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

Pulmonary Embolism and Pulmonary Hypertension in the Setting of Negative Computed Tomography

Peter V. Bui, MD

Sapna Bhatia, MD

Dona J. Upson, MD, MA

Department of Internal Medicine

Division of Pulmonary, Critical Care, and Sleep Medicine

The University of New Mexico and Raymond G. Murphy VA Medical Center

Albuquerque, NM

Abstract

Introduction: Chronic pulmonary hypertension (PH) can display acute elevations in pulmonary arterial pressure (PAP) in the setting of hypoxemia, pulmonary embolism (PE), and possibly sepsis.

Case Description: A 68-year-old man with chronic obstructive pulmonary disease, heart failure, recent tobacco cessation, and recent 2-vessel coronary artery bypass grafting (CABG) presented with one to two weeks of respiratory symptoms and syncope on the day of admission. He was found to have a urinary tract infection and Escherichia coli bacteremia. Transthoracic echocardiography found a systolic PAP of 100-105 mmHg, increased from a mean PAP of 32 mmHg before CABG. PE was not seen on computed tomography angiography (CTA). Ventilation-perfusion scan two days later found evidence of subsegmental PE. PAP prior to discharge was 30-35 mmHg plus right atrial pressure.

Conclusion: PAP can rise substantially in the acute or subacute setting, particularly when multiple disease processes are involved, and decrease to (near) baseline with proper therapy. Chronic PH may even be protective. In a complex clinical setting with multiple possible etiologies for elevated PAP, clinicians should have a high suspicion for PE despite a negative CTA.

Abbreviation List

ADHF acute decompensated heart failure

CABG coronary artery bypass grafting

COPD chronic obstructive pulmonary disease

CTA computed tomography angiography

CXR conventional chest radiograph
EF ejection fraction

HCAP healthcare-associated pneumonia

HFpEF heart failure with preserved ejection fraction

INR international normalized ratio

LV left ventricle

PAP pulmonary arterial pressure

PCWP pulmonary capillary wedge pressure

PE pulmonary embolism

PH pulmonary hypertension

RA right atrium/atrial

RV right ventricle/ventricular

RHC right heart catheterization

SaO2 arterial oxygen saturation

TTE transthoracic echocardiography

UTI urinary tract infection

VTE venous thromboembolism

VQ ventilation-perfusion

Introduction

Pulmonary hypertension (PH) is classified into five groups (1). In the United States, the incidence and prevalence of PH and each of its five groups are largely unclear. Group 2, due to left heart disease, has a prevalence as high as 83% by transthoracic echocardiography (TTE) in patients with heart failure with preserved ejection fraction (HFpEF) (2). For group 3, due to chronic lung disease, in a study measuring pulmonary arterial pressure (PAP) by right heart catheterization (RHC), the prevalence of PH among patients with chronic obstructive pulmonary disease (COPD) was 36% (3). Changes in PAP in the setting of acute or subacute pulmonary embolism (PE) are unknown. We present a patient found to have transient severely elevated PAP in the setting of a negative computed tomography angiography (CTA) and positive ventilation-perfusion (VQ) scan with distractors including HFpEF, COPD, and sepsis.

Case Presentation

A 68-year-old man with severe COPD on four liters per minute of supplemental oxygen, a 50-pack-year smoking history with cessation two months before admission, HFpEF, 3-vessel coronary artery disease, myocardial infarction involving the left circumflex artery, recent 2-vessel coronary artery bypass grafting (CABG), recurrent urinary tract infections (UTIs), chronic prostatitis, and prostatic calculi presented after a syncopal episode. One day prior to admission, he experienced fevers to 40°C and shaking chills. On the day of admission, the patient woke up struggling for breath and experienced syncope while getting out of bed. He had been having altered mental status and one week of productive cough with greenish sputum. He did not have any other respiratory, urinary, and constitutional symptoms. He presented to an outside hospital, where he was treated for presumed sepsis secondary to a UTI and started on an antibiotic. He was transferred to our facility and admitted for a UTI and possible healthcare-associated pneumonia (HCAP).

