumonia and 2 (9.1%) had URI, with mortality rates of 27.5% and 0.7%, respectively (p 0.0001) (data not shown). A log-rank test revealed increased mortality when treatment was started 48 h from symptoms onset (p 0.001) (Figure 2). Patients who had pneumonia and died developed progressive respiratory failure, while those with URI who died had progressive underlying malignant diseases; one died after withdrawal of care.
Discussion In the current study, we describe the clinical presentations and outcomes of influenza infections in a relatively large cohort of hematology/oncology patients who developed influenza during the 2009 pandemic and the first post-pandemic seasons. Our study was conducted in a single cancer center where screening for and management of influenza were consistent over both seasons, and followed locally adapted guidelines that were developed at the onset of the pandemic. There are several important findings that need to be highlighted. First, the severity of influenza was comparable in the pandemic and post-pandemic seasons. Indeed, in the post-pandemic season the rates of pneumonia (24.5% vs 18.4%) and mortality were higher (8.4% vs 4.8%) but the differences were not statistically
Cancer and pandemic/post-pandemic influenza
7
significant. Similarly, several studies on the general population showed increased rates of pneumonia and mortality in the post-pandemic season [6–10]. The reasons behind these findings are not well understood. Yet we and other investigators observed significant differences between the two seasons that could have contributed to the severity of influenza in the post-pandemic season. Patients in the postpandemic season presented later [8,10], were older [7,8,10,11], and were more likely to have co-morbid conditions [7,8]. Second, clinical presentations were similar in the pandemic and post-pandemic seasons except for fever and sore throat, which were more common in the pandemic season. Furthermore, patients infected with the pH1N1 versus non-pandemic viruses were more likely to present with fever, cough, sore throat, and shortness of breath. Several studies have reported certain clinical manifestations to be more common in pH1N1 versus seasonal and post-pandemic influenza [10,12–14]. Nonetheless, the majority of patients in these and other studies have presented with nonspecific influenza-like illnesses; this indicates that pandemic influenza cannot be differentiated from seasonal influenza in individual patients on clinical grounds alone and emphasizes the need to confirm the diagnosis by more objective tests. Third, while pH1N1 was the most common circulating virus in the pandemic season, representing 84.1% of infections, the post-pandemic season was characterized by the circulation of various influenza viruses. In particular, influenza B was more common
Figure 2. Log-rank test for patients who received antiviral treatment within 48 h of onset of symptoms versus those who did not (p 0.001).
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8
M. Saad et al.
during the post-pandemic season than pH1N1 and non-pandemic influenza A viruses. This is different from reports on influenza in the first post-pandemic season in the general population [6,11,15], where pH1N1 was the cause of influenza in 67–98% of infections. The difference in the circulating viruses observed may partly be due to the fact that our cohort only included hematology/oncology patients and is the only study reported from our region. In our study, three patients had dual co-infections with pH1N1 and influenza B viruses; a finding reported previously by Calistri et al. [16]. Furthermore, dual co-infections with two seasonal influenza viruses have also been described [17,18]. Fourth, patients infected with the pH1N1 virus were more likely than patients subjected to nonpandemic strains to be admitted to the hospital and to develop pneumonia. But, in multivariate analysis, pH1N1 virus was not an independent risk factor for the development of pneumonia. Additionally, the type of influenza virus had no impact on influenzaassociated mortality. Similarly, Choi et al. and Chaves et al. [19,20] reported increased incidence of pneumonia following pH1N1 versus seasonal influenza, but pH1N1 had no impact on influenza-associated mortality. Fifth, our study showed three factors, namely delayed initiation of antiviral treatment, healthcare acquisition of infection, and low albumin, to be independent risk factors for the development of pneumonia. The effect of delayed antiviral treatment on the development of pneumonia has been described previously [4,5,19,21]. However, healthcare acquisition of influenza and low albumin seem to be unique to our study. Although these findings were reported by other investigators, they were not shown to be independent risk factors for the development of pneumonia [22,23]. Patients who have low albumin are usually malnourished and tend to be more ill and hence more susceptible to develop severe complications once infected. In particular, the ability of the body to synthesize essential proteins will be affected, which may include those produced by the immune system to defend against different infectious pathogens. In contrast to our study, Ljungman et al. [22], Choi et al. [19], and Chemaly et al. [5] reported older age, moderate to severe immunodeficiency, and lymphopenia as independent risk factors for the development of pneumonia. While the rationale behind the differences between our study and these studies is not apparent, their study populations were different from ours; they included older patients (median 38.3–42 vs 14.5 years), patients from different countries/ regions, and patients with either solid tumors or HSCT [5,19,22].
Sixth, the overall mortality rate in our cohort was 6.3%. This rate is high compared with the mortality from pandemic influenza in the general population, which was reported to be 0.5% [2]. In contrast, mortality rates in hematology/oncology patients with pH1N1 infection were reported at a wide range of estimates (0–22%) in different studies [5,22,24–28]. In our study, almost all patients who died had pneumonia with progressive respiratory failure. Our data, in agreement with other reports [5,8,19], show that delayed initiation of antiviral treatment is an important risk factor for poor outcome in patients with influenza infections. Our study has several limitations inherent to its design. First, this is a retrospective study with data collection from laboratory reports and medical records. This carries the potential for incomplete recording of data and/or variation of data entry according to the healthcare provider. Second, data on vaccination of patients were not available to study the impact of immunization on the epidemiology of influenza. Third, during the first 3 weeks of the pandemic, only RT-PCR tests that detect pH1N1 were used. So, we could have missed non-pandemic influenza cases during that period and this could have affected our results. Finally, no data on viral shedding or resistance were available to study their impact on influenza outcomes. In conclusion, our study on hematology/oncology patients demonstrates that the first post-pandemic season was similar in severity to the 2009 pandemic season. Patients infected with the pH1N1 virus were more likely to present with pneumonia. Delayed initiation of antiviral treatment, healthcare acquisition of infection, and low albumin were independent risk factors for the development of pneumonia. Mortality significantly increased in patients who received antiviral therapy 48 h after symptoms onset. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] New influenza A (H1N1) virus: global epidemiological situation, June 2009. Releve epidemiologique hebdomadaire/ Section d’hygiene du Secretariat de la Societe des Nations Weekly epidemiological record/Health Section of the Secretariat of the League of Nations 2009;84:249–57. [2] Writing Committee of the WHOCoCAoPI, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362:1708–19. [3] World Health Organization declares post-pandemic phase. Euro Surveill 2010;15(32). Available from: URL: http:// www.eurosurveillance.org/ViewArticle.aspx?ArticleId 19636
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