Postepy Hig Med Dosw. (online), 2013; 67: 595-600
Original Article
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The Clinical Course of Late Diagnosed Fatal Casesof A (H1N1) Influenza in Poland
Przebieg kliniczny późno rozpoznanych śmiertelnych przypadków grypy A (H1N1) w Polsce
Marta Rorat1,2  ABDEF, Tomasz Jurek1  AD, Ernest Kuchar2  DF, Leszek Szenborn2  D
1Department of Forensic Medicine, Wroclaw Medical University, Poland
2Department of Paediatrics and Infectious Diseases, Wroclaw Medical University, Poland
Corresponding author
Marta Rorat, M.D. Department of Forensic Medicine, Wroclaw Medical University, Mikulicza Radeckiego 4, 50-368 Wroclaw, Poland; e-mail: rorat.marta@gmail.com

Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection

Received:  2013.01.07
Accepted:  2013.05.15
Published:  2013.06.20

Summary
Introduction: The most frequent complication of A (H1N1) influenza and the leading cause of death was pneu­monia with a primary viral or mixed viral and bacterial etiology. 182 patients had died because of a pandemic influenza in Poland by 31st July 2010.
Material and Methods: A retrospective study of 6 fatal cases of pandemic influenza, aged 23-41, including 3 women, hospi­talised between November 2009 and February 2011 in different Polish medical centres.
Results: We present the clinical course of 6 late diagnosed cases of A (H1N1) influenza. All patients presen­ted typical flu-like symptoms in the beginning. 4/6 patients had severe disease risk factors: pre­gnancy, arthritis, Wegener granulomatosis and obesity. All patients were seen by doctors, no one had received antiviral therapy, 4/5 were treated with antibiotics before they were hospitalized. One patient had nosocomial infection. Patients were admitted to the hospital on the 3rd to 8th day of the disease. They received oseltamivir treatment on the 4th to 9th day. All patients developed pneumo­nia complicated by acute respiratory distress syndrome. Death appeared between the 4th and 27th day after the onset of symptoms. Autopsies were performed in 5 cases and revealed haemorrhagic pneumonia in 2 patients.
Conclusion: Delayed diagnosis and antiviral treatment initiation has a significant impact on mortality in A (H1N1) influenza. During the influenza epidemic, patients presenting typical symptoms should always be suspected of having influenza. Antiviral treatment has to be initiated immediately, especially if there are risk factors of severe disease.
Key words: swine influenza • pneumonia • pandemic • delayed diagnosis • antiviral agents




Introduction
In April 2009, in Mexico, there was an outbreak of a new A (H1N1) influenza virus [5]. The virus spread rapidly world­wide. The highest level of an influenza pandemic was an­nounced by the WHO on 11th June 2009 [23]. Spain was the first European country with a laboratory to confirm a H1N1 influenza pandemic [18]. Mortality in H1N1 cases was similar to that of seasonal influenza [3,20]. The first case in Poland was documented on 6th May 2009. The highest incidence of H1N1 influenza occurred in November and December 2009. A total of 182 patients had died because of A (H1N1) influ­enza by 31st July 2010 [4]. As some studies showed, pan­demic influenza was different to the seasonal one. It mainly concerned relatively young people (under the age of 60), who were relatively healthy beforehand. As with seasonal influenza, people with underlying health conditions and pregnant women were in the group with an increased risk of a severe disease. Obesity and delayed antiviral treatment have been identified as major risk factors of a severe out­come and higher mortality [6,7,11,14,16,19,20,22]. The most frequent complication in H1N1 influenza was pneumonia with a primary viral or mixed viral and bacterial aetiology (especially Streptococcus pneumoniae and Staphylococcus au­reus) [7,13,14,22]. Death usually occurred as a result of acute respiratory distress syndrome (ARDS) [7,14,17]. During the influenza H1N1 pandemic, due to the infection's prophylaxis limitations, the crucial tasks were prompt diagnosis, assess­ing the risk of severe disease and the immediate initiation of adequate antiviral therapy.
Material and Method
A retrospective analysis of six fatal cases during the A (H1N1) influenza pandemic of patients hospitalised between No­vember 2009 and February 2011 in different Polish medical centres was performed. All patients were confirmed with 2009 H1N1 influenza by rRT-PCR - using pharyngeal or na­sopharyngeal swabs. The study protocol included the fol­lowing information: age, sex, comorbid conditions, contact with people with acute respiratory infection, the time from the onset of symptoms to the first visit to the doctor, num­ber of visits to the doctors until hospitalisation, the time from the onset of symptoms until hospitalisation, the time from hospital admission to ICU admission, the time spent in hospital, the time from the onset of symptoms to death, and the time from the onset of symptoms to the initiation of an­tiviral therapy. The study protocol comprised data included in medical records as well as testimony provided by medical staff and patients' family members during court proceedings on the alleged malpractice. Obesity was defined as a BMI ?30. We recorded the clinical course - signs, symptoms, selected laboratory results, blood gas analysis, radiological findings and the history of treatment.
