2��� H1N1 In�uenza In�ection�Related Hospital Admissions� A Single Center Experience with Adult Patients in West Texas

Background . Clinical information collected during the �rst wave of in�uenza pandemics may provide important pro�ections about disease activity during subsequent waves. Methods . We performed a retrospective study of hospitalized patients with 2009 H1N1 in�uenza infection during the second wave and compared our �ndings with literature reports from the �rst wave. Results . ere were 31 admissions, including 15 to the intensive care unit (ICU). Twenty-�ve patients (81 % ) had at least one chronic medical condition; 12 patients (39 % ) were obese. irty-three percent of the ICU patients and 75 % of the non-ICU patients were admitted within 48 hours of symptom onset ( 𝑃𝑃 𝑃 𝑃𝑃𝑃𝑃 ). In�ltrates on C�R were seen in 60 % of the ICU group and 19 % of the non-ICU group within 48 hours of admission ( 𝑃𝑃 𝑃 𝑃𝑃𝑃𝑃 ). Forty-three percent of the ICU patients and 71 % of the non-ICU patients received oseltamivir within 48 hours of illness. All non-ICU patients survived; 73 % of the ICU patients survived ( 𝑃𝑃 𝑃 𝑃𝑃𝑃𝑃𝑃 ). Conclusions . Our patients in the second wave resembled patients reported from the �rst wave of the 2009 pandemic and had similar mortality rates. Delayed medical attention possibly explains the high number of ICU admissions in our study.


Introduction
e H1N1 in�uenza pandemic began in April 2009, and lasted until April 2010, in the USA. ere were 61 million cases of 2009 H1N1 infection in the USA, resulting in 274,000 hospitalizations and 12,470 deaths [1]. In contrast to seasonal in�uenza, more than 50% of cases, hospitalizations and deaths occurred in patients between 18 and 64 years of age [1][2][3]. During this pandemic, there were two waves of in�uenza activity in the USA [1]. e �rst wave started in mid-April and peaked in June; the second wave peaked in mid-October and declined quickly in December. Multiple waves of in�uenza activity have been observed in the past three pandemics, and the number of cases with pandemic in�uenza infection is usually higher a�er the �rst wave [4,5]. In addition, the second or third wave of the past pandemics is usually more lethal than the �rst wave [4][5][6]. Patients younger than 45 had a notably higher mortality rate than the elderly in all three waves of the 1918 pandemic [5][6][7][8][9][10]. Our hospital had no cases during the �rst wave but had multiple cases during the second wave. We report clinical information on hospitalized adults with 2009 H1N1 in�uenza infection during the second wave and compare important outcomes to published information on the �rst wave. We also brie�y discuss the community health implications of multiple waves of in�uenza activity. Data Collection. Data were collected for the following categories: epidemiologic characteristics, chronic medical conditions, clinical presentations, diagnostic laboratory, antiviral treatment, intensive care unit (ICU) admissions, and outcomes. Epidemiologic characteristics included age, sex, body mass index (BMI), smoking habit, and alcohol consumption. Chronic medical conditions included diabetes, hypertension, chronic kidney diseases, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease (COPD), asthma, pulmonary hypertension, organ transplant, and malignancy. Clinical presentations included date of the �rst symptom, date of admission, systemic symptoms, respiratory symptoms, gastrointestinal symptoms, vital signs, and oxygenation.

Materials and Methods
Diagnostic laboratory included complete blood counts and differentials, complete metabolic panels, RT-PCR assays for 2009 H1N1 in�uen�a on nasopharyngeal (NP) or oropharyngeal (OP) sample, chest X-rays, and blood cultures. Antiviral treatment included date of treatment initiation and duration of treatment. Intensive care unit admissions included time of admission, ventilator use, vasopressor use, and duration of ICU admission. Outcomes included diagnosis of acute respiratory distress syndrome (ARDS), septic shock, secondary bacterial infections, survival, and status at discharge.
Statistical Analysis. Statistical analysis was performed using SAS soware (version 9.2, SAS Institute, Cary, NC, USA) and SPSS soware (IBM SPSS version 19, Chicago, IL, USA). We report continuous variables as means and standard deviations and categorical variables as percentages. e 2 test or Fisher's exact test was used for comparison of categorical variables. e Student's t-test was used for comparison of continuous variables. Logistic regression analysis was used to identify factors associated with ICU admission and with death. All statistical tests were two-sided, and comparisons at P < 0.05 were considered signi�cant.

