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Fibrosing Mediastinitis

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2007, 2012

NORD is very grateful to James Loyd, MD, Pulmonary and Critical Care at Vanderbilt University Medical Center, for assistance in the preparation of this report.

Synonyms of Fibrosing Mediastinitis

Disorder Subdivisions

General Discussion

Fibrosing mediastinitis is the least common, but the most severe, late complication of histoplasmosis. Many physicians believe fibrosing mediastinitis 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 fibrosing mediastinitis, which are termed idiopathic fibrosing mediastinitis. 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 fibrosing mediastinitis is characterized by invasive, calcified fibrosis centered at locations of 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 scar tissue occurs very slowly (1 mm/year) in most cases, but in others the scar tissue may grow at a rapid rate. Symptoms may appear suddenly, even though the scar progressed slowly for months or years, because the scar growth itself causes no symptoms. When scar has developed in a major vessel to the extent that it restricts blood flow to or from a lung, the decreased blood flow may cause infarction, with pain of pleurisy.

Histoplasmosis is due to the most common endemic parasitic fungus in the United States, Histoplasma capsulatum. In the endemic area, along the Mississippi and Ohio River valleys, nearly all 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 typically 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. 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 were drawn into buildings through air conditioning systems.

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, 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, .] The yeasts are immobilized in lymph nodes around critical mediastinal structures, and may actually be dead organisms, but are not destroyed nor removed, and that may be part of the problem. They persist for years, maybe indefinitely, and may release antigen to stimulate an ongoing immune response. Calcification of the infected lymph nodes is typical, but may require years to develop. When calcium stones (broncholith) of substantial size work their way 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.

Patients with histoplasmosis-related fibrosing mediastinitis present with signs of fatigue, shortness of breath (dyspnea), cough with blood (hemoptysis) or without, chronic chest (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 vein 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, 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 veins (sometimes visible on the anterior chest) 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.

Patients with idiopathic fibrosing mediastinitis present symptoms of fever, chills, sweats, shortness of breath, cough and chest pain. They may also have fibrosis elsewhere in the body which may cause symptoms at those other sites.

Causes

In the majority of patients, histoplasmosis-related fibrosing mediastinitis is triggered by the body's abnormal excessive immune reaction to exposure of Histoplasma capsulatum or histoplasmosis, the fungus found in soil in the endemic 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, Wegeners granulomatosis, HyperImmunoglobulin G disease, rheumatic fever, radiation therapy, severe viral infections of coxsackieB, or trauma. In addition, it can occur in association with other idiopathic fibroinflammatory disorders at sites outside the chest, such as retroperitoneal fibrosis, sclerosing cholangitis, Ridel thyroiditis, pseudotumor of the orbit, and others.

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 several hundred people in the United States. Post Histo FM is not seen in individuals who did not reside in the endemic region sometime during their life. The number of persons with idiopathic fibrosing 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 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. Fibrosing mediastinitis is comprised of solid fibrotic scar, whereas Mediastinal Granuloma is comprised of semiliquid contents with a thin capsule. The enlargement can cause 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 progress to fibrosing mediastinitis but the best evidence now supports that they are separate conditions.

Patients with idiopathic fibrosing mediastinitis may develop pneumonia, congestive heart failure, or chest infection that can be treated with antibiotics.

Standard Therapies

There is no standard therapy for either form of fibrosing mediastinitis. The natural history of Idiopathic FM is not known, but there are reports of individual patients who had a pharmacologic response or spontaneous improvement, which has not been seen with post Histoplasmosis FM. Currently there are no drugs identified that will stop the histoplasmosis-related fibrous tissue from growing. Because the scar of post Histoplasmosis FM grows very slowly in most patients, treatment would be needed for many years or decades to be effective.

Reports of individual patients describe treatment of patients with idiopathic fibrosing mediastinitis with the following drugs: prednisone, tamoxifen, non-steroid anti-inflammatory medication such as indomethacin, and immunosuppressants such as azathioprine or cyclosporin. Data is not available about the effectiveness of these treatments, and most reports are individual cases. When fluid retention occurs, 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 appear to provide some benefit for some patients, but can also cause serious side effects. Regular exercise is beneficial for heart and muscle function, and is encouraged for all patients as tolerated.

Diagnosis
Diagnosing either form 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 reduction in 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 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 loss of volume of a lung are sometimes present when the central airways are affected. Pulmonary venous obstruction may lead to pulmonary hypertension. A Magnetic Resonance Angiography (MRA) of the heart can be helpful in special circumstances, especially to evaluate the pulmonary veins where they enter the Left Atrium.

