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Eyes and Ears

Interferon may be irritable to the eyes of some people.

-itching-
Itching eyes are not unusual on interferon therapy. Interferon may irritate mucus membranes causing itching. Saline eye drops may reduce irritation. For many people, this side effect occurs during the first few weeks on interferon, then resolves on its own. If itchy eyes persists, or is accompanied by redness, swelling or discharge, the treating physician should be notified.

-burning-
Some people describe burning or irritated eyes during interferon treatment. Generally, this improves after the first month on therapy and may be managed with soothing eye drops, such as saline solution or "natural tears".

-blurry vision-
Some people receiving interferon therapy describe blurry vision. Because interferon has been known to rarely cause changes to the retina, blurry vision should be brought to the attention of the treating physician.

-loss of vision-
Loss of vision in one eye (or both eyes), or a sudden change in vision such as a "hole" , "tunnel" or "window shade" may be a serious event which requires immediate medical attention.

HealthWise: Hepatitis Seeing
Lucinda Porter, RN

No organ is more important than any other, but try to convince us of that when it comes to our eyes. This point was demonstrated recently when a patient I was working with developed vision problems. Six months earlier he had completed hepatitis C (HCV) treatment. Naturally he wondered if there was a correlation between his eye condition and the treatment.

His liver specialist and other experts in the field did not believe there was a correlation in this particular case. Eye diseases are common, particularly as we age. According to the National Eye Institute (NEI), in the 2000 U.S. census there were more than 119 million adults over age 40 with age-related eye diseases. This number is expected to double in the next three decades.
Some eye conditions are associated with HCV. The most common of these is dry eye syndrome. HCV treatment may cause or worsen some eye problems. Corneal ulcers are associated with HCV and its treatment. Prescription information for peginterferon-alpha with ribavirin warns of ophthalmologic (eye) disorders such as decreased, blurred or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema. Let’s discuss these and other terms.

Courtesy of the National Eye Institute – www.nei.nih.gov

The outer most layer of the eye is the cornea. Ulcerations on the cornea may be caused by a variety of factors, HCV being one of them. One example, Mooren’s ulcer is discussed in the HCV Advocate’s Medical Writers’ Circle’s Extrahepatic Manifestations of Chronic Hepatitis C, by Remoroza and Bonkovsky.

Retinopathy refers to retina problems. The retina is a nerve-rich area in the back of the eye. It receives light and transmits images to the brain. Many factors cause retinopathy. People with high blood pressure or diabetes have a higher risk for retinal problems. White puffy spots on the retina are called cotton wool spots and may indicate nerve damage. A retinal thrombosis is a blockage in one of the retinal vessels. A retinal hemorrhage is a bleeding vessel. Treatment-related retinopathy usually ceases after medication is stopped.

The macula lies near the center of the retina. It is responsible for clarity of sight. Macular edema means that there is swelling caused by fluid accumulation.

Optic neuritis is swelling of the optic nerve. This nerve transmits information from the retina to the brain. The head of the optic nerve is the optic disc. If the disc swells due to an increase in pressure from the brain or spinal fluid, the result is known as papilledema.

When undergoing HCV treatment, report eye problems immediately. Many of these problems turn out to be minor, often caused by dry eyes or even fatigue. However, since some eye problems can contribute to permanent vision impairment, let your doctor evaluate the situation.

Dry eye syndrome or keratoconjunctivitis sicca is common, more so in people with HCV. It can be caused by insufficient or improper tear production or when tears evaporate too quickly. Inflammation may accompany dry eyes. This condition may be uncomfortable or painful. Ulcers, scars, and even vision loss may occur if dry eye syndrome is not treated.

Certain factors may intensify dryness, such as air travel, dry climates, menopause, and some medications. Antihistamines, decongestants, antidepressants, tranquilizers, estrogen and interferon may cause eye dryness. Some people develop dry eyes after vision surgery, such as the Lasik procedure.

Eye dryness is associated with other diseases, particularly autoimmune disorders. Those with HCV have an increased risk of autoimmune disease, so your medical provider may want to rule out other causes before assuming that dry eyes are related solely to HCV.

Treatment of dry eyes begins with understanding the cause of the problem. Over-the-counter tear replacement drops or ointment may be suggested. Choose preservative-free artificial tears if you use them more than 4 times daily. Avoid sun and glare. Use sunglasses that wrap around your head and block out UVA and UVB rays. Your specialist may suggest a dietary supplement, such as omega-3 fatty acids. Since too much or too little of certain vitamins may contribute to dryness or other problems, do not take a supplement without first discussing it with your medical provider. Your eye specialist may prescribe medication or recommend plugging your eyes’ tear drainage holes.

