Comparison of characteristics of outpatients with 2009 H1N1 pandemic and seasonal influenza

George Theocharis,1, MD, Evridiki K. Vouloumanou,2, MD, Spyridon G. Barbas, MD,1, Theodore Spiropoulos, MD,1 Petros I. Rafailidis,2,3, MD, MRCP UK, MSc, Matthew E. Falagas,2,3,4, MD, MSc, DSc

  1. SOS Doctors, Athens, Greece
  2. Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece
  3. Department of Medicine, Henry Dunant Hospital, Athens, Greece
  4. Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA

Corresponding author: Matthew E. Falagas, MD, MSc, DSc
Alfa Institute of Biomedical Sciences (AIBS),
9 Neapoleos Street, 151 23 Marousi, Athens, Greece
Tel: +30 (694) 611-0000,
Fax: +30 (210) 683-9605
E-mail: [email protected]

Short title: Characteristics of outpatients with pandemic and seasonal influenza.
Conflict of interest: None
Funding: None
Word counts: abstract: 250, text: 2363
Number of tables: 2
Number of references: 20

Abstract

Background

The latest influenza pandemic intensified the interest in this infection.

Objective

We aimed to compare the epidemiological, clinical, and treatment characteristics of outpatients with seasonal and pandemic influenza.

Methods

We retrospectively collected and analyzed data regarding outpatients that sought medical advice from a network of physicians performing house-call visits at the area of Attica, Greece and underwent a direct influenza test during a period of seasonal influenza (1/1/2009-1/5/2009), as well as the 2009 H1N1 pandemic influenza period (17/5/2009-15/4/2010).

Results

A total of 195 and 1317 patients had a direct influenza test during the seasonal and pandemic influenza period, respectively. A percentage of 50.7% and 32% of these patients had a positive test result for influenza, respectively. Patients tested, as well as those with a positive test result during the pandemic influenza period were younger, had milder clinical manifestations, and were treated with more antibiotic agents compared to the respective patients evaluated during the seasonal influenza period. On the contrary, patients tested, as well as those found positive during the seasonal influenza period had more severe clinical manifestations and were prescribed antiviral agents (oseltamivir) more frequently. Patients found positive during the pandemic period were less likely to have any kind of comorbidity, as opposed to the seasonal period.

Conclusion

Our findings suggest that patients with pandemic influenza were younger, had milder clinical manifestations, and were less likely to have any kind of comorbidity, compared to patients with seasonal influenza. However, the methodological limitations of our study should also be considered.

Introduction

The recent influenza pandemic intensified the interest of health organizations, physicians, media, as well as the public in this infection. Specifically, issues regarding the epidemiological features, diagnosis and treatment of influenza underwent a re-evaluation under the perspective of the latest pandemic.

In particular, published reports have suggested that, contrary to the knowledge gained from seasonal influenza, younger age groups were predominantly affected by the 2009 H1N1 pandemic influenza.1-3 Moreover, in a considerable number of published studies pregnant and obese patients, as well as patients with other types of comorbidity constituted a considerable percentage among more severely afflicted 2009 H1N1 pandemic influenza cases (including hospitalized and cases admitted in the intensive care unit), as well as among fatalities.2-4

With regard to influenza diagnosis, direct influenza tests have been used in various clinical settings. Evidence from relevant studies suggests that their use has been associated with reduced unnecessary antibiotic prescriptions, hospitalizations and laboratory tests.5-7 On the other hand, although one may expect that rapid direct influenza tests could have provided an important aid for the timely identification of pandemic influenza cases, the experience of the use of the direct influenza test during the pandemic period was rather disappointing, as the sensitivities reported in studies evaluating its application in various clinical settings were considered as suboptimal.8-10 The issue of influenza treatment was also re-evaluated during the pandemic period, as the potential of the emergence of pandemic viral strains resistant to oseltamivir,11 made physicians reluctant to prescribe antiviral agents, even though many reports pointed out the benefit of the early administration of antiviral treatment to pandemic cases.12-14

The aim of this study was to compare the epidemiological and treatment characteristics of outpatients that sought medical advice from a network of physicians performing house call visits in the area of Attica, Greece, and had a positive direct influenza test, during the 2009 H1N1 pandemic period, as well as the preceding seasonal (2008-2009) influenza period. Secondly, in a complementary analysis, we compared the above-mentioned characteristics of all the patients that underwent a direct influenza test in this specific clinical setting, at the respective influenza periods.

Methods
Patient population
Eligible patients were patients that sought medical advice from a network of physicians performing house-call visits at the area of Attica, Greece and underwent a direct influenza test during the latest period of seasonal influenza (1/1/2009-1/5/2009), and those that underwent a direct influenza test during the consecutive period of 2009 H1N1 pandemic influenza (17/5/2009-15/4/2010). Since the 1st confirmed case of 2009 H1N1 pandemic influenza in Greece was reported at the 16th of May 2009, we excluded the period 1/5/2009-1/15/2009 from our analysis. The direct test was performed at the discretion of the physician performing the house-call visit. The diagnosis was also at the discretion of the physician; specifically, it was based on the patient’s clinical manifestations, along with epidemiological aspects (if any).

