During April 2009, Mexico reported an outbreak of respiratory disease , which was subsequently determined to be caused by a novel swine-origin influenza A (H1N1) virus with molecular features of North American and European swine, avian, and human influenza viruses [2,3]. Two months later, the World Health Organization (WHO) classified the global spread of the virus as a pandemic of international concern . The H1N1 influenza A pandemic has been characterized by its high transmissibility. Since the first alarm in Mexico, the virus spread quickly worldwide, such that in less than two months 160 countries had both mild and severe cases of the disease. As the epidemic spread, international scientific information began to be disseminated rapidly, and in six months both the clinical behavior of the disease and its level of severity worldwide were well understood. In this article we have reviewed the Mexican experience and that of diverse authors abroad to compile a detailed description of the clinical behavior of influenza A (H1N1) virus, the spectrum of the disease, and its complications. Emphasis has been placed on the clinical differences between the mild (without pneumonia) and severe (with pneumonia) forms of the disease.
Influenza is the most frequent cause of acute respiratory illness requiring medical intervention . It usually causes an acute, self-limiting febrile illness but can also lead to severe complications or death, particularly in patients with compromised immunity (e.g., pregnant women, elderly persons, HIV-infected patients, and so on) or underlying medical conditions (e.g., cardiac or pulmonary disease). The new influenza pandemic is still under study but, to date, the clinical presentation of the novel swine-origin influenza virus (S-OIV) A (H1N1) appears to resemble that of seasonal influenza, and the majority of patients infected with the pandemic virus experience mild symptoms and recover fully within a week, even without medical treatment [6,7].
TRANSMISSION AND SPECTRUM
Influenza virus is present in respiratory secretions of infected persons . Influenza usually spreads from person to person in respiratory droplets when an infected person coughs or sneezes. Occasionally, a person may become infected by touching a surface with influenza virus on it and then touching his/her mouth, nose or eyes. Transmission of the virus on the hands of patients or their caregivers has also been described. Small-particle aerosols in the vicinity of infected individuals are another source of transmission.
Healthy adults may be able to infect other people at least one day before symptom onset and up to five days after becoming ill, making it possible to infect another person before the ‘contagious person’ is aware of his/her condition . Because many patients with H1N1 influenza had complaints of diarrhea, fecal/oral transmission should be considered a potential route of transmission . Therefore, cleansing and hand hygiene are important measures for the prevention of infection dissemination.
The disease demonstrates a wide spectrum of clinical presentation, including asymptomatic infection or mild illness with a rapid recovery time without complications . The typical symptoms of 2009 H1N1 influenza virus may include fever, cough, sore throat, runny or stuffy nose, body aches, headache, chills, fatigue, nausea, diarrhea, and vomiting [8,11,12]. Depending on the case series, the proportion of persons with laboratory-confirmed 2009 H1N1 infection who are febrile ranges from ~10% to 50% [10-12]. A minority of the cases present severe pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan dysfunction syndrome that may progress to death [11-13] (Figure 1).
||Figure 1. The highest percentage of H1N1 influenza A cases show mild illness with predominant upper-airway symptoms and short duration. However, in some individuals, illness may progress to more severe forms, which may result in acute respiratory failure and death. An inverse relationship between the use of health resources and disease severity is shown. Although severe cases are less frequent, resource utilization is higher. In contrast, mild cases are more frequent and resource utilization is less.
The principal determinant of the severity of a flu pandemic, as measured by the numbers of cases of serious illness and deaths, is the virulence of the virus. Nevertheless, many other factors influence the overall impact of a pandemic.
Even a pandemic virus that initially provokes mild symptoms in healthy persons may be harmful. This may be due to the highly mobile society that we live in, where worldwide travel is common and frequent. Also, the same virus that causes a mild illness in one country may provoke in another country an illness producing high morbidity and mortality. Such is the case of the 2009 H1N1 influenza virus. For example, in Mexico, which was the first country identified in the pandemic, the severity of cases was higher than in other countries . Also, the inherent virulence of the virus may change over time as the pandemic advances in subsequent waves of national and international dissemination.
