May 2018 Pulmonary Case of the Month

Kenneth K. Sakata, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 70-year-old man was referred because of new anemia and a heme-positive stool. Esophagogastroduodenoscopy (EGD) was performed which revealed gastritis. Ascites developed and a chest x-ray noted a left pleural effusion. He was managed with weekly high-volume thoracentesis and paracentesis. He was referred to pulmonary medicine.

Past Medical History, Social History and Family History

He has a history of coronary artery disease having undergone coronary bypass grafting in 2016. He also has type 2 diabetes mellitus managed by diet and recently diagnosed orthostasis. He smokes about ½ pack of cigarettes per day but does not drink alcohol. He denies any inhalational exposures. He is Native American and works as a judge. There is no family history of any similar disorders.

Physical Examination

• No acute distress
• Slight bruise to left eye
• No lymphadenopathy
• Decreased breath sounds on left
• Protuberant distended abdomen
• Significant left leg edema
• Discoloration of a few nails

A point of contact ultrasound is performed (Figure 1).

Figure 1. Image from the point of contact ultrasound.

What should be done next? (Click on the correct answer to proceed to the second of seven pages)

1. Needle biopsy of pleural mass
2. Thoracentesis
3. Thoracic surgery consultation for video-assisted thorascopic surgery (VATS)
4. 1 and 3
5. All of the above

Cite as: Sakata KK. May 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(5):237-44. doi: https://doi.org/10.13175/swjpcc059-18 PDF 

Tobacco Company Campaign Contributions and Congressional Support of Tobacco Legislation

Richard A. Robbins, MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Abstract

Although it is widely held that campaign contributions influence Congressional support for legislation, the impact of these contributions is unclear. Three bills involving tobacco regulation were introduced into the 2017-8 Congress and were co-sponsored in both the House of Representatives and Senate. One was pro-tobacco (HR564/S294-Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2017) and two were anti-tobacco (HR4273/S2100-Tobacco to 21 Act, HR2878/S1341-Children Don't Belong on Tobacco Farms Act). The association between tobacco political action committee (PAC) campaign contributions with sponsorship of these bills was examined. Tobacco PAC contributions to sponsors of pro-tobacco HR564/S294 were significantly larger [$18218, 95% confidence interval (CI) $15077-$21359, p<0.01] than to non-sponsors ($8730, 95% CI, $6959-$10501). Sponsors of the anti-tobacco HR4273/S2100 received significantly smaller contributions ($2114, 95% CI $0-$4833, p<0.01) than non-sponsors ($12048, 95% CI, $10289-$13707). Similarly, sponsors of the anti-tobacco HR2878/S1341 also received significantly smaller contributions ($2500, 95% CI $0-$5284, p<0.01) than non-sponsors ($12097, 95% CI $10429-$13765). These data demonstrate a significant correlation between campaign contributions and legislative support of pro- and anti-tobacco legislation.

Introduction

Previously, it has been shown tobacco contributions influence state legislators in terms of tobacco control policy-making and support by Southwest US Members of Congress of The Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2015 (HR 662/S 441, aka the "Cigar Bill") (1,2). Although it is widely held that campaign contributions influence elected legislators, Powell (3) notes "political scientists have had great difficulty determining whether and how much influence contributions have on the legislative process". Studies have been inconsistent, with some demonstrating a linkage between campaign contributions and influence while others do not, suggesting that there are other influences in addition to contributions. Powell (3) has pointed out that the influence of donations is likely to occur early in the legislative process, such as during sponsorship for legislation or by directing that funds should be spent on a specific project (earmarks).

During the current 115^th Congress, the pro-tobacco “The Traditional Cigar Manufacturing and Small Business Jobs Preservation Act” was reintroduced (HR564/S294) (4). In addition, two anti-tobacco bills were introduced (HR4273/S2100 and HR2878/S1341) (4). Tobacco PAC contributions were examined for their association with sponsorship of these bills.

Methods

Tobacco Bills

The website Congress.Gov (4) was searched with the key word tobacco. Three bills were identified that had reached sufficient maturity to be introduced into the House of Representatives and the Senate and had co-sponsors listed in both the House and Senate. One was the pro-tobacco (HR564/S294-Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2017) and two were anti-tobacco (HR4273/S2100-Tobacco to 21 Act, HR2878/S1341-Children Don't Belong on Tobacco Farms Act) (Table 1).

Table 1. Tobacco related legislation introduced during the 115^th session of Congress.

Sponsors and cosponsors were identified as listed on Congress.Gov.

Campaign Contributions

Tobacco company political action committee (PAC) contributions to members of Congress were obtained from the Campaign for Tobacco-Free Kids website (5). Contributions from the years listed (2006-18) were summed and no effort was made to separate recent from more past contributions.

Statistics

The relationship between sponsorship of the tobacco-related bills and tobacco PAC campaign contributions was done by Fisher's exact test using a 2X2 contingency table. Amounts of campaign contributions were expressed as means with 95% confidence intervals. The Mann-Whitney U test was used to calculate comparisons of the amounts of campaign contributions.

Results

Tobacco PAC Contributions

Sixty-five percent of the members of Congress have received a tobacco PAC contribution since 2006 (Appendix 1). The average reported was $11,637. Ten members received over $80,000, of which the largest was to Sen. Richard Burr (R-NC)($124,022); all but three were from what is referred to as the deep South. Over $6 million was donated in total; 82% of the donations went to Republicans.

Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2017 (HR564/S294)

Ninety-four percent of the members of Congress who cosponsored the pro-tobacco "Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2017 (aka Cigar Bill)" had received tobacco PAC campaign contributions (Appendix 2). In contrast, 53% of who were not cosponsors had received contributions (p<0.01 by Fisher's Exact Test). Furthermore, the amount of contributions was larger for those who had cosponsored the bill larger ($18218, 95% CI $15077-$21359) than non-sponsors ($8730, 95% CI, $6959-$10501, p<0.01 by Mann-Whitney U test).

Tobacco to 21 Act (HR4273/S2100)

Eighty-two percent of the members of Congress who cosponsored the anti-tobacco " Tobacco to 21 Act" had not received tobacco PAC campaign contributions (Appendix 3). In contrast, 35% of who were not cosponsors had not received contributions (p<0.01 by Fisher's Exact Test). Furthermore, the amount of contributions was smaller for those who had cosponsored the bill ($2114, 95% CI $0-$4833) than non-sponsors ($12048, 95% CI, $10289-$13707, p<0.01 by Mann-Whitney U test).

Children Don't Belong on Tobacco Farms Act (HR2878/S1341) 

Data were similar with the anti-tobacco “Children Don't Belong on Tobacco Farms Act”. Seventy-eight percent of the members of Congress who sponsored the bill had not received tobacco PAC campaign contributions (Appendix 4). Thirty-five percent of the members of Congress who had not cosponsored the bill did not receive contributions (p<0.01 by Fisher's Exact Test). Furthermore, the amount of contributions was smaller for those who had cosponsored the bill ($2500, 95% CI $0-$5284) than non-sponsors ($12097, 95% CI $10429-$13765), p<0.01 by Mann-Whitney U test).

Discussion

This manuscript shows an association between tobacco PAC campaign contributions and sponsorship of both pro- and anti-tobacco legislation. More members of Congress who supported the pro-tobacco “Traditional Cigar Manufacturing and Small Business Jobs Preservation Act of 2017” had received tobacco PAC campaign contributions and the contributions were larger compared to those not sponsoring the legislation. The data was the opposite for the anti-tobacco “Tobacco to 21 Act” and “Children Don't Belong on Tobacco Farms Act”. The percentage of the members of Congress who had not received tobacco PAC contributions was higher for those who sponsored the legislation compared to those who did not. Taken together these data suggest an influence of campaign contributions on the sponsoring of tobacco legislation in the US Congress.

The data in this manuscript confirms and extends the previous observations that tobacco contributions to state legislators and Southwest Members of Congress influence support of tobacco legislation (1,2).  The Southwest US is not a major tobacco growing or manufacturing region (7). Furthermore, tobacco consumption tends to be low in Southwest US (7). The Southwest is a good area to study the influence of campaign contributions because of the lack of confounding influences from a constituency that makes a living by tobacco growing or manufacturing or has a high prevalence of smokers. Reexamination of the correlation between tobacco PAC contributions and Congressional sponsorship of the "Cigar Bill" shows similar results with the data in 2016 (1, Appendix 1). The present study shows that association occurred in Congress as a whole and extended to anti-smoking legislation.

The title of HR564/S294 is deceiving. The “Traditional Cigar Manufacturing and Small Business Jobs Preservation Act” is titled to conjure up images of small businesses hand-rolling premium cigars. However, many of the cigars affected by the legislation are not the large, thick, and expensive ones manufactured with fine tobacco but rather small, thin, cheap cigars that are often flavored (8).

There is no doubt that smoking tobacco is harmful including cigars where the risk can be as high as or exceed those of cigarette smoking (9). Cigarette consumption in the United States is decreasing, compelling US tobacco companies to search for new markets (10). The cigar market, especially the flavored cigar market, represents one strategy to increase tobacco consumption and profits. Flavored cigar use is increasing in US middle and high school students (11). Therefore, tobacco companies support of the "Cigar Bill" is not surprising. By removing regulation, the tobacco companies can increase advertising to children and grow the candy-flavored cigar market (8).

The amount of money donated by the tobacco PACs is quite large and would seem to exceed anything that anti-tobacco smoking organizations could muster. Sixty-five percent of the members of Congress have received contributions totaling over 6 million dollars since 2006. The influence of these contributions may make regulation of tobacco quite difficult.

This manuscript has several limitations. Receiving tobacco PAC contributions and sponsoring pro-tobacco legislation does not necessarily represent cause and effect. It seems likely that tobacco companies would be more likely to support legislators that they perceive as sympathetic. It also seems likely that the tobacco PACs would be less likely to donate to supporters of anti-tobacco legislation.

References

1. Monardi F, Glantz SA. Are tobacco industry campaign contributions influencing state legislative behavior? Am J Public Health. 1998 Jun;88(6):918-23. [CrossRef] [PubMed]
2. Robbins RA. Tobacco company campaign contributions and congressional support of the cigar bill. Southwest J Pulm Crit Care. 2016;13(4):187-90. [CrossRef]
3. Powell LW. The influence of campaign contributions on legislative policy. The Forum: A Journal of Applied Research in Contemporary Politics 2013;11(3):339-55. [CrossRef]
4. Congress.gov. Available at: https://www.congress.gov/ (accessed 3/26/18).
5. Campaign for Tobacco-Free Kids. Tobacco company political action committee (PAC) contributions to Federal candidates. Available at: https://www.tobaccofreekids.org/what-we-do/us/tobacco-campaign-contributions  (accessed 3/26/18).
6. Statistica. Statistics and facts about the tobacco industry. Available at: http://www.statista.com/topics/1593/tobacco/ (accessed 3/26/18).
7. Campaign for tobacco-free kids. Key state-specific tobacco-related data & rankings. Available at: https://www.tobaccofreekids.org/assets/factsheets/0176.pdf (accessed 3/26/18).
8. American Thoracic Society. ATS Joins Letter Opposing Cigar Exemption. October, 2017. Available at: https://news.thoracic.org/washington-letter/2017/ats-joins-letter-opposing-cigar-exemption.php (accessed 3/26/18).
9. Chang CM, Corey CG, Rostron BL, Apelberg BJ. Systematic review of cigar smoking and all cause and smoking related mortality. BMC Public Health. 2015 Apr 24;15:390. [CrossRef] [PubMed]
10. Centers for Disease Control. Current Cigarette Smoking Among Adults in the United States. Available at: https://www.cdc.gov/tobacco/data_statistics/fact_sheets/adult_data/cig_smoking/index.htm (accessed 3/26/18).
11. King BA, Tynan MA, Dube SR, Arrazola R. Flavored-little-cigar and flavored-cigarette use among U.S. middle and high school students. J Adolesc Health. 2014 Jan;54(1):40-6. [CrossRef] [PubMed]

Cite as: Robbins RA. Tobacco company campaign contributions and congressional support of tobacco legislation. Southwest J Pulm Crit Care. 2018;16(4):232-6. doi: https://doi.org/10.13175/swjpcc053-18 PDF 

Social Media: A Novel Engagement Tool for Miners in Rural New Mexico

Shreya Wigh¹

William Cotton Jarrell, CMSP³

Elizabeth Kocher, MPH¹

Roger Karr²

Xin Wang, MS¹

Akshay Sood, MD, MPH^1,2

¹University of New Mexico Health Sciences Center School of Medicine

Albuquerque, NM, USA

²Miners Colfax Medical Center

Raton, NM, USA

³Peabody New Mexico Services

Grants, NM, USA

Abstract

Background: New Mexico miners usually live in rural areas. As compared to urban areas, rural areas in the United States demonstrate a lower use of the Internet and lower adoption of new technologies such as the smartphone and social media. Our study objective was to examine the use of these technologies among miners in rural New Mexico. Our long-term goal is to utilize these technologies to increase our program’s engagement with miners to provide medical screening and education services. Methods: We anonymously surveyed 212 miners at two town hall meetings in rural New Mexico communities, predominantly Hispanic and American Indian, in 2017. We then compiled that data in a Research Electronic Data Capture (REDCap) database and performed a statistical analysis using Statistical Analysis Software (SAS). IRB approval was obtained. Results: 60.8% of the 212 surveyed miners reported using social media. Among social media users, 88.4% reported using Facebook.  Most miners expressed willingness to use social media to keep in contact with other miners (51.2% overall) or to receive information about our miners’ program services (53.9% overall); and social media users were more likely to do so than non-users (p<0.001 for both analyses). Additionally, 79.7% of miners who owned a smartphone utilized it for texting. Conclusions: A majority of miners in rural New Mexico report use of social media and express willingness to use social media to network with other miners and with our program. The adoption of these communication technologies by rural New Mexico miners in our study is comparable or superior to that reported by rural Americans overall. It is possible to utilize this newer technology to increase program engagement with miners.

Introduction

New Mexico miners usually live in rural and medically underserved areas and suffer from multiple chronic diseases, particularly dust related lung diseases or pneumoconiosis. Rural counties in northern New Mexico have among the highest mortality rates for silicosis and pneumoconiosis, including coal workers’ pneumoconiosis, in the United States (1). To address this challenge, Miners’ Colfax Medical Center and the University of New Mexico have partnered in a federally funded medical screening program for rural miners.  As compared to urban areas, those who live in rural areas reportedly have a lower use of the Internet and are less willing to adopt new communication technologies such as the smartphone and social media (2). We have previously published that the primary source of information about miners’ health related activities for attendees at our miners’ health screening programs are traditional routes of communication such as a relative, friend, and community newspaper or flyer (3). Traditional media is, however, a one-way communication system that doesn’t create program engagement or work towards promoting word-of-mouth - the hallmark of social media (4). Our programs could utilize social media to promote awareness, encourage miner engagement, and increase the spread of accurate health messaging among New Mexico miners. Serving older, less educated, poorer, racial/ethnic minority, miners living in geographically remote and medically underserved rural areas of New Mexico may however affect the use and effectiveness of this communication tool.

The objective of our study was to examine the use of Internet-based smartphone and social media technology among miners in rural New Mexico. We hypothesized a low usage rate of these novel communication technologies among rural miners in New Mexico. Our long-term goal is to use these technologies to increase bidirectional engagement with miners with our federally funded Black Lung and Radiation Exposure Screening and Education Programs that currently provide medical screening, health care, and education services to coal and uranium miners in New Mexico.

Methods

Study design: This is a cross sectional survey of 212 miners, mostly coal miners, at two town hall meetings held in rural and medically underserved communities of Grants and Socorro, New Mexico, in 2017. These communities are predominantly American Indian and Hispanic respectively. The town hall meetings were held in conjunction with mobile health screening clinics for miners.

Survey creation: We created a survey on the use of the smartphone and social media, which asked construct-specific questions with either Yes/No responses or multiple choices. Examples of questions included whether miners would be willing to use social media to stay in touch with the mining community and if they had access to a computer with internet. The questions were formatted for an eighth-grade vocabulary, since our previous studies have shown that 57.2% of New Mexico miners do not complete high school education (3).

Survey administration: The paper copy of the survey was given to miners to fill out during the town hall meeting by the mine safety officer, on a voluntary and anonymous basis.

Analytic and database strategy: We compiled the survey data into a Research Electronic Data Capture (REDCap) database. We compared characteristics between social media users with social media non-users. Statistical analysis included an analysis of frequency distributions and Chi-square test, using Statistical Analysis Software (SAS 13.0, Cary, NC). A p-value less than 0.05 was considered statistically significant. We obtained human Institutional Review Board (IRB) approval for research exempt status (HRPO 14-058). The study was sponsored by Health Resource Services and Administration (HRSA) and Patient Centered Outcomes Research Institute (PCORI).

Results

60.8% of the 212 miners surveyed reported using social media. Among the social media users, 88.4% reported using Facebook, 27.9% reported using Instagram, and 26.4% reported using Snapchat.  Social media users reported utilizing the technology for an average of 47.9 ± 134.3 (SD) minutes daily, for approximately 6.0 ± 4.4 (SD) years. Most miners expressed willingness to use social media to keep in contact with other miners (51.2% overall) or to receive information about our miners’ program services (53.9% overall); and social media users were more likely to do so than non-users (p<0.001 for both analyses, Table 1).

Table 1. Difference in characteristics between self-reported social media users and nonusers, among rural miners in New Mexico.

86.3% of the miners surveyed also reported possessing a smart phone (93.8% versus 74.7% of the social media users and non-users respectively; p<0.001). 79.7% of miners owning a smartphone utilized it for texting (91.5% versus 61.5% of social media users versus nonusers respectively; p<0.001).

94.3% of rural miners reported having access to the Internet. Social media users were more likely to report having Internet access via computer or via phone than non-users (p = 0.08 and <0.001 respectively, Table 1). 24.0% of all miners however reported poor Internet connection as a challenge, and as compared to nonusers, social media users were more likely to report this challenge (p=0.01). 13.2% of all miners complained of the high expense of the Internet and the social media user status did not predict this characteristic (p=0.67). There was also no difference between the two groups with respect to the reported difficulty in navigating social media sites (p=0.32).

Discussion

Based on our results, we conclude that the majority of miners in rural New Mexico use Internet-based smartphone and social media technologies and are willing to use social media to network with other miners or programs that deliver health services to miners. We found that Facebook was the most popular social media site. The adoption of these communication technologies by rural New Mexico miners in our study is comparable or superior to that reported by rural Americans overall. This suggests that it is possible to use smartphone texting and social media technology to increase bidirectional program engagement with miners in rural New Mexico.

In 2017, the proportion of US population with a social media profile was variably estimated at 69-81% (5-7). Rural Americans in the US were approximately 8% less likely to use social media than urban Americans (2). The market leader in social media was Facebook, used by 68% and 79% of all and online American adults respectively (7). In our study, 60.8% of the rural miners reported using social media and 53.8% reported using Facebook, which is comparable to that reported in other US rural communities. In 2017, the proportion of American adults who owned a smartphone was 83%, 78%, and 65% for urban, suburban, and rural locations respectively (8). In comparison, 86.3% of rural miners in our study reported possessing a smartphone, indicating a higher level of smartphone possession than that reported by rural Americans overall. In 2017-2018, 89% of all American adults used the Internet (9). In an earlier survey from November 2016, 81% of rural Americans used the Internet, as compared to 89% of urban Americans (10). 63% of rural Americans had a broadband Internet connection at home, 10 percentage points less likely than Americans overall (10). In comparison, 94.3% of rural New Mexico miners in our study reported having access to the Internet, indicating a higher level of Internet access than that reported by rural Americans overall. Contrary to our initial hypothesis, we found that rural New Mexico miners in our study reported adoption of newer communication technologies at a level that was comparable or superior to that reported by rural Americans overall.

Racial/ethnic and health status-related disparities exist with respect to Internet access in the U.S. (9). However, among those with Internet access, these characteristics do not affect their social media use (11). New Internet-based technologies including smartphone and social media, may be changing the communication pattern throughout the U.S. and the world but this change has not been well studied, particularly in rural areas (11).  Potential overarching benefits of social media for health communication are (1) increased interactions with others, (2) more available, shared, and tailored information, (3) increased accessibility and widening access to health information, (4) peer/social/emotional support, (5) public health surveillance, and (6) potential to influence health policy (12). Our findings indicate that social media can similarly be used for health communication purposes among rural miners in New Mexico. Our HRSA-funded miners’ health and benefits programs in New Mexico have established a social media platform to provide rural miners with information on our clinical programs, research, education and other interventions as well as to provide opportunities for bidirectional engagement between the program and miners as well as among miners themselves. Our program has also launched a social media literacy campaign for miners, with the help of a rural mine safety officer.

