Tuberculosis, commonly referred to as TB, is an infectious disease caused by bacteria. The symptoms of TB can be problematic and can prove to be fatal if left unattended. Therefore, in this blog, we will unravel the enigma surrounding this infectious disease that has left an indelible mark on human history. Stay with this blog as we discuss the causes of tuberculosis, how it happens, what its subtle symptoms are, and unveil the array of treatments that modern medicine has devised to combat this condition.

What is Tuberculosis?

Tuberculosis is a bacterial infection that primarily affects your lungs but is capable of spreading to other organs of your body.

When you inhale air containing the TB bacteria, these microscopic invaders find a home in your lungs and start multiplying, marking the initiation of the infection. TB usually affects in 3 stages. As the bacteria settle, they form tubercles, clusters that induce inflammation within your lung tissue, marking the primary stage, often characterised by a persistent cough and, at times, chest pain.

Despite the symptoms, the infection can enter a dormant stage for years (latent TB), akin to a hibernation within your body. There is a possibility that this dormant stage will turn into an active TB stage later. Moreover, if your immune system weakens, the bacteria can resurface, leading to the active stage of TB disease.

How Common is Tuberculosis?

You may be surprised to learn that TB remains a global health concern, affecting millions each year.

The World Health Organization estimates that over 10 million people annually contract TB, with around 1.5 million succumbing to the disease. Despite medical advancements, TB persists, particularly in regions with limited healthcare access. Therefore, this is just a reminder that, even in the 21st century, TB continues to impact communities worldwide, emphasising the importance of public health initiatives and global collaboration to address and reduce its incidence. 

Are There Different Types of Tuberculosis?


Certainly, there are different types of tuberculosis, each presenting unique challenges for diagnosis and treatment.

  • One distinct type is pulmonary tuberculosis, which affects your lungs and is often characterised by a persistent cough, chest pain, and respiratory issues.
  • Extra-pulmonary TB involves infections in organs beyond your lungs, such as the kidneys, bones, liver, brain or lymph nodes, posing diagnostic complexities.
  • Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have emerged as formidable variants. MDR-TB resists the two most potent TB drugs, isoniazid and rifampicin, while XDR-TB additionally withstands second-line medications. These drug-resistant forms heighten the difficulty of managing and treating the disease, necessitating specialised approaches.
  • Latent TB infection where you may carry the bacteria without exhibiting symptoms.

What Causes Tuberculosis?

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis. While tuberculosis is contagious, it typically requires prolonged exposure to an infected individual for transmission to occur easily. This means that casual contact, such as sitting next to someone on a bus or sharing utensils, will not cause the infection. However, factors like weakened immune systems can increase your vulnerability to TB disease.

How is Tuberculosis Spread?

Tuberculosis spreads through the air when an infected person with active TB disease expels respiratory droplets into the environment through coughing, sneezing, or talking. These tiny droplets, containing the bacterium Mycobacterium tuberculosis, can be unknowingly inhaled by individuals in close proximity, leading to new infections.

The transmission of TB is more likely to occur in enclosed spaces with poor ventilation, making crowded areas such as public transportation or prisons a higher risk for infection. However, it is important to note that not everyone exposed to the bacteria becomes infected. Factors like the duration and area of exposure, as well as the infectiousness of the source case, play an important role in determining the transmission rates. Moreover, if you are suffering from conditions like HIV/AIDS or malnutrition, you can be more sensitive to contracting and developing active TB after exposure.

What are the Signs and Symptoms of Tuberculosis?

TB symptoms include a persistent cough, often with sputum or blood. Thrdr TB symptoms can be subtle initially, potentially leading to delayed diagnosis.

  • Chest pain, fatigue, weight loss, and night sweats are common indicators of TB infection.
  • Loss of appetite is another common TB symptom.
  • Difficulty breathing and fever may accompany the above TB symptoms.
  • Latent TB infection may not present noticeable signs or symptoms.

What Kinds of Tests are Used to Diagnose Tuberculosis?

Several tests are employed to diagnose tuberculosis, each serving a specific purpose in the identification of the infection:

  • Tuberculin Skin Test: The Tuberculin Skin Test (TST) injects a small amount of tuberculin under your skin to assess your immune system's reaction.
  • IGRA: Interferon-Gamma Release Assays (IGRAs) measure specific immune system substances released in your body's response to TB antigens.
  • Imaging analysis: Chest X-rays or CT scans can detect TB-related abnormalities in your lungs.
  • Sputum test: This test examines your respiratory secretions for Mycobacterium tuberculosis, confirming active TB.
  • PCR: Molecular tests, like the Polymerase Chain Reaction (PCR), rapidly identify TB DNA for quicker results.
  • Culture techniques: Culturing techniques involve growing bacteria from your sample to confirm TB presence and determine drug susceptibility.

How Do I Know if I Should Get Tested for Tuberculosis?

Determining whether you should get tested for tuberculosis involves considering various factors related to your health and potential exposure risks:

  • Symptoms: If you are experiencing symptoms of TB, such as a persistent cough, chest pain, fatigue, weight loss, or night sweats, it is advisable to seek medical attention. These symptoms may indicate an active TB infection.
  • Contact with TB Patients: If you have been in close contact with someone diagnosed with active TB, you may be at risk of infection. Close and prolonged exposure increases the likelihood of transmission, warranting testing.
  • High-Risk Groups: Individuals in high-risk groups, such as those with weakened immune systems (due to conditions like HIV/AIDS or certain medications), healthcare workers, and individuals residing in or travelling to areas with high TB prevalence, should consider testing.
  • Health Screenings: If you are undergoing routine health screenings, discuss your risk factors with your doctor. Some healthcare settings may include TB testing as part of routine check-ups.
  • Immunosuppressive Conditions: If you are suffering from conditions that compromise the immune system, such as diabetes, cancer, kidney disease or certain medical treatments, you should discuss TB testing with your healthcare provider.

How is Tuberculosis Treated?

Tuberculosis treatment typically involves a combination of antimicrobial medications to eradicate the bacteria, prevent recurrence, and minimise the risk of drug resistance.

The standard tuberculosis treatment regimen consists of a multi-drug approach, often incorporating isoniazid, rifampicin, ethambutol, rifapentine and pyrazinamide. You should adhere to the prescribed medication regimen for successful tuberculosis treatment and to prevent the development of drug-resistant strains.

Monitoring and periodic assessments are essential throughout tuberculosis treatment to gauge your response and ensure your well-being. With advancements in healthcare, tuberculosis treatment has become more streamlined, offering improved outcomes.

Complications/Side Effects of Tuberculosis Treatment

Tuberculosis treatment, while essential, may pose complications and side effects in your body. Common issues that you may experience include gastrointestinal disturbances, liver toxicity, and skin reactions. Rifampicin, a key medication, can cause your bodily fluids to turn orange, and some drugs may interact negatively with other medications. Severe complications, though rare, may include drug-induced hepatitis.

How Soon After Starting Treatment for Active TB Will I Feel Better?

Improvement in symptoms after starting tuberculosis treatment for active TB varies. While some individuals experience relief within weeks, others may take months. Prompt medical attention, coupled with completing the full course of treatment, increases the likelihood of a quicker response.

Can Tuberculosis be Cured?

Yes, you can completely cure tuberculosis with appropriate and timely medical treatment.

What Can You Do to Prevent the Spreading of Tuberculosis?

For tuberculosis prevention, you can take several proactive measures. For instance:

  • If diagnosed with active TB, make sure you take all your medications and follow your doctor's advice correctly.
  • You should attend scheduled follow-up appointments for monitoring to track your progress and adjust treatment as needed.
  • If in close contact with a TB patient, undergo testing and consider preventive treatment to minimise the risk of infection.
  • Practice good respiratory hygiene by covering your mouth and nose when coughing or sneezing to prevent the release of infectious droplets. Regularly wash your hands.
  • Maintain proper ventilation in living and working spaces, as TB spreads more easily in enclosed areas.
  • Promote awareness in your community about the importance of early detection, treatment, and following preventive measures.

Is There a Vaccine to Prevent Tuberculosis?

Yes, a tuberculosis vaccine called Bacillus Calmette-Guérin (BCG) exists. Administered in infancy, the BCG tuberculosis vaccine is widely used in countries with high TB prevalence. While it provides partial protection against severe forms of TB in children, its efficacy against adult pulmonary TB varies.

Research into improving the tuberculosis vaccine and developing new ones continues, highlighting the ongoing efforts to tackle this disease.

What is the Outlook (Prognosis) for Someone With Tuberculosis?

With prompt and adequate treatment, the prognosis for tuberculosis is generally favourable. You can experience improvement within weeks to a few months. Regular medical monitoring ensures effective management and reduces the risk of complications, contributing to a positive outlook for your recovery.

When Should I See My Healthcare Provider?

If you experience symptoms like a bad cough (more than two weeks), chest discomfort, weakness, weight loss, and fever, consult a doctor promptly. Additionally, seek medical attention if you have been in close contact with someone diagnosed with TB. If you are in a high-risk group, discuss this with your doctor.

Conclusion

Tuberculosis remains a global health challenge, and we need more awareness and proactive measures. Early diagnosis, following the doctor's prescription religiously, and preventive strategies are very important. With ongoing research and collective efforts, there is hope for improved diagnostics, treatments, and, eventually, a world where the impact of tuberculosis is significantly reduced. If you or your loved ones suspect TB infection and want to get tested precisely and swiftly, Metropolis Healthcare is the number 1 choice! Offering a diverse range of TB tests such as Tuberculin test, IGRA test, sputum test and other blood tests. So, book your test today!

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Introduction

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a leading cause of disease-associated morbidity and mortality among patients with chronic obstructive pulmonary disease (COPD).1 AECOPD also accounts for impaired lung function and poor quality of life and is the largest component of the socioeconomic burden of COPD.2–4 Early assessment of the severity of AECOPD may facilitate risk-stratified clinical management, including outpatient treatment or early supported discharge for patients with mild AECOPD and timely escalation or appropriate palliation for patients with severe AECOPD.5 Several prognostic scores that stratify patients hospitalized for AECOPD according to their risk of short-term mortality have been published, the most notable being BAP-65 and DECAF.6,7 Most of the scores performed well in the derivation cohort, but the results of subsequent validation studies were controversial.8,9 Thus, current international guidelines do not recommend the use of a prognostic score for predicting the risk of adverse outcomes among patients with AECOPD admitted to the hospital. The Global Initiative on Obstructive Lung Disease (GOLD) has been recommending a classification of AECOPD severity based on post facto medication use and hospitalizations,4 which cannot provide practical information for making clinical decisions.

In light of this, a group of international COPD experts recently proposed a new severity classification of AECOPD, called the Rome proposal, through a Delphi process based on a thorough literature review and discussion.10 In this new classification, six objectively measured variables are used to mark the event severity: dyspnea (assessed by a visual analog scale (VAS), which is on a scale of 0–10, arterial oxygen saturation (SaO2), respiratory rate (RR), heart rate (HR), serum C-reactive protein (CRP) and, in selected cases, arterial blood gases (ABG). Based on these variables, AECOPD is subsequently classified as mild, moderate or severe. However, since the severity classification of AECOPD by the Rome proposal is based on the Delphi methodology, its predictive performance needs to be validated in real-world settings. To date, a few studies applied this new severity classification in small and single-center cohorts with AECOPD,11–13 but to our knowledge, it has not been validated in large multicenter cohorts or in Chinese populations with AECOPD.

