Antibiotics as Anti-inflammatories in Pulmonary Diseases

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Abstract

The currently available evidence for the use of chronic antibiotic therapy, principally macrolides and tetracyclines, as anti-inflammatory therapy in pulmonary disorders is reviewed. Historically, treatment of a number of chronic diseases with tetracyclines showed modest benefits but reports of the successful treatment of diffuse panbronchiolitis with erythromycin stimulated research in other lung diseases as well as shifting the focus from tetracyclines to macrolides. Chronic macrolide therapy is now recommended for patients with frequent exacerbations of cystic fibrosis and COPD and considerable evidence exists for potential benefits in asthma. There is also evidence of macrolide efficacy in the prevention of obliterative bronchiolitis after lung transplantation. Small trials have suggested possible benefit of macrolides in IPF. Taken together these suggest a potential for antibiotics, particularly macrolides, in some pulmonary inflammatory disorders.

History

Based on responses to antibiotics the concept arose over 70 years ago that several common diseases might have an infectious origin. In 1949, Thomas McPherson Brown reported favorable results of tetracycline treatment for rheumatoid arthritis patients at the 7th International Congress on Rheumatic Diseases (1). It was hypothesized these effects were due to a mycoplasma infection. However, the beneficial effects of cortisone in the treatment of arthritis were described at the same meeting. The effect of tetracycline paled beside that of steroids, and the salutary effects of antibiotics on rheumatoid arthritis were largely ignored.

Acne rosacea is a common, chronic dermatologic condition, whose cause remains unknown. Tetracyclines were the first systemic drugs used in the treatment of rosacea, and have been the mainstay therapy for more than 50 years (2). More recently, sub-antimicrobial doses of tetracyclines have been shown to be effective in rosacea presumably through an anti-inflammatory effect (3). Dermatitis herpetiformis is a disease now thought to be secondary to gluten sensitivity. However, this disorder has been treated with dapsone for over 60 years despite its non-infectious origin (4).

Tetracyclines have long been used for periodontal disease with clinical benefit presumed to be from their antimicrobial properties. However, as early as 1983, Golub (5) proposed that tetracyclines might have a beneficial effect by modifying inflammation. Now the tetracyclines are thought to exert their beneficial effects by anti-inflammatory effects, anti-collagenase effects, and a reduction in bone loss (6).

In 1959 the late Neil Cherniack published a double-blind study of 67 patients with chronic bronchitis or bronchiectasis treated with tetracycline, penicillin, a combination of oleandomycin and penicillin, or placebo for 3 to 22 months (7). Patients who received tetracycline had significantly fewer lower respiratory illnesses than those treated with placebos or penicillin. The average duration of these illnesses was also shorter in patients treated with tetracycline.

The anti-inflammatory effects of the macrolides were brought to light because of their effects on an uncommon pulmonary disease, diffuse panbronchiolitis (DPB). DPB is a rare disease seen in Japan and characterized by a chronic inflammatory neutrophilic inflammation of the airways, DPB has a 5-year survival rate of just 63% but only 8% when patients’ airways became colonized with Pseudomonas aeruginosa (8). However, in the early 1980s it was discovered that chronic treatment with erythromycin resulted in dramatically improved 5-year survival to 92% (8). This improvement occurred despite a failure to eliminate the bacterial colonization and was associated with a dramatic decrease in the accumulation of airway neutrophils (8,9). Interestingly, the effect on neutrophilic inflammation was found to be a nonspecific effect of the macrolides. Other macrolides (clarithromycin, roxithromycin and azithromycin) produced a similar suppression of the neutrophilic inflammation (10).

Gradually, with a better understanding of the pathogenesis of these common disease and basic studies examining anti-inflammatory effects, the macrolides and tetracyclines were recognized as anti-inflammatories. Inflammation is proposed to play a role in the pathogenesis of a number of pulmonary disorders. The encouraging results of the above suggested that macrolides and tetracyclines might be beneficial in pulmonary inflammatory conditions. Studies have examined a number of disorders including cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and asthma.

Anti-inflammatory Mechanisms of Action

Macrolides and tetracyclines exert their antibacterial effects by inhibiting bacterial protein synthesis. Although the anti-inflammatory mechanisms of action of the tetracyclines and macrolides are likely multiple, one important mechanism by both is a reduction in production of a multitude of pro-inflammatory cytokines. Most of these cytokines are regulated at the transcriptional level through proteins such as nuclear factor-κβ (NF- κβ), activator protein-1 (AP-1) and/or p38 mitogen-activated protein kinases (p38 MAPK). Although the studies have varied depending on the in vitro systems examined, most have described a shortening of the half-life of pro-inflammatory cytokine mRNA usually through effect on one or more of the transcriptional control proteins (10-13).

Cystic Fibrosis

A major step in the use of antibiotics as anti-inflammatories occurred with the introduction of macrolides as adjunctive therapy in cystic fibrosis in 2003. Like diffuse panbronchiolitis, airways of cystic fibrosis patients show chronic inflammation with neutrophils which are often infected with Pseudomonas aeruginosa. Saiman et al. (14) conducted a multicenter, randomized, double-blind, placebo-controlled trial of azithromycin in cystic fibrosis patients infected with Pseudomonas. They found a reduction in exacerbations and greater weight gain in those treated with azithromycin compared to control. Following several confirming studies, cystic fibrosis patients are now commonly treated with macrolide antibiotics, especially when infected with Pseudomonas (15).

Tetracyclines have been less commonly used probably because of the staining of teeth and bone in younger, growing children. However, a recent small trial of 19 adult cystic fibrosis treated with chronic doxycycline showed an improvement in FEV1 and an increase in time to the next exacerbation compared to 20 placebo-treated controls (16). This might suggest an alternative in older patients or those at high risk for side effects from macrolides.

Non-CF Bronchiectasis

Long-term treatment with antibiotics has been recommended in patients with bronchiectasis and frequent exacerbations (17). This is based on studies showing decreased rates of exacerbations and some improvement in quality of life. It is not clear whether this effect is due to the antibacterial or anti-inflammatory properties of macrolides. In addition to Cherniak’s tetracycline trial which included bronchiectatics (7), an early MRC trial in 1957 showed that long-term twice weekly oxytetracycline over 1 year led to reduced sputum purulence, fewer days confined to bed and fewer days off work (18). Later trials in non-CF bronchiectasis have been done primarily with azithromycin and it is noted that there is an increased risk of macrolide-resistant organisms developing in these patients, as well as other risks associated with macrolide therapy including ototoxicity and QT prolongation (19).

