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THE JOURNAL OF INFECTIOUS DISEASES • VOL 124, NO.1· JULY 1971 © 1971 by the University of Chicago. All rights reserved. REVIEW Viral Infections and Diseases of the Endocrine System From the Virology Section, Laboratory of Microbiology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland The etiology of most endocrine disorders remains unknown. Although viruses have been suggested as possible etiologic agents, this area has received relatively little attention. Scattered throughout the literature, however, are a number of case reports which contain clinical and pathological evidence of endocrine involvement during and after certain viral infections. The purpose of this report is to review the clinical and experimental literature, critically examine the relationship between viral infections and endocrine disease, and discuss experimental approaches which might aid in studying the effect of viruses on endocrine function. that acute infections would simply bring the patient under the care of a physician, whereupon unrecognized diabetes might be discovered. Recently, Gamble et al. [11] used serologic techniques to study the relationship between newly diagnosed diabetes and a variety of viral infections. Serum was collected from a large number of patients with newly diagnosed diabetes and appropriate control subjects. Antibody was measured against mumps (S and V antigens), influenza A, Band C, parainfluenza, respiratory syncytial virus, measles, herpes simplex, adenovirus, and coxsackie (A and B). Gamble and coworkers failed to find any relationship between antibody against mumps and diabetes. Only neutralizing antibody to coxsackie B, particularly type 4, appeared more often and in higher titer in the diabetics than in the controls. Furthermore, the titer of antibody bore an inverse relationship to the duration of the diabetes. Since infections with coxsackie virus are relatively common, the possibility that the rise in antibody may have represented an anamnestic response or that the "latent diabetics" may simply have developed a more severe viral infection, which in turn resuIted in a greater antibody response, cannot be excluded. Several other viral infections, including measles, polio, influenza, rubella and tick-borne encephalitis, have been associated temporally with the onset of diabetes, but the number of cases are few and the evidence is weak [5, 12-15]. Viral hepatitis also has been associated with the onset of diabetes [16, 17], but the effect of hepatic dysfunction and steroid therapy on glucose metabolism makes the etiology of the diabetes unclear. Severe cytomegalic inclusion disease [18, 19], coxsackie B infection [20], and the hemorrhagic fevers [21, 22] produced lesions in the islets of Langerhans, but there was no information Pancreas The role of infectious agents in the pathogenesis of diabetes mellitus has been the subject of considerable controversy [1]. Many case reports have appeared in the literature showing a temporal relationship between certain viral infections and the onset of diabetes. In a number of these cases, diabetic symptoms appeared within 1-8 weeks after infection, and persistent diabetes, rather than a transient alteration in metabolism of glucose, ensued. Of all the viral infections, mumps has been most frequently associated with diabetes [2-9]. However, many of the cases were reported before 1940 and did not contain laboratory data to confirm the diagnosis of mumps, nor any real proof that the viral infection had caused diabetes. In fact, it was argued by Marble [10] Received for publication February 1, 1971, and in revised form April 1, 1971. Please address requests for reprints to Dr. A. L. Notkins, Virology Section, Laboratory of Microbiology, National Institute of Dental Research, National Institutes of Health, Bethesda, Md. 20014. 94 Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 Nelson L. Lcvy and Abner Louis Notkins 95 Viruses and Endocrine Disease Investigators from Italy also have some evidence that a viral infection can produce diabetes in animals [27-30]. These workers noted that a few days to weeks after an epizootic of foot-andmouth disease in Perugia, a number of cattle developed severe emaciation, anorexia, and polyuria. Laboratory tests revealed hyperglycemia and glycosuria. Examination of the pancreas from four animals revealed almost total absence of the islets of Langerhans with infiltration of round cells and some acinar and ductal necrosis. Lesions in the pituitary and adrenals were noted, but the extent of the lesions and the functional