A subset of the patients in the 1st study period were included in a recent publication focusing on the impact that the introduction of the direct influenza had on the decision making, particularly the prescribing pattern, of the network of SOS Doctors.7

Data collection
We retrospectively reviewed the electronic databases of the SOS-Doctors network and retrieved data regarding the patient’s demographic characteristics, types of comorbidity, signs/symptoms that the patients complained for, types of diagnosis, treatment prescribed, as well as the need for immediate hospitalization.

Data analysis
Our primary analysis referred to the comparisons regarding the demographic characteristics, types of comorbidity, symptoms, diagnosis, as well as the need for immediate hospitalization were performed between the subgroups of the patients that had a positive direct test for influenza during the evaluated influenza periods. In addition, in a complementary analysis we compared the above-mentioned features for the sub-groups of all the evaluated patients that were tested for influenza during the seasonal and pandemic period, respectively. The chi square test was used for all the evaluated dichotomous variables, whereas the Student's t-test or its non-parametric analogue, the Mann-Whitney U test, were used when appropriate for all the evaluated continuous variables. A p-value<0.05 was considered as indicative of statistical significance. The Open Epi software was used to perform the comparisons regarding the outcomes expresses as dichotomous variables,15 whereas the SPPS Software was used for the continuous variables.

Results

Primary analysis: (patients with a positive direct influenza test result during seasonal vs pandemic influenza period)
A total of 99 and 424 patients had a positive test for influenza during the seasonal and pandemic influenza period respectively, constituting the 50.7% and 32% of the patients tested for influenza during the respective evaluated influenza periods. No difference was found regarding sex between the compared groups. Patients found positive during the pandemic period were younger compared to patients that were found positive during the seasonal influenza period [mean age ± standard deviation (SD): 38.2 ± 19.2 vs 33 ± 17.2, p=0.008]. Additionally, pediatric patients constituted a significantly higher percentage among patients with a positive test during the pandemic (23%) period, compared to those with a positive test during the seasonal period (13%). In addition, patients that did not have any type of comorbidity constituted a significantly higher percentage among patients with a positive test during the pandemic (62%) period, compared to those with a positive test during the seasonal period (45%). No difference was observed in the comparisons regarding the other evaluated types of comorbidity (detailed data are presented in Table 1).

Regarding the signs and symptoms for which the evaluated patients complained for, febrile episodes, cough, rigor, nasal congestion/discharge, headache, and myalgia/arthralgia were reported significantly more frequently from patients that were found positive during the pandemic period, whereas the patients that were found positive during the seasonal period complained significantly more frequently for sore throat. No differences were observed in the remaining comparisons (Table1).

With regard to treatment characteristics, antivirals (oseltamivir), anticongestants, and anti-asthmatic agents were prescribed significantly more frequently to patients found positive during the pandemic period, whereas antibiotics were prescribed significantly more frequently to patients that were found positive during the seasonal period. Specific data regarding the remaining comparisons of treatment characteristics are presented in Table 1. Finally, no difference was observed between the compared groups regarding the need for immediate hospitalization.

Secondary analysis: (patients that underwent a direct influenza test during seasonal vs pandemic influenza period)
A total of 195 and 1317 patients underwent a direct influenza test during the seasonal and pandemic influenza period, respectively. No difference was found regarding sex between the compared groups. Patients tested during the pandemic period were younger compared to patients that were tested during the seasonal influenza period (mean age ± SD: 41.1 ± 20.6 vs 36.7 ± 19.5, p=0.02). Moreover, pediatric patients were encountered significantly more frequently in the pandemic (17%) versus the seasonal period (8%). Detailed data regarding comorbidity were not available for a considerable percentage of the evaluated patients. In this regard, we were precluded from comparing the types of comorbidity between patients that were tested for influenza during the pandemic and the preceding seasonal influenza period.

Febrile episodes, cough, rigor, nasal congestion/discharge, headache, and myalgia/arthralgia were reported significantly more frequently from patients that were tested during the seasonal influenza period compared to those tested during the pandemic influenza period. On the other hand, patients tested during the pandemic period complained for sore thought significantly more frequently compared to those tested during the seasonal influenza period. No differences were observed regarding the evaluated signs and symptoms between the compared groups (Table 2).

Influenza diagnosis was significantly more frequent in patients tested during seasonal influenza period (50.8%), compared to those tested during the pandemic period (32.2%), whereas the diagnoses of viral infection, pharyngitis/pharyngotonsillitis, and acute bronchitis were significantly more frequent in patients tested during the pandemic period. No differences were observed regarding the remaining evaluated diagnoses. Detailed data are presented in Table 2. Furthermore, antivirals (oseltamivir), anticongestants, and anti-asthmatics were prescribe significantly more frequently to patients tested during seasonal influenza period, whereas antibiotics were prescribed significantly more frequently to patients tested during the pandemic period. No differences were observed regarding other treatment characteristics (Table 2). No difference was also observed between the compared groups regarding the need for immediate hospitalization.