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is one of the most expensive diseases to treat (20). A number of studies examining costs of COPD have shown that exacerbations, especially those resulting in hospitalization, account for the majority of costs (21,22). Although treatment with glucocorticoids, long-acting beta2-agonists, and long-acting muscarinic antagonists reduce the frequency of acute exacerbations, COPD patients receiving all three of these medications still average 1.4 acute exacerbations per year (23). Beginning in the early 2000’s there were a number of studies that reported an improvement in COPD exacerbations with macrolides (24-27). This culminated in a large, NIH-sponsored, randomized, placebo-controlled, multi-center trial demonstrating that azithromycin decreased COPD exacerbations by about 20% (28).

However, despite overwhelming data that macrolides modestly reduce COPD exacerbations and professional society recommendations for macrolide use in COPD patients at high risk for COPD exacerbations, adoption of chronic therapy with macrolides in COPD has been slow (29). The major reason appears to be concerns over side effects (29). Although azithromycin is well tolerated in the majority of patients, the drug can have serious adverse effects as noted in the trials in non-CF bronchiectasis including hearing loss and QT prolongation (29). The latter is especially concerning given that within less than one year of publication of the azithromycin NIH trial in the New England Journal of Medicine, a large trial the same reported a near 3-fold increase in mortality in patients receiving macrolides (30).

Despite early trials demonstrating efficacy in decreasing COPD exacerbations, tetracyclines have received little attention compared to macrolides. In addition to Cherniak’s study (7) there is a confirming report by Norman in 1962 (31). Tetracyclines might represent an alternative to macrolides in patients at high risk for complications from the macrolides.

Asthma

Asthma, like cystic fibrosis and COPD, is an inflammatory airway disease although usually characterized by eosinophilic inflammation. Studies suggesting macrolides might be useful as anti-inflammatories in asthma go back as far as 1970 (32). After the initial study by Itkin and Menzel (32), few studies were performed until the 2000’s. However, a 1993 study from National Jewish suggested troleandomycin might be useful as a steroid-sparing agent in children with asthma and two Japanese studies published in 1999 and 2000 with roxithromycin and clarithromycin both gave positive results in small numbers of patients (33-35).

In studies whose logic is reminiscent of Thomas McPherson Brown’s concept of mycoplasma infection in rheumatoid arthritis, Kraft et al. (36) investigated chronic chlamydia and mycoplasma infection in asthma and the response to macrolide therapy. In 2002 they reported that clarithromycin treatment increased FEV1 in asthmatics but only in those with evidence of C. pneumoniae or M. pneumoniae infection by PCR in upper and lower airway samples. Sutherland and co-workers (37) also showed improvement in airway hyper-responsiveness with clarithromycin therapy but in both PCR-positive and negative groups. The difference likely resides in identifying and chronic chlamydia and mycoplasma infection. A positive PCR does not necessarily equate to chronic infection and the serologic results from different assays are variable complicating these studies (38,39).

A number of studies have been conducted since Kraft’s investigation examining clarithromycin or azithromycin and assessing various clinical responses and inflammatory parameters in asthma (40-47). These studies have been inconsistent with some showing benefits while others did not. A Cochrane review in 2005 by Richeldi et al. (48) and a review article in 2014 by Wong et al. (49) both concluded that insufficient data existed to recommend chronic macrolide therapy in asthma.

The inconsistency in these results might be explained by the small patient numbers and because various phenotypes of asthma were included. Brusselle et al. (47) reported that azithromycin treatment significantly reduced exacerbation rates only in patients with severe neutrophilic asthma compared with placebo. However, neutrophilic asthma has been associated with increased bacterial load confusing whether benefits are due to an anti-inflammatory or an antibiotic effect (50). Furthermore, clarithromycin reduces neutrophil numbers in patients with severe asthma and it has been suggested that those patients with a neutrophilic phenotype might respond better to the anti-inflammatory effects of macrolide therapy (44,51).

A recent well-done recent study from Australia might tip the balance in favor of chronic macrolide therapy in difficult-to-control asthma. Gibson et al. (52) performed a randomized, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in 420 adults with symptomatic asthma despite current use of inhaled corticosteroid and a long-acting bronchodilator. Patients were randomly assigned to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Azithromycin reduced asthma exacerbations by nearly half and significantly improved asthma-related quality of life.

Tetracyclines as anti-inflammatories in asthma have received much less attention than the macrolides. In 2008 Daoud et al. (53) reported that minocycline allowed for a reduction in steroid dose in asthmatics who were steroid-dependent. A study from India demonstrated an improvement in post bronchodilator FEV1, the FVC, and the FEF (25-75) in asthmatics treated with doxycycline (54).

Obliterative Bronchiolitis

Obliterative bronchiolitis (OB) has historically gone by a variety of terms including bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP) and, more recently, cryptogenic organizing pneumonia (COP) although some now separate OB as a separate entity (55). Histologically OB is very similar to diffuse panbronchiolitis, and in fact, panbronchiolitis has been grouped with OB (55). The OB histological pattern is now most commonly seen after lung transplantation or hematopoietic stem-cell transplantation (HSCT). However, OB can be seen with autoimmune disease, particularly rheumatoid arthritis; exposure to inhalational toxins such as sulfur dioxide, hydrogen sulfide, nitrogen oxides, and fly ash; and as an unusual complication following infection with adenovirus, measles virus, or mycoplasma (55).

The treatment of OB is usually corticosteroids or other immunosuppressants (55). However, since OB can result in death or decreased respiratory function, studies with adjunctive therapy or prevention of OB have been of interest. Azithromycin has resulted in improved pulmonary function in approximately 50% of lung-transplant recipients with obliterative bronchiolitis (56,57). A retrospective analysis indicated that the administration of azithromycin in patients with obliterative bronchiolitis after lung transplantation is associated with improved survival (58). Studies examining azithromycin after HSCT were done given the beneficial effects after lung transplantation. Surprisingly, the results were completely different. In a randomized clinical trial that included 465 patients, 2-year airflow decline-free survival was significantly worse for the azithromycin group than for the placebo group (59). The trial was terminated early for a significant increased risk in the azithromycin group of hematological relapses. The FDA recently issued a warning against using chronic azithromycin therapy in HSCT.

