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Article Summary Line
The first wave of Pandemic (H1N1) 2009 in Portugal was characterized by mild cases and a high compliance with containment measures
Running Title
Influenza A (H1N1) 2009 Pandemic in the North of Portugal.
Keywords
Influenza A pandemic; swine-origin influenza A (H1N1), pandemic (H1N1) 2009 virus, containment measures.
Title
Pandemic Influenza A (H1N1)v in the North of Portugal – Epidemiology and Clinical Characteristics During the Containment Phase.
Authors
Ana Verónica Cardoso.
Author affiliations
Faculty of Medicine of the University of Porto, Porto, Portugal
Abstract
After the appearance of pandemic (H1N1) 2009 in April 2009, on May 31 the first case of influenza A was identified in the Northern Region of Portugal. During the
containment phase, that lasted until the end of August 2009, all suspected cases were referred to hospital and had a respiratory specimen tested for pandemic (H1N1) 2009 virus. This study describes the epidemiological and clinical characteristics of the first 325 consecutive laboratory-confirmed pandemic (H1N1) 2009 cases in the North of Portugal. Additionally, by means of a follow-up telephone interview to 175
respondents, we assessed the impact of the infection on patient’s life. Eighty percent of patients were younger than 30 and 80% reported travel history seven days before symptoms onset. Forty-two had chronic illness and thirteen adults had pneumonia. Twelve percent were hospitalized, three in an ICU. The case fatality rate was 0%. The first wave of pandemic (H1N1) 2009 in Portugal was characterized by mild cases and a high compliance with recommended containment measures.
Text
Three influenza pandemics were observed during the XX century: in 1918, due to the H1N1 virus ("Spanish influenza"), in 1957 to the H2N2 virus ("Asian influenza") and in 1968 to the H3N2 virus ("Hong Kong influenza") [1-3]. The 1918 pandemic was undoubtedly the most devastating (40 million deaths), and followed by a disruption of the demographic, the social and the economic development[1].
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During March and April 2009, several outbreaks of acute respiratory infection were identified in Mexico and the United States [4-7]. The first reported cases were a boy and a girl of 10 and 9 years respectively, living in Mexico. The viruses isolated in both cases were genetically related and contained a unique combination of gene segments of swine, bird and human viruses, never before identified in United States or elsewhere. In mid April 2009, the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recognized a dramatic increase in the number of influenza cases. The lack of recent exposure to pigs in most cases raised the possibility that the virus had the ability to be transmitted among humans [4]. We were facing the suspicion of a new influenza pandemic.
Genetic analysis of this new strain has shown that the virus resulted from a reassortment between the triple-reassortant swine influenza A virus, which has been circulating among pigs in the United States since 1998, and a Eurasian swine influenza virus [8-11].
As of June 11, 2009, about 30 000 laboratory-confirmed cases of infection with pandemic (H1N1) 2009 virus, including 144 deaths, had been reported to WHO from 74 countries in 5 WHO regions (including Europe) [13]. Of these, approximately 90% of reported cases have occurred in the Americas. With the emergence of a growing number of cases, the WHO raised the pandemic alert to phase 6, signaling the beginning of a new influenza pandemic, 41 years after Hong Kong Pandemic. Phase 6 is characterized by sustained human-to-human transmission caused by community-level outbreaks in at least 1 country in ≥2 WHO regions. [13-14].
On May 31 the first case of influenza A was identified in the Northern Region of Portugal, at Hospital São João. During the containment phase, that lasted until the end of August 2009 [15] all suspected community cases of influenza A infection were referred to an hospital and had a respiratory specimen tested for pandemic (H1N1) 2009 virus using a real-time reverse transcription PCR (rRT-PCR) assay. Additionally during this phase it was recommend early identification and isolation of patients with suspected or proven influenza, contact tracing and antiviral prophylaxis for household and other close contacts (in schools and workplaces).
This study describes the epidemiological and clinical characteristics of the first 325 consecutive laboratory-confirmed pandemic (H1N1) 2009 cases admitted at the referral hospital for the Northern region of Portugal. Additionally, by means of a follow-up telephone interview we assessed the impact of the infection on patient’s life.
