Article, Pulmonology

Pulmonary capillary leak syndrome after influenza A (H1N1) virus infection

Case Report

Pulmonary capillary leak syndrome after influenza A (H1N1) virus infection

Abstract

Pulmonary capillary leak syndrome after influenza A (H1N1) virus infection was not previously reported. We report 5 cases. The diagnosis of noncardiogenic pulmonary edema due to pulmonary capillary leak syndrome after influenza A (H1N1) virus infection was obtained by a medical committee of 6 physicians of our intensive care unit (intensive care unit physicians). Cases of 2009 H1N1 influenza were confirmed by testing nasal aspirates or combined nasal and throat swabs with the use of a real-time reverse-transcriptase polymerase chain reaction assay at Tunisian national laboratory. All 5 patients with a confirmed influenza A (H1N1) virus infection have respiratory distress. All patients have a respiratory distress with lung crackles on auscultation of one or both lungs and with alveolar pulmonary edema on the chest roentgenograms. The cardiogenic nature of pulmonary edema was ruled out in all cases by a transthoracic echocardiography showing normal systolic and Diastolic functions. All patients were treated with oxygen +- noninvasive ventilation (NIV); oseltamivir and steroids in addition to Empiric antibiotics were commenced. Bacterial cultures of blood, urine, and sputum and serologic reaction for atypical Respiratory pathogens were negative in all cases. Evolution was marked by a good outcome in all patients. Infection by influenza A (H1N1) virus can leads to acute respiratory distress due to pulmonary capillary leak syndrome. Evolution is usually favorable under oxygen +- NIV; oseltamivir and steroids in addition to empiric antibiotics were commenced.

In early April 2009, cases of human infection with 2009 pandemic influenza A (H1N1) virus were identified in the United States [1,2] and Mexico [3], and the virus then spread rapidly to other regions of the world [4,5]. The 2009 H1N1 virus is a triple reassortant influenza virus containing genes from human, swine, and avian influenza viruses [6-8]. The most common symptoms were fever and cough [1-3]. Severe cases of patients with 2009 H1N1 influenza present clinically as respiratory failure, and most patients died of Refractory hypoxemia. The pathophysiology of the Pulmonary findings

is that of a pulmonary capillary leak syndrome, and the heart is not directly affected.

However, pulmonary capillary leak syndrome was not previously reported after influenza A (H1N1) virus infection. We describe 5 cases of acute respiratory failure that occurred and rapidly progressed after influenza A (H1N1) virus infec- tion. The diagnosis of pulmonary capillary leak syndrome was confirmed in all cases. All cases were improved under symptomatic therapy-associated Noninvasive ventilation , oseltamivir, steroids, and empiric antibiotics.

The diagnosis of noncardiogenic pulmonary edema due to pulmonary capillary leak syndrome after influenza A (H1N1) virus infection was obtained by a medical committee of 6 physicians of our intensive care unit (ICU) (ICU physicians). Cases of 2009 H1N1 influenza were confirmed by testing nasal aspirates or combined nasal and throat swabs with the use of a real-time reverse-transcriptase polymerase chain

reaction assay at Tunisian national laboratory.

The diagnosis of noncardiogenic pulmonary edema was prospectively obtained by a medical committee of six ICU physicians who had examined all the available data. The medical committee took into consideration the presence of clinical and radiologic features of noncardiogenic pulmonary edema and on the presence of arterial hypoxemia. The medical committee took particularly into account the presence of signs of respiratory distress (polypnea, cyanosis, and others) and the presence of lung crackles on auscultation of one or both lungs. In addition, the medical committee looked for signs of interstitial and/or alveolar pulmonary edema on the chest roentgenograms. The cardiogenic nature of pulmonary edema was ruled out in all cases by a transthoracic echocardiography showing a normal systolic and diastolic functions.

In all cases, bacterial cultures of blood, urine, and sputum were negative. Moreover, atypical respiratory pathogens such as Mycoplasma pneumoniae, Coxiella burnetti, and Chlamydia pneumoniae coinfection were ruled out by a negative serologic reaction.

Finally, serologic reaction for Legionella pneumophila was not performed in all cases because this atypical respiratory pathogen is rarely observed in our country.

We describe 5 cases of acute respiratory failure that occurred and rapidly progressed after influenza A (H1N1) virus infection.

