Update and Arizona Thoracic Society Position Statement on Stem Cell Therapy for Lung Disease

Summary

Infusions of stem cells are increasingly being offered for a variety of diseases, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. However, the potential for harm, the lack of any proven benefit, and the high fees that many of these programs charge make recommending stem cell therapy untenable. At the time of this writing (April 2019) it appears that stem cell therapy can be safely performed, although the long-term side effects remain unknown. However, the little data available show no benefit in meaningful outcomes, such as mortality, morbidity or patient well-being, for stem cell treatment of chronic lung disorders. Patients with severe, incurable diseases may be motivated to seek innovative therapies. We encourage such patients to contact their primary care physician or pulmonologist. Clinical trials in the United States and Canada investigating stem cell therapy for lung diseases can be found on the website of the National Institutes of Health at Clinicaltrials.gov. The Arizona Thoracic Society encourages regulatory agencies to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

Introduction

A central component of the mission of medical societies is to translate new scientific information into patient education. There appears to be increasing direct-to-consumer advertising of untested, unapproved, and potentially ineffective “stem-cell” treatments for a variety of diseases, including lung disorders (1). One may come across information regarding stem cell therapy for chronic obstructive pulmonary disorders and fibrotic lung disease, in the United States and worldwide, on the internet, patient support groups, or other sources. Recently, a direct mailing to the home of one of the members of the Arizona Thoracic Society was received (Figure 1).

Figure 1. Direct mailing for stem cell therapy for several diseases including COPD received by one of the members of the Arizona Thoracic Society.

These programs are often characterized by:

• Exorbitant fees
• Misrepresentation of risks and benefits
• Overreliance on, and advertisement of, patient testimony
• Poor patient follow-up
• Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies.

Chronic Obstructive Pulmonary Disease (COPD)

Stem cells can differentiate into several different lung cell types, including the alveolar epithelial cells. Since COPD is a disease associated with destruction of alveoli induced by cigarette smoke, the concept of rebuilding the alveoli through stem cell therapy is attractive. Pre-clinical trials in animal models have suggested regeneration of alveolar-like structures, repair of emphysematous lungs, and reduction of inflammatory responses, with the greatest success being in acute lung injury models.

Currently, regenerative therapies are divided into extrinsic therapeutic strategies and intrinsic cell therapy methods. Extrinsic cell therapy refers to the vascular infusion of (or endotracheal installation) of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), mesenchymal stem cells (MSCs), and human lung stem cells (hLSCs). Intrinsic therapy refers to the delivery of small molecules (retinoid compounds have been the most studied) that can stimulate the endogenous lung stem/progenitor cells to regenerate and replace damaged structures.

A number of recent review articles have summarized the current state of research in the use of stem cells in COPD (2-4). These review articles all contain summaries of trials conducted to date using both extrinsic and intrinsic therapies. There have been several phase I clinical trials, primarily assessing safety, and a handful of small phase II clinical trials that have been negative for meaningful clinical outcomes. Sun et al. (3) point out that the available trials have all been conducted on patients with advanced COPD. The authors suggest that further research is required on how to enhance the engraftment of exogenous mesenchymal stem cells in damaged lungs. Further, considering the anti-inflammatory and immunomodulatory effects of exogenous mesenchymal stem cells, they may be most effective potentially in treating acute lung disease, as opposed to chronic progressive disease with severe structural damage.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease of unknown etiology characterized by a combination of histological changes, including extracellular matrix (ECM) deposition, phenotypic changes of fibroblasts, and alveolar epithelial cells, the formation of fibroblastic foci, and scattered areas of aberrant wound healing interspersed with normal lung parenchyma (5).

There are two approved compounds for the treatment of IPF: pirfenidone and nintedanib. Pirfenidone is an antifibrotic compound with an unclear mechanism of action, targeting several molecules, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin 6 (6). Nintedanib is a tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) (7). While the use of pirfenidone and nintedanib has been shown to slow the progression of IPF, neither is curative and morbidity and mortality from IPF remains high (8,9).

Because of the inadequacy of therapy in IPF, the use of mesenchymal stem cells (MSCs) has attracted interest as a potential option. Early clinical studies have shown that the MSCs can be safely administered (5,10-12). A phase Ib study of endobronchially administered autologous adipose-derived MSCs showed not only acceptable safety outcomes, but also improvements in quality of life parameters (12). However, there were no significant differences in any of the studied functional parameters (FVC, FVC%pred. and DLCO% pred.) at baseline and 6 and 12 months following 3 endobronchial infusions of MSCs.