DIFFERENCES BETWEEN SEASONAL AND PANDEMIC INFLUENZA IN TERMS OF SEVERITY AND INFECTION RATES
Seasonal influenza varies in terms of timing, duration, and severity and may cause mild to severe illness, occasionally leading to death . Each year in the United States, an average of 36,000 persons die from flu-related complications and >200,000 persons are hospitalized due to flu-related causes. Of those persons hospitalized, 20,000 are children <5 years old. Over 90% of deaths and ~60% of hospitalizations occur in persons >65 years . In general, in many developing countries there is no awareness of this viral infection and annual vaccination is uncommon.
The pandemic 2009 H1N1 flu differs in its pathogenicity from seasonal influenza in three respects: 1) transmissibility appears substantially higher compared with seasonal influenza . In one study, the secondary attack rate of the strain causing this pandemic was estimated to be 22% to 33% compared with 5% to 15% for seasonal influenza ; 2) it has caused greater disease burden in persons <25 years of age than in older persons . At this time there are relatively fewer cases and deaths reported in persons 65 years and older, which is unusual when compared with seasonal flu . However, pregnancy and other previously recognized high-risk medical conditions from seasonal influenza appear to be associated with increased risk of complications from the 2009 H1N1 influenza ; 3) the pandemic virus can infect the lower respiratory tract and cause rapidly progressive pneumonia, especially in children and young to middle-aged adults .
The signs and symptoms of influenza caused by pandemic H1N1 influenza A virus are similar to those of seasonal influenza, although gastrointestinal manifestations appear to be more common with pandemic H1N1 influenza A [11,21,22]. The severity has been less than what was observed during the influenza pandemic of 1918-1919 .
The World Health Organization  has developed clinical guidelines and, according to the presence or absence of complications, they are divided into 1) uncomplicated influenza and 2) complicated influenza.
The most common clinical findings of the uncomplicated 2009 H1N1 influenza were the sudden onset of symptoms of fever (usually high), headache, tiredness (may be extreme), cough, sore throat, runny or stuffy nose, body aches, diarrhea and vomiting (more common in children than adults), some of which are unusual features of seasonal influenza [12,25-27]. The presence of fever >37.8 C accompanied by cough or sore throat in the absence of a known cause other than influenza is sufficient to consider a suspected case of influenza . Other frequent findings included chills, hemoptysis, myalgias, and arthralgias [25,26]. Certain groups such as infants, the elderly, and immunocompromised hosts may have atypical presentations. In addition, subclinical infection has rarely been reported , although further study is required to determine its frequency.
A recently published Chinese study , which included 426 patients with confirmed cases of infection who were hospitalized with mild influenza, allowed accurate determination of the time of virus excretion and duration of symptoms in patients with mild influenza. The investigators measured viral load daily in the patients from the time of hospital admission to hospital discharge, duration of symptoms and viral shedding. The median incubation period was two days (range: 1-7 days); 67.4% of the patients had fever. Headache and lymphopenia were more common in patients with fever. The median time from onset of illness to a negative test result, according to real-time reverse transcriptase (RT)-PCR, was six days (range: 1-17 days). The median duration of fever after treatment was three days (range: 1-17 days). The median interval from the time the temperature returned to normal to the time when a negative test result was obtained was three days. Among all the patients, 96% had a negative test result, determined by real-time RT-PCR, within one week after the body temperature returned to normal. Factors for prolonged viral infection on the basis of real-time RT-PCR test results were age <14 years (OR 1.94: 95% CI 1.13–3.31) and a period of >48 hours between disease onset and treatment with oseltamivir (OR 4.46: 95% CI 2.58–7.72). In general terms, these H1N1 influenza cases in China demonstrate that disease severity is lower if patients are treated early.
The usual signs of influenza, such as fever and cough, are less prevalent in young children than in older children and adults .
Infants may present with fever and lethargy and may not have cough or other respiratory symptoms. Symptoms of severe disease in infants and young children may include apnea, tachypnea, dyspnea, cyanosis, dehydration, and altered mental status. Young children (<5 years of age and, especially, <2 years of age) are at increased risk for influenza complications .
