Progressive Massive Fibrosis in Workers Outside the Coal Industry: A Case Series from New Mexico

Landon Casaus, MD¹

Sapna Bhatia, MD¹

Akshay Sood, MD, MPH^{1, 2}

¹Department of Internal Medicine

University of New Mexico School of Medicine

Albuquerque, NM, USA

²Miners’ Colfax Medical Center

Raton, NM USA

Abstract

Four clinical patterns of diffuse lung disease may be seen with silicosis: acute silicosis or silicoproteinosis (the latter resembling pulmonary alveolar proteinosis), simple nodular sclerosis, accelerated silicosis, and progressive massive fibrosis (PMF). The intensity and duration of exposure as well as host susceptibility dictates the presentation and progression of PMF. Although most cases of PMF in the literature are reported among coal miners in whom this disease has shown a recent increase in prevalence, this disease can also be seen in exposed workers outside the coal industry. In this article, we will review the clinical, physiological, and pathological manifestations of the disease, illustrated by three case examples of PMF among non-coal miners from New Mexico. Diagnosis and management of patients with PMF can be difficult, and carries medicolegal implications for the patient. Physicians and policymakers need to be aware of PMF in workers exposed to silica within and outside the coal industry.

Introduction

The worldwide prevalence of silicosis peaked by the beginning of the 20^th century during the development of mechanized industry (1). Outbreaks of silicosis are still noted in the developed world, particularly where workers are consistently exposed to silica particles that are small enough to be inhaled (≤10 µm in diameter) and at levels above a “safe” concentration (action level of 25 µm/m³ as a time-weighted average over an 8-hour work day, as recommended by the U.S. Occupational Safety and Health Administration or OSHA) (2,3). The four Appalachian coal mining states of Pennsylvania, West Virginia, Virginia, and Kentucky accounted for more than 75 percent of all silicosis-related deaths in the United States (U.S.) in 2007 (4).  A recent study however indicates that the age-standardized mortality rate from silicosis in the U.S. in 2014 was amongst the highest in the mining intense regions of the Southwest, particularly in the Four Corners area where the borders of New Mexico, Arizona, Utah, and Colorado meet (5). The number of diagnosed silicosis cases has increased in New Mexico between 2000 and 2011, and residents of New Mexico are twice as likely to die from or with silicosis when compared to the rest of the country for reasons that are unexplained (6).

Four clinical patterns of diffuse lung disease may be seen with silicosis: acute silicosis or silicoproteinosis (the latter resembling pulmonary alveolar proteinosis), simple nodular sclerosis, accelerated silicosis, and progressive massive fibrosis (PMF). PMF represents the coalescence of multiple small pneumoconiotic opacities to form larger opacities or conglomerate masses measuring over 10 millimeters in size on a chest radiograph, with smaller rounded opacities usually seen in simple silicosis. Silicotic opacities are classified on their shape, size, and profusion using the International Labour Organization’s (ILO) International Classification of Radiographs for Pneumoconiosis system (commonly referred to as B reads) (7-9). The 1970-2017 radiographic data from the National Institute for Occupational Safety and Health (NIOSH) surveillance program concluded that the national prevalence of coal workers’ pneumoconiosis in coal miners with 25 years or more of tenure now exceeds 10% (10). This is an increase from the previous estimate of 7% in 2012 (11,12). A resurgence of progressive massive fibrosis in coal miners has also been described, particularly those working in smaller mines (13). The rate of PMF in silica exposed workers outside of the coal mine industry, similar to those illustrated in this paper, is unknown. We herein describe three New Mexico non-coal miners with PMF that were followed at the University of New Mexico Occupational Pulmonary Medicine Clinic. Each of the three cases had already received compensation under the United States Energy Employees Occupational Illness Compensation Program, based upon prior abnormal B reads of chest radiographs. The epidemiology, pathogenesis, and management of PMF is also reviewed.

Case reports

Case 1

An 83-year-old man presented in 2017 with worsening dyspnea over the prior 10 years. He worked at a federal national laboratory in northern New Mexico, from 1962-1992 as a construction worker. His work included digging ditches, removing insulation, demolishing buildings, breaking up concrete with jackhammers, and working around sandblasters in enclosed areas, without any respiratory protection. He had a 5-pack year smoking history, and quit 50 years prior.

A 2017 chest radiograph showed small, upper lobe predominant, nodular opacities. A high-resolution computed tomography (CT) scan in 2009 showed innumerable micronodules in the upper lobes of the lung with a centrilobular distribution.  A repeat CT scan obtained in 2017 (Figure 1) showed new-onset coalescence of several upper lobe nodules, as large as 1.5 cm x 2 cm.

Figure 1. Computed tomography scan of the chest showing several silicotic opacities in both lung apices and coalescence to progressive massive fibrosis in right apex.

His pulmonary function tests (PFT) showed mild obstruction with evidence of air trapping. A diagnostic bronchoscopy showed no evidence of infection or neoplasm.

Case 2

A 78-year-old man presented in 2014 with several-years history of progressive New York Heart Association Class III dyspnea. The patient worked as an underground uranium miner from 1960 to 1989 where he was exposed to hauling, “mucking” (a term referring to the loading of fragmented ore), and blasting. He wore a respirator intermittently. He had a five-pack year smoking history, quitting in 1981.

Chest x-ray showed innumerable micronodules, predominately in the upper lobes.  A CT scan of the chest with 3 mm cuts in 2012 showed innumerable upper lobe predominant micronodules in a perilymphatic and centrilobular distribution, with coalescence in the upper lobes. Repeat CT scans in 2014 and 2015 demonstrated no disease progression (Figure 2).

Figure 2. Computed tomography scan of the chest demonstrating progressive massive fibrosis in the right upper lung and several silicotic opacities in bilateral upper lungs.

PFTs showed a mild restrictive defect. An infectious etiology was ruled out by negative sputum acid fast bacilli (AFB), and bacterial smears and cultures.

Case 3

A 79-year-old man presented with dyspnea at rest and upon exertion, and chronic bronchitis symptoms, with occasional hemoptysis. The patient worked as an underground uranium miner from 1959-1980 performing drilling, blasting and “mucking”, with significant self-reported exposure to dust and without use of respiratory protection. The patient reported a 15-pack year smoking history, but quit in 1976.

A chest x-ray showed hilar and mediastinal nodal calcifications with small scattered lung nodules. A HRCT scan of the chest in 2016 (Figure 3) showed multiple calcified nodules as well as calcified hilar and mediastinal lymph nodes.

Figure 3. Computed tomography scan of the chest demonstrating progressive massive fibrosis with evidence of traction in both lobes.

Conglomerate masses in the upper lobes measuring up to 3.3 cm were noted and moderate background emphysematous changes were also noted.  The PFTs on initial evaluation were within normal limits. He was noted to be hypoxic on room air, necessitating 2 L/min oxygen supplementation. Sputum AFB smears and cultures were negative.

