Congenital infection with cytomegalovirus and Epstein-Barr virus.

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period the patient had no further attacks of abdominal pain or fever. The serum creatinine concentration during this in- terval remained stable at 0.9 to 1.1 mg/dL.
instituted. Over a 20-month follow-up

period the patient had no further attacks of abdominal pain or fever. The serum creatinine concentration during this interval remained stable at 0.9 to 1.1 mg/dL. The 24-hour urinary protein excretion was 2.4, 1.7 and 1.3 g 9, 14 and 20 months, respectively, after institution of therapy. The total serum protein concentration after 14 months was 6.5 g/dL and the serum albumin concentration was 4.2 g/dL. Because of religious convictions the patient was unwilling to accept blood transfusions; it was not considered appropriate, therefore, to perform another renal biopsy.

Discussion In this case the family history, clinical features, renal biopsy findings and response to therapy supported the diagnosis of familial Mediterranean fever with secondary renal amyloidosis. Although improvement in the clinical symptoms of this disorder (fever, abdominal pain and polyserositis) may occur with colchicine therapy,1. there is little detailed information regarding the effect of this medication on the complicating renal amyloidosis. In 1976 a group of Israeli investigators described improvement in proteinuria in patients with familial Mediterranean fever treated with colchicine; however, clinical and renal biopsy data were not

given.5 In a recent review of the use of coichicine therapy in this disease the effects of therapy on renal amyloidosis and urinary protein excretion were not mentioned.' As detailed in a recent issue of this journal7 there are two major types of amyloid fibril proteins, one related to immunoglobulins and the other unrelated. In familial Mediterranean fever the major component of the amyloid fibrils is a nonimmunoglobulin protein, designated AA, consisting of 76 amino acids and having a molecular weight of 7000 to 9000 daltons. Although rare reports have described resolution of primary amyloidosis during chemotherapy,t there is no known therapy for the type of amyloidosis that complicates familial Mediterranean fever. Long-term colchicine therapy is not totally free of side effects. Azoospermia may occur9 and chromosomal nondysjunction leading to Down's syndrome in offspring of patients receiving colchicine therapy has been described.10 In a serious and disabling disease such as familial Mediterranean fever, however, these risks appear justified. The precise mechanisms involved in human amyloidogenesis are unknown. Although studies have suggested inhibition of amyloid formation by colchicine in animals,""2 the mechanism of the

apparent beneficial effects of this medication on the renal amyloidosis in our case remain speculative and await better understanding of the nature of amyloid. References 1. WRIGHT DG, WOLFF SM, FAucI AS, et al: Efficacy of intermittent coichicine therapy in familial Mediterranean fever. Ann Intern Med 86: 162. 1977 2. ZEMER D, REVACH M, PEAS M, et al: A

controlled trial of coichicine in preventing

attacks of familial Mediterranean fever. N

Engi I Med 291: 932, 1974

3. DINARELLO CA, WOLFF SM, GOLDFINOER SE,

et al: Coichicine therapy in familial Mediterranean fever: a double-blind trial. Ibid, p 934 4. ELIAKIN M, LICHT A: Colchicine-aspirin for recurrent polyserositis (familial Mediterranean fever). Lancet 2: 1333, 1973 5. ZEMER D, PRAS M, SOHAR E, et al: Colchicine in familial Mediterranean fever (C). N Engi I Med 294: 170, 1976 6. HASSAN A, IsAansI B, FARID Z: Colchicine for familial Mediterranean fever. N Engi I Med 290: 973, 1974 7. KATZ A, PRUZANSKI W: Newer concepts in

amyloidogenesis (E). Can Med Assoc 1 114: 872, 1976 8. CoHEN HJ, LEssIN LS, HALLAL 3, et al: Resolution of primary amyloidosis during chemotherapy. Ann Intern Med 82: 466, 1975 9. MERLIN HE: Azoospermia caused by colchicine: a case report. Fertil Steril 23: 180, 1972 10. FERREIRA NR, BuoNicown A: Trisomy after colchicine therapy. Lancet 2: 1304, 1968 11. KEDAR I, ROvID M, SOHAR E: Coichicine inhibition of casein-induced amyloidosis in mice. Isr I Med Sci 10: 787, 1974 12. SHIRAHAMA T, COHEN AS: Blockage of amyloid induction by coichicine in an animal model. I Exp Med 140: 1102, 1974

Congenital infection with cytomegalovirus and Epstein-Barr virus J.H. JONCAS, MD, PH D; A. WILLS, M Sc; B. MCLAUGHLIN, MD

Congenital infection with cytomegalovirus (CMV) is a well established entity. The occurrence of congenital infection with Epstein-Barr virus (EBV) has never been demonstrated conclusively and must be rare. EBVpositive lymphoblastoid cell lines have been established from the cord blood leukocytes of two infants. Serologic tests for EBV yielded negative results in the first 2 years of life of one of the infants.1 In the other case serologic testing for EBV was not done.2 In a third case virus was detected in the saliva of an infant aged 16 days and serologic testing was done only at age 2 months and later.2 This paper reports a case in which congenital infection with CMV was From the pediatric research centre and the department of microbiology, H8pital SainteJustine, Montr6al Reprint requests to: Dr. J.H. Joncas, Department of microbiology, H8pital Sainte-Justine, 3175 chemin C8te Sainte-Catherine, Montreal, PQ H3T iCS

associated with congenital or very early neonatal infection with EBV.