The aim of this study is to assess the validity of the Rome severity classification in distinguishing the severity of AECOPD based on short-term mortality and other adverse outcomes, including ICU admission, MV and IMV, et al, through a large, real-world and multicenter cohort of patients hospitalized for AECOPD in China.

Materials and Methods

Ethical Considerations

Our study complies with the Declaration of Helsinki. And it was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University, and the Ethics Committee of the other nine academic medical centers that participated. Written informed consent was obtained from all participants.

Study Design and Participants

We performed a secondary analysis based on the data collected from the prospective, multicenter and noninterventional cohort study, MAGNET AECOPD (MAnaGement aNd advErse ouTcomes in inpatients with acute exacerbation of COPD) Registry study (ChiCTR2100044625) in China. In the MAGNET study, adult inpatients diagnosed with AECOPD were consecutively enrolled between September 2017 and July 2021 in ten hospitals and followed-up by telephone, outpatient visits, or rehospitalization when necessary. The admission, arrangement of auxiliary examinations and treatment of patients were at the discretion of the attending physicians, and no additional direct intervention was performed. The inclusion criteria, as well as the diagnosis criteria of AECOPD include: (1) a history of COPD defined according to 3 items: 1) exposure to risk factors (eg, tobacco smoking, specific environmental exposure); 2) long-term dyspnea (progressive, on exertion or persistent), chronic cough, or sputum production; 3) post-bronchodilator spirometry testing performed (forced expiratory volume in 1-second/forced vital capacity ratio (FEV1/FVC) <70%); and (2) an acute worsening of respiratory symptoms resulting in additional therapy. Patients were excluded from the analysis if they met any of the following criteria: (1) age less than 40 years; (2) no available information on parameters to assess the severity according to the Rome classification, including HR, RR, CRP, SaO2 or the evidence of VAS scores.

Data Collection and Severity Classification

A standardized case report form including baseline demographics, comorbidities, symptoms, vital signs, laboratory tests, radiological findings, treatments and adverse outcomes was completed for every patient enrolled in the MAGNET AECOPD Registry study. RR, HR and other vital signs were taken and recorded within 2 hours after admission. Almost all blood test results were obtained within 24 hours of admission.

Based on the information gathered at admission, all AECOPD patients were categorized as mild, moderate, or severe (Table S1). First, severe AECOPD events are defined by arterial blood gas values indicating hypercapnia (PaCO2>45 mm Hg) and acidosis (pH< 7.35). If one’s arterial blood gas values could be obtained and show hypoxemia (PaO2<60 mmHg) and/or hypercapnia (PaCO2 >45 mmHg) but no acidosis (pH >7.35), the patient would be identified as moderate. Patients were also classified as moderate when they met at least 3 of the 5 variables: dyspnea VAS≥5, RR≥24 breaths/min, HR≥95 bpm, CRP≥10 mg/L or resting SaO2<92% when breathing ambient air or usual oxygen prescription. The other patients were directly categorized as mild. As VAS scores were not routinely obtained in clinical practice, we retrospectively determined VAS scores based on the medical records and nurse’s description of the severity of dyspnea on admission.

Study Outcomes

The primary outcome was defined as 60-day all-cause mortality after admission. Secondary outcomes involved in-hospital all-cause mortality, ICU admission, MV, IMV and length of stay (LOS). The usage of glucocorticoids and antibiotics was also included in the analysis, as they can reflect disease severity.

Statistical Analysis

Quantitative variables with normal distribution were denoted as the mean values with standard deviation (SD) and compared using ANOVA tests. Quantitative variables with skewed distribution were depicted as medians with interquartile ranges (IQRs) and were compared using the Mann–Whitney U-test. The Kolmogorov–Smirnov test was used to assess the normality of distributions. Qualitative variables (categorical variables) were displayed as absolute frequencies with percentages, and Pearson’s chi-squared test (Fisher’s exact test for frequencies <5) was used for group comparisons. Dunn’s test with a Bonferroni correction for multiple comparisons was applied. Univariate regression analysis reporting odds ratios (ORs) with 95% confidence intervals (95% CIs) was conducted to determine whether there was a relationship between the Rome severity classification and adverse outcomes. Time-to-event analyses were performed with Kaplan‒Meier curves to evaluate the cumulative risks of 60-day mortality among the mild, moderate, and severe groups. All statistical analyses were conducted using SPSS version 22.0 (IBM, New York, United States). All P values were two-tailed, and a P value <0.05 indicated a statistically significant difference.

Results

Study Population

A total of 14,007 patients were consecutively enrolled in the MAGNET AECOPD Registry study. Among them, 7712 were included in this analysis. The main reasons for exclusion were as follows: (1) age less than 40 years (n=27); (2) lacking HR record on admission (n=11); (3) lacking RR record on admission (n=28); (4) lacking CRP record (n=3805); (5) lacking SaO2 record on admission (n=1297); and (6) lacking evidence of VAS on admission (n=1127). The mean age of the population was 72.68±10.61 years, and 77.6% were male. Approximately 18.9% were active smokers. According to the Rome severity classification, 3230 (41.88%) AECOPD inpatients were categorized as mild, 3110 (40.33%) were categorized as moderate and 1372 (17.79%) were categorized as severe. The 60-day mortality and in-hospital mortality rates were 3.1% and 2%, respectively. A total of 785 (10.2%) patients were admitted to the ICU during the hospital stay, 2000 (26.9%) patients received MV, and 378 (4.9%) patients received IMV during their hospital stay. The flow chart of the study is shown in Figure 1.

Figure 1 Flow chart of the study.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; HR, heart rate; bpm, beats per minute; RR, respiration rate; CRP, C-reactive protein; SaO2, Arterial Oxygen Saturation; VAS, visual analog scale.

Baseline and Clinical Characteristics of Included AECOPD Patients

The baseline characteristics are summarized according to the severity of AECOPD based on the Rome classification in Table 1. Gender and current smoker distribution were comparable among groups. It is surprising that the patients who experienced a mild AECOPD event were older, while those who experienced a severe AECOPD event were slightly younger. Patients were more likely to experience reduced mobility, a history of exacerbation in the last year, or accept long-term home oxygen therapy if their severity gradings were classified more severe. A negative association was observed between body mass index (BMI) and severity of AECOPD, as the proportion of BMI≤17 kg/m2 in the mild group were less than those in the moderate or severe group. Additionally, the FEV1 pred% of the mild group was significantly higher compared to the moderate or severe group. Higher DECAF scores and BAP-65 scores were related to more severe severity according to the Rome classification. The incidence of most comorbidities, including coronary heart disease, heart failure, arrhythmia, stroke, bronchiectasis, interstitial lung disease (ILD), chronic pulmonary heart disease, active cancer, diabetes, chronic renal failure, anxiety or depression and osteoporosis, was higher in the mild or moderate group than in the severe group. The prevalence of hypertension, pulmonary tuberculosis, obstructive sleep apnea-hypopnea syndrome (OSAHS) and gastroesophageal reflux disease (GRED) was generally comparable among the groups.

Table 1 Baseline Characteristics of Patients According to AECOPD Severity Based on the Rome Severity Classification

Table 2 shows symptoms, vital signs and laboratory parameters for patients stratified according to the Rome classification. The moderate and severe groups were more likely to have sputum and lower diastolic blood pressure than the mild group. The complete blood counts demonstrated higher red blood cell (RBC), white blood cell (WBC) and neutrophil percentages in the moderate and severe groups compared with the mild group; in contrast, the moderate and severe groups had lower eosinophil percentages than the mild group. The levels of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and troponin T (cTNT) were higher in the moderate and severe groups than in the mild group. Radiologic abnormalities, including consolidation and pleural effusion, were more commonly seen in patients classified as moderate.

Table 2 Clinical Features of Patients According to AECOPD Severity Based on the Rome Severity Classification

Variables Included in the Rome Severity Classification

As shown in Tables 3 and S2, patients in the moderate group had significantly faster RR (21 vs 20 breaths/min), HR (93 vs 82 bpm), higher CRP (17.1 vs 6.78 mg/L), PaCO2 (49.0 vs 38.0 mmHg), and proportion of dyspnea with VAS score >5 (33.2% vs 13.3%) as well as lower levels of SaO2 (95.7 vs 97.0%) and PaO2 (78.0 vs 84.7 mmHg) than those in the mild group (all P < 0.001). The value of PaCO2 and proportion of VAS score >5 indicated a significantly worse breathing condition in patients classified as severe compared with those classified as moderate (68.05 vs 49.0 mmHg, 100% vs 33.2%, respectively). However, the value of CRP (11.09 vs 17.1 mg/L) was unexpectedly lower and the level of PaO2 (85.4 vs 78.0 mmHg) was unexpectedly higher in the severe group than in the moderate group.

Table 3 Criteria for Determining AECOPD Severity According to the Rome Classification

Clinical Outcomes According to the Rome Severity Classification

The comparison of outcomes is shown in Table 4, and the multiple comparison is shown in Figure 2. The incidence of ICU admission (6.4% vs 12.0% vs 14.9%, P <0.001), mechanical ventilation (11.7% vs 33.7% vs 45.3%, P <0.001) and invasive mechanical ventilation (1.4% vs 6.8% vs 8.9%, P <0.001) increased with the severity of AECOPD from the mild group to the severe group according to the Rome severity classification. Although the moderate and severe groups had higher 60-day mortality than the mild group (3.5% vs 1.9%, 4.3% vs 1.9%, P <0.05, respectively), mortality in the severe group was very close to that in the moderate group (3.5% vs 4.3%, P >0.05). The results for in-hospital mortality showed the same trend, difference of in-hospital mortality between the moderate and severe groups was not significant (2.5% vs 2.6%, P >0.05) despite the moderate group and severe group had higher mortality than the mild group respectively (2.6% vs 1.1%, 2.5% vs 1.1%, P <0.05). The administration of systemic glucocorticoids increased with the severity of AECOPD from the mild group to the severe group (P<0.001), while the moderate group received antibiotics more often than the mild or severe group.

Table 4 Outcomes According to AECOPD Severity Based on the Rome Classification

Figure 2 Multiple comparison of adverse outcomes in inpatients with varied AECOPD severity according to the Rome classification (*P value<0.05).

Abbreviation: ICU, intensive care unit.

The results of univariate logistic analysis on adverse outcomes in inpatients with AECOPD are shown in Table 5 and Table 6. Similarly, the risk of death at 60 days after admission was significantly higher in the moderate and severe groups than in the mild group (ORs: 2.38 vs 1, 1.92 vs 1.00, respectively, P=0.001), while there was no significant difference in the risk of 60-day mortality between the severe group and the moderate group (ORs: 0.81 vs 1.00, P=0.206). The increase in the Rome severity classification was significantly associated with an increased risk of ICU admission (mild vs moderate vs severe ORs: 1.00 vs 1.97 vs 2.55, P <0.001) and IMV (mild vs moderate vs severe ORs: 1.00 vs 5.15 vs 6.91, P <0.001). The Kaplan–Meier curves also demonstrated similar results (Figure 3). That is, the severe and moderate groups had significantly worse 60-day survival than the mild group (both P <0.05), but the survival was not significantly different between the severe group and the moderate group (P >0.05).