0735-6757/$ – see front matter (C) 2010

A 47-year-old woman was admitted to ICU for acute respiratory failure after H1N1 Influenza infection. This patient was admitted in pneumology department with a history of 5 days of sore throat, lethargy and myalgias, fever, dyspnea, and a clear chest x-ray. Therapy with oseltamivir in addition to empiric antibiotics was commenced. Two days later, evolution was marked by prominence of dyspnea leading to acute respiratory distress and productive cough. Examination on ICU admission shows that the patient was febrile (39?C) and had tachypnea (respiratory rate, 48 breaths per minute) and hypoxia (oxygen saturation measured by pulse oximetry [SpO2], 89% on 10 L/min oxygen via face mask). Pulmonary auscultation showed bilateral lung crackles. The blood pressure was 120/60 to 135/70 mm Hg, and the heart rate was 110/min. Her admission chest x-ray showed diffuse bilateral infiltrates without cardiome- galy (Fig. 1A), chest computed tomographic (CT) scan obtained on ICU admission in patient clearly shows signs of alveolar pulmonary edema (Fig. 1B). She had a leukopenia with white cell count (WCC) of 2.3 x 109/L but an elevated serum C-reactive protein level of 288 mg/L. Troponin level was less than 0.01 ug/L.

Transthoracic echocardiography showed a normal sys-

tolic function with left ventricular ejection fraction at 65%

and normal diastolic function. There was no sign of left ventricular asynergy and volume overload. Therefore, the patient was diagnosed as having pulmonary capillary leak syndrome. She was treated with NIV. Moreover, therapy with oseltamivir and steroids in addition to empiric antibiotics was commenced. Bacterial cultures of blood, urine, and sputum and serologic reaction for atypical respiratory pathogens were negative.

Patient was clearly improved 48 hours after ICU admission. Chest x-ray performed 72 hours later showed a dispiriting of diffuse bilateral infiltrates (Fig. 1C). She was discharged from ICU within 6 days after admission.

An 30-year-old Postpartum woman presented with a 6-day history of cough, fever, headache, and rhinorrhea without vomiting or diarrhea. She was admitted in pneumology department. Therapy with oseltamivir in addition to empiric antibiotics was commenced. Two days later, evolution was marked by prominence of dyspnea leading to acute respiratory distress and productive cough. She was transferred to ICU. Examination on ICU admission shows that the patient was febrile (39.6?C) and had tachypnea (respiratory rate, 32 breaths per minute) and hypoxia (SpO2, 92% on 8 L/min oxygen via face mask). Pulmonary auscultation showed bilateral lung crackles. The

Fig. 1 (A and C) Chest radiographs showing (A) diffuse bilateral infiltrates without cardiomegaly and revealing a clear improvement (C).

(B) Computed tomographic scan of the chest of patient obtained on admission to the ICU shows alveolar pulmonary edema.

blood pressure was 105/70 mm Hg, and the heart rate was 95/min. Her admission chest x-ray showed diffuse bilateral infiltrates without cardiomegaly. She had a normal WCC of

5.8 x 109/L but an elevated serum CRP level of 59 mg/L. Troponin level was less than 0.01 ug/L.

Transthoracic echocardiography showed a normal systol- ic function with left ventricular ejection fraction at 60% and normal diastolic function. There was no sign of left ventricular asynergy and volume overload. Therefore, the patient was diagnosed as having pulmonary capillary leak syndrome. She was treated with NIV. Moreover, therapy with oseltamivir, steroids, and diuretics in addition to empiric antibiotics was commenced. Bacterial cultures of blood, urine, and sputum and serologic reaction for atypical respiratory pathogens were negative.

Patient was clearly improved 72 hours after ICU admission. Chest x-ray performed 72 hours later showed a dispiriting of diffuse bilateral infiltrates. She was discharged from ICU within 4 days after admission.

A 9-year-old boy was admitted to ICU for acute respiratory failure after H1N1 influenza infection. This patient was admitted in pneumology department with a history of 3 days of sore throat, lethargy and myalgias, fever, polypnea, and a clear chest x-ray. Therapy with oseltamivir was commenced. Two days later, evolution was marked by prominence of dyspnea and productive cough.

Examination on ICU admission shows that the patient was febrile (38.5?C) and had tachypnea (respiratory rate, 28 breaths per minute) and hypoxia (SpO2, 92% on 8 L/min oxygen via face mask). Pulmonary auscultation showed bilateral lung crackles. The blood pressure was 105/62 mm Hg, and the heart rate was 95/min. Her admission chest x-ray showed diffuse bilateral infiltrates without cardiome- galy. She had a normal WCC of 5.3 x 109/L with a normal serum CRP level at 3.5 mg/L. Troponin level was less than

0.01 ug/L.