Discussion

PMF is seen in workers employed in industries that cut, grind, or drill silica-containing materials such as concrete, masonry, tile and/or rock (3). Most cases of PMF in the literature have been reported among coal miners, likely a reflection of the fact that coal miners undergo active surveillance due to governmental regulations (12). Although more commonly believed to occur in underground coal miners, PMF can be seen in surface coal miners as well (14). PMF outside the coal industry has been described in limited studies of barium miners, sandblasters, blacksmiths, welders, metal polishers, and quartz surface fabricators (15-17). More recently, PMF has been reported in ‘distressed’ denim jean industry workers (18). In this case series, we report PMF in New Mexico construction and uranium workers.

The latency for PMF is usually 10-30 years. Latency is greatly impacted by the exposure concentration and duration, as well as type of silica exposure. Additionally, it is influenced by underlying diseases, genetics, and smoking. Although PMF typically occurs in a setting of high cumulative dust exposures (14), some studies indicate that the host patterns of deposition and clearance of dust may be more relevant (19).

The pathogenesis of PMF is not completely understood; however, it is known that alveolar macrophages initiate a complex cascade results in inflammation and fibrosis (20). Histopathological findings include nodules, usually located near the respiratory bronchioles, composed of silica particles surrounded by whorled collagen in concentric layers. Larger masses of collagen define the lesion of PMF, which may be associated with avascular necrosis in the center and endarteritis in the periphery (21). The extensive fibrotic reaction in PMF is associated with high serum levels of interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1, which are important as neutrophil attractants and adhesion molecules (22).

The clinical diagnosis of PMF has three requirements: the patient must have a history of inhalational silica exposure significant enough to cause disease; chest imaging must be consistent with PMF; and other illnesses that mimic PMF must be reasonably ruled out (1). The disease presentation of PMF is highly variable. Patients may have debilitating symptoms of dyspnea on exertion and exercise intolerance, obstructive and/or restrictive patterns on PFTs, as well as experience complications such as cor pulmonale, spontaneous pneumothorax, and hypoxic respiratory failure (23). On the other hand, a normal spirogram is described in up to 11% of subjects with PMF, as also noted in Case 3 above (23).  The level of pulmonary impairment in patients with PMF generally increases with increasing radiologic size of large opacities (23). Spirometry is repeated upon follow-up visits to assess for functional deterioration (24). Invasive tests such as arterial blood gas or cardiopulmonary exercise test are usually not indicated. Surveillance chest radiographs are classified for small and large opacities using the International Labour Organization’s (ILO) International Classification of Radiographs for Pneumoconiosis system (7-9). CT scan of the chest is more sensitive in diagnosing PMF than chest radiographs, and may be considered if the radiograph fails to show large opacities but demonstrates small opacities of relatively larger diameter or a tendency for opacities to coalesce (25,26). Lung tissue for histology or mineral analysis is rarely needed. The presence of atypical features in a patient with simple silicosis such as fever, hemoptysis, worsening dyspnea, weight loss, disproportionate fatigue, and the presence of a new infiltrate or cavitation of a pre-existing lesion on chest imaging should prompt the clinician to look for PMF, tuberculosis, or lung cancer. Patients with PMF are at elevated risk for concomitant tuberculosis. This risk is directly proportional to the level of profusion of silicotic small opacities (27), and the risk in patients with the highest level of profusion is comparable to that in patients with HIV infection (3). Autopsy studies from Welsh coal workers during the period 1952–1954 demonstrated tubercle bacilli in as many as 35% of cases with PMF (21). A recently published study from Brazil reported coexisting microbiologically confirmed tuberculosis in about half of patients with PMF, raising concerns about tuberculosis infection as a risk factor for the development of PMF ¹⁵. Patients with silicosis are also at high risk for lung cancer (28), with a greater risk for lung cancer described in patients with PMF as compared to patients with simple coal workers pneumoconiosis in one study (29). Positron emission tomography with F-18 fluorodeoxyglucose is of limited utility in differentiating malignancy from PMF lesions (30).

The prevention of PMF remains a focus at the exposed workplace. This includes primary prevention such as worker education; control of airborne dust exposure via engineering and work practice interventions such as improving ventilation, providing a means of exhaust, adding water to the cutting surface, and using enclosed cabs or booths; and use of respiratory protective devices (3). In June 2018, OSHA mandated personal breathing zone air sampling to monitor exposure and medical surveillance of workers with exposure above the permissible exposure limits (31). Medical surveillance constitutes secondary prevention, facilitating early diagnosis and treatment. Surveillance should be done periodically and should include a medical examination and occupational questionnaire, chest radiograph with B read interpretation, tuberculosis screening, and spirometry, with referral of affected workers to a pulmonologist or occupational medicine physician for further evaluation (32).

Once PMF has been diagnosed, it is important to immunize the patient against influenza and pneumococcal infection, assess the need for oxygen supplementation, and encourage pulmonary rehabilitation. Exclusion of active tuberculosis is recommended and screening for latent tuberculosis infection by either skin testing or interferon gamma release assay should be considered (33). Systemic corticosteroids, inhaled aluminum citrate, poly(vinlypyridine-N-oxide) and whole lung lavage are unlikely to benefit patients with PMF and lung transplantation may be considered (4). 

Patients with PMF are considered ‘totally disabled’ from coal mine employment under the Black Lung Benefits Act in the United States. Outside the coal industry, they may be eligible for benefits under the Social Security Impairment system or the state workers’ compensation systems.

Conclusion

PMF represents the coalescence of smaller radiographic pneumoconiotic opacities to those over 10 millimeters in size. The rate of PMF in American coal miners has recently increased. Although most cases of PMF are reported among coal miners, this is likely a reflection of the fact that coal miners undergo active surveillance due to governmental regulations ¹². In this case series, we report PMF in workers outside the coal industry. Physicians and policymakers need to be aware of this condition in workers exposed to silica within and outside the coal industry.

Acknowledgments

Guarantor: Landon Casaus, M.D., takes responsibility for the content of the manuscript, including the data and analysis.

Author contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed substantially to the data analysis and interpretation and the writing of the manuscript.

Financial/non-financial disclosures: All authors report no conflict of interest.