Currently there is a limited amount of literature evaluating the use of social media for sustained engagement of diverse communities in health promotion (13,14). For instance, the Youth Voices Research Group has reported creating novel opportunities to engage young people to explore health topics ranging from tobacco use, food security, mental health, and navigation of health services, by combining social organizing with arts-informed methods for creative expression, using information technology (14). Creating opportunities for engagement alone is however insufficient. The information exchanged needs to be monitored for quality and reliability, users’ confidentiality and privacy need to be maintained (12), and its impact evaluated. Use of social media in health promotion in underserved populations, such as indigenous populations in Australia, is associated with limited evidence of benefit (15). Online social network health behavior interventions are reported to have small effect sizes, often statistically nonsignificant, with high participant attrition and low fidelity (16). It is therefore necessary for our program to critically evaluate the role and effectiveness of these new technologies in health promotion and health care for our population of rural miners.

The strength of our study includes inclusion of miners from rural and predominantly Hispanic and American Indian communities. Limitations of our study include small sample size and lack of information on individual demographic characteristics. Although our study was limited to New Mexico, our findings may be generalizable to other rural and medically underserved areas of the United States outside of New Mexico.

Conclusions

Most miners in rural New Mexico have Internet access, use smartphones and social media, and are willing to use social media to network with other miners or programs that deliver health services to miners. Rural New Mexico miners in our study report adoption of newer communication technologies at a level that is comparable or superior to that reported by rural Americans overall. This study provides preliminary information on a potential and novel way in which rural mining communities and miners’ health and benefits programs can engage with each other to promote miners’ health by assisting in clinical programs, research, education and other interventions. Miners’ program may consider interactive blogging, photograph elicitation, and video documentaries, alongside real-world social media projects, to promote this engagement. Potential barriers in rural miners include low social media literacy and poor Internet connection. Low social media literacy can however be addressed by targeted education of miners. Emerging areas of research include evaluating the effectiveness of the use of smartphones and social networking platforms such as Facebook, in building effective interventions for health promotion and providing healthcare for miners in rural communities.

Acknowledgments

SW, WCJ, EK, RK, KW, AS made substantial contributions to the conception or design of the work; SW, WCJ, EK, RK, KW, AS made substantial contributions to the acquisition, analysis, or interpretation of data for the work. SW, WCJ, EK, RK, KW, AS made substantial contribution towards drafting the work or revising it critically for important intellectual content. SW, WCJ, EK, RK, KW, AS provided the final approval of the version to be published. SW, WCJ, EK, RK, KW, AS agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References

1. Dwyer-Lindgren L, Bertozzi-Villa A, Stubbs RW, et al. Trends and Patterns of Differences in Chronic Respiratory Disease Mortality Among US Counties, 1980-2014. JAMA. 2017;318(12):1136-49. [CrossRef] [PubMed]
2. Perrin A. Social Networking Usage: 2005-2015. Pew Research Center. 2015. Available at: http://www.pewinternet.org/2015/10/08/2015/Social-Networking-Usage-2005-2015/, last accessed on March 28, 2018.
3. Evans K, Lerch S, Boyce TW, et al. An innovative approach to enhancing access to medical screening for miners using a mobile clinic with telemedicine capability. J Health Care Poor Underserved. 2016;27(4A):62-72. [CrossRef] [PubMed]
4. Hausman A. Social media versus traditional media. 2014. Available at https://www.hausmanmarketingletter.com/social-media-versus-traditional-media/, accessed on January 9, 2018.
5. Statistica – The Statistics Portal. Percentage of U.S. population with a social media profile from 2008 to 2017. 2018. Available at https://www.statista.com/statistics/273476/percentage-of-us-population-with-a-social-network-profile/, accessed on March 28, 2018.
6. Perrin A. Social Media Fact Sheet. Pew Research Center. 2018. Available at: http://www.pewinternet.org/fact-sheet/social-media/, last accessed on March 28, 2018.
7. Perrin A. Social Media Update 2016. Pew Research Center. 2016. Available at: http://www.pewinternet.org/2016/11/11/social-media-update-2016/, last accessed on March 28, 2018. 2016.
8. Statistica – The Statistics Portal. Share of adults in the United States who owned a smartphone from 2011 to 2017, by location. 2018. Available at https://www.statista.com/statistics/195003/percentage-of-us-smartphone-owners-by-geographic-location/; accessed on March 28, 2018. 2018.
9. Perrin A. Internet/Broadband Fact Sheet. Pew Research Center. 2018. Available at: http://www.pewinternet.org/fact-sheet/internet-broadband/, last accessed on March 28, 2018.
10. Perrin A. Digital gap between rural and non-rural America persists. 2017. Pew Research Center. Available at: http://www.pewresearch.org/fact-tank/2017/05/19/digital-gap-between-rural-and-nonrural-america-persists/, last accessed on March 28, 2018.
11. Chou WY, Hunt YM, Beckjord EB, Moser RP, Hesse BW. Social media use in the United States: implications for health communication. J Med Internet Res. 2009;11(4):e48. [CrossRef] [PubMed]
12. Moorhead SA, Hazlett DE, Harrison L, Carroll JK, Irwin A, Hoving C. A new dimension of health care: systematic review of the uses, benefits, and limitations of social media for health communication. J Med Internet Res. 2013;15(4):e85. [CrossRef] [PubMed]
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Cite as: Wigh S, Jarrell WC, Kocher E, Karr R, Wang X, Sood A. Social media: A novel engagement tool for miners in rural New Mexico. Southwest J Pulm Crit Care. 2018;16(4):206-11. doi: https://doi.org/10.13175/swjpcc017-18 PDF

April 2018 Pulmonary Case of the Month

Ashely L. Garrett, MD

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 74-year-old woman with known chronic obstructive pulmonary disease (COPD) presented to emergency department on 2/4/18 with dyspnea. She had been hospitalized at another hospital from 12/29/17 - 1/30/18 for a COPD exacerbation and health care associated pneumonia described as a cavitary pneumonia. She was treated with various doses of systemic steroids and antibiotics. Her course was complicated by atrial fibrillation with a rapid ventricular response. She eventually was discharged to a skilled nursing facility.

Past Medical History, Social History and Family History

She has a known history of COPD with an FEV1 of 22% of predicted and is on 2L/min of O2 by nasal cannula. There is also a history of:

• Hypertension.
• Hypercholesterolemia.
• Paroxysmal atrial fibrillation, not on anticoagulation.
• Right 4 mm PICA aneurysm

She lives in rural Kingman, AZ with some dust and outdoor bird exposure.

Family history is noncontributory.

Medications

• Alprazolam 0.25 mg p.o. b.i.d.
• Symbicort two puffs inhaled b.i.d.
• Diltiazem 120 mg p.o. q.12h
• Disopyramide 150 mg p.o. q.6h
• Furosemide 20 mg p.o. daily
• Levalbuterol 0.31 mg q.6 days p.r.n.
• Meperidine 50 mg p.r.n. pain
• Metoprolol succinate 12.5 mg p.o. b.i.d
• Prednisone 10 mg p.o. daily

Physical Examination

• Vitals: BP 110/65 mm Hg, P 130 irregular beats/min, T 37° C, Respirations 20 breaths/min
• General: Appears in mild respiratory distress
• Lungs: Distant breath sounds
• Heart: Irregular rhythm with distant tones
• Abdomen: no organomegaly, masses or tendernesses
• Extremities:  No edema

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

1. Arterial blood gases (ABGs)
2. Chest x-ray
3. Electrocardiogram
4. 1 and 3
5. All of the above

Cite as: Garrett AL. April 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(4):174-82. doi: https://doi.org/10.13175/swjpcc050-18 PDF

First-Line Therapy for Non-Small Cell Lung Cancer Including Targeted Therapy: A Brief Review

Richard A. Robbins, MD*

Thomas D. Kummet, MD**

*Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

**Sequim, WA USA 

Abstract

Operative removal of non-small cell lung cancer remains the mainstay of therapy. When this is not possible, cytotoxic chemotherapy and/or radiotherapy can be given but are marginally effective in prolonging overall survival. However, with a better understanding of the pathobiology of the lung cancer cells, new targeted therapies have been developed which may produce dramatic responses in selected patients. This brief review will emphasize these newer therapies in this rapidly evolving field.

Introduction

Lung cancer is extremely common and remains by far the most frequent cause of cancer-related death with approximately 154,050 deaths estimated to occur during 2018 (1). Although lung cancer deaths have declined in men, the deaths have risen in women and now account for nearly half of all women’s cancer deaths (1). Unfortunately, the vast majority are diagnosed with advanced, unresectable disease that remains incurable (1). Overall the five-year survival rate is <1% for advanced (stage IVB) disease, while the five-year survival rate for all stages is approximately 15 % (1).

Data linking cigarette smoking to human lung cancer is incontrovertible (2). The risk increases with both the amount of smoking and the duration of smoking (2). Passive or second-hand smoke is also associated with an increase in the risk of lung cancer, although this increase is far lower than that observed with active smoking (2). Smoking cessation clearly decreases the risk of lung cancer (2).

Primary lung cancers can be divided into two main types based on their histology, small cell lung cancer and non-small cell lung cancer (NSCLC) (3). NSCLC constitute about 85% of lung cancers with the rest consisting of small cell and some rarer cancers (3). A basic understanding of the pathobiology of NSCLC has shown that the tumor cells depend on the formation of new blood vessels (angiogenesis), transfer of a phosphate group from ATP to tyrosine on proteins (tyrosine kinase), and regulation of programmed death ligands (checkpoint proteins) (4). Targeted therapy against these pathobiologic processes have shown dramatic effects in some NSCLC patients (4).

NSCLC is divided into 4 stages designated by roman numerals (5). The stages are based on the size of the tumor; whether it has metastasized locally or distally; and use the TNM classification where T designates tumor size; N regional lymph node metastasis; and M distant metastasis. Stages I and II are limited to the chest but stage III has metastasized to the pleura and/or regional lung lymph nodes. Stage IIIA means the cancer has metastasized to lymph nodes that are on the same side of the chest as the cancer (ipsilateral) while stage IIIB signifies metastasis to lymph nodes on the opposite side of the chest (contralateral). Stage IV denotes there are distant metastasis outside the chest. The above is admittedly an oversimplification and there are subtle nuances that define the stages which can be found at the National Cancer Institute website (5).

An overall summary of standard preferred by the National Cancer Institute for NSCLC by stage is shown in Table 1 (6).

Table 1. Standard preferred therapy for NSCLC by stage (6).