state of these organs were not described. A virus was isolated from these animals and passaged in tissue culture [30]. Inoculation of this virus into normal cattle resulted in some evidence of hyperglycemia in about 25 % of the animals. Since a very small number of animals were used and rigorous controls were not included, the ability of foot-and-mouth disease to produce diabetes awaits confirmation. Pancreatic lesions also have been observed in other viral infections (e.g., foot-and-mouth disease in guinea pigs and mice [31, 32], coxsackie B in mice [33, 34], and infectious pancreatic necrosis virus in fish [35]), but the lesions did not always involve the islets of Langerhans and the reports contained little or no information on metabolism of glucose. The possibility that at least some cases of diabetes mellitus may have a viral etiology merits serious consideration. In humans, attempts should be made to identify viral antigens and recover latent or persistent viruses from the pancreas of known diabetics. Few, if any, experiments of this type have been reported in the literature. In animals, efforts should be made to study the effect of a variety of known viruses on the functional state of the beta cells. These experiments might prove useful in uncovering new models for diabetes. Thyroid A number of investigators have suggested that subacute thyroiditis may be of viral origin. This disease frequently is preceded by a nonbacterial infection of the upper respiratory tract and clusters of thyroiditis have been reported during certain epidemics of viruslike diseases [36-40]. Several viruses have been implicated in the patho- Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 as to whether these patients developed clinical symptoms of diabetes. In some infections, especially mumps, insular damage might be secondary to diffuse virus-induced pancreatitis. Since only a few beta cells are needed to maintain glucose metabolism [13], extensive destruction of the islets of Langerhans must occur before clinical diabetes would appear. Experiments in animals provide the best evidence for virus-induced diabetes. Craighead and coworkers [23-24a] found that infection of mice with the M variant of encephalomyocarditis virus resulted in a syndrome similar to diabetes in over 40% of the surviving mice. Within four to eight days after infection, the immunoreactive insulin in the pancreas had decreased to onefourth the control value and the immunoreactive insulin in the plasma had increased approximately threefold. Shortly thereafter, insulin in the plasma decreased markedly and hyperglycemia and glycosuria followed. The glucose in blood from fasting infected mice was two- to threefold above the uninfected controls ( 117 mg/ 100 ml). Infectious virus was recovered from the pancreas during the acute phase of the infection. Although a certain percentage of the animals recovered, abnormal metabolism of glucose and hyperglycemia persisted in some mice for as long as 11 months. Histologic examination of the pancreas during the hyperglycemic phase revealed a decrease in the number and size of the islets of Langerhans, focal necrosis, and marked degranulation of the beta cells. The exocrine portion of the pancreas appeared intact, the level of amylase in serum was not elevated, and lesions were not found in the liver, adrenals, or pituitary. Genetic factors seem to play a role in the development of this diabeteslike syndrome. Craighead and Steinke [24a] found that the incidence of diabetes was substantially lower in females than males and that the severity of the diabetes was dependent upon the strain of the mouse. It often has been suggested that a specific genetic predisposition might be involved in the development of diabetes in humans. If, in fact, such a predisposition does exist, it might be due to such factors as genetically determined receptor sites for a specific virus or altered immunologic responsiveness to a particular viral antigen. Differences in the genetic susceptibility of the host have been reported with other viral infections [25, 26]. 