Although symptom onset in complicated influenza is similar to that in uncomplicated cases, the clinical course is more severe , and some alarming signs are present, including shortness of breath/dyspnea, tachypnea, hypoxia, cyanosis, and mental confusion, among other symptoms. In addition, there may be radiological signs of lower respiratory tract disease (e.g., pneumonia), central nervous system involvement (encephalopathy, encephalitis), severe dehydration, and/or the presence of complications such as renal failure, multiorgan failure and septic shock. Less frequently, myocarditis, myositis and rhabdomyolysis have been reported. Another cause of complicated influenza is the exacerbation of underlying chronic disease, including chronic obstructive pulmonary disease (COPD), asthma, diabetes, or other cardiovascular conditions . Table 1 summarizes the findings of eight case series, which allows comparison of the main symptoms in uncomplicated and complicated influenza A (H1N1) virus infection.
||TABLE 1. Baseline characteristics of patients with suspected or confirmed influenza A/H1N1
Physical examination in severe cases
Patients with severe cases arrived at the emergency room with the triad of tachycardia, tachypnea and hypotension . The average heart rate was 102 beats/min (range: 67-144), the average respiratory rate was 28 respirations/min (range: 16-48), and the mean arterial pressure was 87 mmHg (range: 50-115). Lung examination revealed bilateral rales.
Severe hypoxemia in the most severe cases was the most apparent problem. In this regard, at the National Institute of Respiratory Disease in Mexico, 56% of the cases during the first outbreak developed ARDS . Absolute lymphopenia (lymphocyte count <1000 cells/mm3) was one of the most common hematological abnormalities , found in 48.5% of patients. Serum lactate dehydrogenase levels >1000 U/liter were found in 42.6% of patients . Elevated serum creatinine ≥2 mg/dL was reported in 7.2% of patients. Mild to moderate elevations of creatine kinase levels were reported in some patients with severe illness . One patient with a creatine kinase level of 27,820 U/L experienced rhabdomyolysis .
Other abnormalities documented in a study of 272 patients requiring hospitalization  were: leukopenia, 50/246 (20%); leukocytosis, 44/246 (18%); thrombocytopenia, 33/234 (14%); and thrombocytosis, 20/234 (9%). Elevated alanine aminotransferase was reported in 58/130 patients (45%), elevated aspartate aminotransferase in 57/131 patients (44%); and anemia in 87/238 patients (37%). Elevated total bilirubin was reported in 6/121 patients (5%).
Of 833 hospitalized patients with probable or confirmed pandemic H1N1 influenza A infection, 547 (66%) had infiltrates suggestive of pneumonia or ARDS . A Mexican study  that included 52 patients hospitalized with H1N1 influenza infection reported that all chest x-ray results taken upon hospital admission were abnormal. Most of the subjects (80%) developed extensive bilateral air space consolidation, as demonstrated by multifocal opacities or multiple areas of attenuation. Opacities were diffuse and more prominent in the lung bases in the majority of patients. Less common abnormalities were focal in 12% of patients. In all patients who required mechanical ventilation, chest x-ray results were consistent with ARDS.
Critically ill patients who underwent computed tomography (CT) of the lungs  had a combination of ground-glass opacities and consolidation; most of these patients had diffuse lung involvement.
In patients with influenza pneumonia, bacterial coinfections are not documented in any of the reported series. It is difficult to establish the role of bacteria in cases with pneumonia associated with H1N1 influenza A. For example, bacterial coinfections of the lung were detected in 46/1088 patients (4%) in California, resulting in hospitalization or deaths , but were detected in 22/77 (29%) fatal cases of pandemic H1N1 influenza A infection in the United States . Of 689 patients in Australia and New Zealand, 140 (20%) requiring intensive care unit (ICU) admission for pandemic H1N1 influenza A infection were found to have secondary bacterial pneumonia . In a recent publication from the US Centers for Disease Control and Prevention (CDC) , Staphylococcus aureus was the most common bacteria found in autopsies of patients who died as a result of influenza H1N1 virus infection. Among the fatal cases described in the United States, ten were due to Streptococcus pneumoniae, six to Streptococcus pyogenes, seven to S. aureus, two to Streptococcus mitis, and one to Haemophilus influenzae; four cases involved multiple pathogens .