There is a paucity of data on treatment of OB with macrolides in non-transplant conditions. In 1993, Ichikawa et al. (60) used erythromycin for 3-4 months in six patients with a diagnosis of bronchiolitis obliterans OP confirmed on histological examination. All improved by the completion of therapy. However, a recent trial of azithromycin in eight patients with post-infectious OB did not produce an improvement in pulmonary function parameters (61). No studies were identified using tetracyclines as therapy in OB.

Cryptogenic Organizing Pneumonia

This entity, which was formerly known as bronchiolitis with organizing pneumonia (BOOP) can involve small airways, but also involves alveolar ducts and alveoli and can present as patchy peripheral opacities (62). It is considered an inflammatory disease which is usually very responsive to corticosteroid therapy, but may relapse when steroid therapy is withdrawn (63). There are several reports now that cryptogenic organizing pneumonia responds to treatment with macrolide and suggest that long term suppression with macrolides can avoid side effects associated with long term steroid therapy (63).

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a condition that has also been associated with neutrophils but with inflammation in the alveoli rather than the airways. With the introduction of nintedanib and pirfenidone and the realization that corticosteroids are of no benefit, the management of IPF has dramatically changed over the past decade (64). A recent publication done during the course of the shift in IPF therapy suggests that azithromycin added to conventional reduced the incidence of acute exacerbations (65). However, these retrospective results need to be interpreted with caution, since as noted above “conventional therapy” for IPF has changed profoundly. For example, many of the patients included in this study were subjected to corticosteroid therapy or other immunosuppressive agents, both of which are no longer recommended in IPF treatment (65). A similar study was performed by Kawamura et al. (66) performed from 2005-16. This single-center retrospective study of patients with IPF demonstrated that treatment of 38 consecutive patients with azithromycin (500 mg/day) for 5 days led to increased survival compared to 47 historical controls treated with a fluoroquinolone-based regimen.

A trial with minocycline in IPF was registered at clinicaltrials.gov but results were apparently never published (67). A small trial in 6 IPF patients treated with doxycycline for 24 weeks showed significant improvement in 6-minute walk time, St. George’s Respiratory Questionnaire, FVC, and quality of life compared to 6 controls (68).

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease that lead to progressive cystic destruction of the lungs. A recent study with doxycycline in LAM patients produced no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life (69). The authors concluded that it is unlikely that doxycycline has a useful effect in LAM.

Summary

Macrolides are clinically useful in reducing exacerbations of cystic fibrosis, chronic obstructive pulmonary disease, bronchiolitis obliterans after lung transplantation, and possibly asthma. Tetracyclines might be considered as a substitute in some situations.

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Cite as: Robbins RA. Antibiotics as anti-inflammatories in pulmonary diseases. Southwest J Pulm Crit Care. 2018;17(3):97-107. doi: https://doi.org/10.13175/swjpcc104-18 PDF 

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia in a Patient with Multiple Pulmonary Nodules: Case Report and Literature Review

Hasan S. Yamin, MD¹

Feras Hawarri, MD¹

Mutaz Labib, MD¹

Ehab Massad, MD²

Hussam Haddad, MD³

Departments of ¹Internal Medicine Pulmonary & Critical Care Division, ²Thoracic Surgery and ³Pathology

King Hussein Cancer Center

Amman, Jordan

Abstract

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disease, where carcinoid tumorlets invade the pulmonary parenchyma and bronchioles. These nests of cells release a variety of mediators including bombesin and gastrin releasing peptide that cause heterogeneous bronchoconstriction, creating a mosaic appearance on chest imaging studies, especially on expiratory scans. Clinically patients usually have long standing symptoms of shortness of breath (SOB) and cough that are difficult to distinguish from asthma. In this article we describe a case of DIPNECH in a patient with several years’ history of SOB and cough, and review 179 cases of DIPNECH reported in the literature since 1992.

Case Presentation

A 72-year-old, non-smoking lady was admitted to the hospital in preparation for bilateral mastectomy. She recently received a diagnosis of bilateral breast invasive ductal carcinoma grade 2, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (HER-2) positive in the left tumor but negative in the right tumor.

Her past medical history was significant for hypertension, long standing cough and dyspnea on exertion labeled as asthma poorly responsive to nebulizers. Socially, she was a house wife with no history of occupational exposure.

The patient was found to be tachypneic (respiratory rate 22 breaths/minute) and hypoxemic (oxygen saturation 86% on room air). Heart rate and blood pressure were within normal limits. She had bilateral decreased breath sounds and diffuse expiratory wheezes.

Chest CT scan revealed diffuse mosaic pattern and multiple pulmonary nodules in both lungs suggestive of metastases (Figure 1).

Figure 1. Representative images form chest CT scan showing a diffuse mosaic pattern and multiple pulmonary nodules in both lung fields suggestive of metastases.

These lesions did not take up fludeoxyglucose (FDG) on positron emission tomography (PET) scan. Her pulmonary function tests (PFT) were unremarkable except for reduction in expiratory reserve volume (ERV) at 22%, and increased residual volume to total lung capacity ratio (RV/TLC) at 136% probably related to air trapping. Diffusion lung capacity was within normal limits.

Video assisted thoracoscopic biopsy of one of the nodules in left lower lobe was done. Pathology showed both a carcinoid tumor and tumorlets invading lung bronchioles (Figure 2A & B) and these tumorlets were positive for chromogranin (Figure 2C & D) and pancytokeratin (Figure 2 E & F).

Figure 2. A & B: histology (H&E stain) showing carcinoid tumorlets invading lung bronchioles; C & D: positive staining for chromogranin; E &F: positive staining for pancytokeratin.

A diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) was made, and the patient was treated with intravenous steroids and nebulizers. Her oxygen saturation improved to 94% on room air. She was later discharged on oral steroids. Her CT scan also showed no significant improvement in changes described above.

