Postoperative hypoxia is a challenge for surgeons. With the advent of better anesthesia and minimal access surgical techniques, the incidence of postoperative hypoxia in elective cases has decreased. However, the incidence in life-saving emergency procedures still poses a possible threat, and cases seem under-reported. We report a series of five cases of postoperative hypoxia after laparotomy. These cases comprise mesenteric laceration, proximal jejunal perforation, perforated duodenal ulcer, abdominal tuberculosis, and fall from height. Despite different etiologies, they landed up with the complication of postoperative hypoxia, which was attributable to the type of procedure they underwent and not the indication of the procedure itself. Thus, they form an interesting collection of post-laparotomy hypoxia cases. We present them with a compilation of probable causes of postoperative hypoxia in such cases.

Postoperative hypoxia presents a diagnostic challenge and requires timely suspicion, prompt intervention to eliminate the cause, and good postoperative care. The major causes include incomplete lung re-expansion, pain-induced restriction in chest-wall/diaphragm mobility, prolonged surgery, a complication of pre-existing lung disease, residual effects of some drugs, and iatrogenic causes. We, therefore, recommend the use of postoperative oxygen support and diligent monitoring of vitals in all cases of laparotomy, allowing prompt and timely patient management. Future studies are warranted to explore the prevalence and possible causes of post-laparotomy hypoxia.

Introduction

Postoperative pulmonary complications (PPCs) are associated with about 20% mortality and are usually life-threatening. The International Classification of Diseases (ICD-11) has described postoperative/postprocedural respiratory failure as the need for ventilation for more than 48 hours after surgery or re-intubation with mechanical ventilation post-extubation. The cases for the same are evolving and are influenced by both the type of surgery and the length of hospital stay [1-3]

The most common threat is postoperative hypoxemia. It is one of the most dangerous complications, which increases postoperative morbidity [4]. The early postoperative period is a 'high-risk' time for the occurrence of hypoxemia [5]. Postoperative hypoxemia may occur secondary to the problem of gas exchange during anesthesia, which may continue in the early postoperative period [6]. It is highly evident that the physiological response of the operated patient is not reversed immediately after arriving in the recovery room and the patient stays at high risk of complications [7].

Hypoxemia can be seen with any type of procedure or anesthesia [4]. Among postoperative complications, PPCs dominate mortality and morbidity. It has been revealed that postoperative hypoxemia affects 30-50% of cases after abdominal surgery [8]. Postoperative hypoxia is expected to be more common in longer surgeries. The literature on postoperative hypoxia after laparotomy is very limited. We report a case series of post-laparotomy hypoxia and follow this with a discussion to add to the literature on the causes of these complications and possible interventions to avoid them.

Case Presentation

Case 1

A 23-year-old male with an alleged history of road traffic accident reported to the ED with abrasions on his lower limbs and severe abdominal pain. On examination, the vitals were stable and the abdomen was rigid and had diffuse tenderness. USG imaging revealed free peritoneal fluid and blood investigations reported hemoglobin of 7.2 g/dL. He was a suspected case of hemoperitoneum and was immediately taken for exploratory laparotomy. Intraoperative findings of mesenteric laceration and perforation at the proximal jejunum were noted. He was operated on for mesenteric repair, segmental intestinal resection, and primary anastomosis. The patient was responding well after surgery and postoperative blood transfusions but the peripheral capillary oxygen saturation (SpO2) suddenly began to fall on day five after the surgery. The chest x-ray revealed the right upper lobe consolidation suggestive of pneumonitis (Figure 1). The patient had no history of respiratory illness or smoking. The patient was diagnosed as a case of sepsis and acute respiratory distress syndrome (ARDS) and was treated with meropenem, vancomycin, and gentamycin as per culture sensitivity. The patient initially recovered but then deteriorated and could not be saved.

Case 2

A 55-year-old male presented to the ED with complaints of upper abdominal pain and palpitations. On examination, he had tachycardia (heart rate: 123 bpm), and other vitals were within normal limits. The abdomen was rigid and had diffuse tenderness. The patient gave a history of previous treatment for duodenal ulcers, for which he took irregular treatment. Imaging reported signs of perforation and the patient was immediately taken for laparotomy. The patient was operated on; he underwent Graham omental patch and a thorough abdominal lavage was done. The patient was recovering well in the postoperative period when on day four after the surgery, he developed a sudden fall in oxygen saturation. He was a chronic smoker and was a known case of chronic obstructive pulmonary disease (COPD). CXR revealed a homogenous opacity on the right side of the chest (Figure 2A) and bronchoscopy revealed a mucus plug in the right bronchus. The mucus plug was removed and he was treated with broad-spectrum antibiotics and was advised to do incentive spirometry. Postoperative chest physiotherapy was also done. The patient responded well, he could maintain normal oxygen saturation within seven days of treatment, and also showed recovery on CXR (Figure 2B). The patient did not report any complications in follow-up.

Case 3

A 65-year-old male presented to the ED with complaints of severe upper abdominal pain. On examination, he had tachycardia (HR - 109 bpm), and other vitals were within normal limits. The abdomen was rigid and tenderness was present in the epigastric region. He had a previous history of burning sensation in the epigastric region, which was relieved on taking food. Imaging reported signs of perforation, and the patient was immediately taken for laparotomy. He was operated on with a pedicled omental flap and a thorough abdominal lavage was done. He was recovering well in the postoperative period when on day two after the surgery he developed a sudden fall in saturation. The CXR revealed homogenous opacity on the left side (Figure 3) and bronchoscopy revealed a mucus plug in the left bronchus (Figure 4). He was treated with broad-spectrum antibiotics and was advised to do incentive spirometry. Postoperative chest physiotherapy was also done. He responded well and could maintain normal oxygen saturation within four days of treatment. He did not report any complications in follow-up.

Case 4

A 50-year-old HIV-positive male with a history of pulmonary tuberculosis five years back reported to the ED with complaints of severe upper abdominal pain. On examination, he had stable vitals, but a per-abdominal exam revealed epigastric tenderness, abdominal rigidity, and rebound tenderness. The patient was investigated and imaging studies were done, which revealed free peritoneal fluid, and the patient was planned for laparotomy. A thorough abdominal lavage was done and a defect of 1.5cm was repaired in the proximal part of the duodenum. The patient developed the complication of fecal fistula and was treated with broad-spectrum antibiotics. The patient was recovering well but developed a sudden fall of saturation on day three after the surgery. His previous CXRs had perihilar pulmonary infiltrates but the recent one developed non-homogenous opacities bilaterally (Figure 5), which were diagnosed as Pneumocystis carinii infection on the basis of sputum microscopy. The patient was treated with broad-spectrum antibiotics, sulfamethoxazole+trimethoprim. The patient was advised to do incentive spirometry and postoperative chest physiotherapy was done. He responded well to treatment and recovered largely within two weeks. No respiratory complications were reported in follow-up.

Case 5

A 49-year-old male was reported to the ED with an alleged history of fall from height. On examination, the patient had a feeble pulse and tachycardia. The abdomen was soft but had tenderness in the right hypochondriac region, epigastric region, and left hypochondriac region. He was referred to the medical college from a peripheral hospital and his investigations revealed a right intertrochanteric fracture and hemoglobin of 7.2 g/dL. Further investigations of USG raised suspicion of splenic injury. A non-contrast computerized tomography (NCCT) abdomen revealed a grade IV splenic injury and minor liver laceration. The patient was taken for emergency laparotomy and he underwent splenectomy with a repair of liver laceration. Adequate blood transfusions and fluid replacements were done. The patient developed postoperative hypoxia on day two of surgery; a CXR revealed haziness on both sides of the chest suggestive of bilateral lower zone pneumonitis (Figure 6). The patient was treated with antibiotics, incentive spirometry, and chest physiotherapy. He recovered well and was later operated on for the intertrochanteric (IT) fracture. The patient was vaccinated for capsulated organisms and counseled for post-splenectomy care. He recovered well and had no further complications to report in follow-up.

The comparative details of all the five cases reported under this series are given in Table 1.

Serial number Age/sex Co-morbidities Past history of respiratory illness Previous CXR History of smoking General Anesthesia Duration of surgery (hours) Pre-anesthetic medications used Post-op hypoxia on day Probable cause of Hypoxia ABG
1 23/M None - WNL - Isoflurane 2 hrs 30 min Ondansetron, glycopyrrolate, fentanyl, midazolam 5 Sepsis secondary to pneumonia; Pain-induced restriction of diaphragmatic mobility  pH: 7.20 PaO2: 79mmHg PaCO2: 30 mmHg HCO3: 27 mEq/L S. Lactate: 3 mmol/L
2 55/M COPD COPD Hyperinflated lungs Chronic smoker - 80 pack years Isoflurane 3 hrs Ondansetron, glycopyrrolate, fentanyl, midazolam 4 Mucus plug obstruction of bronchus; Pain-induced restriction of diaphragmatic mobility pH: 7.43 PaO2: 82mmHg PaCO2: 43mmHg HCO3: 25 mEq/L
3 65/M Hypertensive - WNL - Isoflurane 2 hrs Ondansetron, glycopyrrolate, fentanyl, midazolam 2 Secondary left lung lower zone pneumonia with left bronchus mucus plug obstruction pH: 7.38 PaO2: 86mmHg PaCO2: 38mmHg HCO3: 26 mEq/L
4 50/M HIV Pneumocystis carinii infection Perihilar pulmonary infiltrates - Isoflurane 3 hrs Ondansetron, glycopyrrolate, fentanyl, midazolam 3 Flaring up of Pneumocystis carinii infection  pH: 7.35 PaO2: 77 mmHg PaCO2: 39 mmHg HCO3: 24 mEq/L
5 49/M None - WNL - Isoflurane 2 hrs Ondansetron, glycopyrrolate, fentanyl, midazolam 2 Pain-induced restriction of Diaphragmatic mobility pH: 7.43 PaO2: 89 mmHg PaCO2:35 mmHg HCO3: 23mEq/L

Discussion

Postoperative hypoxia is a common challenge faced by surgeons. The earlier data suggested its incidence to be around 55% [9], but with the introduction of new and short-acting anesthetic drugs, minimally invasive surgical procedures, enhanced postoperative care, and the advent of day-care surgery, the incidence has fallen down to just around 20% in elective surgeries [10-11]. A catena of studies has highlighted the causes of postoperative hypoxia. These include but are not limited to incomplete lung re-expansion, pain-induced chest-wall/diaphragm mobility, prolonged surgery, a complication of pre-existing lung disease, residual effects of some drugs, and iatrogenic causes (Figure 7) [12].

Laparotomy is a major general surgical procedure that frequently proves to be life-saving. The existence of hemodynamic instability, prolonged surgical time, major surgical trauma, and associated mental trauma all push the major surgery of laparotomy to the verge of postoperative hypoxia. An interplay between the stated factors contributes to post-laparotomy hypoxia, forming it a less-reported identity, warranting attention.

Most cases present within a few hours of surgery with desaturation and are mainly attributed to prolonged drug effects [4]. Delayed presentation within days to week post-surgery is rarely seen these days and may be under-reported because of the dearth of data on post-laparotomy hypoxia.

In our case series, we reported five cases that developed post-laparotomy hypoxia, which was influenced by a myriad of factors as described in Table 1. The major cause that we could decipher was restricted diaphragmatic movement during and post-surgery. Incomplete lung base expansion during the long duration of laparotomy surgery, and later in the postoperative phase, the pain-induced restriction in diaphragmatic mobility highly contributes to postoperative hypoxia. Some specific causes were seen in individual cases: In Case 2 and Case 3, bronchoscopy revealed a mucus plug, which may have been the prime cause in those cases. In Case 4, a flare-up of Pneumocystis carinii infection was the main cause.

The findings in our case series were also in congruence with the findings of Melesse et al., who suggested longer duration of surgery had high chances of postoperative hypoxia [13]. The cases recovered well after being treated with supplemental oxygen and broad-spectrum antibiotics. The response to broad-spectrum antibiotics in some cases suggests a possible link between post-op infection and poor outcomes.

Perioperative physiotherapy has been shown to improve patient outcomes in abdominal surgeries. It can help prevent the number of PPCs [14]. In our cases, the patients were also promoted for incentive spirometry and were given chest physiotherapy post-surgery, which did contribute to a better recovery.

Conclusions

Postoperative hypoxia presents a diagnostic challenge and requires timely suspicion and prompt intervention to eliminate the cause. We, therefore recommend the use of postoperative hypoxia oxygen support, peri-operative chest physiotherapy, and diligent monitoring of vitals in all laparotomy cases allowing efficient patient management. Future studies are warranted to explore the prevalence and possible causes of post-laparotomy hypoxia.



Source link

The resurgence of Covid-19 in some countries including Sri Lanka, and the seasonal influenza virus circulating across the world has led to a surge in respiratory infections, prompting the chest physicians to urge those susceptible to developing respiratory infections to take precautions against them without delay.

Here, Consultant Respiratory Physician, District General Hospital and District Chest Clinic Trincomalee, Dr. Upul Pathirana explains what causes many of these infections, how to treat them and most importantly how to avoid them with easy to follow simple hygienic measures.

Excerpts

Q: Pulmonary infections such as pneumonia are now on the rise across the world. Of these infections what are the most serious diseases associated with pulmonary infection that you find in Sri Lanka and what part of the body is affected by them?

A. The infections hit on the respiratory system starting from nose to lungs and pleura. The medical community names these infections based on the anatomical sites and involved organisms. Covid-19 pneumonia is one of our concerns since December 2019 and there is a resurgence of Covid-19 in some countries including Sri Lanka. Seasonal influenza virus is circulating all over the world and it is one of the concerns for us as well.

Q: Can anyone get respiratory infections?

A. There are people who are susceptible to develop respiratory infections even though any of us can catch such infections. Individuals with risk factors are prone to develop severe infections and complications; otherwise it might be an acute simple self-limiting disease in most of the healthy persons.

Q: As Pneumonia is one of the most critical and common of these infections what exactly is pneumonia?

A. There is a spectrum of bugs including viruses, bacteria, fungi and parasites, which can cause respiratory infections. We call it pneumonia when affecting the air sacs (alveoli) within the lungs. Uncomplicated infections such as rhinitis and pharyngitis (affecting the nose and pharynx respectively) are more common than pneumonia.

Q: Are there different types of pneumonia? If so, name the most common in this part of the world?

A. We classify pneumonia based on the site involved within the lungs, causative factor, involved organism, acquired environment and many more. Microorganisms might not be the source of pneumonia in some instances but it might be following recurrent and long-standing exposure to some environmental particles at your home or working environment. Rarely, our own immune system stands against body tissues and gives rise to pneumonia, which needs specific treatment guided by a respiratory physician. Either bacteria or viruses cause by far the commonest pneumonia and it is acquired from the community in most cases.

Q: Is it contagious? How?

A. Even though the human-to-human transmission is well recognised in pneumonia, there is no evidence to say that this is true for all types of pneumonia. Most of the viral pneumonias spread rapidly within the community through air, droplets and/or contact routes. Pulmonary tuberculosis is one form of pneumonia with distinct features and it passes on to others from an infected person who has active disease.

Q: If air-borne what is the distance that the virus travels if one is in the same room when he or she coughs or sneezes?

A. This is a bit complex and technical topic and I will simplify for better absorption. The respiratory infections are transmitted through particles of different sizes. The particles could be either more than or less than 5 μm and they are called respiratory droplets and droplet nuclei respectively.

Droplet transmission occurs when a person is in in close contact (within 1 m) with someone who has respiratory symptoms (e.g., coughing or sneezing) and is therefore at risk of having his/her mucosa (mouth and nose) or conjunctiva (eyes) exposed to potentially infective respiratory droplets.

Airborne transmission is different from droplet transmission as it refers to the presence of microbes within droplet nuclei, which can remain in the air for long periods of time and be transmitted to others over distances greater than 1 m.

Q: What precautions should one take to prevent getting infected?

A. The source control is one of the best strategies to minimie or prevent respiratory infections. Practicing hand hygiene is a simple yet effective way to prevent infections. A person with symptomatic illness has the potential to infect others even though an infected asymptomatic individual also spreads the disease. Therefore, if you have flu-like symptoms or any other respiratory symptoms, wear a facemask to cover your mouth and nose. The Centres for Disease Control and Prevention (CDC) also recommend sneezing into a disposable tissue, and then throwing it away and washing your hands clean. However, if you can’t access a tissue in time, sneezing into your elbow is the next best option to sneezing into the air.

Q: Can you give us a simple demonstration of these rules?

A. l Bury your mouth and nose in your inner elbow.

lSneeze, and then wait a few seconds to see if there is another sneeze on the way.

lIf you touch your sleeve, wash your hands before touching anyone or anything.

Q: Are respiratory infections curable?

A. The vast majority of respiratory infections are self-limiting or settle with symptomatic treatment as they are viral in origin. However, for pneumonia regardless of viruses or bacteria, you should seek medical advice early as timely intervention can cure pneumonia in most cases.

Q: Is it fatal especially if it affects the lungs?

A. Yes. Pneumonia is one of the most serious infections that affect humans. One suffering from pneumonia may develop complications like respiratory failure or septic shock (a state of low blood pressure) necessitating Intensive Care Unit (ICU) treatment. Mortality is high in severe complicated pneumonia all over the world.

Q: How do you prevent it?

A. Respiratory hygienic measures such as good hand hygiene, protective facemask, and avoiding sneezing or coughing in crowded places minimise the spread of infection. BCG vaccine administered to all newborns prevents complications of Tuberculosis in early childhood. Influenza and Pneumococcal vaccines can prevent influenza and pneumococcal pneumonia. There are many more to discuss about preventive measures and it is beyond the scope of this article.