Persons of any age with certain conditions, including chronic lung or cardiovascular disease and immunosuppressive conditions, have an elevated risk for invasive bacterial infection . Bacterial coinfection may be important in ventilated patients but not in patients without mechanical ventilation. However, failure to document bacterial lung infections may reflect the difficulty of establishing specific bacterial diagnoses among persons with bacterial coinfections, as suggested by the report of the CDC . One problem is that routine clinical tests used to identify bacterial infections among patients with pneumonia do not detect many of these infections. Systematic studies with novel methods using PCR are needed to clearly determine the role of coinfection in hospitalized patients, but not necessarily in those not requiring mechanical ventilation.
CHARACTERISTICS OF H1N1 INFLUENZA A PANDEMIC IN MEXICO: SEVERE CASES
During the onset of the 2009 H1N1 pandemic in Mexico, the presentation of cases of severe pneumonia with rapid respiratory failure, ARDS, and multisystem organ failure was striking and, in some cases, ended in death [11,13,21,27]. For example, from March 24 to April 29, 2009, 2155 cases of severe pneumonia were reported in Mexico, including 821 hospitalizations and 100 deaths . During this period, which represented the early phase of the S-OIV epidemic, a pronounced shift in morbidity was evident, with 71% of cases of severe pneumonia occurring in patients between the ages of 5 and 59 years, as compared with an average of 32% of cases in that age group during previous periods . Similarly, there was a marked change in the mortality pattern, with an increase in the mortality rate in the 5- to 59-year-old age-group as compared with the rates observed in these same age groups during previous periods of epidemic influenza (87% vs 17%) .
The National Institute of Respiratory Diseases (INER) treated >200 patients during the first outbreak and this experience allowed us to characterize severe cases that were not observed in many countries. During the early stages of the influenza A (H1N1) outbreak, 18 cases of pneumonia and confirmed S-OIV infection were identified. All these patients had bilateral pneumonia and complaints of fever, cough, and dyspnea. All had increased serum lactate dehydrogenase levels, creatinine kinase levels were increased in 62% of patients, and lymphopenia was present in 61% of patients. Twelve patients required mechanical ventilation, and seven patients died . All pneumonias were radiologically confirmed, with 11 patients having bilateral patchy alveolar opacities (predominantly basal) affecting three or four quadrants . Mortality rates from the H1N1 pandemic differed from those reported in other countries, probably because Mexico was the first country to have intensive circulation.
The severity of the disease in Mexico may also reflect the delay between symptom onset and arrival at the hospital. Series of cases studied in the United States showed that patients sought medical care within an average of three days , whereas INER patients arrived after an average of seven days (range: 1-20 days). A case series report of 6945 influenza patients in Mexico  showed that the time from symptom onset to admission was longer for persons who died than for those who survived in the hospital (7 vs 3 days). The odds ratio increased with every day of delay. As in other Latin American countries, it is not usual in Mexico for persons to seek medical care for symptoms of influenza-like illnesses. In fact, patients tend to self-medicate with previously prescribed pills (including antibiotics). This delay may also explain why Mexico reported a higher number of serious and fatal cases than other countries.
Among patients requiring hospitalization in the United States, ~70% had at least one underlying condition known to increase the risk of influenza complications [12,32]. The prevalence of certain underlying conditions was higher among patients requiring hospitalization for pandemic H1N1 influenza A in the United States than in the general population [37,38]. As an example, 32% of these patients had asthma compared with only 8% of the U.S. population . In a cohort study of patients in Australia and New Zealand admitted to the ICU with confirmed pandemic H1N1 influenza A infection between June 2009 and August 2009, the proportion of patients who were pregnant, had chronic lung disease, body mass index >35 or were indigenous to Australia or New Zealand was higher in comparison to the general population . One-third of the patients were young or middle-aged and did not have an identifiable risk factor for severe disease. Similar to what was observed among the indigenous populations of Australia and New Zealand, a disproportionately high percentage of the indigenous population of Canada was affected by severe pandemic H1N1 influenza A infection .