Review of the Literature

Methods

We searched PubMed for all cases of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia reported in the English literature since 1992 when the entity was first described. A total of 179 patients were identified in 55 articles, in the form of case reports and case series. In this article we contribute an additional patient (1-55).

Patient Characteristics

A total of 180 patients (including our patient) were identified. There were 161 females (89.5%) and only 19 males (10.5%). Mean age at diagnosis was 57.75 years (males tended to present at a younger age of 52 years, compared to 58.4 years in females). Most patients were never smokers 52.8%, smokers/exsmokers 27.2%, and in 20% smoking status was not mentioned.

The majority of patients presented with cough (91 patients, 50.5%), followed by exertional dyspnea (81 patients, 45%), and hemoptysis (6 patients, 3.3%). Incidental imaging findings led to diagnosis in 22 patients (12.2%). Mean duration of symptoms before diagnosis was 8.25 years (Table 1).

Table 1. Patients` characteristics and presenting symptoms.

Diagnosis, Therapy and Outcome

Most patients underwent imaging with chest CT scan, the most common findings were nodules in 148 patients (82.2%), ground glass opacities/mosaic pattern in 66 patients (36.6%), and bronchial wall thickening in 37 patients (20.5%). Most patients had an abnormal spirometry: obstructive pattern (48.9%), restrictive (5%), or mixed obstructive restrictive pattern (6.7%) (Table 2).

Table 2. Spirometry and imaging.

Because of their symptoms, and spirometry findings 45 patients (25%) were labeled with another disease including asthma in 29 patients (16.1%), COPD in 12 patients (6.6%) and bronchiolitis in 4 patients (2.2%).

The diagnosis was made using surgical lung biopsy in 148 patients (82.2%), bronchoscopic biopsy in 10 patients (8 transbronchial biopsy, 2 endobronchial biopsy) (5.6%), CT-guided biopsy in 7 patients (3.9%), postmortem diagnosis in 3 patients (1.7%), post lung transplantation in 2 patients (1.1%) and clinically in 2 patients (1.1%). The diagnostic method was not mentioned in 8 patients (4.4%).

Patients received a variety of therapies including inhaled bronchodilators, inhaled or systemic steroids, and somatostatin analogues among others. Response to treatment was mentioned for 89 patients, (59 patients reported that their symptoms remained stable, 11 patients improved with treatment, while 18 patients reported symptom progression and 2 patients died. (Table 3).

Table 3. List of DIPNECH articles ordered by publication year. This table shows number of patients in each article, diagnostic method, therapy given and outcome.

Of note, 15 out of 23 patients who received a somatostatin analogue reported stable, or improvement in their symptoms (65.2%), which did not necessarily translate into improvement in air flows on spirometry (27, 29, 46, 51).

Discussion

Pulmonary neuroendocrine cell hyperplasia was described early in the previous century (56), however the significance and role of the pathologic changes were not precisely determined. It was thought that they were secondary to other lung diseases such as interstitial lung disease, bronchiectasis, cystic fibrosis, smoking exposure, or in people who live at high altitude. In addition to the previously mentioned associations, hyperplasia of pulmonary neuroendocrine cells was also thought to be a pre-neoplastic process, since the lesions can potentially progress to carcinoid tumors even without causing symptoms or airflow limitation. In 2004 the changes were recognized by WHO as one end of the spectrum of pulmonary neuroendocrine tumors.

The relationship between carcinoid tumorlets and other pulmonary diseases and its role in precipitating respiratory symptoms remains puzzling. The term DIPNECH was coined in 1992 by Aguayo (1) who described a new entity where idiopathic hyperplasia or dysplasia of pulmonary neuroendocrine cells occurred in the absence of other lung disorders. The changes were associated with physiologic and radiologic airflow limitation similar to obliterative bronchiolitis. This was the first description of pulmonary neuroendocrine hyperplasia as a primary process.

Because of similar symptoms, an obstructive pattern on pulmonary function tests, and chest imaging suggestive of air trapping, many patients receive a diagnosis of asthma for several years before the correct diagnosis is made. This similarity to other obstructive lung diseases can be explained by the pathologic changes of airway obstruction seen on biopsy. Pulmonary neuroendocrine cells, or Kulchitsky cells, are normally present in small numbers in airways, where they release a myriad of bioactive amines and peptides like serotonin, chromogranin A, gastrin-releasing peptide (GRP), and calcitonin.

Airway obstruction is believed to occur both due to physical obstruction of bronchioles by tumorlets and smooth muscle constriction caused by active mediators released. Bombesin and related peptides like gastrin releasing peptide, neuromedin B and neuromedin C are thought to cause bronchoconstriction indirectly through the release of several other bronchoconstrictors that act on smooth muscle cells (57). However, in vitro studies in guinea pig lungs suggest that bombesin may act directly by binding to specific receptors on smooth muscle cells (58).

Pulmonary neuroendocrine pathology occurs in a spectrum of three forms: hyperplasia, tumorlets and carcinoid tumors. DIPNECH is characterized by proliferation of neuroendocrine cells initially limited to the basement membrane of airways, when disease extends beyond the lumen of airway it is called carcinoid tumorlets. Tumorlets larger than 0.5 cm become carcinoid tumors and appear as nodules on chest CT scans. Diagnosis requires lung biopsy, with a surgical biopsy procedure more likely to provide diagnostic tissue than bronchoscopic transbronchial biopsies.

According to Aguayo`s definition of DIPNECH, patients have pulmonary symptoms with radiographic and physiologic abnormalities suggestive of obstructive lung disease, but in our review 12.2% of patients had no symptoms at all, and 15.5% had normal spirometry. We believe hyperplasia, tumorlets and carcinoid tumors represent different aspects of the same disease, the occurrence of symptoms, radiologic and physiologic airflow limitation depends on the time frame at which diagnosis was made, should those patients be followed up, they could develop symptoms and airflow limitation in the future. Thus, we propose to expand the definition to include patients with no symptoms or spirometry abnormalities. However, it remains uncertain whether asymptomatic patients who are diagnosed at an earlier stage need specific treatment or not.