Discussion
According to the findings of our study, patients that had a positive direct test for influenza during the 2009 pandemic period were younger and had milder clinical manifestations (as inferred by the signs and symptoms that the patients complained for) compared to those that had a positive test during the seasonal influenza period. Yet, otherwise healthy patients (without any type of comorbidity) and pediatric patients were represented by significantly higher percentages among patients found positive for influenza during the pandemic versus the seasonal period. With regard to treatment characteristics, antivirals, oseltamivir in particular, were prescribed more frequently to patients found positive for influenza during the seasonal period, whereas antibiotics were prescribed more frequently to patients found positive for influenza during the seasonal period. The above findings were consistent in the complementary analysis regarding the patients that had a direct influenza test (regardless of the test result) during the respective influenza periods.

Our findings are in accordance with another recently published study that focused on the comparison of the epidemiological characteristics of outpatients, as well as inpatients with seasonal and 2009 H1N1 pandemic influenza. Specifically, this study suggested that patients with pandemic influenza were younger compared to patients with seasonal influenza.16 This finding was also consistent in another study focusing on the comparison of the characteristics of hospitalized patients with seasonal versus pandemic influenza,17 as well as with studies evaluating the preliminary reports on the epidemiological characteristics of the latest influenza pandemic.2, 3

In addition, with regard to patients’ comorbidity, no difference was observed between patients with seasonal and pandemic influenza, with the exception of pregnancy,16 in the first of the above-mentioned studies, whereas the other study noted that hospitalized patients with pandemic influenza were less likely to be immunocompromised as opposed to patients with seasonal influenza.17 In our study, otherwise healthy patients were encountered more frequently among patients with a positive test result during the pandemic period, compared to those found positive during the seasonal influenza period. This observation may reflect the high transmissibility rate of the 2009 H1N1 pandemic influenza virus.18 Yet, even though, preliminary reports on pandemic influenza cases have suggested that patients with specific types of comorbidity, such as obese, morbidly obese, and pregnant patients, constituted considerable proportions of the confirmed influenza cases, and more severely afflicted influenza cases,2, 3 no differences were observed regarding any of the evaluated types of comorbidity between patients that were found positive during the pandemic and those found positive during the seasonal influenza periods. However, the retrospective methodological nature of our study may potentially account for this finding. Specifically, comorbidity data may have been less likely to be reported, as opposed to data regarding clinical symptoms and treatment. On the other hand, as inferred from the evaluation of the reported clinical signs and symptoms that the evaluated patients complained for, the patients that were tested, as well as the patients that had a positive direct test for influenza during the seasonal influenza period, had more severe clinical manifestations compared to the respective patients, evaluated during the pandemic period. Indeed, most of the pandemic influenza cases, apart from those with considerable comorbidity that were considered to predispose for more severe disease (including obesity and pregnancy), were cases of mild severity.19, 20

In the complementary analysis, involving patients that underwent a direct influenza test during the seasonal and pandemic influenza periods, the patients with a positive test constituted a significantly higher percentage among patients tested during the seasonal versus the pandemic influenza period. Many factors may possibly account for this specific observation. Firstly, physicians from the network of SOS doctors may have been more eager to use the direct influenza during the pandemic period test as an adjunctive diagnostic method, in order to enable a prompt identification of the pandemic cases. Indeed, the number of patients tested during the pandemic period, by far exceeds those tested during the seasonal influenza period (1317 versus 195 patients respectively). However, one may also take into consideration that the performance of direct influenza test during the recent influenza pandemic has been questioned. Specifically, the reported sensitivities of such tests were considered as rather low.8, 9

On the other hand, the differences observed regarding treatment characteristics, seem to be in accordance to the above observations, as significantly more antiviral agents (oseltamivir) were prescribed to patients tested during the seasonal, as opposed to the pandemic influenza period. Yet, significantly more antiviral agents were prescribed to patients found positive for influenza during the seasonal compared to the pandemic influenza period. An explanation that may possibly account for this observation may be the fact that the potential of the emergence of a pandemic influenza strain that would have been resistant to the contemporary commercially available antiviral agents may have intensified physician’s reluctance to prescribe these drugs.

Specific limitations must be taken into consideration before the extrapolation of the findings of our study. Firstly, the retrospective methodology of data collection and presentation may have potentially influenced our findings. We acknowledge that a prospective study design might have potentially enabled the identification of differences in the epidemiological characteristics between seasonal and pandemic influenza, specifically, regarding patients with specific types of comorbidity, including obese and pregnant patients. Moreover, in our study, influenza diagnosis was based on the results of a direct influenza test, whereas no other confirmatory methods like viral culture or polymerase chain reaction (PCR) were available in this specific primary-care clinical setting.

In conclusion, our findings suggest that patients with a positive direct test result during the pandemic influenza period were younger, had milder clinical manifestations, and were less likely to have any type of comorbidity compared to patients with a positive test result during the evaluated seasonal influenza period. Even though the methodological limitations induced due to the retrospective study design should not be underestimated, our study provides useful comparative data regarding the epidemiological, clinical, as well as treatment characteristics of a considerable number of outpatients evaluated in a primary care setting during the latest pandemic influenza, as well as the preceding seasonal influenza period.

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