Q: Who are those most at risk of getting it? Why?

A. Any of us can catch respiratory infections although individuals with risk factors are prone to develop more severe infections and complications. Uncontrolled blood sugar is one of the commonest reasons to acquire any type of severe infections including pneumonia. Less ambulatory people, patients with neurological disorders and other organ failures, cancer patients, chronic lung disease, people living with Acquired Immunodeficiency Syndrome (AIDS), malnutrition and those on medications which impair the immune system are at most risk.

Q: What about persons with underlying lung diseases including cystic fibrosis, asthma, or chronic obstructive pulmonary disease (emphysema)?

A. The patients with chronic lung diseases are at risk of acute exacerbations of their underlying lung disease due to respiratory infections.

Q: Those who have had a recent viral upper respiratory tract infection including influenza- are they too vulnerable?

A. Yes, although these infections look very simple, they can damage the surface of the wind tubes (airway epithelium) favoring adhesions and establishment of secondary bacterial infections.

Q: What are the symptoms to look out for?

A. Runny nose, sneezing, nasal block, sore throat, painful swallowing, cough and fever are the commonest of upper respiratory tract infections. When the organisms reach the lungs causing pneumonia, the patients develop high swinging fever, productive cough with yellow or rusty sputum, reduced appetite, chest pain during breathing and breathlessness. Extremes of ages such as elderly people can have unusual presentations like confusion as the sole manifestation of pneumonia.

Q: Who should patients with any of these symptoms consult initially?

A. A consultation with your family doctor is enough in most cases. However, if you are sicker, you can straight away seek institutional care from a hospital. Those with risk factors should consult a doctor as early as possible.

Q: How is it detected?

A. The doctors make the initial diagnosis after listening to the patient and carrying out physical examination. Initial blood investigations, sputum testing and chest x-ray in selected cases will confirm the diagnosis.

Q: Who makes the final diagnosis? What is the procedure involved?

A. After assessing the patient, the doctor will direct you for either home based care or institutional care. An experienced physician attends to all the pneumonia patients and decides the level of care such as in-ward or Intensive Care Unit.

Q: What tests are required for the patients to undergo? Why are they necessary?

A. The objectives of testing are to first confirm the pneumonia and then identify the causative organism. These patients might undergo further investigations to catch complications and to monitor the disease course and treatment. The investigations include sputum testing, blood investigations, imaging like X-ray, ultrasound and Computed Tomography. In selected cases, fibro optic bronchoscopic examination and sampling will be helpful.

Q: What are the complications (short term and long term) of Pneumonia?

A. Pneumonia affects your lungs through which the oxygen from the environment is entering your blood. Therefore, the oxygenation can be failed when the pneumonia is severe and it is called respiratory failure. Due to the effect of toxins produced by the involved microorganisms and our own body’s reaction to infection could create a state of low blood pressure called septic shock. There are other complications like lung abscess and pleural effusion (fluid between lung and chest wall). Despite the fact that even severe pneumonia can recover completely without any long-term consequences, some patients can have persistent residual lung damage.

Q: How do you treat pneumonia?

A. The mainstay of treatment is antibiotic and antiviral therapies. They need other supportive care for overall management.

Q: Is the treatment given tailored to the needs of the patient? Or is it a blanket treatment for all?

A. One size fit for all theory has now moved away from the medical practice. All the treatments are individualised in pneumonia patients as directed by an experienced physician.

Q: What is the usual recovery period?

A. There is no black and white answer in the form of number of days for recovery period. The recovery is quick within a few days in some cases and others it is prolonged.

Q: Do you have a message for our readers on avoiding risks of pneumonia? Any Do’s and Don’ts they should follow?

A. Good respiratory hygiene will protect you and those around you. If you are infected with a respiratory infection, act responsibly to prevent transmission of infection to others. Be alert and if there are alarming symptoms such as breathlessness consult a doctor early. Regular treatment under the supervision of your family doctor or relevant specialty doctor for those who have chronic diseases can reduce the morbidity and mortality associated with respiratory infections. Diabetes is a common disease in our country and those with uncontrolled blood sugar are at risk of complications including severe respiratory infections. Therefore, you should make sure that you periodically check blood sugar and keep it well controlled.

Source link

Background: Most of the acute exacerbations of chronic obstructive pulmonary disease (COPD) are due to infections, mostly due to bacteria and viruses. There is a need to study the outcome of microbe-induced airway inflammation.

Materials and methods: It is an observational follow-up study from the pulmonary medicine department of Kalinga Institute of Medical Sciences with the participation of the Regional Medical Research Center, Bhubaneswar, from October 2018 to February 2022. Patients who were admitted with acute exacerbation of COPD and treated as per GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2021 guidelines were included in the study. Those patients in the severe category, who had clinically recovered, had undergone pulmonary physiotherapy, were on prescribed medications and home oxygen therapy after discharge, were followed up every three months by telephone calls. Any exacerbation, clinical stability, or mortality information was recorded.

Results: Out of 197 cases, the majority were elderly, males, smokers, and belonged to urban areas; in total, 102 (51.8%) microbes were isolated as etiological agents of infective exacerbation in which 19.79% were viruses and 23.35% were bacteria, while coinfection was found in 8.62% cases. Among the viruses, rhinovirus, influenza virus, and respiratory syncytial virus were the major isolates. Among the bacteria, mostly gram-negative organisms such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa were isolated. Readmission was more among patients with coinfection.

Conclusion: Acute exacerbation of COPD was mostly seen in males in the age group of 61-80 years. Rhinovirus and influenza A virus were the two most common viral isolates, and among the bacterial isolates, Acinetobacter baumannii and Klebsiella pneumoniae were predominantly detected. Poor clinical outcomes were noticed more among the coinfection group.

Introduction

Worldwide, COPD is one of the major causes of illness and the sixth highest cause of death. According to research on the Global Burden of Diseases in 2017, it contributed to 50% of all chronic respiratory diseases. It is currently the third leading cause of death worldwide, accounting for nearly 3.23 million deaths, with nearly 80% of deaths occurring in the middle- and low-income countries, and is expected to rise from the 12th leading cause of disability-adjusted life-years (DALYs) in 1990 to the fifth leading cause in 2020 [1,2].

Acute exacerbations of COPD are significant events in the course of illness because they have a negative influence on health status, hospitalization rate, and disease progression. It is believed that respiratory infections are an important risk factor for COPD exacerbations, with viruses accounting for 22%-64% [3]. The increased exposure to viruses in winter has been correlated to an increase in the frequency of exacerbations in winter in some areas of the world [4]. Co-infections have also been linked to an increase in the severity of COPD exacerbations. The simultaneous discovery of bacteria and viruses in patients with acute exacerbation of COPD is responsible for the worsening lung function, prolonged hospital stay, and risk of recurrence of a similar event [5,6].

This study analyses the prevalence and pattern of viral and bacterial infections in patients presenting with acute exacerbation of COPD, correlates the type of infection with the severity of exacerbation among the patients, and finds out the long-term outcome of the severe follow-up cases after discharge in terms of readmission, clinical stability, or death.

Materials & Methods

The study was conducted from October 2018 to February 2022 among the patients admitted to critical care, Respiratory and General Medicine unit of Kalinga Institute of Medical Sciences, Bhubaneswar, in collaboration with Regional Medical Research Centre (ICMR), Bhubaneswar.

The sample size was calculated by using the formula: 

n = Z2 P(1−P)/d2

where n is the sample size; Z is the statistic corresponding to a 95% level of confidence, which is equal to 1.96; P is the expected prevalence (proportion of COPD patients with infectious etiology = 78.3% in a study conducted by Jahan et al.) [7]; d is the absolute precision (it has been taken as 6%). The sample size was found to be 179; adding a 10% non-response rate, the final sample size was 179 + 18 = 197.

Admitted cases underwent clinical assessment and other routine investigations. Empirical treatment was given as per standard treatment guidelines. The nasopharyngeal swab was taken and transported in a viral transport medium within 24 hours to the Regional Medical Research Centre (RMRC) for the detection of respiratory viruses. Samples were tested by real-time reverse transcription-polymerase chain reaction (RT-PCR). The test was done using recommended commercial kit (FTD, UK) following the manufacturer’s instructions on Applied Biosystems-7500 (ABI-7500) equipment (ABI, USA). After thorough rinsing of the oral cavity, respiratory secretions were sent in a sterile container to our institute laboratory for bacterial culture and sensitivity study by VITEK 2 compact instrument (bioMérieux, France).

Apart from the procedural guidelines, depending on the severity of the cases, patients were treated with microbe-targeted antibiotics, oxygen support, either parenteral or oral, nebulized corticosteroid, and bronchodilator and were classified as mild, moderate, and severe as per the GOLD guidelines. The severe cases underwent pulmonary physiotherapy (diaphragm strengthening, pursed-lip breathing, lower limb muscle training, and chest percussion) session one week after clinical stability.

The patients were contacted over telephonic/telemedicine services every three months (due to the COVID pandemic, physical follow-up was not done) to ensure that they were continuing to perform the exercises at home and consuming medications, and any clarifications sought were addressed. Outcome data were collected with respect to clinical stability, worsening of clinical symptoms requiring admission, or mortality at the end of one year of follow-up.

This is an observational follow-up study conducted in the pulmonary medicine department of the Kalinga Institute of Medical Sciences. Ethical clearance was obtained from Institutional Ethics Committee (vide letter no.: KIIT/KIMS/113). All patients (including those on ventilation) with acute exacerbation of COPD (based on acute onset of cough, increased sputum with or without purulence, and breathing difficulty) admitted to the pulmonary medicine department were included in the study. Patients with pulmonary tuberculosis (TB), bronchiectasis, bronchial asthma, pneumonia, and acute lung injury (based on history and evaluation) and patients unwilling to give consent were excluded from the study.

Statistical analysis

Descriptive statistics were done after the collection of data. Frequency distributions of categorical variables (occupation, gender, place of residence, smoking status, type of pathogens found, clinical features, comorbidities, and follow-up data) were calculated. For continuous data (age, total leukocyte count [TLC], and duration of hospital stays), mean and standard deviations were calculated. These were presented in tables using SPSS version 20.0 (IBM Corp., Armonk, NY) and Microsoft Excel 2007 (Microsoft Corporation, New Mexico, USA).

Type of infection, isolated organisms, and clinical outcomes after one year were identified. Chi-square and p-values were calculated to measure the associations between the type of infection and isolated organisms, type of infection, and readmission after one year.

Results

A total of 197 subjects were included in the study, out of which 138 (70.06%) were males and 59 (29.94%) were females. The maximum number of subjects (130 [65.9%]) were within the age group of 61-80 years. The total number of patients more than 80 years of age was 25 (12.69%). The mean age of the patients was 69.24 ± 11.08 years (Table 1).

Age group (years) Male Female Total
40-60 25 17 42
61-80 92 38 130
>80 21 4 25
Total 138 59 197

The total number of patients who had a smoking history was 126 (63.95%). Most of the study subjects were farmers (37.06%), and the least belonged to the category of laborer (2.54%). Out of the total subjects, only 83 (42.13%) patients were from rural areas (Table 2).

Variables Frequency Percentage (%)
Smoking history
Smoker 126 63.96
Non-smoker 71 36.04
Occupation
Teacher 16 8.12
Businessmen 21 10.66
Laborer 5 2.54
Farmer 73 37.06
Housewife 47 23.86
Unemployed 35 17.77
Area of residence
Urban 114 57.87
Rural 83 42.13

Out of 197 patients,102 (51.78%) had been isolated with bacteria or viruses, or both. Isolated viral infection was seen in 39 (19.79%) cases, while 46 (23.35%) had only bacterial exacerbations. In another 17 (8.62%) cases, both bacteria and viruses were detected. No etiology for exacerbation could be detected in 95 (48.2%) cases (Table 3).

Infection detected No. of cases Percentage (%)
Virus only 39 19.79
Bacteria only 46 23.35
Coinfection with both 17 8.62
No pathogen found 95 48.24
Total no. of patients 197 100

Out of 56 cases, in three cases of viral exacerbations, more than one virus (i.e., two) was detected, and in one case of viral exacerbation, more than one virus (i.e., three) was detected. A total of 62 viruses were isolated. Rhinovirus and Flu-A (H3N2) were isolated most frequently (30.35% and 25%, respectively) followed by respiratory syncytial virus (RSV) and parainfluenza virus 3 (PIV-3) (10.71% each; Table 4).

List of viruses No. of cases with viral infection (N = 56) % of patients with the isolated virus
Rhinovirus 17 30.35
Flu-A (H3N2) 14 25.0
RSV-B 6 10.71
Flu-B 4 7.14
PIV-3 6 10.71
Flu-A/PDM 09 4 7.14
HMPV 3 5.35
Adenovirus 2 3.57
RSV-A 2 3.57
COVID-19 4 7.14

A total of 63 bacteria were isolated in which gram-negative bacilli were most common, which include Acinetobacter baumanniiKlebsiella pneumoniae, and Pseudomonas aeruginosa. Among the gram positives, Staphylococcus aureus was the most common.

Rhinovirus was most commonly associated with bacterial coinfection in four cases (2.03%) followed by Flu-A and COVID-19. Acinetobacter baumannii was associated with a viral infection in most cases (five cases; 2.53%). This was followed by the detection of Pseudomonas aeruginosa and Klebsiella pneumoniae in two cases each (Table 5).

List of bacteria No. of cases with bacterial infection (N = 63) % of total bacteria isolated
Acinetobacter baumannii 14 22.22
Klebsiella pneumoniae 14 22.22
Pseudomonas aeruginosa 12 19.05
Staphylococcus aureus 5 7.94
Escherichia coli 8 12.70
Enterobacter cloacae complex 5 7.94
Serratia marcescens 2 3.17
Enterococcus faecium 1 1.59
Streptococcus pneumoniae 1 1.59
Staphylococcus haemolyticus 1 1.59
Sphingomonas paucimobilis 1 1.59

Breathlessness and cough were the most frequent complaints at the time of presentation. In cases with isolated viral exacerbation, 38 out of 39 cases (97.4%) had a shortness of breath, while 34 out of 39 (87.2%) cases had a cough. Fever was present in 14 out of 39 (32%) cases. However, sore throat was reported only in patients with isolated viral exacerbation, and chest pain was reported in patients with isolated bacterial exacerbations. Hypertension was the most common comorbidity reported in both bacterial and viral infections. Diabetes mellitus was mostly seen in patients who had a coinfection (Table 6).

Clinical feature Type of infection
Isolated viral Isolated bacterial Coinfection
Fever 14 19 6
Cough 34 36 13
Expectoration 9 10 4
Breathlessness 38 43 17
Chest pain 0 2 0
Sore throat 9 0 0
Altered sensorium 2 0 0
Comorbidities
Hypertension 11 16 4
Diabetes mellitus 5 5 6
Parkinson’s disease 0 2 0
Coronary artery disease 0 4 0
Cerebrovascular accident 1 2 0
Chronic kidney disease 1 1 0
Cushing syndrome 1 0 0
Chronic liver disease 1 0 0
Carcinoma larynx 0 1 0
Alzheimer’s disease 0 1 0
Congenital heart disease 0 0 1

Among the 102 patients with infective exacerbations, patients with viral exacerbation had relatively lower mean TLC, while patients with exacerbation due to coinfection had the highest mean TLC. However, the results were not significant (p = 0.641). Among the patients with infective exacerbations, those with viral exacerbation had the least mean duration of hospital stay (7.33 ± 4.8 days), while patients with bacterial exacerbation spent the highest number of days in the hospital (10.082 ± 5.89 days). The 17 patients with coinfection had a mean duration of hospitalization of 6.8 ± 5.03 days. The results were not statistically significant (p = 0.071). Ten (26%) patients with viral exacerbation, 24 (52%) with bacterial exacerbation, and nine (53%) patients with a coinfection required respiratory support and hence needed admission to ICU. Severity was most commonly noticed in coinfection cases (p = 0.020). Two deaths were reported in viral infections, four in bacterial exacerbation, and three in coinfections (Table 7).

Parameters Mean Value P-value
  Isolated viral infection (n = 39) Isolated bacterial infection (n = 46) Coinfection (n = 17)
Mean age (years ± SD) 68.36 ± 3.45 71.8 ± 11.73 73 ± 8.33 0.084NS
Total leukocyte count (cells/mm3) 11.139 ± 4.8 12.49 ± 5.435 12.66 ± 7.3 0.641NS
Mean duration of hospital stay (in days) 7.33 ± 4.8 10.052 ± 5.89 6.8 ± 5.03 0.071NS
Type of cases
Mild 12 (31%) 0 (0%) 0 (0%) 0.041S
Moderate 17 (43%) 22 (48%) 8 (47%) 0.062NS
Severe 10 (26%) 24 (52%) 9 (53%) 0.020S
No. of deaths among the severe cases 2 4 3 NA

The number of patients who had a severe disease was 43 (Table 7). Out of them, nine died. The rest 34 cases were advised pulmonary rehabilitation, oxygen therapy, inhaler-based medication as self-management home-based delivery, and were on telehealth monitoring. Five cases were lost to follow-up. In the rest 29 cases, information was documented after follow-up for one year that consisted of six viral infection, 17 bacterial infection, and six coinfection cases (Table 8).