At presentation at our facility, vital signs included a temperature of 36.8°C, heart rate of 87 beats per minute, blood pressure of 124 mmHg / 69 mmHg, respiratory rate of 18 breaths per minute, and oxygen saturation of 96% on three-to-four liters per minute of supplemental oxygen. The physical examination was notable for expiratory wheezing and trace lower extremity edema. White blood cell was 13.5 K/mm³, neutrophilia of 80.4%, troponin I of 0.048 ng/mL, N-terminal pro-brain natriuretic peptide of 2800 pg/mL, and urinalysis suggestive of UTI. An arterial blood gas was deemed unnecessary for unchanged supplemental oxygen, normal mentation, and lack of respiratory distress. Electrocardiography showed normal sinus rhythm, nonspecific ST and T wave abnormalities, and previously identified signs of inferior-posterior infarction without evidence of acute right heart strain. He did not receive chemoprophylaxis for venous thromboembolism (VTE) because of possible surgical intervention.

Ten days before admission (Table 1), he made a long distance drive to see Cardiothoracic Surgery for post-CABG follow-up.

Table 1. Timeline of events surrounding the patient’s hospitalization. Computed tomography angiography (CTA). Coronary artery bypass grafting (CABG). Conventional chest radiographs (CXR). Ejection fraction (EF). International normalized ratio (INR). Pulmonary arterial pressure (PAP). Pulmonary embolism (PE). Transthoracic echocardiography (TTE). Urinary tract infection (UTI). Ventilation-perfusion (VQ).

He had an increased oxygen requirement from three-to-four to four-to-five liters per minute, bilateral lower extremity edema, and supratherapeutic international normalized ratio (INR) of 4.4 on warfarin for postoperative atrial fibrillation, that had since resolved. TTE showed a normal sized left ventricle (LV), LV ejection fraction of 50-55%, inferolateral wall akinesis, basal inferior wall akinesis, mildly dilated right ventricle (RV), mildly reduced RV systolic function, mildly dilated right atrium (RA), PAP of 70-80 mmHg, and right atrial pressure of 10-15 mmHg. The patient refused hospitalization. Furosemide and metolazone were increased, and warfarin discontinued. His INR was 1.4 four days before admission.

Outpatient medications included amiodarone, simvastatin 10 mg, aspirin 81 mg, metoprolol 25 mg three times a day, and furosemide 80-100 mg daily. Six weeks prior to admission, RHC found RA pressure of 12 mmHg, RV pressure of 45/15 mmHg, PAP of 45/25 mmHg with a mean pressure of 32 mmHg, pulmonary capillary wedge pressure (PCWP) of 15 mmHg, cardiac output of 7.98 L/min, cardiac index of 3.55 L/min/m², SaO2 97%, mixed venous saturation of 71%, pulmonary vascular resistance of 2.1 dynes-sec-cm^-5, and system vascular resistance of 782 dynes-sec-cm^-5.

At presentation, his respiratory symptoms were attributed to pneumonia and not acute decompensated heart failure (ADHF) or COPD. Initial antibiotics for HCAP and UTI coverage were cefepime and vancomycin. Conventional chest radiographs (CXRs) (Figure 1) on hospital day 0 and the CTA a few days later were not suggestive of pneumonia.

Figure 1. Conventional radiography of the chest showing no acute cardiopulmonary findings but enlarged pulmonary arteries.

An influenza viral panel was negative. Outside blood cultures grew Escherichia coli, while blood, urine, and sputum cultures from our facility were negative. CXRs over the following week were unchanged.

Because of the elevated PAP found prior to admission, Pulmonology was consulted for pulmonary hypertension. TTE on hospital day 3 found a normal RV size, mildly reduced RV systolic function, mildly dilated RA, systolic PAP of 100-105 mmHg, and RA pressure of <5 mmHg. His Wells score for PE was 3.0 to 4.5, suggesting moderate risk (4). The CTA did not identify a PE. In view of a high suspicion for PE, Pulmonology reviewed the CTA with a chest radiologist, who noted that the images were of suboptimal thickness. A VQ scan (Figure 2) was ordered on hospital day 5 and showed multiple bilateral VQ defects consistent with a high probability for PE.

Figure 2. Ventilation-perfusion scan on hospital day 5 showing multiple bilateral ventilation-perfusion defects. The study was consistent with a high probability for pulmonary embolism.

Ultrasound Doppler studies of the lower extremities on hospital day 6 were normal. Repeat TTE on hospital day 5 found a normal sized LV, LV EF of 45-50%, basal inferior wall akinesis, inferolateral wall akinesis, mildly dilated RV, mildly reduced RV systolic function, normal RA size, and PAP of 30-35 mmHg plus RA pressure. The patient was discharged on anticoagulation and antibiotics.

