The burden of laboratory-confirmed influenza infection in Lebanon between 2008 and 2016: a single tertiary care center experience

Acute respiratory infections constitute a major cause of morbidity and mortality globally [1]. According to the updated 2004 World Health Organization (WHO) report, the death toll from acute lower respiratory infections caused by bacterial and viral infections reached 4.2 million and accounted for 7.2% of all deaths worldwide [1, 2]. Data from the Global Burden of Disease study estimated that the mortality rate from lower respiratory tract infections due to influenza reached 0.9 per 100,000 population in the WHO Middle East and North Africa (MENA) region and the hospitalization rate ranged from 100 to 299 per 100,000 population [3].

Influenza is a major cause of both influenza-like illness (ILI) and more importantly severe acute respiratory infection (SARI) across the globe [4, 5]. Several studies in different regions of the world have indicated that influenza is a significant underlying cause for hospitalization of patients with acute respiratory infection (ARI) [6‐9].

Infection with influenza may manifest in a wide spectrum of illness levels ranging from asymptomatic infection to death. Different studies reported asymptomatic cases to account for 14% up to 77% of influenza infections [10‐12]. The major cause for hospital admission due to influenza is the development of pneumonia, which could be either primary viral or secondary to bacterial co-infection, and acute respiratory distress syndrome [13, 14]. In severe cases of influenza infection, death may ensue even in the absence of comorbidities [15].

Annual seasonal influenza vaccination can reduce the chances of getting infected and subsequently prevent spread of the virus. Vaccines are available in two forms: the inactivated influenza vaccine (IIV), which is administered intramuscularly or intradermally, and the live attenuated influenza vaccine, administered intranasally, (LAIV). Vaccination is recommended by the Centers for Disease Control, USA, annually to everyone above 6 months of age and should be given before influenza season commences, usually during early fall or late summer [16]. However, in many countries, especially developing ones, there is a lack of data on the epidemiology of influenza disease leading to a lack of appreciation of its true burden by public health authorities and impeding the introduction of influenza vaccine on national vaccination schedules. Accordingly, the WHO recommended the generation of country-specific epidemiological data in order to identify high priority groups, emphasizing the inclusion of pregnant women, and the optimal timing of vaccination against influenza [17].

Given the epidemic nature of the illness, there has been an increasing interest in the burden resulting from its outbreaks in addition to concerns about its association with myocardial infarctions, glycemic variation in diabetic patients, and the exacerbation of other chronic illnesses [1, 18‐27]. While data on the epidemiology and severity of this disease has been primarily obtained from studies in temperate developed countries, developing regions including the MENA region have also begun investigating this burden in their hospitals allowing the formation of more complete global data [28].

In Lebanon, the influenza burden of disease is unknown. Since 2008, surveillance of influenza virus among ILI patients at the American University of Beirut Medical Center (AUBMC), was performed at the Center for Infectious Diseases Research (CIDR) [29‐33]. The Ministry of Public Health started reporting influenza activity as part of its SARI surveillance since 2015. Whereas these surveillance programs furnish important information about influenza activity in Lebanon, they do not reflect the total burden of disease of influenza. In fact, an ideal study to look at the burden of influenza diseases would be population-based, prospective, and armed with a highly sensitive and specific test for influenza to be conducted both in outpatient and inpatient settings. However, such a study is not feasible and too expensive to conduct. An alternative approach that we chose was to conduct a retrospective review on laboratory-proven influenza at our center, a major academic medical center in Lebanon, where both inpatient and outpatient services exist. The objective of this review is to contribute to the understanding of the burden of disease of influenza in Lebanon. This may help inform public policy about prevention of influenza infections.