Condition of the patients after one year of follow-up Viral infection (6 cases) Bacterial infections (17 cases) Coinfections (6 cases) P-value
Clinically stable 6 (100%) 16 (94%) 2 (33%) 0.034s
Exacerbation (admission) 0 1 (6%) 4 (67%)

All viral infection cases were clinically stable and did not require admission. Out of 17 bacterial infection cases, 16 (94%) were clinically stable and only one (6%) required hospital admission due to exacerbation. But in the six coinfection cases, two (33%) were clinically stable and the rest four (67%) cases required hospital admission, and the data was found to be statistically significant (p = 0.034). This shows most of the coinfection cases required rehospitalization during the period of follow-up (Table 8).

Discussion

Acute exacerbation of COPD results in deterioration of pulmonary function, morbidity, and death. In our study, the mean age of the patients was 69.24 ± 11.08 years with a majority of the patients belonging to the age group of 61-80 years (Table 1). In a recent study conducted at the All India Institute of Medical Sciences (AIIMS), Bhubaneswar, the mean age was 65.49 ± 10.40 years [7]. As per another Indian study by Mood et al., the mean age of patients was 66.8 ± 11.4 years and the maximum prevalence was observed in the age group 70-79 years [8]. In another study that involved both European and American subjects, the proportion of females was 36.7% among Europeans and 33.3% among Americans, which is in accordance with our findings [9]. A study by Hajare et al. reported a male-to-female ratio of 2.3:1 [10]. The preponderance of males being affected can be attributed to the fact that males are more involved in outdoor activities and hence are more exposed to environmental pollutants [8]. Smoking is a risk factor for COPD and also its exacerbation as it decreases mucociliary clearance, which is amply proved in our study where smoking as a risk factor was noticed among 64% of patients [11]. In our study, the two main occupations that had increased the prevalence of COPD were farmers and housewives (Table 2). In a study published in 2016, occupations that were at COPD risk were seafarers, coalmine operatives, and cleaners [12]. In a study in Bangladesh, occupational exposures in farmers, hazardous exposures in tanners, and cotton dust exposures in garments were among the most prominent risk factors for the development of COPD [13]. In our study, the urban population comprised the majority (57.8%, Table 2), which correlates well with a study done in India where the prevalence of COPD was more in the urban areas. But there has been a significant increase in the prevalence in rural areas where it was reported to be 8.8% in a study done in India, whereas in our study, the prevalence is around 22% [14]. The disparity in the urban-rural divide is reversed in the United States, where the prevalence of COPD in rural communities is nearly double that in urban areas [15].

The complex interactions between environment, host, and microbes are responsible for exacerbations in COPD and increased morbidity and mortality [16]. As per studies, the major cause of acute exacerbations is infections [7]. In our study, infection was detected in 51.7% of cases (Table 3). In an Indian study, around 78.3% of cases had a respiratory infection [7]. Our study illustrates that only bacterial infection was found in 23.35% of cases; only viral etiology was found in 19.79% of cases, and bacterial and viral coinfection was found in 8.62% of cases. Other studies have reported bacterial infection in around 42%-49% of cases, viral infections in around 20%-64% of cases, and bacterial-viral coinfection in 27% of cases [7,17,18]. There has been an increased report of respiratory viruses as a causative agent in the acute exacerbation of COPD. With the application of molecular techniques in patients’ samples, viruses have been implicated in around 47%-66% of cases [11]. A total of 56 viruses were isolated (Tables 3, 4). The most common viruses isolated were rhinovirus, followed by Flu-A and RSV-B. Human rhinovirus (HRV) has been reported as a common viral isolate in various studies [18]. The study by Koul et al. also reported rhinovirus and influenza virus as the most common virus causing acute exacerbation of COPD [19]. The high rate of isolation of influenza virus may be attributed to the transmission of the influenza virus in the community and the need to have immunization [20]. In our study, more than one virus was isolated in three cases. Similar results have been found in a recent study in India [7]. The most common bacterial isolates in our study are Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa making up around 21.9% (for both Acinetobacter and Klebsiella) and 18.8%, respectively. Among the gram-positive bacteria, Staphylococcus aureus (7.8%), Enterococcus faecium (1.6%), and Streptococcus pneumoniae (1.6%) were the most common isolates. In the study by Jahan et al., the most common bacteria isolated were Pseudomonas aeruginosa (28%), followed by Acinetobacter baumannii and Klebsiella pneumoniae in seven cases each (21%) [7]. In another study, the most common bacterial isolates were P. aeruginosa (30.7%) followed by K. pneumoniae (20.3%) and S. pneumoniae (8.6%) [8].

It is to be noted that most of the studies implicate Pseudomonas aeruginosa as the most common bacteria causing exacerbation, whereas Acinetobacter baumannii and Klebsiella pneumoniae are the most common bacteria causing exacerbations as per (Table 5) of our study [21]. The predominance of Acinetobacter spp. in our study is a novel finding, and further studies are needed to know if this is the emerging trend in acute exacerbation of COPD as MDR (multidrug-resistant). Acinetobacter baumannii is implicated in the etiology of various other infections [22]. Jahan et al. reported coinfection with virus and bacteria in 24.9% of cases of acute exacerbations of COPD [7]. In our study, coinfection was detected in 9.63% of cases (Table 3). However, this may not represent a natural course as many patients are chronically infected with multiple pathogenic bacteria before a viral pathogen is detected. Conversely, viruses have been shown to be frequently followed by secondary bacterial infection. Most of the coinfections were seen to be associated with rhinovirus and influenza A virus, whereas it was mostly associated with both influenza A and influenza B in another study by Jahan et al. [7]. In another study, the viruses implicated alone or as coinfections are picornaviruses (especially rhinovirus), influenza virus, and respiratory syncytial virus [23]. Comorbidities were associated with eight cases of viral exacerbation with hypertension being the most common (Table 6). Similar findings were also reported by Koul et al. where hypertension was seen in 60.52% of cases followed by heart ailments (14.16%) [19]. No significant correlation was observed between the various subgroups. Breathlessness and cough were the most common clinical presentation in cases of exacerbation in our study. Sore throat, however, was reported only in viral exacerbation and not in bacterial or coinfection (Table 6). The outcome of viral exacerbation has improved over time, owing to an increase in adult vaccination and early treatment. Among the etiological agents, in our study, we noticed poor outcomes among the coinfection group probably as a consequence of systemic inflammation (Table 7). As per a study in Japan, gram-negative bacilli were significantly associated with prolonged hospitalization [24].

The severe category of patients who were discharged was put on telemedicine advice on pulmonary physiotherapy, medications, and home oxygen. Among them, the coinfection group had exacerbation that needed admission, and the rest of the cases were clinically stable (Table 8). There are not many studies that correlate the long-term outcome of acute exacerbation of COPD with infective causes. As per a review by Wang et al., it is observed that in cases where there is coinfection with bacteria and virus, the lung function impairment is greater and the duration of hospitalization is also longer [25]. In another study published in Lung India, where the outcomes were followed up for readmission for two years, 12% mortality was observed; readmission was seen in 54% of cases, and two or more readmissions were seen in 45% of cases [26].

Thus, a proportion of patients appear to be more susceptible to exacerbation. Hence, prevention and mitigation should be the key goals. The application of technological advancement in communication during the COVID pandemic enabled us to overcome the challenge through tailored prescription and telemedicine intervention.

Conclusions

The clinical course of COPD is punctuated by exacerbation. These events are associated with accelerated loss of lung function, poor quality of life, increased health care costs, and mortality. Infection is the most important cause of exacerbation. Klebsiella pneumoniae and Acinetobacter baumannii among the bacterial isolates and rhino and influenza A viruses among the viral isolates were predominantly detected. During the telehealth follow-up, it was observed that those patients who had co-infections were more prone to readmission, whereas those who had isolated bacterial or viral etiology had better clinical stability. Pulmonary physiotherapy and appropriate medical measures for the mitigation of exacerbation can prevent further decline of disease progression.



Source link

Background

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is not fully reversible.1 It is associated with chronic inflammation, both locally and systemically, which increases further during acute exacerbations (AEs).2 It has been known that some inflammatory biomarkers are associated with AE,3 disease progression, and severity of airflow obstruction.4–6 Identification of these biomarkers not only provides a method of predicting prognosis but also helps with better understanding of the pathogenesis of COPD.

A key modulator of inflammation and fibrosis development, as well as tissue injury,7 fibrinogenhas been approved by the US Food and Drug Administration as a COPD biomarker for severity assessment.8 Higher baseline fibrinogen is associated with increasing incidence of COPD, COPD hospitalization, and all-cause mortality9 and related to severity of COPD.10 One study found that fibrinogen level was higher during AE of COPD (AECOPD) and returned to baseline 40 days after exacerbation.11 Fifteen-year follow-up data from the CARDIA study of 2,132 individuals showed an association between higher fibrinogen and greater loss of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), regardless of smoking status.12 Other studies have suggested that increasing fibrinogen levels are associated with the occurrence of COPD complications.13,14 However, there has been little research on the role of fibrinogen during AECOPD and its association with noninvasive positive-pressure ventilation (NPPV). Our study aimed to explore whether circulating fibrinogen could be used as a surrogate to measure the severity and predict the prognosis of AECOPD.

Methods

Study Design and Participants

A total of 535 patients diagnosed with AECOPD at Beijing Chao-Yang Hospital (west campus) from January 2016 to June 2021 were retrospectively enrolled in this study. The patient-selection process is shown in Figure 1. The hospital’s ethics committee determined that this study qualified for waiving patient consent according to its policies, because it analyzed a large data set without patient identifiers, which is in compliance with the Declaration of Helsinki regarding patient-data confidentiality (2016-KE-95).

Figure 1 Patient-selection flowchart.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; NPPV, noninvasive positive-pressure ventilation; non-NPPV, no use of NPPV; NPPV-S, NPPVsuccess; NPPV-F, NPPVfailure.

Inclusion criteria were age ≥45 years, primary diagnosis of COPD determined by spirometry data of airflow obstruction with bronchodilator (FEV1/FVC <0.7, previous spirometry also considered, since a minority of patients had had pulmonary function tests during AE period), and admission to hospital due to AECOPD (defined as an acute worsening of respiratory symptoms requiring additional treatment). Indications for NPPV use during hospitalization were arterial blood pH <7.35 and/or PaCO2 >45 mmHg and/or presence of dyspnea at rest assessed using accessory respiratory muscles or paradoxical abdominal breathing.

Exclusion criteria were presence of other severe pulmonary diseases (such as severe bronchiectasis or pulmonary tuberculosis), end-stage chronic diseases (eg, chronic kidney failure, chronic heart failure, and malignancy) with <1 year of expected survival, requiring intubation before admission, incomplete data, and endotracheal intubation for other diseases (such as acute heart failure, kidney failure, and shock). For patients with multiple admissions during the study period, only the last was selected.

NIPPV failure was defined as worsening of pH and PaCO2 in arterial blood (defined as arterial pH <7.25 with PaCO2 increased by >20% compared with baseline or PaO2 <60 mmHg, despite maximum tolerated supplemental oxygen), clinical signs suggestive of severely decreased consciousness (eg, coma, delirium), excessive respiratory secretions with weak cough, use of accessory respiratory muscles or paradoxical thoracoabdominal movement, severe upper gastrointestinal bleeding with aspiration or vomiting, and severe hemodynamic instability despite fluid repletion and use of vasoactive agents.15

Data Collection

Baseline characteristics of age, sex, length of stay (LOS), heart rate, systolic pressure, diastolic pressure, temperature, respiratory rate, history of smoking, history of long-term oxygen therapy (LTOT), and history of domestic noninvasive ventilation (DNV) were recorded. In addition, data on comorbidities, ie, deep-vein thrombosis/pulmonary thromboembolism, emphysema, pneumonia, hypertension, diabetes, Cor pulmonale, chronic heart disease, atherosclerosis, chronic kidney disease, cerebrovascular disease, and other malignancies were collected. Arterial blood gas and peripheral venous blood (routine blood, CRP, and coagulation index <24 hours after admission) and the use of antibiotics and management of NPPV were also reviewed.

Concentration of serum fibrinogen was measured using immuno-scatter turbidimetry with a Werfen ACL Top 700. Normal fibrinogen levels are 2–4 g/L. Concentration of serum CRP were measured using immunoscatter turbidimetry with a Goldsite Aristo. Normal CRP levels are 0–5 mg/L. Parameters for noninvasive ventilation were set according to clinical practice and patients’ tolerance. An oronasal mask was used for all subjects. Arterial blood gas was intermittently analyzed by physicians according to clinical needs. When the patient reached the criteria for NPPV failure, a physician made the clinical decision (intubation or continuation of NPPV) based on laboratory data, symptoms, signs, and the inclination of the patients and their family members. The prognosis of each patient was recorded.

Statistical Analysis

Descriptive data are expressed as medians with IQRs or numbers with percentages as appropriate. Differences between groups were measured with the Mann–Whitney U test for continuous variables and x2 test for categorical variables. Spearman correlations were used for correlation analysis, and the results are displayed as correlation coefficients with P values. Multiple linear regression models were applied to identify independent risk factors of increasing fibrinogen levels. Differences in laboratory parameters among non-NPPV, NPPV-success (NPPV-S), and NPPV-failure (NPPF-F) groups were examined using the Kruskal–Wallis H test. Receiver-operating characteristic (ROC) curves were constructed to evaluate the ability of inflammatory markers to predict NPPV failure. For each ROC curve, the optimal cutoff, sensitivity, specificity, Youden’s index, area under the curve (AUC), and 95% CI were calculated. Logistic regression analyses with a conditional forward stepwise–regression model were used to determine whether any factors were independently associated with NPPV failure. All analyses were two-tailed, and differences were considered statistically significant at P<0.05. SPSS 21.0 was utilized for all statistical analysis.

Result

Baseline-Characteristic and Laboratory-Data Comparison Between Higher and Lower Fibrinogen Values

In sum, 1,925 AECOPD patients were screened and 535 selected. Among the latter, 312 (58.3%) were not managed with NPPV and 223 (41.7%) received NPPV management. Of all patients managed with NPPV, 177 (79.4%) were categorized as NPPV-S and 46 (20.6%) NPPV-F (Figure 1). In the NPPV-F group, 20 patients were intubated and 26 not, with three and 18, respectively, dying (Figure 1).

No significant differences in terms of age, sex, LOS, systolic pressure, temperature, smoking history, pH, PaCO2, HCO3, or BMI were identified between patients with low (≤4 g/L) and high (>4 g/L) fibrinogen levels. However, as suggested in Table 1, patients with higher fibrinogen (>4 g/L) presented faster heart beats and respiratory rates. There were more patients managed with LTOT and DNV in the high-fibrinogen group than the low-fibrinogen group. DVT/PTE, emphysema, pneumonia, and atherosclerosis were more commonly observed among patients with >4 g/L fibrinogen. In addition, increased CRP levels and leukocyte and neutrophil counts, decreased lymphocyte counts and PaO2/FiO2, and more frequent use of antibiotics were observed among patients with increased fibrinogen.

Table 1 Baseline characteristics of AECOPD subjects according to fibrinogen value

Next, we examined differences among the non-NPPV, NPPV-S, and NPPV-F groups and discovered that patients in the NPPV-F group had higher levels of fibrinogen, CRP, leukocytes, and neutrophils including those in the non-NPPV and NPPV-S groups (Figure 2). In addition, there were significant differences among the non-NPPV, NPPV-S, and NPPV-F groups in terms of lymphocytes, pH, PaCO2, and PaO2/FiO2. For HCO3 levels, there were differences between the non-NPPV and NPPV-S groups and non-NPPV and NPPV-F groups, but none between the NPPV-S and NPPV-F groups.

Figure 2 Laboratory-parameter comparisons among non-NPPV, NPPV-S, and NPPV-F. (A) Comparison of fibrinogen. (B) Comparison of CRP. (C) Comparison of leukocyte between non-NPPV, NPPV-S and NPPV-F. (D) Comparison of neutrophils. (E) Comparison of lymphocytes. (F) Comparison of pH. (G) Comparison of PaCO2. (H) Comparison of PaO2/FiO2. (I) Comparison of HCO3.

Abbreviations: non-NPPV, no use of noninvasive ventilation; NPPV-S, noninvasive ventilation success; NPPV-F, noninvasive failure.

Risk Factors of Increased Fibrinogen Levels During AECOPD

Table 2 shows positive correlations between fibrinogen levels and heart rate (x=0.130, P=0.003), respiratory rate (x=0.098, P=0.023), CRP (x=0.461, P<0.001), leukocytes (x=0.280, P<0.001), neutrophils (x=0.316, P<0.001), and PaCO2 (x=0.098, P=0.024). Negative correlations between fibrinogen and lymphocytes (x=−0.144, P=0.001) and PaO2/FiO2 (x=−0.147, P=0.001) were identified. In the multiple linear regression model, we included emphysema, pneumonia, atherosclerosis, LTOT, DNV, HR, RR, CRP, leukocytes, neutrophils, lymphocytes, PaCO2, and PaO2/FiO2 as covariates and found that emphysema, pneumonia LTOT, CRP, and leukocytes were independent factors associated with circulating fibrinogen levels during AECOPD (R2=0.302, P<0.001; Table 3).