Discussion

We describe a patient who developed transiently elevated PAP in the setting of sepsis secondary to UTI and E. coli bacteremia, acute or subacute PE, HFpEF, and COPD. At baseline, he likely had PH from COPD and HFpEF out of proportion to PCWP. The increased PAP to 70-80 mmHg 1.5 weeks prior to admission was thought to be due to the hypervolemia observed by outpatient Cardiothoracic Surgery. Recent CABG, long-distance travel, and infection predisposed him to VTE. PE may have caused the dyspnea and syncope experienced on the day of admission. The negative CTA and systolic PAP of 100-105 mmHg on TTE on hospital day 3 may have reflected movement of PE downstream to the subsegmental or smaller arteries and thus inability to be seen on CTA, especially given the suboptimal thickness of the images. Volume status and vascular changes in the setting of recent hypervolemia, possibly due to HF or PH, and concurrent infection may have contributed to this elevated PAP. In light of the presentation of unexplained dyspnea and syncope, Wells score of 3.0 to 4.5, and elevated PAP, suspicion for PE was high. The high pretest probability of PE precipitated obtaining a VQ scan on hospital day 5. The scan supported the presence of bilateral PE, likely in the subsegmental or smaller arteries. PAP of 30-35 mmHg on subsequent TTE suggested resolution of PE.

CTA is the most common study to diagnose acute PE. A number of early studies found CTA to be at least as equivalent in sensitivity and specificity to VQ scan (5-10). Studies using data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II found the sensitivity and specificity of CTA to be 83% and 96%, respectively, and of VQ scan to be 77.4%. and 97.7%, respectively (11, 12). However, CTA miss up to 20% to 36% of PE in subsegmental and smaller arteries (13-15). A meta-analysis of Wells criteria found sensitivity and specificity of 0.84 and 0.58, respectively, for a cutoff score of less than 2 and 0.60 and 0.80, respectively, for a cutoff score of 4 or less (16).

The degree to which HFpEF, COPD exacerbation, acute or subacute PE, and sepsis affect PAP has had limited investigation. In patients with ADHF, Aronson et al. (17) found PH in 42.6% and pulmonary arterial systolic pressures as high as 70 to 80 mmHg. Sibbald et al. (18) found that 57% of septic patients developed PH and had increases in mean PAP (27 ± 7 mmHg in septic patients found to have PH versus 15 ± 3 mmHg in septic patients found not to have PH, p < 0.01). In patients with chronic bronchitis who went into acute respiratory failure, Abraham et al. (19) found transient increases in mean PAP of approximately 15-20 mmHg (mean PAP 52.2 mmHg at admission and 36.5 mmHg prior to discharge).

The mechanism of PH can be mechanistically complex or intuitively simple. PH involves changes in nitric oxide, endothelin, thromboxane, and prostacyclin pathways, among other possible cellular and biological pathways of pulmonary endothelial dysfunction (20-25). Proinflammatory signals such as during infection affect these pathways (26). Other mechanisms include vascular congestion in HF, physical obstruction from PE, and vasoconstriction in hypoxemia leading to elevated PAP and subsequent PH (27-31). In our patient, there was likely a combination of several mechanisms contributing to his elevated PAP and PH.

Our patient may have been able to tolerate such an acute rise in pulmonary hypertension because of the effects of chronic pulmonary hypertension, although the pathophysiologic mechanisms have not been fully elucidated. Vonk-Noordegraaf et al. (32) described adaptive and maladaptive remodeling in pulmonary hypertension. In adaptive remodeling, the RV size is normal to moderately dilated; the RV mass/volume ratio is higher than normal, as seen in concentric remodeling; and the RVEF is normal to mildly decreased. For our patient, multiple TTE suggested adaptive remodeling, although our cardiologists did not comment on concentric remodeling.

We present the case of a patient with multiple comorbidities including HFpEF and COPD that likely caused the baseline PH seen on previous RHC and the subsequent development of severely increased PAP in the setting of sepsis and acute or subacute PE. His underlying chronic PH may have been protective given that he did not develop acute right HF from the sudden increase in PAP, and survived. The transient elevation in PAP in our patient reiterates that many disease processes can affect PAP, whether directly or indirectly, through simple or complex mechanisms. A CTA to evaluate possible PE should be verified to have the proper technique. A high suspicion for PE in the setting of acute PH despite a negative CTA warrants further investigation.

Acknowledgements

Dr. Loren Ketai of the Department of Radiology of The University of New Mexico reviewed the images of the computed tomography angiography and ventilation-perfusion scans.

Cecilia Kieu assisted in the preparation of the figures for this manuscript.

