Fibrosing Mediastinitis Conference 2012

Fibrosing Mediastinitis Primer

University of Kansas on FM

General Discussion

Mediastinal fibrosis is the least common, but the most severe, late complication of histoplasmosis. Many physicians believe mediastinal fibrosis to be an abnormal immunologic response to antigens released by the soil-based fungus histoplasma capsulatum. It should be differentiated from the many other less-severe mediastinal complications of histoplasmosis, and from other causes of mediastinal fibrosis, which are termed idiopathic mediastinal fibrosis. Idiopathic fibrosing mediastinitis is even less common, but may have multiple causes, none of which are related to histoplasmosis. Accordingly, there are two types of fibrosing mediastinitis; histoplasmosis-related fibrosing mediastinitis, and idiopathic fibrosing mediastinitis which may have multiple causes unrelated to histoplasmosis.

Both types are rare disorders caused by proliferations of collagen, fibrosis tissue and associated inflammatory cells within the mediastinum (the space between the lungs).

Post histoplasmosis mediastinal fibrosis is characterized by invasive, calcified fibrosis centered on lymph nodes, which, by definition, occludes major vessels or airways.

Often symptoms of fibrosing mediastinitis do not develop until the disease has progressed to a level at which there is damage to some vessel or organ. The build up of the scar tissue can be slow growing in some cases and in others the scar tissue may grow at a rapid rate.

Histoplasmosis, the most common endemic parasitic fungus in the United States, is caused by Histoplasma capsulatum. In the endemic area, along the Mississippi and Ohio River valleys, most persons are infected in childhood. Histoplasmosis also occurs in isolated spots around the world, but is most common in North and Central America, with isolated cases reported from Southeast Asia and Africa. Pulmonary infection is asymptomatic or only mildly symptomatic in the infected person. Some infected persons may suffer flu-like symptoms. H. capsulatum appears to have precise growth requirements related to humidity, acidity, temperature and nitrogen content. It flourishes in soil fertilized by bird droppings, and is carried in bat guano, although birds themselves are not infected with H. capsulatum, bats' intestinal systems may be colonized with the organism. However, chickens are known to harbor the organism in their feathers. For example, H. capsulatum has been traced to chicken feathers in pillows. Chicken houses and bat guano under bridges and their environs are notorious sources of H. capsulatum infection.

Histoplasmosis has also been found in urban settings and is occasionally referred to as an urban disease as well. In urban settings where the soil is disturbed, the fungus spores become air borne. The University of Texas Southwest Medical Center reported between 600 and 700 cases of Histoplasma infection during a 20-year period when buildings were under construction. Although a bird sanctuary existed in the area, most cases occurred in employees who had no direct contact with the sanctuary. The spores invaded buildings through air ducts.

An outbreak of histoplasmosis occurred in 384 students in a junior high school in Ohio. On Earth Day, a courtyard was raked and swept, and the entire school building was contaminated with air containing Histoplasma spores. The epidemic was short-lived and influenza-like. In 1975, bird droppings swept from the roof of a courthouse in Arkansas were distributed through the building by window air-conditioners. Overall, human histoplasmosis is considered usually to be an asymptomatic and clinically insignificant infection. In the vast majority of the many millions of infected persons, infection and recurrent infection follow a generally benign course.

The number of persons with the more severe complication, fibrosing mediastinitis, is a small fraction, estimated to total only a few hundred in the US, of the millions of individuals infected by histoplasmosis. It is not known why some individuals are predisposed to excessive immune response to the organism, which leads to excessive scarring and obstruction of major vessels or airways that characterizes FM. [Patients with deficient immune systems who are exposed, develop disseminated histoplasmosis, which is at the opposite end of the spectrum from FM, in which patients have excessive immune response to the organism. The spores are merely contained in place, and may actually be dead, but are not really destroyed, and that may be part of the problem. They persist for years, maybe indefinitely, and can release antigen to stimulate ongoing immune response.] Calcification of the infected lymph nodes is a component of healing of a chronic granulomatous process. When calcium stones of substantial size are extruded into the airways, they may cause bronchial obstruction.

Symptoms

Typically, people with fibrosing mediastinitis have become infected with H. capsulatum as children but the symptoms begin in most patients between the ages of 21 and 40 years of age. There is no evidence that it has a preferred ethnic origin or gender and it seems to affect as many males as it does females.