Your HCV medical provider may know something about eye diseases, but you should see an eye specialist to manage these. Unless you have a severe problem or need surgery, you will likely see a doctor of optometry (O.D.). Optometrists have 4 years of advanced training in their field. Although they are not physicians, optometrists can prescribe medication and handle most eye problems except surgery. If the problem is more complicated, you may be referred to an ophthalmologist (M.D.). This specialist has attended medical school and can perform surgery. If you need glasses, you may see an optician. This professional dispenses glasses and in some states, contact lenses, but does not treat eye diseases.

Patients should have a baseline eye exam prior to beginning HCV treatment. Those with diabetes or hypertension should consult with an ophthalmologist before treatment. Patients with multiple health conditions, such as HIV and diabetes, need close monitoring during HCV treatment.

HCV patients who need a liver transplant are at risk for post-operative eye infections that may occur in all post-transplant situations. Post-transplant patients with vision or eye problems are encouraged to report these immediately.

Eye problems are a concern for those living with HCV, but can occur in anyone. In spite of the numbers, many of us are tempted to blame every ache and pain on hepatitis C. It is a natural response to living with a chronic disease. Others operate in the opposite extreme and deny having any aches or pains of any cause. Learning to live somewhere in between is sensible. It takes knowledge and practice to navigate illness. While you are practicing, keep your eyes wide open.

http://www.hcvadvocate.org/news/newsLetter/2008/advocate0708.html#4

Retinal Toxicity During Pegylated Alfa Interferon Therapy for Chronic Hepatitis C

By Ronald Baker, PhD

There have been documented and anecdotal reports of ocular side effects during therapy with pegylated interferon and ribavirin. The aim of the current study was to evaluate the effect of therapy with pegylated interferon and ribavirin on the eyes of patients with chronic hepatitis C.

In this small study, 10 patients receiving peginterferon alfa-2a (Pegasys) and ribavirin and 10 healthy volunteers underwent full ophthalmic investigations and multifocal electroretinogram testing at baseline, and at regular intervals during treatment and post-treatment. The multifocal electroretinogram maps retinal function. Responses were compared with sequential recordings from healthy volunteers.

Results

All patients had normal clinical ophthalmic investigations at baseline. During therapy a single patient experienced central visual disturbance lasting 24 h with no prolonged ill effect.

No other patient was aware of any change in vision.

Fundal abnormalities [relating to the retinal area] appeared in five patients during treatment.

The multifocal electroretinogram showed reductions in retinal function in five patients.

Nine of 10 patients exhibited abnormalities on at least one multifocal electroretinogram or fundoscopic investigation.

The authors conclude, "Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy."

Department of Clinical Physics and Bioengineering, Gartnavel General Hospital, Glasgow, UK.

Treatment with Pegylated Interferon May Cause Eye Complications in Patients with Chronic Hepatitis C

Commentary

Serious ocular disorders do not appear to occur frequently among patients using standard interferon or the peginterferons plus ribavirin. However, such problems can occur. If vision problems develop, patients should immediately call their physician and set up an appointment to see an ophthalmologist for a complete eye examination.

The product information on the pegylated interferons contains a warning about potential ophthalmologic disorders. The following text is excerpted from the WARNINGS section of the Pegasys Product Information (9). There is a similar WARNING on potential ocular disorders associated with peginterferon alfa-2b in the Peg-Intron/Rebetol product information:

“Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema are induced or aggregated by treatment with PEGASYS or other alpha interferons.

“All patients should receive an eye examination at baseline. Patients with preexisting opthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic opthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination.

“Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.” [emphasis added]

Selected Excerpts from the Literature on Retinal Toxicity Related to Therapy with Standard Interferon and/or Pegylated Interferon:

“The incidence of serious ocular pathology associated with anti-HCV therapy may be very high and is probably associated with peg-IFN alpha-2b. Increased monitoring of patients treated with peg-IFN alpha-2b for retinal and visual changes is warranted.” C Farel et al (3).

“Although ocular toxicity is uncommon, it should be emphasized that it can occur any time after the start of interferon therapy, and physicians now treating chronic hepatitis C patients with pegylated interferon must be aware of this potentially serious adverse event.” RA Willson (8).

The multifocal electroretinogram can detect retinal dysfunction in chloroquine retinopathy even when the full-field electroretinogram is normal and retinal alterations are subtle. Kellner et al (5).