Diagnosis in many cases is delayed, often for many years because symptoms are not specific. Erroneous initial diagnoses include pneumonia, chronic obstructive 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. The current widespread use of CT of the chest has greatly improved diagnosis of FM.

Treatment
Successful treatment of post histoplasmosis FM generally uses a mechanical approach, because there are no well documented responses to any pharmacologic agent.
When FM patients cough blood, catheterization of the aorta to perform bronchial artery embolization is effective to block the arteries that are the source of bleeding in most patients. This procedure is available by interventional radiologists in most major medical centers.
FM can block the airways or the vessels going to, or returning from the lungs. When structures of only one lung are blocked, it can cause pain or coughing blood, but most patients do reasonably well overall, as long as the other lung has no problem. When structures of both lungs are affected, this can be serious and life threatening, and for some patients opening of the blocked vessels can be achieved by catheterization with stenting (Albers 2011). Blockage of the superior vena cava requires no treatment unless there are symptoms, but if there is swelling of the arms and neck, associated headache or other symptoms then stenting or bypass should be considered.

Itraconazole is an oral antifungal treatment which is sometimes used to treat patients who are believed to have fibrosing mediastinitis due to histoplasma. Antifungal therapies are highly effective for some forms of histoplasmosis, but not for FM, which is due more to reaction by the patient immune system, rather than growth of organisms. Regardless, a trial is commonly used because FM can be a serious problem.

If the scar tissue in FM is localized, surgical resection has been used rarely, but is high risk and appropriate for very few patients. This option may require extensive reconstruction of the vasculature or airways. Procedures of this nature are offered at only 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 severe airway obstruction may be life-saving, but should only be done by expert thoracic surgeons who are very experienced with fibrosing mediastinitis.

Prognosis
The mortality rates for fibrosing mediastinitis depend on the form and its extent. Idiopathic fibrosing mediastinitis has not been well studied, but appears to rarely be life threatening. The mortality of post histoplasmosis FM is substantial in individuals who have critical structures obstructed in both lungs. Patients who have lost function of one lung can do surprisingly well for many years or decades, as long as the other lung has no problem.

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

Contact for additional information about fibrosing mediastinitis:

James E. Loyd, MD
Rudy W. Jacobson Professor of Medicine
Division of Allergy, Pulmonary & Critical Care
Department of Medicine
Room T1218, Vanderbilt Med Ctr North
Vanderbilt University School of Medicine
1161 21st Ave S
Nashville, TN 37232-2650
Department Phone: 615-322-3412 / 2386
Direct Office Phone: 615-322-3071
FAX: 615-343-7448
Beeper: 615 835 7841
Email: jim.loyd@vanderbilt.edu

Organizations related to Fibrosing Mediastinitis

References

TEXTBOOKS
Carol A. Kauffman CA. Clinical Mycology. In: Histoplasmosis. New York, NY: Oxford University Press, Inc.; 2003:285-298.

JOURNAL ARTICLES
Stone JH, Zen Y, Deshpande V . IgG4-related disease. N Engl J Med. 2012;366(6):539-51.

Albers EL, Pugh ME, Hill KD, Wang L, Loyd JE, Doyle TP. Percutaneous vascular stent implantation as treatment for central vascular obstruction due to fibrosing mediastinitis. Circulation. 2011;123(13):1391-9.

Merkel PA, McCarty D, Sharma A, Stone JR. Case records of the Massachusetts General Hospital. Case 31-2008. A 39-year-old man with chest pain, arthralgias, and a mediastinal mass.N Engl J Med. 2008;359(15):1603-14.

Luby JP, Southern PM, Haley CE, Vahie KL, Munford RS, Haley RW. Clinical Infectious Diseases. 2005;41:170-176.

Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JRFibrosing Mediastinitis. Radiographics. 2001;21:737-757.

Davis AM, Pierson RN, Loyd JE. Mediastinal Fibrosis. Seminars in Respiratory Infections. 2001;16:119-130.

Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal Fibrosis Complicating Histoplasmosis. Medicine. 1988;67:295-309.

Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in Normal Hosts. Medicine. 1981;60:231-266.

INTERNET
Loyd J, Enix L, McIntosh C. Idiopathic Fibrosis Mediastinitis Questions and Answers. http://www.fibrosing-mediastinitis.com/interview_with_dr_loyd.htm. July 2003. Accessed March 9, 2012.

Report last updated: 2012/03/15 00:00:00 GMT+0