Patients with histoplasmosis-related fibrosing mediastinitis present with signs of fatigue, shortness of breath (dyspnea), cough with (hemoptysis) or without blood, chronic lung (pleuritic) pain and recurrent pulmonary infection. Typically these symptoms occur because there is an occlusion of one of the main vessels in the body such as the superior vena cava (the vessel that returns blood from the head and neck, upper limbs, and thorax to the right atrium formed in the superior mediastinum by union of two brachiocephalic veins), the central airways, esophagus, or pulmonary arteries and/or veins. Superior vena cava syndrome, the swelling that develops in some patients due to obstruction of the vena cava, is a common symptom. Some patients do not have the syndrome, despite having obstruction of the SVC, if collateral alternative vessels enlarge sufficiently to return blood to the heart. Cough and shortness of breath are the most common symptoms when obstruction of the central airways is occurring. Pulmonary venous obstruction usually presents with shortness of breath and coughing blood (hemoptysis). Symptoms can be present for years before diagnosis and before there is a life-threatening event.

Patients with idiopathic fibrosing mediastinitis present symptoms of fever, chills, sweats, shortness of breath, coughing and severe chest pains.

Causes

In the majority of patients, histoplasmosis-related fibrosing mediastinitis is kicked off by the body's abnormal excessive immune reaction to exposure of Histoplasma capsulatum or histoplasmosis, the fungus found in soil in the epidemic region of the United States along the Mississippi and Ohio River valleys. Although the fungus resides in the soil, and the fungus is fertilized by bird droppings, birds are not themselves infected. Spores become airborne when the soil is disturbed, and birds and bats also transport the spores.

Idiopathic fibrosing mediastinitis is not related to histoplasmosis. It has been reported in the setting of autoimmune disease, Behcet disease, rheumatic fever, and radiation therapy, severe viral infections of coxsackieB, or trauma. In addition, it can occur in association with other idiopathic fibroinflammatory disorders such as retroperitoneal fibrosis, sclerosing cholangitis, Ridel thyroiditis, and pseudotumor of the orbit.

Affected Populations

It is estimated that, of the population who contract histoplasmosis, less than 1% of that group has an excessive healing response to the fungal infection that is the basis of FM. Reliable prevalence information is not available, but the affected population of histoplasmosis-related fibrosing mediastinitis is estimated to be only a few hundred people in the United States. The number of persons with idiopathic fibrosis mediastinitis is estimated to be several dozen in the United States.

Related Disorders

Symptoms of the following disorders can be similar to, or caused by, fibrosing mediastinitis. Understanding of each condition may be critical for correct diagnosis.

Superior vena cava syndrome occurs as a result of compression or occlusion of the superior vena cava vessel. The symptoms that arise from this condition often lead to the diagnosis of fibrosing mediastinitis. In addition, signs of right heart failure may be prominent.

Mediastinal granuloma is a complication from histoplasmosis and can often be compared or confused with fibrosing mediastinitis. Mediastinal granuloma affects the mediastinal lymph nodes and causes substantial enlargement of the lymph nodes. The enlargement can cause mild compression on the airways and major vessels and possibly displacement of the esophagus. Mediastinal granuloma can also be caused by mycobacteria, so tuberculosis skin testing and/or culture should be performed in those patients. Symptoms may include fatigue and dyspnea, or pain while swallowing. Initially it was thought that mediastinal granuloma would eventually turn into fibrosing mediastinitis but evidence now suggestions they are independent conditions.

Patients with idiopathic fibrosing mediastinitis frequently develop pneumonias, congestive heart failure, heart attacks and chest infections that can be treated with antibiotics.

Standard Therapies

There is no standard therapy for either form of fibrosing mediastinitis. Currently there are no drugs identified that will stop the histoplasmosis-related fibrous tissue from growing. Some have reported the tissue may grow 1 mm per year.

Individual reports describe treatment of patients with idiopathic fibrosing mediastinitis with the following drugs: tamoxifen, prednisone, non-steroid anti-inflammatory medication such as indomethacin, and immunosuppressants such as azathioprine. There is not good data about the effectiveness of these treatments. If there is fluid build-up, patients are treated with a diuretic therapy, which may require supplementing potassium. Antibiotics can be used to treat complications such as pneumonia and chest infections. Corticosteroids such as prednisone can cause serious side effects. It has been demonstrated that carefully supervised cardiovascular exercise workouts at least four days a week can improve a patient's functional status and sense of well-being.