Table 5 Univariate Logistic Analysis on 60-Days Mortality in Inpatients with AECOPD

Table 6 Univariate Logistic Analysis on ICU Admission and Invasive Ventilation Use in Inpatients with AECOPD

Figure 3 Kaplan–Meier estimates in-hospital survival in patients with varied AECOPD severity.

Abbreviation: AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

Discussion

Through a large multicenter cohort of AECOPD patients, we revealed that the Rome severity classification could excellently distinguish the risk of ICU admission, MV and IMV. However, more studies are needed to determine whether it can reliably discriminate the risk of short-term mortality.

Several studies have been published, aiming to validate the Rome severity classification in AECOPD patients. A retrospective study conducted in 200 Spanish inpatients with AECOPD revealed that the Rome classification lacked the capacity to classify the severity of AECOPD compared with the Spanish COPD Guidelines (GesEPOC) classification.11 Carmen et al applied the Rome classification to a cohort of 364 hospitalized patients with AECOPD in the Netherlands and found that the Rome classification can differentiate between exacerbation events with different short-term mortality rates.12 The study conducted by Lee et al in Korea found excellent performance of the Rome classification for predicting ICU admission and the need for noninvasive mechanical ventilation (NIV) or IMV and acceptable performance for predicting in-hospital mortality by comparing the Rome classification with the DECAF score and GesEPOC 2021 criteria.13 Our findings concerning the association between the Rome severity classification and the need for ICU admission and MV were highly consistent with Lee’s findings. However, the Rome classification worked poorly in our cohort compared to Lees and Carmen’s studies in identifying the difference in mortality rates between the moderate and severe groups. The inconsistent results might be attributed to differences in the characteristics of patient cohorts and the geographical setting of different studies. The global variability in the available resources to treat patients with AECOPD and local customs may affect the criteria for hospital visits and admissions and thus may also contribute to the differences in study results. Notably, the three studies mentioned above are all single-center, small-sample studies, which inevitably induces selection bias and weakens the power of these studies. In the present study, we consecutively included unselected inpatients with AECOPD from 10 tertiary general hospitals in China, which should represent real-world situations.

The physiologic parameters (VAS, HR, RR, SaO2) and inflammatory biomarkers (CRP) included in the Rome severity classification are all easy to obtain and have been tested as prognostic factors of AECOPD in some previous studies. The VAS offers the benefit of quantitatively representing ventilatory demand on a scale from 0 to 10,14 and the scale has been validated against respiratory loads in patients with COPD.15 The proportion of VAS scores >5 increased with disease severity in our cohort. Several studies showed that an elevated HR or RR was associated with exacerbation,16,17 readmission9,18 and correspondingly early mortality in COPD patients.19,20 We also found faster HR and RR in the moderate and severe groups than in the mild group in the study. Furthermore, the two variables could be measured easily and noninvasively in the clinic.21 It is not difficult to foresee that the two variables could facilitate the application of the Rome classification in the management of COPD, as smartphones and wearable device technology are gradually used to facilitate early detection and treatment of AECOPD.22,23 CRP, an acute-phase protein that can be measured accurately within minutes at the point of care, is a biomarker for assessing AECOPD since elevated CRP is associated with the need for antibiotics and higher mortality.24,25 Although using CRP as a marker of airway inflammation may lack specificity, CRP is widely recognized as a useful and sensitive marker of infections and AECOPD.26 SaO2 is a reflection of gas exchange in AECOPD patients. It is more practical and widely available to measure pulse oximetry in all clinical settings, although SaO2 is less reliable than arterial blood gas analysis. Some studies showed that a reduction in oxygen saturation was associated with AECOPD risk;23,27 unfortunately, the change in SaO2 from baseline was not used to distinguish mild versus moderate events because of its unavailability in this post-hoc analysis. Therefore, future studies are needed to validate the reduction in SaO2 in assessing the severity of AECOPD. Acute respiratory failure with hypoxemia and/or hypercapnia and acidosis is the first and possibly most important clinical feature observed in patients with severe AECOPD,28 and the mortality risk is higher at lower pH values.29 Based on this fact, arterial blood gas analysis was the only criterion that was used to determine the severe group in the Rome classification. Theoretically, the incorporation of objective, easy and ready-to-measure variables in this proposed classification may assist in a better delineation of clinically different AECOPD.

However, the Rome classification should not be considered as a complete version. First, the criteria included in the severity classification are single-minded based on a review of the literature and discussion. ABG alone may not be sufficient to determine severe AECOPD events. It is unquestionable that COPD is a heterogeneous illness underpinned by diverse clinical characteristics and pathophysiological mechanisms.30 Although there are several markers that potentially indicate AECOPD severity, none have received widespread acceptance. As stated by Ramakrishnan et al, the different endotypes of AECOPD severity cannot be assessed by solely focusing on inflammatory or pathophysiological parameters.31 Our research team previously discovered that blood urea nitrogen (BUN), a component of BAP-65, was linked to an increased risk of in-hospital death and other adverse outcomes in AECOPD inpatients.6,32 Moreover, the baseline parameters, especially dyspnea in the stable stage, may have an impact on how this exacerbation may turn out.33,34 Comorbidities like heart failure, arrhythmia, coronary heart disease, and diabetes, which are highly prevalent in COPD patients, also contribute to event severity in the real-life clinical setting. Therefore, baseline parameters and the existence of comorbidities may also need to be considered to incorporate into the severity assessment for AECOPD. Second, the threshold setting seems to be arbitrary. Taking CRP as an example, in our research, serum CRP levels were interestingly the highest in moderate events, with 62.2% of patients having a CRP above 10 mg/L. Similar results were also found by the two studies mentioned earlier and conducted in the Netherlands and Korea, respectively.12,13 This revealed that a cutoff value of 10 mg/L may lack specificity to distinguish a moderate event from a severe one, and the mechanism linking CRP to the exacerbations of COPD may be complex and requires further researches. Probably due to the two flaws mentioned above, the Rome classification is valid in discriminating between mild and more severe AECOPD but fails to distinguish between moderate and severe AECOPD. Last, it is currently difficult to suggest optimal medical treatments according to AECOPD severity based on the Rome classification. In this cohort study, patients admitted with mild Rome AECOPD were slightly older and suffered from more comorbidities, suggesting that these factors, rather than the severity of acute respiratory events, contributed to the indication for hospitalization. Therefore, whether the Rome classification could be used as an indicator for hospitalization for AECOPD is debated. In addition, patients in the severe group needed more ICU admissions and mechanical ventilation than those in the moderate group, while the mortality did not increase accordingly. A possible explanation is that the strengthened treatments received by severe AECOPD patients may contribute to an improve in short-term survival; a more likely explanation is that this classification does lack a distinction between moderate and high mortality risks because of the flaws mentioned above. Consequently, the Rome classification needs to be optimized in the selection of variables and corresponding thresholds based on prospectively studies.

To our knowledge, this is the first large-scale multicenter cohort study to validate the Rome classification. Moreover, the consecutive inclusion of unselected inpatients with AECOPD and comprehensive collection of information in our study ensured high data quality and true associations between the Rome classification and risk of adverse outcomes in the real-world setting. Importantly, this study provided important initial insights into the distinctive value of the proposed classification in the Chinese population, and the Rome severity classification is the first step to differentiate clinically different AECOPD. Nevertheless, our study has several limitations. First, the VAS score was retrospectively evaluated based on the medical records and nurse’s description of the severity of dyspnea on admission, which inevitably leads to a bias. Fortunately, not all patients require a VAS score to be classified, and only those who already meet two out of the 5 moderate criteria need a VAS score to determine whether they are moderate. In addition, an exact VAS score was not necessary; alternatively, we only needed to evaluate whether the patient had significant dyspnea (VAS≥5 vs <5), which facilitates the accuracy of this retrospective evaluation based on detailed medical records on admission. Second, our study only allows the applicability of the Rome classification to be assessed in the hospital setting and not in the primary care setting, and how the Rome classification works in outpatient clinics or communities is still unclear. Finally, the exclusion of patients because of missing data may result in selection biases and affect the external validity of the results. But the original data is from an noninterventional cohort study, and the arrangement of auxiliary examinations and treatment of patients were at the discretion of the attending physicians, which should reflect the real-world application circumstance of Roma classification in China. Additionally, we found that the excluded patients tend to have milder conditions, with lower mortality rates (data not shown) and a greater likelihood of being classified to the mild group. So even if these patients were included, we believe the results would hardly change. Thus, optimization and prospective validation of the classification and a deeper exploration of its prognostic applicability in making therapeutic decisions remain pending.

Conclusion

It is essential for an AECOPD severity assessment tool to accurately identify patients at high risk for adverse outcomes. In this large cohort study, the Rome severity classification demonstrated excellent performance in predicting ICU admission and the need for MV or IMV but failed to distinguish the risk of short-time mortality between the moderate and severe groups. Studies are warranted to validate whether it could accurately evaluate the risk of mortality, and further optimization may still be needed before clinical application.

Abbreviations

AECOPD, Acute exacerbations of chronic obstructive pulmonary disease; COPD, Chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MAGNET AECOPD, MAnaGement aNd advErse ouTcomes in inpatients with acute exacerbation of COPD) Registry; FEV1/FVC, forced expiratory volume in 1-second/forced vital capacity ratio; HR, heart rate; bpm, beats per minute; RR, respiration rate; CRP, C-reactive protein; VAS, visual analog scale; PaCO2, arterial carbon dioxide tension; pH, hydrogen ion concentration; PO2, arterial oxygen tension; SaO2, Arterial Oxygen Saturation; ICU, intensive care unit; MV, mechanical ventilation; IMV, invasive mechanical ventilation; LOS, length of stay; SD, standard deviation; ANOVA, one-way analysis of variance; IQR, interquartile range; ORs, odds ratios; 95% Cis, 95% confidence intervals; SPSS, Statistic Package for Social Science; BMI, body mass index; Kg/m2, kilogram per square meter; ILD, interstitial lung disease; LTOT, Long-term home oxygen therapy; RBC, red blood cell; WBC, White blood cell; NEUT, neutrophil percentage; EOSR, Percentage of eosinophils; SBP, Systolic blood pressure; DBP, diastolic blood pressure; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; cTNT, Cardiac troponin T; NIV, noninvasive mechanical ventilation; GesEPOC, Spanish COPD Guidelines; BUN, serum urea nitrogen.

Data Sharing Statement

The data will be shared on reasonable request to the corresponding author.

Ethics Approval and Informed Consent

This study was approved by the Ethics Committee of the ten academic medical centers that participated. Written informed consent was obtained from all the participants. This study complies with the Declaration of Helsinki.

Funding

This study was supported by the National Natural Science Foundation of China (82370021), the Sichuan Science and Technology Program (2022YFS0262), the Suzhou Collaborative Medical Health Foundation (Y117) and National Key Research Program of China (2016YFC1304202).