“This case report underlines the necessity of an EOG on patients with INF-alpha therapy. Until now, the pathogenesis of this retinal toxicity has been poorly understood. These results show that the retinal pigmented epithelium is probably implicated at an early stage in this retinal toxicity.” M Crochet et al (2)

“Subclinical retinal toxicity during anti-viral therapy with pegylated alpha-interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy.” Chisolm et al (1)

‘Subclinical neurovisual impairment is a frequent, largely unrecognized complication of low-dose IFN therapy, and patients with chronic hepatitis B and older age appear to be most susceptible. This apparently innocuous complication is long lasting, possibly irreversible in some patients, with yet undetermined consequences on visual function.” Manesis et al (6)

“8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.” Jain et al (4)

04/06/05

Citations

(1) J A Chisholm and others. Retinal toxicity during pegylated alpha-interferon therapy for chronic hepatitis C: a multifocal electroretinogram investigation. Alimentary Pharmacology & Therapeutics. 21(6): 23-32. March 15, 2005.

(2) M Crochet and others. Retinopathy caused by interferon alpha associated with ribavirin therapy and the importance of the electro-oculogram: a case report. Journal of French Ophthalmolology 27(3):257-262. March 2004.

(3) C Farel and others. Serious ophthalmic pathology compromising vision in HCV/HIV co-infected patients treated with peginterferon alpha-2b and ribavirin. AIDS 18(13):1805-9. September 3, 2004.

(4). K Jain and others. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. British Journal of Ophthalmology 85(10):1171-3. October 2001.

(5). U Kellner, Kraus H, Foerster MH.. Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction. Graefe's Archive for Clinical and Experimental Ophthalmology 238(1): 94-97. January 2000.

(6). E K Manesis and others. Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 27(5):1421-7. May 1998.

(7). A Tsolakos and N Zalatimo. Hepatitis C: a review of diagnosis, management, and ocular complications from treatment. Optometry 74(8): 517-23. August 2003.

(8). R A Willson. Visual side effects of pegylated interferon during therapy for chronic hepatitis C infection. Journal of Clinical Gastroenterology 38(8): 717-722. September 2004.

(9). Hoffman-La Roche. WARNINGS: Ophthalmologic Disorders. Pegasys Product Information. Page 10. January 2004.

Ophthalmological Side Effects of Hepatitis C Treatment are Related to Vascular Endothelial Growth Factor Levels

Ophthalmological side effects, including vision problems, are sometimes reported by patients receiving interferon-based therapy for chronic hepatitis C.

To determine the incidence and cause of these adverse events, researchers prospectively screened interferon-treated patients for vascular ophthalmological side effects, and looked for evidence of activation of angiogenesis (proliferation of new blood vessels).

The study included 34 chronic hepatitis C patients; 18 were treated with 180 micrograms/week of pegylated interferon alfa-2a (Pegasys) plus 800 mg/day of ribavirin, while 16 received 1.5 micrograms/kg/week of pegylated interferon alfa-2b (Peg-Intron) plus 800-1200 mg/day of ribavirin.

Complete ophthalmological evaluation and serum levels of vascular endothelial growth factor (VEGF) -- a cytokine that promotes blood vessel proliferation -- were assessed before and at the end of therapy.

Results

13 patients (38.2%) developed vascular ophthalmological side effects during interferon therapy; 8 patients (23.5%) developed subconjunctival hemorrhage, and 5 (14.7%) had evidence of retinopathy.

In 3 of the 13 patients, visual acuity was affected, and 2 had residual lesions during post-treatment follow-up.

These side effects were not associated with age, sex, HCV genotype, antiviral schedule, type of interferon, or response to therapy.

At the end of treatment, the group with vascular ophthalmological side effects had significantly higher serum VEGF levels than the group without detectable ophthalmological side effects (281 vs 117 pg/mL; P = 0.05).

These differences increased when VEGF values were adjusted for platelet count.

In the ophthalmological side effects group, baseline VEGF (164 vs 64 pg/mL, P = 0.046) and VEGF/platelet values (0.920 vs 0.320 pg/106 platelets, P = 0.024) were also significantly higher.

In a multivariate model, VEGF/platelet values at the end of treatment and hepatic fibrosis stage were the only predictors of vascular ophthalmological side effects.

Conclusion

The authors concluded that in this exploratory study, antiviral therapy for chronic hepatitis C "frequently induces vascular ophthalmological side effects, apparently through an activation of angiogenesis."

7/21/06

Reference
R J Andrade, F J Gonzalez, L Vazquez, and others. Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels. Antiviral Therapy 11(4): 491-498. 2006.