Methods
Selection of Participants and Data Collection
This is a retrospective evaluation of the cases of infection with pandemic (H1N1) 2009 virus identified in Hospital São João (HSJ) - referral hospital for
Pandemic Influenza in the North of Portugal - between 31 May and 01 September 2009. During the period considered, all patients who met clinical (sudden onset of fever (temperature ≥ 38 ° C) or history of fever and at least one of the following symptoms: cough, headache, myalgia, arthralgia, sore throat, runny nose, vomiting or
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diarrhea or pneumonia or other serious illness suggestive of infectious etiology or death from acute respiratory illness of unknown cause) and epidemiological criteria (stay or residence in an area where there is community transmission of the disease by pandemic (H1N1) 2009 virus or close contact with an probable or confirmed case of infection with pandemic (H1N1) 2009 virus, during the symptomatic phase or person working in the laboratory where the processing biological samples for pandemic (H1N1) 2009 virus) were considered suspect cases and were instructed to investigation of possible infection with pandemic (H1N1) 2009 virus.
Among all adult (≥17 years) and pediatric (<17 years) patients consecutively admitted to HSJ with suspected influenza A, those with rRT-PCR positive for pandemic (H1N1) 2009 virus were included in the study.
From May 31 to September 1 2009, 401 cases with laboratory-confirmed pandemic (H1N1) 2009 were identified in the North of Portugal. Those 325 cases admitted to the Hospital São João were eligible for the study and for clinical files abstraction. After exclusion of participants living abroad or institutionalized, or those with wrong or non subscribed telephone numbers, 245 participants were eligible for telephone interview using computer assisted telephone interview (CATI). The
questionnaire provided socio-demographic, epidemiological and clinical characteristics. We included information about the patient’s socio-demographic characteristics, clinical signs and symptoms, disease severity, travel to a country with confirmed case of
infection with pandemic (H1N1) 2009 virus, close contact with a confirmed or probable case, underlying medical conditions, status with respect to seasonal influenza
vaccination, laboratory and chest X-ray results, antiviral treatment, clinical
complications, clinical outcome, absenteeism, and need for antiviral prophylaxis of contacts. As an indicator of social class, we used the educational level, grouped into three classes (0-9 years, 10-12 years, and more than 12 years of schooling) and, additionally, the crowding index calculated as the ratio between the number people living in the house and the number of rooms (bedrooms and living rooms) and classified into three groups (<1.0, 1.0 and> 1.0 person per room).
A telephone interview was successfully performed for 175 (53.8%) patients. Considering the number of eligible participants for the interview (245), the response rate was 71.8%, with only 4 (1.6%) refusals. The interviewed participants with those not reached were compared concerning sex, age, symptoms at admission, symptoms
duration, hospitalization, level C-reactive protein and pneumonia. Except for pneumonia at presentation there were no significant differences between participants.
Laboratory
Combined nasal and pharyngeal swab specimens or nasopharyngeal or tracheal aspirates were collected from all patients at admission and were placed in transport medium and kept at temperature 2 to 4ºC. RT-PCR testing was performed according to guidelines from the Center Disease Control and Prevention (CDC)[16].
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We calculated descriptive statistics for all study variables. We report data for continuous variables as medians (with interquartile ranges) and for categorical variables as percentages. We compared characteristics between groups using the χ2 test or Ficher exact test for categorical data and the Wilcoxon signed-rank test for continuous
variables. Ethics
This study was approved by the Hospital São João Ethical Board. During the telephone interview participants were informed about the aim and methods of the study, confidentiality and voluntary nature of participation was guaranteed. Consent for
participation was obtained verbally and refusals were recorded.
Results
From May 31 through September 1, 2009, a total of 401 patients with confirmed pandemic (H1N1) 2009 virus infection were identified in the North of Portugal (Figure 1). Of these cases, 325 were observed in HSJ (Figure 2). The number of confirmed cases increased considerably during the first week of August, peaking in mid August and decreasing during the last week of this month (Figures 1 and 2). Initially, cases were reported amongst travelers. The first indigenous infections was reported on July 12. From August 4 the proportion and number of indigenously acquired cases has steadily increased. Among those cases (“indigenous other”, Figure 2), three outbreaks of confirmed pandemic (H1N1) 2009 virus infection were identified: eight cases
reported in a music festival (Paredes de Coura), nine cases reported in a Lisbon summer camp and twelve cases in another summer camp in Viana do Castelo.
