Influenza A (H1N1) virus pneumonia in intensive care unit

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intensive care unit

Nalan ADIGÜZEL¹, Zuhal KARAKURT¹, Merih KALAMANOĞLU BALCI¹, Eylem ACARTÜRK¹, Gökay GÜNGÖR¹, Özlem YAZICIOĞLU MOÇİN¹, Semra BATI KUTLU², Adnan YILMAZ¹

1 SB Süreyyapaşa Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, Solunumsal Yoğun Bakım Ünitesi, İstanbul,

2 SB Süreyyapaşa Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, İnfeksiyon Hastalıkları, İstanbul.

ÖZET

Yoğun bakımda influenza A (H1N1) virüsü pnömonisi

Bu çalışmada hastalar, influenza A (H1N1) virüsü infeksiyonuna sekonder gelişen ciddi akut solunum yetmezliği nedeniy- le yoğun bakım üniteleri (YBÜ)’nde takip edildiler. Biz bu çalışmada, YBÜ’de; influenza A (H1N1) virüsü infeksiyonuna bağlı gelişen ciddi solunum yetmezliği ile takip edilen 19 hastanın klinik ve epidemiyolojik özelliklerini tanımlamayı amaç- ladık. Çalışma 20 yataklı düzey-III solunumsal YBÜ’de tanımlayıcı olgu serisi olarak dizayn edildi. İnfluenza A (H1N1) vi- rüsü infeksiyonu tanısı için gerçek zamanlı revers transkriptaz polimeraz zincir reaksiyonu (RT-PCR) testi kullanıldı. Has- taların demografik, epidemiyolojik ve klinik özellikleri, tedavi, mortalite ve akıbetleri kaydedildi. 10 Kasım- 31 Aralık 2009 tarihleri arasında yedi laboratuvar olarak teyit edilmiş yedi hasta, yüksek klinik şüpheye sahip 12 hasta olmak üzere top- lam 19 hasta influenza A (H1N1) virüsü infeksiyonuna bağlı akut solunum yetmezliği tanısıyla YBÜ’de tedavi edildi. Yük- sek klinik şüpheye sahip 12 hastanın üçünde RT-PCR testi negatif iken, dokuz hastada test yapılamadı. Hastaların ortala- ma yaşı 41.6 ± 11.9 (21-61) yıl idi. Ortanca akciğer zon tutulumu 4 (IQR: 3-4) olup, PaO₂/FiO₂oranı 105 (IQR: 85-165) idi.

Ortalama APACHE II ve SOFA skorları sırasıyla 13 ± 4 ve 4.0 ± 1.3 idi. Hastaların %68.4 (n= 13)’üne noninvaziv mekanik ventilasyon, %21.1 (n= 4)’ine invaziv mekanik ventilasyon ve %31.5 (n= 6)’ine oksijen tedavileri uygulandı. Oseltamivir te- davisi 12 hastaya 2 x 75 mg, yedi obez hastaya da 2 x 150 mg uygulandı. Ortanca YBÜ’de kalış günü altı (IQR: 4-8) olup, YBÜ mortalitesi %21.1 idi. İnfluenza A (H1N1) virüsü infeksiyonuna bağlı gelişen pnömoni ve akut solunum yetmezliği ile YBÜ’de takip edilen hastalar ağırlıklı noninvaziv mekanik ventilasyon ile başarılı bir şekilde tedavi edildiler. Sonuç olarak, kli- nisyenler influenza A (H1N1) virüsü infeksiyonunun pulmoner komplikasyonları açısından bilgilenmeli ve hastalar, sağlık ça- lışanları için gerekli önlemler alınarak noninvaziv mekanik ventilasyon ile tedavi edilebilirler.

Anahtar Kelimeler: H1N1 virüsü infeksiyonu, yoğun bakım.

