Recovery of pulmonary functions, exercise capacity, and quality of life after pulmonary rehabilitation in survivors of ARDS due to severe influenza A (H1N1) pneumonitis

Background Acute respiratory distress syndrome (ARDS) due to severe influenza A H1N1 pneumonitis would result in impaired pulmonary functions and health‐related quality of life (HRQoL) after hospital discharge. Objectives The recovery of pulmonary functions, exercise capacity, and HRQoL in the survivors of ARDS due to 2009 pandemic influenza A H1N1 pneumonitis (H1N1‐ARDS) was evaluated in a tertiary teaching hospital in northern Taiwan between May 2010 and June 2011. Patients and Methods Data of spirometry, total lung capacity (TLC), diffusing capacity of carbon monoxide (DLCO), and 6‐minute walk distance (6MWD) in the patients survived from H1N1‐ARDS were collected 1, 3, and 6 months post‐hospital discharge. HRQoL was evaluated with St. George respiratory questionnaire (SGRQ). Results Nine survivors of H1N1‐ARDS in the study period were included. All these patients received 2 months’ pulmonary rehabilitation program. Pulmonary functions and exercise capacity included TLC, forced vital capacity (FVC), forced expiratory volume in the first second (FEV 1), DLCO, and 6MWD improved from 1 to 3 months post‐hospital discharge. Only TLC had further significant improvement from 3 to 6 months. HRQoL represented as the total score of SGRQ had no significant improvement in the first 3 months but improved significantly from 3 to 6 months post‐discharge. Conclusion The impaired pulmonary functions and exercise capacity in the survivors of H1N1‐ARDS improved soon at 3 months after hospital discharge. Their quality of life had keeping improved at 6 months even though there was no further improvement of their pulmonary functions and exercise capacity.


| INTRODUC TI ON
In March 2009, cases of flu-like illness in Mexico caused by a novel H1N1 influenza virus were reported and this novel virus spread rapidly across the globe within weeks. It was estimated that approximately 23 000 persons had been infected in Mexico by late April, giving an estimated case fatality rate of 0.4%. 1 More than one million people became ill with novel H1N1 influenza between April and June 2009 in the United States. 2 4 Severe H1N1 pneumonitis would result in acute respiratory distress syndrome (ARDS) and multi-organ failure, and associated with prolonged use of mechanical ventilation or even extracorporeal membrane oxygenation (ECMO). 5 The mortality associated with severe H1N1 infections was reported as high as 20%-40%. 6 In a study of 320 pandemic influenza pneumonia in Japan, 43 (13.4%) had received invasive mechanical ventilation and 7.8% died of severe pneumonia. 7 Pulmonary function impairment and reduced exercise capacity had been found in about half of the survivors of ARDS. One year after hospital discharge for ARDS, up to 80% of the patients demonstrated reduced diffusing capacity, one-fifth of them had airflow obstruction, and one-fifth had chest restriction. 8 Besides the impairment of pulmonary function, the survivors of ARDS also had reduced health-related quality of life.
The aim of this study was to assess the recovery from ARDS due to severe influenza A (H1N1) pneumonitis (H1N1-ARDS). Pulmonary functions, exercise capacity, and health-related quality of life in the survivors of H1N1-ARDS after hospital discharge in a tertiary teaching hospital in northern Taiwan were analyzed.