Results
Clinical characteristics
We describe 6 fatal cases of 2009 H1N1 influenza, treated in 6 different Polish hospitals from November 2009 to Febru­ary 2010. The age of the patients ranged from 23 to 41 years. There were 3 males and 3 females. Four patients had under­lying conditions - one had unidentified chronic arthritis treated with methylprednisolone, one was newly diagnosed with Wegener granulomatosis treated with methylpredniso­lone and cyclophosphamide, one was pregnant (31 weeks) and one was extremely obese (BMI 40). The others did not have any identifiable risk factors of any severe disease. Four patients had family contact with people who had a flu-like illness (H1N1 not confirmed). One patient with Wegener granulomatosis was infected during hospitalisation in the internal medicine and nephrology department; therefore, the study protocol does not fully apply to this case. None of the patients had been vaccinated against pandemic H1N1 influenza. The duration of symptoms before the first visit to the doctor ranged from 1 to 4 days. The duration of symp­toms before hospitalisation ranged from 3 to 8 days. None of the patients received antiviral treatment before admission to hospital, though all of them sought medical help several times (ranging from 3 to 5 times). All patients had a fever over 38°C, a cough and fatigue before admission to hospital - 4 complained of a sore throat and myalgia/arthralgia, 2 complained of nausea/vomiting, 2 had diarrhoea (Table 1).
Table 1. Symptoms observed in patients with A (H1N1) influenza before hospitalization

The other symptoms were rhinorrhoea, haemoptysis, head­ache and chest pain. The patients were diagnosed with phar­yngitis, tracheitis, bronchitis, viral infection, respiratory infection and in one case seasonal influenza. The first symp­toms of influenza in the patient with Wegener granuloma­tosis were fever, fatigue and diarrhoea. After 2 days, the cough and dyspnoea appeared. In 5 cases, the main cause for visiting the hospital was lack of improvement in the physi­cal condition or intensification of symptoms despite the treatment. Upon admission, 3 patients had dyspnoea and 2 had auscultatory phenomena. During hospitalisation, all the patients developed respiratory failure and required inten­sive care. The time from hospital admission to ICU transfer was < 12 h in 3 out of 5 cases. Consequently, the interval between the onset of symptoms and ICU admission ranged from 6 to 9 days. The patient with Wegener granulomatosis required mechanical ventilation after 3 days of symptoms. He was also haemodialysed because of kidney failure, which appeared during the course of the underlying disease (be­fore the influenza).
Diagnostics
In all patients, at the time of hospital admission, we found ab­normalities in their blood morphology (Table 2). 4/5 patients had lymphopenia with normal total white blood counts and 2/5 had thrombocytopenia. The patient with Wegener granu­lomatosis had pancytopenia because of his underlying dis­ease. C-reactive protein concentration was elevated in all cases, but in one case it was extremely high (422 mg/dl). Slightly increased liver transaminase activity (GOT - glu­tamic oxaloacetic transaminase; and GPT - glutamic pyruvic transaminase) was found in 2 patients - one was extremely obese and developed liver failure during hospitalisation. In all cases, blood gas analyses proved hypoxemia, which per­sisted regardless of oxygen therapy. All patients had chest X-rays on the day of hospital admission and they all had bi­lateral infiltrates indicating pneumonia.
Table 2. Diagnostic findings

All patients were tested for A (H1N1) influenza using real time PCR. In 2 cases, a rapid influenza test was performed - the results were negative. Microbiology diagnostics re­vealed bacterial superinfection in 2 cases. In the first pa­tient, Staphylococcus aureus MLSB (+) was isolated from the sputum. In the second (the patient with Wegener granulo­matosis), Acinetobacter baumannii sensitive to cefoperazone and colistin was isolated from the blood. The patient with Wegener granulomatosis also had CMV reactivation (CMV DNA in the blood).
