Correlation between the Severity of Chronic Inflammatory Respiratory Disorders and the Frequency of Venous Thromboembolism: Meta-Analysis

Stella C. Pak, MD

Andrew Kobalka, BS

Yaseen Alastal, MD

Scott Varga, MD 

Department of Medicine

University of Toledo Medical Center

Toledo, OH, USA 43614

Abstract

The present study aims to integrate the growing body of evidence on the possible association between the severity of chronic inflammatory respiratory disorders (CIRDs) and the frequency of venous thromboembolism (VTE). Eight studies were analyzed to assess the correlation between the severity of CIRDs and the incidence of VTE. Our results suggest that there is no significant increased risk of VTE in patients with severe CIRD compared to mild or moderate CIRD, OR=0.92 (95% CI 0.59 – 1.43; I² = 74%). Further studies are indicated to explore this possible association. Gaining a better understanding of the VTE risk for patients with CIRDs will enable clinicians to provide better individualized risk management and preventive care.

Introduction

In this age of rapid developments in health care, pioneering attempts are being made to improve the management of chronic inflammatory respiratory disorders (CIRDs). Despite significant public health efforts over the past few decades, the prevalence of CIRDs continues to rise. Common types of CIRDs include asthma, chronic obstructive pulmonary disorder (COPD), and bronchiectasis. Bronchiectasis, a pathologic description of lung damage characterized by inflamed and dilated thick-walled bronchi (1), is most commonly caused by respiratory infections or other pro-inflammatory events such as toxin inhalation (2). Patients with recurrent airway damage due to impaired mucociliary clearance secondary to genetic alterations commonly develop bronchiectasis (2); the overall percentage of bronchiectasis patients with cystic fibrosis is approximately 5-6% (3,4).

There is a growing body of evidence suggesting that individuals with CIRDs are at increased risk for developing venous thromboembolism (5-7). Multiple studies indicate one tenth of patients with acute COPD exacerbation develop VTE (5). Despite this, the possible correlation between CIRD severity and VTE risk has not been sufficiently explored in the literature.

Two plausible mechanisms for VTE in CIRDs are inflammation-induced thrombosis and steroid-induced thrombosis. Inflammation-induced thrombosis involves interaction among activated platelets, leukocytes, and endothelial cells promoting excessive procoagulant activity of endothelium (8). Steroids are also postulated to induce prothrombotic state by increasing the serum concentration of von Willebrand factor and plasminogen activator inhibitor-1 (9).

Subtypes of VTE including PE and DVT can lead to significant chronic complications. Nearly 50% of patients who have DVT develop post-thrombotic syndrome within 2 years despite being on anticoagulant therapy (10). Chronic thromboembolic pulmonary hypertension, which is reported to occur in 0.5 to 4% of patients with history of PE, can lead to right-sided heart failure, exercise intolerance, and dyspnea (11). A recent study showed that pulmonary embolism led to higher mortality in patients with severe COPD compared to general population (12). Episodes of VTE and their sequelae complicate the management of patients with CIRDs. Considering this burden from VTE, preventive measures with risk stratification are needed.

Assessing the correlation between the severity of CIRDs and the risk for VTE would improve the quality of care by allowing accurate risk assessment and proper risk management. Furthermore, demystifying this association would give patients agency in their own care. A recent study showed that 84% of activated protein C-resistant women on combined oral contraceptives changed their method of contraception after finding out that they had increased risk for VTE, and a majority were pleased to learn of their APC resistance status (13). Understanding the correlation between the severity of CIRDs and VTE would help clinicians provide better education and lifestyle advice to patients with CIRDs.

The goal of this study is to assess the correlation between the severity of CIRDs (including COPD, asthma, and cystic fibrosis) and the frequency of VTE. Gaining a better understanding of these correlations will offer significant clinical benefits and facilitate better individualized care for patients with varying severity of CIRDs.

Methods

Search Strategy

English language studies published up to March, 10^th 2017 were located via a search of MEDLINE, EMBASE, Cochrane Library, CINAHL, and Web of Science. Key search terms included the following: “CIRD,” “COPD,” “Asthma,” “CF,” “DVT,” “PE,” and “VTE.” Appendix 1 describes specific search terms used in each database.

Inclusion Criteria

The criteria for inclusion required studies: 1) to include adult patients with CIRDs with different severity based on objective index or score system 2) to include the frequency of VTE among participants 3) to be prospective or retrospective observational studies, and 4) to report raw number of patients found to have VTE in different severity group.

