# Clinical Findings in Albanian Patients with 2009 Influenza AH1N1 Admitted to the Intensive Care Unit

Authors: Arben Ndreu; Dhimitër Kraja; Silva Bino; Artan Simaku; Iris Hatibi; Najada Çomo; Arjan Harxhi; Ilir Ohri; Kastriot Shytaj; Entela Kolovani; Hektor Sula; Arben Pilaca; Shane Morrison; Vania Rashidi; Ervin Çerçiz Mingomataj
Journal: ISRN Emergency Medicine
 (2013)

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## Abstract

Background. The 2009 AH1N1 (H1N1) epidemics expanded rapidly around the world by the current ease of cross-continent spread of infectious diseases. We aimed to describe clinical characteristics of admission, demographic characteristics, treatment, and outcome for critically ill patients with laboratory-confirmed H1N1 virus. Methods. This is an observational prospective study of 31 Albanian patients, admitted to Intensive Care Unit (ICU) of the Infectious Disease Department during the period from November 2009 to March 2010. Demographic data, symptoms, comorbid conditions, days of stay at ICU, radiologic/laboratory findings, and clinical outcomes were collected using a case report form. Results. The median age of patients was 35 years, and 54% of them were female. Five patients (16%) required endotracheal intubation; in 15 (48%) patients O2-therapy was given via nasal sound and mask, and 11 (35%) of patients received O2-therapy with noninvasive ventilation (NIV). All patients were treated with oseltamivir. Four patients did not survive during the disease’s course. Conclusion. Critical illness from 2009 influenza H1N1 in ICU predominantly affects young adults. The NIV could have a beneficial effect in 2009 influenza H1N1 infection-related hypoxemic respiratory failure and was associated with severe hypoxemia, pneumonia, requirement for prolonged mechanical ventilation, and the frequent use of antiviral therapy.


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## Body

## 1. Introduction

In April 2009, a new strain of human H1N1 influenza A virus (H1N1) was identified in USA [1, 2].  Until November of the same year, it has caused hundred of thousands cases worldwide and deaths in many countries (WHO (2009) Influenza H1N1—update 14. http://www.who.int/csr/don/2009_05_04a/en/index.html) [3]. The circulation of influenza H1N1 virus has been associated with acute respiratory distress syndrome and with excess pneumonia [4, 5].The first laboratory-confirmed case of novel pandemic influenza H1N1 2009 in Albania was reported on May 2009. During the period July–October, Albania experienced a moderate wave of virus transmission; a stronger wave began in November, and a peak in incidence occurred during the first week of December. The hospitalization rates in Infectious Diseases Hospital (IDH) were reported every week during the influenza season, which further allowed for the collection of information on the number of people with influenza-related complication and outpatient’s consultation (Figure1). The aim of this survey is the description of clinical characteristics of admission, demographic characteristics, and comparison of treatments and their corresponding outcomes for critically ill patients with laboratory-confirmed H1N1 virus, admitted to Intensive Care Unit (ICU) of the IDH. A cornerstone of treatment is the use of antiviral and, if necessary, antibacterial agents. A matter of debate is which administration mode for the ventilatory support (oxygen therapy) is more effective. This treatment can be essential because of severe lung affection during the H1N1 infection.Figure 1
Total and ICU admission for H1N1 influenza at Infectious Diseases Hospital.


## 2. Methods

This observational prospective study was approved by the Albanian Ethical Committee. The case series described the clinical and epidemiologic characteristics of 31 patients with laboratory-confirmed influenza H1N1 infection admitted to ICU of the IDH—University Hospital Centre in Tirana, Albania—during the period November 15, 2009–March 27, 2010. Data were collected and analyzed regarding (1) influenza-like illness (ILI) visits to hospital emergency department, (2) ILI hospitalizations, and (3) confirmed 2009 H1N1 admissions. Days of stay at ICU admission, X-ray thoracic examination and CT examination, laboratory serologic findings, and the metabolic panel were undergone in all cases. Blood gases were measured as PCO2, PO2, HCO3, BE, and pH. Outcome at discharge was recorded for each patient. Nasopharyngeal-swab specimens were collected at admission, and bronchial-aspirate samples were obtained after tracheal intubation. Specimens were tested by RT-PCR at the National Influenza Laboratory (Institute of Public Health), according to a WHO protocol (WHO (2009) CDC protocol of real time RT-PCR for influenza H1N1. http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/en/index.html). All study patients had confirmed influenza H1N1 2009 infection.