Table 2 Correlations between fibrinogen levels and baseline characteristics/laboratory results

Table 3 Multiple linear regression analysis of fibrinogen

Risk Factors of NPPV Failure

The ROC curves for fibrinogen, CRP, leukocytes, neutrophils, and lymphocytes in the NPPV-F group are presented in Figure 3. As shown in Table 4, the AUC for fibrinogen (0.899, 95% CI 0.846–0.952) was higher than those for CRP (0.71, 95% CI 0.625–0.795), leukocytes (0.724, 95% CI 0.637–0.812), neutrophils (0.795, 95% CI 0.724–0.867), and lymphocytes (0.792, 95% CI 0.707–0.876). Cutoffs for predicting NPPV-F were fibrinogen >3.55 g/L, CRP >17 mg/L, leukocytes >8.05×109/L, neutrophils >6.72×109/L, and lymphocytes <0.68×109/L. Associations between NPPV-F and clinical parameters were analyzed by multivariate logistic regression, and the results showed that fibrinogen (OR 7.702, 95% CI 2.984–19.875) was independently associated with NPPV-F (Figure 4).

Table 4 ROC-curve data

Figure 3 ROC curve of fibrinogen, CRP, leukocytes, neutrophils, and lymphocytes for predicting NPPV failure.

Abbreviation: ROC, receiver-operating characteristic.

Figure 4 ORs for NPPV failure.

Abbreviations: LTOT, long-term oxygen therapy; DVT/PTE, deep-vein thrombosis/ pulmonary thromboembolism; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen.

Discussion

In this study, we found that 16.1% (n=86) of patients in the current study had fibrinogen >4 g/L, which was associated with a more robust inflammatory response. The fibrinogen level during AECOPD was related to CRP expression and leukocyte counts, as well as the presence of LTOT, emphysema, and pneumonia. Among those managed with NPPV, circulating fibrinogen (OR 7.702, 95% CI 2.984–19.875; P<0.001) was the independent factor predicting NPPV-F in the laboratory data.

Synthesized mainly by the liver and converted into fibrin by thrombin during blood coagulation,16 fibrinogen is a major acute-phase reactant, and its synthesis is upregulated in response to inflammation. Polatli et al discovered that the level of fibrinogen during AECOPD (4.48±1.28 mg/L) was higher than in stable periods (3.49±0.92 mg/L).17 However, Valipour et al found no difference in fibrinogen between stable COPD (4.24 g/L) and AECOPD (4.19 g/L).18 Since the current study did not include data prior to hospitalization and focused on the AE period only, we were not able to compare differences in fibrinogen levels between stable COPD and AECOPD; therefore, conclusions drawn from this study should be applied to the AECOPD population only.

Elevated fibrinogen induces a state of hypercoagulability that may lead to the progression of thrombosis.19 In this study, the incidence of DVT/PET during AECOPD was 6.7% overall, and more patients developed DVT/PTE in the high-fibrinogen group than the low-fibrinogen group. Furthermore, the incidence of atherosclerosis was much higher in the >4 g/L fibrinogen group. A multicenter prospective observational study based in China of 1,144 AECOPD patients showed that 78 (6.8%) were diagnosed with VTE, including 24 PE, 64 DVT, and ten combined PE and DVT,20 which is consistent with our results. A meta-analysis involving 3,170 AECOPD patients showed that the prevalence of PTE and DVT in AE-COPD patients was 17.2% and 7.1%, respectively.21 However, the link between fibrinogen and DVT/PTE is unclear, since Watz et al found that fibrinogen was inversely associated with levels of physical activity,14 and the lack of physical exertion is itself a risk factor of the development of DVT/PTE. AECOPD patients tend to have reduced physical exercise due to respiratory dysfunction and/or muscle weakness, which could partly contribute to higher levels of fibrinogen.22 Also, COPD is characterized by excessive activation of neutrophils in both stable and AECOPD periods, and neutrophil extracellular traps (NETs), a defense mechanism of neutrophils, have been demonstrated to play an important role in atherosclerosis and thrombosis.23 In the current study, there was a significant positive correlation between neutrophil counts and fibrinogen, which might explain the presence of atherosclerosis and DVT/PTE being higher in the AECOPD individuals with increased levels of fibrinogen. Further study will be required to elucidate associations among the incidence of COPD comorbidity, fibrinogen levels, and neutrophil counts.

It has been suggested that fibrinogen levels >3.93 g/L can predict COPD-related hospitalization. In a COPD-related study of 20,192 subjects, mean fibrinogen was 3.07 g/L and 10% of the sample had levels >3.93 g/L.9 Singh et al used 3.5 g/L as a cutoff to predict AE, and the ratios were 1.03 for moderate exacerbations, 1.08 for moderate/severe exacerbations, and 1.30 for severe exacerbations.24 In the current study, we grouped the patients using a cutoff of 4 g/L. Mean fibrinogen was 3.33 g/L, and 16.1% of the patients had levels >4 g/L. Differences in mean numbers and percentages of patients with high fibrinogen between this and other studies might be due to the fact that the current study included only AECOPD individuals. Valvi et al9 included not only AECOPD subjects but also stable ones, individuals with respiratory symptoms in the absence of any lung-function abnormality, and even healthy controls. The current study demonstrated that AECOPD patients with >4 g/L fibrinogen had a more robust inflammatory response and that it is possible that fibrinogen could be used as a marker of ongoing airway inflammation.

This study revealed that emphysematous AECOPD patients tended to have higher levels of fibrinogen and that the presence of emphysema can significantly affect fibrinogen level. It has been proved that the end product of fibrinogen is elevated in emphysematous stable COPD compared to patients without emphysema.25 Papaioannou et al reached a similar conclusion that among stable COPD individuals, those with emphysema were prone to have higher plasma-fibrinogen levels.26 Fibrinogen combined with other biomarkers is highly predictive of emphysema and associated with progression of emphysema.27 Emphysema is a key contributor to airflow limitation in COPD individuals, and fibrinogen itself is closely related to faster decline in lung function;28 therefore, there might be an association between fibrinogen and emphysema, but the mechanism and causality of the association is not well established. In the current study, patients with elevated ibrinogen (>4 g/L) had significantly lower PaO2/FiO2, and patients managed with LTOT and DNV at baseline had increased fibrinogen, which could be partially attributable to the fact that higher circulating fibrinogen correlated with the emphysema. According to the natural disease progression of COPD, individuals with progressive emphysema were prone to have an advanced stage of airway and lung-parenchyma inflammatory response, which could lead to worse gas-exchange functioning, and were more likely to require oxygen therapy and noninvasive ventilation support. In the future, studies on whether anti-fibrinogen agents could slow the progression of emphysema should be conducted for further evaluation of the association between fibrinogen and emphysema.

Another independent factor that can affect fibrinogen levelse during AECOPD is the presence of pneumonia. One study demonstrated that inflammatory response was different between infection-induced AECOPD and uninfectious AECOPD.29 Patients with moderate–severe COPD who have pathogenic microorganisms (PPMs) in their sputum have an exaggerated airway inflammatory response and higher levels of plasma fibrinogen than subjects with non-PPMs in their sputum.30 It has been found that fibrinogen was significantly higher in the presence of purulent sputum, a symptomatic cold, or increased cough among AECOPD patients.31 Furthermore, it has been demonstrated that fibrinogen increases threefold during acute-phase stimulation in response to increased IL6 production,32,33 which is commonly observed in community-acquired pneumonia-associated AECOPD patients.34,35 The fact that the presence of pneumonia contributed to a higher level of fibrinogen makes it a reasonable assumption that patients with fibrinogen >4 g/L had higher inflammatory response and more frequent use of antibiotics.

Failure of noninvasive ventilation was associated with increased mortality among AECOPD patients, and the current study showed that fibrinogen might be used in identifying those at great risk and who may therefore benefit from more aggressive treatment like early intubation. It has been demonstrated that low molecular–weight heparin significantly reduces fibrinogen and mean duration of mechanical ventilation among AECOPD individuals.36 We found that fibrinogen is an independent risk factor of NPPV-F with an AUC value higher than other traditional inflammatory markers, including CRP, leukocytes, neutrophils, and lymphocytes. This finding was not surprising, considering the fact that an inverse correlation between circulating fibrinogen and FEV1 has been proved in previous studies already,28,37,38 and the fact that fibrinogen can reflect the severity of AECOPD.24 Correlations between the incidence of domestic noninvasive ventilation and fibrinogen value and between PaCO2 and fibrinogen in this analysis showed that AECOPD individuals with higher fibrinogen tended to have worse ventilation function. Pathogens of airway colonization were associated with higher fibrinogen than those with no detectable airway pathogens in two small studies.30,39

Pillay et al found that increased circulating concentrations of fibrinogen during the acute-phase response can act as a natural antagonist of neutrophil recruitment by inhibiting neutrophil adhesion,40 which is an essential step in its antimicrobial function. This imbalance between pathogen overload and suppression of neutrophil immunofunction made the inflammatory response during AECOPD more intense, which was reflected by higher CRP, leukocytes, and neutrophils. Although the cutoff value for fibrinogen to predict NPPV failure was 3.55 g/L, less than 4 g/L, in Table 2 the median fibrinogen value of NPPV-F patients was 4.10 g/L, which was higher than that of non-NPPV and NPPV-S individuals. The NPPV-F population included in this study was relatively small (n=46), and maybe the cutoff for fibrinogen deduced from a large population would be different. Collectively, fibrinogen levels suggested reduced ventilation functioning together with more intense inflammation, which might eventually contribute to NPPV-F among AECOPD individuals.

Given the evidence of an association between fibrinogen and the incidence of COPD, presence of exacerbations, and mortality, certain anti-inflammatory drugs targeting fibrinogen may shed new light on the treatment of COPD. A p38 MAPK inhibitor was showed to reduce plasma fibrinogen by 11% in individuals with stable COPD after a 3-month treatment.41 Clinically relevant improvement accompanied by a decline of fibrinogen should be further determined, but the effect on the level of fibrinogen may suggest the potential utility of biomarkers in response to treatment and help the physician to identify individuals who might benefit from certain interventions.

Limitations

A number of limitations must be acknowledged in the current study. Firstly, it was a single-center retrospective observational study with a small sample, and thus our results may not be generalized to a broader population. Secondly, a substantial proportion of pulmonary function data was missing, because most AECOPD patients were not able to undergo a spirometry test during their hospital stay. Thirdly, NPPV-related data, such as pressure and tidal volume, were unavailable, since they are not collected routinely in clinical settings.

Conclusion

The current study suggested that circulating fibrinogen value during AECOPD strongly correlated with traditional inflammatory markers and can reflect the severity of systematic inflammatory response. Increased fibrinogen may indicate a need for antibiotics. Moreover, fibrinogen was a better marker for predicting NPPV-F than traditional inflammatory ones, and this indicated that it might be used for identifying AECOPD patients who may not benefit from NPPV. However, further study with a larger sample is needed to determine whether using fibrinogen as a biomarker to assess AECOPD individuals could actually result in clinical benefit.

Abbreviations

Fib, fibrinogen; LOS, length of stay; HR, heart rate; SP, systolic pressure; DP, diastolic pressure; RR, respiratory rate; LTOT, long-term oxygen therapy; DNV, domestic noninvasive ventilation; DVT/PTE, deep-vein thrombosis/pulmonary thromboembolism; PaCO2, partial pressure of carbon dioxide; PaO2, partial pressure of oxygen; FiO2, fraction of inspired oxygen; HCO3, bicarbonate; BMI, body-mass index; non-NPPV, no use of noninvasive ventilation; NPPV-S, noninvasive ventilation success; NPPV-F, noninvasive failure; ROC, receiver-operating characteristic; AUC, area under the curve.

Data Sharing

The data sets used and/or analyses during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The study protocol was approved by the Institutional Review Board for Beijing Chao-Yang Hospital (2016-KE-95) and conducted according to the principles of the Declaration of Helsinki. The need to obtain informed consent was waived, due to the retrospective nature of the study.

Author Contributions

All authors made a significant contribution to the work reported, whether in conception, study design, execution, acquisition of data, analysis and interpretation, or all these areas, took part in drafting, revising, or critically reviewing the article, gave final approval to the version to be published, have agreed on the journal to which the article has been submitted, and agree to be accountable for all aspects of the work.

Funding

This work was funded by the National Key Research and Development Program of China (grant 2019YFC0121700) and Beijing Hospitals Authority Youth Programme (grant QML20180303).

Disclosure

The authors declare that they have no competing interests in this work.

References

1. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347–365. doi:10.1164/rccm.201204-0596PP

2. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86. doi:10.1016/j.ccm.2013.10.004

3. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–1138. doi:10.1056/NEJMoa0909883

4. Celli B, Locantore N, Yates JC, et al. Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort. Eur Respir J. 2021;57(3):2001339. doi:10.1183/13993003.01339-2020

5. Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(6):1008–1011. doi:10.1164/ajrccm.164.6.2010067

6. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250–255. doi:10.1164/rccm.200605-713OC

7. Wang J, Pathak R, Garg S, Hauer-Jensen M. Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy. World J Gastroenterol. 2017;23(26):4701–4711. doi:10.3748/wjg.v23.i26.4701

8. Available from: www.copdfoundation.org/PressRoom/ArticlesPressReleases/News/187.aspx. Accessed May 23, 2022.

9. Valvi D, Mannino DM, Mullerova H, Tal-Singer R. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis. 2012;7:173–182. doi:10.2147/COPD.S29892

10. Garcia-Rio F, Miravitlles M, Soriano JB, et al. Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res. 2010;11:63. doi:10.1186/1465-9921-11-63

11. Koutsokera A, Kiropoulos TS, Nikoulis DJ, et al. Clinical, functional and biochemical changes during recovery from COPD exacerbations. Respir Med. 2009;103(6):919–926. doi:10.1016/j.rmed.2008.12.006

12. Kalhan R, Tran BT, Colangelo LA, et al. Systemic inflammation in young adults is associated with abnormal lung function in middle age. PLoS One. 2010;5(7):e11431. doi:10.1371/journal.pone.0011431

13. Fowkes FG, Anandan CL, Lee AJ, et al. Reduced lung function in patients with abdominal aortic aneurysm is associated with activation of inflammation and hemostasis, not smoking or cardiovascular disease. J Vasc Surg. 2006;43(3):474–480. doi:10.1016/j.jvs.2005.11.018

14. Watz H, Waschki B, Kirsten A, et al. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest. 2009;136(4):1039–1046. doi:10.1378/chest.09-0393

15. Cao Z, Luo Z, Hou A, et al. Volume-targeted versus pressure-limited noninvasive ventilation in subjects with acute hypercapnic respiratory failure: a multicenter randomized controlled trial. Respir Care. 2016;61(11):1440–1450. doi:10.4187/respcare.04619

16. Vilar R, Fish RJ, Casini A, Neerman-Arbez M. Fibrin(ogen) in human disease: both friend and foe. Haematologica. 2020;105(2):284–296. doi:10.3324/haematol.2019.236901

17. Polatli M, Cakir A, Cildag O, Bolaman AZ, Yenisey C, Yenicerioglu Y. Microalbuminuria, von Willebrand factor and fibrinogen levels as markers of the severity in COPD exacerbation. J Thromb Thrombolysis. 2008;26(2):97–102. doi:10.1007/s11239-007-0073-1

18. Valipour A, Schreder M, Wolzt M, et al. Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci. 2008;115(7):225–232. doi:10.1042/CS20070382

19. van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thrombos Haemost. 2003;1(12):2677–2678. doi:10.1111/j.1538-7836.2003.0543b.x

20. Pang H, Wang L, Liu J, et al. The prevalence and risk factors of venous thromboembolism in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease. Clin Respir J. 2018;12(11):2573–2580. doi:10.1111/crj.12959

21. Fu X, Zhong Y, Xu W, et al. The prevalence and clinical features of pulmonary embolism in patients with AE-COPD: a meta-analysis and systematic review. PLoS One. 2021;16(9):e0256480. doi:10.1371/journal.pone.0256480

22. Waschki B, Spruit MA, Watz H, et al. Physical activity monitoring in COPD: compliance and associations with clinical characteristics in a multicenter study. Respir Med. 2012;106(4):522–530. doi:10.1016/j.rmed.2011.10.022

23. Moschonas IC, Tselepis AD. The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis. Atherosclerosis. 2019;288:9–16. doi:10.1016/j.atherosclerosis.2019.06.919

24. Singh D, Criner GJ, Dransfield MT, et al. InforMing the PAthway of COPD treatment (IMPACT) trial: fibrinogen levels predict risk of moderate or severe exacerbations. Respir Res. 2021;22(1):130. doi:10.1186/s12931-021-01706-y

25. Manon-Jensen T, Langholm LL, Rønnow SR, et al. End-product of fibrinogen is elevated in emphysematous chronic obstructive pulmonary disease and is predictive of mortality in the ECLIPSE cohort. Respir Med. 2019;160:105814. doi:10.1016/j.rmed.2019.105814

26. Papaioannou AI, Mazioti A, Kiropoulos T, et al. Systemic and airway inflammation and the presence of emphysema in patients with COPD. Respir Med. 2010;104(2):275–282. doi:10.1016/j.rmed.2009.09.016

27. Zemans RL, Jacobson S, Keene J, et al. Multiple biomarkers predict disease severity, progression and mortality in COPD. Respir Res. 2017;18(1):117. doi:10.1186/s12931-017-0597-7

28. Jiang R, Burke GL, Enright PL, et al. Inflammatory markers and longitudinal lung function decline in the elderly. Am J Epidemiol. 2008;168(6):602–610. doi:10.1093/aje/kwn174

29. Lieberman D, Lieberman D, Gelfer Y, et al. Pneumonic vs nonpneumonic acute exacerbations of COPD. Chest. 2002;122(4):1264–1270. doi:10.1378/chest.122.4.1264

30. Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD. Eur Respir J. 2004;23(5):685–691. doi:10.1183/09031936.04.00056804

31. Wedzicha JA, Seemungal TA, MacCallum PK, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost. 2000;84(2):210–215. doi:10.1055/s-0037-1613998

32. Gabay C, Kushner I, Epstein FH. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–454. doi:10.1056/NEJM199902113400607

33. Mackiewicz A, Speroff T, Ganapathi MK, Kushner I. Effects of cytokine combinations on acute phase protein production in two human hepatoma cell lines. J Immunol. 1991;146(9):3032–3037.

