Clinical Practice Guideline

for

SARCOIDOSIS

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

 

Overview: Sarcoidosis is a disease of unknown etiology with the highest incidence among the 20-40 age group.Distribution is worldwide, with marked variability in prevalence and pattern of organ involvement.The characteristic histopathologic finding is that of multiple noncaseating epithelioid granulomas which may resolve spontaneously, or proceed to fibrosis.The commonest clinical presentations in North America are asymptomatic abnormal CXR findings (usually bilateral hilar and right paratracheal adenopathy), and nonspecific respiratory symptoms (cough, dyspnea).Natural history of the disease is highly variable; most cases (80%) presenting with bilateral hilar adenopathy (BHA) alone resolve spontaneously within 2 years, while those with symptoms at presentation are less likely to regress.However, even those with asymptomatic BHA have a 5-10% chance of developing progressive pulmonary fibrosis.Ten to 50 percent will have erythema nodosum (with Europeans, especially females, predominating); the presence of erythema nodosum is the most reliable indicator of a favorable outcome.Fifteen percent will have uveitis, and severe vision loss is possible due to secondary glaucoma.The presence of ocular involvement or chronic tonsillitis has been reported to be associated with a worse prognosis.Although liver biopsy will show sarcoid granulomas in 70% of cases, altered liver function due to granulomatous hepatitis is rare.Diabetes insipidus is most often due to granulomatous involvement of the hypothalamus, resulting in either primary polydipsia or defective release of vasopressin.Lytic or sclerotic bone lesions are present in 10% of cases.Disordered calcium metabolism, due to granulomatous conversion of vitamin D, most often results in hypercalciuria, with an attendant risk of nephrolithiasis; hypercalcemia is much less common.

 

Of primary interest to aviation medicine is the risk of cardiac or neurosarcoidosis.The true prevalence of cardiac involvement among sarcoidosis patients is unknown, since the gold standard is necropsy.Autopsy series show a 3-5% prevalence of cardiac involvement in the United States, but since involvement of other organs is rarely fatal, cardiac involvement is over represented in autopsy studies.The best estimate seems to be that 5% of sarcoidosis patients will have myocardial involvement.The most common cardiac conduction abnormalities are heart block, bradyarrhythmias, and ventricular tachycardia.One study reports a risk of 40-50% for sudden death among those with cardiac sarcoid.The left ventricle and interventricular septum are most often involved.Cardiomyopathy, CHF, mitral valve abnormalities, papillary muscle dysfunction, and pericardial effusions are the more common structural cardiac abnormalities.Since healed myocardial granulomata may lead to arrhythmias, patients in remission who have had myocardial involvement remain at risk for sudden death. Nervous system involvement may manifest as basilar meningitis, cranial nerve palsies, mass lesions, or seizures, among others.Prevalence of neurosarcoidosis has been calculated to be 5% based on literature reports, but this is almost certainly an overestimate resulting from reporting bias.

 

Common corticosteroid regimens consist of prednisone or methylprednisolone, although recommended dosages vary widely.Corticosteroids accelerate clearance of symptoms, physiologic disturbances, and X-ray changes, but it is not clear that long term prognosis is altered by steroid therapy.Treatment is indicated for those with progressive pulmonary disease, cardiac involvement, CNS disease, uveitis, or hypercalcemia. For the 10% requiring treatment who fail to respond to corticosteroids, chlorambucil and methotrexate are alternative medications.

 

Military patients should be grounded while undergoing steroid treatment, and should remain grounded after cessation of therapy until the adrenal-pituitary axis is capable of responding to stress.In civil aviation an equivalent dose of 20 mg. or greater of prednisone is not allowed.Unless the illness is in remission without evidence of the other systemic manifestations, medical certification will not likely be granted.

 

Aeromedical Concerns: Uncomplicated, asymptomatic sarcoidosis found incidentally on CXR usually proves to be of little aeromedical concern.However, roughly 10% of sarcoidosis cases develop systemic complications.Myocardial involvement (arrhythmias, conduction block, sudden death), restrictive pulmonary disease, CNS disease (cranial nerve palsies, encephalopathy, seizures), ocular complications (uveitis, iritis, chorioretinitis), and renal calculi all have direct aeromedical implications.As a general rule, afflicted aviators should be restricted from flying as long as the disease process is active because of possible symptoms and abnormal oxygen diffusing capacity, or if corticosteroid therapy is necessary.In the military services once the disease is in remission, and steroids have been discontinued, a return to flying can be considered.

 

Medical Work-up: Diagnosis by clinical/radiographic means, without histologic confirmation, is often used clinically.Whether a biopsy is necessary to confirm sarcoid in a patient with asymptomatic BHA is controversial.However, such a conservative course requires at least a year of follow-up to effectively rule out lymphoma or TB.Such prolonged grounding without a diagnosis is rarely acceptable when dealing with an aviator, thus tissue confirmation is required.If physical examination demonstrates involvement of superficial lymph nodes, skin, conjunctivae, or salivary glands, biopsy should be directed toward that site.If not, transbronchial biopsy is the procedure of choice, with a yield of 70-80%.Liver biopsy is not recommended due to low specificity.Scalene fat-pad biopsy is obsolete.Recent chest x-ray, lymphocyte count (leukopenia is common), angiotensin converting enzyme (unreliable as a diagnostic test, but serial values are helpful in tracking disease progress/remission), serum calcium, 24 hour urinary calcium, pulmonary function testing, 24 hour Holter monitor with resting 12-lead EKG, and ophthalmology consultation with slit lamp exam, are required at the time of first submission of the waiver package.Echo, thallium, and cardiac MRI should only be considered if Holter results suggest myocardial sarcoidosis.Neurology consultation is indicated only in cases of positive findings on the H&P.With the exception of ophthalmology consultation, all the tests required for the initial waiver need to be repeated for follow-up waiver requests.