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Cite as: Bui PV, Bhatia S, Upson DJ. Pulmonary embolism and pulmonary hypertension in the setting of negative computed tomography. Southwest J Pulm Crit Care. 2016 Mar;12(3):116-25. doi: http://dx.doi.org/10.13175/swjpcc016-16 PDF 

Interval Development of Multiple Sub-Segmental Pulmonary Embolism in Mycoplasma Pneumoniae Bronchiolitis and Pneumonia

Peter V. Bui¹

Sapna Bhatia²

Ali I. Saeed²

¹Department of Internal Medicine

²Division of Pulmonary, Critical Care, and Sleep Medicine

The University of New Mexico

Albuquerque, NM, USA

Abstract

Introduction: Cases of pulmonary embolism (PE) concurrent with Mycoplasma pneumoniae infection are rare in the medical literature. We describe a patient with M. pneumoniae bronchiolitis and pneumonia who developed multiple right-sided, sub-segmental PE.

Case Description: A 54-year-old man presented following one week of respiratory and constitutional symptoms. He was admitted for respiratory distress and started on ceftriaxone, azithromycin, and oseltamivir. Because of a lack of clinical improvement, antibiotics were escalated to vancomycin and piperacillin-tazobactam. M. pneumoniae IgM and IgG serologies returned positive, and antibiotics were narrowed to azithromycin, with clinical improvement and gradual decrease in supplemental oxygen requirement. One week into the hospitalization, the patient abruptly developed an increased oxygen requirement. Computed tomography angiography (CTA) of the chest found stable M. pneumoniae bronchiolitis and pneumonia and the interval development of multiple right-sided, sub-segmental PE. He was treated with unfractionated and then low-molecular-weight heparin as a bridge to warfarin, azithromycin, and a prednisone taper. In the outpatient setting, repeat CTA revealed resolution of M. pneumoniae infection and PE. 

Discussion: Although the mechanism and association are unclear, other case reports have proposed that M. pneumoniae infection promotes hypercoagulability or a prothrombotic state, predisposing patients to thromboembolism. In a patient with M. pneumoniae infection who develops sudden respiratory distress or failure despite appropriate treatment, clinicians should have a high suspicion for PE, and a CTA should be considered as part of further evaluation.

Introduction

Mycoplasma pneumoniae is one of thirteen Mycoplasma species isolated from humans and less commonly causes lower respiratory tract infections, of which atypical pneumonia occurs at higher rates (1). These lower respiratory tract infections have been reported to present similarly to other disease processes such as asthma and pulmonary embolism (PE) (2, 3). M. pneumoniae pneumonia typically has a benign course with low mortality. A study by von Baum et al. found a mortality of 0.7% in patients with M. pneumoniae pneumonia, with the deaths occurring in hospitalized patients (4). Despite this low mortality, rare complications may contribute to morbidity and mortality, although to what degree, if any, is unclear. A case report in the medical literature describes a PE and a hypercoagulable state associated with M. pneumoniae pneumonia in an adult during the peri-infectious period (5). We present a case with radiographic evidence of the interval development of multiple segmental PE in a patient with M. pneumoniae bronchiolitis and pneumonia.

Case Description

A 54-year-old man with a 15-pack-year smoking history, positive purified protein derivative treated with isoniazid, occupational exposures including asbestos and dust, and a current history of ethanol abuse presented to the emergency department with a one-week history of a productive cough with yellow sputum, weakness, shortness of breath, and dyspnea on exertion. He also noticed diffuse papular cutaneous lesions over his back.

In the emergency department, he was hypoxic with a need for supplemental oxygen. Cardiopulmonary examination was unremarkable. Initial laboratory studies including complete blood count, chemistry panel, and hepatic function panel were notable for a leukocytosis of 13.6 k/μL with a neutrophilia of 83%, aspartate transaminase of 108 units/L, alanine transaminase of 152 units/L, alkaline phosphatase of 175 units/L, and total bilirubin of 1.5 mg/dL, and creatine kinase of 563 units/L. Conventional chest radiograph (Figure 1) showed a left lower lobe infiltrate.

Figure 1. Conventional chest radiograph on day zero of the hospitalization. The images show a left lower lobe infiltrate.

The patient was admitted to the hospital and started on ceftriaxone and azithromycin for community-acquired pneumonia as well as oseltamivir over concerns for influenza.