34. Huerta A, Crisafulli E, Menéndez R, et al. Pneumonic and nonpneumonic exacerbations of COPD: inflammatory response and clinical characteristics. Chest. 2013;144(4):1134–1142. doi:10.1378/chest.13-0488

35. Damera G, Pham TH, Zhang J, et al. A sputum proteomic signature that associates with increased IL-1β levels and bacterial exacerbations of COPD. Lung. 2016;194(3):363–369. doi:10.1007/s00408-016-9877-0

36. Qian Y, Xie H, Tian R, Yu K, Wang R. Efficacy of low molecular weight heparin in patients with acute exacerbation of chronic obstructive pulmonary disease receiving ventilatory support. Copd. 2014;11(2):171–176. doi:10.3109/15412555.2013.831062

37. Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995–2004. doi:10.1378/chest.128.4.1995

38. Shibata Y, Abe S, Inoue S, et al. Relationship between plasma fibrinogen levels and pulmonary function in the Japanese population: the Takahata study. Int J Med Sci. 2013;10(11):1530–1536. doi:10.7150/ijms.7256

39. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(9):1618–1623. doi:10.1164/ajrccm.164.9.2105011

40. Pillay J, Kamp VM, Pennings M, et al. Acute-phase concentrations of soluble fibrinogen inhibit neutrophil adhesion under flow conditions in vitro through interactions with ICAM-1 and MAC-1 (CD11b/CD18). J Thrombos Haemost. 2013;11(6):1172–1182. doi:10.1111/jth.12250

41. Lomas DA, Lipson DA, Miller BE, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 2012;52(3):416–424. doi:10.1177/0091270010397050

Source link

Spontaneous pneumomediastinum (SPM) is a rare and self-limiting condition characterized by the presence of air in the mediastinum not related to trauma or surgical procedures [1]. Described by Laennec in 1819 as a complication of trauma, Hamman 120 years later published his case series of SPM. This condition typically affects young adults aged 20-30 years, with a male preponderance of 8:1. SPM is associated with other medical conditions, including asthma, connective tissue disease, interstitial lung disease, diabetic ketoacidosis, chronic obstructive airway disease, and influenza-like syndrome. [1] SPM is reported to develop in 10% of cases of intubated COVID-19 with acute respiratory distress syndrome (ARDS) even with low tidal volume strategies [2,3]. One unmatched case control study of 271 patients showed the incidence of SPM among non-intubated acute COVID-19 patients at 3.3%, similar to our patient [4]. The case we described would fit into this group. 

The cause of COVID-19, SARS-CoV 2, is a novel coronavirus associated with wide heterogeneity in clinical presentation ranging from asymptomatic to critical illness. The first infection was detected in late 2019 in Wuhan, China, after which it rapidly spread worldwide. Mortality was high among those with advanced age and significant comorbidities. The acute phase of COVID-19 infection lasts approximately three to four weeks. After four weeks of infection, SARS-CoV 2 no longer has the capability to replicate, and residual illness in this stage is called the post-acute COVID-19 syndrome [5]. Symptoms associated with the infection may persist, such as lethargy, easy fatigability, and shortness of breath, with some requiring prolonged supplemental oxygenation. To our knowledge, the incidence and risk factors of SPM among patients who have recovered from COVID-19 infection, i.e., patients in the post-acute phase, is yet to be studied.

We present a case of SPM in a patient with post-acute COVID-19 syndrome who received high flow nasal oxygen therapy in the acute stages of the disease.

The patient was a 58-year-old Chinese gentleman who never smoked. He had a BMI of 29.4kg/m2 and was fully vaccinated for COVID-19 (last dose was given three months prior to admission). He was admitted to the emergency room complaining of a productive cough accompanied by shortness of breath. A nasal pharyngeal swab for polymerase chain reaction (PCR) detecting SARS‐CoV‐2 ribonucleic acid (RNA) resulted in a positive. His significant medical history included hypertension and hyperlipidemia. He had no prior trauma, asthma history, diabetes, pulmonary tuberculosis, or connective tissue disease.

On admission, physical examination showed decreased breath sounds on both lungs and diffuse systolic murmur. He was febrile at 38 degrees Celsius, with a blood pressure of 114/77mmHg, heart rate of 143 per minute, and respiratory rate of 35 per minute. Oxygen saturation was at 89% on 100% non-rebreather mask. Arterial blood gas showed type 1 respiratory failure with a P/F ratio of 46. Therefore, we decided to start oxygen therapy with a high-flow nasal cannula (HFNC) (FiO2: 100%, flow: 60 L/min with SpO2: 96%). Initial chest X-ray (CXR) revealed right middle and lower zone patchy airspace opacities without pleural effusion or pneumothorax (Figure 1).

The full blood count showed a white blood cell count (WBC) of 6.95x10^9/L, hemoglobin 15.2g/dL, platelets 191x10^9/L, C-Reactive protein (CRP) 151.1mg/L (N=1.0-5.0mg/L), procalcitonin 1.2ng/mL (N=0.5 to 2.0ng/mL), serum lactate 1.9mmol/L (N=0.6-1.4mmol/L), serum urea 6.8mmol/L (N=2.4 to 6.6mmol/L) and beta-hydroxybutyrate 0.35mmol/L (N=0.02-0.27). His International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) 4C score was nine, signifying high risk and an in-hospital mortality of 31.4 to 34.9%. The patient was prescribed intravenous dexamethasone before transferring to medical intensive care unit (MICU).

In the medical intensive care unit, he received empiric intravenous amoxicillin-clavulanic acid and oral doxycycline. Blood cultures and sputum cultures, which were taken from endotracheal tube (ETT), were all reported as no bacterial growths. Fever persisted, and a repeat chest X-ray showed worsening bilateral airspace opacities. Antibiotics were escalated to intravenous piperacillin-tazobactam while on intravenous dexamethasone therapy. Blood cultures and sputum cultures were repeated and were negative. On day six of illness, he received the first dose of a five-day course of intravenous remdesivir. Due to persistent hypoxia, he received two doses of intravenous tocilizumab on day six and day 26 of illness.

He also developed starvation ketosis and revealed newly diagnosed diabetes mellitus with HbA1c of 8.1%. Subcutaneous (SC) intermediate-acting insulin (Insulatard) was prescribed. Thromboprophylaxis with subcutaneous enoxaparin was given during the pulmonary phase of the illness. The HFNC setting for the first 15 days was on maximum flow of 60L/min, with a taper to 40L/min on the remaining seven days. Initial FiO2 on HFNC was at 100%, with subsequent gradual weaning to 40% on day 28 of illness. On day 10 of illness, he received a trial of continuous positive airway pressure ventilation (CPAP), but HFNC was resumed as no significant improvement was seen on oxygenation. CRP levels improved from 151mg/L to 72.8mg/L, and by day 28 of illness, the CRP was at 4.4mg/L. The patient performed awake prone positioning to improve oxygenation.

On day 30 of illness, he was weaned off to a non-rebreather mask and managed to sustain adequate oxygen saturation on nasal cannula oxygenation at 5-liter oxygen. He was transferred to the general ward for rehabilitation. He remained afebrile and normotensive with a resting tachycardia at 100-110/min. Despite mild dyspnea and easy fatigability, oxygen saturations were at 98% on 4-liter oxygen nasal cannula. Intravenous dexamethasone was gradually tapered down.

On day 34 of illness, COVID-19 PCR with cycle threshold (CT) ratio was 33.34/33.37. Despite this, his saturations dropped to 77% while on 4-liter oxygen nasal cannula. He was put on 100% non-rebreather mask, and oxygen saturations increased to 96-99%. Repeat CXR showed stable bilateral diffuse airspace opacities with no evidence of pneumothorax. Repeat arterial blood gas revealed type 1 respiratory failure with a P/F ratio of 119 and CRP of 0.7mg/L. An electrocardiogram showed normal sinus rhythm at 73/min. A computed tomography pulmonary angiogram (CTPA) was arranged to rule out acute pulmonary embolism. SC enoxaparin was restarted at a therapeutic dose. The scan was negative for pulmonary embolism but detected a pneumomediastinum (PM), pneumopericardium (PP), and subcutaneous emphysema (Figure 2, 3). Respiratory medicine service recommended keeping him on non-rebreather mask oxygenation, and he was deemed a poor candidate for positive pressure ventilation in the event of current deterioration. On examination, he was alert tachypneic with bilateral scattered crackles in the middle and lower zones on auscultation. He developed subcutaneous emphysema at the neck but no change in the quality of his voice. After discussion with the patient and his family, he opted for maximum ward management in the event of further deterioration. The family was hopeful for his full recovery. On day 36 of illness, he developed atrial flutter with a pulse rate of 160bpm on 12-lead electrocardiography (ECG) with a blood pressure of 109/79mmHg. He received rate control measures, including intravenous amiodarone, oral bisoprolol, and digoxin, and his heart rate improved to sinus rhythm at 76bpm on 12-lead ECG.

On day 40 of illness, the patient was found unresponsive with pulseless electrical activity on the cardiac monitor. Cardiopulmonary resuscitation (CPR) was initiated and he was intubated by the on-call airway team. Despite the resuscitation team’s best efforts, no return of spontaneous circulation was achieved, and the patient was pronounced demised.

There are a number of mechanisms that lead to the development of spontaneous pneumomediastinum. First is the alveolar rupture secondary to inflammation and diffuse alveolar pressures due to coughing. The escaping air from the ruptured alveoli tracks along the bronchovascular sheaths, dissecting into the pulmonary hila and escaping into the mediastinal space. This is seen on thoracic computed tomography scans demonstrating the Macklin effect, described as linear collections of air continuous to the bronchovascular sheaths dissecting into the pulmonary hilum [6]. Second is the direct viral invasion of the lung parenchyma, visceral and parietal pleura causing disruption of the parenchymal and pleural integrity or ruptured alveoli leading to subsequent air leak [7]. Third is the prothrombotic effect of COVID-19 infection-causing pulmonary vascular thrombosis and subsequent necrosis in the alveolar membranes. Fourth is cytokine storm-induced diffuse alveolar injury or direct viral infection of type 1 and type 2 pneumocytes increasing the risk of alveolar rupture [3].

COVID-19 related SPM affects an older population aged 38-72 years of age versus 5-34 years for non-COVID SPM [8]. COVID-19 related SPM has been associated with a more severe course of the disease and a mortality rate of 28.5% versus non-COVID SPM, which has an estimated mortality rate of 5.6% [1].

We highlight the risk of SPM, PP, and subcutaneous emphysema developing in COVID-19 patients without the usually associated conditions who did not receive invasive positive pressure ventilation at the post-acute phase of the disease. We also hope this launches further investigations comparing the non-invasive and invasive modalities of oxygen supplementation and the respective settings for severe COVID-19 to achieve the optimal oxygenation profile while minimizing the risk of barotrauma and PP and PM. We also anticipate more studies that look into developing multidisciplinary treatment protocols for patients who develop COVID-19 related PP and PM. The question is: which modality achieves optimal oxygenation while minimizing the risk of barotrauma and SPM? 



Source link

Huajing Yang,1,&ast; Zihui Wang,1,&ast; Shan Xiao,1 Cuiqiong Dai,1 Xiang Wen,1 Fan Wu,1,2 Jieqi Peng,1 Heshan Tian,1 Yumin Zhou,1,2 Pixin Ran1,2

1National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China

Correspondence: Pixin Ran; Yumin Zhou, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86 2083205187, Fax +86 20-81340482, Email [email protected]; [email protected]

Background: The effect of serum uric acid (SUA) levels on lung function in chronic obstructive pulmonary disease (COPD) people remained unclear. We aimed to investigate the association between SUA and lung function.
Methods: A cross-sectional study was performed to measure the SUA levels and lung function in 2797 consecutive eligible individuals. Of these, individuals in our study were divided into two groups, the COPD group (n=1387) and the non-COPD group (n=1410). The diagnosis of COPD is defined as post-bronchodilator first second of forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio of less than 0.70. Multivariable adjustment linear models were applied to estimate the effect of SUA levels on FEV1% predicted, FVC% predicted, and FEV1/FVC stratified by COPD status.
Results: After multivariable adjustment, each 1 mg/dL increase of SUA was significantly associated with a decrease in FEV1% predicted (− 1.63%, 95% confidence interval [CI] − 2.37 to − 0.90), FVC % predicted (− 0.89%, 95% CI − 1.55 to − 0.24), and FEV1/FVC (− 0.70%, 95% CI − 1.10 to − 0.30). In the COPD group, each 1 mg/dL increase of SUA was significantly associated with decreases in FEV1% predicted (− 1.87%, 95% CI − 2.91 to − 0.84), FVC% predicted (− 1.35%, 95% CI − 2.35 to − 0.34), and FEV1/FVC (− 0.63%, 95% CI − 1.18 to − 0.08). However, no significant association between lung function and SUA was found among people without COPD.
Conclusion: High SUA levels were associated with lower lung function, especially in COPD patients. However, no statistically significant effect of SUA on lung function was found in people without COPD.

Introduction

Serum uric acid (SUA) is the final breakdown product of purines or purine-containing compounds and is present at high concentrations in the epithelial lining fluid of the airway and in plasma.1–3 SUA has the double-edged characteristic of having antioxidant properties as well as pro-oxidant and pro-inflammatory properties.4,5 Based on these characteristics, there are complicated interpretations of whether SUA has a beneficial or noxious effect on lung function.6–8 An experimental study revealed that high SUA levels could improve emphysematous phenotype and lung dysfunction by reducing oxidative stress in mice with chronic obstructive pulmonary disease (COPD), and also found no significant effects of SUA on the lung function in non-diseased mice.9 What they found suggests that SUA levels may only affect lung function in individuals with impaired lung tissue but not normal lung structure.

Impairment of lung tissue reduces oxygen intake, which may result in tissue hypoxia. Tissue hypoxia elevates the SUA levels by inducing the degradation of adenosine.10 Previous studies have found a negative association between SUA levels and measures of lung function, such as forced vital capacity (FVC) and the first second of forced expiratory volume (FEV1) in individuals with COPD.8,11 Another study found no effect of SUA on lung function in the same population.12

For the population with normal lung structure, the effect of high SUA levels on lung function have been conflicting in cross-sectional studies; while a positive effect was found in a large Korean population (n=69,928) without any clinical diseases,6 a negative effect was observed in the Korean National Health and Nutrition Examination Survey,13 and also no significant effect was found in young adults aged 22–29 years.14

Current researchers have paid greater attention to differential effects of SUA on lung function stratified by smoking status15 or gender status,13 but no attention to respiratory disease status. To the best of our knowledge, this is the first epidemiological study focusing on the different effects of SUA on lung function in individuals with or without COPD. In currently available research, the relationships between SUA and lung function stratified by COPD status are not well-characterized for reasons of different populations and the heterogeneous analysis methods among others.

Based on this, our study aimed to identify the relationship between SUA and lung function in individuals with or without COPD.

Methods

Study Population and Blood Tests

Our study applied the baseline data set of a cohort study of people with chronic airway disease in Guangdong, China (ChiCTR1900024643), which was a population-based, multicenter randomized survey of COPD, conducted from June 2019 to June 2021. This study included people: 1) people aged over 30 years old; 2) people who had signed informed consent; 3) who returned complete COPD-related questionnaires; 4) who had undergone the standardized spirometry; 5) who had completed blood tests. Exclusion criteria were the following: 1) a history of malignancy; 2) acute inflammatory diseases or infectious diseases (such as pneumonia, bronchiectasis with infection and active pulmonary tuberculosis); 3) acute exacerbation of COPD within four weeks; 4) cardiovascular or chronic pulmonary diseases (such as hypertension, asthma, bronchiectasis, pneumoconiosis, and interstitial lung diseases), which can affect SUA levels.

Initially, a total of 3160 study subjects were considered as eligible subjects and included in our study. After excluding those without a laboratory examination (n=118), without a complete questionnaire (n=62) and lacking available spirometry data (n=183), 2797 participants were enrolled in our study (Figure 1). Invited participants were required to undergo anthropometric measurement, the spirometer examination, laboratory assessment, and also answered COPD related-questionnaires. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No.2018–53). All participants gave written informed consent. This present study was in line with the principles of the Declaration of Helsinki.

Figure 1 Study flow chart.

Blood samples were obtained from invited participants after 12 h of fasting. SUA levels were determined by the uricase-peroxidase method and by the creatinase-peroxidase method, respectively.16

Outcome Definitions

Invited participants were required to complete a questionnaire based on the questionnaires from the International Burden of Obstructive Lung Disease Study17 and a 2007 Chinese epidemiological study,18 that included potential risk factors for COPD and also chronic respiratory symptoms (such as cough, phlegm production, and dyspnoea). The technicians who were responsible for administering this questionnaire had been strictly trained and also passed a training test. The presence of cough was assessed with “Do you usually cough for three consecutive months or more per year for two years? ” Phlegm production was assessed with “Do you usually bring up phlegm for three consecutive months or more per year for two years?” Dyspnoea was assessed with “Have you had shortness of breath either when walking up a slight hill or brisk walking on the level?”