During the study period spanning 8 influenza seasons from January 1st, 2008 till June 30th, 2016, a total of 11,288 patients presented to AUBMC with a respiratory illness for which they were tested for influenza infection. Out of all patients tested, 1829 patients (16%) had a positive test result for influenza; 542 influenza cases (29.6%) were identified during the 2009 influenza pandemic. Of the 1829 positive cases, 1529 (84%) were caused by influenza A, 242 cases (13%) by influenza B, and 55 cases (3%) had co-infection with both types (type was not reported in three cases). During the 2009 pandemic, 97.6% of the infections were caused by influenza A and 2% were co-infected. However, subtyping was done for only 35 cases during the pandemic, of which 28 cases were caused by influenza A (H1N1)pdm09.

Our results show that seasonal influenza causes a substantial burden in the Lebanese population. The AUBMC serves an annual average of around 400,000 persons including in-hospital admissions, clinic visits and ED visits. A total of 11,288 patients were tested for influenza virus during the study period that extended over 8 influenza seasons of which 1829 (16%) patients were positive for either influenza A, B or both. A total of 475 (26.6%) subjects were hospitalized. On average, hospitalization rate attributable to influenza accounted for 0.24% annually. However, this number is likely an underestimate of the true influenza-related hospitalizations rate because influenza testing is done at the request of the physician and not every patient was tested for influenza. Therefore, a population based prospective surveillance study is needed to better estimate the burden of Influenza-related hospitalizations. The average annual positivity rate (the number of positive tests divided by the total number of requested tests) for tested patients was 14% and this is similar to the positivity rate (13.4%) reported by the Lebanese SARI Sentinel Surveillance conducted by the Ministry of Public Health for the 2015/2016 season [37]. Moghoofei et al. estimated an influenza infection prevalence of 10% in the Middle East that approaches our positivity rate in Lebanon [38]. In his systematic review, 71 studies were included of which only one study was from Lebanon but included a very small sample size [30].

According to the WHO Global Epidemiological Surveillance Standards for Influenza, a standard age grouping into 6 groups is suggested for analysis [5]. We further subdivided the population into an additional 7th ‘adolescent’ age group (10–19 years). Results from the SARI surveillance by the MOH showed a similar distribution, with higher positivity rates among those 15–49 years reaching 26% in the southern sentinel site and a positivity rate of 21% for those 5–15 years in the Beirut sentinel site [37]. According to a cross-sectional review published in 2015, influenza vaccine uptake among Lebanese adults was only 27.6% during the 2014/2015 season [39]. The vaccination rate for our population reached 22.4%. Unfortunately, we did not have vaccination data for most of our paients and the majority of available data was for pediatric patients. It is important to recall that although influenza vaccines were thought to be mostly effective for children 2 years and older, recent data showed high vaccine efficacy reaching 60% in infants as young as 6 months [36, 40‐44].

Our analysis showed that all severity parameters, except for hospital and ICU stay duration, were highly present within two age groups: below 2 years and ≥ 65 years. These results demonstrate that extremes of age have a more severe course of disease including a higher mortality rate. Several recommending bodies consider these age groups at higher risk for severe disease and mortality and thus recommend early initiation of antiviral therapy and emphasize the importance of vaccination [45, 46]. Unfortunately, vaccination is not recommended for these age groups nor included in the national immunization program in Lebanon [47].

The presence of at least one co-morbidity, mainly cardiovascular diseases, asthma, malignancy and diabetes mellitus, in 71% of hospitalized patients and 31% of outpatients is worrisome especially with recent data on influenza being a trigger for exacerbation of these illnesses and vice versa. Several papers have showed an association between influenza infection and myocardial infarction, chronic obstructive pulmonary disease exacerbations and diabetic crises [18, 23, 24, 27, 48, 49]. This also means that at least half of the study population were probably at higher risk for severe influenza disease and outcome including death [50].