| Patients
Patients aged greater than 18 years with ARDS due to severe influenza A (H1N1) pneumonitis admitted to medical intensive care unit (ICU) at Linkou Chang-Gung Memorial Hospital, Taiwan, between May 2010 and June 2011 and survived to be discharged from the hospital were eligible for analysis in this study. The influenza infection was confirmed either by real-time RT-PCR assay or influenza virus rapid test performed on the nasopharyngeal swab or specimens aspirated from the endotracheal tubes. Specimens were collected at the time of admission. Patients fulfilled with all of the listed criteria of the Berlin definition were diagnosed as ARDS 9 : (i) new or worsening symptoms during 1 week, (ii) bilateral opacities consistent with pulmonary edema be present on a chest radiograph or computed tomographic (CT) scan, (iii) the ratio of arterial oxygen tension to fraction of inspired oxygen less then 300 mm Hg with positive endexpiratory pressure of 5 cm H 2 O or more, (iv) no clinical evidence of congestive heart failure or fluid overload. Patients with H1N1-ARDS were transferred to the ward when they were hemodynamically stable and were liberated from mechanical ventilation. Those willing to participate pulmonary rehabilitation program received a course of up to 2 months' exercise training, simplified strength training, and breathing exercise. They had regular follow-up of pulmonary functions, exercise capacity, and St. George's Respiratory Questionnaire (SGRQ) evaluation at 1, 3, and 6 months after hospital discharge.
All data were retrieved from the hospital records. Those without pulmonary function tests, six-minute walk test, or did not receive pulmonary rehabilitation were excluded for analysis. This study was approved by the Institutional Review Board of Chang-Gung Medical Foundation, and patient consent was waived.

| Pulmonary function tests
Pulmonary function testing (PFT) was performed using the MasterLab system (MasterLab; Jaegger, Germany) and was performed by technicians in the pulmonary function laboratory. All tests were proceeded according to American Thoracic Society guidelines. 10 The expiratory volume in the first second (FEV 1 ) and vital capacity (FVC) during forced expiration were recorded. Static lung volumes were measured using the plethysmography method, and diffusing capacity of the lung for carbon monoxide (DLco) was measured using the single breath-hold method. 11

| Six-minute walk test
Six-min walk test (6MWT) was performed by respiratory therapists in the pulmonary rehabilitation center according to American Thoracic Society guidelines. 12 The 6MWT was performed 1, 3, and 6 months after discharge from hospital. The distances the patients walked quickly in a period of 6 minutes (6MWD) were recorded.

| Health-related Quality-of-Life questionnaire
SGRQ was used to evaluate quality of life. The SGRQ results are grouped into 3 domains (symptoms, activity, and impacts) and a total score. A 4-point change in SGRQ has been determined to be clinically significant difference. 13 The SGRQ was also performed 1, 3, and 6 months after discharge from the hospital by respiratory therapists in the pulmonary rehabilitation center.

| Statistical analysis
The measurements of pulmonary function testing, 6MWD, and scores of SGRQ at different time points were compared with Wilcoxon signed rank sum test. The statistical analyses were performed using the SPSS (SPSS for Windows, SPSS Inc., Chicago, IL, USA), and the significance level (α) was set at 0.05, and P < .05 was considered statistically significant.

| General characteristics
Nine patients with confirmed ARDS due to severe influenza A (H1N1) pneumonitis admitted to medical ICU at Linkou Chang Gung Memorial Hospital, Taiwan, between May 2010 and June 2011 were recruited. The baseline characteristics of these patients are listed in Table 1. The mean age was 45.11 ± 5.48 years, and all were males.
Two of these patients received ECMO support for 11 and 12 days.
The mean mechanical ventilation use and ICU stay of these patients were 14.88 ± 2.38 days and 16.89 ± 2.51 days, respectively. The mean hospital stay was 33.55 ± 4.23 days. Most of the patients had no major comorbidity, except one had diabetes mellitus and the other two had hypertension. All these patients received 2 months' pulmonary rehabilitation program including endurance exercise training with cycle ergometer, breathing exercise, and simplified weight training three times a week during hospitalization and after discharge from the hospital.

| Pulmonary function tests
According to the diagnostic criteria of American Thoracic Society guideline, 10 six (66.7%) of 9 patients had mildly to moderately decreased FEV 1 and 4 (44.4%) of 9 patients presented with mildly to moderately reduced FVC, and one (11.1%) had severely reduced FVC 1 month after discharge from the hospital ( Figure 1A Nevertheless, compared with the data at 3 months, there was no further significant improvement of lung function measurements except TLC at 6 months ( Figure 1D).