Surgery

Operative removal of the lung cancer is the cornerstone of management for patients with early-stage (stages I–II) NSCLC and selected patients with stage IIIA disease (7). Lobectomy is the operation of choice for localized NSCLC based on a randomized trial of lobectomy versus more limited resection (8). Operative intervention should be offered to all patients with stage I and II NSCLC who clinically are medically fit for surgical resection. However, patients may be unable to undergo a lobectomy for a variety of reasons such as: 1. severely compromised pulmonary function; 2. multisystem disease making lobectomy excessively hazardous; 3. advanced age; or 4. refusal of the operation. Some patients who cannot tolerate a full lobectomy but may be able to tolerate a more limited sublobar operation (6). For patients in whom complete tumor resection cannot be achieved with lobectomy, sleeve lobectomy is recommended over pneumonectomy because it preserves pulmonary function (6). In addition, the question of whether video-assisted thorascopic surgery (VATS) is equivalent to thoracotomy for patients with lung cancer comes up often, particularly in patients that are less than ideal surgical candidates. In a series of 741 patients with stage IA NSCLC, 5-year survival was similar but VATS was associated with fewer complications and a shorter length of hospital stay (9).  Therefore, VATS is an optional surgical approach particularly in poorer risk patients.

Radiotherapy

Although lobectomy is the treatment of choice for NSCLC patients with early-stage disease, some are unable to undergo an operation due to reasons listed above. For those patients, radiotherapy can be administered with curative intent, albeit with lower overall survival rates when compared to surgery (10,11).

The radiation oncology community is excited about the potential of stereotactic body radiation therapy (SBRT) (12,13). SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). Although there is no data yet, trials are ongoing comparing SBRT with surgery in early stage NSCLC.

Adjuvant Therapy

Adjuvant chemotherapy. Adjuvant chemotherapy is chemotherapy that is given in addition to either surgical and/or radiation therapy. Data from recent randomized adjuvant clinical trials and a meta-analysis support the use of adjuvant chemotherapy in NSCLC (14). A 5.4% five-year survival benefit was observed in a meta-analysis of five randomized trials compared to observation. Not surprisingly, the survival benefit varied according to stage but the benefit was most pronounced for patients with stage II and IIIA disease. Survival benefit in patients with stage IB disease did not reach statistical significance. Importantly, patients with stage IA disease appeared to do worse with adjuvant chemotherapy, and therefore, is not currently recommended.

Adjuvant radiotherapy. The PORT meta-analysis of 2,128 patients demonstrated that the use of post-operative radiotherapy was associated with a detrimental effect on survival (15,16). The decrease in survival was more pronounced for patients with lower nodal status. The PORT meta-analysis has been criticized for its long enrolment period and use of different types of machines, techniques and radiation doses. Despite these criticisms, three randomized phase III trials support the PORT meta-analysis’ conclusion that the use of post-operative radiotherapy provides no survival benefit (17-19). For patients with N2-positive disease, however, a retrospective analysis demonstrated higher survival for those patients who had received post-operative radiotherapy (20). On the basis of the above studies, most do not recommend routine post-operative radiotherapy with the possible exception of those with N2 disease.

Locally Advanced Disease

About a third of patients with NSCLC present with disease that remains localized to the thorax but may be too extensive for surgical treatment (stage III) (21). Concurrent chemotherapy and radiation therapy is considered the standard therapy for this situation but results in only a modest, although statistically significant, survival benefit compared with sequential administration (21). However, significant toxicity results from this approach and so it is usually offered only to those with good performance status.

Surgery after chemotherapy in patients with N2 disease was tested in two randomized trials. A European trial used three cycles of cisplatin-based chemotherapy, then randomized the patients to surgery or sequential thoracic radiotherapy (22). There was no significant difference in overall survival or progression-free survival. An American trial used a slightly different protocol (23). Patients with N2 disease were given two cycles with concurrent radiotherapy and then randomized to further radiation or surgery. This trial showed a better progression free survival with surgery but no difference in overall survival.

Metastatic Disease

About 40% of patients with NSCLC present with advanced stage IV disease. Until recently, cytotoxic chemotherapy was the cornerstone of treatment for stage IV disease but is now recommended as first line therapy alone only for patients with low or no expression of markers for targeted therapy (24). Unfortunately, in stage IV NSCLC standard cytotoxic chemotherapy alone is minimally effective. A meta-analysis that included 16 randomized trials with 2,714 patients demonstrated that cytotoxic chemotherapy offers an overall survival advantage of only 9% at 12 months compared with supportive care (25). Two-drug chemotherapy (doublets) appears to be superior to either a single agent or three-drug combinations (26). Cisplatin-based doublets are associated with a marginal one-year survival benefit compared with platinum-free regimens (27). Platinum-free regimens can be given as an alternative especially in patients who cannot tolerate platinum-based treatment (24). Although gemcitabine, vinorelbine, paclitaxel or pemetrexed are often added to either cisplatin or carboplatin, the choice of the second drug does not appear to matter in increasing survival (28).

Targeted Therapies

Starting in the early 2000s, NSCLC subtypes have evolved from being histologically described to molecularly defined. The use of targeted therapies in lung cancer based on molecular markers is a very rapidly changing field. At the time this article was being written (February 2018) the information was current but recommended therapies are likely to change with development of new therapies and research. It is important to point out that despite these advances, there remains no cure for stable IV NSCLC. Table 2 represents a summary of targets and targeted therapy along with the American Society of Clinical Oncology (ASCO) recommendations for stage IV NSCLC as of February 2018 (24).

Table 2. Targets and targeted therapies for NSCLC (24).

*Currently not recommended for clinical use by ASCO.

The need for adequate tissue to perform molecular studies creates challenges for pulmonologists doing bronchoscopic procedures. Whereas it was previously adequate to obtain diagnostic material. However, it is now important to obtain adequate tissue to perform additional molecular testing to allow determination of whether targeted therapies are appropriate. Sometimes tissue is inadequate which might necessitate a second procedure if clinically warranted.  

Vascular Growth Factors

Epidermal Growth Factor Receptor (EGFR). The EGFR pathway represents the pioneer of personalized medicine in lung cancer. EGFR is a transmembrane receptor that is highly expressed by some NSCLCs. Binding of ligands (epidermal growth factor, tumor growth factor-alpha, betacellulin, epiregulin or amphiregullin) to the extracellular EGFR domain results in autophosphorylation through tyrosine kinase activity (29). This initiates an intracellular signal transduction cascade that affects cell proliferation, motility and survival (29). Inhibition of ligand and EGFR binding or the activation of tyrosine kinases inhibit the downstream pathways resulting in inhibition of cancer cell growth (29).

Initial studies showed that most patients with NSCLC had no response to the tyrosine kinase inhibitor (TKI), gefitinib, which targets phosphorylation of EGFR (30). However, about 10 percent of patients had a rapid and often dramatic clinical response (30). An explanation for these results occurred with the identification of mutations of the tyrosine kinase coding domain (exons 18–21) of the EGFR gene. Subsequent research linked these mutations to the clinical response to gefitinib (31,32). Although about 10% of Caucasian NSCLC have these mutations, the mutations were observed more commonly in Asian patients, particularly non-smoking women (33). There is now overwhelming and consistent evidence from multiple trials that all the approved EGFR-TKIs (gefitinib, erlotinib, or afatinib) have greater activity than platinum-based chemotherapy as the first-line treatment of patients with advanced NSCLC with activating EGFR mutations (24).  These agents have more favorable toxicity profiles than platinum-based chemotherapy and have demonstrated improvements in quality of life. The choice of which EGFR-TKI to recommend to patients should be based on the availability and toxicity of the individual therapy. Randomized clinical trials are ongoing comparing EGFR-TKIs. The results of these trials may help refine this in the future.

Despite high tumor response rates with first-line EGFR-TKIs, NSCLC progresses in a majority of patients after 9 to 13 months of treatment. At the time of progression, approximately 60% of patients (regardless of race or ethnic background) are found to have a Thr790Met point mutation (T790M) in the gene encoding EGFR (34). The presence of the T790M variant reduces binding of first-generation EGFR-TKIs to the leading to disease progression (34). Osimertinib is an irreversible EGFR-TKI that can bind to EGFR despite the T790M resistance mutations and has recently become clinically available (35). Currently it is recommended for T790M mutations that occur after the first-line EGFR-TKIs have failed (24).

Cetuximab is a monoclonal antibody directed against EGFR itself. In the past, addition of cetuximab to cisplatin doublet chemotherapy in EGFR positive tumors was usual. However, cetuximab has recently been shown to shorten progression free survival with some adverse effects and is no longer recommended (24).

Vascular endothelial growth factor (VEGF). Angiogenesis, the formation of new blood vessels, is a fundamental process for the development of solid tumors and the growth of secondary metastatic lesions. Vascular endothelial growth factor (VEGF) acts to promote normal and tumor angiogenesis. Bevacizumab, a recombinant, humanized, monoclonal antibody against VEGF, was previously recommended as first-line therapy in stage IV NSCLC patients without a contraindication. However, the most recent ASCO guidelines finds insufficient evidence to recommend bevacizumab in combination with chemotherapy as first-line treatment (24).

Other Kinase Inhibitors. Receptor tyrosine kinase 1 (ROS1) and the structurally similar anaplastic lymphoma kinase (ALK) are enzymes that are critical regulators of normal cellular activity. In NSCLC rearrangements of these genes can cause them to act as oncogenes, or genes that transform normal cells into cancer cells. Rearrangements in the ROS1 or ALK genes are found in a small percentage of patients with NSCLC. Crizotinib is a molecule that blocks both the ROS1 and ALK proteins. Crizotinib reduced tumor size in ALK+ or ROS1+ positive patients although the most recent ASCO guidelines consider the evidence only moderate with ALK+ and weak with ROS1+ patients (24,36-8).

Checkpoint Inhibitors. An important part of the immune system is its ability to tell the difference between normal cells and those that are “foreign”. To do this, it uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response (39). NSCLC can use these checkpoints to avoid being attacked by the immune system. Programmed cell death protein 1 (PD-1) is a checkpoint protein on T cells. It normally acts as an “off switch” when it attaches to programmed death-ligand 1 (PD-L1), a protein on some normal (and cancer) cells. Some NSCLCs have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against NSCLC cells. In patients with NSCLC with >50% of their tumor cells PD-1+ (tumor proportion score >50%), pembrolizumab, a monoclonal antibody against PD-1, significantly prolonged progression-free and overall survival compared to platinum-based chemotherapy (40). Based on this trial, pembrolizumab is now recommended by ASCO for patients with a tumor proportion score >50% for PD-1 (23). A number of other PD-1 (e.g., nibolumab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab) exist but ASCO recommends only pembrolizumab at this time (39,40). As more of these checkpoint inhibitors are developed and tested this will likely change.