The social-demographic, contact and travel exposure characteristics of the 325 patients with confirmed pandemic (H1N1) 2009 were presented in Table1. Figure 3 represented the distribution of cases by age group and gender. The patients age ranged from 10 months to 71 years (median, 21 years). More than half of the patients were between 10 and 29 years old and 80% were 29 years old or younger. A total of 191 patients (59%) were male. More than 90% of patients lived in Portugal, 260 (80%) were from Porto and Braga. For the socioeconomic status, more than half of the patients had more than 12 years of education and presented a crowding index less than one.
Of the 325 cases, 252 (78%) reported history of travel in the seven days before the onset of symptoms. Traveling within Portugal, mainly to Algarve, and to Spain accounted for more than 75% of destinations. Of the remaining 73 cases who hadn´t history of travel, 44 (14%) had close contact with a suspected or confirmed case of influenza A in the seven days before the onset of symptoms. Twenty-nine patients (9%) had no history of travels or contact exposure.
The clinical characteristics of the 325 patients with confirmed pandemic (H1N1) 2009 virus infection were presented in Table 2. Among the 204 patients whose
underlying medical conditions was know, 42 (21%) had chronic illness: asthma (n=23), cardiovascular disease (n=9), type II diabetes mellitus (n=8), neurological disease (n=7), immunosuppression by drugs (n=1), pancytopenia (n=1) and renal failure (n=1).
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Forty-six (39%) adult patients (age ≥ 17 years) who were interviewed were smokers. Only 11% of children (age ≤16 years) and 25% of adults reported seasonal influenza vaccination in 2008-2009. When asked about the intention to take the
pandemic influenza A vaccine if they hadn´t been infected with pandemic (H1N1) 2009 virus, 72 patients answered yes (43% of children’s parents and 40% of adults).
A total of 310 patients (95%) had fever, with temperatures higher than 38ºC (median, 39ºC). More than half of the patients had cough (84%) and myalgias and/or arthralgias (70%), the latter being most common in adults than children. In addition 23% of patients had diarrhea and/or vomiting and/or nausea. The time between onset of symptoms and admission to the hospital were in media 1 day for child (interquartile range, 1 to 2) and 2 days for adults (interquartile range, 1 to 3).
At the time of admission, thirteen adults (1%) had radiologically confirmed pneumonia (with bilateral alveolar opacities in two cases). Of the child, anyone had radiologically confirmed pneumonia. Among the 205 patients tested, eight (4%) (one child and seven adults) had hypoxemia (oxygen saturation <92% or arterial partial pressure of oxygen <60 mmHg). Only five of the thirteen patients with pneumonia had concomitant hypoxemia.
At admission, complete blood counts were available for 108 patients, showing leukopenia (<5000 leukocytes per cubic millimeter) in 23 (21%), lymphopenia (<1000 lymphocytes per cubic millimeter) in 42 (39%) and trombocytopenia (<150,000 platelet per cubic millimeter) in 32 (30%). Ten patients (9%) had more than 10,000 leukocytes per cubic millimeter. C-reactive protein levels were available for 113 patients, and 27 (24%) of them presented increased levels (C-reactive protein > 40mg/L).
Of the 325 patients, 35 (11%) required hospitalization, 12 children and 23 adults (Figure S1and S2 of the Supplementary Appendix). Seventeen patients (49%) were hospitalized due to disease severity (moderate to severe disease), three (9%) required hospitalization in the intensive care unit and two (6%) had acute respiratory distress syndrome requiring mechanical ventilation, lasting 1 day in one case and in another 26 days. During the hospital stay, two patients admitted to an intensive care unit had cardiovascular complications: decompensated heart failure in one patient and stroke in the other. The case fatality rate was 0%.
A total of 104 patients (32%) were treated with oseltamivir. Of the 59 patients treated with oseltamivir interviewed, 56 completed therapy with the recommended dose (adherence to therapy 95%), 8 (14%) reported adverse effects of the oseltamivir
(nauseas in five patients, vomiting in two and epigastric pain in one).
The median duration of fever was 2 days for children (interquartile range, 2 to 3) and 3 days for adults (interquartile range, 2 to 4). The median duration of other
symptoms was 4 days for child (interquartile range, 3 to 7) and 5 days for adults (interquartile range, 3 to 8). Of the 175 patients interviewed, 170 (97%) reported that they complied with the prevention and control measures proposed (hand washing, face-masks, quarantine measures) and 131 (75%) affirmed that these measures had much more impact in reducing their quality of life than flu symptoms by themselves. The telephone interviews of 175 patients, allowed to calculate that 625 related persons had
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post-exposure prophylaxis with oseltamivir and a total of 318 days of absenteeism from work.
