Evidence for Association

Plausibility

Pancreatitis is a well-recognized clinical feature of epidemic parotitis, with an incidence ranging from less than 1 to as high as 25 percent (Association for the Study of Infectious Disease, 1974; Craighead, 1975). Since 1899, there have been many reports of abrupt-onset IDDM in individuals of all ages within a few days to weeks following mumps infection or exposure to mumps infection in household members or close contacts (Harris, 1899; Hinden, 1962; Kremer, 1947; McCrae, 1963; Messaritakis, 1971; Otten et al., 1984; Patrick, 1924; Peig et al., 1981). One study found a significant excess of consultations for mumps in the 6 months before the onset of IDDM, particularly in the month prior to the onset of symptoms, in 1,663 children with recently diagnosed IDDM in Great Britain and Wales (P < 0.001) (Gamble et al., 1980).

There have been reports of clusters of IDDM following epidemics of mumps disease (Dacou-Voutetakis et al., 1974) and cyclic variations in incidence curves for IDDM resembling those seen for epidemics of infectious diseases (Gundersen, 1927; Sultz et al., 1975). Some data demonstrate that the curves of the incidence rates of IDDM in children parallel those for epidemics of parotitis and mumps encephalitis, with a lag of from 2 to 4 years (Gundersen, 1927; Sultz et al., 1975). Some investigators attribute the sharp rise in the incidence of IDDM in boys in 1950 to 1960 to the common practice of purposefully exposing boys to mumps in the 1950s, since mumps orchitis occurs less commonly as a complication of mumps disease in children than adults (Sultz et al., 1975).

There have been numerous case reports of IDDM following infection with viruses other than the mumps virus, the most common being coxsackievirus and rubella virus. One of the most convincing reports of the ability of viruses to induce acute-onset IDDM was published by Yoon and colleagues in 1979. They isolated a variant of coxsackievirus B4 from autopsy specimens of a 10-year-old boy's pancreas. The child had developed diabetic ketoacidosis within 3 days of onset of symptoms of a flu-like illness and died 7 days later. He had lymphocytic infiltration of the islets of Langerhans, necrosis of beta cells, and a rise in the neutralizing antibody titer to this virus. One of several inbred strains of mice inoculated with the human viral isolate developed diabetes, and fluorescein-labeled antiviral antibody staining revealed antigens of the same virus in the mouse beta cells.

Since then other cases of a temporal association between the onset of IDDM and well-documented coxsackievirus B4 and B5 infections have been reported (Champsaur et al., 1982; Gladisch et al., 1976). Additional evidence suggesting that coxsackieviruses may cause pancreatic damage and



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