96 with cytomegalic inclusion disease [18, 19, 56], hemorrhagic fever with renal syndrome [57], and Marburg virus infection [58]. Myxedema has been reported in patients following infection with mumps [59-61], but a coincidental association cannot be excluded. Only in rare cases [37, 62] are reports found in the literature of attempts to identify viral antigens or isolate virus from diseased human thyroid tissue. Experiments in animals also have received little attention. Recently, Lungu and coworkers [63, 64] reported that infection of rats with influenza virus resulted in hypertrophy of the thyroid and an increase in both uptake of iodine and basal metabolism. Infection of rats with pseudorabies virus, however, inhibited uptake of iodine and depressed basal metabolism. Data were obtained only during the first three days after infection, hormone levels were not measured, and whether these viruses acted directly on the thyroid gland or through the central nervous system was not determined. Efforts should be made to develop additional animal models and to rigorously evaluate the effect of viral infections on thyroid function. AdrenaJs Although it has been known for years that adrenocortical hormones could affect the susceptibility of the host to viral infections [65], the effect of viral infections on the functional capacity of the adrenals has received relatively little attention. In fact, viral infections of the adrenals were thought to be rare [66]. However, there are a number of case reports in which adrenal lesions were associated with severe generalized viral infections. Adrenalcortical necrosis has been observed in generalized infection with herpes simplex virus [67-70]. This form of the disease is particularly severe in patients with underlying immunologic disorders or eczema. Shock and electrolyte imbalance have been reported in fatal cases, presumably on the basis of adrenal insufficiency. Hemorrhage, necrosis, and inclusion bodies have been reported in the adrenals of patients with cytomegalic inclusion disease, particularly in those with chronic debilitating illnesses [18, 19, 56, 71-73]. Adrenal lesions also have been observed in severe cases of coxsackie B infection [74-76] and in overwhelming infections with varicella [77-80] Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 genesis of subacute thyroiditis. In 1957, Eylan and coworkers [37] reported 15 cases of thyroiditis during an epidemic of mumps in Israel. Ten out of the 11 patients tested had complement fixation titers of at least 1: 80 for antibody to mumps, while only eight out of 87 controls had titers as high as 1: 20. A virus thought to be identical with mumps was recovered from two out of four thyroid biopsies but was not recovered from the blood or feces. Although these results were encouraging, the rise in antibody might have represented a subclinical infection unrelated to the etiology of the thyroiditis, or a nonspecific anamnestic response provoked by the inflammatory thyroid lesions. Moreover, except for several case reports [41-43], there has been little additional evidence over the last 14 years linking mumps to subacute thyroiditis. Recently, it was suggested that infection with mumps virus might initiate an autoimmune reaction to thyroid tissue [44, 44a] and that relapses of thyroiditis might be produced by a second attack of mumps [44]. Similarly, it has been postulated that the immune response of the host to virus-induced antigens on the surface of infected thyroid cells might playa role in the pathogenesis of thyroiditis [45]. Serologic evidence of recent coxsackie [46, 47], ECHO [46], and adenovirus [39, 43, 46, 48] infections also has been reported in association with subacute thyroiditis. As in the case of mumps, the rise in antibody might represent a subclinical infection unrelated to the thyroiditis. Other investigators have reported cases of subacute thyroiditis following clinical cat-scratch fever [49], measles [50, 51], influenza [52, 53], parainfluenza [43, 53], and infectious mononucleosis [40, 54, 55]. However, in many of the cases, identification of the virus and the diagnosis of thyroiditis was not clearly established. Volpe et aI. [46] hypothesized that subacute thyroiditis might represent the stereotypical response of the thyroid gland to any one of several viral infections. Although the data summarized here suggest that under certain conditions viral infections might result in subacute thyroiditis, additional clinical and experimental studies are needed to confirm this hypothesis. Thyroid lesions have been observed in other viral infections but the number of cases are relatively small. Edema, focal necrosis, and giant cells have been noted in the thyroid gland of patients Levy and Notkins Viruses and Endocrine Disease Pituitary There are relatively few reports of pituitary lesions in viral diseases. However, examination of the pituitary from severe cases of hemorrhagic fever with renal syndrome, Dengue hemorrhagic fever, and infection with Marburg virus revealed petechial hemorrhages, endothelial damage, infiltration of mononuclear cells, and necrosis [22, 57, 