Cystic Fibrosis

Cystic fibrosis (CF) is a genetic syndrome usually resulting in a high mortality rate due to progressive lung disease. Several drugs targeting specific mutated cystic fibrosis transmembrane regulator (CFTR) proteins are already in clinical trials. However, new therapies, based on stem cells, are also emerging. Interest has focused on induced pluripotent stem (iPS) cells. It is possible to make iPS cells using cells from people with CF, and then use gene editing to correct CFTR mutations in those cells (13). This suggests the possibility of re-implanting the corrected iPS cells into the lungs of people with CF to generate healthy lung cells. Currently, three trials examining the safety of stem cells in cystic fibrosis are ongoing according to Clinicaltrials.gov. 

Adult Respiratory Distress Syndrome (ARDS)

Four clinical trials are listed on Clinicaltrials.gov for ARDS and stem cells; one, which involved 3 patients, has been completed (14). No outcome information is available.

Other Lung Diseases

We are unaware of any human trials at this time with outcomes in other lung diseases.

Regulatory and Legal Actions

The Food and Drug Administration (FDA) and the Attorney General of New York have both expressed concern over stem cell therapy. The concerns follow reports of three patients becoming blind after receiving injections of stem cells into the eye and twelve patients who became seriously ill after receiving injections that purportedly contained stem cells from umbilical cord blood (15,16). The FDA has issued warning letters to stem cell clinics, including one letter claiming violation of Federal law, and another 20 warnings to clinics of that their claims and actions were subject to FDA approval. The NY Attorney has filed a lawsuit against a for-profit stem cell clinic, Park Avenue Stem Cell, claiming it performed unproven procedures on patients with a wide range of medical conditions, from erectile dysfunction to heart disease (17).

The Arizona Thoracic Society encourages further investigation into stem cell transplantation in lung disease. However, we do not at this time encourage non-investigational use of stem cells since the therapy has not been shown to have meaningful patient benefits. We also encourage state and local regulatory agencies in the Southwest to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

References

1. American Lung Association. Statement on Unproven Stem Cell Interventions for Lung Diseases (July 2016). Available at: https://www.thoracic.org/members/assemblies/assemblies/rcmb/working-groups/stem-cell/resources/statement-on-unproven-stem-cell-interventions-for-lung-diseases.pdf (accessed 4/5/19).
2. Balkissoon R. Stem Cell Therapy for COPD: Where are we? Chronic Obstr Pulm Dis. 2018;5(2):148-53. [CrossRef] [PubMed]
3. Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018 Feb;10(2):1084-98. [CrossRef] [PubMed]
4. Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int. 2017;2017:8916570. [CrossRef] [PubMed]
5. Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal stem cells for the treatment of idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018 May 15;5:142. [CrossRef] [PubMed]
6. Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57. [CrossRef] [PubMed]
7. Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15:1483–9. [CrossRef] [PubMed]
8. King TE, Bradford WZ, Castro-Bernardini S, et al. Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. [CrossRef] [PubMed]
9. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. [CrossRef] [PubMed]
10. Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: a real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53. [CrossRef] [PubMed]
11. Tzouvelekis A, Koliakos G, Ntolios P, et al. Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011;9:182. [CrossRef] [PubMed]
12. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171. [CrossRef] [PubMed]
13. The Cystic Fibrosis Foundation. Stem cells for cystic fibrosis therapy. Available at: https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Stem-Cells-for-Cystic-Fibrosis-Therapy/ (accessed 4/5/19).
14. Clinicaltrials.gov. Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START). Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT01775774?term=Stem+cells&cond=ARDS&rank=4 (accessed 4/5/19).
15. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-53. [CrossRef] [PubMed]
16. Grady D. 12 People hospitalized with infections from stem cell shots. NY Times. Dec. 20, 2018. Available at: https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html?action=click&module=RelatedCoverage&pgtype=Article&region=Footer (accessed 4/9/19).
17. Abelson R. N.Y. attorney general sues Manhattan stem cell clinic, citing rogue therapies. NY Times. April 4, 2019. Available at: https://www.nytimes.com/2019/04/04/health/stem-cells-lawsuit-new-york.html (accessed 4/9/19).