OPHTHALMOLOGIC EFFECTS

A variety of visual changes can occur among patients treated with interferon-based

therapy, including retinal hemorrhage, vision changes, and vision loss.1 Ophthalmologic

toxicity of interferon is usually reversible, but consideration should be given to treatment

discontinuation when it occurs. Any patient with ophthalmologic symptoms should be

sent for an ophthalmology consult.

PATHOPHYSIOLOGY

The underlying pathogenesis of retinopathy associated with interferon is not clear and

is probably multifactorial. Lohmann et al2 reports that although the mechanism of

interferon-associated anterior ischemic optic neuropathy is unclear, it is most likely to be

linked to an immunologic process. It has been postulated that interferon alfa is able to

produce autoantibodies, and subsequently causes deposition of immune complexes in

the small retinal or optic nerve arteries. Interferon is also an immunomodulator that

stimulates other cytokines, such as various interleukins, and upregulates

histocompatibility complex class II proteins. These interleukins can cause an

inflammatory reaction of the blood vessels and lead to ischemia. Unfortunately, such

ischemia and vision loss may be permanent. The incidence of ophthalmologic

complications does not seem to be influenced by the type or dose of interferon. However,

there is a reported higher incidence of complications in patients with certain clinical

entities, specifically diabetes, hypertension, retinal arterial sclerosis, and anemia.3 High

levels of low-dose lipoprotein cholesterol and atherosclerotic index may also influence

the likelihood of the development of retinopathy.3

There may be a physiologic relationship between the presence of retinal complications

and levels of plasma-activated complement 5 (C5a), which is a known potent

intravascular aggregator of granulocytes.4,5 In specific clinical studies, when retinal

hemorrhage occurred, C5a levels were significantly increased. A high C5a level may be

an important step in the pathogenesis of retinal capillary infarction, microvascular

emboli, hemorrhage, and cotton wool spot formation.

The time of onset after administration is nonspecific, though there are reports of patients

with HCV infection who have experienced retinal hemorrhage and/or cotton wool spots

early in the course of therapy (ie, within the first 8 weeks).3 There seems to be no

relationship between the incidence of retinopathy and the levels of liver enzymes, but

increased incidence is reported in patients after the WBC and the platelet count have

reached a nadir. Sudden bilateral visual loss with disc-related field defects and segmental

optic disc edema has been reported but is rare. Permanent loss of vision is thought to be a

result of closure of the retinal capillaries.

In a Japanese study,6 50 patients treated with interferon for chronic HCV, HBV, or renal

cell carcinoma were examined for retinal complications. Retinal hemorrhages or cotton

Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 15

wool spots were observed in 23 patients (46%). Hemorrhage without cotton wool spots

was found in 14 patients, cotton wool spots without hemorrhage in 5 patients, and both

conditions in 4 patients. These findings were potentially reversible. There was one case

of branch retinal artery occlusion and one case with micro-aneurysm. RBC decreased

significantly in patients with retinopathy compared with those without retinopathy

(P <.05%). In another study,7 cotton wool spots disappeared after interferon treatment

was stopped and they did not return unless interferon therapy was restarted. However, in

three cases, the cotton wool spots disappeared despite continued therapy. These cases

emphasize the need for careful retinal surveillance of patients treated with interferon to

diagnose this potentially reversible retinal ischemia.

Special note: Patients with chronic HCV are known to have circulating immune

complexes, and patients with hypertension and/or diabetes have been shown to have

damage to endothelial cells, retinal ischemia, and capillary nonperfusion.8 It may be in

this population of patients, in whom this combination of factors exists, that the most

severe problems are more likely to be seen.

BASELINE TESTS RECOMMENDED9

· Ocular examination, including:

· Photographic documentation

· Recording of visual evoked responses (VERs)

· Electroretinograms

· Visual acuity

· Visual fields

All healthcare providers should be aware of potential risk to patients treated with

interferons. Patients without conditions predisposing to vascular nonperfusion should be

followed closely and visual complaints investigated thoroughly.8 Delayed clinical

diagnosis or delays in follow-up of subjective complaints are likely to be associated with

poor visual outcomes.

COMMON SUBJECTIVE SYMPTOMS* FREQUENTLY NOTED CLINICAL FINDINGS1-3,7,8,10-12

· Abnormal vision · Latency in VERs

· Blurred vision · Subconjunctival hemorrhage

· Diplopia · Cotton wool spot formation

· Dry eyes · Retinopathy

· Eye pain · “Splinter hemorrhages”

· Nystagmus · Macular edema

· Photophobia · Optic tract neuropathy

· Vision loss · Capillary nonperfusion

· Coinfected patients: vision changes, loss · Anterior ischemic optic neuropathy

· Rule out CMV retinitis

*Patients may be asymptomatic early in treatment.

Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 16

TREATMENT STRATEGIES2,11,13

1. Discontinue interferon-based therapy. After discontinuation, treatment-associated

neurovisual abnormalities may resolve. There are reports of persistent complications,

so careful monitoring of patients is required. If the physician elects to resume

interferon therapy; advise him/her to obtain a letter of clearance from an

ophthalmologist.

2. Obtain a CBC with differential.

3. Consider aspirin and prednisone for anterior ischemic optic neuropathy.

4. Recommend, for local symptomatic relief:

a. Artificial tears/lubricants

b. Cool cloths over eyes

c. Reduced exposure to light: close blinds/drapes, dim lights, use sunglasses

5. Recognize that patients with a history of CMV retinitis will commonly relapse during

antiviral therapy.

Special Note:

1. Postliver transplantation symptomatic complications can occur.14

2. Ocular complications have been reported in 2% of patients with 65% of these being

opportunistic infections such as14:

a. Herpes viral retinitis

b. Fungal chorioretinitis

c. Central retinal vein occlusion

d. Herpes zoster ophthalmicus

e. Herpetic keratitis

f. Cyclosporine retinopathy

3. There are reported clinical trials of interferon alfa-2a for the treatment of choroid

neovascularization membranes.10

REFERENCES

1. Kadayifcilar S, Boyacioglu S, Kart H, Gursoy M, Aydin P. Ocular complications with highdose

interferon alpha in chronic active hepatitis. Eye. 1999;13:241-246.

2. Lohmann CP, Kroher G, Bogenrieder T, Spiegel D, Preuner J. Severe loss of vision during

adjuvant interferon alfa-2b treatment for malignant melanoma. Lancet. 1999;353:1326.

3. Kawano T, Shigehira M, Uto H, et al. Retinal complications during interferon therapy for

chronic hepatitis C. Am J Gastroenterol. 1996;91:309-313.

4. Sugano S, Suzuki T, Ishii K, et al. Elevated plasma C5a levels as a possible risk factor of

retinal bleeding during interferon-alfa therapy for chronic hepatitis C. Hepatology. 1996;24

(4 part 2):277.

5. Sugano S, Suzuki T, Watanabe M, Ohe K, Ishii K, Okajima T. Retinal complications and

plasma C5a levels during interferon alpha therapy for chronic hepatitis C. Am J

Gastroenterol. 1998;93:2441-2444.

6. Chuman T, Nao-i N, Sawada A, Kawano T, Shigehira M. Interferon-induced retinal changes.

Journal of Japanese Ophthalmology. 1994;98:616-621.

7. Guyer DR, Tiedeman J, Yannuzzi LA, et al. Interferon-associated retinopathy. Arch

Ophthalmol. 1993;111:350-356.

8. Chambers RB, Downie A, Foote B, Davidorf FH. Interferon alfa-associated retinopathy. J Am

Osteopath Assoc. 1997;97:43-45.

Side Effects Management Handbook • X. Neurologic/Ophthalmologic • p. 17

9. Manesis EK, Moschos M, Brouzas D, et al. Neurovisual impairment: a frequent complication

of alpha-interferon treatment in chronic viral hepatitis. Hepatology. 1998;27:1421-1427.

10. Thoelen A, Menozzi M, Huber C, Messmer E. Treatment of choroidal neovascularization in

age-related macular degeneration with interferon alpha-2a: a short term, nonrandomized pilot

study. Geriatric Journal of Ophthalmology. 1995;4:137-143.

11. Purvin VA. Anterior ischemic optic neuropathy secondary to interferon alfa. Arch

Ophthalmol. 1995;113:1041-1044.

12. Shahidullah AB, Cerulli MA, Berman DH. Interferon may cause retinopathy during hepatitis

therapy. Am J Gastroenterol. 1995;90:1543.

13. Woodruff R. Symptom Control in Advanced Cancer. Melbourne, Australia: Asperula Pty Ltd;

1997:90-91.

14. Ng P, McClusky P, McCaughan G, Glanville A, MacDonald P, Keogh A. Ocular

complications of heart, lung, and liver transplantation. Br J Ophthalmol. 1998;82:423-428.