### 2.1. Statistical Analysis

Data analysis was conducted using SPSS statistical software 18. Days of stay at ICU admission and outcome at discharge were recorded for each patient. Clinical characteristics were compared between patients who died and those who survived. Cox proportional-hazards regression was used to analyze the effect of several risk factors on survival. The comparison of survival curves for patients requiring endotracheal intubation in the first 24 hours after admission was done by the use of the logrank test. All reportedP values are two sided and were not adjusted for multiple testing.


## 2.1. Statistical Analysis

Data analysis was conducted using SPSS statistical software 18. Days of stay at ICU admission and outcome at discharge were recorded for each patient. Clinical characteristics were compared between patients who died and those who survived. Cox proportional-hazards regression was used to analyze the effect of several risk factors on survival. The comparison of survival curves for patients requiring endotracheal intubation in the first 24 hours after admission was done by the use of the logrank test. All reportedP values are two sided and were not adjusted for multiple testing.


## 3. Results

### 3.1. Patients’ Data

Characteristics of the 31 study patients with confirmed 2009 influenza H1N1 infection are listed in Table1. The ages of the patients ranged from 15 to 78 years (median, 35 years). Twenty-two patients (71%) were between 15 and 50 years of age, and 8 of them (25.8%) were over 50 years of age. Thirteen patients (42%) were male and 18 (58%) were female.Table 1
Characteristics of the 31 study patients who had confirmed infection with 2009 influenza H1N1 virus.
Variable
N
%
Gender
Male
13
42
Female
18
58
Age group (total)
0–5 yr
6–10 yr
11–15 yr
1
3.2
15–50 yr
22
71.0
>50 yr
8
25.8
Age group (deceased)
0–5 yr
6–10 yr
11–15 yr
15–50 yr
2/22
9.1
>50 yr
2/8
25.0
Symptoms/outcome
Fever (temperature > 38°C)
31
100.0
Myalgia or arthralgia
28
96.8
Headache
25
80.6
Acute respiratory distress
12
38.7
Productive cough
30
96.8
Chronic illnesses
11
35.5
Endotracheal intubation
5
16.1
Death
4
12.9
Days from onset of symptoms to admission—median (range)
4
(2–7)
Days from admission to death—median (range)
3.5
(1–6)
Laboratory findings—median (range)
Leukocyte count—per mm3
6800
1670–20,000
Lymphocyte count—per mm3
1690
770–4800The time between onset of symptoms and admission to the hospital ranged from 2 to 7 days (median, 4), and hospitalization lasted between four days and four weeks (see Table2 and Figure 2). All patients had fever with temperatures higher than 38°C, cough with sputum, and dyspnea or respiratory distress. Four (13%) of them had emesis and 9 (29%) abdominal pain. None of the patients had diarrhea.Table 2
Survival and death among the 31 study patients with confirmed infection to swine influenza H1N1 virus.
Variable
Patients who survived(N = 27)
Patients who died(N = 4)
Hazard ratio for death (95% CI)
P
Age
Median
32
50
1
0.5
Range
15–78
19–55
0.96–1.07
Gender
Female no./total no.
15/27
3/4
1.8  (0.2–17.4)
0.6
Days from illness onset to admission
0.5
Median
4
4.5
1.2
Range
2–7
4–6
0.6–2.4
Lymphocyte count per mm3
0.48
Median
1850
1465
0.96
Range
770–4800
890–3020
0.9–1.1
Endotracheal intubation
1/27
4/4
0.01
**
PaO2 (mm Hg)
0.21
Median
70.4
60.8
0.94
Range
43.1–90
54.9–63.5
(0.9–1.0)
PaCO2 (mm Hg)
0.16
Median
33.7
41.0
1.18
Range
22.8–44.8
31.5–41.5
(0.9–1.4)
Oximetry O2-Sat
0.07
Median
87
64
0.91
Range
57–93
64–79
(0.8–1.0)
ph
0.02
Median
7.4
7.3
6.01 × 10−13
Range
7.3–7.5
7.32–7.43
0.0–0.013
PaO2/FiO2 (mm Hg)
0.03
Median
171
61
0.92
Range
86–250
52–101
0.84–0.98
Acute resp. distress syndrome
9/27
3/4
4.8 (0.51–46.0)
0.1
BE
0.07
Median
−1.3
−3.7
0.6
Range
−6.5–8
−4.5–−2.1
0.4–1.1
Opacity in 3 or 4 lung quadrants in initial radiograph—no./total no.
14/27
3/4
2.5 (0.26–23.8)
0.4
**Logrank test.Figure 2
Patients’ outcomes and their hospitalization duration during the period November 2009–April 2010.