Cite as: Arizona Thoracic Society*. Update and Arizona Thoracic Society position statement on stem cell therapy for lung disease. Southwest J Pulm Crit Care. 2019;18(4):82-6. doi: https://doi.org/10.13175/swjpcc020-19 PDF

*The below contributed to the update and position statement on stem cell therapy

• Bhargavi Gali, MD
• Michael B. Gotway, MD
• Kenneth S. Knox, MD
• Timothy T. Kuberski, MD
• Stuart F. Quan, MD
• George Parides, DO
• Richard A. Robbins, MD
• Gerald F. Schwartzberg, MD
• Allen R. Thomas, MD
• Lewis J. Wesselius, MD

September 2018 Pulmonary Case of the Month: Lung Cysts

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

Pulmonary Case of the Month CME Information

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

0.50 AMA PRA Category 1 Credit(s)™

Estimated time to complete this activity: 0.50 hours

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

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

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

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

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

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

Financial Support Received: None

History of Present Illness

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

Past Medical History, Social History, Family History

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

Physical Examination

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

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

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

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

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.

References

1. Aguayo SM, Miller YE, Waldron JA, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327:1285-8. [CrossRef] [PubMed]
2. Miller RR, Müller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol. 1995 Jun;19(6):653-8. [CrossRef] [PubMed]
3. Armas OA, White DA, Erlandson RA, et al. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol. 1995;19(8):963-70. [CrossRef] [PubMed]
4. Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT–pathologic correlation. AJR Am J Roentgenol. 1997;168:1561-2. [CrossRef] [PubMed]
5. Alshehri M, Cutz E, Banzhoff A, et al. Hyperplasia of pulmonary neuroendocrine cells in a case of childhood pulmonary emphysema. Chest. 1997 Aug;112(2):553-6. [CrossRef] [PubMed]
6. Lee JS, Brown KK, Cool C, et al. Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr. 2002;26:180-4. [CrossRef] [PubMed]
7. Ruffini E, Bongiovanni M, Cavallo A, et al. The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms. Eur J Cardiothorac Surg. 2004;26(1):165-72. [CrossRef] [PubMed]
8. Fessler MB, Cool CD, Miller YE, et al. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly. Respirology. 2004;9(2):274-7. [CrossRef] [PubMed]
9. Carmichael MG, Zacher LL. The demonstration of pulmonary neuroendocrine cell hyperplasia with tumorlets in a patient with chronic cough and a history of multiple medical problems. Mil Med. 2005;170:439-441. [CrossRef] [PubMed]
10. Swigris J, Ghamande S, Rice TW, et al. Diffuse idiopathic neuropathic cell hyperplasia an interstitial lung disease with airway obstruction. J Bronchol. 2005;12:62-65. [CrossRef]
11. Terminella L, Duarte A. Obliterative bronchiolitis due to diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest 2005; 128:467S–468S. [CrossRef]
12. Adams H, Brack T, Kestenholz P, et al. Diffuse idiopathic neuroendocrine cell hyperplasia causing severe airway obstruction in a patient with a carcinoid tumor. Respiration. 2006;73(5):690-3. [CrossRef] [PubMed]
13. Johney EC, Pfannschmidt J, Rieker RJ, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and a typical carcinoid tumor. J Thorac Cardiovasc Surg. 2006;131:1207-8. [CrossRef] [PubMed]
14. Reyes LJ, Majó J, Perich D, et al. Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease. Respir Med. 2007 Aug;101(8):1840-3. [CrossRef] [PubMed]
15. Singhania N, Liang Q, Cool C, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in a patient with cough and dyspnea resistant to standard therapy. J Allergy Clin Immunol. 2007;119:S173. [CrossRef]