Yazışma Adresi (Address for Correspondence):

Dr. Nalan ADIGÜZEL, Nil Caddesi No: 39 A7 Blok Daire: 4 Maltepe, İSTANBUL - TURKEY

e-mail: nlnadiguzel@yahoo.com.tr

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Infection with the 2009 pandemic influenza A (H1N1) virus came out in Mexico and spread toward all over the world (1). A Centers for Di- sease Control and Prevention (CDC) report in May 2009 stated details of the 30 patients who were hospitalized in California, six patients were admitted to an intensive care unit (ICU) and four required mechanical ventilation (2). Ac- cording to Spanish study (SEMICYUC working group), 32 patients with confirmed influenza A (H1N1) virus infection were admitted to ICU with severe respiratory failure between 23 Ju- ne and 31 July, 2009 and 24 (25%) of them required mechanical ventilation (3). From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus were admitted to an ICU in Austra- lia or New Zealand (4). Reports of critical ill-

ness caused by influenza A (H1N1) virus stated that obesity and pregnancy were the risk fac- tors for pulmonary complications in patients with H1N1 infection (3,4).

In addition to drug therapy, invasive mechanical ventilation was employed for patients with acute respiratory failure (ARF) due to pneumonia caused by influenza A (H1N1) virus infection; however there are some contra-versions for impli- cation of non-invasive mechanical ventilation (NIMV) when H1N1 virus pneumonia presents with ARDS findings (5-7).

In this report, we described demographic, epidemiologic characteristics, treatment modalities and outcome of patients ARF due to influenza A (H1N1) virus infection in our respiratory intensive care unit (ICU).

SUMMARY

Influenza A (H1N1) virus pneumonia in intensive care unit

Nalan ADIGÜZEL¹, Zuhal KARAKURT¹, Merih KALAMANOĞLU BALCI¹, Eylem ACARTÜRK¹, Gökay GÜNGÖR¹, Özlem YAZICIOĞLU MOÇİN¹, Semra BATI KUTLU², Adnan YILMAZ¹

1 Respiratory Intensive Care Unit, Sureyyapasa Chest Diseases and Chest Surgery Training and Research Hospital, Istanbul, Turkey,

2 Infectious Diseases, Sureyyapasa Chest Diseases and Chest Surgery Training and Research Hospital, Istanbul, Turkey.

Patients with influenza A (H1N1) virus infection have been admitted to intensive care units (ICU) due to development of se- vere respiratory failure. We described the clinical and epidemiologic characteristics of the 19 patients admitted to ICU due to influenza A (H1N1) virus infection. Study design is a descriptive case series in a third level-20 bed respiratory ICU at tra- ining hospital in Istanbul/Turkey. Influenza A (H1N1) virus infection was laboratory confirmed in specimens using real-ti- me reverse transcriptase-polymerase-chain-reaction (RT-PCR). We collected data concerning demographic, epidemiologic and clinical characteristics of the patients, treatment mortality and outcome. From November 10 to December 31 2009, a to- tal of 19 patients; 7 laboratory confirmed, 12 with high clinical suspicion were treated at ICU. Among 12 patients with high clinical suspicion; 3 patients had negative RT-PCR testing for influenza A (H1N1) virus, 9 patients had no tests. Mean age was 41.6 ± 11.9 (range 21 to 61). Median number of lung zone involvement was 4 (IQR= 3-4). Median PaO₂/FiO₂was 105 (IQR= 85-165). Mean severity (APACHE II) and organ failure score (SOFA) were 13 ± 4 and 4.0 ± 1.3 respectively. Non-in- vasive mechanical ventilation (68.4%, n= 13), invasive mechanical ventilation (21.1%, n= 4) and nasal cannula oxygen (31.5%, n= 6) were implicated. The median length of ICU stay was 6 (IQR= 4-8). Oseltamivir therapy was given as 75 mg bid to 12 patients and 150 mg bid to 7 obese patients. ICU mortality rate was 21.1%. Presenting patients with pneumonia and acute respiratory failure due to influenza A (H1N1) virus infection were treated predominantly and successfully with non invasive mechanical ventilation. Clinicians should be aware of pulmonary complications of influenza A (H1N1) virus infection and that patients can be treated with non invasive mechanical ventilation paying attention to protective measures for health care providers.