Of the 213 patients for whom data were available, 93 (44%) were referred to HSJ by the telephone advice line “Saúde24”, 40 (19%) came on their own initiative, and 40 (19%) were transferred from other hospitals.
Discussion
On June 11, 2009 the WHO raised the pandemic influenza phase to 6, indicating the beginning of a new influenza pandemic, the first of the 21st century, 41 years after Hong Kong influenza. Until September 1, 2009, a total of 401 cases of human infection with a novel pandemic (H1N1) 2009 virus have been identified in North of Portugal. In this report, we describe the clinical, epidemiological and prognostic characteristics of the 325 laboratory-confirmed cases of infection with pandemic (H1N1) 2009 virus which were identified and reported in HSJ (reference hospital of North of Portugal for pandemic influenza) during the containment phase.
In the North of Portugal, the first wave of influenza A pandemic occurred in the summer with a peak at weeks 33-34.Most cases were imported or acquired in the Algarve (region of Portugal chosen by many foreigners and Portuguese citizens for summer holidays ) where there was a circulation of influenza virus in the community, even in a limited way.
Most confirmed cases of pandemic (H1N1) 2009 virus infection have been characterized by self-limited, uncomplicated febrile respiratory illness and symptoms were similar to those of seasonal influenza (fever, cough, myalgia/arthralgia, headache, sore throat and rhinorrhea), but approximately 23% of patients had also vomiting or diarrhea or nausea, neither of which typical of seasonal influenza. Seventeen patients (5%) have been hospitalized with moderate or severe disease, three required admission to an intensive care unit and two required mechanical ventilation, but the fatality rate was 0%.
The observation that more than half patients were between 10 and 29 years-old and 80% were less than 30 years-old confirms that children and young adults may be more susceptible to S-OIV infection [10, 17]. This trend can also be explained by of differences in networks [10]. In this report, three outbreaks (one in a music festival and two in summer camps) have been clearly identified, mostly involving children or young adults. It is also possible that elderly persons may have some level of previous
immunity due to circulation of earlier influenza viruses [7, 17-21]. The CDC has assessed the level of cross-reactive antibody to the pandemic (H1N1) 2009 virus in cohorts of children and adults before and after vaccination with the recent (2005--2009) seasonal influenza vaccines [20]. In children, before vaccination, there were no cross-reactive antibodies to pandemic (H1N1) 2009 virus. Among adults, before vaccination, cross reactive antibodies were detected in 6-9% of those aged 18-64 years, and in 33% of those aged >60 years. The vaccination with the recent (2005--2009) seasonal
influenza vaccines did not elicit a cross-reactive antibody response to S-OIV in both groups.
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The reproductive number (R0, the number of new cases attributable to a single established case) is a key quantitative measure for assessing pandemic potential. Some studies suggested that R0 is substantially higher than of seasonal influenza and
comparable with the lower estimated of R0 obtained in previous influenza pandemics [22-23]. This strengthens the importance of prevention and infection control measures for a new influenza A virus. As recommended by WHO or CDC, Portuguese Ministry of Health also recommended that health care workers who provide direct care for patients with known or suspect pandemic (H1N1) 2009 virus infection should wear gowns, gloves, goggles, and disposable FFP2 or N95 respirators. Additionally, Hospital de São João also adopted during the containment phase recommendations on early identification and isolation of patients with suspected or proven influenza, contact tracing and antiviral prophylaxis for household and other close contacts. For hospital discharged patients with suspect or laboratory-confirmed influenza A were
recommended respiratory protection, enhanced hand hygiene, home quarantine during 7 days after onset of symptoms and avoidance of social contact. In this study we found a reported high compliance by patients and their household contacts with this prevention and control measures, which may have prevented that a much larger number of people had had been infected with influenza A.
In the North of Portugal, a national network for surveillance and control of influenza A pandemic 2009 was promptly organized and the objective of containment was achieved. During this phase, the overall impact of new influenza A (H1N1) virus infection on health-care services was considered to be low to moderate (that is, the demands on health-care services have caused some stress to systems above usual levels, but below maximum capacity).