Diagnosis
Diagnosing both forms of fibrosing mediastinitis is best accomplished by chest CT, a scan that shows the abnormal tissue in the mediastinum (the space between the lungs). A ventilation/perfusion nuclear medicine scan is the best test to show the location of any abnormality in the distribution of blood flow to each lung. Sometimes surgical biopsy of the abnormal tissue in the mediastinum is needed to exclude malignancy such as a lymphoma, especially if the CT scan shows that the tissue does not have dense calcification, which is typical for the form that occurs after histoplasmosis.

If the patient has occlusion of the vena cava and there are collateral veins that have developed, the superior mediastinum may be widened. Pneumonia and/or collapse of a lung are sometimes present when the central airways are affected. Pulmonary venous obstruction will show localized pulmonary hypertension. A Magnetic Resonance Angiography (MRA) can be helpful in special circumstances.

Diagnosis in most cases is delayed, often for a period of years. Erroneous initial diagnoses include pneumonia, chronic obstruction lung disease, pulmonary embolism with infarction, and, in a few, mitral stenosis and congestive heart failure either as independent diagnoses or together, a symptom complex produced by obstruction of the pulmonary veins as they enter the left atrium.

Treatment:
Treatment options include systemic antifungal or corticosteroid treatment, local therapy for complications and possibly surgical resection. Each option has its complications and risks associated.

Itraconazole is an oral antifungal treatment which is sometimes used to treat patients who are believed to have contracted fibrosing mediastinitis from the histoplasma organism. There is limited evidence or clinical studies to indicate that any antifungal therapy will control FM, but treatment is reasonably safe and some data suggest it may help in some patients.

If there is occlusion of the superior vena cava or pulmonary veins and arteries, it may be possible to utilize balloon dilation and/or the placement of a stent(s) to open the vessels. These methods of treatment have been successful in a number of patients. It is also possible to perform a surgical bypass of the occluded vena cava by using a spiral vein graft. The most common tool to manage the occlusion of vessels involves the placement of stents in the vessel.

If the scar tissue in FM is localized, and in the form of a mass, surgical resection may improve symptoms, but is very high risk and appropriate for very few patients. This option may require extensive reconstruction of the vascular or airways structures. Procedures of this nature are only offered at a few medical locations. This is not a preferred method of treatment and should only be used in the most extreme cases due to a high level of morbidity and mortality. Very rarely, surgical reconstruction of serious airway obstruction may be life-saving, but should only be done by thoracic surgeons who are very experienced with fibrosing mediastinitis.

The mortality rates for fibrosing mediastinitis have been reported as high as 30% and are typically the result of infection, coughing blood (hemoptysis) or heart disease caused by thickening of the heart muscle. If both lungs of a patient are involved the mortality rate may be higher.

Investigational Therapies

James Loyd, M.D., Professor of Medicine, Division of Allergy, Pulmonary & Critical Care at Vanderbilt University School of Medicine in Nashville, Tennessee, is conducting a study of fibrosing mediastinitis, using persons with fibrosing mediastinitis who voluntarily submit their medical test results. For more information, please contact:

James E. Loyd, MD
Vanderbilt University Medical Center
Nashville, TN 37232-2650
615-322-3412
jim.loyd@vanderbilt.edu

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

References

TEXTBOOKS
Carol A. Kauffman, MD. 2003. Clinical Mycology. Chapter 18: Histoplasmosis. 285- 298. Oxford University Press, Inc.

Mediastinal Fibrosis. 2001. W.B. Saunders Company.

ARTICLES
Santiago E. Rossi, MD, H. Page McAdams, MD, Melissa L. Rosado-de-Christenson, Col, USAF, MC, Teri J. Franks, MD and Jeffrey R. Galvin, MD. (2001). Fibrosing Mediastinitis. Radiographics. 2001;21:737-757.

Robert A. Goodwin, James E. Loyd, Robert M. Des Prez. Histoplasmosis in Normal Hosts. Medicine. 1981; 60: 231-266.

James P. Luby, Paul M. Southern, Jr., Charles E. Haley, Kirby L. Vahie, Robert S. Munford, and Robert W. Haley. Clinical Infectious Diseases. 2005;41:170-176.

Angela M. Davis, Richard N. Pierson, and James E. Loyd. Mediastinal Fibrosis. Seminars in Respiratory Infections. 2001. 16:119-130.

James E. Loyd, Barry F. Tillman, James B. Atkinson, Roger M. Des Prez. Mediastinal Fibrosis Complicating Histoplasmosis. Medicine. 1988. 67:295-309.