Second and Third-Line NSCLC Therapy

Second and third-line therapy for NSCLC is beyond the scope of this brief review. It is a rapidly evolving field which should include close collaboration between the pulmonologist, oncologist and other members of the patient’s NSCLC treatment team.

After an initial response, lung cancers can become resistant to therapy. One example mentioned above is the development of the T790M mutation in EGFR+ NSCLC.  In selected instances rebiopsy of the primary tumor or metastases can direct a new, effective therapy. Obviously, it is not possible to rebiopsy every NSCLC patient after failure of the initial therapy. However, other techniques are being investigated. One is liquid biopsy where blood is drawn and subjected to molecular techniques to determine a possible cause for tumor resistance.  Multiple liquid biopsy molecular methods are presently being examined to determine their efficacy as surrogates to the tumor tissue biopsy (41).

Future Directions

The combination of a variety of existing therapies for NSCLC is being evaluated. These will likely yield revised recommendations for therapy. In addition, a variety of therapies, both existing for other cancers, or newer therapies in development are being tested.  These include both monoclonal antibodies and biologic inhibitors (Table 3).

Table 3. Potential new targeted therapies for NSCLC (42,43).

The numbers of pathways and drugs being tested is very impressive and the clinical responses can be dramatic in some patients. One might be tempted to conclude that these therapies might result in a “cure” for NSCLC. However, most of these mutations occur in a small minority of NSCLCs. Furthermore, even if initially successful, resistance to targeted therapies may quickly develop limiting their clinical usefulness in NSCLC.

Targeted therapies may also have potential as adjuvant therapies. In support of this concept, a recent phase 3 study compared durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy (44). The progression-free survival was 16.8 months with durvalumab versus 5.6 months with placebo (p<0.001). It seems likely that more trials using targeted therapy earlier in cancer therapy will be done.

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Cite as: Robbins RA, Kummet TD. First-line therapy for non-small cell lung cancer including targeted therapy: A brief review. Southwest J Pulm Crit Care. 2018;16(3):157-67. doi: https://doi.org/10.13175/swjpcc038-18 PDF 

March 2018 Pulmonary Case of the Month

Thomas D. Kummet, MD

Sequim, WA 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 panel of the activity. 

0.25 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.25 hours

Lead Author(s): Thomas D. Kummet, 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: University of Arizona College of Medicine at Banner University Medical Center Tucson

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

Financial Support Received: None

History of Present Illness

The patient was a 62-year-old woman who complained of a sudden severe increase in a three-month history of mild left upper extremity pain. 

PMH, SH and FH

The patient had no significant past medical history. She is a non-smoker. Family history is non-contributory.

Physical Examination

• Vital Signs: Pulse 102 beats/min, blood pressure 140/84 mm Hg, respirations 16 breaths/min, Temperature 37.4º C, SpO2 94% on room air.
• Lungs: Clear.
• Heart: Regular rhythm.
• Abdomen: without organomegaly, masses or tendernesses.
• Extremities: Both upper extremities were unremarkable. The left shoulder had a full range of motion. Pulses were intact bilaterally and equal.
• Neurologic: Upper extremity strength was good and equal. Light touch and pin prick were intact. Deep tendon reflexes were well preserved.

Which of the following are indicated in management at this time? (Click on the correct answer to proceed to the second of seven pages)

1. Reassurance that the pain will improve
2. Shoulder x-ray
3. Treatment with oxycodone
4. 1 and 3
5. All of the above

Cite as: Kummet TD. March 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(3):110-6. doi: https://doi.org/10.13175/swjpcc033-18 PDF

February 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 75-year-old woman was diagnosed with a thymic carcinoid tumor in April, 2015 (Figure 1).

Figure 1. Representative image from the preoperative CT scan performed in April 2015 showing an anterior mediastinal mass (arrow).

This was treated with surgical resection followed by radiation therapy.

She began having cough and dyspnea 1 to 2 months later and in August, 2015 had a thoracic CT scan of her chest (Figure 2).

Figure 2. Representative image in lung windows from the second thoracic CT scan performed in August 2015.

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

1. Bronchoscopy should be performed
2. She should be given an empiric course of antibiotics
3. The most like diagnosis is radiation pneumonitis
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. February 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(2):55-61. doi: https://doi.org/10.13175/swjpcc020-18 PDF 

January 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

 Departments of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 67-year-old man from Idaho was seen in November 2017 for a second opinion. He has a history of slowly progressive dyspnea on exertion for 7 to 8 years. He has a significant smoking history of 50 pack-years, but is still smoking “a few cigarettes”.

He saw an outside pulmonologist in September 2017 and was noted to have abnormal pulmonary function testing with the primary abnormality being a low DLco. A thoracic CT Scan was reported to be abnormal with evidence of interstitial lung disease. He underwent video-assisted thorascopic surgery and the biopsies were reported to show usual interstitial pneumonitis (UIP). His pulmonologist questioned whether this was interstitial pulmonary fibrosis or UIP associated with rheumatoid arthritis.

PMH, SH and FH

He has a history of rheumatoid arthritis and had been treated with methotrexate for approximately 8 years. His methotrexate had been discontinued in September with no change in symptoms. FH is noncontributory.

Medications

Prednisone 5 mg/daily and tiotropium (these also did not change his dyspnea).

Physical Examination

• Chest:  bibasilar crackles.
• Cardiovascular:  regular rhythm without murmur.
• Ext:  no clubbing, no edema, no joint deformity noted

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

1. Obtain a complete blood count and rheumatoid factor
2. Begin pirfenidone or nintedanib
3. Review his pulmonary function testing and radiographic studies
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. January 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(1):8-13. doi: https://doi.org/10.13175/swjpcc157-17 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

Necrotizing Pneumonia: Diagnosis and Treatment Options

Brian D. Skidmore, BS¹ and Veronica A. Arteaga, MD²

¹College of Medicine and ²Department of Medical Imaging

Banner-University Medical Center

University of Arizona

Tucson, AZ USA

Abstract

We present the case of a patient who was initially diagnosed with community-acquired pneumonia that was later discovered to have necrotizing changes. The case illustrates the challenges in diagnosing necrotizing pneumonia and the preferred treatment methods.

Case Presentation

History of Present Illness

The patient is a 51-year old woman who presents with right upper lobe pneumonia and a failed outpatient regimen of levofloxacin. She returned one week after being seen in the emergency department with worsening dyspnea, productive cough, and fever in addition to new symptoms of right chest pain and post-tussive emesis. The chest pain is stabbing in quality and constantly present. She denied any calf pain/swelling, previous history of deep venous thrombosis, or long trips or travels.

Physical Exam

Upon admission, blood pressure was 103/56 with a pulse of 114 and respiratory rate of 18. Her temperature was 38.1 °C (100.5 °F) but spiked at 39.5 °C (103.1 °F) and her SpO₂ was 94.0% on room air. Her breathing was unlabored and her lungs were clear to auscultation bilaterally except for crackles in the right upper lung field. The remainder of the exam was unremarkable.

Laboratory and Imaging

A chest radiograph was initially obtained and showed a right upper lobe consolidation consistent with community-acquired pneumonia (Figure 1).

Figure 1. Chest radiograph showing right upper lobe consolidation with possible volume loss.

One week later, a contrast-enhanced chest CT was performed and revealed a heterogeneously enhancing right upper lobe consolidation with cavitation and foci of air diagnostic of necrotizing pneumonia (Figure 2).

Figure 2. Contrast-enhanced chest CT showing right upper lobe pneumonic consolidation with peripheral enhancement, central necrosis, and small foci of air.

Laboratory studies revealed a markedly elevated C-reactive protein of 16.61 mg/dL and a white blood cell count of 18,000 cells/ μL. In addition, the red blood cell count, hemoglobin, and hematocrit were all reduced with values of 3,390,000 cells/ μL, 10.0 g/dL, and 31.0% respectively.

Hospital Course

A chest CT was ordered and the patient was diagnosed with necrotizing pneumonia. She was given IV vancomycin and piperacillin-tazobactam as empiric therapy. Tylenol was administered for fever management and steroids were deferred because her CURB-65 score for pneumonia severity was 0.

Attention was then given to identifying the infectious agent. Blood and respiratory cultures were obtained and a TB test was ordered. The cultures showed no growth and the TB test was negative. A bronchoalveolar lavage showed a highly neutrophilic cell count, however no pathogen was ever identified.

Given improvement with empiric therapy, during her hospital course she was discharged on oral amoxicillin and clavulanate until follow up with pulmonary in outpatient 6 weeks later. Imaging at that time showed post inflammatory changes and no evidence of infection.

Discussion

Necrotizing pneumonia is a rare complication of bacterial lung infections affecting 4% of all patients with community-acquired pneumonia (1). The infection can be patchy, segmental, or involve the entire lung. While the pathogenesis of necrotizing pneumonia is not clearly defined, most studies indicate that it is either an inflammatory response to toxins produced by the pathogen or it is the result of associated vasculitis and venous thrombosis. Patients typically present with common symptoms of pneumonia such as fever, cough, shortness of breath, and chest pain but can also rapidly develop hemoptysis, septic shock, and respiratory failure as the necrosis progresses (2). Because necrotizing pneumonia is associated with increased morbidity and mortality, it is important to distinguish it from non-necrotizing cases (3).

The diagnosis of necrotizing pneumonia may be difficult to make because of its similar presentation to non-necrotizing pneumonias and the limitations of standard chest radiographs. Chest radiographs may show an area of consolidation but are limited in identifying the extent of parenchymal disease (Figure 1) (2). Therefore, contrast-enhanced chest CT is an optimal exam for diagnosing necrotizing pneumonia. Disease may first appear as an in-homogeneously enhancing consolidation with focal areas of low attenuation (Figure 2).  Foci of air may subsequently develop in these areas of hypo-enhancing necrotic tissue indicating cavitation (4).

Laboratory studies may also be helpful in diagnosing necrotizing pneumonia. When compared to pneumonias without a necrotizing component, patients with necrotizing pneumonia show more elevated white blood cell counts and inflammatory markers (1). In one study, patients with necrotizing pneumonia had an average WBC count of 14,970/μL, an average ESR of 70 mm/h, and an average CRP of 18.8 mg/dL. Average values for patients with non-necrotizing pneumonia were significantly lower at 10,130/μL, 48 mm/h, and 11.4 mg/dL respectively (p<0.001) (3). These changes are also evident in the presented case with elevated WBC and CRP values of 18,000/μL and 16.61 mg/dL.

Necrotizing pneumonia is initially treated with intravenously administered broad-spectrum antibiotics that should target pathogens that commonly cause necrotizing changes. The most common microbes are Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae, however several other bacteria species may also cause necrosis (Table 1) (2).

