NORD gratefully acknowledges James Loyd, MD, Pulmonary and Critical Care at Vanderbilt University Medical Center, for assistance in the preparation of this report.
Typically, people with fibrosing mediastinitis were originally 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 there is a preferred ethnic origin or gender disparity.
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 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, and upper limbs 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 occurs. 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 may 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.
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 coxsackie B, 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, Riedel thyroiditis, pseudotumor of the orbit, and others.
It is estimated that, of the entire population who contract histoplasmosis, far less than 1% has the 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 seen only in individuals who lived in an endemic region sometime during their life. The number of persons with idiopathic fibrosing mediastinitis is estimated to be several dozen in the United States.
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 a hallmark sign of 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 on imaging studies. 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 lung infarction, and, in a few, mitral stenosis and congestive heart failure, 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 detection and diagnosis of FM.
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 have fibrosing mediastinitis due to histoplasma. Although, antifungal therapies are highly effective for some forms of histoplasmosis, they are not shown to change the course 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, and itraconazole is safe.
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 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.
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.
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, so it is not possible to be sure whether a response was actually caused by the treatment. When fluid retention occurs, patients are treated with 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 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.
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A review of FM (Peikert 2011) described B lymphocyte accumulation in mediastinal tissue, and proposed a trial of B lymphocyte depletion. A recent report describes response to rituximab, a monoclonal antibody treatment that decreases B lymphocytes, in a pilot trial in 3 FM patients (Westerly 2014). This is an exciting preliminary result, so it is hoped that well designed treatment trials will support the finding.
James Loyd, M.D., Professor of Medicine, Division of Allergy, Pulmonary & Critical Care at Vanderbilt University School of Medicine in Nashville, Tennessee, has volunteered to provide consultation for patients with fibrosing mediastinitis. One of the goals is to understand what is the stimulus that drives post Histoplasmosis fibrosing mediastinitis.
For more information, contact:
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
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