58, 83-86]. On rare occasions, hemorrhage and necrosis also have been reported in the pituitary of patients with rubella, varicella, coxsackie B, and cytomegalovirus [18-20, 91, 92]. MacKay and Margaretten [86] postulated that disseminated intravascular coagulation might be responsible for both the adrenal and pituitary lesions associated with these viral infections. Very little is known, however, about the effect of these virus-induced lesions on the functional capacity of the pituitary. Endocrine dysfunction also might be produced by any process which irritates the basilar region of the brain or meninges, presumably by disrupting the hypothalamo-neurohypophysial tract [93]. Abnormal secretion of antidiuretic hormone and the development of diabetes insipidus have been reported during acute viral encephalitis [93, 94]. Lederer reported two cases of thyroid insufficiency following infection with poliovirus [95]. Since these patients responded positively to thyroidstimulating hormone and showed no other clinical signs of endocrine dysfunction, he suggested that the primary lesion was in the "thyroid-regulating capacity" of the hypothalamus. Other investigators also reported prominent hypothalamic syndromes following poliomyelitis [96, 97]. Clinical and laboratory data indicated varying degrees of adrenal, gonadal, thyroidal, and hypophyseal dysfunction. Since inflammation and necrosis in the supraoptic and paraventricular areas of the hypothalamus can occur during the acute phase of poliomyelitis, endocrine dysfunction might be a sequela of these lesions. Lesions in the hypothalamus with subsequent symptoms of endocrine dysfunction have been reported on rare occasions following other viral encephalitides including smallpox and varicella [93, 98, 99]. Perhaps the best evidence for virus-induced disease of the hypothalamo-neurohypophysial system comes from the field of "slow" viruses. Infection of sheep with scrapie virus results in emaciation, obesity, thirst, craving for salt, intolerance to cold, and fluctuations in body temperature. This clinical picture is consistent with the reported degeneration and gliosis of the hypothalamus and the decreased neurosecretory material in the posterior pituitary [l Ou]. The anterior pituitary remained essentially normal. Infection of mice with scrapie resulted in less striking lesions, but there was a decrease in the number of Gomori-positive astrocytes around the ventricular walls [101]. It has been suggested that these cells might play a role in the transport of neurosecretory material and that the effect of scrapie on these cells might affect indirectly the neuroendocrine system. Another "slow" virus, Kuru, produced degenerative changes in the hypothalamo-neurohypophysial tract, but the lesions were less severe than in sheep Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 and vaccinia viruses [81, 82]. Congestion, hemorrhage, and necrosis of the adrenal cortex and medulla have been reported in fatal cases of hemorrhagic fever with renal syndrome and in Dengue hemorrhagic fever [21, 22, 83-85]. The clinical picture and laboratory data were consistent with adrenal insufficiency. Several investigators have suggested that disseminated intravascular coagulation, triggered directly or indirectly by viral infections, might be the principal cause of the adrenal hemorrhage and necrosis [86, 87]. In Dengue hemorrhagic fever, it has been postulated that the immune response of the host (especially to a subsequent infection with a related strain of virus) may somehow be involved in the pathogenesis of this disease [88]. In general there is very little quantitative information on the relationship between the severity of virus-induced adrenal lesions and the functional capacity of the adrenal glands. Increased levels of cortisol have been reported in patients with encephalitis associated with rubella, varicella, and mumps [89, 90], but it is not known whether the increased secretion of cortisol was a direct effect of the virus on the adrenals or an indirect effect through the central nervous system. Tests of adrenal function should be used to evaluate the status of the adrenal glands during and after clinical and experimental viral infections, and the possible role of low grade, persistent viral infections in the pathogenesis of adrenal disease (e.g., Addison's disease) should be explored. 