Transthoracic echocardiography showed a normal systol- ic function with left ventricular ejection fraction at 65% and normal diastolic function. There was no sign of left ventricular asynergy and volume overload. Therefore, the patient was diagnosed as having pulmonary capillary leak syndrome. She was treated with oxygen via face mask; therapy with oseltamivir and steroids in addition to empiric antibiotics was commenced. Bacterial cultures of blood, urine, and sputum and serologic reaction for atypical respiratory pathogens were negative.

Chest x-ray performed 48 hours later showed a dispiriting of diffuse bilateral infiltrates. She was discharged from ICU within 4 days after admission.

A 12-year-old girl, with antecedent of scoliosis, presented to the pneumology department with a history of 5 days of sore throat, lethargy and myalgias, fever, vomiting, dyspnea,

Fig. 2 (A and C) Chest radiographs showing (A) diffuse bilateral infiltrates without cardiomegaly and revealing a clear improvement (C).

(B) Computed tomographic scan of the chest of patient obtained on admission to the ICU shows alveolar pulmonary edema.

productive cough, and pleuritic chest pain. She was febrile (39?C) and had tachypnea (respiratory rate, 40 breaths per minute) with hypoxemia (SpO2, 73% under air room). Her admission chest x-ray showed widespread alveolar infil- trates. She was rapidly transferred to ICU.

Examination on ICU admission shows that the patient was febrile (39.5?C) and had tachypnea (respiratory rate, 54 breaths per minute) and hypoxia (SpO2, 92% on 6 L/min oxygen via face mask). Pulmonary auscultation showed bilateral lung crackles. The blood pressure was 133/81 mm Hg, and the heart rate was 93/min. Her admission chest x-ray showed diffuse bilateral infiltrates without cardiomegaly (Fig. 2A). Moreover, Chest CT scan obtained on ICU admission in patient clearly shows signs of alveolar pulmonary edema (Fig. 2B). She had a normal WCC of

4.2 x 109/L with a normal serum CRP level at 84 mg/L. Troponin level was less than 0.01 ug/L.

Transthoracic echocardiography showed a normal systol- ic with left ventricular ejection fraction at 70% and normal diastolic function. There was no sign of left ventricular asynergy and volume overload. Therefore, the patient was diagnosed as having pulmonary capillary leak syndrome. She was treated with oxygen via face mask; therapy with oseltamivir and steroids in addition to empiric antibiotics was commenced. Bacterial cultures of blood, urine, and

sputum and serologic reaction for atypical respiratory pathogens were negative.

Chest x-ray performed 7 days later showed a partial dispiriting of diffuse bilateral infiltrates (Fig. 2C). She was discharged from ICU within 9 days after ICU admission.

A 19-year-old girl, without any pathologic antecedent, presented to the pneumology department with a history of

5 days of sore throat, lethargy and myalgias, fever, productive cough, and pleuritic chest pain. She was febrile (38.3?C) and had tachypnea (respiratory rate, 32 breaths per minute) with hypoxemia (SpO2, 92% on 6 L/min oxygen via face mask). Her admission chest x-ray showed widespread alveolar infiltrates. She was rapidly transferred to ICU.

Examination on ICU admission shows that the patient was febrile (38.5?C) and had tachypnea (respiratory rate, 34 breaths per minute) and hypoxia (SpO2, 86% under air room and 94% on 6 L/min oxygen via face mask). Pulmonary auscultation showed bilateral lung crackles. The blood pressure was 115/70 mm Hg, and the heart rate was 110/ min. Her admission chest x-ray showed diffuse bilateral infiltrates without cardiomegaly (Fig. 3A). Moreover, chest CT scan obtained on ICU admission in patient clearly shows signs of alveolar pulmonary edema (Fig. 3B). She had WCC of 13 500 x 109/L with a normal serum CRP level at 184 mg/L. Troponin level was less than 0.01 ug/L.

Fig. 3 (A and C) Chest radiographs showing (A) diffuse bilateral infiltrates without cardiomegaly and revealing a clear improvement (C).

(B) Computed tomographic scan of the chest of patient obtained on admission to the ICU shows alveolar pulmonary edema.

Transthoracic echocardiography showed a normal systolic function with left ventricular ejection fraction at 65% and normal diastolic function. There was no sign of left ven- tricular asynergy and volume overload. Therefore, the patient was diagnosed as having pulmonary capillary leak syn- drome. She was treated with oxygen via face mask; therapy with oseltamivir and steroids in addition to empiric antibiotics was commenced. Bacterial cultures of blood, urine, and sputum and serologic reaction for atypical respiratory patho- gens were negative. Chest x-ray performed 5 days later showed a dispiriting of diffuse bilateral infiltrates (Fig. 3B).