Treatment
Four patients were treated with antibiotics before admission to hospital. One person received one type and 3 patients received two types of antibiotics. The most commonly used antibiotic was cefuroxime, which was administered in 3 cases. The other antibiotics were doxycycline, amoxicillin, azithromycin and gentamicin. In all cases, the antibiotic therapy was changed or initiated after hospital admission. Three patients received cefuroxime (in one case cefuroxime plus amikacin), 3 received amoxicillin with clavulanic acid - in one case ciprofloxacin and in another erythromycin was added. All patients also received oseltamivir. The time from the onset of the illness to the initia­tion of oseltamivir therapy was 7-9 days. None of the patients were given the test for the resistance of the H1N1 influenza vi­rus to oseltamivir. The patient with Wegener granulomatosis was initially treated with amoxicillin with clavulanic acid and ciprofloxacin. After two days cefuroxime was added, which was changed to another antibiotic - imipenem. The time from the onset of illness to the initiation of oseltamivir therapy was 4 days. All patients were treated in the ICU because of respira­tory distress. They all required mechanical ventilation. In the pregnant woman, because of impaired oxygenation, a caesar­ean section was performed. In this case, high frequency oscil­latory ventilation and ventilation in the supine position were also used. Interventions such as ECMO or extracorporeal CO2 removal were not used in any case.
Death
Death appeared between the 4th and 27th day after the on­set of symptoms - later in patients without severe course risk factors. All patients developed acute respiratory distress syndrome (ARDS). The final cause of death in 4 patients was cardiorespiratory failure. In 2 patients it was multi-organ dysfunction syndrome. Autopsies were performed in 5 cases, all by a pathologist. The post-mortem examination was not performed in the patient with Wegener granulomatosis. In all cases the autopsy revealed features of pneumonia. In two cases haemorrhagic pneumonia was found (in one of them an image of purulent pneumonia), in two others lung fibrosis. In the obese patient and the pregnant woman, liver steatosis was also diagnosed.
Discussion
We have presented six fatal cases of pandemic (H1N1) influ­enza relating to patients who were hospitalised in Poland be­tween November 2009 and February 2010. All patients devel­oped pneumonia and consequently ARDS, and they required treatment in the ICU. All our patients were young - age ranged from 23 to 41 years. As many studies have shown, the H1N1 in­fluenza virus mostly infected people between 60 and 65 years old [6,7,11,14,17,19,20,22,25].
In our study, 4 patients had risk factors of severe diseases: chron­ic arthritis, Wegener granulomatosis, pregnancy and obesity. Despite many disturbing reports on the dramatic increase in the number of overweight/obese people (obesity epidemic) and the health consequences of this condition [8,15], excessive body weight is still commonly perceived as a physiological status - a variant of the norm. People rarely recognize the correlation between obesity and the prevalence of chronic, more infectious diseases. In pandemic influenza cases, excessive body weight has proved to be a very important risk factor of severe illness, associated with higher mortality [6,7,11,20,22]. For example in the Cui et al. [6] study 32% and in the Viasus et al. [22] study 28% of hospitalised patients were obese.
The next risk factor was pregnancy. The studies showed that the mortality in the severe course of H1N1 influenza in pregnant women was up to 20% [19,20,22,25]. High risk of influenza with a poor outcome during pregnancy was associated with respira­tory, cardiac and immune system changes [9]. It was higher in women with chronic diseases, especially with asthma and obe­sity. Complications occurred more often in the second and third trimester of pregnancy and in multigravida patients [11,16,25]. During the pandemic, the rate of premature birth also increased - 30.2% in the Siston et al. [16] study and 57.8% in the Zhang et al. [25] study. This was clearly associated with a higher rate of neonatal death [16,25].
In our study, two patients had pre-existing medical conditions, which predispose to a poor outcome. In one case, it was chronic arthritis which appeared in the course of the undetermined sys­temic disease. The woman was treated with steroids for several months. Based on the medical records, the authors established that the patient was not treated regularly and her ailments, in the period preceding the A (H1N1) infection, were exacer­bated. The second patient was immunocompromised because of Wegener granulomatosis. Many authors have presented the relation between the severity of the influenza, the higher death rate and pre-existing medical conditions. Besides obesity, the most common underlying medical conditions were asthma, chronic obstructive pulmonary disease, diabetes, cardiac and liver diseases, neoplasms, renal failure and immunosuppres­sion [6,7,11,14,17,19,22]. Tabarasi et al. [19] also highlighted drug abuse.
The other important risk factor which influenced the mortal­ity rate during the pandemic was bacterial co-infection. The most common identified strains were Streptococcus pneumoniae and Staphylococcus aureus [7,11,13,22]. In our study, one patient had pneumonia caused by a coexisting H1N1 virus and Staphy­lococcus aureus. In the patient with Wegener granulomatosis, Acinetobacter baumannii was isolated from the blood. Because of immunosuppressive treatment, he also had CMV reactivation. Viasus et al. [22] showed that early treatment with oseltamivir was associated with less evidence of pneumonia and bacterial co-infections.