Key Words: H1N1 virus infection, intensive care unit.

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MATERIALS and METHODS

We retrospectively studied all critically ill patients with confirmed and high clinical suspicion for influenza A (H1N1) virus infection admitted to third level-20 bed ICU of training hospital between November 10, 2009, and December 31, 2009.

Influenza A (H1N1) virus infection was confirmed in nasal-swab specimens with the use of a real-time reverse-transcriptase-polymerase- chain-reaction (RT-PCR) assay at reference laboratory. According to Turkish Republic Ministry of Health policy, diagnostic RT-PCR testing for influenza A (H1N1) virus was performed only for patients admitted to ICU so nasal-swab specimens were collected at ICU admission. Nazal- swab specimens were placed in transport medium and kept at a temperature from 2 to 4°C. RT- PCR testing was done according to published guidelines from the U.S. Centers for Disease Control and Prevention (CDC) (8).

All study patients had acute onset of fever and influenza-like illness (with cough, myalgia, sore throat) plus bilateral opacities on the chest radiograph (revealing pneumonia) and acute respiratory failure requiring ICU admission. Confir- med cases had positive RT-PCR assay for influenza A (H1N1) virus. High clinical suspicion cases fulfilled the clinical parameters for influenza A (H1N1) virus infection although they had negative RT-PCR assay or even no test.

Data Collection

Data was collected from inpatient medical re- cords. The recorded data were: demographic data, comorbid conditions, time of illness onset and ICU admission, time to first dose of antiviral therapy, microbiologic findings, laboratory findings, arterial blood gas analysis, chest radiologic findings at ICU admission. Severity of illness was assessed using the Acute Physiology and Chro- nic Health Evaluation II (APACHE II) score and organ failure was assessed using the Sequential Organ Failure Assessment (SOFA) scoring system (9,10). In addition, type of ventilatory support required, length of ICU stay, ICU mortality, adverse events during ICU stay were registered.

Statistical Analysis

This study was designed as descriptive case series. Data analysis was conducted using SPSS 16.0 software. Descriptive data were presented as frequencies (percentages) for discrete variables and as means ± standart deviation (SD) or medians with 25^th to 75^th interquartile range (IQR) for continuous variables.

RESULTS

As of November 10, 2009, a total of 19 patients were admitted to our ICU with acute respiratory failure due to influenza A (H1N1) virus infection.

Of these, 7 (36.8%) were confirmed by RT-PCR for pandemic influenza A (H1N1) virus. Altho- ugh RT-PCR for H1N1 virus at ICU admission was negative in 3 patients (15.8%), because of high clinical suspicion, these patients were not confirmed further and they were accepted as H1N1 cases. For remaining 9 (47.3%) patients, RT-PCR test couldn’t be performed as special transport medium for nasal-swabs were absent and those patients were clinically considered to have H1N1 infection. Demographics and characteristics of patients and signs at physician presentation were summarized in Table 1 and 2, respectively.

Nine patients (47.3%) were reported as obese [body mass index (BMI) > 30 kg/m²] and one (5.3 %) was pregnant. Diabetes mellitus (4/19), hypertension (3/19), ankylosing spondylitis (1/19) were the main co-morbidities reported.

Sputum gram stain and nonspecific cultures were done in 8 patients; 1 ankylosing spondylitis patient with Stenotrophomonas maltophilia and two patients with Enterobacteriaceae co-infecti- on were reported. All patients received initial empiric antibiotic therapy. Most frequent regi- mens were beta-lactam plus fluoroquinolones (n= 7, 36.8%), beta-lactam plus fluoroquinolones plus teicoplanin/linezolid (n= 6, 31.6%) and 4 (21.0%) patients received moxifloxacin as mo- notherapy. In addition, 4 patients (21.0%) received intravenous steroids at ICU admission. Me- an delay between illness onset to initiation of antiviral therapy was 5.8 ± 2.5 (range: 1 to 10) days. Eighteen (94.7%) patients had single organ dysfunction (respiratory). One (5.3%) patient required vasopressor drugs.