Several complications have been linked to influenza infection including both pulmonary and extra-pulmonary. Both bacterial and viral pneumonias are established complications of influenza infection and have been reported as an independent risk factor for increased severity and mortality [51‐53]. Our review showed that radiologically confirmed pneumonia was a risk factor for increased mortality among hospitalized patients (Table 4); however, it was not found to be an independant risk factor for mortality in the multivariable logistic regression (Table S2). It was the most common complication reported with highest incidence in older age groups > 50 years. We could not determine whether these were primary viral pneumonias or bacterial co-infection in most of the cases. Inflammatory markers including C-reactive protein and procalcitonin were not used regularly especially in outpatients, so we did not track them. Regardless, 89% of these cases received antimicrobial treatment according to the treating physician’s judgment. Of these pneumonia cases, 16 (6.6%) progressed to acute respiratory distress syndrome (ARDS).

Our population also displayed a wide array of extra-pulmonary complications including myocardial infarction, encephalopathy, shock, renal failure and liver failure. These complications have been reported in several articles [54‐59] and interest in determining their real burden is increasing as these extra-pulmonary complications actually represent a significant burden related to influenza infection that is sometimes overlooked [55].

According to the global burden of diseases study, influenza accounted for 0.26% of all-cause mortality globally. It also estimated that 0.6 per 100,000 population died from influenza in Lebanon [3]. In our review, we identified 18 fatalities representing 3.8% of all hospitalized laboratory proven influenza cases during an 8-year period. In Egypt, according to influenza surveillance data from 2007 to 2014, influenza positivity was 17% among SARI cases with a mortality rate reaching 2% [60]. In Oman, influenza-associated deaths from 2012 to 2015 were estimated at 0.9 per 100,000 population and was highest among those ≥65 years (18.6 per 100,000 population) [61]. This was similarly reported by the Global Burden of Diseases study where the population attributable fraction (PAF) for adults older than 70 years was 6.3% compared to 2.9% for children younger than 5 years [3]. This is similar to our data where the highest mortality was in those ≥65 years (3.6%) compared to 1.5% in those below 2 years. According to our results, factors found to be associated with increased mortality were underlying neurological disease, malignancy, moderate to severe disease, proven viral or bacterial co-infection, and presence of pneumonia (P-value < 0.05). However, after multivariate logistic regression, only the presence of a proven viral or bacterial co-infection, pneumonia and neurological disease were independent risk factors for increased mortality. Unlike the data from Egypt [60], we didn’t find any association between influenza type and mortality. A systematic review by Klein et al. showed a very variable range in the incidence of bacterial co-infection with influenza from 2 to 65% in different studies [62]. It is however associated with an increased incidence of morbidity and mortality in all age groups for both seasonal and pandemic influenza with Staphylococcus aureus and Streptococcus pneumoniae being the most common pathogens identified [62, 63]. With the advance in the detection methods used to identify causative viral pathogens, several papers have discussed the increasing incidence of viral co-infection and its role in the severity of influenza infection [64, 65]. Though our results did show a higher rate of viral co-infection in the mortality cases, most of these viruses were not respiratory viruses. With the advent of routine use of a multiplex PCR respiratory panel at many centers around the world, more cases of co-infection with other respiratory viruses are likely to be detected.