Clinical Information on All Admissions with 2009 H1N1
In��en�a Infection. ere were 31 hospital admissions for RT-PCR-con�rmed 2009 H1N1 in�uen�a infection between September 2009 and January 2010. Fieen patients (48%) were admitted to the ICU, and four (13%) died. Fiy-two percent were female; the mean age was 45 years (Table 1). Twenty-�ve patients (81%) had at least one chronic medical condition, including 12 patients (39%) with a BMI greater than 30 (Table 1). Symptoms and selected vital signs are detailed in Table 2. Seventeen patients (55%) presented to the hospital within 48 hours of the onset. Sixty-�ve percent had abnormal chest X-ray (Table 3). Ninety percent of the abnormalities were consistent with interstitial pneumonitis. Fiy-�ve percent had lobar pneumonia based on their chest X-ray �ndings. e abnormalities on chest X-ray were identi�ed within the �rst 48 hours of admission in 12 patients (39%). e RT-PCR assay for 2009 H1N1 in�uen�a was positive in 28 NP samples and in 8 OP samples. Treatment, complications, and outcomes are detailed in Table 4.

Clinical Comparisons between ICU and Non-ICU Admis-
sions. ere were no important differences in baseline characteristics between the ICU and non-ICU patients ( Table 1). e mean time from the onset of illness to hospital admission was 3.5 days in the ICU patients and 2.1 days in the non-ICU patients (P = 0.014) ( Table 2). irty-three percent of the ICU group presented to the hospital within 48 hours of their onset of illness; 75% of the non-ICU group presented within 48 hours (P = 0.03). All of the 15  X-rays consistent with interstitial pneumonitis ( Table 3); 19% of the non-ICU patients had interstitial pneumonitis on chest X-rays (P < 0.001). In�ltrates within chest X-ray within the �rst 48 hours of admission were seen in 60% of the ICU patients and 19% of the non-ICU group (P = 0.03). Eighty percent of the ICU group required mechanical ventilation, and 47% required vasopressors. In logistic regression analysis, higher respiratory rate was associated with ICU admission (Table 5). Due to the small sample size and the high correlation of some of the variables with each other, we only included the four most signi�cant variables in this analysis.
All non-ICU admissions survived the infection and were discharged; 73% of the ICU admissions survived and were discharged (P = 0.043). ree deaths had interstitial pneumonitis within 48 hours of admission. All of the four deaths had at least one of the three complications (ARDS, septic shock, and bacterial infections). Logistic regression analysis demonstrated that septic shock increased the likelihood of death (odds ratio = 39.2, 95% CI = 1.8-857.3, P = 0.02, aer adjustment for age, gender, and BMI). Ventilator use, vasopressor use, and ICU admission were not entered into the logistic regression analysis, even though they were signi�cant factors in the univariate analysis. ese clinical factors were all highly correlated with septic shock and with each other.