### 3.2. Underlying Condition

Twelve patients (39%) had preexisting medical conditions. Four patients had arterial hypertension, one patient had both diabetes mellitus and hypertension; two patients were obese, one patient suffered from congenital heart disorder, and one from psychiatric disorders, and renal transplant was found in one patient. Two of the deceased patients were pregnant; one had diabetes and one mitral stenosis (Table3). None of the patients had undergone seasonal influenza vaccination in 2008-2009, and none of them had a history of pneumococcal vaccination. None of the patients sought medical care at other institutions as outpatients before hospitalization and were not treated with antibiotics.Table 3
Frequency of underlying conditions in hospitalized patients infected with pandemic H1N1 influenza virus.
Comorbidities
Survivedn (%)
Deceasedn (%)
Pregnancy
1 (3.7)
1 (25)
Arterial hypertension
4 (7.4)
Diabetes
1 (25)
Chronic respiratory disease
2 (7.4)
Obesity
2 (7.4)
Cardiac insufficiency or valvulopathy
1 (25)
Renal transplant
1 (3.7)
Congenital heart disorder
1 (3.7)
Psychiatric disorders
1 (3.7)


### 3.3. Laboratory Findings

Twenty-six patients (84%) had pneumonia, confirmed with radiological examination. This examination revealed bilateral patchy alveolar opacities (predominantly basal), affecting three or four lung quadrants in 17 patients (Figure3). Findings on chest radiographs were consistent with the acute respiratory distress syndrome in all patients requiring mechanical ventilation.Bilateral patchy alveolar opacities in X-ray examination. (a) A patient at hospitalization and (b) a patient after 3 days of treatment.
(a)
(b)


### 3.4. Clinical Course During Hospital Stay and ICU Monitoring

Respiratory distress requiring endotracheal intubation developed in 5 patients within the first 24 hours after admission. These patients had a median oxygen saturation of 64% (interquartile range, 64 to 77) in the absence of supplementary oxygen. The noninvasive oxygen therapy (NIV) was used in 15 patients (48%) via nasal tube. Continuous positive airway pressure (CPAP) and PSV oxygen masks were used in 11 patients (35%). Altered consciousness was found in 9 (30%) of patients. Respiratory tract was free from inflammatory obstructions or foreign bodies.Regarding hemodynamic parameters, the predominating symptom was the arterial hypotension. Only four patients presented with higher arterial pressure values over 150 mmHg. With respect to pulse oximetry, SpO2 ranged 70–91%, while diuresis was generally maintained at a median of 2 L/24 h (range 200–2700 mL).