Abbreviations List

• AFB: Acid fast bacilli
• CT: computed tomography
• HIV: Human immunodeficiency virus
• HRCT: High resolution computed tomography
• IL: interleukin
• ICAM: Intercellular adhesion molecule
• NIOSH: National Institute for Occupational Safety and Health
• OSHA: Occupational Safety and Health Administration
• PMF: Progressive massive fibrosis
• PFT: Pulmonary function test
• US: United States

References

1. Banks D. Silicosis. In: Rosenstock L, Cullen M, Brodkin C, Redlich C, eds. Textbook of clinical occupational and environmental medicine. 2nd edition ed. China: Elsevier Saunders; 2005.
2. Occupational Safety and Health Administration. Occupational Exposure to Respirable Crystalline Silica; Final Rule. In. Federal Register. Vol 81. Washington DC: Government Publishing Office; 2016:16285-16890. [PubMed]
3. Adverse effects of crystalline silica exposure. American Thoracic Society Committee of the Scientific Assembly on Environmental and Occupational Health. Am J Respir Crit Care Med. 1997 Feb;155(2):761-8. [CrossRef] [PubMed]
4. National Institute for Occupational Safety and Health, Department of Health and Human Services Centers for Disease Control and Prevention. The Work-Related Lung Disease Surveillance Report 2007. Available at: https://www.cdc.gov/niosh/docs/2008-143/default.html.
5. Dwyer-Lindgren L, Bertozzi-Villa A, Stubbs RW, Morozoff C, Shirude S, Naghavi M, Mokdad AH, Murray CJL. Trends and Patterns of Differences in Chronic Respiratory Disease Mortality Among US Counties, 1980-2014. JAMA. 2017;318(12):1136-49. [CrossRef] [PubMed]
6. New Mexico Occupational Health Surveillance Program New Mexico Department of Health. Silicosis in New Mexico Infographic. Available at https://nmhealth.org/about/erd/eheb/ohsp/.
7. Welch LS, Hunting KL, Balmes J, Bresnitz EA, Guidotti TL, Lockey JE, Myo-Lwin T. Variability in the classification of radiographs using the 1980 International Labor Organization Classification for Pneumoconioses. Chest. 1998 Dec;114(6):1740-8. [CrossRef] [PubMed]
8. Halldin CN, Blackley DJ, Petsonk EL, Laney AS. Pneumoconioses Radiographs in a Large Population of U.S. Coal Workers: Variability in A Reader and B Reader Classifications by Using the International Labour Office Classification. Radiology. 2017 Sep;284(3):870-6. [CrossRef] [PubMed]
9. International Labor Organization. Guidelines for the use of the ILO International Classification of Radiographs of Pneumoconioses. In. Vol Occupational Safety and Health Series, No. 22. 2000 ed. Geneva: International Labor Office; 2002.
10. Blackley DJ, Halldin CN, Laney AS. Continued increase in prevalence of coal workers' pneumoconiosis in the United States, 1970-2017. Am J Public Health. 2018 Sep;108(9):1220-2. [CrossRef] [PubMed]
11. Laney AS, Weissman DN. Respiratory diseases caused by coal mine dust. J Occup Environ Med. 2014 Oct;56 Suppl 10:S18-22. [CrossRef] [PubMed]
12. Blackley DJ, Halldin CN, Laney AS. Resurgence of a debilitating and entirely preventable respiratory disease among working coal miners. Am J Respir Crit Care Med. 2014 Sep 15;190(6):708-9. [CrossRef] [PubMed]
13. Blackley DJ, Halldin CN, Wang ML, Laney AS. Small mine size is associated with lung function abnormality and pneumoconiosis among underground coal miners in Kentucky, Virginia and West Virginia. Occup Environ Med. 2014 Oct;71(10):690-4. [CrossRef] [PubMed]
14. Halldin CN, Reed WR, Joy GJ, et al. Debilitating lung disease among surface coal miners with no underground mining tenure. J Occup Environ Med. 2015 Jan;57(1):62-7. [CrossRef] [PubMed]
15. Ferreira AS, Moreira VB, Ricardo HM, Coutinho R, Gabetto JM, Marchiori E. Progressive massive fibrosis in silica-exposed workers. High-resolution computed tomography findings. J Bras Pneumol. 2006 Nov-Dec;32(6):523-8. [CrossRef] [PubMed]
16. Friedman GK, Harrison R, Bojes H, Worthington K, Filios M; Centers for Disease Control and Prevention (CDC). Notes from the field: silicosis in a countertop fabricator - Texas, 2014. MMWR Morb Mortal Wkly Rep. 2015 Feb 13;64(5):129-30. [PubMed]
17. Seaton A, Ruckley VA, Addison J, Brown WR. Silicosis in barium miners. Thorax. 1986;41(8):591-5. [CrossRef] [PubMed]
18. Bakan ND, Özkan G, Çamsari G, Gür A, Bayram M, Açikmeşe B, Çetinkaya E. Silicosis in denim sandblasters. Chest. 2011;140(5):1300-4. [CrossRef] [PubMed]
19. Douglas AN, Robertson A, Chapman JS, Ruckley VA. Dust exposure, dust recovered from the lung, and associated pathology in a group of British coalminers. Br J Ind Med. 1986 Dec;43(12):795-801. [CrossRef] [PubMed]
20. Sayan M, Mossman BT. The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases. Part Fibre Toxicol. 2016 Sep 20;13(1):51. [CrossRef] [PubMed]
21. Davies DG, James WR, Rivers D, Thomson S. The prevalence of tuberculosis at necropsy in progressive massive fibrosis of coalworkers. Br J Ind Med. 1957 Jan;14(1):39-42. [PubMed]
22. Lee JS, Shin JH, Choi BS. Serum levels of IL-8 and ICAM-1 as biomarkers for progressive massive fibrosis in coal workers' pneumoconiosis. J Korean Med Sci. 2015 Feb;30(2):140-4. [CrossRef] [PubMed]
23. Yeoh CI, Yang SC. Pulmonary function impairment in pneumoconiotic patients with progressive massive fibrosis. Chang Gung Med J. 2002 Feb;25(2):72-80. [PubMed]
24. Fernandez Alvarez R, Martinez Gonzalez C, Quero Martinez A, Blanco Perez JJ, Carazo Fernandez L, Prieto Fernandez A. Guidelines for the diagnosis and monitoring of silicosis. Arch Bronconeumol. 2015;51(2):86-93. [CrossRef] [PubMed]
25. Martinez Gonzalez C, Fernandez Rego G, Jimenez Fernandez-Blanco JR. [Value of computerized tomography in the diagnosis of complicated pneumoconiosis in coal miners]. Arch Bronconeumol. 1997;33(1):12-5. [CrossRef]
26. Ooi GC, Tsang KW, Cheung TF, Khong PL, Ho IW, Ip MS, Tam CM, Ngan H, Lam WK, Chan FL, Chan-Yeung M. Silicosis in 76 men: qualitative and quantitative CT evaluation-clinical-radiologic correlation study. Radiology. 2003;228(3):816-25. [CrossRef] [PubMed]
27. Rees D, Murray J. Silica, silicosis and tuberculosis. Int J Tuberc Lung Dis. 2007 May;11(5):474-84. [PubMed]
28. Poinen-Rughooputh S, Rughooputh MS, Guo Y, Rong Y, Chen W. Occupational exposure to silica dust and risk of lung cancer: an updated meta-analysis of epidemiological studies. BMC Public Health. 2016 Nov 4;16(1):1137. [CrossRef] [PubMed]
29. Tomaskova H, Jirak Z, Splichalova A, Urban P. Cancer incidence in Czech black coal miners in association with coalworkers' pneumoconiosis. Int J Occup Med Environ Health. 2012 Jun;25(2):137-44. [CrossRef] [PubMed]
30. Reichert M, Bensadoun ES. PET imaging in patients with coal workers pneumoconiosis and suspected malignancy. J Thorac Oncol. 2009 May;4(5):649-51. [CrossRef] [PubMed]
31. Occupational Safety and Health Administration. Respirable crystalline silica. In. Vol 1926. Washington DC: Occupational Safety and Health Administration; Federal Register; 2016:1153. Available from: https://www.osha.gov/silica/SilicaConstructionRegText.pdf  (last accessed 2018 Jul 1125).
32. Deslauriers JR, Redlich CA. Silica Exposure, Silicosis, and the New Occupational Safety and Health Administration Silica Standard. What Pulmonologists Need to Know. Ann Am Thorac Soc. 2018 Dec;15(12):1391-1392. [CrossRef] [PubMed]
33. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017 Jan 15;64(2):111-5. [CrossRef] [PubMed] 