Lung Function Measures

Participants aged over 30 years were required to finish standardized spirometry. Participants who were physically incapable of taking standardized spirometry (ie, thoracic, abdominal, or eye surgery, retinal detachment or myocardial infarction in past three months; pregnant or breastfeeding; antibacterial chemotherapy for tuberculosis) were excluded.19 Before and after bronchodilator spirometries were performed by using a portable spirometer (CareFusion MasterScreen Pneumo, Germany) according to the European Respiratory Society/American Thoracic Society standards (ERS/ATS 2005).19 Manoeuvre of American Thoracic Society quality grade C or above were acceptable for analysis.20 Standardized spirometry was conducted during the summer, from 2019 to 2020. The diagnosis of COPD is defined by post-bronchodilator (Salbutamol Sulfate Aerosol, 400 μg, 20 min later) FEV1/FVC ratio of less than 0.70.21 The predicted value for FVC and FEV1 is calculated according to the Report Working Party Standardization of lung function tests,22 adjusted by an equation obtained in a representative Chinese population.23

Covariate Definitions

We collected demographic data, including sex, age, and also body index mass (BMI). Never smokers were defined as adults who reported having smoked less than 100 cigarettes in their lifetime. Current smokers were defined as adults who reported having smoked more than 100 cigarettes in their lifetime and also currently smoke some days or every day. Former smokers were defined as adults who reported having smoked more than 100 cigarettes in their lifetime but quit smoking more than three months.

Statistical Analyses

The normality of distribution of variables was evaluated with the Kolmogorov–Smirnov test. Continuous variables were exhibited as the mean ± SD when in a normal distribution, and as medians (interquartile ranges) when in a skewed distribution. Student’s t-test was applied to compare differences among individuals with and without COPD. Categorical variables were expressed as numbers (percentages), and the Chi-square test or Fisher’s exact test were used to assess the inter-group difference. Continuous SUA values were also transformed into categorical variables according to their terciles. The ANOVA test was applied to investigate the significant differences between different SUA- levels groups.

Binary logistic models were applied to investigate the relationships between the SUA levels, the presence of COPD, and the chronic respiratory symptoms (cough, phlegm production, and dyspnea), either adjusted or unadjusted sex, age, smoking status, cumulative tobacco smoking, and body mass index (BMI). To investigate the different effects of SUA on lung function, we also conducted a multivariate analysis among individuals with or without COPD. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate the strength of this association.

Multivariable adjustment linear models were implied to estimate the effect of SUA levels on FEV1%, FVC%, and FEV1/FVC. We also tested the assumptions of normality, linearity, and homoscedasticity graphically by using plots of observed versus predicted values as well as also plots of residuals versus predicted values or the observed exposure values. No major violations were found.

In the sensitivity analysis, the same analyses were performed in the different groups by smoking statuses to explore any differential effects of SUA based on smoking status. Analyses of the gender subgroups were also conducted. The relationship between SUA and spirometer measurement after bronchodilators was also estimated.

All tests were two-sided, and p-values less than 0.05 were considered statistically significant. Data were analyzed using R statistical software (version 4.1.0).

Results

Study Population

A total of 2797 participants who met inclusion criteria and had available data were enrolled in our study, including 1410 (50.41%) non-COPD subjects and 1387 (49.58%) COPD patients. The clinical characteristics and biochemical biomarkers of invited participants are presented in Table 1. Participants were divided into two groups based on their current status of COPD. Significant differences between the two groups were found, such as sex, age, BMI, smoking status, pre-bronchodilator spirometric values, and also chronic respiratory symptoms. Additionally, overall SUA levels were higher in individuals with COPD, as 4.17 ± 1.10 mg/dl, versus 3.79 ± 1.14 mg/dl in the non-COPD group (Table 1; Figure 2). Individuals with high SUA levels were older, with higher values of BMI, and more likely to be current smokers compared to individuals in the lowest SUA group. Those in the highest terciles were also more likely to have lower FEV1% predicted, lower FVC % predicted, and low FEV1/FVC. Compared to the lowest SUA tertiles, individuals in the two highest terciles were more likely to report a risk of cough, phlegm production, and also dyspnoea.

Table 1 The Association of Baseline Participant Characteristics with SUA and COPD (N=2797)

Figure 2 Serum uric acid levels in people with and without chronic obstructive pulmonary disease. ***p value less than 0.001.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease.

Uric Acid and COPD

Unadjusted logistic regression analysis showed no significant effect of SUA on the prevalence of COPD (unadjusted OR,1.33; 95% CI 1.25 to 1.44) (Table 2). After multivariable adjustment, the OR (95% CI) of the prevalence of COPD was 1.15 (95% CI 1.06 to 1.25) with p-value less than 0.001 per 1 mg/dL increase of SUA (Table 2; Figure 3). Similar results were also found both in the never-smoker and ever-smoker groups (online supplementary Figure A1), but not in the female population (online supplementary Figure A2).

Table 2 Association Between SUA, Lung Function and Chronic Respiratory Symptom in People with or Without COPD

Figure 3 Association of SUA levels with study outcomes. Shown are odds ratio or estimate effect for each outcome for each 1 mg/dl increase in serum uric acid, adjusted for age, sex, BMI, smoking status, and cumulative tobacco consumption. Bold values means that all participants were in the analysis. *p value less than 0.05.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease; FEV1% predicted, percent predicted forced expiratory volume in 1 s; FVC% predicted, percent predicted forced vital capacity; 95% CI, 95% confidence interval.

Uric Acid and Lung Function

After multivariable adjustment, each 1 mg/dl increase of SUA was associated with a 1.63% decrease in FEV1% predicted (95% CI −2.37 to −0.90) (Table 2; Figure 3; Figure 4). Each 1 mg/dl increase of SUA was significantly associated with a 1.87% (95% CI −2.91 to −0.84) decrease in FEV1% predicted, but no significant relationship was found in the non-COPD group (0.39%,95% CI −1.18 to 0.40). After multivariable adjustment, each 1 mg/dl increase of SUA levels was associated with a −0.89% decrease (95% CI −1.55 to−0.24) in FVC % predicted. Similar results were found in the COPD group, (−1.35% [95% CI −2.35 to −0.34]) but not in the non-COPD group (−0.42% [95% CI −1.26 to 0.43]). Additionally, after multivariable adjustment, each 1 mg/dL increase in SUA levels was associated with a −0.7% (95% CI −1.10 to −0.30) decrease in FEV1 /FVC. Each 1 mg/dl increase in SUA was associated with a 0.63% decrease in FEV1 /FVC in the COPD group, while no significant association between SUA levels and FEV1 /FVC was found in the Non-COPD group (p-value 0.987). The associations between SUA levels and lung function after using bronchodilators were also evaluated, with similar results were found (online supplementary Figure A3.).

Figure 4 Regression of lung function on SUA in people with or without COPD. The analysis was multi-variable adjusted for age, sex, BMI, smoking status, and cumulative tobacco consumption. Regression values in the top and 95% CIs were shown as the shaded area around the regression line.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease; FEV1% predicted, percent predicted forced expiratory volume in 1 s; FVC% predicted, percent predicted forced vital capacity.

Uric Acid and Symptoms of Airway Disease

The OR of dyspnea was 1.12 (95% CI 1.05 to 1.21) with each 1 mg/dl higher SUA (Table 2; Figure 3). This association remained significant after adjustment for potential confounders. People with COPD had a higher risk of dyspnea than did those without COPD (adjusted ORs, 1.11 in the COPD group and 1.07 in the non-COPD group). No significant effect of SUA on dyspnoea was found in the non-COPD group (adjusted OR,1.00; 95% CI 0.88 to 1.13).

Discussion

This observational study analyzed 1387 individuals (49.58%) with COPD. Individuals with COPD had significantly higher SUA levels than did individuals without COPD (4.17 ± 1.10 vs 3.79 ± 1.14, respectively). In addition, we found that increased SUA levels were significantly associated with decreased in FEV1% predicted, FVC% predicted, and FEV1/FVC, and with increased risk of COPD as well as chronic respiratory symptoms. Negative associations between SUA and FEV1% predicted, FVC% predicted, and FEV1/FVC were found in the COPD group, but no significant association between lung function and SUA levels was found in the non-COPD group. To the best of our knowledge, this is the first epidemiological study focusing on the different effects of SUA on lung function based on individuals with or without COPD.

Cross-sectional studies have estimated that higher SUA levels were positively6 and inversely24 associated with lung function. Previous epidemiological results have been rather inconsistent whether in COPD populations or healthy populations. Two studies found that increased SUA levels accelerated lung function decline in COPD patients,12,25 while another found no significant effect of SUA on lung function in individuals with COPD.12 Similarly, the contradictory effect of SUA on lung function was found in individuals without COPD. In comparison, a positive effect was observed in a large Korean population (n=69,928) of healthy subjects,6 a negative effect was reported in the Korean National Health and Nutrition Examination Survey,13 and another analysis of young adults aged 22–29 years found no significant effect.14 With the heterogeneity of the above studies, such as in term of demographic data and statistical analysis, and so on, it is difficult to draw a clear relationship between SUA and lung function and to explore potential mechanisms, which may explain the discrepancy in current epidemiological studies.

The potentially different effects of SUA on lung function may depend on differential mechanisms. Shaheen suggested that interpretation of previous studies need to be careful26 and provided several possible mechanisms, such as the pro-oxidant and pro-inflammatory properties of SUA, a poor proxy for epithelial lining fluid concentrations, and also potential for confounding. Previous studies have demonstrated that SUA levels were inversely correlated with lung function in the female general population but not the male population.13,24 Though the cause of these sex differences between SUA and lung function remain uncertain, one study has suggested that sex hormones may affect SUA metabolism, making the relative health effect of SUA may be stronger in female generations.27 Further, our study provides a new insight to explain the contradictory relationship between SUA and lung function, the health effect of SUA levels on lung function, which is that health effect of SUA levels on lung function could be influenced by COPD status.

Previous experimental studies have estimated that high SUA levels do not affect reactive oxygen species levels, which can initiate inflammation or airway remodeling26,28–30 under normal conditions, and do not affect lung function under the same condition.9 Experimentally induced hypoxia models found that SUA levels were higher in hypoxia status compared to normal status in lung tissue,31 which means that hypoxia may promote purine catabolism,32,33 which could increase the levels of SUA, and those elevated SUA levels can cause systemic inflammation, potentially damaging lung function. A previous epidemiological study revealed that SUA levels were higher in people with more severe airflow limitation, and were also increased in the presence of hypoxia and systemic inflammation.25 Braghiroli et al suggested that compared to the healthy population, SUA levels were significantly increased in individuals with COPD in hypoxia status but not in those without.32 In a cross-sectional study, Nicks et al found that lower SUA levels were associated with COPD severity in the cross-sectional study.7

This is consistent with our findings; high SUA levels impaired the lung function in the COPD patients but not in non-COPD people with normal oxygen saturation.34,35 Although oxygen saturation values were not collected in our studies, we identified the positive correlation between the high SUA levels and the risk of dyspnoea. As people with the symptom of dyspnoea have different levels of hypoxia,36 that may support our assumptions. Meanwhile, further research is needed to explore the relationships among SUA, lung function, and oxygen saturation in respiratory disease, especially in COPD patients.

A variety of factors such as air pollution and smoking are suggested to have more influence on lung function in COPD patients and therefore have attracted significant attention. Quitting smoking and avoiding air pollution are important suggestions to prevent decreased lung function in COPD patients, but blood biomarkers such as higher SUA levels cannot be ignored. A meta-analysis demonstrated that SUA levels might be a useful biomarker for COPD,37 and an independent predictor of mortality, and are associated with a higher risk of acute exacerbation of COPD.25,38 For better management of COPD, further research about the effect of SUA on lung function, especially in COPD patients, is required.

The strengths of this study include its large sample size and also the amount of data available. Subjects in our study were enrolled from the community but not the clinic, without any severity underlying disease except COPD. Additionally, we were also able to analyze the effect of SUA on lung function after bronchodilation, which could not observed in the previous studies. Similar results were found when compared to SUA levels and lung function before bronchodilation.

Some limitations in our study should be considered. First, the population in our study consisted mostly of males (71.9%), and the percentage of females (28.1%) was lower than in other studies,6,39 which may have influenced the overall results. Nonetheless, the observed association between SUA and lung function persisted in a gender-adjusted model. Second, several possible factors that may influence SUA levels were not completely ruled out, including chronic kidney disorders, alcohol consumption, food intake, metabolic syndrome, and also cardiovascular disease. However, after adjustment for major confounders (age, gender, BMI, smoking status, and cumulative tobacco consumption), logistic regression analysis showed that SUA levels continued to be a significant predictor of COPD risk. Similar results were seen in the linear regression model. Based on this, we believe that the influence of biases from unknown confounding that the model did not adjust for did not significantly affect the outcome. Thirdly, though SUA levels have been suggested to be an imperfect proxy for epithelial lining fluid concentration,1 SUA from epithelial lining fluid concentration is thought to be secreted by submucosal nasal glands after uptake from plasma.3 Lastly, because the design of our study was retrospective and cross-sectional, the causal relationship between uric acid and lung function could not be determined.

Conclusion

In conclusion, the high SUA level was associated with a higher risk of COPD and chronic respiratory symptoms, and lower lung function. What’s more, significant effects of SUA on lung function were found in individuals with COPD, but not individuals without COPD.

Abbreviations

SUA, serum uric acid; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BMI, body mass index; ORs, odds ratios.

Data Sharing Statement

With the permission of the corresponding authors, we can provide participant data without names and identifiers. The corresponding authors have the right to decide whether to share the data based on the research objectives and plan provided. Data will be immediately available after publication. No end date. Please contact correspondence author for data requests.

Ethics Approval and Informed Consent

The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University. All participants gave written informed consent.

Consent for Publication

This article has not been published elsewhere in whole or in part. All authors have read and approved the content, and agree to submit it for consideration for publication in your journal. There are no ethical/legal conflicts involved in the article.

Acknowledgments

We thank all the participants who contributed to this study. Thanks are due to Zhishan Deng, Youlan Zheng, Lifei Lu, Ningning Zhao, Jianwu Xu, Peiyu Huang, Xiaopeng Ling, Shaodan Wei, Qiaoyi He, Wenjun Lai and Yunsong Chen (National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou. Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Nan shan Medical Development Foundation of Guangdong Province) for Data collection.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The present study was supported by The National Key Research and Development Program of China (Grant number 2016YFC1304101), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155), the National Natural Science Foundation of China (81970045), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA2020003, ZNSA-2021012, and ZNSA-2020013) Basic and Applied Basic Research Fund of Guangdong Province (2020A 1515110915) and National Natural Science Foundation of China (82000044).

Disclosure

We declare that there are no financial or personal competing interests associated with the study.

References

1. van der Vliet A, Neill O, Cross CE, et al. Determination of low-molecular-mass antioxidant concentrations in human respiratory tract lining fluids. Am J Physiol. 1999;276(2):L289–L296. doi:10.1152/ajplung.1999.276.2.L289

2. Kelly FJ, Blomberg A, Frew A, et al. Antioxidant kinetics in lung lavage fluid following exposure of humans to nitrogen dioxide. Am J Respir Crit Care Med. 1996;154:1700–1705. doi:10.1164/ajrccm.154.6.8970358

3. Peden DB, Hohman R, Brown ME, et al. Uric acid is a major antioxidant in human nasal airway secretions. Proc Natl Acad Sci U S A. 1990;87:7638–7642. doi:10.1073/pnas.87.19.7638

4. So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120(6):1791–1799. doi:10.1172/JCI42344

5. Lyngdoh T, Marques-Vidal P, Paccaud F, et al. Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS One. 2011;6(5):e19901. doi:10.1371/journal.pone.0019901

6. Song JU, Hwang J, Ahn JK. Serum uric acid is positively associated with pulmonary function in Korean health screening examinees. Mod Rheumatol. 2017;27:1057–1065. doi:10.1080/14397595.2017.1285981

7. Nicks NE, O’Brien MM, Bowler RP. Plasma antioxidants are associated with impaired lung function and COPD exacerbations in smokers. COPD. 2011;8:264–269. doi:10.3109/15412555.2011.579202

8. Kobylecki CJ, Vedel-Krogh S, Afzal S, et al. Nordestgaard, Plasma urate, lung function and chronic obstructive pulmonary disease: a Mendelian randomisation study in 114 979 individuals from the general population. Thorax. 2018;73(8):748–757. doi:10.1136/thoraxjnl-2017-210273

9. Fujikawa H, Sakamoto Y, Masuda N, et al. Higher blood uric acid in female humans and mice as a protective factor against pathophysiological decline of lung function. Antioxidants. 2020;9(5):387. doi:10.3390/antiox9050387

10. Elsayed NE, Nakashima JM, Postlethwait EM. Measurement of uric acid as a marker of oxygen tension in the lung. Arch Biochem Biophys. 1993;302(1):228–232. doi:10.1006/abbi.1993.1204

11. Kahnert K, Alter P, Welte T, et al. Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach. Respir Res. 2018;19(1):110. doi:10.1186/s12931-018-0815-y

12. Garcia-Pachon E, Padilla-Navas I, Shum C. Serum uric acid to creatinine ratio in patients with chronic obstructive pulmonary disease. Lung. 2007;185(1):21–24. doi:10.1007/s00408-006-0076-2

13. Jeong H, Baek SY, Kim SW, et al. Gender-specific association of serum uric acid and pulmonary function: data from the Korea National Health and Nutrition Examination Survey. Medicine. 2021;57:953.