During the initial hospitalization, the patient required supplemental oxygen for hypoxia with a rapid increase in fractional inspired oxygen (F_iO₂) to maintain oxygen saturation above 90%. Because of a lack of clinical improvement, antibiotics were broadened to include vancomycin and piperacillin-tazobactam. Since he continued to require a F_iO₂ of 60% on day four of the hospitalization, additional workup for atypical bacterial, viral, and fungal pathogens were performed after consultation with pulmonology. Acid-fast bacillus cultures and stains were negative. Sputum cultures were not obtained. An arterial blood gas prior to evaluation by Pulmonology found a pH of 7.42, partial pressure of carbon dioxide of 38 mmHg, partial pressure of oxygen of 86 mmHg, HCO₃ of 24 mmol/L, and F_iO₂ of 95%. Computed tomography (CT) of the chest (Figure 2) showed extensive bronchiolitis with focal areas of consolidation involving bilateral lower lobes.

Figure 2. Computed tomography of the chest on day four of the hospitalization. The image shows an extensive bronchiolitis with focal areas of consolidation involving bilateral lower lobes.

Oseltamivir was discontinued after the respiratory viral panel returned negative. Broad spectrum antibiotics were narrowed to azithromycin after M. pneumoniae IgM and IgG serologies returned positive. His oxygen requirement gradually improved over the next two days, and he was transitioned to nasal cannula.

On day seven of his hospitalization, the patient suddenly developed moderate respiratory distress with an increase in oxygen requirement. CT angiography (CTA) of the chest (Figure 3) done at this juncture showed unchanged parenchymal findings with interval development of multiple sub-segmental pulmonary emboli in the right lung.

Figure 3. Computed tomography angiography of the chest on day five of the hospitalization. The images show unchanged parenchymal findings with interval development of multiple sub-segmental pulmonary emboli in the right lung (see white arrows in Figure 3A).

Doppler ultrasound found no evidence of deep venous thrombosis (DVT) in both lower extremities. He was subsequently started on therapeutic anticoagulation with unfractionated heparin and then low-molecular-weight heparin as a bridge to warfarin. The patient subsequently improved on a 14-day course of azithromycin 500 mg orally once daily and 3-month tapered course of prednisone 60 mg orally once daily for M. pneumoniae infection, a 3-month course of warfarin for the PE, and supplemental oxygen. During follow-up in the outpatient setting, CTA of the chest showed the infection and PE to have resolved, and all therapies related to the infection and PE were discontinued.

Discussion

We herein describe a case of M. pneumoniae bronchiolitis and pneumonia complicated by right-sided PE. The reported occurrences of venous thromboembolism (VTE) during M. pneumoniae infection are limited to case reports. In our review of the literature, we found one case of M. pneumoniae infection associated with PE in the adult population. Ascer et al. (5) presented the case of a 28-year-old male with right-sided pneumonia and right-sided PE who was found to have antiphospholipid antibodies. For the PE, this patient was successfully treated with recombinant tissue-type and plasminogen activator and heparin and was discharged with hydroxychloroquine sulphate, aspirin, and warfarin. However, Ascer did not publish additional follow up for this seemingly prothrombotic state. In a case without PE, Senda et al. (6) reported on a 21-year-old patient with a left middle cerebral artery embolus and DVT in bilateral femoral veins in the setting of a M. pneumoniae infection. This patient had a transient increase in prothrombin time, partial thromboplastin time, fibrin/fibrinogen degradation products, thrombin-antithrombin III-complex, antiphospholipid antibodies, and IgM anticardiolipin antibodies and decrease in protein C activity.

The pediatric medical literature has additional case reports linking M. pneumoniae to PE. Brown et al. (7) described a 6-year-old male child with M. pneumoniae pneumonia, right-sided ileofemoral thrombosis, and right-sided PE found to have anticardiolipin IgG and IgM antibodies, lupus anticoagulant, and acquired activated protein C resistance. This prothrombotic state subsequently resolved after treatment of the infection with antibiotics and the PE with unfractionated heparin and then dalteparin. In another case report, during workup for a 13-year-old male child with right-sided PE in the setting of a left lower lobe M. pneumoniae pneumonia, Graw-Panzer et al. (8) found lupus anticoagulant, anticardiolipin IgG and IgM antibodies, and an underlying protein S deficiency. The transient prothrombotic markers returned to normal levels during subsequent follow-up for his acute illness.