Cite as: Casaus L, Bhatia S, Sood A. Progressive massive fibrosis in workers outside the coal industry: A case series from New Mexico. Southwest J Pulm Crit Care. 2019;18(1):10-9. doi: https://doi.org/10.13175/swjpcc110-18 PDF 

December 2018 Pulmonary Case of the Month: A Young Man with Multiple Lung Masses

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 28-year-old man from Tennessee has been feeling ill with malaise and weight loss for the past 3 months. He had been in the in the Palm Springs area a few weeks prior to becoming ill. He works as a musician.

Past Medical History, Social History and Family History

He has a history of Wolf-Parkinson-White syndrome and had a prior ablation procedure at age 16. He does not smoke tobacco but does smoke marijuana occasionally. Family history is noncontributory.

Physical Examination

Physical examination was unremarkable.

Which of the following are indicated at this time? (Click on the correct answer to be directed to the second of eight pages)

1. Bronchoscopy with EBUS
2. Chest X-ray
3. VATS
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. December 2018 pulmonary case of the month: a young man with multiple lung masses. Southwest J Pulm Crit Care. 2018;17(6):138-45. doi: https://doi.org/10.13175/swjpcc118-18 PDF 

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.

References

1. Clark HW. Thomas McPherson Brown, M.D.: treatment of rheumatoid disease. The Arthritis Trust of America. 2000. Available at: http://arthritistrust.org/wp-content/uploads/2013/03/Thomas-McPherson-Brown-MD-Treatment-of-Rheumatoid-Disease.pdf (accessed 8/15/18).
2. Sneddon IB. A clinical trial of tetracycline in rosacea. Br J Dermatol. 1966;78:649-52. [CrossRef] [PubMed]
3. Valentín S, Morales A, Sánchez JL, Rivera A. Safety and efficacy of doxycycline in the treatment of rosacea. Clin Cosmet Investig Dermatol. 2009 Aug 12;2:129-40. [PubMed]
4. Morgan JK, Marsden CS, Coburn JG, Mungavin JM. Dapsone in dermatitis herpetiformis. Lancet. 1955 Jun 11;268(6876):1197-1200. [CrossRef]
5. Golub LM, Lee HM, Lehrer G, et al. Minocycline reduces gingival collagenolytic activity during diabetes: preliminary observations and a proposed new mechanism of action. J Periodontal Res 1983;18:516-26. [CrossRef] [PubMed]
6. Paquette DW, Williams RC. Modulation of host inflammatory mediators as a treatment strategy for periodontal diseases. Periodontol 2000. 2000 Oct;24:239-52. [CrossRef] [PubMed]
7. Cherniack NS, Vosti KL, Dowling HF, Lepper MH, Jackson GG. Long-term treatment of bronchlectasis and chronic bronchitis; a controlled study of the effects of tetracycline, penicillin, and an oleandomycinpenicillin mixture. AMA Arch Intern Med. 1959 Mar;103(3):345-53. [CrossRef] [PubMed]
8. Kudoh S, Azuma A, Yamamoto M, et al. Improvement of survival in patients with diffuse panbronchiolitis treated with lowdose erythromycin. Am J Respir Crit Care Med. 1998;157:1829–32. [CrossRef] [PubMed]
9. Oda H, Kadota J, Kohno S, Hara K. Erythromycin inhibits neutrophil chemotaxis in bronchoalveoli of diffuse panbronchiolitis. Chest. 1994 Oct;106(4):1116-23. [CrossRef] [PubMed]
10. Amsden GW. Anti-inflammatory effects of macrolides—an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother. 2005 Jan;55(1):10-21. [CrossRef] [PubMed]
11. Hoyt JC, Robbins RA. Macrolide antibiotics and pulmonary inflammation. FEMS Microbiol Lett. 2001 Nov 27;205(1):1-7. [CrossRef] [PubMed]
12. Harvey RJ, Wallwork BD, Lund VJ. Anti-inflammatory effects of macrolides: applications in chronic rhinosinusitis. Immunol Allergy Clin North Am. 2009 Nov;29(4):689-703. [CrossRef] [PubMed]
13. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007 Dec;7(4):232-6. [CrossRef] [PubMed]
14. Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003 Oct 1;290(13):1749-56. [CrossRef] [PubMed]
15. Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013 Apr 1;187(7):680-9. [CrossRef] [PubMed]
16. Hill AT. Macrolides for Clinically Significant bronchiectasis in adults: who should receive this treatment? Chest. 2016 Dec;150(6):1187-93. [CrossRef] [PubMed]
17. Medical Research Council. Prolonged antibiotic treatment of severe bronchiectasis; a report by a subcommittee of the Antibiotics Clinical Trials (non-tuberculous) Committee of the Medical Research Council. BMJ. 1957;2:255–9. [PubMed]
18. Kelly C, Chalmers JD, Crossingham I, et al. Macrolide antibiotics for bronchiectasis. Cochrane Database Syst Rev. 2018 Mar 15;3:CD012406. [CrossRef] [PubMed]
19. Xu X, Abdalla T, Bratcher PE, et al. Doxycycline improves clinical outcomes during cystic fibrosis exacerbations. Eur Respir J. 2017 Apr 5;49(4). pii: 1601102. [CrossRef] [PubMed]
20. Druss BG, Marcus SC, Olfson M, Pincus HA. The most expensive medical conditions in America. Health Aff (Millwood). 2002;21:105-11. [CrossRef]
21. Friedman M, Hilleman DE. Economic burden of chronic obstructive pulmonary disease. Impact of new treatment options. Pharmacoeconomics. 2001;19(3):245-54. [CrossRef] [PubMed]
22. Strassels SA, Smith DH, Sullivan SD, Mahajan PS. The costs of treating COPD in the United States. Chest. 2001;119:344-52. [CrossRef] [PubMed]
23. Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-55. [CrossRef] [PubMed]
24. Gomez J, Banos V, Simarro E, et al. Prospective, comparative study (1994-1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD. Rev Esp Quimioter. 2000;13:379-83. [PubMed]
25. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest 2001;120:730-3. [CrossRef] [PubMed]
26. Seemungal TAR, Wilkinson TMA, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139-47. [CrossRef] [PubMed]
27. Blasi F, Bonardi D, Aliberti S, et al. Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther. 2010;3:200-7. [CrossRef] [PubMed]
28. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011 Aug 25;365(8):689-98. [CrossRef] [PubMed]
29. Taylor SP, Sellers E, Taylor BT. Azithromycin for the prevention of copd exacerbations: the good, bad, and ugly. Am J Med. 2015 Dec;128(12):1362.e1-6. [CrossRef] [PubMed]
30. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90. [CrossRef] [PubMed]