It is also clinically difficult to establish a causal relationship, or determine the direction of the relationship between pulmonary neuroendocrine cell hyperplasia and other concomitant lung disorders, or harmful exposures (1,59, 60). In our review 27.2% of patients were active or previous smokers, only one patient lived at high altitude (more than 2000m) (14), 29 patients had a history of previous or current malignancy including 8 lung cancers (not shown in table), 13 patients had evidence of bronchiectasis, and one patient had honeycombing on imaging. These findings are similar to data obtained from individual case reports and series (2, 6, 14, 17, 19, 22, 29, 33, 37, 46, 47 and 53).

When the diagnosis is made, therapeutic options may include observation for mild symptoms, inhaled or systemic steroids, in addition to bronchodilators, especially if patients who show reversible airway obstruction on PFT. Other potential therapies are somatostatin analogues, however more studies are needed to determine their precise role. (27, 29, 43, 46)

Conclusion

DIPNECH is a rare clinical entity that requires a high clinical suspicion. Because of clinical, spirometry, and imaging similarity to other obstructive lung diseases, and the requirement for lung biopsy to make the diagnosis, DIPNECH is probably an under-diagnosed entity, with still limited treatment options. The diagnosis should probably be considered in any patient with difficult to treat obstructive lung disease, unexplained bronchiolitis, particularly if there are multiple small lung nodules present on chest CT scan. We propose to expand the definition of DIPNECH to include patients with even no symptoms or spirometric evidence of airflow limitation, as development of these abnormalities depends on the time frame at which diagnosis is made. It is also difficult to establish a causal relationship with other concomitant lung conditions, the presence of which should not rule out a diagnosis of DIPNECH.

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Cite as: Yamin HS, Hawarri F, Labib M, Massad E, Haddad H. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia in a patient with multiple pulmonary nodules: case report and literature review. Southwest J Pulm Crit Care. 2017;15(6):282-93. doi: https://doi.org/10.13175/swjcc139-17 PDF

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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2. Athanazio R. Airway disease: similarities and differences between asthma, COPD and bronchiectasis. Clinics (Sao Paulo). 2012;67:1335-43. [CrossRef] [PubMed]
3. Verra F, Escudier E, Bignon J, Pinchon MC, Boucherat M, Bernaudin JF, de Cremoux H. Inherited factors in diffuse bronchiectasis in the adult: a prospective study. Eur. Respir. J. 1991 Sep; 4(8)937-44. [PubMed]
4. Girodon E, Cazeneuve C, Lebargy F, Chinet T, Costes B, Ghanem N, Martin J, Lemay S, Scheid P, Housset B, Bignon J, Goossens M. CFTR gene mutations in adults with disseminated bronchiectasis. Eur. J. Hum. Genet. 1997 May-Jun; 5(3):149-55. [PubMed]
5. Ambrosetti M, Ageno W, Spanevello A, Salerno M, Pedretti RF. Prevalence and prevention of venous thromboembolism in patients with acute exacerbations of COPD. Thromb Res. 2003;112: 203-7. [CrossRef] [PubMed]
6. Lippi G, Favaloro EJ. Allergy and venous thromboembolism: a casual or causative association. Semin Thromb Hemost. 2016;42: 63-8. [CrossRef] [PubMed]
7. Takemoto CM. Venous thromboembolism in cystic fibrosis. Pediatr Pulmonol. 2012;47: 105-12. [CrossRef] [PubMed]
8. Aksu K, Donmez A, Keser G. Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des. 2012;18: 1478-93. [CrossRef] [PubMed]
9. Stuijver DJ, Majoor CJ, van Zaane B, Souverein PC, de Boer A, Dekkers OM, Büller HR, Gerdes VEA. Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study. Chest. 2013;143: 1337-42. [CrossRef] [PubMed]
10. Baldwin MJ, Moore HM, Rudarakanchana N, Gohel M, Davies AH. Post-thrombotic syndrome: a clinical review. J Thromb Haemost. 2013;11: 795-805. [CrossRef] [PubMed]
11. Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev. 2014;28: 221-6. [CrossRef] [PubMed]
12. Bahloul M, Chaari A, Tounsi A, et al. Incidence and impact outcome of pulmonary embolism in critically ill patients with severe exacerbation of chronic obstructive pulmonary diseases. Clin Respir J. 2015;9: 270-7. [CrossRef] [PubMed]
13. Lindqvist PG, Dahlback B. Reactions to awareness of activated protein C resistance carriership: a descriptive study of 270 women. Acta Obstet Gynecol Scand. 2003;82: 467-70. [CrossRef] [PubMed]
14. Prescott SM, Richards KL, Tikoff G, Armstrong JD, Jr., Shigeoka JW. Venous thromboembolism in decompensated chronic obstructive pulmonary disease: a prospective study. Am Rev Respir Dis. 1981;123: 32-6. [CrossRef] [PubMed]
15. Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med. 2006;144: 390-6. [CrossRef] [PubMed]
16. Majoor CJ, Kamphuisen PW, Zwinderman AH, Ten Brinke A, Amelink M, Rijssenbeek-Nouwens L, et al. Risk of deep vein thrombosis and pulmonary embolism in asthma. Eur Respir J. 2013;42(3):655-61. [CrossRef] [PubMed]
17. Nadeem O, Gui J, Ornstein DL. Prevalence of venous thromboembolism in patients with secondary polycythemia. Clin Appl Thromb Hemost. 2013;19:363-66. [CrossRef] [PubMed]
18. Mermis JD, Strom JC, Greenwood JP, Low DM, He J, Stites SW, Simpson SQ. Quality improvement initiative to reduce deep vein thrombosis associated with peripherally inserted central catheters in adults with cystic fibrosis. Ann Am Thorac Soc. 2014;11: 1404-10. [CrossRef] [PubMed]
19. Kim V, Goel N, Gangar J, Zhao H, Ciccolella DE, Silverman EK, Crapo JD, Criner GJ; and the COPD Gene Investigators. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis. 2014;1 :239-49. [CrossRef] [PubMed]
20. Børvik T, Brækkan SK, Enga K, Schirmer H, Brodin EE, Melbye H, Hansen JB. COPD and risk of venous thromboembolism and mortality in a general population. Eur Respir J. 2016;47: 473-81. [CrossRef] [PubMed]
21. Guo L, Chughtai AR, Jiang H, Gao L, Yang Y, Yang Y, Liu Y, Xie Z, Li W. Relationship between polycythemia and in-hospital mortality in chronic obstructive pulmonary disease patients with low-risk pulmonary embolism. J Thorac Dis. 2016;8: 3119-31. [CrossRef] [PubMed]
22. Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg. 2010;126:2234-42. [CrossRef] [PubMed]