Disclosure

The authors report no conflicts of interest in this work.

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  • Source link

    Introduction

    The SARS-CoV-2 virus, which can harm several human organs, is the origin of COVID-19. The respiratory system is the organ system that is affected the most frequently. The range of pulmonary complications includes pneumonia brought on by alveolar injury, acute respiratory distress syndrome (ARDS), and changes to the coagulation cascade that result in lung infarction via thrombi and emboli. Patients who are brought to the ICU after being diagnosed with COVID-19 pneumonia frequently have invasive mechanical ventilation, and in these situations, the mortality risk is substantial for patients with advanced disease. In critically ill patients, pneumothorax is a frequent side effect of invasive mechanical ventilation (IMV).1

    Pneumothorax is a potentially fatal complication and a medical emergency and is described as the presence of air in the gap between the parietal and visceral pleura, with or without lung collapse. Pneumothoraxes can be categorized as spontaneous, which can be primary, secondary, or traumatic, depending on the origin. Diagnostic or therapeutic procedures, including central venous catheter implantation, thoracentesis, lung and/or pleural biopsy, barotrauma, and similar procedures, might result in traumatic pneumothorax.2–4

    Pneumothorax occurs about 1% of the time in COVID-19 patients who need hospital admission and 2% of the time in ICU patients. IMV usage among COVID-19 hospitalized patients ranges from 17% to 42% overall, with non-survivors experiencing higher rates of usage (57% to 59%) compared to survivors (1–15%).2,3 Pneumothorax is more common in critically ill COVID-19 patients with ARDS. ARDS and pneumothorax together have led to a protracted hospital stay and a high fatality rate.3–5

    The majority of COVID-19 patients have higher oxygen requirements, which raises the need for intensive care and invasive mechanical ventilation. This places a significant strain on healthcare systems. These patient populations have relatively high rates of pneumothorax.2,6,7

    The occurrence of pneumothorax in COVID-19 ICU patients who were placed on invasive ventilation has been detailed in numerous papers.1,2 Advanced age, prior lung problems, disease stage, and comorbidities like hypertension, diabetes mellitus, and malignancy are additional risk factors.2,6

    There is conflicting information regarding the link between pneumothorax and mortality in COVID-19 patients; previous studies reported it as a separate indicator of a bad prognosis, whereas newer research has tended to support the link between pneumothorax and high mortality. When IMV, septic shock, and tension physiology are present, the mortality and recovery rates for individuals who have pneumothorax are lower than for those who experience procedure-related pneumothorax.2,3,5

    However, there is a scarcity of data on the complications associated with the use of invasive mechanical ventilation in the treatment of COVID-19. Previous research indicated that the prevalence of problems was rising internationally in critically ill patients and that clinical observations during the previous year in the ICU indicated a rise in the incidence of pneumothorax. The information gained on the magnitude and associated factors for the development of pneumothorax in COVID-19 patients will help clinicians and policymakers prevent the burden of the disease at some level.8,9 The study aimed to assess factors associated with pneumothorax among mechanically ventilated COVID-19 ICU patients at Eka Kotebe General Hospital, Addis Ababa, Ethiopia.

    Methods

    Study Area and Period

    This study was conducted at Eka Kotebe General Hospital, the national COVID-19 treatment centre in Addis Ababa, Ethiopia. The date when data were accessed for research purposes was between August 1, and August 31, 2022, GC.

    Study Design

    A case-control study design was employed to conduct the study.

    Study and Source Population

    The source population for the cases was COVID-19 patients admitted to Eka Kotebe General Hospital ICU ward who were mechanically ventilated and diagnosed with pneumothorax.

    The source population for the control group was COVID-19 patients admitted to Eka Kotebe General Hospital ICU ward who were mechanically ventilated and were not diagnosed with pneumothorax.

    The study population for the cases was all selected COVID-19 patients who were admitted to Eka Kotebe General Hospital ICU Ward and who were on mechanical ventilation and diagnosed with pneumothorax during the study period.

    The study population for the control group was all selected COVID-19 patients who were admitted to Eka Kotebe General Hospital ICU Ward and who were on mechanical ventilation and were not diagnosed with pneumothorax during the study period.

    Inclusion and Exclusion Criteria

    For cases, all medical records of COVID-19-confirmed ICU patients who were mechanically ventilated and diagnosed with pneumothorax were included, and patients with incomplete medical records were excluded from the study.

    For controls, all medical records of COVID-19-confirmed ICU patients who were mechanically ventilated and were not diagnosed with pneumothorax were included, and patients with incomplete medical records were excluded from the study.

    Sample Size Determination and Sampling Procedure

    The sample size was calculated using Open Epi software based on factors associated with pneumothorax.3,5 Using an odds ratio of 2.20, 95% CI, 80% power, 35% of controls exposed, and the ratio of controls to cases 2, which yields a total sample size of 281 after adding 10% for chart loss.

    A simple random sampling technique was used to select the study participants for both cases and controls. There were a total of 1200 mechanically ventilated (both invasive and non-invasive ventilation) patients admitted at Eka Kotebe General Hospital from March 2021 to April 2022. From this, a total of 281 mechanically ventilated patients were selected from the chart using a simple random sampling technique at Eka Kotebe General Hospital, of which 94 were cases and the rest 187 were controls.

    Dependent Variable

    Independent Variables

    • Demography: Age, Sex, Occupation, Residence
    • Clinical conditions: Status of a patient at admission, Onset of dyspnea, Smoking history, History of chronic lung disease, Severity status and duration of ARDS, Need for tracheostomy, Duration of Invasive Mechanical ventilation
    • Comorbidities: Asthma, COPD, Cardiovascular diseases, Diabetic Mellitus, Chronic kidney diseases, Malignancy, Pulmonary TB, HIV/AIDS
    • Imaging and Lab Profile: Change in lung structure such as the presence of fibrosis, consolidation, emphysema-like change or pulmonary cyst, leukocyte count
    • Change in MV reading: PEEP, FiO2, Peak pressure.

    Data Collection Tools and Procedure

    The data was collected by using a pretested, structured checklist that was adopted from reviewing different related literature.2,10,11 The checklist had five major sections: socio-demographic, comorbidities, clinical conditions, imaging and lab profiles, and changes in MV readings. A total of 281 mechanically ventilated patients’ charts were reviewed. The data was collected by an electronic data collection tool, ODK (Kobo Tool Box), by three general practitioners working in the ICU and supervised by a senior general practitioner working at the ICU from August 1, 2022, to August 31, 2022.

    Data Management and Analysis

    After training was given to data collectors and supervisors to ensure the validity and reliability of the data collection tool, a pre-test was done on 5% of the total sample size before the actual data collection, and the questionnaires were checked for clarity, understandability, and simplicity.

    The principal investigator checked the collected data, and any incomplete documents were cleaned and checked for quality before being exported from the Kobo Toolbox to SPSS for analysis.

    Descriptive analysis was done using simple frequencies and proportions, and the results were presented in tables, graphs, and words. A binary logistic regression model was used to assess the association between the independent variable and the outcome variables. Odds ratio, p-value, and 95% CI for odds ratio were used for testing significance and interpreting results. Variables with a p-value of =0.05 were considered to have statistical significance.

    Ethical Consideration

    An ethical clearance paper was obtained from the Eka Kotebe General Hospital institutional review board with a reference number of Eka/150/5/132. In each step, the data obtained from this study was kept confidential and secured not to be used for any other purpose except for this study, and patient consent to review their medical records was not required by the approving ethics committee. Additionally, authors did not have access to information that could identify individual participants during or after data collection. The study complies with the Declaration of Helsinki.

    Result

    Socio-Demographic Characteristics

    A total of 281 (94 cases and 187 controls) charts of admitted patients over the past two years in the ICU were carefully reviewed and data entered. The mean age of patients who were ventilated during the study period was 58.1 (SD = 16.7), where 94 years was the maximum and the minimum age recorded was 19 years. Sixty (63.8%) of the cases and 118 (63.1%) of the controls were males, while thirty-four (36.2%) of the cases and 69 (36.9%) of the controls were found to be females. Patients who came from the main city (Addis Ababa) constituted the largest portion (cases 82 (87.2%) and controls 163 (87.2%)); followed by the Oromia region (cases 5 (5.3%) and controls 11 (5.9%) (Table 1).

    Table 1 Socio-Demographic Characteristics for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU in Addis Ababa, Ethiopia, 2022 (n=281)

    Presenting Symptoms, Comorbidity, and COVID-19 Severity Status

    Cough was the dominant presenting symptom among admitted patients, contributing 92 (97.9%) for cases and 174 (93.0%) for controls, followed by shortness of breath, 85 (90.4%) for cases, and 166 (88.8%) for controls. The third and fourth presenting symptoms were fatigue and fever, which contributed 77 (81.9%) for cases, 149 (79.7%) for controls, and 72 (76.6%) for cases and 121 (64.7%) for controls, respectively. Loss of sense of smell and taste were more common among controls than cases (26.7%, 28.3%, 23.4%, and 22.3%, respectively). Controls were presented with symptoms of headache more commonly than cases (42.2%) and 40.4%, respectively. The onset of dyspnea or shortness of breath before hospital admission was more common among cases (92.6%) than controls (88.2%), while the onset after hospital admission was less common among cases (7.4%) than the controls (11.8%). On the other hand, COVID-19 severity status at admission was more likely to occur among cases (61.7%) than controls (60.4%), and patients with mild or moderate admission status were more common in the controls group (2.1%) than cases (1.1%). Patients with critical status during hospital admission had an almost equal occurrence rate among cases (37.2) and controls (37.3) (Table 2).

    Table 2 Presenting Symptoms, Comorbidity, Admission Vital Signs, and COVID-19 Severity Status for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n = 281)

    Vital Signs of the Study Participants During Admission

    Normal pulse rate was more common among cases (67.0%) than controls (58.8%), while high pulse rate was recorded more commonly among controls than cases. A nearly equal number of patients with high respiratory rates were present among the cases (92.6%) and controls (95.7%) groups. The majority of patients maintain their oxygen saturation level above 89% among cases and controls during admission while they are on oxygen support. Patients who came with an oxygen requirement of 1–5 liters, 6–25 liters, and mechanical ventilation were more likely to develop pneumothorax as compared to the control group, whereas those who did not need any oxygen support during admission were more likely to belong to the control group (Table 3).

    Table 3 Admission Vital Signs for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=281)

    Comorbidity Status of the Respondents

    Comorbid diseases were most likely to occur among both cases (69.1%) and controls (71.7%). Hypertension was more common among cases (38.3) than controls (33.7%), while diabetes mellitus was less common among patients with pneumothorax (27.7%) than patients with no pneumothorax (41.7%). Chronic obstructive pulmonary disease, malignancy, and pulmonary tuberculosis were the least common comorbid conditions among both cases and controls (Table 4).

    Table 4 Comorbidity Status for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=281)

    ICU Admission Laboratory Profiles and Imaging

    Most patients had a high WBC count when they were admitted to the ICU; the high count was more prevalent among cases (79.8%) than controls (77.5%). Patients who were categorized as cases were more likely to experience high BUN and creatinine counts during ICU admission than those who were”controls. Chest X-ray features of consolidation, GGO, and infiltration were more likely to happen among cases (Table 5).