31. Norman PS, Hook EW, Petersdorf RG, et al. Long-term tetracycline treatment of chronic bronchitis. JAMA. 1962;179(11):833-40. [CrossRef] [PubMed]
32. Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the treatment of asthma. J Allergy. 1970 Mar;45(3):146-62. [PubMed]
33. Kamada AK, Hill MR, Iklé DN, Brenner AM, Szefler SJ. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol. 1993;91:873-82. [CrossRef]
34. Shoji T, Yoshida S, Sakamoto H, Hasegawa H, Nakagawa H, Amayasu H. Anti-inflammatory effect of roxithromycin in patients with aspirin-intolerant asthma. Clin Exp Allergy. 1999;29:950-6. [CrossRef] [PubMed]
35. Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol. 2000 Jun;84(6):594-8. [CrossRef]
36. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782-8. [CrossRef] [PubMed]
37. Sutherland ER, King TS, Icitovic N, et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J Allergy Clin Immunol. 2010;126:747–53. [CrossRef] [PubMed]
38. Daxboeck F, Krause R, Wenisch C. Laboratory diagnosis of Mycoplasma pneumoniae infection. Clin Microbiol Infect. 2003;9:263-73. [CrossRef] [PubMed]
39. Dowell SF, Peeling RW, Boman J, et al. Standardizing Chlamydia pneumoniae assays: recommendations from the Centers for Disease Control and Prevention (USA) and the Laboratory Centre for Disease Control (Canada). Clin Infect Dis. 2001;33:492-503. [CrossRef] [PubMed]
40. Kostadima E, Tsiodras S, Alexopoulos EI, et al. Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma. Eur Respir J. 2004;23:714-7. [CrossRef] [PubMed]
41. Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006;1: e11. [CrossRef] [PubMed]
42. Piacentini GL, Peroni DG, Bodini A, et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc 2007; 28: 194–98. [CrossRef] [PubMed]
43. Strunk RC, Bacharier LB, Phillips BR, et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate to-severe childhood asthma study. J Allergy Clin Immunol 2008;122:1138-44. [CrossRef] [PubMed]
44. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008; 177:148-55. [CrossRef] [PubMed]
45. Hahn DL, Grasmick M, Hetzel S, Yale S, and the AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012;25:442-59. [CrossRef] [PubMed]
46. Cameron EJ, Chaudhuri R, Mair F, et al. Randomised controlled trial of azithromycin in smokers with asthma. Eur Respir J. 2013;42:1412-5. [CrossRef] [PubMed]
47. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68:322-9. [CrossRef] [PubMed]
48. Richeldi L, Ferrara G, Fabbri LM, Lasserson TJ, Gibson PG. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2005;4:CD002997. [CrossRef]
49. Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014 Aug;2(8):657-70. [CrossRef]
50. Wood LG, Simpson JL, Hansbro PM, Gibson PG. Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia. Free Radic Res. 2010;44:146-54. [CrossRef] [PubMed]
51. Brusselle GG, Joos G. Is there a role for macrolides in severe asthma? Curr Opin Pulm Med. 2014 Jan;20(1):95-102. [CrossRef] [PubMed]
52. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 12;390(10095):659-68. [CrossRef]
53. Daoud A, Gloria CJ, Taningco G, et al. Minocycline treatment results in reduced oral steroid requirements in adult asthma. Allergy Asthma Proc. 2008 May-Jun;29(3):286-94. [CrossRef] [PubMed]
54. Bhattacharyya P, Paul R, Bhattacharjee P, et al. Long-term use of doxycycline can improve chronic asthma and possibly remodeling: the result of a pilot observation. J Asthma Allergy. 2012;5:33-7. [CrossRef] [PubMed]
55. Barker AF, Bergeron A, Rom WN, Hertz MI. Obliterative bronchiolitis. N Engl J Med. 2014 May 8;370(19):1820-8. [CrossRef] [PubMed]
56. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med. 2003;168:121-5. [CrossRef] [PubMed]
57. Federica M, Nadia S, Monica M, et al. Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant. 2011;25:E381-9. [CrossRef] [PubMed]
58. Jain R, Hachem RR, Morrell MR, et al. Azithromycin is associated with increased survival in lung transplant recipients with bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2010;29:531-7. [CrossRef] [PubMed]
59. Bergeron A, Chevret S, Granata A, et al. Effect of Azithromycin on Airflow Decline-Free Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized Clinical Trial. JAMA. 2017;318(6):557-66. [CrossRef] [PubMed]
60. Ichikawa Y, Ninomiya H, Katsuki M, et al. Low-dose/long-term erythromycin for treatment of bronchiolitis obliterans organizing pneumonia (BOOP). Kurume Med J. 1993; 40:65–7. [CrossRef] [PubMed]
61. Zeynep Seda Uyan ZS, Levent Midyat L, Erkan Çakir E, et al. Azithromycin therapy in children with postinfectious bronchiolitis obliterans. Eur Respir J. 2016;48 (suppl 60):PA1602.
62. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:152-8.
63. Pathak V, Kuhn JM, Durham C, Funkhouser WK, Henke DC. Macrolide use leads to clinical and radiological improvement in patients with cryptogenic organizing pneumonia. Ann Am Thorac Soc. 2014 Jan;11(1):87-91. [CrossRef] [PubMed]
64. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19. [CrossRef] [PubMed]
65. Kuse N, Abe S, Hayashi H, et al. Long-term efficacy of macrolide treatment in idiopathic pulmonary fibrosis: a retrospective analysis. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:242-6. [PubMed]
66. Kawamura K, Ichikado K, Yasuda Y, Anan K, Suga M. Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. BMC Pulm Med. 2017 Jun 19;17(1):94. [CrossRef] [PubMed]
67. Minocycline therapy for lung scarring in patients with idiopathic pulmonary fibrosis - a pilot study. Available at: https://clinicaltrials.gov/ct2/show/NCT00203697 (accessed 8/29/18).
68. Mishra A, Bhattacharya P, Paul S, Paul R, Swarnakar S. An alternative therapy for idiopathic pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India. 2011 Jul;28(3):174-9. [CrossRef] [PubMed]
69. Chang WY, Cane JL, Kumaran M, et al. A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis. Eur Respir J. 2014;43:1114-23. [CrossRef] [PubMed]

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 

September 2018 Pulmonary Case of the Month: Lung Cysts

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

Completion of an evaluation form is required to receive credit and a link is provided on the last page of the activity. 