16. Ge Y, Eltorky MA, Ernst RD, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Ann Diagn Pathol. 2007 Apr;11(2):122-6. [CrossRef] [PubMed]
17. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007 Mar;62(3):248-52. [CrossRef] [PubMed]
18. Alqdah M, Jokhio S, El-zammar O. Diffuse idiopathic pulmonary neuroendocrine hyperplasia (DIPNECH). Chest 2007; 132:711S. [CrossRef]
19. Warth A, Herpel E, Schmahl A, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in association with an adenocarcinoma: a case report. J Med Case Reports. 2008;2:21. [CrossRef] [PubMed]
20. Coletta EN, Voss LR, Lima MS, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia accompanied by airflow obstruction. J Bras Pneumol. 2009; 35:489-94. [CrossRef] [PubMed]
21. Sanaee MS, O'Byrne PM, Nair P. Diffuse idiopathic pulmonary neuroendocrine hyperplasia, chronic eosinophilic pneumonia, and asthma. Eur Respir J. 2009; 34:1489-92. [CrossRef] [PubMed]
22. Lim C, Stanford D, Young I, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a report of two cases. Pathol Int. 2010; 60:538-41. [CrossRef] [PubMed]
23. Irshad S, McLean E, Rankin S, et al. Unilateral diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and multiple carcinoids treated with surgical resection. J Thorac Oncol. 2010; 5:921-3. [CrossRef] [PubMed]
24. Stenzinger A, Weichert W, Hensel M, et al. Incidental postmortem diagnosis of DIPNECH in a patient with previously unexplained 'asthma bronchiale'. Pathol Res Pract. 2010 Nov 15;206(11):785-7. [CrossRef] [PubMed]
25. Tippett V M, C G Wathen. Diffuse idiopathic neuroendocrine cell hyperplasia: an unusual cause of breathlessness and pulmonary nodules. BMJ Case Rep. 2010 Dec 1;2010. pii: bcr0520103006. [CrossRef] [PubMed]
26. Cameron C M, Roberts F, Connell J, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an unusual cause of cyclical ectopic adrenocorticotrophic syndrome. Br J Radiol. 2011 Jan;84(997):e14-7. [CrossRef] [PubMed]
27. Nassar AA, Jaroszewski DE, Helmers RA, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184:8-16. [CrossRef] [PubMed]
28. Falkenstern-Ge RF, Kimmich M, Friedel G, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome. J Cancer Res Clin Oncol. 2011 Oct; 137(10):1495-8. [CrossRef] [PubMed]
29. Gorshtein A, Gross DJ, Barak D, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer. 2012 Feb 1;118(3):612-9. [CrossRef] [PubMed]
30. Patel C, Tirukonda P, Bishop R, Mulatero C, Scarsbrook A. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) masquerading as metastatic carcinoma with multiple pulmonary deposits. Clin Imaging. 2012 Nov-Dec;36(6):833-6. [CrossRef] [PubMed]
31. Montoro Zulueta FJ, Martínez Prieto M, Verdugo Cartas MI, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with multiple synchronous carcinoid tumors. Arch Bronconeumol. 2012 Dec;48(12):472-5. [CrossRef] [PubMed]
32. Walker CM, Vummidi D, Benditt JO, et al. What is DIPNECH? Clin Imaging. 2012 Sep-Oct;36(5):647-9. [CrossRef] [PubMed]
33. Mireskandari M, Abdirad A, Zhang Q, et al. Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung. Pathol Res Pract. 2013 Sep;209(9):578-84. [CrossRef] [PubMed]
34. Dvořáčková J, Mačák J, Buzrla P. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: case report and review of literature. Cesk Patol. 2013 Apr; 49(2):99-102. [PubMed]
35. Oba H, Nishida K, Takeuchi S, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha. Endocr Pathol. 2013 Dec;24(4):220-8. [CrossRef] [PubMed]
36. Karnatovskaia LV, Khoor A, Mira-Avendano I. Sarcoid-like reaction in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Am J Respir Crit Care Med. 2014 Nov 15;190(10):e62-3. [CrossRef] [PubMed]
37. Al-Ayoubi AM, Ralston JS, Richardson SR, Denlinger CE. Diffuse pulmonary neuroendocrine cell hyperplasia involving the chest wall. Ann Thorac Surg. 2014 Jan;97(1):333-5. [CrossRef] [PubMed]
38. Killen H. DIPNECH presenting on a background of malignant melanoma: new lung nodules are not always what they seem. BMJ Case Rep. 2014 Feb 26;2014. pii: bcr2014203667. [CrossRef] [PubMed]