Transition to oral antibiotics may be considered for patients that show improvement (1). A more focused treatment plan should be initiated once a specific pathogen is identified, however this is only accomplished in approximately 26% of cases (3).

Surgical resection may also be considered for patients who show no progress on antibiotic therapy and continue to decline. However the optimal timing and indications for surgery are not clearly defined. The extent of the resection should always be as conservative as possible and commonly involves debridement or segmentectomy of the damaged tissue. In cases where the parenchyma is extensively affected, lobectomy or pneumonectomy may be required (2).

References

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3. Seo H, Cha SI, Shin KM, et al. Clinical relevance of necrotizing change in patients with community-acquired pneumonia. Respirology. 2017;22(3):551-8. [CrossRef] [PubMed]
4. Walker CM, Abbott GF, Greene RE, Shepard JO, Vummidi D, Digumarthy SR. Imaging Pulmonary Infection: Classic Signs and Patterns. AJR Am J Roentgenol. 2014;202(3) 479-92. [CrossRef] [PubMed]

Cite as: Skidmore BD, Arteaga VA. Necrotizing pneumonia: diagnosis and treatment options. Southwest J Pulm Crit Care. 2017;15(6):274-7. doi: https://doi.org/10.13175/swjpcc137-17 PDF

December 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD¹

Michael B. Gotway, MD²

Departments of ¹Pulmonary Medicine and ²Radiology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 52-year-old woman from Iowa sought a second opinion for a left hilar mass. She travels to Phoenix regularly to visit family. She began feeling ill in late 2016 with cough and sputum production and was treated with multiple courses of antibiotics without improvement.

PMH, SH and FH

Past medical history is unremarkable. She is a nonsmoker. FH is noncontributory.

Physical Examination

Physical examination was normal.

Radiography

In March of this year she had chest radiograph in Phoenix which suggested left hilar adenopathy. A thoracic CT scan was performed (Figure 1).

Figure 1. Representative images from the thoracic CT scan in lung windows (A-E) and soft tissue windows (F).

Which of the following are diagnostic considerations? (Click on the correct answer to procced to the second of seven pages)

1. Lung cancer  
2. Lymphoma
3. Sarcoidosis
4. Tuberculosis
5. All of the above

Cite as: Wesselius LJ, Gotway MB. December 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(6):232-40. doi: https://doi.org/10.13175/swjpcc144-17 PDF

First Report of Splenic Abscesses Due to Coccidioidomycosis

Shabnam Assar, MD^I and Tim Kuberski, MD, FIDSA²

¹Department of Medicine, Virginia Tech Carilion, Roanoke, Virginia USA

²Department of Medicine, University of Arizona School of Medicine-Phoenix,

Phoenix, Arizona USA

Abstract

Involvement of the spleen by Coccidioides is uncommon. It is usually associated only with disseminated infection and manifests as microscopic granulomas in the spleen. We report an immunosuppressed dermatomyositis patient who presented with splenic abscesses demonstrated on a computed tomography (CT) scan which was presumed to be bacterial in origin. At splenectomy the spleen was found to be filled with aggregates of spherules due to Coccidioides. Finding large splenic abscesses on CT scan due to Coccidioides has not been previously described. We offer a hypothesis for why the abscesses occurred in this unique patient.

Introduction

Involvement of the spleen by coccidioidomycosis is usually associated with disseminated disease, however the development of splenic abscesses has not been reported. Splenic involvement by coccidioidomycosis is usually manifest as microscopic miliary splenic granulomas which have been demonstrated at autopsy in patients with disseminated infection (1,2). We report an immunocompromised dermatomyositis patient who was found to have splenic abscesses due to Coccidioides spherules which were diagnosed at splenectomy.

Case Presentation

A 33-year-old Hispanic man with dermatomyositis for five years and a history of disseminated coccidioidomycosis for two years, presented to the emergency room because of left upper quadrant abdominal pain, fever and chills. Treatment of his dermatomyositis was ongoing over the previous five years and included prednisone, azathioprine and courses of intravenous immunoglobulin (IVIG) at doses of 2 g/kg (3). Treatments of his coccidioidomycosis over the previous two years included intravenous liposomal amphotericin B followed by oral fluconazole. The patient would periodically be non-compliant about taking the fluconazole and then experience relapses of his coccidioidomycosis which required additional courses of intravenous liposomal amphotericin B.

Physical Examination and Course: Admission vital signs - temperature 38.4⁰ C; blood pressure 147/81 mmHg; heart rate 106 bpm; respiratory rate 18 breaths/minute and pulse oximetry 90% on room air. There was pigmentation of his face consistent with dermatomyositis, tenderness in the left upper quadrant and significant weakness of all extremities. He was bedridden and could barely move his arms and legs against gravity. His medications on admission were fluconazole and prednisone. An admission CT scan of the abdomen was performed because of the left upper quadrant tenderness and revealed multiple splenic abscesses (Figure 1).

Figure 1. CT scan of abdomen demonstrating splenic abscesses (arrow).

An admission urine culture grew >10⁵ colony forming Klebsiella pneumoniae which was noted on day two of hospitalization. Blood cultures were negative. It was initially believed that the splenic abscesses were due to a Klebsiella infection because of the admitting urine culture results. Prednisone was stopped on admission and the oral fluconazole continued. Piperacillin-tazobactam was started empirically on admission. In addition, IVIG was given for a presumed dermatomyositis exacerbation. On hospital day four his abdominal pain and fevers had not improved. To avoid a splenectomy, a splenic biopsy was performed to determine the cause of the splenic abnormalities. The biopsy was consistent with a Coccidioides infection. A laparoscopic splenectomy was then preformed on hospital day seven.

The pathology on the removed spleen showed multiple necrotizing granulomatous foci containing numerous aggregated Coccidioides spherules (Figure 2).

Figure 2. Pathology of splenic abscesses demonstrating aggregated Coccidioides spherules.

Post-operatively, fluconazole was empirically replaced by voriconazole (4) and the patient was restarted on prednisone for his dermatomyositis. The fever and chills eventually resolved and he was discharged. At four months follow-up he had returned to his usual state and was encouraged to not stop taking the voriconazole.

Discussion 

This patient illustrates an unusual complication of disseminated coccidioidomycosis. Prior to the advent of CT scans, splenic granulomas were described mainly at autopsy in patients with disseminated infection. Splenic involvement at autopsy was described as granulomas due to the invasion of the Coccidioides into the spleen from the blood stream. Usually there was granuloma formation described as microscopic military nodules. Reports of gross Coccidioides abscesses in the spleen have not been described.

We considered the potential reasons for the development of splenic abscesses in this unique patient. His dermatomyositis was present for about five years and the coccidioidomycosis, two years. He had received repeated doses of IVIG for flares of his dermatomyositis prior to, and after, his Coccidioides infection. Investigating his past medical history revealed that he would develop a febrile illness when off fluconazole - usually due to non-compliance. The clinical presentation was consistent with either a relapse of his Coccidioides infection, an exacerbation of his dermatomyositis, or both. The febrile episodes would cause him to be admitted to the hospital, often into the intensive care unit, and then he would receive more IVIG for his dermatomyositis, as well as antifungals. It is known that fungemia occurs in immunosuppressed patients who have significant coccidioidomycosis (5). The fact that he had a large Coccidioides burden in his spleen suggests he likely experienced episodes of fungemia, presumably associated with his poor antifungal compliance.

Our hypothesis for why the abscesses formed in the spleen of this patient is illustrated in Figure 3.

Figure 3. Hypothesis of Coccidioides abscess formation in the spleen.

We theorized that Coccidioides endospores in the blood stream became coated with the gamma globulins when he received the IVIG given for his dermatomyositis (6).  The opsonization of the organisms by the IVIG presumably facilitated the spleen to take up viable endospores into the spleen and reticuloendothelial system (Figure 3, part 3). This resulted in the localization of the organisms promoting the formation of an abscess within the spleen (Figure 3, part 4). We suggest that these unusual circumstances of fungemia and IVIG were responsible for facilitating the appearance of abscesses in this patient's spleen.

We believe true splenic abscesses are uncommon with disseminated coccidioidomycosis. The unusual circumstances of this patient's relapsing Coccidioides infection with fungemia (due to poor compliance with antifungals) and the repeated IVIG treatments for his dermatomyositis, combined to provide a reasonable explanation for why splenic abscesses occurred in this patient.

References

1. Forbus WD, Bestebreurtje AM. Coccidioidomycosis; a study of 95 cases of the disseminated type with special reference to the pathogenesis of the disease. Mil Surg. 1946 Nov;99(5):653-719. [PubMed]
2. Fiese MJ. Coccidioidomycosis: Springfield, IL: Charles C. Thomas 1958; p 111.
3. Wang DX, Shu XM, Tian XL, Chen F, Zu N, Ma L, Wang GC. Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol. 2012 May;31(5):801-6. [CrossRef] [PubMed]
4. Prabhu RM, Bonnell M, Currier BL, Orenstein R. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis. 2004 Oct 1;39(7):e74-7. [CrossRef] [PubMed]
5. Rempe S, Sachdev MS, Bhakta R, Pineda-Roman M, Vaz A, Carlson RW. Coccidioides immitis fungemia: clinical features and survival in 33 adult patients. Heart Lung. 2007 Jan-Feb;36(1):64-71. [CrossRef] [PubMed]
6. Adkinson NF, Yunginger JW, Busse WW, et al. Middleton's Allergy Principles & Practice (6th ed) Philadelphia, PA: Mosby, 203; 72-73.

Cite as: Assar S, Kuberski T. First report of splenic abscesses due to coccidioidomycosis. Southwest J Pulm Crit Care. 2017;15(5):214-8. doi: https://doi.org/10.13175/swjpcc125-17 PDF 

November 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 67-year-old man developed a right neck mass and underwent a right radical neck dissection. It was initially thought to be a high-grade sarcomatoid cancer, but after review was determined to be metastatic melanoma.

Past Medical History, Social History and Family History

He had no significant past medical or family history. He was a nonsmoker.

Physical Examination

His initial physical examination showed a right neck mass but was otherwise unremarkable. No abnormal skin lesions were identified.

PET/CT Scan

A positron emission tomography/computed tomography (PET/CT) scan showed increase uptake in the neck (Figure 1A) but his chest showed no increased uptake (Figure 1B).

Figure 1. Panel A: PET/CT scan showing increased tracer uptake in the right neck (arrow). Panel B: No abnormal tracer uptake is seen within the chest.