M. pneumoniae pulmonary infections have been reported in the pediatric medical literature to be associated with an underlying hypercoagulability. Creagh et al. (9) reported on a left femoral vein thrombosis in a 10-year-old female with M. pneumoniae pneumonia who was found to have type I familial antithrombin III deficiency. In another case report of two children describing splenic infarcts associated with M. pneumoniae pneumonia, Witmer et al. (10) found elevated D-dimer, lupus anticoagulant, and elevated anticardiolipin and β2-glycoprotein antibodies that resolved following successful treatment of the infection with antibiotics and a three-month course of anticoagulation and, in one patient, an additional course of aspirin (10). No specific etiology was found for the infarctions, but Witmer et al. attributed the infarctions to possible thrombosis. Other case reports in the pediatric literature that found antiphospholipid antibodies include a patient with cardiac thrombus and internal carotid artery occlusion (11, 12). However, in their report of right popliteal artery thrombosis in a 5-year-old male child with M. pneumoniae pneumonia and right popliteal artery thrombosis, Joo et al. (13) did not find abnormalities in their limited hypercoagulability workup.

Our lack of hypercoagulability workup limits comparison with the available medical literature. We did not perform a hypercoagulability workup because the patient did not meet any Wells criteria and did not have a family history of hypercoagulability. Based on the available case reports, the underlying pathophysiology can be inferred to be related to a transient formation of antiphospholipid antibodies during a M. pneumoniae infection. Additionally, the thromboembolism can be expected to occur within a short period of time following the onset of symptoms. The rate that hypercoagulability occurs in infected patients and the practical clinical relevance of such a prothrombotic state without or without an inherited or congenital deficiency are unknown at this time. These questions would benefit from further investigation.

An alternative interpretation is a preexisting hypercoagulability may predispose patients to M. pneumoniae infection, which can exacerbate the hypercoagulability, further increasing the risk of VTE. This interpretation may be relevant for the patients of Graw-Panzer et al. (8) and Creagh et al. (9) who had underlying hypercoagulable conditions and subsequently suffered M. pneumoniae infection and then developed VTE. The Worcester Venous Thromboembolism study found an association between infection and VTE, and Rosendaal’s review of the literature found an association between hypercoagulability and increased risk of thrombosis (14-16). With the available case reports and epidemiological studies, this alternative interpretation has not been elucidated.

In this report, we described the interval development of PE in a patient with M. pnuemoniae bronchiolitis and pneumonia. The mechanism for the hypercoagulability during M. pneumoniae infection is unclear. A CTA of the chest should be obtained if a patient with M. pneumonia infection fails to show clinical improvement or suddenly develops clinical worsening of his or her respiratory status, so as to exclude PE. However, clinicians should take into account that Mycoplasma pneumonia may present with the symptoms of PE (3).

Acknowledgements

We would like to acknowledge Cecelia Kieu for assisting in the preparation of the figures for this manuscript.

References

1. Cha SI, Shin KM, Kim M, Yoon WK, Lee SY, Kim CH, Park JY, Jung TH. Mycoplasma pneumoniae bronchiolitis in adults: Clinicoradiologic features and clinical course. Scand J Infect Dis. 2009;41(6-7):515-9. [CrossRef] [PubMed]
2. Vasudevan VP, Suryanarayanan M, Shahzad S, Megjhani M. Mycoplasma pneumonia bronchiolitis mimicking asthma in an adult. Respir Care. 2012;57(11):1974-6. [CrossRef] [PubMed]
3. Simmons BP, Aber RC. Mycoplasma pneumoniae pneumonia. Symptoms mimicking pulmonary embolism with infarction. JAMA. 1979;241(12):1268-9. [CrossRef] [PubMed]
4. von Baum H, Welte T, Marre R, Suttorp N, Luck C, Ewig S. Mycoplasma pneumoniae pneumonia revisited within the German Competence Network for Community-acquired pneumonia (CAPNETZ). BMC Infect Dis. 2009;9;62. [CrossRef] [PubMed]
5. Ascer E, Marques M, Gidlund M. M pneumonia infection, pulmonary thromboembolism and antiphospholipid antibodies. BMJ Case Rep. 2011;2011. [CrossRef] [PubMed]
6. Senda J, Ito M, Atsuta N, Watanabe H, Hattori N, Kawai H, Sobue g. Paradoxical brain embolism induced by Mycoplasma pneumoniae infection with deep venous thrombosis. Intern Med. 2010;49(18):2003-5. [CrossRef] [PubMed]
7. Brown SM, Padley S, Bush A, Cummins D, Davidson S, Buchdahl R. Mycoplasma pneumonia and pulmonary embolism in a child due to acquired prothrombotic factors. Pediatr Pulmonolo. 2008;43(2):200-202. [CrossRef] [PubMed]
8. Graw-Panzer KD, Verma S, Rao S, Miller ST, Lee H. Venous thrombosis and pulmonary embolism in a child with pneumonia due to Mycoplasma pneumoniae. J Natl Med Assoc. 2009;101(9):956-8. [PubMed]
9. Creagh MD, Roberts IF, Clark DJ, Preston FE. Familial antithrombin III deficiency and Mycoplasma pneumoniae pneumonia. J Clin Pathol. 1991;44:870-1. [CrossRef] [PubMed]
10. Witmer CM, Steenhoff AP, Shah SS, Raffini LJ. Mycoplasma pneumoniae, splenic infarct, and transient antiphospholipid antibodies: a new association? Pediatrics. 2007;119:292–5. [CrossRef] [PubMed]
11. Bakshi M, Khemani C, Vishwanathan V, Anand RK. Mycoplasma pneumonia with antiphospholipid antibodies and a cardiac thrombus. Lupus 2006;15:105–6. [CrossRef] [PubMed]
12. Tanir G, Aydemir C, Yilmaz D, Tuygun N. Internal carotid artery occlusion associated with Mycoplasma pneumoniae infection in a child. Turk J Pediatr. 2006;48(2):166-71. [PubMed]
13. Joo CU, Kim JS, Han YM. Mycoplasma pneumoniae induced popliteal artery thrombosis treated with urokinase. Postgrad Med J. 2001;77:723–724. [CrossRef] [PubMed]
14. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999;353(9159):1167-73. [PubMed]
15. Spencer FA, Emery C, Joffe SW, Pacifico L, Lessard D, Reed G, Gore JM, Goldberg RJ. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis. 2009;28(4):401-9. [CrossRef] [PubMed]
16. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21(7):722-7. [CrossRef] [PubMed]