### 3.5. Treatment

Therapeutic protocol was based on recommendation of Centers for Disease Control and Prevention [4]. None of the patients had received oseltamivir before admission; all patients received it in the hospital, at a dose of 75 mg twice a day for a minimum of 5 days. After admission, 19 patients received ceftriaxone and 6 received clarithromycin. Additional antibiotics were prescribed in several patients, on the basis of their clinical course. Adjuvant therapy consisted on the administration of prednisolone (50–100 mg/24 h), O2-therapy, enteral nutrition, parenteral liquids and electrolytes, vitamins, human albumin, and comorbidity-related medication.Four out of 5 patients requiring endotracheal intubation died, and 27 recovered and were discharged from the hospital. Patients died between 1 and 6 days (median, 3.5 days) after admission (see also Table2).


## 3.1. Patients’ Data

Characteristics of the 31 study patients with confirmed 2009 influenza H1N1 infection are listed in Table1. The ages of the patients ranged from 15 to 78 years (median, 35 years). Twenty-two patients (71%) were between 15 and 50 years of age, and 8 of them (25.8%) were over 50 years of age. Thirteen patients (42%) were male and 18 (58%) were female.Table 1
Characteristics of the 31 study patients who had confirmed infection with 2009 influenza H1N1 virus.
Variable
N
%
Gender
Male
13
42
Female
18
58
Age group (total)
0–5 yr
6–10 yr
11–15 yr
1
3.2
15–50 yr
22
71.0
>50 yr
8
25.8
Age group (deceased)
0–5 yr
6–10 yr
11–15 yr
15–50 yr
2/22
9.1
>50 yr
2/8
25.0
Symptoms/outcome
Fever (temperature > 38°C)
31
100.0
Myalgia or arthralgia
28
96.8
Headache
25
80.6
Acute respiratory distress
12
38.7
Productive cough
30
96.8
Chronic illnesses
11
35.5
Endotracheal intubation
5
16.1
Death
4
12.9
Days from onset of symptoms to admission—median (range)
4
(2–7)
Days from admission to death—median (range)
3.5
(1–6)
Laboratory findings—median (range)
Leukocyte count—per mm3
6800
1670–20,000
Lymphocyte count—per mm3
1690
770–4800The time between onset of symptoms and admission to the hospital ranged from 2 to 7 days (median, 4), and hospitalization lasted between four days and four weeks (see Table2 and Figure 2). All patients had fever with temperatures higher than 38°C, cough with sputum, and dyspnea or respiratory distress. Four (13%) of them had emesis and 9 (29%) abdominal pain. None of the patients had diarrhea.Table 2
Survival and death among the 31 study patients with confirmed infection to swine influenza H1N1 virus.
Variable
Patients who survived(N = 27)
Patients who died(N = 4)
Hazard ratio for death (95% CI)
P
Age
Median
32
50
1
0.5
Range
15–78
19–55
0.96–1.07
Gender
Female no./total no.
15/27
3/4
1.8  (0.2–17.4)
0.6
Days from illness onset to admission
0.5
Median
4
4.5
1.2
Range
2–7
4–6
0.6–2.4
Lymphocyte count per mm3
0.48
Median
1850
1465
0.96
Range
770–4800
890–3020
0.9–1.1
Endotracheal intubation
1/27
4/4
0.01
**
PaO2 (mm Hg)
0.21
Median
70.4
60.8
0.94
Range
43.1–90
54.9–63.5
(0.9–1.0)
PaCO2 (mm Hg)
0.16
Median
33.7
41.0
1.18
Range
22.8–44.8
31.5–41.5
(0.9–1.4)
Oximetry O2-Sat
0.07
Median
87
64
0.91
Range
57–93
64–79
(0.8–1.0)
ph
0.02
Median
7.4
7.3
6.01 × 10−13
Range
7.3–7.5
7.32–7.43
0.0–0.013
PaO2/FiO2 (mm Hg)
0.03
Median
171
61
0.92
Range
86–250
52–101
0.84–0.98
Acute resp. distress syndrome
9/27
3/4
4.8 (0.51–46.0)
0.1
BE
0.07
Median
−1.3
−3.7
0.6
Range
−6.5–8
−4.5–−2.1
0.4–1.1
Opacity in 3 or 4 lung quadrants in initial radiograph—no./total no.
14/27
3/4
2.5 (0.26–23.8)
0.4
**Logrank test.Figure 2
Patients’ outcomes and their hospitalization duration during the period November 2009–April 2010.