She was discharged from ICU within 7 days after ICU admission.

Risk factors, including asthma, chronic lung disease, smoking, obesity, and pregnancy, were identified as having had increased morbidity and mortality after H1N1 virus infection in the CDC reports [9]. In our reported cases, only one had risk factors (case 2: postpartum woman).

Acute respiratory failure is a rare but major complication of A (H1N1) virus infection [10]. This typically presents as a subacute clinical syndrome characterized by severe dyspnea, cough, tachypnea, fatigue, and fever. Patients with respira- tory failure secondary to H1N1 virus infection are usually markedly hypoxemic, with crackles on auscultation and chest radiography showing confluent alveolar consolidations almost identical to those seen in congestive heart failure and a normal-sized heart [10].

The basic pathophysiology of this respiratory failure is a generalized increase in capillary permeability that results from endothelial damage leading to pulmonary capillary leak syndrome. Possible mechanisms of damage include direct injury to the respiratory epithelium with a secondary cytokine storm [10]. The increased capillary permeability gives rise to widespread protein-rich edema. The Endothelial cells appear swollen.

Postmortem lung examination shows necrosis of bron- chiolar walls, a neutrophilic infiltrate, and diffuse alveolar damage with prominent hyaline membranes [10]. In another autopsy study, 4 of 5 patients had edema, hemorrhage, or necrosis in the upper respiratory tract [11]. Four patients had evidence of diffuse alveolar damage (hyaline membranes, alveolar septal edema), hyperplasia of type II pneumocytes, fibrin thrombus in the vascular lumen, and necrosis of bronchiolar walls. Three patients had inflammatory infil- trates below the endothelium and partial loss and adherence of the endothelium in the medium and small intrapulmonary blood vessels.

Diagnosing pulmonary capillary leak syndrome is an exercise of exclusion, as there is no diagnostic test available. Diagnosis relies upon clinical manifestations, typical radio- graph findings, and the documented exclusion of heart dysfunction and any other infectious, metabolic, or cancer- related causes.

In our patients, the diagnosis of H1N1 influenza virus infection were confirmed by testing nasal aspirates or combined nasal and throat swabs with the use of a real-

time reverse-transcriptase polymerase chain reaction assay at Tunisian national laboratory. The echocardiogram showed normal left ventricle function in all cases. However, we cannot rule out pulmonary bacterial infection or coinfection with other respiratory viruses.

In H1N1 influenza virus-infected patients and any patient with respiratory distress or severe hypoxia (requiring an FIO2 of N 0.5) and Pulmonary infiltrates on chest x-ray should be referred to an intensive care specialist for further assessment. Mechanical ventilation for these patients is complex and requires expertise and specialized equipment. inhaled nitric oxide and restrictive fluid therapy with apparent success. Noninvasive ventilation temporarily improves oxygenation and reduces the Work of breathing. The need for NIV is an indication of severe disease and the likelihood of intubation and mechanical ventilation. In our cases, evolution was marked during the following days by a gradual improvement of the oxygenation and chest infiltrates under intravenous corticos- teroids, diuretic therapy, and respiratory support with NIV.

In summary, acute respiratory failure is a rare but major complication of A (H1N1) virus infection due to pulmonary capillary leak syndrome. Possible mechanisms of damage include direct injury to the respiratory epithelium with a secondary cytokine storm. Treatment is based on a good oxy- genation, intravenous corticosteroids, and diuretic therapy.

Mabrouk Bahloul MD Hassen Dammak MD Anis Chaari MD Rania Allala MD

Department of Intensive Care Habib Bourguiba University Hospital Sfax, Tunisia E-mail address: [email protected]

Leila Abid MD

Department of Cardiology Hedi Chaker University Hospital Sfax, Tunisia

Sondes Haddar MD

Department of Radiology Habib Bourguiba University Hospital Sfax, Tunisia

Hedi Chelly MD

Department of Intensive Care Habib Bourguiba University Hospital Sfax, Tunisia

Abdelkader Ayoub MD

Department Pneumology Hedi Chaker University Hospital Sfax, Tunisia

Chokri Ben Hamida MD Mounir Bouaziz MD Department of Intensive Care

Habib Bourguiba University Hospital Sfax, Tunisia

doi:10.1016/j.ajem.2010.01.033

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