    Table 5 Laboratory Profiles and Imaging Features for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=281)

    Medication, Ventilation, and Tracheostomy

    Almost all patients took antibiotics, steroids, and anticoagulants during their hospitalization. Remdesevir was found to be a rarely administered drug, but only 22.3% of cases and 25.7% of controls took it during their hospital stay. Most patients who were under control (82.9%) took noninvasive/CPAP ventilation compared to cases (74.5%) which resulted in a mean duration of 5.23 (SD = 3.90) days. Twenty and 100% were the maximum PEEP and FIO2 the patients were getting, respectively. On the other hand, nearly all patients were on invasive ventilation among cases (91.5%) compared to controls (61.5%). The maximum number of days a patient stayed on invasive ventilation was 36, while a day was the minimum period a patient was intubated (Table 6).

    Table 6 Medication, Ventilation and Tracheostomy for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients at Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=287)

    ARDS and Outcome

    Acute respiratory distress syndrome (ARDS) was the dominant feature among cases that resulted in 87 (92.6%) patients experiencing the disease, while 60.4% of patients without pneumothorax developed the syndrome. Most of the patients who had pneumothorax were dead (94.3%) as compared to the control group (74.3%). However, patients who belonged to the control group had a higher chance of being discharged to their homes or transferred to another facility (Table 7).

    Table 7 ARDS and Outcome for Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients Who Were Admitted to the Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=287)

    Duration of Pneumothorax Diagnosed After Hospital Admission, Mechanical Ventilation, and Site of Pneumothorax the Patient Developed

    Patients tended to develop pneumothorax on average 13.14 (SD = 7.6) days after hospital admission and 7.81 (SD = 6.13) days after invasive or noninvasive ventilation. 48.9% of patients developed pneumothorax in both lungs, followed by the right lung. Only 19 patients out of 94 were diagnosed with pneumothorax on the left side of their lungs.

    Factors Associated with Pneumothorax

    The following list of variables showed a significant association with pneumothorax in the bivariable analysis. Among socio-demographic factors included in the study, age <= 35 years, fever, cough, chest pain, oxygen requirement, DM, noninvasive ventilation, invasive ventilation, tracheostomy done for ARDS, and outcome (death) showed a significant association with pneumothorax in the bi-variable analysis.

    After adjustment for possible confounders in multivariable binary logistic regression analysis, ARDS and invasive ventilation have a significant association with the outcome variable at 95% CI (p <0.05) (Table 8).

    Table 8 Logistic Regression Analysis on Determinants of Pneumothorax Among Mechanically Ventilated COVID-19 Patients at Eka Kotebe General Hospital ICU, Addis Ababa, Ethiopia, 2022 (n=281)

    Discussion

    Pneumothorax has been a recognized complication among COVID-19 patients, with an increased incidence among mechanically ventilated patients.1,3,4,8,11 In our study, pneumothorax was observed in our patients on an average of 13 days after admission, while some studies reported pneumothorax in the post-COVID-19 phase.12,13 Pneumothorax develops more frequently on the right side, followed by the left, with a few having bilateral disease. This was not demonstrated in our study, where 48.9% had bilateral disease, followed by right-side disease, and lastly, left-side pneumothorax. Our study showed that 63.8% of the patients with pneumothorax were men, this could be explained by smoking status which is common in men, and this result agrees with findings in many papers.1,3,4,8,9,11,14,15 Cough (97.8%), shortness of breath (90.4%), fatigue (81.9%), and fever (76.6%) were the most common symptoms among this group. Laboratory parameters in these patients showed that they were more likely to have an elevated white count. A study from Spain, also demonstrated that COVID-19 patients developing spontaneous pneumothorax more frequently had an increased leukocyte count.2

    Although 69.1% of the patients with pneumothorax had associated comorbidities, this did not reach statistical significance. Like the majority of the studies, the presence of comorbidities is not associated with an increased risk of developing pneumothorax, but some suggest patients with an underlying lung disease have an increased incidence.1,4,7,14–16 This study also found that those under the age of 35 had a lower incidence of the disease, unlike the conclusion made by other studies.

    In this study, the odds of developing pneumothorax in patients who had not been on invasive ventilation were reduced by 69% compared to those patients who were on invasive ventilation. Similarly, a study conducted in the USA showed the overall incidence of pneumothorax in critically ill patients was 83/842 (10%), and in mechanically ventilated patients was 80/594 (13%). Retrospectively collected and analyzed medical records of COVID-19 patients complicated by pneumothorax in China showed a 56% prevalence rate of the disease in patients that require invasive mechanical ventilation as compared to other noninvasive ventilator support.7

    The study also revealed that patients who have been diagnosed with ARDS have a 71% higher risk of developing pneumothorax than those who were not diagnosed with ARDS. A similar study from China showed that major factors contributing to the development of pneumothorax were the onset of dyspnea, chronic lung disease, smoking history, severity and duration of ARDS, and changes in lung structure during ARDS (fibrosis, consolidation, pulmonary cysts, and emphysema-like changes).7 This could be explained by the severity of COVID-19 infection with concomitant secondary bacterial infection that results in compromised lung function and features of acute respiratory distress syndrome, which leads to invasive or noninvasive ventilation requirements and the development of pneumothorax.

    COVID-19 patients with pneumothorax are known to have a higher mortality rate compared to those without pneumothorax. The mortality rate has ranged from 47.2% to 86.3%.3,4,7,8,11,12,14–16 The association between in-hospital mortality and pneumothorax was also reported in another meta-analysis.17 This study found that 94.3% of COVID-19 patients with pneumothorax admitted to the ICU died, compared to 74.3% of those without pneumothorax. As a result, we can state that pneumothorax played a major role in deaths of cases compared to deaths of controls that had been invasively or noninvasively ventilated. Thus, it is unequivocally demonstrated that preventing pneumothorax and its associated complications in this specific patient group significantly enhances survival outcomes.

    Conclusion and Recommendation

    In this research, ARDS and invasive ventilation have been significantly associated with the development of pneumothorax. There is a high chance of developing pneumothorax when a patient is put on mechanical ventilation for respiratory support at the COVID-19 ICU and being diagnosed with acute respiratory distress syndrome may lead to the development of pneumothorax through the requirement of invasive or noninvasive ventilation.

    Health facilities should be well equipped with recent medical equipment in the intensive care unit and with well-trained and organized manpower. All health professionals should follow their patients who are on invasive or noninvasive mechanical ventilation cautiously in the intensive care unit, high dependency unit, and other severe wards and look for any clinical signs and symptoms of ARDS, sepsis, or any respiratory disorders. Clinicians should look for any signs of pneumothorax, make a diagnosis, and treat it as early as possible.

    There has to be further prospective research done to look for other variables, with further imaging and other COVID-19 treatment centres included.

    Abbreviations

    ARDS, acute respiratory distress syndrome; CLD, chronic lung disease; COPD, chronic obstructive pulmonary disease; FIO2, fraction of inspired oxygen; MERS, Middle East Respiratory Syndrome; PEEP, positive end-expiratory pressure; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus-2; SP, spontaneous pneumothorax.

    Acknowledgments

    We would like to thank Eka Kotebe General Hospital for giving the ethical clearance letter timely and we would like to pass our gratitude to GAMBY Medical and Business College, data collectors, and supervisors.

    Disclosure

    The authors report no conflicts of interest in this work.

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    12. Chopra A, Al-Tarbsheh AH, Shah NJ, et al. Pneumothorax in critically ill patients with COVID-19 infection: incidence, clinical characteristics and outcomes in a case-control multicenter study. Respir Med. 2021;184:106464. doi:10.1016/j.rmed.2021.106464

    13. Shah S, Pokhrel A, Chamlagain R, et al. Case report of a spontaneous pneumothorax after the recovery from COVID‐19 pneumonia: delayed complication. Clin Case Rep. 2021b;9(10). doi:10.1002/ccr3.4971

    14. Geraci TC, Williams D, Chen S, et al. Incidence, management, and outcomes of patients with COVID-19 and pneumothorax. Ann Thorac Cardiovasc Surg. 2022;114(2):401–407. doi:10.1016/j.athoracsur.2021.07.097

    15. Starshinova A, Guglielmetti L, Rzhepishevska O, Ekaterincheva O, Zinchenko Y, Kudlay D. Diagnostics and management of tuberculosis and COVID-19 in a patient with pneumothorax (clinical case). J Clin Tuberculosis Other Mycobacterial Dis. 2021;24:100259. doi:10.1016/j.jctube.2021.100259

    16. Udwadia ZF, Toraskar KK, Pinto L, et al. Increased frequency of pneumothorax and pneumomediastinum in COVID-19 patients admitted in the ICU: a multicentre study from Mumbai, India. Clin Med. 2021;21(6):e615–e9. doi:10.7861/clinmed.2021-0220

    17. Woo W, Kipkorir V, Marza AM, et al. Prognosis of spontaneous pneumothorax/pneumomediastinum in coronavirus disease 2019: the CoBiF score. J Clin Med. 2022;11(23):7132. doi:10.3390/jcm11237132

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    Introduction

    Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory condition that represents the third leading cause of death worldwide.1,2 According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 definition, COPD is a

    Heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.2

    People with HIV (PWH) are particularly vulnerable to the development and progression of COPD, with both higher rates of COPD and an earlier and more rapid decline in lung function than in the general population, even after accounting for cigarette smoking and other known risk factors, such as intravenous drug use.3–7 The exact mechanisms that underlie HIV-associated COPD are incompletely known, but environmental exposures, heightened immune activation and systemic inflammation, accelerated aging, a predilection for the development of pneumonia, and alterations in the lung microbiome likely play important roles (Figure 1).8–11 The purpose of this review is to describe what is currently understood about the epidemiology and pathobiology of COPD among PWH, to indicate selected areas of active investigation, and to outline screening, diagnostic, prevention, and treatment strategies.

    Figure 1 Drivers of COPD in PWH.