0.50 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.50 hours

Lead Author(s): Lewis J. Wesselius, MD. All Faculty, CME Planning Committee Members, and the CME Office Reviewers have disclosed that they do not have any relevant financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

Learning Objectives: As a result of completing this activity, participants will be better able to:

1. Interpret and identify clinical practices supported by the highest quality available evidence.
2. Establish the optimal evaluation leading to a correct diagnosis for patients with pulmonary, critical care and sleep disorders.
3. Translate the most current clinical information into the delivery of high quality care for patients.
4. Integrate new treatment options for patients with pulmonary, critical care and sleep related disorders.

Learning Format: Case-based, interactive online course, including mandatory assessment questions (number of questions varies by case). Please also read the Technical Requirements.

CME Sponsor: The University of Arizona College of Medicine-Tucson

Current Approval Period: January 1, 2017-December 31, 2018

Financial Support Received: None

History of Present Illness

A 67-year-old woman was referred for mild shortness of breath for several years, but worse since January 2018.  She has dyspnea on exertion after 1 block. An outside chest x-ray, electrocardiogram and echocardiogram are reported as normal. She was begun on prednisone at 40 mg/day and her symptoms improved. However, her symptoms worsened when the dose tapered to 5 mg/day. She gained 35 pounds while on the prednisone and tried a steroid inhaler therapy without benefit. She is still dyspneic after 1 block of exertion.

Past Medical History, Social History, Family History

• Her past medical history was only positive for gastroesophageal reflux for which she takes ranitidine and hypertension for which she takes lisinopril.
• She was a life-long nonsmoker.
• There was no occupational history, hot tub or bird exposures.
• Family history is noncontributory.

Physical Examination

• Her SpO2 was 94% on room air.
• Chest:  few crackles noted at right base.
• Cardiovascular: regular rate and rhythm without a murmur.
• Extremities: no edema or clubbing.

Which of the following should be done at this time? (Click on the correct answer to be directed to the second of eight pages)

1. Measure her SpO2 after exercise
2. Reassure the patient the patient that she has hysterical dyspnea
3. Pulmonary function testing
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. September 2018 pulmonary case of the month: lung cysts. Southwest J Pulm Crit Care. 2018;17(3):85-92. doi: https://doi.org/10.13175/swjpcc101-18 PDF 

Infected Chylothorax: A Case Report and Review

Louis Eubank¹, Luke Gabe¹, Monica Kraft¹, and Dean Billheimer²

¹Departments of Medicine and Biostatistics, College of Medicine

²Department of Biostatistics, College of Public Health

University of Arizona Health Sciences Center

Tucson, AZ USA

Abstract

Infected chylothorax is a rare complication of a rare pathology with limited literature entirely consisting of case reports, meeting abstracts, and letters to the editor. The case of a 56-year-old male with a spontaneous infected chylothorax successfully treated and discharged to home without any residual effects is described. A systematic review of the literature revealed 11 prior cases of infected chylothoraces. Their etiologies (when known), initial pleural fluid values, and treatment are described. These cases show that while infected chylothorax has a varied presentation and affects a broad range of patients, conservative management including antibiotics, pleural fluid drainage, and symptomatic relief is a safe and appropriate starting point.

Introduction

Chylothorax, a pleural effusion caused by chyle accumulation from obstruction or disruption of the thoracic duct (please see SWJPCC’s Image of the week: chylothorax for an image of non-infected chyle fluid), is a rare condition that may arise from a diversity of etiologies broadly categorized as traumatic or non-traumatic/spontaneous (1). Traumatic causes commonly include iatrogenic injury and chest trauma, although insults as minor as sneezing, light exercise and emesis have been reported (1-3). Non-traumatic chylothorax has been linked to several immunologic and infectious etiologies (1). Regardless of the underlying mechanism, chyle has classically been considered inherently bacteriostatic (1). We present a case of spontaneous infected chylothorax and the first review of infected chylothoraces reported in the literature.

Case Report

A 56-year-old man with alcoholic cirrhosis and remote right-sided hepatic hydrothorax presented to the emergency department complaining of shortness of breath. Patient reported slowly worsening dyspnea over the last six weeks without any other symptoms that had acutely worsened on morning of presentation

Initial vital signs were temperature 38.0°C, heart rate 115, blood pressure 81/60mmHg, and respiratory rate 30 breaths/min on 4L O₂ by nasal cannula; labs significant for white blood cell count of 3100/mm³ and lactate 5.0 mmol/L (normal <2.0 mmol/L).  Physical exam demonstrated a fatigued patient with accessory muscle use on inspiration and absent breath sounds at the left lung base. Computed tomography (CT) study of the chest showed a large free-flowing left-sided pleural effusion (Figure 1A&B) as well as subacute rib fractures (Image 1C).

Figure 1. Thoracic CT on the day of presentation. Panel A: Axial view showing pleural effusion. Panel B: Sagittal view showing pleural effusion. Panel C: Coronal view showing rib fractures (white arrows).

Chart review demonstrated an emergency department visit five months previously for a fall with acute left-sided rib fractures and minimal left-sided pleural effusion.

Thoracentesis removed two liters free-flowing, brown, milky, purulent fluid; analysis significant for 58,880 total nucleated cells (32,800 RBCs), 94% neutrophils, glucose <5, LDH 573 IU/dL (serum 193 IU/dL), triglycerides 191 mg/dL, albumin 1.8 g/dL (serum albumin 2.6 g/dL, laboratory lower limit of normal 3.4 g/dL).

The patient remained hypotensive despite fluid boluses, tachypneic with increasing oxygen requirements, and a repeat lactate was 6.4 mmol/L. Norepinephrine and broad-spectrum antibiotics were started and patient was admitted to the intensive care unit.

Pleural fluid and blood cultures grew Escherichia coli resistant to fluoroquinolones. Chest x-ray showed persistent pleural effusion; a chest tube was placed which drained an additional 1.6 L over the following 24 hrs. The patient subsequently improved: serum lactate normalized within 24 hours, vasopressors were weaned within 36 hours, and supplemental oxygen was discontinued within 72 hours.

Chest tube output decreased to less than 200 ml/day within 48 hours of placement; however, repeat thoracic CT demonstrated a persistent multi-loculated left pleural effusion. Surgical evacuation and pleurodesis were considered given the lack of literature regarding intrapleural lytic therapy in infected chylothorax (a single case report described use of streptokinase in a persistent non-infected chylothorax, 1).  However, the patient’s operative risk was considered prohibitively high. He was managed conservatively with a fat-free diet to reduce chyle leak.

Eleven days after initial presentation fluid studies were significant for triglyceride 45mg/dL with negative cultures. Given that a pleural fluid triglyceride level <50mg/dL yields a less than 5% likelihood of being chylous and the clinical stability of the patient, the chylothorax was felt to be resolved (1). The patient was discharged to home twelve days after initial presentation.