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

1. Bronchoscopy should be performed to search for bronchial melanoma
2. Radiation and oncology consultation should be obtained
3. The pathologic diagnosis is likely wrong since no primary melanoma can be identified
4. 1 and 3
5. All of the above

 Cite as: Wesselius LJ. November 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(5):181-7. doi: https://doi.org/10.13175/swjpcc117-17 PDF 

Treatment of Lymphoma and Cardiac Monitoring during Pregnancy

Stella Pak, MD

Yan Yatsynovich, MD 

Damian Valencia, MD

Calvert Busch, MD

Emily Vannorsdall, MD

Department of Medicine

Kettering Medical Center

Kettering, OH USA

Abstract

Limited data is available regarding fetal-maternal outcomes with chemotherapy during pregnancy, including cardiovascular toxicity and evaluation thereof. Early cardiovascular evaluation and initiation of cardioprotective therapies should be considered. Herein, we report a case of a 33-year-old woman treated with R-CHOP chemotherapy for large B-cell lymphoma found to have some degree of reversible cardiac strain.

Introduction

There are no guidelines specific for cardiotoxicity monitoring in pregnant patients undergoing chemotherapy. Pregnant patients are more vulnerable to cardiovascular complications, such as congestive heart failure, from chemotherapy as their cardiovascular system is under considerable stress from increasing physiological demands in pregnancy. With elevated cardiac output and circulatory volume from baseline, these patients do not have much cardiopulmonary reserve to compensate for cardiac strains from chemotherapy side effects (1). Therefore, it would be critical for clinicians to be aware of increased risk of cardiovascular adverse effect from chemotherapeutic agents in pregnant patients. Herein, we report a case of a 33-year-old woman treated with R-CHOP chemotherapy for large B-cell lymphoma found to have some degree of reversible cardiac strain.

Case Presentation

An otherwise healthy 33-year-old Caucasian female, G2P1 at 24 weeks gestation presented with a chief complaint of cough, chest pressure, and swelling in the neck and face. Physical exam was notable for a negative Pemberton’s sign, two lymph nodes in the right supraclavicular region measuring approximately 2 cm without axillary or groin lymphadenopathy. Cardiac exam demonstrated distant heart sounds with a faint I-II/VI systolic murmur in the left second intercostal space, without presence of bruits or lower extremity edema. Lung exam was positive for occasional wheezing in the left lower lobe. Breast exam was normal. Initial chest x-ray (Figure 1) and computed tomography (CT) scan (Figure 2) of the chest revealed a mediastinal mass (11 x 9.2 x 8.7 cm) and a moderate sized pericardial effusion.

Figure 1. Roentgenogram of chest demonstrating a large mass on left lower lobe and pericardial effusion.

Figure 2. Computerized tomography of chest revealing a large homogeneous left mediastinal mass (92.1 mm X 87.1 mm).

Follow up CT-guided biopsy yielded a diagnosis of large B-cell lymphoma. Bronchoscopy done at that time demonstrated diffuse tracheal and bronchial involvement, likely pointing to primary mediastinal derivation of the tumor. Interestingly, the patient had a history of lymph node biopsy of two areas on her right lateral neck and right medial supraclavicular node; pathology reports were consistent with granulomatous disease at that time. Due to pregnancy, baseline positron emission tomography (PET)/CT was not performed, however, the patient did undergo staging with a CT scan of the chest and abdominal/pelvic and magnetic resonance imaging (MRI), both of which were negative for metastatic disease. Bone marrow biopsy obtained was negative for malignancy as well. Dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, oncovin, cyclophosphamide, hydroxydaunorubicin) was replaced with R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, prednisolone) due to the teratogenic effects of etoposide. Embryologic toxicity has previously been observed with etoposide including skeletal abnormalities, exencephaly, encephalocele and anophthalmia. Monitoring of cardiac function was performed before, during and after treatment. Initial echocardiogram demonstrated preserved ejection fraction (EF) of 60% with a large pericardial effusion and early signs of tamponade. No strain studies were done prior to initiation of chemotherapy. The patient had undergone a total of six cycles with a good response. Upon treatment completion fluoro-D-glucose (FDG)-PET/CT did show persistent uptake mostly in the manubrium as well as a persistent mediastinal mass with a low standardized uptake values (SUV).

The patient had initially considered radiotherapy in her post-delivery course, but given her most recent PET scan with a Deauville score of less than 4, the patient decided to avoid radiation and opted for close follow-up with repeat imaging. The Deauville 5-point scoring system is an internationally accepted point based scale used to characterize fluorodeoxyglucose (FDG) avidity of malignant tumor mass as seen on FDG positron emission tomography (PET) scan. Scores between 1 and 2 are considered negative, a score of 3 is typically paired with other studies and clinical signs to determine progression of disease, a score of 4 and 5 are considered positive for malignancy progression. Her pericardial effusion had resolved with chemotherapy.

Echocardiographic cardiac strain evaluation performed during follow-up evidenced a drop in her longitudinal strains from 22.8 to -15% just prior to delivery. Ejection fraction remained preserved at >60%. Low-dose carvedilol was considered during treatment however patient was not agreeable. The patient had an uneventful delivery and strain studies post-delivery showed a stable -15% strain. Echocardiogram performed 6 months post-chemotherapy demonstrated an ejection fraction of 72% and normalization of longitudinal strain. In the light of chemotherapy with known cardiotoxic adverse effects, as well as pregnancy strain on cardiac function, the patient did well and underwent an uneventful course.

Discussion 

The majority of data on maternal and fetal cardiotoxic effects of chemotherapy during pregnancy is based on case reports and retrospective data collection (2).

Registry data seems to suggest that the incidence of toxic side effects is not significantly increased during pregnancy and in the current literature there is no mention of an increased frequency of heart failure or left ventricular dysfunction during pregnancy (3-5). A study by Van Calsteren et al. (6), suggested that serum levels of chemotherapy, including anthracyclines, measured in pregnant women, were lower compared with those in nonpregnant women although the differences were not statistically significant. Despite the lower serum levels, cardiotoxicity might have a more significant impact on the maternal cardiovascular system in a context of increased hemodynamic loading. The use of cardiotoxic medications during pregnancy requires further attention, however no standard cardiac follow-up protocols are currently in place (7).

There may be a need for clinical cardiac assessments and an echocardiographic functional evaluation, including cardiac strain monitoring, prior to starting chemotherapy and repeat echocardiographic evaluation prior to every dose. If changes in cardiac function are observed, less cardiotoxic treatments might be considered or cardioprotective agents could be used. In this particular patient population, baseline echocardiography with strain study is crucial. Evidence of abnormal strain study during any part of the treatment should prompt initiation of cardioprotective therapy as per standards of the current heart failure guidelines. In addition, we suggest consideration for close cardiac follow-up monitoring, including a repeat echocardiogram study at 12 months post completion of chemotherapy/radiotherapy treatment. It is still unclear whether prophylactic therapy with cardioprotective agents would be safe and beneficial in these patients. Though we may be able to extrapolate data from trials performed on non-pregnant patients undergoing therapy and apply it to this particular niche of patients. The 2013 ACC/AHA heart failure guidelines state that it may be reasonable to evaluate those who are receiving (or who have received) cardiotoxic chemotherapy agents for left ventricular dysfunction as well as use echocardiographic techniques or biomarkers to identify increased heart failure risk in those receiving chemotherapy (8). In addition, the 2012 European Society of Medical Oncology (ESMO) guidelines stress on importance of serials cardiac function monitoring at baseline, 3, 6 and 9 months during treatment and then at 12 and 18 months after initiation of treatment (9).

Today, there is still no clear consensus with regards to cardioprotective therapy in patients exposed to cardiotoxic agents. As of 2016, the ACC/AHA guidelines did not reflect any change in recommendations in this particular field. Risk-stratification and prophylactic cardioprotective therapy remain an ultimate goal in pregnant patients undergoing chemotherapy, but how that should be done is still being studied. Early cardiology involvement and possible early initiation of prophylactic heart failure therapy should be considered.

References

1. Fadol AP, Lech T, Bickford C, Yusuf SW. Pregnancy in a patient with cancer and heart failure: challenges and complexities. J Adv Pract Oncol. 2012 Mar;3(2):85-93. [PubMed]
2. Gziri MM, Amant F, Debiève F, Van Calsteren K, De Catte L, Mertens L. Effects of chemotherapy during pregnancy on the maternal and fetal heart. Prenat Diagn. 2012 Jul;32(7):614-9. [CrossRef] [PubMed]
3. Cardonick E, Dougherty R, Grana G, Gilmandyar D, Ghaffar S, Usmani A. Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J. 2010;16(1):76-82. [CrossRef] [PubMed]
4. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010 Feb 1;28(4):683-9. [CrossRef] [PubMed]
5. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004 May;5(5):283-91. [CrossRef] [PubMed]
6. Van Calsteren K, Verbesselt R, Ottevanger N, et al. Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. Acta Obstet Gynecol Scand. 2010 Oct;89(10):1338-45. [CrossRef] [PubMed]
7. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010 Oct;7(10):564-75. [CrossRef] [PubMed]
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):1810-52. [CrossRef] [PubMed]
9. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012 Oct;23 Suppl 7:vii155-66. [CrossRef] [PubMed]

Cite as: Pak S, Yatsynovich Y, Valencia D, Bushch C, Vannorsdall E. Treatment of lymphoma and cardiac monitoring during pregnancy. Southwest J Pulm Crit Care. 2017;15(4):154-8. doi: https://doi.org/10.13175/swjpcc106-17 PDF 

October 2017 Pulmonary Case of the Month

Eric A. Jensen, MD

Department of Radiology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 56-year-old woman presented with 3 days of non-productive cough, low-grade fever and severe right-sided pleuritic chest pain.

Past Medical History, Social History and Family History

She was diagnosed with coccidioidomycosis 5 years previously. She reports that she has had pneumonia every 6 to 12 months since her diagnosis with valley fever. She does not smoke. Family history is noncontributory.

Physical Examination

Her vital signs were unremarkable and she was afebrile but did cough frequently during the examination. Her lungs were clear and the rest of the physical examination was unremarkable.

Chest Radiography

She brings in two prior chest x-rays, one from 2011 (Figure 1, Panels A & B) and another from 2012 (Figure 1, Panel C).

Figure 1. Chest radiograph from 2011 (A & B) and from 2012 (C).