| Health-related Quality of Life (HRQoL)
Eight of nine patients had completed their SGRQ. All but one H1N1-ARDS survivor were associated with worse pulmonary diseasespecific HRQoL in all 3 domains at baseline. Compared with baseline SGRQ total score, all but one of our patients had 4 or more points decrease at 6 months after discharge, with median values decreased from 29.4 to 4.8 during the 6-month follow-up. The only one without significant decrease in total score of SGRQ had a low score of 5 at 1 month and remained 5 at 6 months. The improvement of total score of SGRQ did not reach to a statistical difference in the initial 3 months (P = .064), but there was a significant improvement from 3 to 6 months after discharge from the hospital ( Figure 1F).

| DISCUSS IONS
Although most patients suffered from influenza A (H1N1) infection had a mild, self-limiting illness of the upper respiratory tract, a certain percentage of patients developed progressive severe pneumonia and ARDS. 15 morbidity despite advanced treatment strategies. Prone positioning and even ECMO were more frequently applied, and ICU stay was significantly longer in patients with H1N1-ARDS, although there was no difference in ICU survival compared with non-H1N1-ARDS patients. 19 These patients experienced not only physical morbidities but also mental and psychological stress that resulted in significantly impairment of health-related quality of life. 20,21 Therefore, the contemporary objective of intensive care in these patients was not only to assure their survival, but also to attain an ideal outcome of quality of life.
In this observational study, we followed the survivors of ARDS resulted from severe influenza A (H1N1) pneumonitis up to 6 months after hospital discharge to evaluate their functional recovery and improvement of health-related quality of life.
Pulmonary function tests including FEV 1 , FVC, TLC, DL CO , and exercise capacity presented as 6MWD improved significantly in the first 3 months but with no further significant improvement from 3 to 6 months after discharge. TLC improved continuously during the 6-month follow-up. Their quality of life, represented as total score of SGRQ, had no statistically significant improvement (P = .064) in the first 3 months, but the mean difference of total score (-9.6) had exceeded minimally clinical improvement difference of 4. The total score of SGRQ decreased significantly from 3 to 6 months after discharge, although most of pulmonary function measurements and exercise capacity did not increase further in this period (Figure 2  due to influenza A H1N1 infection, all patients had normal spirometry and DL CO at 6 months after discharge. 22 Toufen et al reported none of three patients had abnormal DL CO at 6 months. 23 Luyt and his coworkers demonstrated that pulmonary function test results were nearly normal at one-year post-ICU discharge and only 5.4% of patients had mild obstruction. Twenty-five of 37 patients (67.6%) in that study still had impaired diffusing capacity at 1 year. 20 These reports had no demonstrable data earlier than 6 months after discharge. With data collected at 1, 3, and 6 months after hospital discharge, most patients in our study had well-recovered pulmonary functions at 3 months. Furthermore, their TLC had significant continuous improvement till the end of 6 months' follow-up. Our results demonstrated the fast recovery of pulmonary functions and exercise capacity in the early stage after hospital discharge in the patients survived from H1N1-ARDS.
In survivors of ARDS not caused by influenza A H1N1, Orme and his coworkers found that approximately 80% of ARDS patients had reduced diffusing capacity, 20% had airway obstruction, and 20% had chest restriction at 1 year after recovery. 8 Another study demonstrated 67% of the patients with ARDS had some alteration of pulmonary function at 6 months after diagnosis. The PFT alteration was characterized by a restrictive pattern in 58% of cases, an obstructive pattern in 6%, and a mixed pattern in 3%. 21 Ong et al also presented some survivors from severe acute respiratory syndrome who had mild impairment of FVC and DL CO during 3 months' follow-up. 24 Our patients, with ARDS due to influenza A H1N1, seemed to have a better pulmo-

| CONCLUSION
Although our study series is small, the results suggest that patients survived from ARDS secondary to influenza A H1N1 pneumonitis had impaired pulmonary functions, exercise capacity, and quality of life after hospital discharge. The impaired pulmonary functions and exercise capacity improved soon at 3 months after hospital discharge, and their quality of life had keeping significant recovery up to 6 months.