    Epidemiology

    Prevalence

    As survival among PWH has improved with the use of antiretroviral therapy (ART), COPD has become an increasingly important comorbidity. PWH develop an earlier and more rapid decline in lung function, even after adjustment for traditional risk factors.3,5–7,12–15 A recent retrospective study evaluating comorbidities in PWH based on hospital discharge data found that COPD was the most common comorbidity across the 10-year study period and that COPD prevalence was higher among PWH than among those without HIV (23.5% versus 14.0%).16 Prevalence estimates of COPD among PWH have ranged from 3.4% to over 40% in prior studies; notably, most of these have been conducted in Europe and North America.17,18 Part of this heterogeneity is due to differences in COPD classification methods, such as self-report, International Classification of Diseases (ICD) diagnostic codes, use of CT scans, and spirometry.17,19 For example, a systematic review and meta-analysis by Bigna et al evaluating the global prevalence of COPD among PWH found that the prevalence varied from 5.6% to 10.6% depending on the diagnostic criteria used, with a higher prevalence when using spirometric criteria instead of self-report or ICD diagnostic codes.4

    Geography

    COPD in PWH occurs anywhere PWH reside. However, the risk factors for the development of COPD in PWH vary regionally due to differences in age, rates and duration of tobacco smoking, exposure to biomass fuels, and prevalence of tuberculosis, all of which have been implicated in COPD development.2,20–22 While the majority of studies on COPD in PWH have been conducted in the US and Europe, most PWH live in sub-Saharan Africa, where there is a high prevalence of both tuberculosis (TB) and exposure to biomass fuels, and where patients are typically younger and less likely to smoke tobacco. While earlier studies suggested that ART itself may be a risk factor for worsening lung function,23,24 Kunisaki et al conducted a multinational randomized controlled trial (RCT) in the modern ART era and did not find a difference in lung function based on timing of ART initiation.25

    Biologic Sex

    Biologic sex may also contribute to differences in COPD trajectories among PWH. In one study of longitudinal lung function changes in PWH, female sex was associated with distinct lung function trajectories, including baseline low diffusing capacity for carbon monoxide (DLco).26 In a study by McNeil et al of virally suppressed adults with HIV and their seronegative counterparts in Uganda, women with HIV demonstrated an accelerated FEV1 decline as compared to women without HIV, a finding that was not seen among men with and without HIV.27 Interestingly, in a large US-based cross-sectional analysis comparing women with and without HIV, women with HIV had a lower DLco than women without HIV, but there were no differences in spirometric outcomes by HIV status.28,29 In another study including the same cohort of women, baseline COPD prevalence was similar among men with and without HIV and women with and without HIV, but COPD incidence was higher among men with HIV when compared to men without HIV.30 In contrast, Abelman et al found in a post-pneumonia Ugandan cohort that women with HIV had over three-fold higher odds of COPD on spirometry compared to men with HIV, a sex-based difference not found in women and men without HIV.31 Further work is currently underway to investigate whether these reported HIV-associated sex-specific differences in COPD rates are driven by immunologic, hormonal, or environmental factors.

    Risk Factors for COPD in PWH

    There are many risk factors for the development of COPD in PWH including HIV itself,5,32 cigarette smoking and other inhalational exposures, air pollution, opportunistic infections and pneumonia, microbiome alterations,33,34 accelerated aging,35–38 and socioeconomic factors.39 This section focuses on the major drivers, such as smoking, as well as potential risk factors under investigation, such as chronic cytomegalovirus (CMV) coinfection.

    Smoking

    Smoking is the key risk factor for COPD in PWH. Smoking is more prevalent among PWH compared to their seronegative counterparts.40–42 However, studies of co-exposure to HIV and tobacco smoke suggest that PWH who smoke may also be more susceptible to smoking-induced lung damage than HIV-uninfected people who smoke. For example, Diaz et al found emphysema to be more prevalent among smokers with HIV as compared to smokers without HIV.43 Further, in a longitudinal multi-center cohort of 13,687 veterans with and without HIV, Crothers et al found that the prevalence and incidence of both COPD and lung cancer were higher among those with HIV compared to those without HIV despite similar levels of smoking.5 Importantly, among PWH on ART, smoking may reduce life expectancy more than HIV itself.44–46 While the pathophysiologic mechanism driving this HIV-associated difference is incompletely known, recent work suggests that, among PWH, tobacco smoke suppresses alveolar macrophage production of T-cell recruiting chemokines. This impairs the migration of cytotoxic T cells from the airway mucosa into the alveolar space, leading to localized airway mucosa inflammation and tissue destruction.47

    Air Pollution

    Air pollution – the leading environmental cause of death globally48 – is now the greatest threat to human health,49 and COPD is a leading cause of the nearly 7 million annual deaths attributed to air pollution.48,50 Air pollution results from a variety of human-related activities and natural events that include emissions from vehicles, factories, and power plants; traffic-related products; biomass fuel burning (ie, charcoal, firewood, animal dung, crop residues) for cooking and heating; dust storms; forest fires; and volcanic eruptions. The dominant pollution sources vary by region. Traffic- and industry-related sources drive exposure in high-income countries and urban settings, while biomass-related sources drive exposure in low- and middle-income countries and rural settings.51 Air pollution causes acute and chronic lung dysfunction, structural lung abnormalities, submaximal lung growth in childhood and adolescence, and augments lung disease risk in vulnerable populations.52–63 Even small acute increases in fine particulate matter (PM2.5) exposure worsen mortality,64 and there is no “safe” level of exposure.65 Biomass-associated COPD, compared to tobacco-associated COPD, is characterized by more small airways disease and fibrosis, less emphysema, higher DLco, and less airflow obstruction – in effect, a more fibrotic and less emphysematous phenotype.66–69 Exposure to biomass fuel smoke has also been associated with defective bacterial phagocytosis.70 In addition, PM2.5 exposure may also potentiate TB risk,21,71,72 which by itself is a risk factor for COPD and an important consideration in TB-endemic regions.

    Similar to the influence of tobacco smoke, PWH may be more susceptible to air pollution-associated lung damage. For example, among PWH living in San Francisco, exposure to higher levels of outdoor air pollution was associated with increased susceptibility to Pneumocystis infection.73–75 Using ambulatory carbon monoxide (CO) sensors to measure personal air pollution exposure among 260 adults with and without HIV in rural Uganda, North et al found that exposure to short-term CO levels that exceed WHO air quality guidelines was associated with self-reported respiratory symptoms among PWH but not among HIV-uninfected comparators.76 Characterizing air pollution exposure among PWH and exploring the potentially outsized influence of air pollution exposure on lung health in this population is an area of ongoing investigation. As global smoking prevalence continues to decline and rapid industrialization and urbanization progresses, air pollution is poised to replace tobacco as the leading cause of chronic lung disease,77–79 and a multifaceted approach that also focuses on this often overlooked risk factor for lung disease among PWH is critical.

    Opportunistic Infections and Pneumonia

    PWH have historically had higher rates of pneumonia, and while incidence of bacterial pneumonia has decreased with the advent of ART,80,81 it remains common in this population.82–84 In the current era, PWH have similar rates of acute respiratory infections as people without HIV, but PWH experience more severe disease.85 Pneumonia has been associated with higher rates of COPD and lung function abnormalities in PWH.86–89 For example, Drummond et al conducted a US-based multi-center study evaluating spirometry in adults with and without HIV and found that participants with airflow obstruction were more likely to have a history of bacterial pneumonia and Pneumocystis jirovecii (PJP) infection.90 Specifically, PJP, an opportunistic infection that occurs in PWH with CD4 counts <200 cells/mm,3 elevated HIV RNA, and colonization by Pneumocystis have each been associated with higher risk of COPD among PWH.88,91,92 There are numerous contributors to the increased risk of pneumonia in PWH, including alterations in immunity, which lead to persistently elevated markers of immune activation and inflammation, as well as environmental and behavioral risk factors, and a higher prevalence of COPD, which is both a consequence of and a risk factor for pneumonia.9,93–96

    Globally, tuberculosis is the leading infectious cause of death among PWH;97 PWH are 19 times more likely to develop TB disease than their seronegative counterparts.98,99 Pulmonary TB has been found to cause permanent scarring, bronchiectasis, pleural fibrosis, damage to small and large airways, as well as lung parenchymal damage, all of which may contribute to permanent lung function impairment.20,100 Whereas during the treatment phase of TB this impairment is typically restrictive, there is increasing evidence of a relationship between prior pulmonary TB infection and the subsequent development of obstruction and COPD.20,87 Rates differ significantly by the population under study, but pulmonary TB has been found to lead to airway obstruction in 18.4–86% of people in the general population.100 HIV is now recognized as a risk factor for post-TB lung disease, although the extent of this relationship is currently under study.87,100–104 There is some evidence to suggest that HIV may be associated with reduced severity of post-TB lung disease, but this is an area that merits further evaluation.100,105,106

    Chronic CMV Infection

    CMV is an important and omnipresent coinfection in HIV that has been associated with cardiovascular and cerebrovascular disease, other non-AIDS events, and increased mortality.107–112 Given the high rates of CMV antibody seropositivity among PWH, CMV IgG titers are commonly used as markers of CMV activity and have been shown to correlate with adverse outcomes.112,113 However, studies of CMV’s effect on lung function and COPD in PWH are limited. While chronic CMV infection in children with perinatally acquired HIV on ART has been associated with an abnormal FEV1,114 CMV’s association with COPD and other chronic lung diseases in adults with HIV has not been evaluated. Emerging data from the general population, however, suggest that chronic CMV infection is associated with COPD,115 and that higher CMV IgG titers are associated with COPD-related mortality.113 CMV is also associated with abnormal DLco in solid organ transplant recipients, although this has not been studied in PWH.116–118

    There are several proposed mechanisms for CMV-mediated systemic immune effects, including persistent immune activation, endothelial dysfunction, and alterations in the gut microbiome.17,119–121 Similar biomarker activation patterns are noted in PWH with CMV and those with COPD. For example, sCD163, sCD14, and IL-6 are increased in both CMV IgG-positive PWH122–124 and PWH with lung function abnormalities, including both abnormal spirometry and abnormal DLco.10,121 These data suggest that there may be a shared mechanistic pathway between chronic CMV infection and chronic lung disease in PWH, but further work is needed to understand and characterize this relationship.

    HIV-Specific Influences on COPD Pathogenesis

    Several HIV-specific mechanisms may contribute to the increased incidence and accelerated development of COPD in PWH. Chronic HIV infection and the direct effects of HIV-related proteins on lung cells, altered lung and systemic immune responses (both immunosuppressive and pro-inflammatory), altered airway and gut microbial communities, impaired response to pathogens, and toxicity from antiretroviral therapies may all contribute to COPD pathogenesis in this population.23,24,125–132

    HIV Infection

    As the lung acts as a reservoir for HIV even after viral suppression, chronic HIV infection may directly contribute to COPD pathogenesis in various ways.132–134 Newly replicated viral particles released slowly over time bind to and interact with many cell types within the lung, which can lead to direct injury, oxidative stress, low-level chronic inflammation, and impaired response to pathogens.128,135 Although other cell types in the lung may be infected, alveolar macrophages are the best studied reservoir of HIV in the lung.132 HIV infection impairs macrophage phagocytic activity, thus hindering response to pathogens.127,132 HIV also skews the macrophage phenotype towards a pro-inflammatory and protease-producing phenotype through the release of a host of cytokines, chemokines, oxidants, and proteases, all of which contribute to COPD pathology. Cytokine and chemokine signaling in HIV-infected macrophages trigger a pro-inflammatory response including neutrophil and lymphocyte infiltration. Kaner et al found that alveolar macrophage expression of proteases such as matrix metalloproteinases 9 and 12 (MMP-9, MMP-12) is higher in PWH who smoke with emphysema than their seronegative counterparts.131 In murine models, MMPs degrade the extracellular matrix, directly contributing to emphysematous tissue destruction.136

    Altered Adaptive Immune Responses

    COPD development is not only mediated by HIV direct effects, but also by the altered cell-mediated adaptive immune responses in PWH, in particular, altered CD4+ T-cell responses. Numerous studies have shown a relationship between low CD4+ T cell counts and COPD or accelerated lung function decline, although conflicting data also exists.23,125,126,137 T cell exhaustion is typically seen in response to chronic antigen stimulation, such as chronic viral infection, and results in decreased functionality. In PWH, CD4+ T cells show signs of exhaustion even in the presence of ART, with an increased expression of programmed cell death protein-1 (PD-1), as well as impaired proliferative capacity.130,138,139 Furthermore, in PWH with COPD, airway mucosal CD4+ T cell numbers are depleted and poorly responsive to pathogens.130 These findings suggest that dysfunctional CD4+ T cell responses may uniquely contribute to COPD pathogenesis in PWH.