The etiology of patient’s infected chylothorax was never fully elucidated. The most likely explanation is the trauma causing rib fractures also caused a traumatic chylothorax that later became infected. The thoracic duct lies alongside the vertebrae until it drains into the left brachiocephalic vein (Figure 2).

Figure 2. Thoracic duct anatomy (black arrows).

A blow to the posterior left thorax sufficient to fracture multiple ribs is more than sufficient to damage the nearby thoracic duct (1-4).  Arguing against this is most patients with large traumatic chylothoraces present within 10 days of injury (1,2).

Another explanation is the patient developed bacterial empyema secondary to hepatic hydrothorax (ascites that has passed through diaphragm from the peritoneal cavity) followed by non-traumatic chylothorax. These empyemas can demonstrate an indolent course and Escherichia coli is one of the most common causative pathogens isolated (1). Arguing against this is the patient’s previous hepatic hydrothorax was right-sided.

Finally, the chylothorax may have arisen from one of the many known causative medical pathologies (2). Chylous ascites secondary to cirrhosis that migrates into the pleural space via diaphragmatic leaks defects is a known phenomenon, albeit extremely rare (2).

In follow-up two months after discharge the patient had total resolution of respiratory symptoms and no recurrence of the effusion.

Systematic Review

Methods

A MEDLINE search (PubMed) from January 1975 to January 2018 and a Google Scholar search (all years) was conducted to identify eligible studies using the following terms: “Infected Chylothorax” (all fields) OR “Infection AND Chylothorax” (all fields) OR “Chylothorax AND Empyema” (all fields) OR “Chylous Empyema” (all fields). The inclusion criteria for studies were patients with infected non-traumatic chylothorax. A triglyceride level > 110 mg/dL or the presence of chylomicrons in pleural fluid was used to confirm the diagnosis of chylothorax; pleural fluid culture speciation was used to confirm the infection. The exclusion criteria were a lack of laboratory data and duplicate data. Two reviewers (LE, LG) independently reviewed the titles, abstracts, and, when necessary, the full text regarding the inclusion/exclusion criteria. Data extraction was performed independently by two reviewers (LE, LG) using data extraction forms defined beforehand. Discrepancies were resolved by consensus discussion with a third reviewer (MK).

Results

Eight case reports, two published abstracts, and one letter to the editor met the inclusion criteria; all eleven were included in the analysis (Figure 3, 13-23). 

Figure 3. Flow diagram of the literature review.

The general characteristics, demographics, and etiology of infected chylothorax are summarized in Table 1, the initial pleural fluid values are reported in Table 2.

Table 1. Population data.

Table 2. Initial pleural fluid values.

There were 11 patients total: six males and five females; age range 5 days-78 years, mean age 40.5 years (standard deviation 28.5 years). One patient was pharmacologically immunosuppressed while others had chronic diseases known to reduce immune system function including diabetes, excessive alcohol intake, and obesity (24-26). Four (36%) were iatrogenic. Three patients (27%) were infected with Streptococcus viridans and five (45%) were infected with Streptococcus genus. In those with available data, three of ten patients (30%) required intravenous vasopressors. No patients required ventilator management for their chylothorax (two patients were already intubated, one for acute respiratory distress syndrome, the other for unstable hemodynamics secondary to large subarachnoid hemorrhage). Two patients (18%) were managed surgically – one was specifically noted to have failed conservative management (17). Of the known outcomes, eight of nine (89%) survived to discharge and all eight remained asymptomatic at follow-up. The mean follow-up duration was 13.3 months (range 6-24 months).

Discussion

Given the paucity of published experience regarding infected chylothoraces, we believe a descriptive summary is warranted. First, there is a large variation in patient characteristics, including age range, immune competence, comorbid medical conditions, and infectious organism (eight different bacterial species and one parasite).

Second, many of the reviewed cases had a more benign presentation than might be anticipated in the context of a large, infected intrathoracic fluid collection.  Seven of the patients (73%) were hemodynamically stable on presentation and the majority of these patients had very mild chief complaints.

Third, the available data suggest a surprisingly good prognosis considering a previously estimated morality of 10-25% in non-infected chylothoraces, depending on etiology (27). The one patient who did not survive to discharge died due to brain herniation. Those with documented outpatient follow-up were asymptomatic up to 16 months post-discharge. 

Fourth, conservative management was frequently efficacious. Eight patients (73%) were medically managed without complication and did not require extensive antibiotic duration, intrapleural lytic therapy, or surgical intervention. The decision to pursue surgical intervention is not well defined given the very limited number of cases requiring surgical management. A brief discussion of non-infected chylothoraces and their management is therefore warranted.

Non-infected chylothorax is universally described as a rare event, although its exact incidence has not been described. Chylous ascites, which sometimes shares pathogenesis with chylothorax and is one of the causes of spontaneous chylothorax, has an occurrence of one in 20,000 hospital admissions (12). Trauma accounts for approximately 50% of chylothoraces, with esophagectomy being the most common iatrogenic cause (28). Thirty percent are due to malignancy; lymphoma accounts for 70-75% of malignant cases (11). While there are no consensus guidelines on how to treat chylothoraces, many authors agree that first line treatment is conservative management with thoracentesis or chest tube drainage, fat free or medium chain triglyceride diet, and consideration of somatostatin or octreotide (1,5,11,27-29). Although somatostatin or octreotide are used at many institutions, data regarding indications & efficacy of these medications are limited and/or inconsistent – some institutions use these medications at the beginning of treatment, others only if/when initial management has failed (5,27).

Additional treatments may depend on the etiology of the chylothorax: it is suggested that earlier surgical intervention in iatrogenic traumatic chylothoraces, especially post-esophagectomy, may be beneficial (30). Conservative management is likely to fail and surgical intervention is recommended in the following situations: 1) daily drainage greater than 1000 mL chyle (adults) or greater than 100mL chyle/kg body weight (children); 2) chyle leak that persists for more than 14 days; 3) unchanged chest tube output for 7-14 days; 4) clinical deterioration (27,28).

Conservative management for infected chylothoraces appears efficacious in our small sample size with the obvious modification of treating the infection. Most antibiotics adequately penetrate the pleural space, although aminoglycosides should be avoided as they appear to be inactivated by the low pH and relative anaerobic conditions (31).

Limitations

The limitation of this systematic review was the inclusion of only case reports, abstracts, and letters to the editor and the small sample size. Unfortunately, given the rarity of infected chylothoraces, studies with sufficient sample size are unlikely to be available.

Conclusion

Infected chylothorax is a rare complication of an already rare pathology. Our case report and literature review show that it can affect any age group, can be caused by several different organisms, and has a variable presentation. Our data suggests that an initial conservative management strategy in infected chylothoraces can be a safe and effective option.