FROM THE INTERNET
James Loyd, MD, Lucille Enix, Candace McIntosh. Idiopathic Fibrosis Mediastinitis Questions and Answers. http//www. fibrosing-mediastinitis.com

Resources

Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
TDD: (888)205-3223
Email: http://rarediseases.info.nih.gov/GARD/EmailForm.aspx
Internet: http://rarediseases.info.nih.gov/GARD

Fibrosing Mediastinitis Informational Website
Email: tlewy1@yahoo.com
Internet: http://www.fibrosing-mediastinitis.com

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.
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This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.
For additional information and assistance about rare disorders, please contact the National Organization for Rare Disorders at P.O. Box 1968, Danbury, CT 06813-1968; phone (203) 744-0100; web site www.rarediseases.org or email orphan@rarediseases.org
Last Updated:  2/2/2007
Copyright  2007 National Organization for Rare Disorders, Inc.

Artist's view of FM

Latest

Hi all. It's been 2 1/2 years since my last angioplasty. I still feel pretty good. In fact, I recently completed a hike and climb to Half Dome in Yosemite. The higher altitudes are a bit of a challenge, but this was a personal thing I wanted to accomplish. It was slow-going, but I did it.

I am hoping to make it another year and a half before I have to have another angioplasty to open my stents.

A Brief Film of My Angioplasty

Dr. Abraham Rothman Ahead of Current Research

I found this study published in March 2001. Dr. Rothman did this exact procedure on me in May 2000 at UCSD.

Treatment of Pulmonary Artery Compression Due to Fibrous Mediastinitis With Endovascular Stent Placement*
Alejandro Guerrero, BA, Eric K. Hoffer, MD, Leonard Hudson, MD, FCCP, Paul Schuler, MD, FCCP and Riyad Karmy-Jones, MD

We present the case of a 32-year-old woman with high-grade right pulmonary artery stenosis secondary to fibrous mediastinitis. The patient was managed with balloon angioplasty and stent placement. Only 15 cases of this nature have been reported in the literature, and this is one of the first to be managed with endovascular stent placement.

Fibrous mediastinitis is a rare condition first described in 1855 by Nathan Oulmont.1 It is typically associated with mycobacterial and mycotic infections.2 Patients typically present with superior vena cava (SVC) syndrome.34 Most cases have a benign clinical course until the lesion constricts a major mediastinal structure.2 Fifteen other cases of fibrous mediastinitis with pulmonary artery compression have been described in the literature.56789101112 In the past 10 years, endovascular approaches have provided an effective treatment option for those individuals suffering from SVC syndrome.1314 Recent advances in endovascular techniques have allowed the dilation and stenting of the pulmonary artery. To our knowledge, only one other case of fibrous mediastinitis has been managed with pulmonary artery endovascular stenting.

A 32-year-old woman from the Mississippi Valley presented with severe shortness of breath and chronic cough. Physical examination demonstrated distended neck veins and symptoms consistent with SVC syndrome. Chest radiograph revealed an area of calcification in the right parasternal region at the level of the third rib (Fig 1 ). A pulmonary perfusion scan was performed that indicated essentially no perfusion to the right lung. A CT scan was performed that revealed a lesion adjacent to the right main pulmonary artery. The patient underwent two mediastinoscopies. Frozen section evaluation and cultures demonstrated a fibrous histology with no evidence of mycobacterial or fungal infection. The patient was prescribed an anti-inflammatory steroid regimen, with some resolution of the SVC syndrome. A CT scan demonstrated a mass approximately 3.0 cm by 2.5 cm by 2.0 cm and SVC stenosis with significant collateral veins. Peripheral administration of contrast was unable to visualize the right pulmonary circulation, so a catheter was employed to administer the contrast proximal to the right pulmonary artery (Fig 2 ). This showed an abrupt stenosis of the right main pulmonary artery. An angiographic study revealed 95% stenosis of the right pulmonary artery at its junction with the right lower pulmonary artery, and total occlusion of the right upper pulmonary artery (Fig 3 ). The stenosis was dilated and stented with a Palmaz 424 medium catheter (Cordis/Johnson and Johnson; Miami, FL) over a 5.8F 10-mm balloon catheter. A poststent angiogram confirmed the appropriate placement of the stent and patency of the right lower and middle pulmonary arteries (Fig 4 ). The patient was prescribed aspirin, 5 grains tid, and discharged.

Shortly after the stent placement, the patient had complete resolution of symptoms. At 3-month follow-up, she had continued absence of symptoms, and a pulmonary perfusion scan indicated appropriate ventilation and perfusion to the right lower and middle lobes.