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 2015 Pulmonary Case of the Month: Collapse of the Left Upper Lobe

G. Zacharia Reagle DO

Andreas Escobar-Naranjo MD

Department of Internal Medicine

Division of Pulmonary and Critical Care

UCSF Fresno

Fresno, CA

History of Present Illness

A 65 year-old woman who recently quit smoking presented to the ER for the third time in the preceding month with dyspnea and cough. She reported some subjective fevers and cough productive of white sputum as well as a seven kilogram unintentional weight loss in the prior four to eight weeks. She had been diagnosed with COPD in the past and on both prior ER visits was treated with oral steroids and antibiotics. She would feel some relief with the steroids but once the course was over she would quickly experience a return of her symptoms. On the third ER presentation she was admitted to the hospital.

Past Medical History:

• Asthma
• HTN
• Hypothyroidism

Past Surgical History:

• C-section x 2
• TAH and BTL
• Appendectomy
• Tonsillectomy

Medications:

• Levothyroxine 0.15mg daily
• Budesonide 40/formoterol 4.5 twice daily
• Tiotropium 18 mcg daily
• Fluoxetine 20mg daily
• Hydroxyzine 50mg three times daily
• Hydrochlorothiazide 50/triamterene 75 daily
• As needed albuterol

Allergies: No Known Drug Allergies

Social History:

A lifelong Californian, she was divorced with two healthy adult children. She is a United States Air Force veteran who served as a broadcaster from 1974-78 including a deployment to Asia. After leaving the service she worked as a Registered Nurse in burn, rehab and home health nursing. A former tobacco smoker with 35+ pack years of tobacco exposure – she quit smoking one month prior to the current admission. She is currently homeless, living in a homeless veteran’s shelter. She is a recovering alcoholic and cannabis addict.

Physical Exam:

General: Alert, mild respiratory distress, mildly anxious.

Vitals: BP: 134/80 HR: 104 RR: 18, SpO2 93% on room air T: 98.4ºF

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

Lungs: equal chest expansion, scattered bilateral wheezes with decreased airflow on the left

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

Abdomen soft, Non-tender, good bowel sounds.

Extremities No edema, nor clubbing.

Neurological: She was alert and oriented with a Glasgow Coma Score of 15, no focal defects noted.

Skin: No rashes noted.

Laboratory:

CBC: WBC 6.9 X 10⁹ cells/L, hemoglobin13.4 g/dL, hematocrit 39.4, platelet count 329 X 10⁹ cells/L

Chemistries: Na+ 139 mEq/L, K+ 3.5 mEq/L Cl- 106 mEq/L, CO2 26 mEq/L  BUN 8 mg/dL, creatinine 0.6 mg/dL, glucose 149 mg/dL, magnesium 2.0 mg/dL, phosphate 3.4 mg/dL

Mycoplasma IgM: (-)

S. pneumoniae urinary antigen: (-)

Legionella urinary antigen: (-)

Blood Cultures: (-)

Imaging:

On admission a chest CT was preformed (Figure 1).

Figure 1. Representative images from the thoracic CT scan showing central and upper zone predominate bronchiectasis, and total collapse of the left upper lobe. There also was some emphysema noted.

Which of the following causes of bronchiectasis should be considered in this case? (Click on the correct answer to proceed to the second of six panels)

1. Allergic bronchopulmonary aspergillosis
2. Autoimmune diseases including rheumatoid arthritis and Sjogren’s syndrome
3. Congenital pulmonary conditions including cystic fibrosis and primary ciliary dyskinesia
4. Immunoglobulin deficiency
5. All of the above are possible causes of bronchiectasis

Reference as: Reagle GZ, Escobar-Naranjo A. June 2015 pulmonary case of the month: collapse of the left upper lobe. Southwest J Pulm Crit Care. 2015;10(6):315-22. doi: http://dx.doi.org/10.13175/swjpcc072-15 PDF 

February 2015 Pulmonary Case of the Month: Severe Asthma

Suresh Uppalapu, MD
Sunil Santhanakrishnan, MD
Rajeev Saggar, MD

Banner Good Samaritan Medical Center

Phoenix, AZ

History of Present Illness

A 50-year-old  African-American woman  with a history of asthma presented to the emergency department with a chief complaint of shortness of breath for 2 weeks. She reported some chest tightness, wheezing  and dry cough. She denied fever, chills, myalgias or arthralgias  at the time of admission.

PMH, SH and FH

In addition to asthma, she has a past medical history of type 2 diabetes mellitus, hypertension, and multiple sclerosis. She admitted to social smoking but states she quit 6 to 7 months ago. She denies alcohol, recreational drug use, or a family history of early coronary artery disease, strokes or cancers. 

Medications

• Montelukast 10 mg daily
• Salmeterol/fluticasone 250/50 inhaled twice a day
• Albuterol inhaler as needed for shortness of breath
• Metformin 500 mg bid.
• Dimethyl fumarate 240 mg bid.
• Omega 3 fish oil.
• Calcium carbonate 600 mg daily
• Naproxen 500 mg BID
• Lisinopril 10 mg daily
• Hydrochlorothiazide 25 mg daily.

Physical Exam

Vitals: Temperature 37.2º C, respiratory rate 33 breaths/min, heart rate 112 beats/min, blood pressure 152/80 mm Hg, SpO2 80% on room air but 98% on 3 liters/min by nasal cannula.

General: Mild respiratory distress.

Lungs: Diminished breath sounds diffusely with mild wheezing.

The rest of her exam was within normal limits.

Laboratory/EKG/Chest Radiography

White blood cells 8.1 X 10³ cells/microliter, hemoglobin 13.9 g/dL, hematocrit 41.7, platelets 289,000 cells/microliter.

Electrolytes blood urea nitrogen, creatinine, glucose, troponin, and brain naturetic peptide were within normal limits

EKG showed sinus tachycardia but was otherwise normal.