    Activated and dysfunctional CD8+ T cells also appear to contribute to the disordered adaptive immune response in chronic HIV infection, and thus could contribute to COPD pathogenesis.138,139 PWH show persistent expansion of CD8+ T cells in blood and alveolar compartments, and the decreased CD4+/CD8+ ratio is associated with lung abnormalities even in PWH on ART.140,141 These expanded CD8+ T cell populations also show dysfunction, which is typically indicative of an accelerated aging or “immunosenescent” response. Like CD4+ T cells, CD8+ T cells display exhaustion markers, including PD-1, and a low proliferative capacity.138,139 The expanded population skews towards memory T cell and terminally differentiated CD8+ T cell populations unable to respond to new insults. Despite their impaired function, these exhausted T-cells produce a low-grade inflammatory response at mucosal surfaces, which is considered central to COPD pathology.

    Changes to the Airway Epithelium

    Alterations to the airway epithelium, the main barrier protecting the lungs from outside insults, such as cigarette smoke, air pollution, and inhaled toxins, can also play a major role in COPD pathogenesis. HIV has both direct and indirect effects on the airway epithelium, contributing to disordered barrier function, decreased mucociliary clearance, and generation of pro-inflammatory mediators. For example, HIV enters epithelial cells and disrupts cell–cell adhesion.129 HIV-associated proteins released from other infected cells disrupt epithelial tight junctions and induce oxidative stress.142 HIV and cigarette smoke synergistically disrupt mucociliary clearance, additively suppressing CFTR expression to decrease mucus hydration in cell culture models and inducing goblet cell metaplasia/hyperplasia to increase mucus production in simian models.143,144 Finally, when HIV binds specifically to basal cells, epithelial progenitor cells release proteases such as MMP-9 and pro-inflammatory mediators that induce migration and proliferation of macrophages and neutrophils.145

    Changes in the Lung and Gut Microbiome

    Lastly, shifts in both the lung and the gut microbiome can also contribute to chronic inflammatory responses in the lung and, hence, COPD pathogenesis. Data are conflicting on whether lung microbial communities differ in PWH based on 16S sequencing.146–148 However, subtle differences in the microbiome at the species or strain level or at a functional level cannot be discerned via these sequencing methods. It is plausible that at least a subset of PWH experience pathologic microbial alterations in the airways because of a more hospitable environment for pathogen growth. If present in PWH, microbiome perturbations could contribute to chronic airway inflammation. Furthermore, microbial translocation from a compromised gut mucosa, stimulating a chronic systemic inflammatory response, may contribute to lung disease in PWH as has been seen in asthma and pulmonary infections.149

    Diagnosis and Clinical Findings of COPD in PWH

    Screening and Diagnosis

    COPD remains both underdiagnosed and misdiagnosed in people with HIV.150,151 While currently the US Preventative Services Task Force does not recommend screening for COPD in the general population,152 higher COPD prevalence among PWH raises the question whether screening should be done in this subpopulation. Currently, there are no screening and diagnostic criteria specific to PWH. While several studies have evaluated different screening approaches, no conclusive recommendations can be made regarding COPD screening and diagnosis in PWH at this time.150,153–156 For example, a group in Canada offered screening spirometry to all patients in an HIV clinic;156 notably, less than a third of the invited participants agreed to participate, and only 11% had airflow obstruction.

    Recruitment and retention throughout the screening-to-diagnosis cascade have been major challenges in all studies. For example, a group in Italy implemented a three-step case-finding program, involving a 5-question screening questionnaire (which included questions about age, smoking history, cough and sputum production, shortness of breath, and exercise limitation), portable spirometry, and diagnostic spirometry.150 They found that 282 participants (19.6%) had a positive screening questionnaire, defined as having a positive answer to at least three questions, but only 33 participants ultimately completed diagnostic spirometry, of whom 22 met criteria for COPD. High participant dropout at each step of the screening process has been similarly reported elsewhere,153–155 even when the authors bypassed the screening spirometry and had a shorter questionnaire.155 Even within these limitations, COPD prevalence based on the screening outcomes has been consistently higher than the known COPD prevalence in each respective clinic,154 further underscoring the underappreciated burden of chronic lung disease in this population. Additional challenges with screening this high-risk population include lack of a high-performing, validated screening questionnaire in PWH and poor correlation between respiratory symptoms and obstruction on pulmonary function tests (PFTs).155 To our knowledge, qualitative studies focused on identifying patient, provider, or systems-level issues contributing to high dropout rates in screening studies among PWH have not been conducted. Having diagnostic spirometry available at the time of a positive screening questionnaire may help reduce high dropout rates.

    Any PWH suspected of having COPD should undergo diagnostic testing with, at a minimum, portable spirometry and, in our opinion, full PFTs with pre- and post-bronchodilator spirometry, total lung capacity and lung volumes if spirometry is abnormal, and DLco measurement. Chest radiography demonstrates classic findings (Figure 2) mostly in individuals with advanced disease but is useful in ruling out alternative etiologies that also present with respiratory symptoms similar to those of COPD. Occasionally, additional testing such as chest computed tomography (CT) scans may be warranted to characterize the observed PFT abnormalities, and certain CT findings such as the presence of large bulla (Figure 3) may lead to consideration of additional therapies (eg, bullectomy).

    Figure 2 Chest radiograph from person with HIV and COPD demonstrating hyperinflation, flattened diaphragms, and bilateral bullous lung disease (Courtesy of Laurence Huang, MD).

    Figure 3 Chest computed tomography from the same person with HIV and COPD demonstrating large, bilateral bullae. This individual eventually underwent bullectomy with dramatic improvement in his respiratory status (Courtesy of Laurence Huang, MD).

    Longitudinal Lung Function Trajectories of COPD in PWH

    While there is a paucity of data on the natural history of COPD in PWH, lung function declines faster in PWH compared to HIV-negative controls, even when HIV is well-controlled and smoking rates are comparable.6,7,157 Notably, findings from the Pittsburgh HIV Lung Cohort suggested that there may be distinct lung function trajectories among PWH, in which differences in the rate of decline are associated with specific symptoms and distinct profiles of elevated immune activation biomarkers.26 Importantly, this study did not exclusively enroll individuals with COPD. In the general population, COPD studies have shown that lung function decline accelerates as COPD severity increases,158 but whether similar trajectories are seen in PWH is an area currently under study. In a study evaluating factors associated with lung function decline among PWH by Li et al, the authors found that lung function decline occurred more rapidly in older individuals and those with GOLD stage 1 than those with GOLD stage 0 COPD.126 Taken together, these studies suggest that PWH with COPD may demonstrate distinct lung function trajectories when compared to their seronegative counterparts, although additional study is needed in this area.

    Lung Function Trajectories in People with Perinatally Acquired HIV

    While this review is focused on COPD in adults with HIV, the growing number of individuals with perinatally acquired HIV and their lung function trajectory should also be considered. Children and adolescents with HIV have a higher risk of pulmonary infections, including TB, and even with early ART initiation they remain more vulnerable to small airways dysfunction and risk of obstructive lung disease and other pulmonary abnormalities on spirometry and imaging.159–166 Even children who were exposed to but not infected with HIV remain at risk for abnormal lung function.167 Further, lung function in children seems to be affected by the timing of maternal ART initiation (pre-pregnancy versus during pregnancy).167 In addition, lung development and the ability to reach maximal lung function is impaired by HIV, repeat infections, smoking, pollution, and poverty, which in turn increases the risk for the development of chronic lung disease in adulthood.168,169 As this vulnerable population ages, we are likely to see an increased burden of chronic obstructive disease earlier in life. As most of our understanding of lung function trajectories in PWH with COPD comes from adult PWH from higher income settings, focused efforts for early screening, diagnosis, and management of this condition are needed in areas with high prevalence of adolescents and adults with perinatally acquired HIV.

    Diffusing Capacity for Carbon Monoxide

    Abnormal diffusing capacity for carbon monoxide is the most prevalent finding on PFTs in PWH, even when spirometry is normal.29,170 DLco impairment is non-specific and can be attributed to emphysema, fibrosis, pulmonary hypertension, or anemia. In PWH, it is also often associated with prior respiratory infections such as PJP, TB, or bacterial pneumonia, and the DLco abnormality may persist long after clinical and radiographic resolution of infection.89,126 Other risk factors for abnormal DLco include HIV infection, CD4 < 200 cells/mm,3 intravenous drug use, and hepatitis C infection.29,101,170–172

    DLco abnormalities can predict the development, symptoms, and outcomes of COPD. Among people who smoke, DLco can become abnormal before spirometric criteria for COPD are met; DLco may also be a marker of early emphysema prior to the development of spirometric obstruction, small airways disease, or early vascular abnormalities.173–175 While there are additional and unique risk factors for abnormal DLco in PWH compared to the general population, perhaps suggestive of an HIV-specific lung function abnormality,10,176 it is also plausible that isolated DLco abnormalities may serve as a marker for early COPD in some patients. Among PWH, abnormal DLco, like abnormal FEV1, is an independent predictor of worse respiratory symptoms (such as dyspnea, cough, and mucus production),170 as well as a worse 6-minute walk test.177,178 Finally, abnormal DLco is an independent predictor of mortality in PWH with COPD.179,180

    Imaging Findings in PWH with COPD

    New techniques for quantitative imaging assessment have allowed in-depth characterization of imaging abnormalities in people with COPD. As current GOLD criteria define COPD based on chronic respiratory symptoms,2 chest imaging findings such as emphysema describe the structural abnormalities that drive this clinical entity. In the general population of people who smoke, studies have found that evidence of small airways disease and air trapping on imaging could predict COPD development and faster spirometry decline.181,182 Importantly, multiple imaging findings such as early interstitial lung abnormalities,183 pulmonary artery to aorta ratio >1,184 pulmonary arterial vascular pruning,185 progression186 and homogeneity of emphysema,187 airway wall thickness,188,189 and air trapping have all been associated with disease severity and adverse outcomes in COPD.181

    Studies in PWH have shown a high prevalence of emphysema even in individuals without overt respiratory disease.190 In addition, Leung et al found that people with low DLco and a combination of centrilobular and paraseptal emphysema were more likely to have progression of emphysema,191 and significant emphysema burden was associated with increased mortality.192 Elevated TNFα and IL-1β, soluble CD14, nadir CD4, and low CD4/CD8 ratio are also independently associated with emphysema in PWH,140,193,194 although reports of a direct association of HIV with emphysema are contradictory.194,195 While the exact mechanisms are an area of active investigation, HIV-mediated chronic inflammation and immune dysregulation likely play an important role in emphysema formation.