Which of the following best describes the chest x-rays? (Click on the correct answer to proceed to the second of five pages)

1. A repeat chest x-ray should be performed
2. A right lower lobe mass is present which appears to have enlarged from 2011 to 2012
3. There is a right lower posterior lung density
4. 1 and 3
5. All of the above

Cite as: Jensen EA. October 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(4):125-30. doi: https://doi.org/10.13175/swjpcc115-17 PDF

September 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 67-year-old woman with history of chronic lymphocytic leukemia (CLL) was referred due to a 6-week history severe cough. Her CLL had recently relapsed and she was begun on ibrutinib (a small molecule drug that binds permanently to Bruton's tyrosine kinase) in addition to acyclovir, sulfamethoxazole/trimethoprim and allopurinol.

Past Medical History, Social History and Family History

Her CLL was initially diagnosed in 2009 and had responded to fludarabine, cyclophosphamide, and rituximab. She had no other chronic medical diseases. She smoked ½ pack per day but quit with the development of her cough. Family history was noncontributory.

Physical Examination

Her vital signs were unremarkable and she was afebrile but did cough frequently during the examination. There were shoddy small lymph nodes noted in both supraclavicular and axillary areas. Lungs were clear and the rest of the physical examination was unremarkable.

Laboratory Evaluation

Her complete blood count revealed her to be mildly anemic with a hemoglobin of 9.0 g/dL, an elevated white count of 33,700 cells/mcL with 88% lymphocytes, and a low platelet count of 60,000 cells/mcL. Her electrolytes were within normal limits and her blood urea nitrogen was 20 mg/dL, creatinine 1.1 mg/dL and uric acid 7.1 mg/dL.

Chest Radiography

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

Figure 1. Initial chest x-ray.

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

1. A pulmonary nodule is present in the left upper lobe (LUL)
2. Ibrutinib is well known to cause a chronic cough
3. Pneumonia is unlikely since she is afebrile
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. September 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(3):94-9. doi: https://doi.org/10.13175/swjpcc108-17 PDF

August 2017 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is a 60-year-old woman with dyspnea on exertion when she had a pulmonary embolism following knee surgery 3 years earlier. She smoked 1 pack per day for the past 40 years. She was seen at another hospital and had pulmonary function testing which showed only a DLco which was 66% of predicted. Serologic studies were negative for a rheumatologic disorder. A CT scan was also performed (Figure 1).

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

The CT scan was interpreted as showing a few small nodules and possible very early interstitial lung disease.

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

1. A pulmonary embolism can reduce the DLco
2. Her CT scan is characteristic of Langerhans cell histiocytosis
3. Smoking can reduce the DLco
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. August 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(2):54-60. doi: https://doi.org/10.13175/swjpcc096-17 PDF 

Tip of the Iceberg: 18F-FDG PET/CT Diagnoses Extensively Disseminated Coccidioidomycosis with Cutaneous Lesions

Benjamin B. Nia¹

Emily S. Nia²

Ngozi Osondu³

John N. Galgiani^3,4

Phillip H. Kuo^2,5

¹College of Medicine, University of Texas Medical Branch, Galveston, TX, USA.

²Department of Medical Imaging

³Department of Medicine, Section of Infectious Disease

⁴Valley Fever Center for Excellence

⁵Departments of Medicine and Biomedical Engineering

University of Arizona

Tucson, AZ, USA.

Abstract

We present a case of an immunocompetent 27-year-old African American man who was initially diagnosed with diffuse pulmonary coccidioidomycosis and started on oral fluconazole. While his symptoms improved, he began to develop tender cutaneous lesions. Biopsies of the cutaneous lesions grew Coccidioides immitis. Subsequent ¹⁸F-FDG PET/CT revealed extensive multisystem involvement including the skin/subcutaneous fat, lungs, spleen, lymph nodes, and skeleton. This case demonstrates the utility of obtaining an ¹⁸F-FDG PET/CT to assess the disease extent and activity in patients with disseminated coccidioidomycosis who initially present with symptoms involving only the lungs.

Report of Case

A 27-year-old African American man, who lived in the desert southwest of the United States for several years, with no significant past medical history presented with chest pain, weight loss, and shortness of breath. After two urgent care visits, he was admitted to the hospital with a chest radiograph showing bilateral pulmonary infiltrates (Figure 1).

Figure 1. Frontal (A) and lateral (B) chest radiography at hospital admission shows extensive reticulonodular opacities suspicious for atypical infection.

Bronchoscopy yielded Coccidioides spp., and immunodiffusion complement fixation (IDCF) was further confirmatory. Laboratory values showed elevated erythrocyte sedimentation rate (ESR) and mildly abnormal liver function tests. He was diagnosed with diffuse pulmonary coccidioidomycosis and discharged home on 400 mg of oral fluconazole per day. At initial follow-up appointment, he reported feeling significantly better with resolution of his chest pain. He was gaining weight and had increased physical activities. At three-month follow-up, he reported continued improvement but complained of three new “spots” on the skin of his lower abdomen (Figure 2).

Figure 2. Photograph of the cutaneous lesions at nine months (red arrows) that were also present at 3- and 6-month follow-up appointments.

On physical exam, the cutaneous lesions were not suspicious for disseminated infection so treatment was continued unchanged. At six-month follow-up, he displayed numerous cutaneous lesions that were now tender. A biopsy of a cutaneous lesion demonstrated Coccidioides spherules on microscopy. An ¹⁸F-FDG PET/CT scan was performed to assess the extent of disease and demonstrated FDG-avid disease involving the skin/subcutaneous tissue, lungs, spleen, multi-station lymph nodes, and the skeleton (Figure 3).

Figure 3. Coronal maximum-intensity projection (A) and axial fused (B) 18F-FDG PET/CT scan shows FDG-avid disease involving the spleen (blue arrow), osseous structures (green arrows), multiple lymph nodes stations (yellow arrows), and soft tissues, including the skin and subcutaneous tissues (red arrows).

After another month, the skin lesions improved and, on further questioning, the patient revealed that he had previously not been taking his fluconazole as prescribed. Because of the skeletal involvement uncovered by the PET/CT scan, the patient’s oral fluconazole dose was increased to 800 mg per day. At nine-month follow-up, patient reported continued improvement and resolution of majority of skin lesions, albeit with residual hyperpigmentation.  

Discussion

Coccidioidomycosis, or “Valley fever” is a fungal infection caused by inhalation of Coccidioides immitis or Coccidioides posadasii spores. Most infections cause little clinically apparent illness and result in lifelong immunity. Approximately one-third of infections produce pulmonary syndromes compatible with a community-acquired pneumonia, whereas <1% are complicated by potentially fatal blood-stream dissemination. Skin involvement is one of the most common manifestations of disseminated coccidioidomycosis. Other common sites of involvement include the bones, joints, and meninges. Unfortunately, nonspecific symptoms, the subacute nature of this disease, and lack of familiarity with this infection result in delayed diagnosis, increasing the risk of dissemination. Risk factors for disseminated coccidioidomycosis include African-American or Filipino ancestry, immunocompromised state, pregnancy, and discrete genetic defects. Coccidioides-endemic areas include parts of the southwestern United States, Central and South America (1,2).

¹⁸F-FDG PET/CT is an imaging modality most commonly utilized to stage malignancies and monitor response to therapy. ¹⁸F-FDG is a radioactive analog of glucose and is taken up by inflammatory cells. Detecting and monitoring infectious and inflammatory processes can be achieved with various imaging techniques, including computed tomography, magnetic resonance imaging, and ultrasonography. However, these techniques rely primarily on structural changes, and differentiation between active and indolent infections can be difficult. PET/CT’s whole-body coverage and high sensitivity can localize all sites of disease and assess level of disease activity (3,4).

This case demonstrates the utilization of ¹⁸F-FDG PET/CT to provide a comprehensive assessment of disease extent and activity in a patient with disseminated coccidioidomycosis. Diagnosing extent of disease is particularly important in this circumstance as osseous coccidioidomycosis predominantly results in osteolytic lesions that increase risk for fractures. Additionally, soft tissue assessment may reveal clinically occult soft tissue abscesses that may require surgical debridement (5). For this patient, the PET/CT scan results provided information that prompted medication dose escalation and emphasized the need for medication compliance. If disseminated coccidioidomycosis is suspected, PET/CT may provide value for the diagnostic evaluation in selected patients.

References

1. Odio CD, Marciano BE, Galgiani JN, Holland SM.Risk factors for disseminated coccidioidomycosis, United States. Emerg Infect Dis. 2017 Feb;23(2). [CrossRef] [PubMed]
2. Nguyen C, Barker BM, Hoover S, Nix DE, Ampel NM, Frelinger JA, Orbach MJ, Galgiani JN. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505-25. [CrossRef] [PubMed]
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5. Gupta NA, Iv M, Pandit RP, Patel MR. Imaging manifestations of primary and disseminated coccidioidomycosis. App Radiol. 2015;44(2):9-21. Available at: http://appliedradiology.com/articles/imaging-manifestations-of-primary-and-disseminated-coccidioidomycosis (accessed 7/10/17).

Cite as: Nia BB, Nia ES, Osondu N, Galgiani JN, Kuo PH. Tip of the iceberg: ¹⁸F-FDG PET/CT diagnoses extensively disseminated coccidioidomycosis with cutaneous lesions. Southwest J Pulm Crit Care. 2017;15(1):28-31. doi: https://doi.org/10.13175/swjpcc069-17 PDF 

July 2017 Pulmonary Case of the Month

Robert W. Viggiano, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is a 19-year-old woman who went to a local Emergency Room 12/23/15 for chest pain she described as pleurisy. She was told she had pneumonia and a chest x-ray was reported to show a lingular infiltrate (Figure 1).

Figure 1. PA (A) and lateral (B) chest radiograph taken 12/23/15.

She was treated with antibiotics and improved. She was well until 9/2/16 when she again returned to the emergency room complaining of hemoptysis. A chest x-ray was reported as showing a lingular infiltrate (Figure 2). 

Figure 2. PA (A) and lateral (B) chest radiograph taken 9/2/16.

She was treated with azithromycin but her cough persisted sometimes with a small amount of blood in her sputum. She was referred because of her persistent symptoms and her abnormal chest x-ray.

Past Medical History, Social History and Family History

• She is now taking fluoxetine daily.
• She has a history of pediatric autoimmune neuropsychiatric disorder associated with Group A Streptococcus and was treated with antibiotics for 4-5 years.
• Nonsmoker.

Physical Examination

Her physical examination was unremarkable.

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

1. Her chest radiographs are consistent with pneumonia
2. Lung cancer is an unlikely consideration in a 19-year-old
3. The chest x-ray findings represent a well-known complication of pediatric autoimmune neuropsychiatric disorder
4. 1 and 3
5. All of the above

Cite as: Viggiano RW. July 2017 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;15(1):1-6. doi: https://doi.org/10.13175/swjpcc082-17 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.

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