Chest x-ray was interpreted as normal.

A thoracic CT scan showed wispy infiltrates but no evidence of pulmonary embolism or other abnormalities.

Which of the following is appropriate management at this time? (Click on the correct answer to proceed to the second of four panels)

1. Bronchodilators
2. Discharge the patient to home
3. Intravenous corticosteroids
4. 1 and 3
5. All of the above

Reference as: Uppalapu S, Santhanakrishnan S, Saggar R. February 2015 pulmonary case of the month: severe asthma. Southwest J Pulm Crit Care. 2015;10(2):57-62. doi: http://dx.doi.org/10.13175/swjpcc010-15 PDF

November 2014 Pulmonary Case of the Month: BAL Eosinophilia

Salma Imran Patel, MD, MPH

Lewis J. Wesselius, MD

Laszlo T. Vaszar, MD

Departments of Internal Medicine and Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 62 year-old- was admitted to the hospital for 2 weeks of worsening cough, yellowish sputum production, shortness of breath and pleuritic chest pain. The patient has had asthma since the 1970s and presently uses salmeterol/fluticasone and albuterol as a rescue inhaler. He was intubated once four years ago, and has had a total of three hospitalizations for his asthma and 15 courses of prednisone. He is sensitive to cold/hot air, all animals, aspirin and acetaminophen.

PMH, FH, SH

In addition to the asthma, he has a history of type 2 diabetes mellitus, hypertension, gastroesophageal reflux disease, and chronic abdominal pain.

Physical Examination

Vital signs: T 36.6º C, HR 98, BP129/69, RR 20 and SPO2 96% on 2 L of oxygen by nasal cannula. He was mildly distressed and coughing. His pulmonary exam showed diffuse inspiratory and expiratory wheezes. The remainder of his exam was unremarkable.

Laboratory

Significant findings on laboratory evaluation include an elevated white blood cell count of 13,400 cells/ɥL, an elevated absolute eosinophil count of 2,820 eosinophils/ɥL, an elevated glucose of 131 mg/dL, and a low sodium of 120 mEq/L.

Imaging

A thoracic CT scan was performed (Figure 1).

Figure 1. Representative images in lung windows from thoracic CT scan.

Which of the following best describes the CT scan? (click on the correct answer to proceed to the next panel)

1. Cavitary changes in both apices
2. Central consolidation
3. Fibrotic changes at the bases
4. Peripheral opacities
5. Normal

Reference as: Palel SI, Wesselius LJ, Vasczar LT. November 2014 pulmonary case of the month: BAL eosinophilia. Southwest J Pulm Crit Care. 2014;9(5):251-6. doi: http://dx.doi.org/10.13175/swjpcc136-14 PDF

Spirometry Use in Patients Prescribed Albuterol

Kevin Park, M.D.

Che' S. Ornelas, M.D.

Richard A. Robbins, M.D.

Phoenix VA Medical Center, Banner Good Samaritan VA Medical Center and the Phoenix Pulmonary and Critical Care Medicine and Research Foundation, Phoenix, AZ

Address correspondence to:     Richard A. Robbins, M.D.

                                             502 E. Vermont Drive

                                             Gilbert, AZ 85295

                                             E-mail: rickrobbins@cox.net

Conflict of Interest Statement: None of the authors have conflicts of interest pertinent to the subject matter of this manuscript. 

Abstract

Background:  Previous studies have shown that spirometry is obtained in only about a third of patients with chronic obstructive pulmonary disease (COPD) in primary care practice. This study evaluated spirometry use in persons prescribed an albuterol inhaler in the primary care clinics at a Veterans Administration (VA) hospital.

Methods: One hundred ninety-seven patients prescribed albuterol were reviewed for age, education level of the primary care practioners, other respiratory medications and diagnosis.

Results: The average age was 63.2 years (SD, 11.5), and 93% of patients were male. Obtaining spirometry was not age or sex-dependent but became more frequent with the use of tiotropium (72.2%), long-acting beta agonists (71.8%), ipratropium (69.4%)  or inhaled corticosteroids (63.5%) compared to albuterol alone (39.4%, p=0.0007). Eighty of the patients had a diagnosis of COPD (40.6%), 40 a diagnosis of asthma (20.3%), 23 other respiratory diagnoses (11.7%) but 54 (27.4%) had no respiratory diagnosis. Patients diagnosed with COPD were more likely to have spirometry performed (71.2%) than patients diagnosed with asthma (35%), other respiratory diagnosis (34.7%) or no respiratory diagnosis (40.7%) (p=0.00068).

Conclusions: The above data demonstrate that spirometry is more frequently used in patients with COPD than previously reported and increases when additional medications are added to albuterol.

Introduction

Spirometry is recommended for the diagnosis of most adult respiratory disease including chronic obstructive pulmonary disease (COPD) and asthma (1-5). However, previous publications have revealed that in patients with COPD spirometry is performed in only about a third of the patients (6-10). Based on this data, we initiated a quality improvement project to examine compliance with spirometry guidelines in primary care.

Most previous investigations have examined patients’ diagnosis of COPD or asthma and examined the percentage of patients who had spirometry. However, the diagnosis of COPD or asthma is frequently incorrect (11-13). Furthermore, these projects may likely both under- and over-diagnose COPD in patients with no symptoms (14). Since albuterol is recommended as initial treatment for both diseases (1-4), we examined recent prescriptions for albuterol at a single VA medical center. Our rationale was that this should eliminate asymptomatic patients or patients with very mild disease. We found that in patients prescribed albuterol who also had a diagnosis of COPD that spirometry was performed over double (72%) of previous reports.

Methods

This project was approved by the institutional review board of the Carl T. Hayden VA Hospital. Using VA records we identified 200 patients seen in primary care who were prescribed an albuterol inhaler and had a primary care visit between November 1-5, 2010 or November 8-12, 2010. The electronic records were reviewed for each patient. Demographic data (age, sex); education level of provider (MD or DO, nurse practioners); diagnosis (COPD, asthma, other respiratory diagnosis or no diagnosis); other respiratory medications, and the presence of spirometry were recorded. When spirometry was available for COPD patients, spirometric values of FEV1/FVC% or FEV1% predicted were recorded and used to classify COPD severity based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (1,15).