Discussion
Studies from several countries have reported clinical observations on hospitalized patients during the �rst wave in both ICU and non-ICU settings [11][12][13][14][15]. ese studies reported that more than 90% of hospital admissions occurred in people younger than 65, and most of them had at least one chronic medical condition [11][12][13][14][15]. Approximately 30% of patients were obese [11][12][13]. Pregnancy was reported in seven to nine percent [11][12][13]15]. �ilateral in�ltrates were noted on chest X-rays on admission in 27-71% of cases [11][12][13]. Mortality rates were between 5% and 17% [11][12][13][14]. Antiviral treatment within 48 hours of the onset was identi�ed as the only variable signi�cantly associated with better outcomes [11]. Ninety percent of the patients admitted to our hospital were younger than 60 years, and 81% had chronic medical conditions, including chronic heart or lung diseases and obesity. e clinical data in our patients hospitalized during the second wave are similar to the information reported from the �rst wave in the medical literature. e high percentage of our ICU admissions may be secondary to delayed medical care. Sixty-seven percent of patients admitted to the ICU presented aer more than 48 hours of illness. Although in the logistic regression analysis P value for the number of days with symptom before admission to the hospital was not below the conventional value of 0.05, it was close (P � 0.06). A study of 2009 �1N1 in�uenza infection-related ICU admissions in Canada also reported delayed medical attention in ICU patients during the �rst wave of the pandemic, with a median time of �ve days from the onset of illness to ICU admission [13]. Seventyone percent of patients in the Canadian study had bilateral in�ltrates on chest X-ray on presentation. Campbell et al. reported that a delay of one day from the onset of illness to hospital admission increased the risk of death by 5.5% [14].
More patients in our ICU group received antiviral treatment aer 48 hours of illness with a mean time from the illness onset to the antiviral therapy of four days in the ICU group. During the �rst wave of the pandemic, 79% of admissions in adult patients received antiviral treatment, but only 32% received it within 48 hours of their onset [11]. Jain et al. reported delayed antiviral treatment in patients admitted to an ICU; antiviral treatment within 48 hours of the onset was identi�ed as the only variable signi�cantly associated with better outcomes [11]. A Chilean study also demonstrated improved outcomes with early treatment [15]. e overall mortality rate in our study was 13%. ree of four patients who died were younger than 50 years, and all had chronic medical conditions except one who was a smoker. Mortality of 2009 �1N1 in�uenza infections during the �rst wave was between 5% and 17% in hospitalized patients [11][12][13][14]. Jain et al. reported that all deaths were in young patients, but almost 70% of these patients had an underlying medical condition [11]. In addition, all patients who died received antiviral treatment aer 48 hours of the illness onset [11].
Multiple factors potentially in�uence the development of successive waves during in�uenza pandemics. �iral transmission depends on the movement of infected source cases from communities with high levels of infection to communities with lower levels of infection. Studies in Peru have demonstrated that cases �rstly occurred in large population centers and then moved to smaller communities [16]. School vacation schedules also appeared to have an important effect on the distribution of infection and the number of cases in younger age groups fell during school vacations. Consequently, schools seem to represent an initial site for the acquisition of infection with transfer into families and communities. e analysis of the spatial-temporal distribution of infection in Europe also suggested that the heterogeneous pattern of cases could potentially be explained by school calendars and by travel patterns [17]. e second factor in the development of successive waves involves changes in viral characteristics. Yang et al. have reported changes in the hemagglutinin gene (based on proteotyping) in H1N1 viruses during successive waves in Taiwan [18]. Consequently, immunity could fall over time if the viral antigens have sufficiently changed so that prior immunity is no longer as effective as it was once. Wessel and coworkers demonstrated that drug pressure can lead to the development of multiple waves, and, of course, the development of drug resistance makes the currently available limited antiviral therapy less effective [19]. Dang and Bauch have suggested that the timing of vaccination in�uences outcomes during successive waves [20]. Populations vaccinated in the late summer or the early fall may have waning immunity in the winter months. During both seasonal in�uenza and this pandemic more frequent ICU admissions occurred during the winter months, this resulted in poorer outcomes and more deaths. ese population studies suggest that community health organizations need to provide real-time information about viral distribution, disease activity, and mortality during in�uenza pandemics. In particular, the timing of vaccinations and possibly revaccination in certain populations seem important. One important lesson that was available early in the 2009 H1N1 pandemic is that the population at risk was in general younger than the usual population at risk in seasonal in�uenza, and that early treatment of sicker cases was essential to reduce morbidity and mortality.
Information collected during the �rst wave should have alerted clinicians to the fact that hospitalization during this pandemic largely involved young adults with chronic medical conditions or obesity and that the mortality rate for younger adults was higher than that observed in seasonal in�uenza infections. Antiviral treatment within 48 hours of symptom onset can decrease morbidity and mortality from in�uenza infection in the general population and in high-risk patients, and vaccination strategies need to consider the possibility of waning immunity during subsequent waves. Public health officials need to communicate information collected during the �rst wave to both the public and the health care providers and provide more information to physicians about the potential for a second wave with higher mortality. Physicians need to organize their clinical practices to provide more rapid access for patients with respiratory symptoms if a second wave starts. ��n��c� �f �n�eres�s e authors declare that they have no con�ict of interests.