From the spring of 2009, influenza caused by the A/California/H1N1/7/2009 strain started to spread from Mexico to other countries all over the world. The morbidity was so high that the epidemic in the USA and Canada evolved into a pandemic [1, 2]. By March 2010 the pandemic virus A(H1N1)pdm had already been registered in almost every country and 17,700 lethal outcomes had been reported by WHO. The significance of the pandemic is witnessed by the fact that in the USA 59 million cases of the A/California/H1N1/7/2009 influenza were registered, with 265,000 patients hospitalized and 12,000 lethal outcomes reported .
The severity of the (H1N1) 2009 influenza epidemic in European countries is difficult to estimate because of differences in the organization of national epidemiological surveillance systems and, consequently, in the character of data provided to ECDC. However, it is known that during weeks 40–53 of 2009, 1,045 lethal outcomes caused by the (H1N1) 2009 influenza were registered in the European Union. During the same period 6,529 severe cases of influenza requiring hospitalization in intensive care units were registered. A total of 70.2% of these cases were caused by (H1N1) 2009 influenza and 1,445 fatal cases were registered [3, 4]. While the pandemic (H1N1) 2009 influenza was spreading in the western hemisphere and Europe, the epidemic process was characterized by various intensities, different frequencies of severe cases requiring intensive care and different numbers of fatal cases. Data on the therapeutic and preventive efficiency of antiviral medicines belonging to the category of influenza virus neuraminidase inhibitors was also quite controversial. Uncertainty concerning information and awareness about the A(H1N1)pdm influenza virus was quite high at the beginning of the epidemic in St. Petersburg.
The epidemic process resulting in the spread of the A(H1N1)pdm influenza virus in Saint Petersburg and the clinical forms of the disease were analyzed. Conclusions were based on data received during weeks 41-53 (from 05.10.2009 to 31.12.2009). Morbidity data for influenza in St. Petersburg during the period of epidemic growth were received by the Directorate of the Federal Service for Surveillance on Consumer Rights Protection and Human Well-Being (Rospotrebnadzor) in the City of St. Petersburg from the Municipal epidemiological bureau. Cases of (H1N1) 2009 influenza were registered by the Municipal epidemiological bureau of the city, with the names of all patients specified. However, the diagnostic laboratory capacity was quite limited even in health institutions, and covered only a part of hospitalized patients with clinical symptoms of influenza.
The incidence data for (H1N1) 2009 influenza confirmed by laboratory diagnostics using PCR or serological investigation were obtained from the department of statistics at the Hospital for Infectious Diseases named after S.P. Botkin. The number of confirmed (H1N1) 2009 influenza cases detected during this period in other facilities of the city was quite low since most of the patients were admitted to the Hospital for Infectious Diseases.
In St. Petersburg and the North-Western region of Russia the (H1N1) 2009 influenza epidemic started 2 weeks later than in the Far East and 2 weeks earlier than in the South of Russia.
The first laboratory-confirmed case of (H1N1) 2009 influenza was detected in May 2009. The patient was an adult. From May to October 2009, 26 confirmed cases of (H1N1) 2009 influenza were registered. The prevalence of influenza-like diseases among adults in St. Petersburg began to grow rapidly from October 16, 2009 (week 42; see Figure 1).From week 46, 52,948 cases of influenza-like diseases were reported and the epidemic threshold was exceeded.
Figure 1. Incidence of influenza and acute respiratory viral infections in St.Petersburg, 2009
Only 25% of the hospitalized patients were tested for (H1N1) 2009 influenza. According to official data from the WHO Regional Centre in St. Petersburg, all cases of influenza-like diseases were considered to have been caused by the A/California/7/2009/ influenza virus. The morbidity peak among adults was registered in weeks 44-49 and the highest morbidity among children under the age of 17 was reported in weeks 41-49.
In St. Petersburg, 529,591 people including 236,542 children visited various health institutions because of influenza-like diseases during the epidemic period. The incidence was 6,046.6 and 44,672 per 100,000 population for adults and children, respectively.
During the epidemic period from October 5 to December 31, 2009, 4,725 adults and 7,055 children were hospitalized. A total of 2,145 adults (45.4%) were admitted to Botkin Hospital for Infectious Diseases, thus indicating the studied cohort was representative. The (H1N1) 2009 influenza was diagnosed among 735 patients constituting 34.3% of all hospitalized patients with influenza-like diseases. This proportion is much higher than the frequency of verified (H1N1) 2009 influenza at other facilities in the city. The clinical manifestations of this influenza included fever, intoxication syndrome and some symptoms of tracheitis and bronchitis of various degrees.