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Table 1. Characteristics of 19 patients with acute respiratory failure who had confirmed/high clinical suspici- on influenza A (H1N1) virus infection.

Variables Value

Age (years)

Mean ± SD (range) 41.6 ± 11.9 (21 to 61)

Sex (female/male) 10/9

Body mass index [mean ± SD (range)] 31.9 ± 9.0 (21 to 55)

Co-morbid diseases, n (%)

Diabetes 4 (21.1)

Hypertension 3 (15.7)

Ankylosing spondylitis 1 (5.3)

Severity scores

APACHE II on admission [mean ± SD (range)] 13.0 ± 4.0 (7 to 20)

SOFA scores [mean ± SD (range)] 4.0 ± 1.3 (1 to 7)

Days from onset of symptoms to ICU admission

Mean ± SD (range) 6.8 ± 3.2 (1 to 13)

Days from onset of symptoms to treatment

Mean ± SD (range) 5.8 ± 2.5 (1 to 10)

Arterial blood gases

pH [mean ± SD (range)] 7.49 ± 0.08 (7.33 to 7.65)

PaCO₂, [mean ± SD (range)] 32.4 ± 6.8 (19 to 46)

PaO₂/FiO₂median (IQR) 105 (85-165)

Laboratory finding [mean ± SD (range)]

Leukocyte count (per mm³) 6968 ± 5145 (1480 to 18700)

C-reactive protein (mg/dL) 132.5 ± 75.2 (18 to 312)

Serum lactate dehydrogenase (U/L) 595 ± 285 (190 to 1158)

AST (U/L) 94.2 ± 50.4 (29 to 191)

ALT (U/L) 53.7 ± 43.5 (15 to 212)

Serum creatine kinase (U/L, n= 12) 419.2 ± 376.7 (20 to 1100)

Opacity in initial X-ray chest, n (%)

1/4 quadrants 1 (5.3)

4/4 quadrants 13 (68.4)

Mechanical ventilation on admission, n (%)

None 6 (31.5)

Non-invasive mechanical ventilation 13 (68.4)

Invasive mechanical ventilation 4 (21.1)

Adverse event, n (%)

Vasopressor drugs 1 (5.3)

SD: Standard deviation, APACHE II: Acute physiology assessment and chronic health evaluation II, SOFA: Sequential organ failure assessment scoring system, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ICU: Intensive care unit.

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Chest radiograph findings were typically bilateral patchy alveolar opacities, predominantly at basal lung zones, affecting three or four quadrants in 15 patients (78.9%; Figure 1).

Two (10.5%) patients had chest computed tomography scan and showed airspace consolida- tion and ground-glass opacity in a multilobar and bilateral distribution (Figure 2).

At the time of ICU admission, all patients were hypoxemic, median PaO₂/FiO₂ ratio was 105 (IQR= 85-165). Seven patients (36.8%) had le- ukopenia less than 3500 leukocytes/mm³(mean 4900 ± 5040 leukocytes/ mm³), only three patients (15.8%) had more than 10.000 leukocytes/mm³. C-reactive protein was measu- red in all patients with a mean of 132.5 ± 75.2 mg/dL (range 18 to 312 mg/dL). Seventeen pa-

tients (89.5%) had elevated lactate dehydrogenase levels (mean 595 ± 285 U/L), 3 (15.8%) above 1000 IU/L. Six patients out of 12 (50%) had increased (mean 419.2 ± 376.7 U/L, range 20-1100 U/L) creatinine kinase levels.