## 3.2. Underlying Condition

Twelve patients (39%) had preexisting medical conditions. Four patients had arterial hypertension, one patient had both diabetes mellitus and hypertension; two patients were obese, one patient suffered from congenital heart disorder, and one from psychiatric disorders, and renal transplant was found in one patient. Two of the deceased patients were pregnant; one had diabetes and one mitral stenosis (Table3). None of the patients had undergone seasonal influenza vaccination in 2008-2009, and none of them had a history of pneumococcal vaccination. None of the patients sought medical care at other institutions as outpatients before hospitalization and were not treated with antibiotics.Table 3
Frequency of underlying conditions in hospitalized patients infected with pandemic H1N1 influenza virus.
Comorbidities
Survivedn (%)
Deceasedn (%)
Pregnancy
1 (3.7)
1 (25)
Arterial hypertension
4 (7.4)
Diabetes
1 (25)
Chronic respiratory disease
2 (7.4)
Obesity
2 (7.4)
Cardiac insufficiency or valvulopathy
1 (25)
Renal transplant
1 (3.7)
Congenital heart disorder
1 (3.7)
Psychiatric disorders
1 (3.7)


## 3.3. Laboratory Findings

Twenty-six patients (84%) had pneumonia, confirmed with radiological examination. This examination revealed bilateral patchy alveolar opacities (predominantly basal), affecting three or four lung quadrants in 17 patients (Figure3). Findings on chest radiographs were consistent with the acute respiratory distress syndrome in all patients requiring mechanical ventilation.Bilateral patchy alveolar opacities in X-ray examination. (a) A patient at hospitalization and (b) a patient after 3 days of treatment.
(a)
(b)


## 3.4. Clinical Course During Hospital Stay and ICU Monitoring

Respiratory distress requiring endotracheal intubation developed in 5 patients within the first 24 hours after admission. These patients had a median oxygen saturation of 64% (interquartile range, 64 to 77) in the absence of supplementary oxygen. The noninvasive oxygen therapy (NIV) was used in 15 patients (48%) via nasal tube. Continuous positive airway pressure (CPAP) and PSV oxygen masks were used in 11 patients (35%). Altered consciousness was found in 9 (30%) of patients. Respiratory tract was free from inflammatory obstructions or foreign bodies.Regarding hemodynamic parameters, the predominating symptom was the arterial hypotension. Only four patients presented with higher arterial pressure values over 150 mmHg. With respect to pulse oximetry, SpO2 ranged 70–91%, while diuresis was generally maintained at a median of 2 L/24 h (range 200–2700 mL).


## 3.5. Treatment

Therapeutic protocol was based on recommendation of Centers for Disease Control and Prevention [4]. None of the patients had received oseltamivir before admission; all patients received it in the hospital, at a dose of 75 mg twice a day for a minimum of 5 days. After admission, 19 patients received ceftriaxone and 6 received clarithromycin. Additional antibiotics were prescribed in several patients, on the basis of their clinical course. Adjuvant therapy consisted on the administration of prednisolone (50–100 mg/24 h), O2-therapy, enteral nutrition, parenteral liquids and electrolytes, vitamins, human albumin, and comorbidity-related medication.Four out of 5 patients requiring endotracheal intubation died, and 27 recovered and were discharged from the hospital. Patients died between 1 and 6 days (median, 3.5 days) after admission (see also Table2).