97 98 infected with scrapie, and signs of hypothalamic dysfunction were minimal [102]. Levy and Notkins thymus [109, 110]. However, the effect of these viruses on the production of thymosin [111] is not known. Gonads Parathyroids, Pineal Glands, and Thymus There is virtually no information on the effect of viral infections on the parathyroid or pineal glands. Wilkins [93] speculated that a virus might be involved in the etiology of chronic idiopathic hypoparathyroidism, but there is little evidence to support this speculation. The pineal gland seldom is examined in routine autopsies, and pineal dysfunction rarely is recognized on the clinical level. Although it is known that viruses can replicate and produce lesions in the thymus, the effect of these lesions on thymic function has not been adequately studied [l08]. Several investigators have suggested that the murine leukemia viruses might exert their immunosuppressive effect through the Discussion The information summarized above shows that certain viral infections can produce gross and microscopic lesions in the endocrine glands. In many cases, however, the pathology in the endocrine glands was only one aspect of a severe and often overwhelming viral infection. Furthermore, most of the reports contain little or no information on the relationship between the endocrine lesions and the functional state of the endocrine glands. In fact, it is not certain whether the lesions in the endocrine glands were due to replication of the virus in hormone-producing cells or were secondary to pathologic processes resulting from replication of virus in other cells. The literature also contains a number of case reports purporting to show a temporal relationship between certain viral infections (e.g., mumps) and the onset of endocrine disease (e.g., diabetes mellitus or subacute thyroiditis). Many of these reports, however, represent isolated cases and are not well documented or appropriately controlled. In order to evaluate the role of viruses in endocrine disorders, a systematic approach involving rigorous epidemiological, clinical, and laboratory studies is needed. Tests of endocrine function must be performed during and after documented viral infections. On the experimental level, in-vivo and in-vitro models should be established. Recent reports from several laboratories suggest that animal models are potentially available. Craighead and coworkers [23-24a] produced a syndrome similar to diabetes mellitus in mice with a variant of encephalomyocarditis virus, investigators from Italy [27-30] claim they have produced diabetes mellitus in cattle with foot-and-mouth disease virus, and Beck et al. [100] produced hypothalamic dysfunction in sheep with scrapie virus. Viruses also can produce tumors of the endocrine glands. Adrenal, thyroidal, and ovarian tumors have been reported in animals infected with polyoma virus [112, 113], thyroidal tumors have been found in animals infected with Moloney sarcoma virus [114], and cells from endocrine glands have been transformed in vitro by oncogenic viruses [115,116]. Although hormone-producing cell lines are available (e.g., Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 A number of viral infections can produce lesions in the gonads, but involvement of the hormoneproducing portion of the gland has not been documented. Although close to 20 % of postpubertal males infected with mumps developed orchitis and one-third to one-half of these patients showed signs of testicular atrophy, neither impotence nor feminization was observed [80]. In fact, Coppage and Cooner [103] reported normal levels of testosterone in plasma of three patients with postmumps azoospermia. Orchitis also has been reported as a complication of coxsackie infection, particularly in association with Bornholm disease [104]. Craighead et al. [105], in fact, isolated a coxsackie virus (group B, type 5) from the testis of a patient with orchitis, but no mention was made of endocrine function. Focal testicular hemorrhage, mononuclear infiltration, and depressed spermatogenesis were reported in cases of smallpox [80], hemorrhagic fever with renal syndrome [22], and infection with Marburg virus [58]. Hemorrhagic and necrotic foci also were observed in the testes and ovaries of infants with fatal cases of varicella [79] and cytomegalic inclusion disease [19], but histologic evidence of involvement of interstitial cells was not detected. Under certain circumstances, severe viral hepatitis might lead to gonadal atrophy by interfering with the liver's ability to metabolize estrogens [106-107a]. 