    Symptoms, Exacerbations, and Mortality

    Compared to HIV-negative individuals, PWH with COPD have a higher respiratory symptom burden, worse quality of life, and an increased risk for COPD exacerbations.24,196–202 For example, PWH with emphysema have a worse chronic cough, increased mucus production, and decreased 6-minute walk distance compared to HIV-negative controls.198 In PWH who inject drugs, obstructive lung disease has been associated with more severe dyspnea than in their seronegative counterparts.203 In addition, PWH perform worse on six-minute walk testing.178 While COPD is associated with increased frailty in individuals with and without HIV, physical limitation scores are worse among PWH.204,205 Finally, COPD in PWH is not only often comorbid with cardiovascular disease, but also a risk factor for myocardial infarction206 and has been associated with increased mortality.180,192

    Management of COPD in PWH

    PWH have historically been excluded from large randomized controlled trials of COPD treatments. Therefore, there are very few HIV-specific data on COPD management, and instead general COPD guidelines for both chronic disease management and COPD exacerbations are applied to PWH.207 These management strategies include guideline-driven inhaler therapy, pulmonary rehabilitation, routine vaccinations, surgical or bronchoscopic lung volume reduction in qualifying patients, and management of other medical comorbidities.2 Here, we will focus on a few HIV-specific considerations.

    Smoking Cessation

    Given the high smoking prevalence among PWH and the excess morbidity and mortality associated with smoking in this population, smoking cessation remains a fundamental aspect of COPD care in PWH. Unfortunately, prescribing rates for smoking cessation therapies have been low for PWH with tobacco use disorder for many reasons, including competing clinical priorities, lack of time, low rates of provider training in smoking cessation interventions, and limited knowledge of nicotine replacement therapies and varenicline.208,209 In addition, PWH face additional challenges on the path to sustained smoking cessation that are due to HIV-related stigma, high rates of comorbid substance use, anxiety and depression, financial instability, lack of insurance, low level of education, and racial biases.210–213 Tailoring smoking cessation therapies to this population is an active area of research.209,214–226 Increased awareness among HIV care providers of the importance of smoking cessation, financial support for smoking cessation initiatives, and intervention studies inclusive of PWH are needed to identify the best ways to support smokers with HIV on their path to quitting.

    Choice of Inhalers

    Special attention should be paid in the treatment of COPD to PWH who are taking ritonavir or other boosted ART regimens. Ritonavir and cobicistat block the CYP3A4 isozyme and can increase the concentration of most corticosteroids. As a result, use of inhaled corticosteroids (ICS) in patients on these medications has been reported to cause Cushing’s syndrome.227–230 Beclomethasone is the ICS drug with the best side effect profile and can be used in PWH treated with ritonavir or cobicistat.230 In PWH who are receiving ritonavir or cobicistat, an added consequence is the inability to use any combination medication for COPD that includes an ICS as fluticasone- and budesonide-containing combination inhaler therapies are contraindicated and beclomethasone is only available as a single, standalone inhaler. Given the already elevated risk of pulmonary tuberculosis and other pneumonias in this population, additional caution should be applied when using ICS, as they can increase the risk of lung infections in this already vulnerable population.231,232

    Modulation of Chronic Inflammation

    While no HIV-specific COPD therapies exist, there is an interest in the role of modulating chronic inflammation to improve lung function and clinical outcomes. For example, in a small double-blind pilot clinical RCT of rosuvastatin taken daily for the management of COPD in PWH, Morris et al showed that after 24 weeks of daily rosuvastatin therapy, FEV1 stabilized and DLco improved significantly.233 Another trial studied the role of weekly azithromycin in HIV-related chronic lung disease, defined as an irreversible obstructive defect with minimal radiographic abnormalities, in children and adolescents.234 While the authors found no improvement in lung function parameters after 72 weeks of treatment, they noted an increased time to and fewer total exacerbations. Furthermore, data in the general population have shown benefit of using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in slowing down the progression of emphysema on chest CT in COPD, albeit with no effect on longitudinal lung function on spirometry.235 A randomized controlled trial by MacDonald et al measured pneumoprotein levels as a proxy for lung function decline in PWH with COPD randomized to placebo or losartan treatment, but did not see any significant changes in the pneumoprotein plasma concentrations after 12 months of follow-up.236 Finally, an NHLBI-funded multi-site randomized controlled trial evaluating the influence of twice daily doxycycline on change in DLco among PWH who smoke is currently underway.237 In sum, findings from prior studies suggest that targeting chronic inflammation has the potential to improve lung function of PWH with COPD, but currently there are no definitive data to support any single drug’s use.

    Prevention of COPD in PWH

    Smoking Cessation

    Smoking is perhaps the single most important modifiable risk factor for COPD among PWH. Evidence suggests that PWH may metabolize nicotine more rapidly than HIV-uninfected smokers,238 which could have important implications for the effectiveness of smoking cessation interventions among this population. A growing body of literature is focused on identifying effective smoking cessation interventions among PWH; Table 1 summarizes the randomized controlled trials that have been conducted or have recently completed enrollment on smoking cessation in PWH.218,220,225,226,239–262 For example, O’Cleirigh et al found that among 41 PWH who smoke and reported motivation to quit, those who were randomized to receive cognitive behavioral therapy for smoking cessation and anxiety/depression treatment in addition to nicotine replacement therapy were more likely to quit smoking compared to those who received nicotine replacement therapy alone,225 highlighting the importance of focusing concomitantly on smoking cessation and mental health in this population. A Cochrane review summarizing 14 randomized controlled trials of smoking cessation interventions among PWH in the United States found that pairing behavioral interventions with medications may facilitate short-term abstinence in comparison to medications alone but did not appear to facilitate long-term abstinence.263 Further, a systematic review of smoking cessation interventions among PWH found that successful smoking cessation was most likely when the intervention included cellphone-based technology.264 Although long-term smoking cessation is the goal, any reduction in exposure to tobacco products is likely to have significant health impacts. Using a Monte Carlo microsimulation model, Reddy et al demonstrated that sustained smoking cessation among PWH could result in over 260,000 expected years of life gained.44 This per-person survival gain is more than the life expectancy gained with early ART initiation or improved ART adherence, and among the general population is more than the life expectancy gained by initiating statins for primary cardiovascular disease prevention or clopidogrel for secondary cardiovascular disease prevention. Therefore, encouraging and supporting smoking cessation must remain a priority in the care for PWH.

    Table 1 Summary of Randomized Controlled Trials of Smoking Cessation in People with HIV

    Air Pollution Mitigation

    Interventions aimed at reducing personal air pollution exposure can be categorized into policy-level approaches (regional, national, international) and personal-level approaches. Overall, there is no level of air pollution exposure below which there are no negative health impacts. In fact, evidence suggests that the greatest gains in health per unit reduction in air pollution exposure may occur at the lowest end of the exposure spectrum.265 While attention is being paid to regional and national air quality guidelines, individuals with HIV can adopt behavioral changes that may reduce their personal exposure. Evidence to guide these decisions is still an area of active research. In 2019, Carlsten et al published a summary of 10 key approaches to reduce personal exposure to outdoor and indoor pollution sources, including: using close-fitting face masks when exposure is unavoidable; preferential use of active transport (walking or cycling) rather than motorized transport; choosing travel routes that minimize near-road air pollution exposure; optimizing driving style and vehicle settings when in polluted conditions; moderating outdoor physical activity when and where air pollution levels are high; monitoring air pollution levels to inform when individuals should act to minimize exposure; minimizing exposure to household air pollution by using clean fuels, optimizing household ventilation, and adopting efficient cookstoves where possible; and using portable indoor air cleaners.266 Unfortunately, the data supporting these strategies are not of high quality, which highlights the importance of future work focused on carefully designed studies leveraging implementation science methodology to characterize the feasibility, acceptability, and effectiveness of behavioral interventions focused on improving air pollution-associated lung disease.

    Infection Prevention

    As pulmonary infections, many of which are preventable, have been implicated in the development of COPD among PWH, infection prevention is important for mitigating COPD risk. First, early ART initiation is imperative, as many pulmonary infections such as PJP are opportunistic infections and develop in the setting of high HIV viral loads and low CD4 counts. Primary prophylaxis for PJP prevention is recommended in PWH with CD4 counts <200 cells/mm3 and considered in those with CD4% <14%.267 Given the high morbidity and mortality associated with pneumococcal infection in PWH, pneumococcal immunization has been recommended in all adults with HIV.268 Consistent with general population recommendations, PWH should also receive annual flu vaccination, as well as the full COVID-19 vaccination series. Given the increased risk of TB disease and its associated mortality among PWH, screening for TB is recommended for all PWH at the time of HIV diagnosis and once a CD4 count ≥200 cells/mm3.269 PWH should be tested annually only if they have a history of a negative test for latent TB infection and are at high-risk for repeated or ongoing exposure to people with active TB disease.269 Among PWH diagnosed with latent TB, TB preventive treatment reduces both mortality and progression to active TB and thus should be offered to all PWH with a positive TB screening test without evidence of active TB disease.269,270

    Future Directions

    Although progress has been made in understanding the underlying mechanisms of COPD among PWH, significant knowledge gaps remain. For example, there are many cross-sectional studies evaluating the prevalence of COPD among PWH but only limited data on the natural disease course of COPD in PWH and whether it differs from the general population. Additionally, while studies suggest that PWH demonstrate a higher risk of COPD and a higher symptom burden, there are no HIV-specific screening guidelines for COPD in PWH. Further research is also needed on the interplay between risk factors such as mode of HIV transmission, biologic sex, aging, CMV infection, air pollution, and TB, as well as a deeper understanding of the epidemiology, development, and progression of chronic lung disease in PWH. Management strategies designed specifically for PWH with COPD are also warranted. Lastly, while much progress has been made in understanding the mechanistic pathways that render PWH particularly vulnerable to developing COPD, we remain limited in our ability to counteract these pathways and prevent COPD development. These are only a few examples highlighting the multiple avenues for future research, all of which have the potential to substantially improve both our scientific understanding of COPD among PWH and our ability to effectively prevent and treat this deadly, irreversible condition.

    Conclusions

    COPD is highly prevalent among PWH. With an aging global population of PWH, high rates of cigarette smoking, and air pollution, COPD is a growing health challenge, and improved diagnosis and treatment of COPD in PWH will become increasingly important. Further research is needed to understand the underlying mechanisms driving COPD in PWH, as well as HIV-specific screening and treatment modalities.

    Disclosure

    Katerina L Byanova and Rebecca Abelman are co-first authors for this study. Dr. Byanova was supported by NIH F32 HL166065. Dr. Abelman was supported by NIH T32 AI060530 and K12 HL143961. Dr. North was supported by NIH K23 HL154863. Dr. Christenson was supported by NIH R01 HL143998, she also reports personal fees from AstraZeneca, Sanofi, Regeneron, GlaxoSmithKline, Amgen, MJH Holdings LLC: Physicians’ Education Resource, Glenmark Pharmaceuticals, and Axon Advisors, outside the submitted work. Dr. Huang was supported by NIH R01 HL128156, R01 HL128156-07S2, and R01 HL143998.

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