Saturday, October 2, 2010

Chronic cough/Pegylated interferon/ribavirin In HCV Therapy

The Cough and HCV Therapy; Is it the interferon or the ribavirin?
Chronic cough associated with interferon/ribavirin therapy for hepatitis C
Journal of Clinical Pharmacy and Therapeutics

Early View (Articles online in advance of print)
P. V. Dicpinigaitis MD, F. R. Weiner MD
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA

*Correspondence: Peter Dicpinigaitis, MD, Weiler Division/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel.: (718) 904 2676; fax (718) 904 2880; e-mail:

Article first published online: 30 SEP 2010
DOI: 10.1111/j.1365-2710.2010.01182.x
© 2010 Blackwell Publishing Ltd


What is known and Objective:  The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.

Case summary: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2–6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C5, the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016).

What is new and Conclusion: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.

Diagnosis and management of interstitial pneumonitis
associated with interferon therapy for chronic hepatitis C

There are some limitations in this review. All the information
came from case reports, whereby cannot be controlled
for confounding factors. Detailed data were not
available from some cases, thus making it difficult to identify
the risk factors for the occurrence of IP. Despite the
limitations, several conclusions can be made based upon
the available data.
IP=( interstitial pneumonitis) can occur at any stage of IFN therapy for HCV
infection. Close monitoring is necessary for the treatment
of HCV with IFN in early stage, especially for older cases.
Prompt discontinuation of medication is the cornerstone,
and corticosteroid therapy may not be essential for patients
with mild- moderate pulmonary functional impairment.
The severity of pulmonary injury may be associated with
the rapid development of IP, indicating that methylprednisolone
pulse therapy, followed by low dose prednisolone
therapy for a short term, is necessary to minimize the risk
of fatal pulmonary damage if signs of significant pulmonary
toxicity occur in earlier stage (within 6 wk) during
antiviral therapy.
Pneumonitis as A Consequence of (Peg)Interferon-Ribavirin Combination Therapy for Hepatitis C: a Review of the Literature

Dig Dis Sci. 2010 March; 55(3): 579–585.
Published online 2009 April 28. doi: 10.1007/s10620-009-0797-1.
Interstitial pneumonitis occurs only rarely as a side-effect of HCV combination treatment and often leads to discontinuation of therapy, which has great implications for patients. In this article we presented our case of pneumonitis during combination therapy and performed a review in order to generate guidelines to manage symptoms and treatment.

Given the paucity of reports with interstitial pneumonitis after ribavirin monotherapy, we suspect that interferon is the culprit.The most common presenting symptom of pneumonitis is any combination of dry cough, dyspnea, fever, and fine inspiratory crackles noted on examination. Hemoptysis, wheezing, and signs of consolidation are rare. Onset of pneumonitis can be at any stage of HCV treatment, supporting the idiosyncratic nature of this side-effect.

Chest radiographs usually show bilateral patchy infiltrates or opacifications, and thin-section CT scans show bilateral patchy consolidation as well as ground-glass attenuation [24].In most cases, symptoms of pneumonitis are reversible after cessation of treatment with (peg)interferon and ribavirin, again in support of drug-induced interstitial pneumonitis.

There is no consensus regarding treatment of interstitial pneumonitis induced by (peg)interferon and ribavirin. Upon review of the literature, three options are possible: first, to stop combination treatment of HCV and wait until the disease resolves, which was done in a limited number of cases [7–10]; second, to give steroids, although dosage and route of administration regimes vary widely [6, 10–18, this study]; and thirdly, in therapy-resistant or relapsing cases, adding azathioprine to steroids may be beneficial in order to resolve the interstitial pneumonitis [11].The relatively high mortality rate in our series suggests that a more aggressive approach is warranted, and favors the early administration of steroids.

One remarkable finding is that mortality occurred exclusively in patients with peginterferon-induced pneumonitis in comparison with conventional interferon (7% versus 0%). The reason for this is unclear, but (peg)interferon has been associated with other pulmonary toxicity such as sarcoidosis, pleuritis, BOOP, and exacerbation of asthma.Patients who died in the combination-therapy group were relatively young and had no relevant pulmonary or other severe diseases in their medical history.

The doses of peginterferon and ribavirin varied but ranged within limits offered by treatment guidelines [25].The mortality, only observed in patients treated with peginterferon and ribavirin combination therapy, raises the issue of whether the peg molecule increases the severity of pneumonitis once it arises. Interferon toxicity is generally dose and duration dependent [26], which leads us to speculate that pulmonary toxicity may occur more severely with long-acting peginterferon; however, we saw no effect of dosage on the occurrence of pneumonitis. Patients died due to different causes (e.g., hypoxia-induced cerebral edema, acute cholestatic hepatitis, and multi-organ failure), all were induced by complications after initially interstitial pneumonitis.

One alternative explanation for the increased mortality might be that all patients with peginterferon were also treated with ribavirin, although ribavirin per se is not associated with pulmonary toxicity.Our data suggest no significant difference between interferon α-2a or 2b, which suggest it is not due to the interferon molecule. In most interferon monotherapy cases of interstitial pneumonitis in HCV treatment in Japan the use of Sho-Saiko-to, a herbal medicine, led to pneumonitis. Sho-Saiko-to has been approved by the Japanese Ministry of Health and Welfare and has often been administered in chronic viral liver disease [27].

The mechanism of this side-effect, probably caused by interferon, remains unclear and several pathophysiological mechanisms have been proposed, centering on the known immunomodulatory activity of interferon [28]. Interferon has direct antiviral and immunomodulatory effect, including cytokine reduction, increased natural killer cell function, and enhanced cellular expression of major histocompatibility class 1 antigens [28–30]. It is plausible that interferon triggers a lung-specific immune-mediated response resulting in interstitial pneumonitis, similar to other autoimmune diseases.

Failure to recognize interferon-associated pulmonary toxicity may result in persistence of pulmonary damage. Mortality was seen only in patients treated with pegylated interferon combination therapy. Therefore, clinicians should be aware of development of interstitial pneumonitis in chronic hepatitis C patients who develop pulmonary symptoms such as cough or dyspnea. The threshold for obtaining chest X-ray or pulmonary HRCT scan in these patients should be low.

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