Here are a few messages from others who have had problems with their eyes while on treatment. You can read these by entering our Chat Room and Message Boards

From:	RADMAN11	Apr-28 12:28 pm
		(2 of 3)

7385.2 in reply to 7385.1

I was on my 9th week of peginton/ribavarin therapy whe I started getting "blurry"vision.I didn't think any thing of it that day.The next day it was still there so I figured I'd call my gastroenterologist+let him know.He referred me the following day to an opthomaligist,at which time my vision was NOTICEABLY worse. The Doc didn't see anything ,but sent me for an MRI 2 days later.At that point my vision was really getting bad,Fast!After nothing showed on the MRI,I was sent for a spinal tap,to see if there was excess spinal fluid pressure.It,too,showed nothing.This was at 7 days after the start of symptoms,at which time I could not see well enough to drive or work.Next day I was sent to a nuero-opthamologist who saw hemorrhaging in both eyes+swelling of the optic nerve(pappiledema).He recommended immediately stopping pegintron/ribavarin.At this point I had about a 1/4 inch round area of vision in my left eye+60% loss in the right(9 days after start of symptoms).That was in nov.'02Iwas finally able to see well enough to return to work in early Feb'03.I now(4-28-03) have about 40% vision in my left eye+80% in the right.The nuero-op doc informed that as probably as good as it was going to get+that after talking to other docs,this is being diagnosed more+more!Some days the vision is'ok"+other days it is not good at all.So.BEWARE! this is a fairly common side effect of this therapy.I am unable to undergo any further treatment,but blood work (done this past week) shows all liver levels normal.GOOD LUCK,

Ears

Fungal infections: compromised immune system or treating with HCV therapies

Fungal external otitis (outer ear infections)
As many as 61 different fungal species have been identified in cases of external otitis, but the most common are Candida and Aspergillus. Fungi were identified in more than 9% of 12000 cases of external otitis in one study. Penicillin species are sometimes found as well. Many cases are actually mixed fungal and bacterial infections, usually S. aureus, Psuedomonas species and Proteus species. Often the symptoms are indistinguishable from bacterial external otitis. The disorder fails to respond to the usual antibacterial topical medications, and that is often the physician's first clue to the diagnosis. Laboratory identification of the fungi is of questionable benefit, for antifungal sensitivity tends to be inconsistently related to fungal species.

The symptoms are as follows

Itching
Drainage from the ear
Flaking on the outside of the ear
Pain
Inflammation of the out side of the ear
Loss of hearing
Low grade fever
A full feeling in your ear
Pain when pulling on your ear lobe or touching your ear

What is "swimmer's ear" or acute external otitis?

External otitis or "swimmer’s ear" is an infection of the skin covering the outer ear canal. Acute external otitis is commonly a bacterial infection caused by streptococcus, staphylococcus, or pseudomonas types of bacteria. Swimmer’s ear is usually caused by excessive water exposure. When water pools in the ear canal (frequently trapped by wax), the skin will become soggy and serve as an inviting culture media for bacteria.
The first sign of infection is that the ear will feel full and it may itch. Next the ear canal will swell and ear drainage will follow. At this stage the ear will be very painful, especially with movement of the outside portion of the ear. The ear canal can swell shut and the side of the face can become swollen. Next, the glands of the neck may enlarge, and it can become more difficult to open the jaw.

What is chronic external otitis?

Chronic external otitis can be caused by a bacterial infection, a skin condition (eczema or seborrhea), fungus (Aspergillosis), chronic irritation (hearing aids, Q-tips), allergy, chronic drainage from middle ear disease, tumors (rare), or it may simply follow from a nervous habit of frequently scratching the ear. In most patients, more than one factor may be involved. For example, a patient with eczema may subsequently develop black ear drainage. This would be suggestive of an accompanying fungus. The standard treatments and preventative measures, as noted below, are often all that is needed to treat even a chronic otitis externa. However, in diabetic or immune suppressed individuals, chronic external otitis can become a serious disease (malignant external otitis). Malignant external otitis is a misnomer because it is not a tumor or a cancer, but rather an aggressive bacterial (Pseudomonas) infection of the base of the skull.

Here are a few corresponding links

http://www.entjournal.com/html/article_4.html

Otitis externa; malignant
http://www.healthcentral.com/mhc/top/000672.cfm

Sudden Hearing Loss in Patients with Chronic Hepatitis C Treated with Pegylated Interferon/Ribavirin

Sudden hearing loss has been reported on standard interferon (IFN) alfa therapy. This is the first report on the occurrence of sudden hearing loss in six cases of chronic hepatitis C in temporal relation to treatment with pegylated (PEG)-IFN alfa-2a or -2b/ribavirin combination therapy.