The estimated mean number of days from illness onset to initiation of antiviral treatment was 5.8 ± 2.5 (1 to 10) days. Empiric antiviral treatment with oseltamivir administered to all patients before test results were available. Higher- dose oseltamivir (150 mg orally twice a day) was used to treat obese patients. The mean duration of treatment with oseltamivir was 7.9 ± 2.1 days (range= 3 to 10).

Six (31.5%) patients were treated with oxygen therapy whereas thirteen patients (68.4%) required NIMV initially and later 4 of these patients (21.1%) underwent orotracheal intubation for invasive mechanical ventilation (IMV). Extracor- Table 2. Signs and symptoms at physician pre-

sentations.

Signs and symptoms Count (%)

Fever (> 38°C) 18 (94.7)

Myalgia 7 (36.8)

Sore throat 2 (10.5)

Cough 12 (63.2)

Nausea/vomiting 7 (36.8)

Headache 7 (36.8)

Figure 1. Chest radiographic finding of a patient with H1N1 virus pneumonia.

Figure 2. Computed tomography scan of a patient with H1N1 virus pneumonia.

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poreal membrane oxygenation was not performed. Four patients treated by IMV died, ICU mortality rate was 21.1%. Median length of ICU stay of all patients was 6 (IQR= 4-8) days. The characteristics of patients with ventilatory support required were shown in Table 3.

In our hospital, infection control measures were performed according to infection control com- mittee advises, such as vaccination of health care providers, isolation of infected patients, use of personal protective equipment for health care workers, strict hand hygiene. However, only one infected health care provider was reported.

DISCUSSION

This case series study presented patients with high clinical suspicion and confirmed influenza A (H1N1) virus pneumonia in our respiratory ICU in two month period (November 10 to De- cember 31, 2009). Majority of patients were successfully treated with NIMV.

Confirmed Cases

According to Turkish Republic Ministry of He- alth report in January 19, 2010, the number of fatal cases with influenza A (H1N1) virus infection (confirmed or clinical high suspicion) were 627 in Turkey (11). As Ministry of Health policy, diagnostic PCR testing for influenza A (H1N1) virus was performed only for patients admitted to ICU. In our report, only 7 patients out of 19 were confirmed influenza A(H1N1) virus infection with RT-PCR testing. RT-PCR testing couldn’t be performed in 9 patients because of special transport medium for nasal swab were absent. Twelve patients, including 3 RT-PCR negative patients, had high clinical suspicion with symptoms, laboratory and radi-

ographic findings. Three patients with negative RT-PCR testing for influenza A (H1N1) virus did not undergo further diagnostic procedures. Rel- lo and coworkers showed that negative result of RT-PCR at admission should not exclude influenza A (H1N1) diagnosis due to the presen- ce of false-negative results in 10% of nasop- haryngeal-swab specimens (3).

Clinical Findings

The clinical manifestations of influenza A (H1N1) virus infection are varied and include flulike symptoms such as fever, cough, sore throat, body aches, headache, chills, and fati- gue. In addition, nausea, vomiting, and/or diarr- hea have been reported (12). In our case series, majority of patients had fever, sore throat, myalgia and vomiting.

Radiologic Findings

In studies, chest X-ray findings indicated that the initial chest radiographic images were generally normal in patients with influenza A (H1N1) virus infection, most of whom were outpatients. The most frequent pattern of abnormality was alveolar disease that was bilateral, with lower and central lung preponderance and in hospitalized patients, the abnormalities progressed to severe air-space disease (13). In present study we used

“opacity lung quadrants” to describe extensive- ness of pneumonia and majority of patients (78.9%) had three or four quadrants opacities.

Oseltamivir Treatment

The 2009 influenza A (H1N1) virus is suscep- tible to neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) but resistant to the ada- mantanes (amantadine, rimantadine). Therefo- re, neuraminidase inhibitors are recommended

Table 3. The characteristics of patients with ventilatory support required, length of ICU stay, ICU mortality.