99 Viruses and Endocrine Disease of the host [125]. If these antigens come from hormone-producing cells, the resulting immune reaction might damage these cells and lead to endocrine dysfunction. This, in part, might account for the autoantibodies found in certain endocrine disorders [45]. Moreover, it is known from studies in mice that under certain conditions viruses can act as immunologic adjuvants, prevent the development of immunologic tolerance, and accelerate the appearance of immunologic disease [126-128]. Thus, viral infections might initiate or enhance the autoimmune process. Second, a picture resembling autoimmune disease could be produced as a result of the host's immune response to virusinduced antigens [129, 130]. If viral antigens are located on the surface of hormone-producing cells, the interaction of sensitized lymphocytes, or viral antibody plus complement, with these neo-antigens might lead to cell destruction and endocrine dysfunction. Third, circulating virus-antibody complexes [131] might playa role in the pathogenesis of endocrine disease. Since deposition of virusantibody complexes in the kidneys can result in glomerulonephritis [132, 133], the possibility exists that these complexes also might become lodged in the endocrine organs and cause injury to cells. In fact, endocrine lesions resulting from disseminated intravascular coagulation might be triggered by complexes of virus and antibody [86, 87]. In summary, there are a number of provocative observations and several promising leads which suggest that under certain circumstances viruses might be involved in disorders of the endocrine system. In general, however, the relationship between viral infections and endocrine disease has been inadequately studied. On the clinical level, a more rigorous approach is needed. On the experimental level, in-vivo and in-vitro models must be established. In view of recent developments and current concepts, the role of persistent viral infections and virus-induced immunopathology merit further consideration in the etiology and pathogenesis of endocrine disease. References 1. Brown, E. E. Infectious origin of juvenile diabetes. Arch. Pediat. 73: 191-198, 1956. 2. Harris, H. F. A case of diabetes mellitus quickly following mumps. Boston Med. Surg. J. 140:465469, 1899. Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 adrenal tumor, pituitary tumor, Leydig cell testicular tumor) [117], the effect of different viral infections on the synthesis and release of hormones has not been studied. This type of information should be relatively easy to obtain and might add to our understanding of the effect of viruses on endocrine function. The search for a viral etiology of the endocrinopathies has centered primarily around clinically recognized viral infections. Many viruses, however, produce subclinical infections and would not be recognized unless serologic techniques were used. Moreover, in recent years, a number of diseases, mainly of the nervous and lympho-reticular systems, have been ascribed to so-called "slow" or persistent viral infections [118-120]. These viruses may take months or years to produce disease, and some can replicate in vitro without producing gross cytopathology. In vivo, however, certain of these viruses can produce disease by affecting cell function; this can result in a variety of manifestations, including impairment of enzyme clearance [121], enhancement or depression of immune function [108], and neoplastic transformation [122, 123]. The possibility thus exists that persistent nonlytic viral infections also might produce endocrine dysfunction. In fact, recent studies with the electron microscope revealed Ctype viral particles in the endocrine glands of leukemic birds and mice, but the effect of these particles on endocrine function was not studied [124]. Attempts to isolate persistent nonlytic viruses by conventional techniques (i.e., inoculating tissue cultures and looking for gross cytopathology) would most likely be unsuccessful. In order to demonstrate such viruses in endocrine disease, it might be necessary to apply some of the same techniques which have been used to identify other nonlytic viruses (e.g., electron microscopy, isopyknic banding of radioisotopically labelled virus, cell fusion, helper viruses, fluorescent antibody). In addition to the direct effect of viral replication on cellular function, the immune response of the host to viral infections might result in damage to cells. This could affect the endocrine system in several ways. First, antigens of the host that are released from cells infected with virus and antigens of the host that become incorporated into the envelope of the maturing virion might reach immunologically competent cells and stimulate the production of antibody against these antigens 100 24a. Craighead, J. E., Steinke, J. Diabetes mellitus-like syndrome in mice infected with encephalomyocarditis virus. Amer. J. Path. 63: 119-130, 1971. 