Interferon alpha (IFN alpha 2a) therapy for herpes virus-associated inflammatory bowel disease (ulcerative colitis and Crohn's disease).
OBJECTIVE
The etiology and pathogenesis of ulcerative colitis and Crohn's disease remain unclear, so that exact causal therapy is not yet possible. In our UC and CD patients, viral infections, particularly of the upper respiratory tract, aggravated the underlying disease. This had led us to use in-situ hybridization to investigate intestinal mucosa for viral agents such as HSV I + II- and Epstein-Barr virus DNA. We found these DNA in the cell nuclei in the surface and glandular epithelia of the affected mucosa of the small intestine and the colon. These findings indicated that viruses may exacerbate these inflammatory bowel diseases.


METHODS
Over a period of 1-4.7 years, we treated 16 patients aged 25-65 with Crohn's disease (12 patients) or ulcerative colitis (four patients). In 14 patients, inflammatory bowel disease had been diagnosed years before (mean, 15.3 years). When we started therapy, 75% of the patients with Crohn's disease had extra-intestinal manifestations; and the CDAI after Best averaged considerably above 150. All patients had been taking either prednisone or prednisolone and/or 5-ASA or SASP and/or azathioprine or metronidazole for many years. Using PCR, mucosal specimens of the small intestine and/or the colon were tested for EBV-, HSV I + II, HHV6- and CMV DNA. In 12 of the 16 patients. EBV- and/or HHV6 DNA were found in the affected mucosa. Since interferon alpha administration has proven effective in chronic hepatitis-B therapy, we decided to administer interferon alpha 2a (13,46,47,55). After stopping the above-mentioned basic therapies, we commenced treatment with 6 million units of interferon alpha 2a subcutaneously 3 times per week for at least six months. Four of the patients showed no signs of improvement, and their therapy was stopped after three months. For the others, therapy was continued until patients were clinically symptom-free and viral DNA could no longer be traced in their mucosal biopsies.


RESULTS
With interferon therapy, 12 of the 16 patients showed slow but continual improvement. Particularly impressive was the remission of the extra-intestinal manifestations, which did not recur in any patient during interferon therapy. Four patients did not show any improvement, and the clinical symptom of diarrhea continued. Two patients with ulcerative colitis suffered relapses three and four years later, after severe bouts of para-influenza of the upper respiratory tract. In these two patients, EBV- and HHV6 DNA was found in the inflamed mucosa of the colon. Renewed therapy with interferon alpha 2a successfully cleared up the inflammation. The patient group needed an average of eight weeks to become clinically symptom-free, and an average of six months to achieve complete virus elimination in the pathologically altered mucosa.


CONCLUSIONS
For herpesvirus-associated ulcerative colitis and Crohn's disease, interferon alpha 2a treatment should be started as early as possible to prevent disease becoming chronic. Whether this kind of antiviral treatment will be as effective in the long term, and whether malignant transformation (herpes viruses are potential tumor inducers) will be delayed or prevented, are questions that can be answered only by future long-term studies.
Center for Internal Medicine, Department of General Internal Medicin, Stuttgart, Germany.
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U
Ruther
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Nunnensiek
H A
HA
Muller
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H
Bader
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U
May
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P
Jipp
D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000150:complications / Q000628:therapy / Q000821:virology; D003424:Crohn Disease / Q000150:complications / Q000628:therapy / Q000821:virology; D003587:Cytomegalovirus / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000150:complications / Q000628:therapy; D004279:DNA, Viral / Q000302:isolation & purification; D006566:Herpesviridae Infections / Q000150:complications / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000235:genetics; D018258:Herpesvirus 2, Human / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics; D015654:Herpesvirus 6, Human / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000628:therapy* / Q000821:virology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000821:virology; D008875:Middle Aged; D011994:Recombinant Proteins; D012141:Respiratory Tract Infections / Q000150:complications
D004279:DNA, Viral; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins