Gamma Interferon Induced Organ Regeneration

Case Report

History

A 79 year-old Caucasian male presented with a several year history of worsening dry cough and dyspnea on exertion. His environmental exposure history was remarkable for work in a university laboratory overseeing graduate students performing experiments on anti-oxidants and food biochemistry. During this work, he was exposed to numerous organic solvents and chemicals.

When he was in his late teens, he was in the Marine Corp and served five years on the front lines in World War II. He spent many weeks in cramped quarters aboard naval vessels in which asbestos was commonly used as insulation and as a fire retardant.

He smoked about one pack of cigarettes per day from his teens until quitting around the age of 52 (about 38 pack years). He drinks alcohol moderately.

Past Medical History

Unremarkable.

Family History

His father and mother both died at the age of 88 of “old age”.  He has a daughter who has at least two autoimmune diseases; autoimmune thyroiditis and Sjögren’s syndrome.

Review of Systems

No known medication allergies; denies fever, chills, intolerance to heat or cold, ENT symptoms were unremarkable except he does require a hearing aid; denies chest pain, or extra heart beats; he denies musculoskeletal pain, except back and knee pain diagnosed as osteoarthritis; he denies headaches, depression, and difficulty in clarity of thinking. His hair has been grey for 25+ years and over the last 10 years he has noted worsening bifrontal hairline recession and occipital hair loss.

Current Medications

Aleve (Bayer Healthcare, naproxen sodium) 20mg p.o., q.d. to t.i.d., p.r.n. for “arthritis”.

Physical Examination

T 97, BP 140/90, P 84, RR 20, weight 157 lbs, height 69 inches HEENT-carotids 2+ bilaterally, no bruits, JVD or adenopathy; sclera white, TM’s intact, pharynx, unremarkable, thyroid without nodules.

Chest: Symmetrical, lungs clear to percussion and auscultation, except bibasilar rales present.

Heart: S1, S2, regular rate and rhythm, no murmurs.

Extremities: No edema, no clubbing.

Laboratory and Imaging Studies

Laboratory tests: ANA positive 1:160, speckled pattern, Rheumatoid factor negative.

Baseline Chest x-ray: Bilateral, prominent interstitial markings consistent with pulmonary fibrosis.

High resolution CT scan of the chest: Diffuse ground glass changes extensively involving both lungs and all lobes, pathopneumonic for interstitial pulmonary fibrosis. Baseline pulmonary function tests were also performed. (See Table 1).

Baseline chest x-ray: Prominent interstitial markings consistent with interstitial lung disease.

Open lung biopsies were performed under general anesthesia and both adequate biopsy specimens showed substantial interstitial fibrotic change, an interstitial mononuclear cell infiltrate and a relative absence of eosinophils. No evidence of asbestosis was present on any of the numerous sections of tissue examined. Several pathologists were consulted and all agreed with the diagnosis of usual interstitial pneumonitis (UIP). Given the positive ANA, the high titer and pattern as well as the inflammatory infiltrate plus the family history of autoimmune disease, an autoimmune basis for this patient’s interstitial pulmonary fibrosis was thought to be possible. The relative absence of eosinophils made a hypersensitivity pneumonitis less likely [7].

Treatment

The patient was treated by mixing n-acetylcysteine 10% for inhalation, with a single vial of gamma interferon-1b (Actimmune®, InterMune, Inc.) containing 100 micrograms of gamma interferon-1b (2 million International Units per vial, 20 million International Units per milligram) in aqueous solution in 0.5 ml such that the total volume in the nebulizer reservoir was 20 ml. The solution was immediately delivered to the patient via a nebulized aerosol into his lungs. The patient was treated daily with one vial (100 mcg) of gamma interferon-1b in this way.

The dose of gamma interferon was increased by one vial per week, with the same diluent and dilution protocol, until side effects became a tolerable problem at 1000 micrograms (20 million International Units) per day.

The patient was then started on high dose intravenous immunoglobulin (HDIVIG) at a dose of 3.0 grams of immunoglobulin per kg of body weight every 3-8 weeks, for its anti-inflammatory activity [15,16], about seven weeks after starting the inhaled gamma interferon.

With the addition of HDIVIG, gamma interferon-1b side effects were greatly reduced. The dose of gamma interferon was increased by one vial per week until side effects again became a problem at 1,200 micrograms (24 million International Units) per day.

Post Treatment Test Results: Fourteen Months Post Treatment

Chest x-ray: Improvement of interstitial markings, normal lung parenchyma probably present.

High Resolution CT scan of the chest: Substantial improvement of ground glass changes and probably generation of new lung parenchyma.

Interestingly, the patient had grey scalp hair for over 25 years and about 5 months into treatment a portion of his hair roots turned blonde. Additionally, his hair has become thicker and he has lost almost all evidence of frontal and occipital thinning or recession. His thinking is sharp, he is working longer hours, and enjoying increased recreational activities. Some of these activities include long, brisk walks and his mood is very positive. The side effects of the treatment have been tolerable. Treatment was discontinued at 14 months with no recurrence of disease at two years. The patient’s pulmonary function tests remained stable off treatment and the data strongly supports the hypothesis that new lung parenchyma had been generated.

Gamma interferon had previously failed in a clinical trial for pulmonary fibrosis [6]. In this study the drug was administered subcutaneously at a dose of 4 million International Units, three times per week.

In the patient described in this report a suprapharmacological dose of ultimately 24 million International Units was delivered via the off-label inhalation route. I hypothesize that to achieve potent fibrosis inhibition suprapharmacologic and local dosing of gamma interferon is necessary because the short serum half life of gamma interferon prohibits therapeutic levels at the site of disease or injury.