Cite as: Bui PV, Bhatia S, Saeed AI. Interval development of multiple sub-segmental pulmonary embolism in Mycoplasma pneumoniae bronchiolitis and pneumonia. Southwest J Pulm Crit Care. 2015;11(6):277-83. doi: http://dx.doi.org/10.13175/swjpcc152-15 PDF 

December 2015 Pulmonary Case of the Month

Zachary M. Berg, MD

Kashif Yaqub, MD 

Brian Wojek, MD

Khang Tran, MD

Karen L. Swanson, DO

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

The patient is a 70-year-old man with a history of a chronic dry cough for 5 years, who presented to the emergency department with worsening cough and shortness of breath.

Two weeks prior to symptom onset, was on trip in the United Kingdom, he developed gastroenteritis which spontaneously resolved.

Past Medical History, Social History, and Family History

• Old healed TB scar with positive PPD at 17 years of age prior to joining Air Force.  No treatment given and patient was asymptomatic from a pulmonary point of view since then.
• Squamous cell carcinoma of the skin on the scalp, status post excision complicated by osteomyelitis, status post surgical graft from hip with prolonged course of IV antibiotics in 2010.
• Fractured left clavicle, status post repair 20 years ago.
• Hay fever.
• Hyperlipidemia.
• Squamous cell carcinoma removed from left arm.
• Varicose veins, lower extremity.
• Married. Retired police officer. Does not smoke.
• Family history is noncontributory

Physical Examination

• General:  In moderate respiratory distress.  
• Vitals: SpO2 on room air of 65%, 94% on high flow oxygen.  Blood pressure 124/84, afebrile  
• Lungs:  Fine bibasilar crackles posteriorly.  
• Heart: Regular rhythm without murmur.
• The remainder of the physical examination was normal.

Laboratory Evaluation

• CBC: unremarkable except white blood cell count 20.5 x 10³ cells/ɥL, neutrophil predominant
• BNP: 366 pg/mL
• Mycobacterium Quantiferon: Positive
• Mycoplasma IgM: Positive at 1.18 U/L

Radiography

Initial chest x-ray is shown in Figure 1.

Figure 1. Initial chest x-ray.