25. Lilly, F. FV-2: Identification and location of a second gene governing the spleen focus response to Friend leukemia virus in mice. J. Nat. Cancer Inst. 45:163-169, 1970. 26. Blumberg, B. S., Friedlaender, J. S., Woodside, A., Sutnick, A. I., London, W. T. Hepatitis and Australia antigen: autosomal recessive inheritance of susceptibility to infection in humans. Proc. Nat. Acad. Sci. U.S.A. 62:1108-1115, 1969. 27. Barboni, E., Manocchio, I. Alterazionia pancreatiche in bovini con diabete mellito post-aftoso. Arch. Vet. Ital. 13:477-489, 1962. 28. Pedini, B., Avellini, G., Morettini, B., Comodo, N. Diabete mellito post-aftoso nei bovini. Atti Soc. Ital. Sci. Vet. 16:443-450, 1962. 29. Pauluzzi, L. Sindrome diabetica post-aftosa nel bovino e nel caprino. Clin. Vet. (Milano) 86: 113-129, 1963. 30. Barboni, E., Manocchio, I., Asdrubali, G. Observations on diabetes mellitus associated with experimental foot-and-mouth disease in cattle. Vet. Ital. 17:362-368, 1966. 31. Potel, K. Zum vorkommen von organveranderungen bei experimenteller maul-und-klauenseuche des meerschweinschens und zur frage ihrer spezifitat, Arch. Exp. Veterinarmed. 11:879-905, 1957. 32. Platt, H. Observations on the pathology of experimental foot-and-mouth disease in the adult guineapig. J. Path. Bact. 76:119-131, 1958. 33. Pappenheimer, A. M., Kunz, L. J., Richardson, S. Passage of coxsackie virus (Connecticut-5 strain) in adult mice with production of pancreatic dissease. J. Exp. Med. 94:45-64, 1951. 34. Dalldorf, G., Gifford, R. Adaptation of group B coxsackie virus to adult mouse pancreas. J. Exp, Med. 96:491-497, 1952. 35. Snieszko, S. F., Wood, E. M., Yasutake, W. T. Infectious pancreatic necrosis in trout. Arch. Path. (Chicago) 63: 229-23 3, 1957. 36. Robertson, W. S. Acute inflammation of the thyroid gland. Lancet 1:930-931, 1911. 37. Eylan, E., Zmucky, R., Sheba, C. Mumps virus and subacute thyroiditis evidence of a causal association. Lancet 1: 1062-1063, 1957. 38. Bergen, S. S., Jr. Acute nonsuppurative thyroiditis; a report of twelve cases and a review of the literature. Arch. Intern. Med. (Chicago) 102:747760, 1958. 39. Swann, N. H. Acute thyroiditis. A clinical report of twelve cases within a four-month period. Ann. Intern. Med. 56:68-71, 1962. 40. Hintze, G., Fortelius, P., Railo, J. Epidemic thyroiditis. Acta Endocr. (Kebenhavn) 45:381-401, 1964. 41. Felix-Davies, D. Autoimmunisation in subacute thyroiditis. Associated with evidence of infection by mumps virus. Lancet 1:880-883, 1958. 42. McArthur, A. M. Subacute giant cell thyroiditis Downloaded from http://jid.oxfordjournals.org/ at Penn State University (Paterno Lib) on September 12, 2016 3. Patrick, A. Acute diabetes following mumps. Brit. Med. J. 2:802, 1924. 4. Gunderson, E. Is diabetes of infectious origin? J. Infect. Dis. 41: 197-202, 1927. 5. John, H. J. The diabetic child. Etiologic factors. Ann. Intern. Med. 8: 198-213, 1934. 6. Kremer, H. U. Juvenile diabetes as a sequel to mumps. Amer. J. Med. 3:257-258, 1947. 7. Melin, K., Ursing, B. Diabetes mellitus som komplikation till parotitis epidemica. Nord. Med. 60: 1715-1717, 1958. 8. Hinden, E. Mumps followed by diabetes. Lancet 1: 1381, 1962. 9. McCrae, W. M. Diabetes mellitus following mumps. Lancet 1: 1300-1301, 1963. 10. Marble, A. Infections in diabetes. In E. P. Joslin, H. F. Root, P. White, A. Marble, C. C. Bailey [ed.] The treatment of diabetes mellitus. 8th ed. Lea and Febiger, Philadelphia, 1946, p. 523-524. 11. Gamble, D. R., Kinsley, M. L., FitzGerald, M. G., Bolton, R., Taylor, K. W. Viral antibodies in diabetes mellitus. Brit. Med. J. 3:627-630, 1969. 12. Grishaw, W. H., West, H. F., Smith, B. Juvenile diabetes mellitus. Arch. Intern. Med. (Chicago) 64:787-799, 1939. 13. Warfield, L. M. Acute pancreatitis followed by diabetes. J.A.M.A. 89:654-658, 1927. 14. Forrest, J. M., Menser, M. A., Harley, J. D. Diabetes mellitus and congenital rubella. Pediatrics 44:445-447, 1969. 15. Vizen, E. M. On the atypical forms of tick-borne encephalitis. [in Russian] Zh. Nevropat. Psikhiat. Korsakov 63: 1462-1466, 1963. 16. GUnther, O. Hepatitis und diabetes. Z. Ges. Inn. Med. 11:656-660, 1956. 17. Kaniak, J. Influence of viral hepatitis on the course of diabetes. [in Polish] Pol. Tyg. Lek. 18:351355, 1963. 18. Worth, W. A., Howard, H. L. New features of inclusion disease of infancy. Amer. J. Path. 26: 17-35, 1950. 19. Smith, M. G., Vellios, F. Inclusion disease or generalized salivary gland virus infection. Arch. Path. 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