## 4. Discussion

The 2009 influenza H1N1 epidemics expanded rapidly around the world due to increased travel and communication between countries [6]. The pathology (mostly shown in previously healthy patients) had an influenza-like symptomatology that progressed during a period of 4 to 7 days. The pneumonia and other findings developed during the first day of hospital admission generally fulfilled the criteria of acute lung injury or acute respiratory distress syndrome (ARDS) [7–9]. This symptomatological development was shown in our patients.The occurrence of this symptom can evolve in a fatal outcome. A contributing factor for lethal outcome in our patients may have been delayed presentation to seek medical care and the subsequent delayed admission to hospital. In Albania, have also been reported a large number of persons with mild disease, through the national surveillance system for influenza. On the period May 2009–March 2010, 545 cases of A1H1 infection were confirmed in our country (among more than 3000 suspected subjects), and of them 363 were admitted to our hospital [10, 11]. The thirty-one patients of our study showed relatively severe altered conscience and ventilation compared to other subjects. Mortality among our patients requiring endotracheal intubation was 80%, and the lung damage was most likely due to the primary effect of infection with influenza virus. Similar results are also reported by other authors [12–14].In our study, 12 subjects had comorbidities and two patients were pregnant. There was no difference between benign and fatal outcome patients in the association with co-morbidities. History of lung diseases, obesity, diabetes, hypertension, psychiatric, and heart diseases were the most common co-morbidities in our study. Comorbidity presence was a risk factor for severe or atypical disease’s pattern [10]. Baehr et al. reported about similar co-morbidity rates (36%) with regards to 2009 H1N1 patients in Chile [15]. The relative absence of serious co-morbidities in our sample emphasizes that young, relatively healthy adults were the primary population affected by severe 2009 influenza H1N1 infection during this outbreak.Ventilatory support indication was based upon evaluation of clinical condition of the patients and measurement of arterial blood gases. According to our data, 61% of patients required ventilator support for profound hypoxemic respiratory failure, requiring high levels of inspired oxygen and PEEP. The survival rate was higher in NIV than in patients with endotracheal intubation. The NIV application rapidly improved vital signs, oxygenation and relieved the patients from tachypnea. Similarly to some reports, none of the patients who received O2-therapy via nasal sound/mask and NIV required invasive ventilation [16, 17]. Also, evaluation of the fluid status was performed regularly to avoid hypovolemia (hemodynamic instability).Several studies have shown that noninvasive ventilatory support may decrease mortality obviating the need for endotracheal intubation [14, 17]. In general, patients respond to NIV within 24 hours. Therefore, nonresponders who will eventually need endotracheal intubation can thus be identified early. Our findings are consistent with these reports, pointing out that NIV is effective and safe in the context of 2009 influenza H1N1 infection. The complex therapy that includes non-invasive O2-support was an effective tool in the management of patients with pandemic influenza H1N1. Moreover, the early administration of oxygen yielded excellent results in the prevention of respiratory complications from the pandemic H1N1 influenza [18, 19]. Our experience with this technique provides strong evidence that NIV can play a role in treating acute respiratory failure patients, reducing the need of ICU beds and improving outcomes.This is the first study that reported about systematical monitoring of influenza admission at ICU in Albania. A limitation of this study is the relatively small sample size and from a single centre. Thus, the use of multivariate analysis was not attempted for patients with fatal outcome, because of the small sample.NIV is recommended for patients with H1N1 virus infection complicated by pneumonia, acute lung injury, and ARDS because it improves oxygenation and reduces the work of breathing in these patients, but treatment should also be based upon published, evidence-based guidelines for sepsis-associated ARDS. Actually, standard lung-protective ventilation strategies are appropriate initially [20, 21].


## 5. Conclusion

It could be concluded that pandemic H1N1 influenza is associated with severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation. The reason for the severe hypoxemia observed in these patients and the mode of O2-therapy application is still an issue of debate, but NIV could be used with good results in 2009 influenza H1N1 infection-related hypoxemic respiratory failure by decreasing atelectatic alveoli, improving pulmonary compliance, and reducing work of breathing. Early diagnosis by the consistent symptoms of fever and a respiratory illness during times of outbreak, with prompt treatment with neuraminidase inhibitors and aggressive support of oxygenation failure and subsequent organ dysfunction, may provide better opportunities to mitigate the progression of illness and mortality observed during this sever pathology.



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*Source: 914840-2013-05-08.xml*