Three patients were treated in an ongoing randomized placebo-controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 microgram PEG-IFN alfa-2a (Pegasys) /wk and 1-1.2 gram ribavirin/day (Copegus) in de novo patients infected with HCV genotype 1.

Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 weeks of treatment, respectively.

Conclusions

Sudden hearing loss may occur in about 1% of patients on PEG-IFN/ribavirin combination therapy. This rate was not different to that observed in an untreated population.

Possible mechanisms involved include direct ototoxicity of IFN, autoimmunity, and hematological changes.

In contrast to published cases on auditory disability due to standard IFN, hearing loss did not fully resolve after discontinuation of therapy with PEG-IFN. On the other hand, symptoms did not worsen on continued treatment.

Therefore, the decision whether to continue or to stop the treatment when signs of ototoxicity appear is based on the clinical judgment of the treating physician.

06/23/04

Reference
E Formann and others. Sudden Hearing Loss in Patients with Chronic Hepatitis C Treated with Pegylated Interferon/Ribavirin. American Journal of Gastroenterology 99(5): 873-877. May 2004.

Elevated ALT/AST

ELEVATED ALT/AST

WARNING:

Hepatotoxicity, including fatality, has been observed in interferon-treated patients. Any

patient developing liver function abnormalities during treatment should be monitored

closely, and if appropriate, treatment should be discontinued. When hepatotoxicity

occurs, it is usually seen in the first 5 to 6 weeks of treatment.

Interferon-based therapy is contraindicated in patients with decompensated liver disease.

There are reports of worsening liver disease, including jaundice, hepatic encephalopathy,

hepatic failure, and death following interferon therapy in such patients. Therapy should

be discontinued for any patient developing signs and symptoms of liver failure. Patients

with a documented rise in aminotransferase levels during interferon therapy should be

further evaluated for AIH and drug toxicities.

ALT/AST ELEVATIONS AND LIVER DISEASE

Liver diseases themselves may be associated with mild, moderate, or marked elevation of

ALT and/or AST levels.1 Although moderate aminotransferase elevations are nonspecific,

certain liver diseases tend to be associated with either mild or marked ALT elevation.

LIVER CONDITIONS ASSOCIATED WITH MILD, ASYMPTOMATIC ELEVATION OF

ALT/AST1

Common Uncommon

· Fatty liver and NASH (40%–60% of cases) · Drug-induced liver disease

· Chronic HCV (20%–40% of cases) · Autoimmune hepatitis

· Chronic HBV · Alpha1-antitrypsin deficiency

· Alcoholic liver disease · Wilson’s disease

· Hemochromatosis · Miscellaneous conditions

DEFINITION OF MILD/MARKED AMINOTRANSFERASES IN LIVER DISEASE1

Test Mild* Moderate Marked

ALT or AST <2–3 2–3 to 20 >20

Alkaline phosphatase <1.5–2 1.5–2 to 5 >5

*Numbers in table refer to multiples of the upper limits of normal for the individual enzyme.

Side Effects Management Handbook • IX. Hematologic • p. 8

LIVER CONDITIONS ASSOCIATED WITH MARKED INCREASE OF ALT/AST

· Acute viral hepatitis

· Drug-induced hepatitis, especially acetaminophen (Tylenol®)/alcohol and antiretroviral therapy

· Hepatic ischemia due to shock or severe right heart failure

· Acute biliary obstruction

· Budd-Chiari syndrome

MANAGEMENT STRATEGIES

1. Monitor liver enzyme levels in accordance with package inserts.

2. If aminotransferase levels flare, reassess for other causes and consider dose reduction

or discontinuation of therapy.

REFERENCE

1. American Digestive Health Foundation/American Liver Foundation. Viral Hepatitis Facts:

Approach to Elevated Liver Enzymes. HBV087R0.

Fatigue

FATIGUE

Fatigue is a common symptom of hepatitis, and it can become worse while treating.