In our data, the clinical features of influenza included fever, cough, fatigue, sore throat, myalgia or arthralgia, nausea/vom­iting, diarrhoea, rhinorrhoea, haemoptysis, headache and chest pain. These symptoms have also been reported in many other studies [6,7]. The laboratory tests performed upon admission showed lymphopenia and thrombocytopenia and the CRP level was elevated in each case. Many authors have reported the as­sociation between increased CRP concentration or lymphopenia and severe illness [14].
In our study group, the H1N1 2009 influenza infection was con­firmed by an rRT-PCR assay. Only 2 patients had a rapid test for H1N1 influenza and in both cases the result was negative. In these cases it was the reason for a one-day delay in treatment. A number of studies have proven the rapid tests to have too low sensitivity. Thus, further proceedings should not be dependent on their negative results [11,21]. The rRT-PCR is the most sen­sitive and specific influenza diagnostic test but false negatives can also occur. According to the CDC the sensitivity in an rRT-PCR assay is 86-100% [1].
During the pandemic, the CDC recommended introducing ear­ly empiric antiviral therapy with oseltamivir in patients with flu-like symptoms without undue delay (without waiting for the test result or the symptoms of severe disease), especially in patients who were at increased risk of complications from influenza [2]. The therapy was most effective if it was initiated within 48 hours from the onset of symptoms [2,24]. Despite this, there were studies that provided evidence that treatment with oseltamivir in patients admitted to hospital even after 48 hours may reduce mortality [11,12,24]. Late initiation of therapy was clearly associated with a higher risk of severe illness and mor­tality [16,19,22]. In all our cases, the initiation of treatment was significantly delayed. It was caused by the fact that the doctors, despite the typical flu-like symptoms, did not suspect a H1N1 infection at the very beginning of the illness. The diagnosis of pandemic influenza was only made during hospitalisation. Polish recommendations for the management of patients sus­pected of having H1N1 influenza were not precise [10]. As a re­sult, many doctors did not know how to deal with such patients.
None of our patients were vaccinated. In Poland, due to the Min­ister of Health's decision, a vaccine against H1N1 influenza was not available, even for healthcare workers. Therefore, preven­tive options were limited. The therapeutic options in patients with severe disease (hospitalised in the ICU) were also limited. Unconventional therapies such as ECMO, high frequency os­cillatory ventilation or extracorporeal CO2 removal were only available in a few hospitals in the country, access to these cen­tres was limited and experience in the use of these therapies in influenza cases was poor.
We excluded one case of a pregnant woman (22 weeks) from the report. The patient was admitted to the hospi­tal in December 2009 with influenza-like symptoms: fever up to 40°C, sore throat, cough, fatigue, myalgia and ar­thralgia, and dyspnoea, and also complaints about dysuric symptoms. The disease lasted 2 days. Upon admission, the patient had peripheral cyanosis and disturbances in blood gas analyses (hypoxemia and acidosis). She also had a uri­nary tract infection. She was treated with oseltamivir (from the first day of hospitalisation) and antibiotics. In this case both the rapid test and PCR were negative. Her condition deteriorated in a couple of days; she developed ARDS and required intensive care with mechanical ventilation in the ICU. During transportation to the other department, she had a cardiac arrest. The ultrasound performed during the resuscitation revealed a rupture of the spleen (perhaps af­ter cardiac massage). She died five days after the onset of symptoms. The autopsy revealed haemorrhagic pneumonia and features of pyelonephritis.
Our study has some limitations. First of all, it refers to a small number of cases. The group is heterogeneous and the patient selection was random. The other issue is the limited material in the histopathological reports. They only include basic informa­tion and lack important details. The reports were prepared by a few different pathologists. The patients were treated in dif­ferent hospitals and did not have the same diagnostics, so not all information required was collected. Nevertheless, this is a good illustration of problems experienced in Poland during the A (H1N1) influenza pandemic.
Conclusions
Delayed diagnosis and antiviral treatment initiation has a signif­icant impact on mortality in A (H1N1) influenza. During the in­fluenza epidemic, patients presenting typical symptoms should always be suspected of having influenza. Antiviral treatment has to be initiated immediately, especially if there are risk fac­tors of severe disease. Diagnostic and therapeutic procedures should concentrate on respiratory sufficiency as pneumonia (viral and secondary bacterial) is a major cause of death.
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The authors have no potential conflicts of interest to declare.