According to the recent guidelines by the Infectious Diseases Society of America (IDSA), antiviral treatment should be started when influenza infection is suspected or confirmed in any hospitalized patient, those with severe or progressive illness, in children ≤2 years and adults ≥65 years old, pregnant females and 2 weeks postpartum, extremely obese patients, children and adolescents receiving salicylate-containing medications, patients with chronic medical conditions including immunosuppression and residents of chronic care centers [46]. Treatment should also be considered for contacts of high-risk patients mentioned above (household or healthcare providers) and when symptoms’ onset is ≤2 days at presentation. When treatment is warranted, a single neuraminidase inhibitor (NAI) should be used [46, 66]. Oseltamivir was almost exclusively used in our population. It was prescribed for almost 70% of the patients. Our review period, however, includes the 2009 pandemic when NAI’s were used extensively; but even when excluded in the analysis, the rate of antiviral use remains high (73%). Our data shows that there was a tendency to follow the guidelines though maybe not completely. Antiviral prescription was significantly higher at the extremes of age reaching 96% in ≥65 years, 95% of hospitalized patients, 84% of patients with underlying high-risk conditions and 84% of pregnant females. Nonetheless, it seems that the duration since onset of symptoms and the severity of disease per se did not influence the decision to initiate antivirals. A more detailed description of each case would further evaluate the level of adherence to the guidelines in order to implement a judicious plan for the use of these antivirals and try to control influenza resistance. On the other hand, prompt use of antivirals may reduce unnecessary use of antibiotics by decreasing the risk of bacterial co-infections, which are reported to be as low as 2% [46, 67, 68]. This implies the need for a more thorough evaluation before the decision to start antibiotics due to the increasing reports of resistant organisms mainly MRSA [62, 69]. Nonetheless, recommendations provided by the IDSA emphasize the use of antibiotics empirically in severe cases of influenza and in those who deteriorate after initial improvement [46]. Antibiotics were prescribed in around 40% of patients, half of which had an underlying pneumonia. A similar rate of antibiotic prescription was reported in Algeria (41%) [70] and Switzerland (45%) [71].

Both influenza A and B co-circulated during the 8 seasons with influenza A being predominant during each season. Historically, there has been more interest in researching influenza A virus mainly because of its capability to cause pandemics and underestimating the burden of influenza B virus. However, our data shows an increased morbidity associated with influenza B evident mainly by the higher incidence of ICU admissions although with no difference in mortality incidence for both types. Earlier published data have shown an increasing burden for influenza B in the USA, [72] whereas data from other countries showed a contradicting role of type B in influenza related morbidity and mortality [60, 72‐75]. Further population-based studies are needed to look further into the real burden of Influenza B and comparing its clinical characteristics to influenza A.

In the MENA region, there is limited data on the circulation patterns of both influenza A and B. It is of paramount importance to determine the timing of influenza circulation for each region in order to decide on the best timing for vaccine delivery, aid healthcare workers in their clinical management of suspected cases in addition to increasing emphasis on prevention of infection and control of transmission [76]. In his review of surveillance data from the MENA region for the time period 2010–2016, Caini et al. reported that most of the region’s countries had a primary peak between January and March with no or barely noticeable secondary peaks [77]. According to the Lebanese SARI sentinel surveillance, the primary peak extended from January till mid of March [37]. This is consistent with our data, which shows that the influenza season starts by November–December and peaks during January and February. These results imply that vaccination should be administered between September and October of each year to ensure optimal protection.

Our study has several limitations. The most significant limitation is the fact that this data was collected retrospectively from chart review. We could not obtain accurate data on vaccination rates in addition to other missing or incomplete data. Another limitation is that all these cases reviewed were from a single center that, despite being a major tertiary medical center, cannot reflect the actual Lebanese burden of influenza. A third limitation is the fact that we included all laboratory proven influenza cases regardless of initial presentation symptoms or reason for admission. As a result, we could not calculate influenza-attributable SARI cases and we could not compare this to other published data. Also, we did not exclude possible health-care associated infections, although they contribute to the burden of influenza. Moreover, mortality rate associated with influenza might not be accurate since we had no follow up data on outpatients and thus significant data was missing.

This study is a first attempt to estimate the burden of influenza in Lebanon including a large number of patients. Despite being a retrospective review, results offer groundwork for further influenza research. Based on the results presented by our review, influenza causes a substantial number of hospitalizations annually in Lebanon with significant morbidity and mortality across all age groups. Even though we had incomplete data on vaccination, a rate of 22% is fairly low. Fortunately, there is an increased interest in influenza research and surveillance along with increased testing for ILI and SARI cases. The SARI sentinel surveillance initiated by the Ministry of Public Health since 2015 promises to provide better data on the burden of influenza on a national level thus aid in developing a better vaccination program and maybe incorporate it into the national immunization program. A population based prospective surveillance study is needed to better estimate the burden of influenza in Lebanon which would help to drive policy on influenza control.