The limitations of the present study need to be considered. The exact timing of patient exposure to a known infectious source was difficult to define. Second, the stratification of cases into primary, secondary and tertiary was not possible. Third, asymptomatic and mild cases were more likely to be missed. Fourth, the phone interview was not successful in approaching all patients. However, no statistically significant differences were found between interviewed and not interviewed cases, except for the proportion of patients presenting pneumonia.
The findings from an evaluation of past pandemics suggest that influenza viruses are unpredictable and that epidemiological patterns will vary within and among
countries and during the different waves of pandemics. A pattern of multiple waves characterized all three XX century pandemics. In the 1918 pandemic, for example, the more lethal wave in autumn was preceded by a first wave in the summer characterized by low mortality [21].
Further studies are needed to better clarify the nature and evolution of influenza pandemic 2009 and to evaluate the response of the health-care services with the
objective of making the system more efficient and effective. It is highly important to maintain epidemiological surveillance.
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We thank all health care workers and staff of Hospital São João Departments (Emergency, Infectious Diseases, Pediatric, Intensive Care and Clinical Pathology Departments) for providing data.
Disclaimers
No potential conflict of interest relevant to this article reported.
The opinions expressed in this article are those of the authors, contributing to this journal do not necessarily reflect the opinions of the Centers for Disease Control and Prevention or the institutions with which the authors are affiliated.
Biographical Sketch
Ana Cardoso is a 6th grade student at the Faculty of Medicine of University of Porto, Porto, Portugal. This study is integrated in his draft choice of the 6th year of Faculty of Medicine.
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Address for Correspondence
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Tables
*IQR – Inter-quartile range.
†Data obtained by telephone interview (n = 175), unless clearly stated in the clinical.
‡In the case of minors or students, the educational level is the parent with the higher education. The educational level is the number of complete years, not including failures.
§ Crowding index was calculated as the ratio of the number of people living in the house and the number of rooms (bedrooms and living rooms), is classified into three groups: <1.0, 1.0 and> 1.0 person per room.
Table 1. Socio-demographic characteristics and travel or contact exposure of the patients with confirmed influenza A (H1N1) 2009 virus infection, according to age [≤16 years (n =100) and ≥17 years (n = 225)].
Characteristic Age ≤16 years Age ≥ 17 years
Age – y
Median 11 24
IQR * 5-14 21-31
Male sex – no. /total no. (%) 55/100 (55.0) 136/225 (60.4)
Country of residence – no. /total no. (%)
Portugal 91/100 (91.0) 204/225 (90.1)
Marital status – no. /total no. (%) †
Single - 82/126 (65.1)
Married/cohabited - 39/126 (31.0)
Divorced/widowed - 5/126 (4.0)
Education level ‡ – no. /total no. (%) †
0-9 9/56 (16.1) 29/119 (24.4)
10-12 10/56 (17.9) 33/119 (27.7)
> 12 37/56 (66.1) 57/119 (47.9)
Crowding index § – no. /total no. (%) †
<1 31/56 (55.4) 77/119 (64.7)
1 18/56 (32.1) 34/119 (28.6)
>1 7/56(12.5) 8/119 (6.7)
Travel history – no. /total no. (%)
No 24/100 (24.0) 49/225 (21.8)
Yes
Portugal 28/100 (28.0) 93/225 (41.3)
Spain 22/100 (22) 48/225 (27.3)
Other European Country 23/100 (23) 20/225 (21.3)
North America 0/100 (0.0) 2/225 (0.1)
South America 3/100 (3.0) 12/225 (5.3)
Close contact – no. /total no. (%)
No/unknown 53/100 (53.0) 173/225 (76.9)
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Table 2. Clinical characteristics of the patients with confirmed influenza A (H1N1) 2009 virus infection, according to age [≤16 years (n =100) and ≥17 years (n = 225)].