Exclusion Criteria

The following criteria were used to exclude studies from this review: 1) Use of subjective measure in severity determination 2) Case study 3) Pediatrics population 4) Non-English literature.

Meta-Analysis

A random effects meta-analysis was performed to determine the association between the severity of CIRDs and VTE risk. The random model was applied to derive the summary estimate. Proportions were calculated using logit transformation (log-odds). Heterogeneity was assessed using the I² value. The funnel plot was constructed to detect and adjust for potential publication bias.  All statistical tests were two-sided and p-values of less than 0.05 were statistically significant. All statistical analyses were performed using the Review Manager 5.3.5 program (Cochrane, London, UK).

Results

A total of 8 trials (23,899 patients) were included for analysis (14-21). Table 1 describes the characteristics of included studies.

Table 1. Characteristics of included studies.

HCT: hematocrit, ATS: American Thoracic Society, GOLD: Global Initiative for Chronic Obstructive Lung Disease, PE: pulmonary embolism, DVT: deep venous thromboembolism, GINA: Global Initiative for Asthma Classification.

The odds ratio of DVT frequency for people with severe COPD compared to those with moderate or mild COPD was 0.92 (95% CI 0.59 – 1.43; I² = 74%) (Figure 1).

Figure 1. Forest plot of studies on chronic inflammatory respiratory disorders and venous thromboembolism with study-type subanalysis.

 In subgroup analysis, the odds ratio for prospective studies was 0.67 (95% CI 0.46 – 0.96; I² = 0%). On the other hand, subgroup analysis from retrospective studies showed odds ratio of 1.34 (95% CI 0.88 – 2.03; I² = 53%). Funnel plot suggests that publication bias minimally influenced retrospective studies (Figure 2). However, the plot suggests that mild publication bias exists among the included prospective studies.

Figure 2. Funnel plot of studies on chronic inflammatory respiratory disorders and venous thromboembolism with study-type subanalysis.

Discussion

Our results indicate no significant association between the severity of CIRDs and VTE risk. Several limiting factors, including substantial variation in the measures of disease severity, may have influenced the final result. Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system, American Thoracic Society (ATS) grading system, and the presence of polycythemia were used as disease severity measures in patients with COPD. Global Initiative for Asthma Classification (GINA) system measured severity of asthma, and ATS grading system measured severity of cystic fibrosis. We tried to use the random effect model to compensate for this heterogeneity. Confounding factors such as smoking status, exercise level, BMI, quality of health care, and ethnicity could also have contributed to the development of VTE in the studied population. Finally, a wide variation in cohort size across studies could have confounded the results.

The outcome of subanalysis on prospective studies was contradictory to those of retrospective studies. The retrospective study design, the researchers tend to have limited control over consistency and accuracy. Major limitation for prospective studies is the loss to follow-up associated with relatively long follow-up period (22). These limitations may have contributed to these contradictory outcomes from subanalyses.

The presence of polycythemia was used as a severity indicator for COPD in three of the studies, while GOLD stages II-IV was used in two of the studies. The decision to use polycythemia as an indicator of COPD severity was based upon the finding that more than 70% of COPD patients with polycythemia are in GOLD stage III or IV (21). However, as not every patient with polycythemia is in GOLD stage III or IV, this novel measure might not be strongly correlated enough with disease severity.

While large-scale prospective and retrospective studies assessing COPD severity and VTE risk have been undertaken, the multiple systems for grading COPD severity limits our ability to compare studies. A uniform disease severity grading system is needed to compare studies in this way.

In summary, our results indicate no significant association between the severity of CIRDs and VTE risk. Further exploration of the relationship between disease severity in patients with CIRDs and risk of VTE is necessary to improve risk stratification system and preventive care for this patient population. We hope the present work helps foster subsequent research on this possible association.

References

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Cite as: Pak SC, Kobalka A, Alastal Y, Varga S. Correlation between the severity of chronic inflammatory respiratory disorders and the frequency of venous thromboembolism: meta-analysis. Southwest J Pulm Crit Care. 2017;14(6):285-91. doi: https://doi.org/10.13175/swjpcc035-17 PDF

June 2017 Pulmonary Case of the Month

Robert Horsley, MD

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 61-year-old woman presented to the emergency department for 3 days of fevers up to 102º F, malaise, and progressive shortness of breath. Her symptoms started immediately after he last naltrexone injection for alcohol use disorder.