1. Get plenty of rest. Sleep more at night and take naps during the day if you can. Try to schedule regular rest periods each day.
2. Limit your activities: Do only the things that are most important to you.
3. Delegate tasks. Don’t be afraid to get help when you need it. Ask family and friends to pitch in with things like child care, shopping, housework, or driving.
4. Eat well, and be sure to include plenty of healthy foods.
5. When sitting or lying down, get up slowly. This will help prevent dizziness.
6. Don’t stand when you can sit.
7. Plan your activities and assemble everything before you start.
8. Reschedule daily tasks so you do some only 3 or 4 times a week so you have time to rest each day.
9. Use a cart, wagon or basket to carry things from one part of the house to the other to eliminate retracing your steps.
10. Sit on a stool in the bathroom while shaving or applying makeup. Prop elbows up on counter if you can.
11. Use warm, not hot water for baths or showers. Hot water increases muscle fatigue.
12. If your fatigue is severe, think about asking your doctor for a handicap sticker for your car.
13. Shop when you are at your peak energy.
14. When shopping alone, ask a grocery clerk to carry out groceries.
15. If you arrive home from grocery shopping tired, put away only the perishables. A family member of friend can do the rest.
16. Shop by phone whenever possible.
17. Avoid peak shopping/traffic hours.

FATIGUE

Fatigue is a multidimensional condition with several theoretic foundations: physiologic,

pathologic, and psychological.1,2 Fatigue may be a subjective feeling of tiredness,

weariness, diminished energy, or temporary loss of physical and emotional energy

preventing response to sensory or motor stimuli.3,4 Moreover, fatigue is often a primary

dose-limiting factor that prevents completion of therapy.5 Fatigue is closely correlated

with other conditions, such as sleep disorders, anxiety, agitation, stress, and depression,

and continued, unmanaged fatigue can lead to deterioration of physical and mental

activities.2

Fatigue is the principal side effect of interferon and ribavirin therapy in each trial listed in Table 1. This is partly a direct side effect of interferon-alpha, with its stimulation of the immune response giving the release of cytokines and other factors that cause fatigue, and is partly related to the anemia caused by ribavirin. Ribavirin is directly toxic to red blood cells, causing them to break down, giving a median decline in hemoglobin of approximately 3 g/dL,(3,4) which will cause most patients to feel fatigued. Fatigue also can clearly be multifactorial, with insomnia, dehydration, and anorexia contributing in individual patients.

Management

Encourage patients to get plenty of sleep, keep well-hydrated, and eat well-balanced meals to maintain their weight if possible.

Acetaminophen (Tylenol) <2 gm per day orally in divided doses, also can be very helpful in combating fatigue, particularly with 325-1,000 mg as a premedication prior to an interferon dose if the fatigue is worse 1-2 days after an interferon injection.

PATHOPHYSIOLOGY

Interferon

Two different types of fatigue are associated with interferon: (1) physical fatigue or

weakness that occurs from activation of the interferon cascade and subsequent flulike

syndrome6; and (2) neuroendocrine system fatigue that is associated with

neuropsychological fatigue (mental or depressive), that may be accompanied by cognitive

(CNS) slowing or decreased performance status that occurs as an effect of these agents.7

Fatigue accompanying interferon administration is frequently a dose-limiting or

treatment-limiting toxicity and may lead to dose reduction in 10% to 49% of all patients.7

Ribavirin

Ribavirin may cause an acute decrease in Hgb during the first 1 to 2 weeks of

administration (a mean Hgb drop of 2.7 g/dL) that can quickly cause a patient to

experience acute fatigue. However, this initial fatigue may often progress slowly to

chronic fatigue from the same mechanisms stated above. Ribavirin also causes

intermittent fatigue when administered to patients infected with HCV.8

Side Effects Management Handbook • VII. Flulike Syndrome • p. 5

CONTRIBUTING RISK FACTORS FOR FATIGUE3

Physiologic Psychologic/Psychosocial Treatment/Situational

· Anemia (impaired aerobic

energy metabolism)

· Metabolic disease

· Cancer

· Poor nutritional status

· Hypermetabolic state (active

tumor growth, infection,

fever, or surgery)

· Cardiovascular disease

· Chronic obstructive

pulmonary disease

· HIV/HCV co infection

· Thyroid or hepatic

dysfunction

· Weakness

· Chronic pain

· Diagnostic tests

(psychologic or physical)

· Anticipatory

nausea/vomiting

· Ethyl alcohol, excess

caffeine, nicotine, other

addictive substances

including illicit drugs

· Sleep disturbances

· Lack of exercise

· Anxiety

· Depression

· Grief, loss

· Social factors/psychosocial stress

–Divorce

–Work difficulties

–Economic status

–Lack of social support

· Stress

· Environmental influence

· Interferon or other bio- or

chemotherapy

· Surgery

· Radiation therapy

· Transplantation

· Dose/timing of

administration: interferon

· Other medications, eg:

–Antibiotics

–Ribavirin

–Analgesics, sedating

antihistamines

–Antihypertensives