39. Zhou H, Ge Y, Janssen B, et al. Double lung transplantation for diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. J Bronchology Interv Pulmonol. 2014 Oct; 21(4):342-5. [CrossRef] [PubMed]
40. Erdini F, Spaltro AA, Ruiu A, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and multiple pulmonary epithelioid hemangioendothelioma (PEH): a case report. Pathologica. 2015 Mar;107(1):37-42. [PubMed]
41. Abrantes C, Oliveira RC, Saraiva J, et al. Pulmonary peripheral carcinoids after diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and tumorlets: report of 3 cases. Case Rep Pulmonol. 2015;2015:851046. [CrossRef] [PubMed]
42. Pietrangeli V, Piciucchi S, Tomassetti S, et al. Diffuse neuroendocrine hyperplasia with obliterative bronchiolitis and usual interstitial pneumonia: an unusual "headcheese pattern" with nodules. Lung. 2015 Dec;193(6):1051-4. [CrossRef] [PubMed]
43. Chauhan A, Ramirez RA. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the role of somatostatin analogs: a case series. Lung. 2015 Oct;193(5):653-7. [CrossRef] [PubMed]
44. Hassan WA, Udaka N, Ueda A, et al. Neoplastic lesions in CADASIL syndrome: report of an autopsied Japanese case. Int J Clin Exp Pathol. 2015 Jun 1;8(6):7533-9. [PubMed]
45. Ofikwu G, Mani VR, Rajabalan A, et al. Case report: a rare case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Case Rep Surg. 2015;2015:318175. [CrossRef] [PubMed]
46. Carr LL, Chung JH, Duarte Achcar R, et al. The clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Chest. 2015 Feb;147(2):415-2. [CrossRef] [PubMed]
47. Baniak NM, Wilde B, Kanthan R. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)--An uncommon precursor of a common cancer? Pathol Res Pract. 2016 Feb;212(2):125-9. [CrossRef] [PubMed]
48. Kuruva M, Shah HR, Dunn AL, et al. 111In-Pentetreotide imaging in diffuse idiopathic neuroendocrine hyperplasia of the lung. Clin Nucl Med. 2016 Mar;41(3):239-40. [CrossRef] [PubMed]
49. Cansız Ersöz C, Cangır AK, Dizbay Sak S. Diffuse neuroendocrine cell hyperplasia: report of two cases. Case Rep Pathol. 2016;2016:3419725. [CrossRef] [PubMed]
50. Ishizaki U, Itoh R, Matsuo Y, et al. Diffuse Idiopathic Pulmonary neuroendocrine cell hyperplasia: a case with long-term follow-up. J Thorac Imaging. 2016 Nov;31(6):W76-W79. [CrossRef] [PubMed]
51. Chatterjee K, Kamimoto JJ, Dunn A, et al. A case of DIPNECH presenting as usual interstitial pneumonia. Pneumonol Alergol Pol 2016;84(3):174-7. [CrossRef] [PubMed]
52. Escudero AG, Zarco ER, Arjona JC. Expression of developing neural transcription factors in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Virchows Arch. 2016 Sep;469(3):357-63. [CrossRef] [PubMed]
53. Trisolini R, Valentini I, Tinelli C, et al. DIPNECH: association between histopathology and clinical presentation. Lung. 2016 Apr;194(2):243-7. [CrossRef] [PubMed]
54. Warren WA, Dalane SS, Warren BD, et al. Ten years of chronic cough in a 64-year-old man with multiple pulmonary nodules. Chest. 2016; 150(3):e81-e85. [CrossRef] [PubMed]
55. Hsu J, Jia L, Pucar D, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and granulomatous inflammation mimicking high-grade malignancy on FDG-PET/CT. Clin Nucl Med. 2017 Jan;42(1):47-49. [CrossRef] [PubMed]
56. Frölich F. Die Helle Zelle der Bronchialschleimhaut und ihre Beziehungen zum Problem der Chemoreceptoren. Frankf Z Pathol. 1949 Apr;60(3-4):517-59.
57. Barnes PJ. Pharmacology of airway smooth muscle. Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 3):S123-32. [CrossRef] [PubMed]
58. Lach E, Haddad EB, Gies JP. Contractile effect of bombesin on guinea pig lung in vitro: involvement of gastrin-releasing peptide-preferring receptors. Am J Physiol. 1993 Jan; 264(1 Pt 1):L80-6. [PubMed]
59. Campanha RB, Matos C, Nogueira F. DIPNECH (diffuse idiopathic pulmonary neuroendocrine cell hyperplasia): a rare syndrome or undiagnosed? J Pulm Respir Med 2015;5:4. [CrossRef]
60. Aubry MC, Thomas CF Jr, Jett JR, et al. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients. Chest. 2007 Jun;131(6):1635-43. [CrossRef] [PubMed]