14. Garcia-Larsen V, Chinn S, Rodrigo R, et al. Relationship between oxidative stress-related biomarkers and antioxidant status with asthma and atopy in young adults: a population-based study. Clin Exp Allergy. 2009;39(3):379–386. doi:10.1111/j.1365-2222.2008.03163.x

15. Horsfall LJ, Nazareth I, Petersen I. Serum uric acid and the risk of respiratory disease: a population-based cohort study. Thorax. 2014;69(11):1021–1026. doi:10.1136/thoraxjnl-2014-205271

16. Domagk GF, Schlicke HH. A colorimetric method using uricase and peroxidase for the determination of uric acid. Anal Biochem. 1968;22(2):219–224. doi:10.1016/0003-2697(68)90309-6

17. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007;370(9589):741–750. doi:10.1016/S0140-6736(07)61377-4

18. Zhou Y, Hu G, Wang D, et al. Community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (COPD) in Guangdong, China: cluster randomised controlled trial. BMJ. 2010;341(2):c6387. doi:10.1136/bmj.c6387

19. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319–338. doi:10.1183/09031936.05.00034805

20. Enright PL, Studnicka M, Zielinski J. Spirometry to detect and manage chronic obstructive pulmonary disease and asthma in the primary care setting. Eur Respir Mon. 2005;31:1–14.

21. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 Report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195:557–582. doi:10.1164/rccm.201701-0218PP

22. Quanjer PH, Tammeling GJ, Cotes JE, et al. Lung volumes and forced ventilatory flows. Eur Respir J. 1993;16:5–40.

23. Zheng J, Zhong N. Normative values of pulmonary function testing in Chinese adults. Chin Med J. 2002;115(1):5054.

24. Aida Y, Shibata Y, Osaka D, et al. The relationship between serum uric acid and spirometric values in participants in a health check: the Takahata study. Int J Med Sci. 2011;8(6):470–478. doi:10.7150/ijms.8.470

25. Bartziokas K, Papaioannou AI, Loukides S, et al. serum uric acid as a predictor of mortality and future exacerbations of COPD. Eur Respir J. 2014;43(1):43–53. doi:10.1183/09031936.00209212

26. Shaheen SO. Uric acid, lung function and COPD: a causal link is unlikely. Thorax. 2018;73(8):697–698. doi:10.1136/thoraxjnl-2017-211230

27. De Vera MA, Rahman MM, Bhole V, et al. The independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study. Ann Rheum Dis. 2010;69:1162–1164. doi:10.1136/ard.2009.122770

28. McNeil JD, Wiebkin OW, Betts WH, et al. Depolymerisation products of hyaluronic acid after exposure to oxygen-derived free radicals. Ann Rheum Dis. 1985;44:780–789. doi:10.1136/ard.44.11.780

29. Uchiyama H, Dobashi Y, Ohkouchi K, et al. Chemical change involved in the oxidative reductive depolymerization of hyaluronic acid. J Biol Chem. 1990;265:7753–7759. doi:10.1016/S0021-9258(19)38993-8

30. McKee CM, Penno MB, Cowman M, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996;98:2403. doi:10.1172/JCI119054

31. Ozanturk E, Ucar ZZ, Varol Y, et al. Urinary uric acid excretion as an indicator of severe hypoxia and mortality in patients with obstructive sleep apnea and chronic obstructive pulmonary disease. Rev Port Pneumol. 2016;22:18–26. doi:10.1016/j.rppnen.2015.06.002

32. Braghiroli A, Sacco C, Erbetta M, et al. Overnight urinary uric acid: creatinine ratio for detection of sleep hypoxemia. Validation study in chronic obstructive pulmonary disease and obstructive sleep apnea before and after treatment with nasal continuous positive airway pressure. Am Rev Respir Dis. 1993;148:173–178. doi:10.1164/ajrccm/148.1.173

33. Saito H, Nishimura M, Shibuya E, et al. Tissue hypoxia in sleep apnea syndrome assessed by uric acid and adenosine. Chest. 2002;122(5):1686–1694. doi:10.1378/chest.122.5.1686

34. Sundh J, Ekström M. Risk factors for developing hypoxic respiratory failure in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:2095–2100. doi:10.2147/COPD.S140299

35. Wells JM, Estepar RS, McDonald MN, et al. Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study. BMC Pulm Med. 2016;16:169. doi:10.1186/s12890-016-0331-0

36. Higashimoto Y, Honda N, Yamagata T, et al. Exertional dyspnoea and cortical oxygenation in patients with COPD. Eur Respir J. 2015;46(6):1615–1624.

37. Li H, Chen Y. Serum uric acid level as a biomarker for chronic obstructive pulmonary disease: a meta-analysis. J Int Med Res. 2021;49(1):300060520983705. doi:10.1177/0300060520983705

38. Zhang X, Liu L, Liang R, Jin S. Hyperuricemia is a biomarker of early mortality in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:2519–2523. doi:10.2147/COPD.S87202

39. Fukuhara A, Saito J, Sato S, et al. The association between risk of airflow limitation and serum uric acid measured at medical health check-ups. Int J Chron Obstruct Pulmon Dis. 2017;12:1213–1219. doi:10.2147/COPD.S126249

Source link

Introduction

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and it is a global health problem with increasing prevalence.1 COPD is characterized by coughing or wheezing, excess sputum production, and shortness of breath.1 A subgroup of patients of COPD have progressive disease and results in the deterioration of cardiopulmonary function.1 These patients tend to have poor exercise capacity and health-related quality of life (HRQL).

Some patients of COPD experience difficulty with physical activity and unpleasant symptoms even under optimal medical treatment. Pulmonary rehabilitation (PR) may help improve physical activity and HRQL in these patients with COPD and the Global Initiative for Chronic Obstructive Disease (GOLD) guideline recommends that PR should be an integral part of COPD treatment. PR is a cornerstone in COPD management but not all patients benefit from PR,2 and this could relate to pre-PR work efficiency (WE). We want to investigate this systematically.

Cardiopulmonary exercise testing (CPET) is used to evaluate exercise intolerance. WE, one parameter of CPET, measures an individual’s oxygen consumption (VO2) during exercise workload (WR).3 WE is a measure of overall oxygen consumption efficiency during exercise. We previously reported that COPD patients with a poor WE also had early anaerobic metabolism, lower exercise capacity, more exertional dyspnea, and poorer HRQL.4 However, whether WE affects the effect of PR in COPD patients with a poor WE remain unknown.

Since no studies to date have examined the effects of PR in patients with a poor WE, here we aimed to investigate the effects of PR in COPD patients with a normal versus poor WE. Specifically, we aimed to determine how different WE affects PR.

Materials and Methods

Study Design

Patients with COPD were recruitment from the outpatient department in Taipei Tzu-Chi Hospital. These patients underwent pre-PR assessments by CPET, questionnaire of HRQL, respiratory muscle strength. They then received a 12-week PR. After PR, they underwent post-PR assessment by CPET, questionnaire of HRQL, respiratory muscle strength again.

In this study, we aimed to investigate whether patients with different WE respond differently to PR. The normal range of WE is 8.6–10.1 mL/min/watt.3 Wasserman et al suggested that a WE <8.6 mL/min/watt indicates a poor WE.3 We therefore divided the patients into two groups: group 1 (Gr 1) were patients with a normal WE and group 2 (Gr 2) were patients with a poor WE. The primary outcome was to assess the changes in WE in patients with a normal WE versus those with a poor WE. The secondary outcomes were to assess circulatory responses, ventilatory responses, gas exchanges, exercise capacity and HRQL in patients with a normal WE versus those a with poor WE.

Patient Recruitment

Forty-five patients with stable COPD were recruited. The diagnosis and severity of COPD was defined according to GOLD guideline.5 The inclusion criteria were absence of acute exacerbations for 3 months before recruitment, ability to ambulate for completion of CPET and PR, and willingness to be included in the study. The exclusion criteria were a history of other lung diseases such as asthma, pulmonary tuberculosis, etc., orthopedic or neurological impairment that unable to perform CPET and PR, unwilling to participate in the PR programs and those had ever participated in a PR program. The ethics committee of Taipei Tzu-Chi Hospital approved the study. All patients provided informed consent.

Pulmonary Function Test

According to the standards of the American Thoracic Society (ATS), the patients used a spirometer (Medical Graphics Corporation; St Paul, MN, USA) for the pulmonary function tests.6 According to the GOLD guidelines,7 we used the percentage of forced expiratory volume in 1 second (FEV1%) to evaluate the degree of airflow obstruction.

Cardiopulmonary Exercise Test

All participants underwent the CPET using a bike ergometer (Lode Corival, Netherlands) through a progressive protocol. Their exhaled air was analyzed by breath analysis (Breeze Suite 6.1; Medical Graphics Corporation, St Paul, MN, USA) to assess their oxygen consumption (VO2), carbon dioxide output (VCO2), end tidal PCO2 (PETCO2) and tidal volume (VT). Their oxygen saturation (SpO2), respiratory frequency (Rf), electrical heart function, blood pressure (BP), and heart rate (HR) were continuously monitored during the CPET.

Peak VO2 (VO2peak) was measured at exercise capacity. WE is the relationship between VO2 and WR during exercise.8 WE is defined as the slope of VO2/WR and determined using linear regression analysis. The VO2 at the anaerobic threshold (AT) was determined by the VCO2 versus VO2 graph.9 The predicted VO2 at AT less than 40% of predicted VO2max indicates a poor AT%.3 Oxygen pulse (O2P) was defined as VO2 divided by HR (O2P = VO2/HR). An O2P at a peak exercise level lower than 80% of the predicted value is considered poor.3 Respiratory gas exchange (RER) is defined as VCO2/VO2.3

Respiratory Muscle Strength

Maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were measured five times with a pressure gauge (Respiratory Pressure Meter; Micro Medical Corp, England), and the highest value was recorded.4,10 For the measurement of MIP, the patients exhaled to the residual volume and then perform a rapid maximal inspiration. For the measurement of MEP, the patients inhaled to the total lung capacity and then exhaled with maximal effort.

Exertional Dyspnea and Leg Fatigue Scores

The dyspnea and leg fatigue scores were evaluated using a modified version of Borg scale at peak exercise during CPET, which is scored 0–10 points; higher scores indicate more severe dyspnea or leg fatigue.11 Dyspnea and leg scores are determined at peak exercise during the CPET.

Health-Related Quality of Life

The Chinese version of the COPD Assessment Test (CAT) was used to assess HRQL. The CAT consists of eight items (cough, phlegm, chest tightness, dyspnea, activity, confidence to leave home, sleeplessness, and energy). The score for each item ranges from 0 to 5,12 and the total score ranges from 0 (best) to 40 (worst) points.12 A total CAT score ≥10 is classified as a high-level symptom.12 The minimum clinically important difference of CAT is 2 points.12

PR Program

All patients performed a 12-week twice-weekly hospital-based PR program. In each training session, formal education, including proper use of medications, breathing exercise (purse-lip and diaphragm breathing), and self-management skills were provided. The exercise training was performed by cycle ergometer. Patients were encouraged to achieve their maximal exercise as possible. The exercise intensity was targeted to 50–100% of peak VO2 as patients’ tolerance. During the exercise training, respiratory therapists monitored the WR, SpO2, Rf, HR, BP, dyspnea, and leg fatigue.

Statistical Analysis

The parameters are shown as mean and standard deviation. A paired t-test was used to compare parameters before and after PR. An independent sample t test was used to compare the pre- and post-PR parameters between the two groups. The changes in parameters were defined as differences between pre- and post-PR and were analyzed by the independent sample t test between the two groups. We perform Normality test of variables to identify the parametric test that is used to analyze normal distribution variables. A statistically significant difference was set at p < 0.05. The statistical analyses were performed using SPSS version 24.0 (SPSS, Inc., Chicago, IL, USA).

Results

Baseline Clinical and Demographic Characteristics

Table 1 shows the demographic and clinical characteristics of all patients. Among the 45 COPD patients, 21 had a normal WE (Gr 1) and 24 had a poor WE (Gr 2). No significant differences were noted in body weight, body height, body mass index, age, gender, smoking status, COPD severity, duration of diagnosis of COPD, comorbidities of congestive heart failure, hypertension and diabetes mellitus between these two groups. Most enrolled patients were COPD group B.

Table 1 Baseline Demographic Characteristics

Effects of PR on Circulatory Parameters of Patients with a Normal versus Poor WE

At baseline, the WE, AT, and O2P were significantly lower in Gr 2 than in Gr 1 (Table 2) but mean blood pressure (MBP) and HR did not differ significantly between Gr 1 and Gr 2. For Gr 1, at post-PR, significant improvement was seen in AT but not in WE, O2P, HR, or MBP. For Gr 2, at post-PR, significant improvement was seen in WE, AT, O2P, and MBP at rest. The improvement in circulatory parameters after PR for each group is shown in Figure 1. The improvements in WE, AT, and O2P after PR were significantly greater in Gr 2 than in Gr 1.

Table 2 Effects of PR on Circulatory Parameters of Patients with a Normal and Poor WE

Figure 1 Degree of changes in circulatory parameters after PR in patients by study groups. The changes of WE (A), AT (B) and O2P (C) of Gr 2 were significantly higher than those of Gr 1. However, changes in MBP at rest (D), MBP during exercise (E), and HR during exercise (F) were not significantly different between the two groups.*p < 0.05, ***p < 0.001, ns: p > 0.05. Yellow and blue dots are outliers.

Abbreviations: AT, anaerobic threshold; Gr, group; HR, heart rate; MBP, mean blood pressure; ns, non-significance; O2P, oxygen pulse; WE, work efficiency.

Effects PR on Ventilatory Parameters of Patients with a Normal and Poor WE

At baseline, the FVC%, FEV1%, FEV1/FVC, MIP, and MEP were significantly lower in Gr 2 than in Gr 1 (Table 3). For Gr 1, there were no significant differences in FVC, FEV1, MIP, MEP, Rf, or VT at pre- versus post-PR. For Gr 2, there were no significant differences in FVC, FEV1, MIP, MEP, and VT at pre- versus post-PR, but Rf at exercise was significantly lower at post- than pre-PR. The improvement in ventilatory parameters at post-PR for each group is shown in Figure 2. No significant intergroup difference in FVC, FEV1, MIP, MEP, Rf, or VT was noted at post-PR.

Table 3 Effects of PR on Ventilatory Parameters of Patients with a Normal and Poor WE

Figure 2 Degree of changes in ventilatory parameters after PR of patients by study groups. The changes of FEV1 (A), FVC (B), MIP (C), MEP (D), Rf at rest (E), Rf at exercise (F), VT at rest (G) and VT at exercise (H) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Gr, group; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; ns, non-significance; Rf, respiratory frequency; VT, tidal volume.

Effects PR on Gas Exchanges of Patients with a Normal versus Poor WE

At baseline, the PETCO2, SpO2 at rest or during exercise and the RER were similar between Gr 1 and 2 (Table 4). The PETCO2 and SpO2 at rest or during exercise and the RER did not differ. The changes in PETCO2, SpO2 at rest or during exercise after PR for each group are shown in Figure 3. The changes in SpO2and PETCO2 after PR were similar between Gr 1 and Gr 2.

Table 4 Effects of PR on Gas Exchanges of Patients with a Normal and Poor WE

Figure 3 Degree of changes in gas exchange after PR in patients by study groups. The changes of SpO2 at rest (A) or exercise (B), and PETCO2 at rest (C) or exercise (D) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: Gr, group; ns, non-significance; PETCO2, end tidal carbon dioxide; SpO2, blood oxygen saturation by pulse oximeter.

Effects of PR on Exercise Capacity of Patients with a Normal versus Poor WE

At baseline, the mean exercise capacity (VO2 and WR at peak exercise) was significantly greater in Gr 1 than in Gr 2 (Table 5). PR significantly improved VO2 and WR at peak exercise in patients of both groups. The changes in VO2 and WR at peak exercise after PR for both groups are shown in Figure 4. The changes in VO2 and WR at peak exercise after PR were similar between groups.

Table 5 Effects of PR on Exercise Capacity of Patients with a Normal and Poor WE

Figure 4 Degree of change in exercise capacity after PR in patients by study groups. The changes of WR (A) and peak VO2 (B) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: Gr, group; ns, non-significance; VO2, oxygen consumption; WR, work rate.

Effects of PR on HRQL, Exertional Dyspnea, and Leg Fatigue Scores of Patients with a Normal versus Poor WE

At baseline, the phlegm, breathlessness, activities, CAT total score, and modified British Medical Research Council (mMRC) score were significantly poorer in Gr 1 than in Gr 2 (Table 6). For patients in Gr 1, PR significantly improved breathlessness, CAT total score, mMRC score, dyspnea, and fatigue at peak exercise. For patients in Gr 2, PR significantly improved phlegm, chest tightness, breathlessness, activities, sleep, CAT total score, mMRC score, dyspnea, and leg fatigue during exercise.

Table 6 Effects of PR on HRQL, Exertional Dyspnea and Leg Fatigue Score of Patients with a Normal and Poor WE

The changes in CAT, mMRC score, dyspnea, and leg fatigue during exercise after PR for each group are shown in Figure 5. The changes in breathlessness, activity, CAT total score, and mMRC score after PR were significantly greater in Gr 1 than in Gr 2.