Noninvasive ventilation (n= 13)

Variable Nasal oxygen therapy Successful Failure (intubated)

(n= 6) (n= 9) (n= 4)

Length of ICU stay, median (IQR), day 5 (4 to 7) 7 (6 to 9) 4 (2 to 8)

Mortality 0 0 4 (21.1)

ICU: Intensive care unit.

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for antiviral treatment of 2009 influenza A (H1N1) virus infections (14,15). Emergence of oseltamivir-resistant influenza A (H1N1) virus during or following treatment has been rarely identified (16,17). Treating with a neuraminidase inhibitor within 2 days after symptom onset was significantly associated with a lower risk of ICU admission or death in hospitalized patients with 2009 influenza A (H1N1) virus infection , as compared with later treatment (p<

0.05) (18). Unfortunately our patients received oseltamivir treatment approximately seven days after symptom onset. Domínguez-Cherit and co-workers reported that, in ICU patients with influenza A (H1N1) virus infection , survi- vors were more likely to have received neuraminidase inhibitor treatment than nonsurvivors (OR 8.5; p= 0.04) (19). Some critically ill patients due to influenza A (H1N1) virus infection have been treated for twice the standard 5 days, and some have received higher dose oseltamivir (20). Higher oseltamivir dosage (e.g., 150 mg orally twice a day for adults) and extending the duration of therapy should be considered for critically ill patients with influenza A (H1N1) virus infection. In present study, oseltamivir has been used 75 mg per oral twice daily for normal body weight, but we have treated obese patients (body weight index >

30) with 150 mg oseltamivir per oral twice daily for ten days duration.

Mechanical Ventilation

In present study, patients with refractory hypoxemia required mechanical ventilation. Initially all patients were treated by tight NIMV. Four of these patients further required orotracheal intubation and invasive mechanical ventilation. A commonly used method of providing NIMV uti- lized an orofacial mask and a double-arm deli- very circuit driven by a high-gas flow-genera- ting ICU ventilator in present study. Hui and collegues showed that substantial exposure to exhaled air was likely to occur within 0.5 m from patients receiving NIV and higher ventilator pressures (ie. IPAP > 18 cmH₂O) resulted in a wider distribution of exhaled air (7). Conti et al. recommended NIMV in patients with influenza A (H1N1) virus infection to prevent further

deterioration and need for intubation in patients with mild to moderate acute hypercapnic respiratory failure, ARF and/or distress due to car- diogenic pulmonary edema, in the absence of pneumonia, multiple organ failure, and refractory hypoxemia (5). Also they suggested that NIMV could be also used to prevent post-extu- bation respiratory failure in patients with resol- ving acute respiratory distress syndrome se- condary to H1N1 infection, preferentially when the patient was no longer contaminated (5).

But in our series, NIMV was used in majority of patients with bilateral pneumonia who had confirmed and highly suspicious for influenza A (H1N1) virus infection with single organ failure. Hypoxemia was successfully reversed by NIMV and, NIMV was continued nearly all day and night with short break intervals. Nutritional support was given via parenteral route. Howe- ver in Rello study, only 6% of H1N1 patients received NIMV (3).

Obesity

In one study, there were 10 patients with influenza A (H1N1) virus infection and there was a high prevalence of obesity, 90% of patients (9/10) had a BMI ≥ 30 kg/m² while 70% (7/10) were extremely obese with a BMI ≥ 40 kg/m²(21). In present study 47.3% of (9/19) patients were obese and 4 of them were morbid obese.

Conclusion

Our analysis of critically ill patients with influenza A (H1N1) virus infection showed that mostly previously healthy young patients were affected and developed severe respiratory insufficiency requiring mechanical ventilation support. These patients with bilateral pneumonia and ARF were treated by NIMV successfully with double circuit ICU ventilator.

Key Messages

1. Patients with high clinical suspicion for influenza A (H1N1) virus pneumonia should be follo- wed up closely due to progression to severe respiratory failure.

2. NIMV can be implicated with double circuit ICU ventilator to patients with H1N1 infection.

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