 

Aeromedical Disposition (military): Aircrew identified as having probable sarcoidosis should be grounded for a minimum of three months, to confirm the diagnosis histologically and determine disease stability.Patients with pulmonary parenchymal disease or abnormal pulmonary function tests should remain grounded, as should those with uveal, cardiac, or CNS involvement.(Except for cardiac or neurologic involvement, a distinction is normally made between histologic involvement versus functional involvement of an organ. For instance, transbronchial biopsy is often positive in a patient with BHA but no radiographic parenchymal involvement; such a finding is evidence of histologic involvement of the lungs, but pulmonary function is rarely affected.)Waiver may be considered for the above cases following resolution of all symptoms; however, those with a history of cardiac or neurologic sarcoid are usually permanently disqualified.††

 

Aeromedical Disposition (civilian): In civilian aviation, denial just on the basis of an abnormal pulmonary function test usually does not occur until the FEV1 reaches 50% or less.Unrestricted waiver should be possible for those with only asymptomatic disease, normal chest x-ray or stable hilar adenopathy, and no evidence of other functional organ involvement.Hypercalcemia is disqualifying; hypercalciuria per se is not.Standard practice in the Federal Aviation Administration is for airmen who are taking 20 mg or more of prednisone or its equivalent to be denied medical certification.Of course, taking steroids in sarcoidosis implies some active form of the disease, which in itself would be disqualifying.Those atypical cases are usually sent to a pulmonologist for an aeromedical recommendation.For continued medical certification in civil aviation the airman is required to provide a current status of their medical condition and pulmonary function study and any necessary laboratory testing on a yearly basis.

 

Waiver Experience (military): One military database had a total of 143 cases of sarcoidosis on file, and of this total, 126 were granted a waiver to continue aviation duties.Essentially all such waivers were granted in the early 1970ís, or earlier, before the complications of cardiac and neurologic sarcoid were widely recognized.Twenty cases were subsequently waived followed periods of initial disqualification, mostly for asymptomatic sarcoidosis, with a few additional cases after steroid use, and for abnormal cardiac exams, which later normalized.Nine of the 17 disqualified cases showed evidence of CAD by ETT, thallium or fluoroscopy.

 

Waiver Experience (civilian): As of October 2004, 84 first-class, 129 second-class and 209 third-class airmen had medical certification with a diagnosis of sarcoidosis.

 

References:

 

Balfour AJC. Sarcoidosis in Aircrew. Aviation, Space, and Environmental Medicine, 1982; 53:269-72.

 

Berkow R, ed. The Merck Manual, 16th ed. Internet Edition. Whitehouse Station: Merck & Co., Inc., 1992: Section I, Chapter 17, Sarcoidosis.

 

Chandra M, Silverman ME, Oshinski J, Pettigrew R, Diagnosis of Cardiac Sarcoidosis Aided by MRI. Chest, 1996; 110:562-65.

 

Eliasch H, Juhlin-Dannfelt A, Sjogren I, Terent A. Magnetic Resonance Imaging as an Aid to the Diagnosis and Treatment Evaluation of Suspected Myocardial Sarcoidosis in a Fighter Pilot. Aviation, Space, and Environmental Medicine, 1995; 66:1010-13.

 

Hill IR. Joint Committee on Aviation Pathology: XII. Sarcoidosis: A Review of Some Features of Importance in Aviation Medicine. Aviation, Space, and Environmental Medicine, 1977;48:953-54.

 

Hull DH. Sarcoidosis and the Aviator. AGARD Lecture Series in Aerospace Medicine, Neuilly-Sur-Seine, France: NATO-AGARD, AGARD-LS-189, 1993;12:1-3.

 

Munson R, Tuomala B, Celio P, Richardson L. Sarcoidosis in U.S. Military Aviators. AGARD Conference Proceedings, Neuilly-Sur-Seine, France: NATO-AGARD, AGARD-Cp-553, 1994;26:1-3.

 

Pettyjohn FS, Spoor DH, Buckendorf WA. Joint Committee on Aviation Pathology: XIII. Sarcoid and the Heart - An Aeromedical Risk. Aviation, Space, and Environmental Medicine, 1977;48:955-58.

 

Rayman, RB, Clinical Aviation Medicine, 3rd edition, Castle Connolly Graduate Medical Publishing, LLC, 2000, pp. 21-23.

 

Shub C, Alexander BB. Persistent Cough - The Presenting Feature in Unsuspected Sarcoidosis: A Case Report. Military Medicine, 1971; 136:757-58.

 

Tice AW. Unilateral Apical Infiltrate as an Initial Presentation of Pulmonary Sarcoidosis. Aviation, Space, and Environmental Medicine, 1982, 52: 702-03.

 

Voge VM. Role of Pre-Existing Disease in the Causation of Naval Aircraft Mishaps. Aviation, Space, and Environmental Medicine, 1981;51: 677-82.

 

 

November 17, 2004