The FM Report


In February 2007, the National Organization for Rare Disorders (NORD) accepted and entered into their database Fibrosing Mediastinitis (FM), recognizing FM as a rare disease. The report, written by Lucille Enix and Tricia Edgell and approved by James Loyd, M.D., has been copyrighted by NORD. NORD offers access to the full report to NORD subscribers at no cost. Visit NORD's FM abstract, then follow the site's instructions to register.

NORD coordinates its information with the National Institutes of Health (NIH) where fibrosing mediastinitis is also listed as a rare disease. In the coming months, NORD will coordinate with the Center for Disease Control and Prevention (CDC) to list FM as a rare disease.

As a courtesy, NORD had granted the authors of the original report permission to write a variation of the original report. The following is a different version from the original NORD report, but it contains the essential information on FM.



Disease Name: Fibrosing Mediastinitis
Writers: Lucille Enix and Tricia Edgell
Reviewer: James Loyd, M.D.
Acknowledgement: NORD is grateful to Dr. James Loyd, Pulmonary and Critical Care at Vanderbilt University Medical Center, for assistance in the preparation of this report.

Synonyms:
  • Sclerosing Mediastinitis
  • Mediastinal Fibrosis
  • FM (abbreviation)
  • FM/MF (abbreviation)
Related Disorders:
  • Superior Vena Cava Syndrome
  • Mediastinal Granuloma
  • Pericarditis
  • Retroperitoneal Fibrosis
  • Autoimmune Disease
  • Riedel Thyroiditis
Fibrosing Mediastinitis:

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).

Histoplasmosis-Related Fibrosing Mediastinitis Discussion:

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 parasitic fungus in the United States, is caused by Histoplasma capsulatum. In the affected 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 without symptoms 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. Birds themselves are not infected with H. capsulate. 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, such as caves, are notorious sources of H. capsulatum infection.

Histoplasmosis found in urban settings is occasionally referred to as an urban disease. In urban settings where the soil is disturbed, the fungus spores become air borne. The University of Texas Southwest Medical Center reported between 600-700 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 without symptoms and a 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 United States, 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.

Histo-Related FM Symptoms:

Typically patients with fibrosing mediastinitis 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 particular ethnic origin or gender. It seems to affect as many males as females.

Patients with histoplasmosis-related fibrosing mediastinitis show signs of fatigue, shortness of breath (dyspnea), cough with (hemoptysis) or without blood, chronic 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 is the swelling that develops in some patients due to obstruction of the vena cava. It 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 shows itself with shortness of breath and coughing blood (hemoptysis). Symptoms can be present for years before diagnosis and before there is a life threatening event.

Idiopathic FM Symptoms:

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

Histo-Related FM Causes:

In the majority of patients, histoplasmosis-related fibrosing mediastinitis originates due to 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. (See Histoplasmosis-Related FM Discussion) Spores become air borne when the soil is disturbed, and birds and bats also transport the spores.

Idiopathic FM Causes:

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.

Histo-Related FM Affected Population:

It is estimated that of the population who contract histoplasmosis that 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.

Idiopathic FM Affected Population:

The number of persons with idiopathic fibrosis mediastinitis is estimated to be several dozen in the United States.

Histo-Related FM 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 (TB) skin testing and/or culture should be performed in those patients. Symptoms may include fatigue, 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.

Idiopathic FM Related Disorders:

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

Histo-Related FM 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.

Idiopathic FM Therapies:

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.

Diagnosing Both FM Forms:

Diagnosing both forms of fibrosing mediastinitis is best accomplished by chest CT, a scan which 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 which 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 is 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.

Histo-Related FM 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 suggests 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.

Mortality Rates:

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 Studies:

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.

References:

  1. Angela M. Davis, Richard N. Pierson, and James E. Loyd. Mediastinal Fibrosis. Seminars in Respiratory Infections. 2001. 16:119-130.
  2. Robert A. Goodwin, James E. Loyd, Robert M. Des Prez. Histoplasmosis in Normal Hosts. Medicine. 1981. 60:321-266.
  3. Carol A. Kauffman, MD. 2003. Clinical Mycology. Chapter 18: Histoplasmosis. 285-298. Oxford University Press, Inc
  4. 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.
  5. James Loyd, MD, Lucille Enix, Candace McIntosh. Idiopathic Fibrosing Mediastinitis Questions and Answers. http//www.fibrosing-mediastinitis.com
  6. James Loyd, MD, Candace McIntosh, Lucille Enix. Fibrosing Mediastinitis Questions and Answers. http///www.fibrosing-mediastinitis.com
  7. James E. Loyd, Barry F. Tillman, James B. Atkinson, Robert M. Des Pres. Mediastinal Fibrosis Complicating Histoplasmosis. Medicine. 1988. 67:295-309.
  8. Mediastinal Fibrosis. 2001. W.B. Saunders Company.
  9. 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. Fibrosing Mediastinitis. Radiographs. 2001. 21:737-757.