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

March 2015 Pulmonary Case of the Month: Sticks and Stones May Break My Bronchi

Syed Amer MBBS

Kenneth Sakata MD

Karen Swanson DO

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 67-year-old woman presented to the emergency department with a chief complaint of persistent cough of 2 months duration, productive of yellow sputum. Her symptoms progressed to include dyspnea despite an outpatient course of antibiotics, bronchodilators, and corticosteroids. She denied fevers, chills, hemoptysis, or chest pain. 

PMH, FH, SH

She was on chronic immunosuppression secondary to a history of liver transplant due to non-alcoholic steatohepatitis and kidney transplant due to calcineurin toxicity. She denied any history of smoking, alcoholism or recreational drug use.  

Medications

• Tacrolimus 3.5 mg bid
• Mycophenolate mofetil 720 mg bid
• Fluconazole 100 mg daily

Physical Examination

Vitals: Temperature 37.1°C, respiratory rate 18 breaths/min, heart rate 88 beats/min, blood pressure 130/76 mm Hg, SpO2 95% on room air.

General: Elderly female in no apparent distress.

Lungs: Scattered inspiratory and expiratory squeaks and pops bilaterally, louder in the left lower lobe

The rest of her exam was within normal limits

Laboratory

WBC 4.8 x 10³ cells/µL, Hemoglobin 8.0 g/dL, Hematocrit 23.5, Platelets 122 x 10³ cells/µL.

Creatinine 1.3, electrolytes, blood urea nitrogen, glucose were within normal limits.

Radiography

Her admission chest x-ray is presented in Figure 1.

Figure 1. Admission chest radiograph.

Which of the following is (are) appropriate at this time? (Click on the correct answer to proceed to the second of 4 panels)

1. Cocci serology
2. Empirically begin antibiotics
3. Thoracic CT scan
4. Sputum culture
5. All of the above

Reference as: Amer S, Sakata K, Swanson K. March 2015 pulmonary case of the month: sticks and stones may break my bronchi. Southwest J Pulm Crit Care. 2015:10(3):99-104. doi: http://dx.doi.org/10.13175/swjpcc026-15 PDF 

January 2015 Pulmonary Case of the Month: More Red Wine, Every Time

Uzair Ghori, MD (UGhori@salud.unm.edu)

Shozab Ahmed, MD  (Sahmed@salud.unm.edu)

University of New Mexico

Albuquerque, New Mexico

History of Present Illness

A 41-year-old man travelling from Texas to Las Vegas, Nevada presents to the Emergency Room in Albuquerque, New Mexico with petechial rash, photophobia and headache of 2 weeks duration. The patient complains of general malaise, arthralgia, trouble sleeping, shortness of breath associated with cough and intermittent bilateral lower extremity swelling of 3 weeks duration.

PMH, SH & FH

The patient was prescribed lisinopril and metformin for hypertension and diabetes mellitus, respectively. He admitted occasional drinking, smoking a variable quantity for 30 years but currently not smoking. He denied any illicit drug use.

Physical Exam

Vitals: Heart Rate-92, Blood Pressure-116/45 mm Hg, Respiratory Rate-44 breaths/min, Temperature- 37.2ºC, SpO2-98% on non-rebreather mask.

General: His mental status was not altered.

HEENT: No papilledema was appreciated on eye exam.

Neck: JVP not appreciated.

Lungs: he had diminished breath sounds bilaterally on auscultation.

Heart: His heart had a regular rate and rhythm with no murmurs rubs or gallops.

Abdomen: No abdominal distention or lower extremity edema appreciated.

Skin: A petechial rash was noted most prominently in the lower extremities.

Based on the initial presentation the most appropriate investigations would be? (Click on the correct answer to proceed to the 2nd of 6 panels)

1. CBC, CT head, echocardiogram, blood cultures, metabolic panel, inflammatory markers
2. CBC, UA, lumbar puncture, chest x-ray, inflammatory markers, metabolic panel
3. Echocardiogram, CBC, UA, venous blood gases, bronchoscopy, CT head
4. Stress test, CXR, inflammatory markers, lumbar puncture, ultrasound abdomen, metabolic panel
5. UA, lumbar Puncture, bronchoscopy, echocardiogram, CT head, inflammatory markers 

Reference as: Ghori U, Ahmed S. January 2015 pulmonary case of the month: more red wine, every time. Southwest J Pulm Crit Care. 2015;10(1):1-7. doi: http://dx.doi.org/10.13175/swjpcc155-14 PDF