What is the best next step in the patient's evaluation? (Click on the correct answer to proceed to the second of five panels)

1. Begin erythromycin or doxycycline for Mycoplasma pneumonia
2. Begin heparin for presumptive pulmonary embolism
3. Thoracic CT scan
4. 1 and 3
5. All of the above

Cite as: Berg ZM, Yaqub K, Wojek B, Tran K, Swanson KL. December 2015 pulmonary case of the month. Southwest J Pulm Crit Care. 2015;11(6):240-5. doi: http://dx.doi.org/10.13175/swjpcc146-15 PDF

October 2014 Pulmonary Case of the Month: A Big Clot

G. Zacharia Reagle DO

Eyad Almasri MD

Stuart J. Maxwell MD

Departments of Internal Medicine, Division of

Pulmonary and Critical Care

and Emergency Medicine

UCSF Fresno

Fresno, CA

History of Present Illness:

A 63 year-old man was brought to the emergency department (ED) with a report of acute onset of dyspnea. The dyspnea had started at rest less than one hour prior to ED presentation. It quickly progressed to severe respiratory distress. His initial vital signs were recorded as a BP of 124/69, pulse of 112, respiratory rate of 26 with an oxygen saturation (SpO₂) of 88% on 15 liters per minute (lpm) of oxygen via a non-rebreather mask. He was placed on non-invasive ventilation with intermittent episodes of brief desaturation into the 60% range. He was subsequently intubated without incident. Immediately following intubation he experienced a pulseless electrical activity (PEA) cardiopulmonary arrest.

Past Medical History:

• Diabetes mellitus
• Coronary Artery Disease
• Hypertension
• Deep Venous Thrombosis

Past Surgical History:

• Coronary Artery Bypass Graft – 2 vessel

Medications:

• Atorvastatin 40mg PO daily
• Insulin glargine 10u SQ daily
• Lisinopril 10mg PO daily
• Warfarin – had been stopped due to difficulty with compliance.

Social History:

• Married
• Owns and manages a series of used car lots.
• Lifetime non-smoker
• Reports a remote history of chronic alcohol use, but quit in 2005 when he was diagnosed with coronary artery disease.
• He denied illicit drug use.

Physical Exam:

General: Intubated, on a fentanyl infusion at 50mcg per hour.

Vitals: BP: 122/63 HR: 123 RR: 24 T: 35.6

HEENT: NC/AT, PERRL, neck supple without JVD noted.

Lungs: equal chest expansion was noted with clear lung sounds.

Heart: Tachycardic and regular with a good S1 and S2, no murmurs or             gallops were appreciated.

Abdomen: soft, obese, good bowel sounds.

Extremities: cold to the touch with no edema, or clubbing.

Neurological: Nonfocal exam with suppressed Glasgow Coma Scale after       sedation for intubation.

Skin: No rashes noted.

Laboratory:

Complete Blood Count (CBC): White blood cell count (WBC) 8.8 x 1000 cells/µL, hemoglobin 14.6 g/dL,   hematocrit 43.7, platelets 191,000 cells/µL

Chemistry: Sodium 139 meq/L, potassium 3.6 meq/L, chloride 106 meq/L, bicarbonate (CO2) 19 meq/L, blood urea nitrogen (BUN) 20 mg/dL, creatinine 0.7 mg/dL, glucose 459 mg/dL, magnesium 2.0 meq/L, phosphorus 3.4 mg/dL

Liver Function Tests: Albumin 4.1 g/dL, ALP 59 U/L, AST 30 U/L ALT 31 U/L. total bilirubin 0.4 mg/dL

Coagulation: Prothrombin time 13.9 seconds, INR 1.1, activated partial thromboplastin time (aPTT) 24.2 seconds

Troponin: 0.007 ng/ml

Brain naturetic peptide (BNP): 39 pg/ml

Arterial Blood Gases (ABG): pH 7.27, pCO2 38, pO2 38

Imaging:

The patient was immediately taken for a chest CT pulmonary angiogram. As he was on the CT scan table, the CT technician discovered that his IV line was malfunctioning. Before the line could be replaced, he had several non-contrast chest CT cuts obtained (Figure 1).  

Figure 1. Images A & C are non-contrast cuts while images B & D are comparison cuts that became available after the contrast study was obtained.

How often are intravascular filling defects seen on non-contrast chest CT images and what is the positive predictive value (PPV) of non-contrast images for pulmonary embolism (PE)? (Click on the correct answer to proceed to the next panel)

1. Filling defects are often seen on non-contrast CT images and are diagnostic for pulmonary embolism.
2. Filling defects can be seen on non-contrast images but have a low PPV.
3. Filling defects indicating pulmonary embolism are never seen on non-contrast images.
4. Filling defects indicating pulmonary embolism are sometimes seen on non-contrast images and have a high PPV for PE.

Reference as: Reagle GZ, Almasri E, Maxwell SJ. October 2014 pulmonary case of the month: a big clot. Southwest J Pulm Crit Care. 2014;9(4):199-207. doi: http://dx.doi.org/10.13175/swjpcc118-14 PDF