Past Medical History, Social History and Family History

• Alcohol use disorder
• Treated with monthly naltrexone injections, received 3 doses total, and gabapentin
• No other previous medical issues
• Nonsmoker

Physical Examination

• Vital signs: Pulse 100, BP 108/90, respiratory rate 34, SpO2 93% 10L non-rebreathing mask
• Cyanotic on room air
• Lungs clear

Radiography

A portable chest x-ray was performed in the emergency department (Figure 1).

Figure 1. AP chest radiograph taken in the emergency department.

A thoracic CT scan was performed (Figure 2).

Figure 2. Representative images from thoracic CT in lung windows.

Laboratory

• CBC showed a white blood cell count of 12,000 cells/mcL.
• The differential showed a left shift.
• Lactate was 5.2 mmol/L

Which of the following is (are) true? (Click on the correct answer to proceed to the second of five pages)

1. A lactate level of 5.2 can be a normal finding in a critically ill patient
2. Her symptoms are likely an allergic reaction to naltrexone
3. The most likely diagnosis is an atypical pneumonia
4. 1 and 3
5. All of the above

Cite as: Horsley R, Wesselius LJ. June 2107 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(6):255-61. doi: https://doi.org/10.13175/swjpcc063-17 PDF

May 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 69-year-old man with known heart failure, COPD and prostate cancer with presented with increased shortness of breath. He denied any fever, chills, cough or sputum.

Past Medical History, Social History and Family History

• Diastolic heart failure with a preserved ejection fraction
• Prostate cancer with bone metastasis treated with leuprolide (Lupron^®) 
• COPD treated with salmeterol/fluticasone and tiotropium
• He is married, retired and had quit smoking a number of years ago.
• Family history was unremarkable

Physical Examination

• Oxygen saturation (SpO2) was 93% on room air.
• Physical examination showed jugular venous distention (JVD), bilateral lung rales a laterally displaced pulse of maximal impulse (PMI) and 1+ pretibial edema.

Radiography

A chest x-ray was performed (Figure 1).

Figure 1. Admission chest x-ray.

Based on the history and chest x-ray which of the following is the most likely diagnosis? (Click on the correct answer to proceed to the second of six pages)

1. Community-acquired pneumonia
2. Congestive heart failure
3. COPD exacerbation
4. Metastatic prostate cancer
5. Pulmonary embolism

Cite as: Wesselius LJ, Viggiano RW. May 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(5):185-91. doi: https://doi.org/10.13175/swjpcc052-17 PDF

April 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Pulmonary Department

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 63-year-old woman with a prior diagnosis of possible rheumatoid arthritis was referred for dyspnea with more vigorous activities in Prescott where she now lives (elevation 5367 ft.). She is receiving hydroxychloroquine 400 mg/day.

Past Medical History, Social History and Family History

She has a past medical history of hypertension. She smoked about a pack per day from age 20 to 40. There is a history of colon cancer in her mother and  lung cancer in a sister.

Physical Examination

• Vitals: BP 155/102, SpO2 93% on room air
• Chest: slightly decreased breath sounds but clear
• Cardiovascular:  regular rhythm without murmur
• Extremities:  no cyanosis, clubbing or edema
• The remainder of the physical examination is normal

What testing would you perform at this time? (Click on the correct answer to proceed to the second of five pages)

1. Chest X-ray
2. Pulmonary function testing
3. Rheumatoid factor
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. April 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(4):129-33. doi: https://doi.org/10.13175/swjpcc040-17 PDF

March 2017 Pulmonary Case of the Month

Maxwell L. Smith, MD 

Department of Laboratory Medicine and Pathology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is 52-year-old man who complained of dyspnea on exertion and a dry cough.

Past Medical History, Social History and Family History

He had a history of gastroesophageal reflux disease (GERD) and was taking a proton pump inhibitor.

He never smoked and had no known exposures.

Family history was noncontributory.

Physical Examination

Physical Examination was unremarkable.

Chest X-ray

A chest x-ray was reported as normal.

Which of the following are indicated? (Click on the correct answer to proceed to the second of five pages)

1. Chest CT scan
2. Endoscopy/bronchoscopy
3. Pulmonary function testing
4. 1 and 3
5. All of the above 

Cite as: Smith ML. March 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(3):89-93. doi: https://doi.org/10.13175/swjpcc014-17 PDF