During the 1918 influenza pandemic, the overall disease-specific mortality rate in pregnant women was 27%, establishing that pregnancy is a risk condition during an influenza pandemic [20,40,41]. In the United States during the 2009 H1N1 influenza A pandemic, increased rates of hospitalization were observed among pregnant women compared with the general population . Other countries also reported an increased risk of severe influenza among pregnant women during the 2009 pandemic, particularly during the second and third trimesters of pregnancy [43,44]. As of late August 2009, 100 pregnant women in the United States required admission to the ICU and 28 of these patients died . The mortality rate from the current H1N1 influenza A pandemic among pregnant women is higher than among the general population. Approximately 6% of deaths caused by pandemic H1N1 influenza A virus in the United States occurred in pregnant women . During previous influenza pandemics, increased rates of spontaneous abortion and preterm birth were reported among pregnant women, especially those with pneumonia . Of five pregnant women requiring hospitalization for pandemic H1N1 influenza A, two developed complications: spontaneous abortion (at 13 weeks of gestation) and premature rupture of membranes (at 35 weeks of gestation) .
Among nonpulmonary complications of seasonal influenza are various forms of central nervous system involvement, including encephalitis, transverse myelitis, aseptic meningitis, and Guillain-Barrè syndrome [46,47].
There are few reports regarding neurological complications in patients with H1N1 influenza A. Four cases of neurological complications associated with S-OIV infection in children have been described in the literature. These patients were aged 7-17 years and were admitted with signs of influenza-like illness and seizures or altered mental status. Three of the four patients had abnormal electroencephalograms. In all four patients, H1N1 influenza A viral RNA was detected in nasopharyngeal specimens but not in cerebrospinal fluid. All four patients recovered fully with no neurological sequelae at discharge. These findings indicate that, as with seasonal influenza, neurological complications may occur after respiratory tract infection with H1N1 influenza A .
As mentioned above, there is a case report of one patient with a creatine kinase level of 27,820 U/L who experienced rhabdomyolysis .
As of November 15, 2009, there were >622,482 laboratory-confirmed cases of pandemic H1N1 influenza A worldwide, including at least 7826 deaths . Using mathematical modeling, the CDC has estimated that ~4000 fatal cases occurred in the United States between April 2009 and mid-October 2009 .
Mortality has been very uneven in different regions reported by WHO . For the Americas up to November 22, 2009, there were 192,765 confirmed cases and 5360 deaths. This contrasts with data reported for the European region, in which 154,000 cases were confirmed, but only 650 deaths were reported. Most deaths have been related to respiratory failure resulting from severe pneumonia with multifocal infiltrates and ARDS [12,27].
Few elderly persons were infected, which may be due to some degree of preexisting immunity in older individuals against antigenically similar influenza viruses. However, age-specific mortality rates represent a combination of incidence and deaths; therefore, elderly infected individuals are still thought to be at increased risk for complications. In a surveillance study of 1088 probable or confirmed cases of pandemic H1N1 influenza A resulting in hospitalization or death in California, individuals ≥50 years of age had the highest mortality rates. This may have been the result of comorbidities because 80% of patients in this age group had underlying medical conditions . One-third of deaths occurred in individuals aged 25–49 years in the United States, which is a higher percentage than occurs with seasonal influenza.
Typical clinical manifestations of H1N1 influenza A, which are very similar to the seasonal influenza, include fever, headache, cough, sore throat, myalgias, chills, and fatigue. Vomiting and diarrhea that have also been common during this pandemic are unusual features of seasonal influenza. During the 2009 pandemic, although there was a high degree of transmissibility, most cases of influenza showed a mild clinical picture. The percentage of cases requiring hospitalization and progressing rapidly to pneumonia, respiratory failure, and ARDS was much lower.
The following lessons should be kept in mind as a result of these epidemics.
- The surprising presentation of the first cases in the early spring of 2009, which was one of the main causes of the high mortality, showed us that this H1N1 influenza A infection may not be seasonal.
- High fever, headache and malaise in subjects who previously were taking antibiotics should alert clinicians to the possibility of viral infection.
- Surprise and panic caused by the disease outbreak may be a more serious effect than the disease per se, underscoring that the population should be educated about early diagnosis that makes this a treatable disease.
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