References

1. McGrath E, Blades Z, Anderson P. Chylothorax: aetiology, diagnosis and therapeutic options. Respir Med. 2010;104:1-8. [CrossRef] [PubMed]
2. García-Tirado J, Landa-Oviedo HS, Suazo-Guevara I. Spontaneous bilateral chylothorax caused by a sneeze: an unusual entitiy with good prognosis. Arch Bronconeumol. 2017 Jan;53(1):32-3. [CrossRef]
3. Torrejais JC, Rau CB, de Barros JA, Torrejais MM. Spontaneous chylothorax associated with light physical activity. J Bras Pneumol. 2006 Nov-Dec;32(6):599-602. [CrossRef] [PubMed]
4. Rodrigues AL, Romaneli MT, Ramos CD, Fraga AM, Pereira RM, Appenzeller S, Marini R, Tresoldi AT. Bilateral spontaneous chylothorax after severe vomiting in children. Rev Paul Pediatr. 2016 Dec;34(4):518-521. [PubMed]
5. Bender B, Murthy V, Chamberlain RS. The changing management of chylothorax in the modern era. Eur J Cardiothorac Surg. 2016 Jan;49(1):18-24. [CrossRef] [PubMed]
6. Verma SK, Karmakar S. Hodgkin's lymphoma presenting as chylothorax. Lung India. 2014 Apr-Jun; 31(2):184-6. [CrossRef] [PubMed]
7. Kuan YC, How SH, Ng TH, Abdul Rani MF. Intrapleural streptokinase for the treatment of chylothorax. Respir Care. 2011 Dec;56(12):1953-5. [CrossRef] [PubMed]
8. Nair SK, Petko M, Hayward M. Aetiology and management of chylothorax in adults. Eur J Cardiothorac Surg. 2007 Aug;32(2):362-9. [CrossRef] [PubMed]
9. Pillay TG, Singh B. A review of traumatic chylothorax. Injury. 2016 Mar;47(3):545-50. [CrossRef] [PubMed]
10. Tu CY, Chen CH. Spontaneous bacterial empyema. Curr Opin Pulm Med. 2012 Jul;18(4):355-8. [CrossRef] [PubMed]
11. Skouras V, Kalomenidis I. Chylothorax: diagnostic approach. Curr Opin Pulm Med. 2010 Jul;16(4):387-93. [CrossRef] [PubMed]
12. Tsauo J, Shin JH, Han K, Yoon HK, Ko GY, Ko HK, Gwon DI.Transjugular intrahepatic portosystemic shunt for the treatment of chylothorax and chylous ascites in cirrhosis: a case report and systemic review of the literature. J Vasc Interv Radiol. 2016 Jan;27(1):112-6. [CrossRef] [PubMed]
13. Bensoussan AL, Braun P, Guttman FM. Bilateral spontaneous chylothorax of the newborn. Arch Surg. 1975 Oct;110(10):1243-5. [CrossRef] [PubMed]
14. Asnis DS, Saltzman HP, Iakovou C, Byrns DJ. Anaerobic empyema and chylothorax. Inf Dis Clin Pract. 1994;3(5):368-70. [CrossRef]
15. Natrajan S, Hadeli O, Quan SF. Infected spontaneous chylothorax. Diagn Microbiol Infect Dis. 1998 Jan;30(1):31-2. [CrossRef] [PubMed]
16. Guarracino JF, Murruni A; Basílico H, Villasboas RM, Halabe K, Barroso S, Demirdjian G. Chylothorax: Unusual complication presented in a burned child with an inflation injury under the effects of mechanical ventilation (Originial title Quilotórax: Complicación pocofrecuente en un ni-o quemado en asistencia respiratoria mecánica por síndrome inhalatorio). Revista Argentina de Burns 2000:15 (1). Available at: http://www.medbc.com/meditline/review/raq/vol_15/num_1/text/vol15n1p30.htm  (accessed 8/24/18).
17. Wang JT, Hsueh PR, Sheng WH, Chang SC, Luh KT. Infected chylothorax caused by Streptococcus agalactiae: a case report. J Formos Med Assoc. 2000 Oct;99(10):783-4. [PubMed]
18. Biswas A, Ghosh JK, Chatterjee A, Basu K, Chatterjee S. Infected chylothorax caused by escherichia coli in a non-immunocompromised child. Indian J Pediatr. 2008 Feb;75(2):192-3. [CrossRef] [PubMed]
19. Alkassis SH, Bou Khalil BK. Infected chylothorax [abstract]. Presented at American Thoracic Society international meeting 2010 https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A4591 (accessed 8/24/18).
20. Epelbaum O, Kazianis J. Chylous empyema or empyematous chylothorax? [Abstract] Presented at American Thoracic Society international meeting 2011. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A6460 (accessed 8/24/18)
21. Wright RS, Jean M, Rochelle K, Fisk D. Chylothorax caused by paragonimus westermani in a native Californian. Chest. 2011 Oct;140(4):1064-6. [CrossRef] [PubMed]
22. Bakar B, Pampal K, Tekkok IH. Infected bilateral chylothorax in a problematic case. Curr Surg. 2012 April;2(2):62-5. [CrossRef]
23. Di Marco Berardino A, Inchingolo R, Smargiassi A, Re A, Torelli R, Fiori B, d'Inzeo T, Corbo GM, Valente S, Sanguinetti M, Spanu T. Empyema cause by prevotella bivia complicating an unusual case of spontaneous chylothorax. J Clin Microbiol. 2014 Apr;52(4):1284-6. [CrossRef] [PubMed]
24. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus. FEMS Immunol Med Microbiol. 1999 Dec;26(3-4):259-65. [CrossRef] [PubMed]
25. Boule LA, Ju C, Agudelo M, et al. Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol. 2018 Feb;66:35-43. [CrossRef] [PubMed]
26. Milner JJ, Beck MA. The impact of obesity on the immune response to infection. Proc Nutr Soc. 2012 May;71(2):298-306. [CrossRef] [PubMed]
27. Schild HH, Strassburg CP, Welz A, Kalff J. Treatment options in patients with chylothorax. Dtsch Arztebl Int. 2013 Nov 29;110(48):819-26. [CrossRef]
28. Rudrappa M, Paul M. Chylothorax. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan. [PubMed]
29. Nadolski G. Nontraumatic Chylothorax: diagnostic algorithm and treatment options. Tech Vasc Interv Radiol. 2016 Dec;19(4):286-90. [CrossRef] [PubMed]
30. Misthos P, Kanakis MA, Lioulias AG. Chylothorax complicating thoracic surgery: conservative or early surgical management? Updates Surg. 2012 Mar;64(1):5-11. [CrossRef] [PubMed]
31. Sahn SA. Diagnosis and management of parapneumonic effusions and empyema. Clin Infect Dis. 2007 Dec 1;45(11):1480-6. [CrossRef] [PubMed]

Cite as: Eubank L, Gabe L, Kraft M, Billheimer D. Infected chylothorax: a case report and review. Southwest J Pulm Crit Care. 2018;17(2):76-84. doi: https://doi.org/10.13175/swjpcc097-18 PDF