The most detailed description of the clinical manifestations of (H1N1) 2009 influenza was based on the data collected at Botkin Hospital for Infectious Diseases. For example, 16.6% of patients hospitalized with (H1N1) 2009 influenza had clinically manifested symptoms of dyspepsia that were mostly registered at the initial stage of disease prior to antiviral therapy. According to PCR results from feces samples, dyspepsia was not associated with Shigella spp., Salmonella spp, Campylobacter spp., Adenovirus, Rotavirus, Norovirus or Astrovirus infection (n = 72). The emergence of total bilateral pneumonia on the second or third day of illness and rapid progress of disease was revealed in several cases. Pregnant women were regarded as a separate group among hospitalized patients with (H1N1) 2009 influenza. Some of the pregnant women (153 women) were hospitalized at Botkin Clinical Hospital. In 16 cases, a severe form of pandemic influenza was diagnosed and special therapy in the resuscitation and intensive care unit (RICU) was required. One lethal outcome was registered among pregnant women (1/153; 0.6%).
The proportion of patients with (H1N1) 2009 influenza who were admitted to the RICU was 4.7% (102/2,145) and most were hospitalized in weeks 46–47. The average age in this category of patients was 38.7 ± 10 years. The mechanical ventilators were necessary for nearly a half of these patients 42,2% (43/102).
During the epidemic period, 41 lethal outcomes were registered in St. Petersburg among the adult patients with influenza, including 31 fatal cases in which the pandemic (H1N1) 2009 influenza was confirmed by laboratory diagnostics and 10 cases of suspected infection. The proportion of case fatality among adults in St. Petersburg was 0.001% (41/3,912,000) and 0.8% (41/4,725) among hospitalized adults. No lethal outcomes were reported among children.
In Botkin Clinical Hospital, 16 lethal outcomes were registered in weeks 41-53. Fatal cases were registered among 0.7% of the total number of patients hospitalized with influenza-like diseases and 2.1% of the total number of patients with laboratory-confirmed (H1N1) 2009 influenza. In all lethal cases, the patients were not vaccinated against seasonal and pandemic influenza. The following risk factors could be associated with lethal outcomes: pregnancy, obesity, HIV infection, diabetes, myeloma and chronic viral hepatitis.
During the epidemic, the dosage regimen of Tamiflu® was modified as follows: 1) the prescribed daily dose was increased up to 150 mg twice per day; 2) the chemotherapy course was prolonged up to 10 days; 3) the medicine could be prescribed at any stage of the disease; 4) patients with severe forms of the disease had the medicine administered via nasogastric tube. The therapy course also included the prescription of Surfactant BL (manufactured in Russia).
Relenza® showed good efficiency when prescribed to patients with moderately severe and severe forms of (H1N1) 2009 influenza depending on the stage of the disease. It was primarily used prior to the artificial lung ventilation. More than 300 packages of Relenza® and 2,900 packages of Tamiflu® were used during the epidemic. Tamiflu® demonstrated good tolerance and high efficiency in doses of 300 mg per day until viral RNA was eliminated from the trachea and bronchi. It was also used for therapy of pregnant women in the resuscitation and intensive care units.
During weeks 41–53, 11.5% of the St. Petersburg population was involved in the epidemic process including 6.05% of adults. However, it is possible that 22–25% of the city population was involved in the epidemic process since the actual incidence is always two times higher than the registered incidence (ЕCDC). This presupposes a low probability for the emergence of a second wave of the epidemic in spring.
The presented data comply with the results of available comprehensive analysis of the global pandemic (H1N1) 2009 influenza. The virus genome was characterized and isolates from different parts of the world showed a high degree of homogeneity. The high replication of the A(2009)pdm virus in the lung tissue of laboratory animals as compared to other A-type viruses is one of the most significant characteristics of A(2009)pdm virus. Investigations addressing the influence of the viral hemagglutinin on receptors of mammalian cells demonstrated the ability of the virus to interact both with α2.6 cell receptors (typical of seasonal influenza viruses) and α2.3 receptors which are located on the conjunctiva, in the distal parts of the respiratory tract and in alveolocytes . This viral feature is thought to be responsible for the development of “early” pneumonia with specific clinical progress and roentgenologic characteristics. In addition, A(H1N1)pdm virus can replicate for a long time in the higher respiratory tract. In uncomplicated cases of pandemic influenza, the virus load found in nasopharyngeal swabs increased rapidly after the emergence of clinical manifestations and gradually lowered after the fever was gone . Some authors believe [6, 7] that the A(H1N1)pdm influenza virus continues to replicate longer than seasonal type-A influenza viruses. For example, on the 8th day of disease viral RNA was found in samples from 74% of patients (adults and teenagers), and the replication of viruses was detected in 13% of cases . In another study, the viral RNA was found in patient samples 8 days after the fever was gone . The viral load was much higher in patients with severe viral pneumonia and decreased much more slowly when compared to patients with noncomplicated disease. The patients who required mechanical ventilators had the highest viral load that was primarily concentrated in the lower respiratory tract. In such cases, viral RNA was found up to the 28th day after the onset of disease [9, 10]. According to our data, the A(H1N1)pdm virus replicated for more than 10 days in cases of severe forms of the disease when the patients were admitted to the resuscitation and intensive care units.