Figure 5 Degree of change in HRQL after PR in patients by study group. There were no significant differences in the changes of cough (A), sputum (B) and chest tightness (C) between the two groups. The improvement of dyspnea (D) and activity (E) were significantly more in the Gr 2 than those in the Gr 1. Changes of confidence (F), sleep (G) and energy (H) were without significant difference between the two groups. The decreases in CAT total score (I) and mMRC (J) were significantly more in the Gr 1 than those in the Gr 1. The changes of dyspnea (K) and leg fatigue (L) Borg scale at peak exercise did not differ between the two groups.*p < 0.05, **p < 0.01, ns: p > 0.05. Yellow and blue dots are outliers.

Abbreviations: CAT, COPD assessment test; Gr, group; mMRC, modified British Medical Research Council; ns, non-significance.

Subgroups Analysis of Patients with Poor WE

Among the 24 patients with a poor WE, WE returned to normal in 7 patients (29%), and WE did not return to normal in 17 patients (71%). We compared the baseline data and response to PR of these two groups of patients, as shown in Table 7. For baseline data, WE, VO2 at AT and O2P were significantly higher in patients with normalized WE than those without normalized WE. However, age, gender, body mass index, exercise capacity, and CAT total score at baseline did not show significant difference between the two groups.

Table 7 Subgroup Analysis of Patients with a Poor WE

Discussion

This is the first study to assess the different effects of PR in COPD patients with a normal versus poor WE. There are some important and novel findings in this study. Compared to COPD patients with a normal WE, those with a poor WE had decreased exercise capacity, more exertional dyspnea, poor HRQL, and poor circulatory parameters. Our PR program was efficient to improve exercise capacity, exertional dyspnea, HRQL, and circulatory parameters for COPD patients with both normal or poor WE. However, greater improvements in VO2 at AT, exercise capacity, and CAT were found in patients with a poor WE than those with a normal WE. Furthermore, improvements in WE, O2P, and Rf in peak exercise, chest tightness, activity, and sleep quality were found only in patients with a poor WE, but not in patients with a normal WE.

In our study, we used high intensity (50–100%) of exercise training and these patients had improvement of exercise capacity and HRQL after such training. Patients with a poor WE further had improvement of WE and O2P. However, it is not known about the effect of low intensity (<50%) exercise training on WE. Besides, most enrolled patients were COPD group B in the current study. This was because that we enrolled stable COPD for PR and we excluded acute exacerbations within three months. Since the majority of patients were COPD group B, it is unclear whether patients of other groups would get the same results after exercise training.

The overall VO2 dynamics during exercise depend on the gas exchange by the respiratory system, oxygen delivery by the circulatory system, and oxygen extraction for exercise by the musculoskeletal system.13 Oxygen extraction further depends on the muscle mass of the limbs, muscular capillary contents, and mitochondrial function of muscle cells.8 A poor WE suggests a poor overall oxygen consumption efficiency that indicates poor oxygen delivery or impaired muscular extraction of oxygen.14

In the current study, patients with a poor WE had early AT, poorer exercise capacity, and poorer HRQL than those with a normal WE. The consequence of a poor WE is early anaerobic metabolism during exercise.14 Anaerobic glycolysis produces lactic acidosis, which further leads to excessive ventilation responses to acidosis-stimulating chemoreceptors.14,15 Hyperventilation during early exercise further results in exertional dyspnea sensation, exercise intolerance, and a poor HRQL.15 This explained that the COPD patients with a poor WE experience early anaerobic metabolism during exercise and are therefore prone to exercise intolerance and poor HRQL.

Wasserman et al previously suggested that trained and untrained patients would have a similar WE regardless of age or gender.8 However, we found that PR improved WE in COPD patients with a poor WE but not in those with a normal WE. Therefore, exercise training is not unable to change WE. It is for patients with a normal WE, exercise training will not increase their WE. But for patients with a poor WE, exercise training will still increase their WE. Patients with a normal WE indicated good oxygen delivery and extraction. Therefore, for patients with a normal WE, there is little room for improvement in WE. Patients with a poor WE indicated poor oxygen delivery or extraction. Exercise training improves their oxygen delivery or extraction.

The mechanisms of the improvement in WE after PR are multiple. One previous study suggested that PR improved the central cardiovascular response such as stroke volume during exercise in COPD.16 We here also showed that O2P, a reliable surrogate marker of stroke volume, was improved in patients with a poor WE. Nasis et al also showed that PR improved cardiac output in patients with COPD.17 The reduction in dynamic hyperinflation after PR is related to the improvement in stroke volume.16 Besides, exercise training is known to improve contractile capacity of cardiomyocyte.18

Skeletal muscle and mitochondrial dysfunction is a systemic manifestation in some patients with COPD.19 Vogiatzis et al revealed that PR increased muscle cross-sectional area and capillary contents.20 Marillier et al also found that exercise training increased muscle cell mitochondrial function.19 According to these studies, exercise training increases muscle mass, muscular capillary contents, and mitochondrial function, which are important factors of oxygen extraction. The improvement in oxygen extraction also resulted in an increase in WE. Although we did not examine mitochondrial function and muscle mass after PR, it is plausible based on these studies that PR leads to improve peripheral muscle mass and mitochondrial function.

There is one previous study about the impact of PR on severe physical inactivity in patients with COPD.2 In this study, most patients of severe physical inactivity (78%) did not change activity level after PR. The result seems to contradict our results that we showed the improvement of WE in patients with a poor WE. However, the two studies aimed at different outcomes. Thyregod et al focused on physical inactivity and we focused on WE. WE is determined by multiple factors. Physical inactivity with muscle deconditioning may be one possible reason of a poor WE, but not all patients in severe physical inactivity result in a poor WE. Most of our enrolled patients also self-reported physical inactivity, but only 24 of 45 patients had a poor WE.

Clinical Implication

Exercise intolerance, exertional dyspnea, poor HRQL are common in patients with COPD.15 An individual’s overall oxygen consumption efficiency depends on oxygen delivery, oxygen extraction, and mitochondrial function.8 WE is a good parameter that provides information about circulatory and tissue oxygen consumption function during exercise. We suggested here that COPD patients with a poor WE have more severe exertional dyspnea, lower exercise capacity, poor circulatory function, earlier anaerobic metabolism, and poorer HRQL. PR improved their exercise capacity, circulatory function, anaerobic metabolism, and HRQL.

Study Limitations

Although our research has many important findings, it still has some limitations. First, patients with a poor WE had poor circulatory function, more severe exercise intolerance, and poorer HRQL. However, the value of WE for predicting long-term outcomes such as the survival of patients with COPD is unclear. Therefore, the long-term impact of PR for improving WE is unknown. Further, PR improved WE in our study, but we could not determine whether this was due to improved circulatory, muscular, or mitochondrial function for these patients. However, it is difficult to determine muscular and mitochondrial function in patients with COPD. Therefore, WE is still an available, effective, and non-invasive parameter for monitoring an individual’s overall cardiovascular, muscular, and mitochondrial function after PR.8

Conclusions

Patients with a poor WE had poor circulatory parameters, exercise capacity and HRQL. PR improved exercise capacity, HRQL, and VO2 at AT in patients of both normal or poor WE. However, greater improvements in VO2 at AT, exercise capacity, and HRQL were found in COPD patients with a poor WE than those with a normal WE. Furthermore, improvements in WE, O2P, and Rf at peak exercise, chest tightness, activity, and sleep quality were found only in patients with a poor WE.

Data Sharing Statement

The datasets used during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Informed Consent

The ethics committee of Taipei Tzu-Chi Hospital approved the study. All participants were informed about the purpose of the study, in accordance with the Declaration of Helsinki. Patient’s written consent has been obtained.

Funding

This study was supported by grants from the Taipei Tzu Chi Hospital and the Buddhist Tzu Chi Medical Foundation (TCRD-TPE-109-59 and TCRD-TPE-109-24(2/3), respectively).

Disclosure

The authors disclose no financial or other potential conflicts of interest in this work.

References

1. Hurst JR, Siddiqui MK, Singh B, Varghese P, Holmgren U, de Nigris E. A systematic literature review of the humanistic burden of COPD. Int J Chron Obstruct Pulmon Dis. 2021;16:1303–1314. doi:10.2147/copd.S296696

2. Thyregod M, Løkke A, Bodtger U. The impact of pulmonary rehabilitation on severe physical inactivity in patients with chronic obstructive pulmonary disease: a pilot study. Int J Chron Obstruct Pulmon Dis. 2018;13:3359–3365. doi:10.2147/copd.S174710

3. Herdy AH, Ritt LE, Stein R, et al. Cardiopulmonary exercise test: background, applicability and interpretation. Arq Bras Cardiol. 2016;107(5):467–481. doi:10.5935/abc.20160171

4. Yang SH, Yang MC, Wu YK, et al. Poor work efficiency is associated with poor exercise capacity and health-related quality of life in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2021;16:245–256. doi:10.2147/copd.S283005

5. Cheng SL, Lin CH, Chu KA, et al. Update on guidelines for the treatment of COPD in Taiwan using evidence and GRADE system-based recommendations. J Formos Med Assoc. 2021;120(10):1821–1844. doi:10.1016/j.jfma.2021.06.007

6. Culver BH, Graham BL, Coates AL, et al. Recommendations for a standardized pulmonary function report. An official American thoracic society technical statement. Am J Respir Crit Care Med. 2017;196(11):1463–1472. doi:10.1164/rccm.201710-1981ST

7. Song JH, Lee CH, Um SJ, et al. Clinical impacts of the classification by 2017 GOLD guideline comparing previous ones on outcomes of COPD in real-world cohorts. Int J Chron Obstruct Pulmon Dis. 2017;13:3473–3484. doi:10.2147/COPD.S177238

8. Wasserman K, Hansen JE, Sue DY, et al. Principles of Exercise Testing and Interpretation. 5th ed. Lippincott Williams & Wilkins; 2012:17.

9. Wu CW, Hsieh PC, Yang MC, Tzeng IS, Wu YK, Lan CC. Impact of peak oxygen pulse on patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2019;14:2543–2551. doi:10.2147/COPD.S224735

10. McConnell AK, Copestake AJ. Maximum static respiratory pressures in healthy elderly men and women: issues of reproducibility and interpretation. Respiration. 1999;66(3):251–258. doi:10.1159/000029386

11. Cheng ST, Wu YK, Yang MC, et al. Pulmonary rehabilitation improves heart rate variability at peak exercise, exercise capacity and health-related quality of life in chronic obstructive pulmonary disease. Heart Lung. 2014;43(3):249–255. doi:10.1016/j.hrtlng.2014.03.002

12. Wiklund I, Berry P, Lu KX. The Chinese translation of COPD assessment test (CAT) provides a valid and reliable measurement of COPD health status in Chinese COPD patients. Am J Respir Crit Care Med. 2010;181:A3575.

13. Takken T, Mylius CF, Paap D, et al. Reference values for cardiopulmonary exercise testing in healthy subjects - an updated systematic review. Expert Rev Cardiovasc Ther. 2019;17(6):413–426. doi:10.1080/14779072.2019.1627874

14. Guazzi M, Bandera F, Ozemek C, Systrom D, Arena R. Cardiopulmonary exercise testing: what is its value? J Am Coll Cardiol. 2017;70(13):1618–1636. doi:10.1016/j.jacc.2017.08.012

15. O’Donnell DE, Elbehairy AF, Faisal A, Webb KA, Neder JA, Mahler DA. Exertional dyspnoea in COPD: the clinical utility of cardiopulmonary exercise testing. Eur Respir Rev. 2016;25(141):333–347. doi:10.1183/16000617.0054-2016

16. Ramponi S, Tzani P, Aiello M, Marangio E, Clini E, Chetta A. Pulmonary rehabilitation improves cardiovascular response to exercise in COPD. Respiration. 2013;86(1):17–24. doi:10.1159/000348726

17. Nasis I, Koulouris N, Vasilopoulou M, et al. Effect of pulmonary rehabilitation on cardiac output responses during exercise in COPD. ERJ. 2012;40:P1904.

18. Kemi OJ, Haram PM, Wisløff U, Ellingsen Ø. Aerobic fitness is associated with cardiomyocyte contractile capacity and endothelial function in exercise training and detraining. Circulation. 2004;109(23):2897–2904. doi:10.1161/01.Cir.0000129308.04757.72

19. Marillier M, Bernard AC, Vergès S, Neder JA. Locomotor muscles in COPD: the rationale for rehabilitative exercise training. Front Physiol. 2019;10:1590. doi:10.3389/fphys.2019.01590

20. Vogiatzis I, Simoes DC, Stratakos G, et al. Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J. 2010;36(2):301–310. doi:10.1183/09031936.00112909

Source link

Torreon, Coahuila. /

The covid-19 virus and its variants has modified not only its behavior, but also its clinical manifestationsbecause in 2019 when this new type of coronavirus appeared the sequelae were particularly respiratory.

Arnulfo Portales Castanedo, an internist and specialist in cardiopulmonary medicine, states that Initially, the most important sequelae were respiratory with an advanced state of pulmonary inflammation..

“Let’s remember that there were no vaccines, so the covids we had were relatively more aggressive, many had a pretty good time and others out of nowhere had a serious respiratory compromise and we ended up with them in intensive care, they were the ones with the most sequelae.”

At that moment it was thought that this type of sequelae would be unique, pulmonary fibrosis, difficulty breathing and the need for chronic use of oxygen and even steroids and cortisone to continue deflating the lung.

“We saw that the patient did not improve, we tried to use antifibrosing drugs of the lung, probably already in very late stages, some respond, others do not and we thought that this was going to be our only sequel.”

The specialist mentioned that Over time and as they saw the different variants of the virus and the transmission capacity, they realized that the population was becoming more vulnerable. and more susceptible to the ravages of transmissibility. The virus became more contagious, although with less lethality and affectation in degrees of severitywhich was modifying their behavior and clinical manifestations.

“We are presented with a challenge to say that it is not covid and although within the same medical environment there are very coined phrases to say, everything is covid and not everything is covid, those are two phrases that pose us a very serious dilemma.”

He considered that a person with a very serious health problem may not be cared for, thinking that it is covid and the time it takes to define whether or not it can be vital for the patient.

“Personally, with the challenge that I have faced the most, it is the first answer that I have to give to see in which area of ​​the hospital I am going to attend to this patient or if I am going to attend to this patient in my consultation or in a unit respiratory, due to the risk it represents for other patients and the second is the diversity of clinical manifestations”.

These are diverse, since in the first variants the affectation was mainly respiratory, while in the latest variants there have been other presentations.

Any infectious process, be it viral, bacterial, fungal, mycobacterial or parasitic, which are what is included in the pathogen, produces an infection and the body as part of the general response is going to inflame.

He explains that this inflammatory response has counterweights, factors that promote it, self-regulatory factors to stop it, and each person responds differently to the same stimulus, in this In the case of an infectious process such as the covid virus, we would only have to see what variant we are facing.

“Each one has its particularities, in this variability and this particular susceptibility of each person, this inflammatory response can be perpetual, it can be replicated or modified depending on the genome, what you have risk factors for developing or simply and simply even if you do not have them. you, you are the family chain that is going to start the change because the virus itself modified that genome.”

It is there where the manifestations of a new disease derived from or as a result of a detonation by the covid infection are triggeredwhich he considered terribly interesting from a medical point of view, but from a health point of view a serious problem.

in different presentations

Armando Abraham de Pablos Leal, an infectious disease doctor, stated that as new variants have existed, they have had a different clinical presentationbecause in the last two variants there have been behaviors at the level of the central nervous system.

Transverse myelitis as well as Guillain-Barré syndrome became more common and although not as frequentbegan to see more cases in the last 2 variants and have even had patients with suicidal ideation.

Anxiety and depression

“We have had many patients with depression who have probably had a very mild flu-like illness, but the patients come to me two weeks later with a lot of anxiety, with easy crying and who go only for this symptom.”

He explained that patients with pericarditis, tachycardia, thyroiditis and encephalitis have frequently been received, which has become more common. “I have come to have the same residents with encephalitis and pericarditis at the same time, this presentation became more and more common.”

He explained that the last two variants had this capacity, due to a protein called Neurofeline that makes it easy to enter the central nervous system. Variants have different presentations at the level of the nervous systembut each time they have had more access capacity.

Although it is true, he indicated, the inflammatory capacity is different in each variant and especially in the last one, which is omicron, which is said to have less inflammatory capacity and was greatly influenced by the vaccine. He mentioned that another problem is immunosuppression, patients with superinfection, aspergillosis, coccidioidomycosis and not only pulmonary tuberculosis, but the body’s response was not sufficient to stop it at the lung level and it is also disseminated.

“The immunosuppressive effect is also going to bring us even more things, perhaps we are just waiting for the latest variants, especially omicron, about what else can be activating us.”

ANDIn the case of older adults, he assured that at first they were the most affected, however, it had a lot to do with the fact that they were the first to be covered with the vaccine and that currently it is what has helped everyone.

Before and after covid Elida Moran Guel, a specialist in emergency medicine and intensive care, pointed out that the history of medicine will have a before and after covid-19 due to what is currently being experienced in the world. “It is a totally different change from what we learned at school, it is a disease that we all had to learn together, students, teachers, we all went hand in hand and I think we continue to learn”.

The specialist commented that with the sequelae that occur in the different variants, a patient can last up to 6 months inflamed, however, something new comes out daily and there are new reports. She indicated that in these two years people have written about her experience and that is what has greatly enriched her.

“Although at first one wrote what was going through his head, they are now more structured studies with greater statistical weight, with greater methodological weight, they are already studies so well done that we can already get an idea of ​​what could be done or what was done on the other side of the world in the face of covid.”

EGO



Source link