Statistical Analysis

Comparisons between the groups with and without spirometry were made with χ2 tests for categoric variables and t tests for continuous variables. The association between having spirometry performed and patient characteristics was evaluated in unadjusted models.

Results

Chart review

Two hundred charts were examined, but 3 patients were excluded, one because they had not been prescribed albuterol and two because of incomplete data. The remaining 197 patients were evaluated.

Demographics

Age was 63+11 years and 7% of the patients were female. Age and sex were not significantly different between those who had spirometry and those who did not (data not shown, p>0.05 both comparisons).

Education Level of Provider

There were 16 MD or DO physician primary care providers and 8 nurse practioners. The physicians saw 136 patients and the nurse practioners 61. Spirometry was present on 73 of the patients seen by physicians (53.7%) and 29 of the patients seen by nurse practioners (47.5%, p=0.45).

Other Respiratory Medications

Numbers of patients with other respiratory medications are shown in Table 1. Many patients were on multiple medications. Patients on albuterol alone were significantly less likely to have spirometry than those on other medications (p=0.0007). Only two patients were receiving theophylline and one oral prednisone.

Table 1. Spirometry and other respiratory medications prescribed

LABA=Long-acting beta agonist

ICS=Inhaled corticosteroid

*p=0.0007 compared to other medications

Diagnosis

COPD was diagnosed in 80 patients (40.6%), asthma in 40 patients (20.3%), other respiratory diagnosis in 23 patients (11.7%) but no respiratory diagnosis was recorded in 54 patients (27.4%). Other respiratory diagnosis included 10 patients with tobacco dependence, 3 with dyspnea, 2 with lung carcinoma, and 2 with obstructive sleep apnea and one each with allergies, cannabis dependence, sinusitis, coin lesion, pulmonary embolus and respiratory disorder not otherwise specified. Patients with COPD were significantly more likely to have spirometry performed than other diagnosis (Table 2).

Table 2. Spirometry and respiratory diagnosis

*p=0.00068 compared to other diagnosis

Of the 57 patients with COPD and spirometry, 5 had very severe disease (FEV1 <30% predicted), 16 had severe disease (30% < FEV1< 50% predicted), 34 had moderate disease (50% < FEV1 < 80% predicted) and 2 had mild disease (FEV1>80% predicted) by GOLD criteria. Six of the 18 COPD patients without spirometry were receiving albuterol alone compared to 11 of the 57 of the COPD patients with spirometry (p=0.5519).

Discussion

The objective of this study was to examine spirometry use in primary care in patients with prescribed albuterol. Overall, the presence of spirometry in patients was low, with only 51.8% of patients having spirometry performed during the analysis period. Patients diagnosed with COPD or who had additional respiratory medications prescribed in addition to albuterol were more likely to undergo spirometry. In the present study, 71.8% of patients with COPD received spirometry.  This is more than twice the percentage of previous reports where only about a third of COPD patients had spirometry performed (6-10).

Spirometry is performed in some general medicine clinics, but in our hospital spirometry is performed in the pulmonary function laboratories or in the pulmonary clinic, a situation that may differ from many health-care systems. However, a previous report from a VA hospital reported only about a third of newly diagnosed COPD patients received spirometry (7). Our study differs in several aspects which might explain at least part of the variance. First, rather than looking at a diagnosis of COPD, we examined patients who were prescribed albuterol. This includes patients with asthma and other respiratory diagnosis. Second, we included patients with long-standing COPD rather COPD recently diagnosed. Previous reports suggest that as the number of visits increases that the likelihood of spirometry also increases (10). Third, many patients are “co-managed”, that is they received health care elsewhere in addition to the VA. It is entirely possible that they may have had spirometry performed elsewhere which is not available in our medical record. However, in contrast to previous studies, chart reviews were performed on each patient. If the patient had a previous spirometry recorded in the chart from another institution this should have been noted in our study. Fourth, the VA pharmacy placed restrictions on primary care physicians prescribing long-acting bronchodilators, especially tiotropium. These patients were usually referred to our pulmonary clinic where spirometry was usually required prior to referral.

Several factors have been previously identified that are related to lower rates of spirometry. Age had been reported as the factor with the most pronounced impact on decreasing the likelihood of undergoing spirometry in a VA population (6). However, we found no influence of age on the likelihood of spirometry performance. COPD diagnosis has also been reported to have a decreased likelihood of spirometry performance (8), but in contrast, we found that COPD actually increased the likelihood of spirometry performance. The use of theophylline has also been associated with decreased levels of spirometry performance. However, only about 1% of our patients were prescribed theophylline.

There are several limitations to our study. First, it is a single site study. It is possible that our primary care physicians are more likely to order spirometry because of increased awareness or restrictions in prescribing long-acting bronchodilators or referral to a pulmonary clinic. Previous reports from the VA have demonstrated that there is a large geographic variation in the use of spirometry to diagnose COPD (8). The location of the present study was in Veterans Integrated Service Network 18 (Arizona, New Mexico and West Texas) where spirometry use (36.9%) approximated the National mean (36.7%). It is unclear whether the results from the present study can be generalized to the VA as a whole or non-VA institutions is unclear. Second, we examined patients prescribed an albuterol inhaler rather than those with a diagnosis of COPD or asthma. This likely eliminates many patients with mild or no symptoms which differs from previous studies. The US Preventive Services Task Forces has recommended against screening asymptomatic patients with spirometry (16).

The patients with no diagnosis given albuterol were a heterogenous group and the indications for the use of albuterol were often absent or unclear. Although albuterol can be empirically prescribed for asthma, cough or COPD, the indications for albuterol were absent in the majority of charts.

This study suggests that in contrast to previous reports, much of the current COPD diagnosis and management is based on spirometric evidence of airway obstruction in addition to symptoms. Although the role of spirometry in routine clinical practice remains unclear, primary care providers at our VA hospital appear to frequently use spirometry in patients with COPD.

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Reference as: Park K, Ornelas CS, Robbins RA. Spirometry use in patients prescribed albuterol. Southwest J Pulm Crit Care 2011;4:25-9. (Click here for a PDF version of the manuscript)