Etiotropic therapy of influenza is very important. At the beginning of the pandemic, the A(H1N1)pdm virus showed resistance to М2 blockers (amantadine and rimantadine). The drugs of choice were therefore oseltamivir (Tamifl u®) and zanamivir (Relenza®). Both drugs were widely used to treat patients with influenza in St. Petersburg. Evidence has been provided in various publications that the virus is developing resistance to oseltamivir due to the H275Y mutation [9-14]. However, resistance was primarily registered among immunocompromised patients who had previously used oseltamivir for the prevention of seasonal influenza. Future use of this medicine in similar situations in St. Petersburg should be reconsidered. Due to the risk of resistance, neuraminidase inhibitors should only be used for therapy of hospitalized patients with influenza. The erratic spread and incidence of (H1N1) 2009 influenza in areas with similar social, economic and environmental conditions (for example, in different countries of Northern Europe) remains the subject of intensive discussion. It is possible that some groups of the population may have developed protective anamnestic antibodies during the previous circulation of the Eurasian lineage swine influenza virus [1, 3, 4].
- Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Infl uenza. Clinical aspects of pandemic 2009 infl uenza A (H1N1) virus infection. N Engl J Med 2010; 362: 1708-19.
- Wu JT, Ma EST, Lee CK et al. Infection attack Rate and Severity of 2009 pandemic H1N1 infl uenza in Hong Kong. Clinical infectious diseases 2010; 51: 1184 –91.
- European Centre for Disease Prevention and Control. The 2009 A (H1N1) pandemic in Europe. Stockholm: ECDC; 2010.
- Nicolle A, McKee M. Moderate pandemic, not many dead-learning the right lesson in Europe from 2009 pandemic. Eur J Public Health 2010; 20: 486-8.
- Childs RA, Palma AS, Wharton S et al. Receptor-binding specifi city of pandemic infl uenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat Biotechnol 2009; 27: 797 – 9.
- Witkop CT, Duff y MR, Macias EA, et al. Novel infl uenza A (H1N1) outbreak at the U.S. Air Force Academy: epidemiology and viral shedding duration. Am J Prev Med 2010; 38: 121-126.
- Uyeki TM. 2009 H1N1 virus transmission and outbreaks. N Engl J Med 2010; 362: 2221-3.
- De Serres G, Rouleau I, Hamelin ME. Contagious period for pandemic (H1N1) 2009 infl uenza. Emerg Infect Dis 2010; 16: 783-8.
- Fleury H, Burrel S, Balick WC et al. Prolonger shedding of infl uenza A (H1N1)v virus: two case reports from France 2009. Euro Surveill 2009 Dec 10;14(49). pii: 19434.
- Lee N. Pathogenesis of pandemic H1N1 in humans (abstract). Presented at the XII International Symposium on Respiratory Viral Infections, Taipei, Taiwan, March 11–14, 2010.
- Smith SM, Gums JG. Antivirals for infl uenza: strategies for use in pediatrics. Pediatric Drugs 2010; 12: 285-99.
- Harvala H., Gunson R, Simmonds P et al. The emergence of oseltamivir-resistant pandemic influenza A (H1N1) 2009 virus amongst hospitalised immunocompromised patients in Scotland, November-December, 2009. Euro Surveill 2010 Apr 8;15(14). pii: 19536.
- van der Vries E, Jonges S, Herfst S et al. Evaluation of a rapid molecular algorithm for detection of pandemic infl uenza A (H1N1) 2009 virus and screening for a key oseltamivir resistance (H275Y) substitution in neuraminidase. J Clin Virol 2010; 47: 34-7.
- Dharan NJ, Gubareva LV, Meyer JJ et al. Infections With Oseltamivir-Resistant Infl uenza A(H1N1) Virus in the United States. JAMA 2009; 301: 1034-41.