Fibrous mediastinitis is a rare condition that was recognized as a cause of SVC obstruction by Osler in 1903.3 Cases may be idiopathic or associated with tuberculosis, histoplasmosis, sarcoidosis, silicosis, or other fungal infections.2 Mediastinoscopy is warranted to distinguish this inflammatory process from a malignancy. Patients with fibrous mediastinitis generally have a benign clinical course until a mediastinal structure is compressed.15 The first and most common structure affected is the SVC, but involvement of the pulmonary artery, phrenic nerve, recurrent laryngeal nerve, and pulmonary veins have also been documented.2

SVC stent placement is an effective approach to managing SVC syndrome associated with fibrous mediastinitis.1213 In addition, steroid therapy may be an appropriate option in patients with mild obstruction, or as an adjunct to other treatment approaches, although this has not been established.16

Endovascular pulmonary artery angioplasty has been used extensively in pediatric patients with tetrad of Fallot.17 The use of this approach in treating pulmonary stenosis with fibrous mediastinitis has been employed only recently.11 We believe it is an appropriate option that should be considered when presented with such a condition.

References

↵ Oulmont, N (1855) Des Oblitérations de la veine cave supérieure. J.B. Ballière. Paris, France:
↵ Fauci, AS, Braunwald, E, Fuselbacher, KJ, et al Harrison’s principles of internal medicine 14th ed. 1998,1476 McGraw-Hill. San Francisco, CA:
↵ Osler, W On obliteration of the superior vena cava. Johns Hopkins Hosp Bull 1903;14,169
↵ Schowengerdt, CG, Suyemoto, R, Main, FB Granulomatous and fibrous mediastinitis: a review and analysis of 180 cases. J Thorac Cardiovasc Surg 1969;57,365-379 MedlineWeb of Science
↵ Sherrick, AD, Brown, LR, Harms, GF, et al The radiographic findings of fibrosing mediastinitis. Chest 1994;106,484-489 Abstract/FREE Full Text
↵ Berry, DF, Buccigrossi, D, Peabody, J, et al Pulmonary vascular occlusion and fibrosing mediastinitis. Chest 1986;89,296-301 Abstract/FREE Full Text
↵ Shure, D, Gregoratos, G, Moser, KM Fiberoptic angioscopy: role in the diagnosis of chronic pulmonary arterial obstruction. Ann Intern Med 1985;103(Pt 1),844-850
↵ Farmer, DW, Moore, E, Amparo, E, et al Calcific fibrosing mediastinitis: demonstration of pulmonary vascular obstruction by magnetic resonance imaging. AJR Am J Roentgenol 1984;143,1189-1191 FREE Full Text
↵ Hicks, GL, Jr Fibrosing mediastinitis: causing pulmonary artery and vein obstruction with hemoptysis. NY State J Med 1983;83,242-244 Medline
↵ Zorn, SK, Schachter, EN, Smith, GJ, et al Pulmonary artery obstruction with fibrosing mediastinitis. Lung 1978;155,91-100 MedlineWeb of Science
↵ Deblanco, TL, Medina, JR, Sadler, TR, et al Bilateral pulmonary artery obstruction due to fibrosing mediastinitis: case report. Mil Med 1976;May; 141,335-339 MedlineWeb of Science
↵ Kandzari, DE, Warner, JJ, O’Laughlin, MP, et al Percutaneous stenting of right pulmonary artery stenosis in fibrosing mediastinitis. Catheter Cardiovasc Interv 2000;49,321-324 CrossRefMedlineWeb of Science
↵ Chazova, I, Robbins, I, Loyd, J, et al Venous and arterial changes in pulmonary veno-occlusive disease, mitral stenosis and fibrosing mediastinitis. Eur Respir J 2000;15,116-122 Abstract
↵ Dodds, GA, III, Harrison, JK, O’Laughlin, MP, et al Relief of superior vena cava syndrome due to fibrosing mediastinitis using the Palmaz stent. Chest 1994;106,315-318 Abstract/FREE Full Text
↵ Mahajan, V, Strimlan, V, Ordstrand, HS, et al Benign superior vena cava syndrome. Chest 1975;68,32-35 Abstract/FREE Full Text
↵ Horikoshi, M, Ebina, A, Imai, T, et al Retroperitoneal fibrosis with involvement up to the mediastinal space. Nihon Kyobu Shikkan Gakkai Zasshi 1996;34,331-335 Medline
↵ Pihkala, J, Nykanen, D, Freedom, RM, et al Interventional cardiac catheterization. Pediatr Clin North Am 1999;46,441-464