Characteristics Age ≤16 years Age ≥ 17 years
Pregnancy – no. /total no. (%) - 1/225 (0.4)
Chronic illness* – no. /total no. (%) † 14/77 (18.2) 28/128 (21.9)
Obesity – no. /total no. (%) † 3/56 (5.3) 0/119 (0.0)
Smoking – no. /total no. (%) † - 46/119 (38.6)
Vaccinated with influenza vaccine during 2008–2009 season – no. /total no. (%) †
6/56 (10.7) 30/119 (25.2)
Would take influenza A vaccine? – no. /total no. (%) † 24/56 (42.9) 48/119 (40.3)
Symptoms at admission – no. /total no. (%)
Fever (temperature>38ºC) 96/100 (96.0) 214/225 (95.1) Cough 83/100 (83.0) 190/225 (84.4) Myalgia/arthralgia 49/100 (49.0) 175/225 (77.8) Headache 40/100 (40.0) 105/225 (46.7) Sore throat 40 /100 (40.0) 101/225 (44.9) Rhinorrhea 50/100 (50.0) 66/225 (29.3) Diarrhea/vomiting/nausea 22/100 (22.0) 53/225 (23.6)
Days from onset symptoms to admission – median (IQR) 1 (1-2) 2 (1-3)
Pneumonia on admission – no. /total no. (%) 0/100 (0.0) 13/225 (5.8)‡
Hypoxemia on admission – no. /total no. (%) 1/35 (2.9) 7/170 (4.1)
Laboratory findings – median (range)
Leukocyte count – per mm3 6970 (3060-14780) 6185 (1910-13690)
Lymphocyte count– per mm3 1675 (720-6680) 1005 (300-2900)
Platelet count 203 (123-319) 206 (0.3-260)
C- reactive protein– mg/L 12 (0-82) 26 (0.3-260)
Abnormal finding – no./total no. (%)
Leukocyte count <5000 per mm3 6/24 (25) 17/84 (20.2)
Leukocyte count >10 000 per mm3 4/24 (16.7) 6/84 (7.1)
Lymphocyte count <1000 per mm3 3/24 (12.5) 39/84 (46.4)
Platelet count <150 2/24 (8.3) 30/84 (35.7)
C- reactive protein >40 mg/L 5/25 (20) 22/88 (25)
Hospitalization – no. /total no. (%)
Ward 12/100 (12.0) 20/225 (8.9)
Intensive care unit 0/100 (0.0) 3/225 (1.3)
Acute respiratory distress syndrome – no. /total no. (%) 0/75 (0.0) 2/220 (0.9)
Mechanical ventilation – no. /total no. (%) 0/100 (0.0) 2/225 (0.8)
Days of hospitalization – median (IQR) 3 (2-3) 4.5 (3-7)
Days of fever – median (IQR) † 2 (2-3) 3 (2-4)
Days of other symptoms – median (IQR) † 4 (3-7) 5 (3-8)
Oseltamivir treatment – no. /total no. (%) 44/100 (44.0) 60/225 (26.7)
Adverse effects of oseltamivir § – no. /total no. (%) † 3/25 (12.0) 5/34 (14.7)
Death – no. /total no. (%) 0/100 (0.0) 0/225 (0.0)
More impact of control measure of infection than symptoms of flu – no. /total no. (%) †
38/56 (67.9) 93/119(78.2)
* Chronic illness were diabetes mellitus, asthma, renal failure, immunosuppression by drugs, cardiovascular disease, hematological disease and neurological disease.
†Data obtained by telephone interview (n = 175), unless clearly stated in clinical file. ‡Bilateral pneumonia in two cases (0.9%).
§ Adverse effects of oseltamivir were nauseas (n=5), vomiting (n=2) and epigastric pain (n=1). ¶ Adults: 75 mg 2x/d for 5d.
Children ≥12 months, >40kg: 75 mg 2x/d for 5d. Children ≥12 months, 24-40 kg: 60 mg 2x/d for 5d. Children ≥12 months, 15-23 kg: 45 mg 2x/d for 5d. Children ≥12 months, <15kg: 30 mg 2x/d for 5d. Children <12 months, 2-3 mg/kg 2x/d for 5d.
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Figures
Figure 1. Epidemic curve of 401 confirmed cases of pandemic (H1N1) 2009 by date of report, North of Portugal (May 31-September 1, 2009).
Figure 2. Origin of 325 confirmed cases of pandemic (H1N1) 2009, Hospital São João (May 31-September 1, 2009).
Figure 3. Pandemic (H1N1) 2009 virus infection cases by age and sex. North of Portugal (May 31-September 1, 2009).
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Supplementary Appendix
Figure S1. Orientation of patients aged ≤ 16 years.