Case report A boy was born weighing 2.027 kg after an uneventful delivery. His 28-yearold mother had had two previous pregnancies, the first ending in abortion, and the second with the birth of a healthy boy now 5 years old. Shortly after birth of the second child a petechial rash over the face and trunk and hepatosplenomegaly were noted. There were no other significant clinical findings except that the head circumference of 29 cm was small for the gestational age of 36 weeks. A roentgenogram of the skull revealed numerous periventricular calcifications. Abnormal laboratory findings included thrombocytopenia and a total serum 1gM concentration of 84 mg/dL at birth, increasing to 160 mg/dL at the age of 5 months. Characteristic intranuclear inclusion bodies were observed in the cells of the urinary sediment, and with negativestaining electron microscopy herpesvirus

particles were seen in the urine on the 1st day of life. CMV was subsequently isolated from the five urine specimens collected between birth and age 30 months. A fourfold or greater increase in titre of IgG antibodies to CMV and EBV was demonstrated in paired sera from blood samples taken at birth and at age 3 months (Table I). EBV 1gM antibodies in the serum at a titre of 1:20 at birth were detected in our laboratory by a method previously reported.3 CMV and EBV 1gM antibodies were also found in the serum from the blood samples taken at 3 and 9 months of age and the titres were confirmed in another laboratory. There was an insufficient amount of serum from the first collection of blood to test for CMV 1gM antibodies in addition to EBY 1gM antibodies. Neither peripheral blood nor cord blood could be obtained from this infant at birth to try to establish a permanent EVB-positive lymphoblastoid cell line. However, permanent EBV-positive lymphoblastoid cell lines were subsequently established spontaneously each time 10

CMA JOURNAL/DECEMBER 17, 1977/VOL. 117 1417

Table 1-Titres of IgG and 1gM antibodies to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in serum from three successive blood samples of infant and mother* Titret CMV lgG Blood sample Infant

Mother

EA

FA to: LA

NA

A B C D

ND 1:640 ND -

ND 1:8000 1:8000 -

A B C

ND 1:1280

> 1:1000 > 1:1000 > 1:1000

D

-

-

EBV lgG (FA) to: CF

lgM.

VCA

EA

NA

lgM§

ND < 1:10 ND 1:1280 > 1:1280 > 1:1280 -

-

*Abbreviations: FA = fluorescent antibody; EA = early antigen; LA = late antigen; NA = nuclear antigen; CF = complement-fixing (antibody)' VCA = viral capsid antigen; ND = not done (insufficient amount of serum). tCMV lgG and 1gM antibody titres were confirmed in two other laboratories, those of Drs. B. Hanshaw and H. Schmitz. EBV lgG and 1gM antibody titres were confirmed in Dr. Schmltz's laboratory and EBNA titres in Dr. W. Henle's laboratory. .Taken at infant's birth (A) and at ages 3 (B), 9 (C) and 12 (D) months. jThe specific 1gM antibody tests were done on whole serum and on corresponding 1gM fractions separated by sucrose density gradients except for sample A of the infant, which was too small to separate into fractions. mL of blood was collected from the infant, and the leukocytes were cultured at ages 3, 9, 15, 21 and 30 months. All the cell lines obtained were EBV-positive, and two of the three tested so far are also CMV-genome positive by molecular hybridization. The characterization of these cell lines and of the CMV and ERV present in them, as well as of the CMV isolated from the urine, have been described elsewhere.4'3 Serum from three blood samples taken from the mother at the same time as from the infant contained high titres of both CMV and EBV IgG antibodies by .pdirect immunofluorescence performed according to methods previously described.6-8 The infant is now 4 years old, microcephalic (head circumference, 45 cm) and grossly retarded. He took a few steps at age 2 years but is still unsteady, falling after three or four steps. Except for a few words his speech is unintelligible.

Discussion Congenital infection with both CMV and EBV could not be established conclusively in this case since neither peripheral blood in sufficient amount nor

cord blood could be obtained at birth to try to establish a permanent EBVpositive lymphoblastoid cell line. How-

ever, serologic evidence of congenital infection with both EBV and CMV was obtained. The possibility of early neonatal infection with EBV could not be ruled out entirely since EBV infection has been shown to give rise not only to EBV 1gM antibodies but also

to cross-reacting CMV 1gM antibodies.9'10 However, to our knowledge CMV infection has not been shown to

induce the formation of cross-reacting EBV 1gM antibodies, which were pres-

ent in the serum of this infant at birth.

Also, we have been able to find, by indirect immunofluorescent screening, a few instances of EBV-negative, CMVpositive human serum but not of EBVpositive, CMV-negative serum. The extremely high titres of antibodies against both CMV and EBV viral capsid antigen in the mother's serum at the time of her son's birth strongly suggest infection by both viruses during pregnancy. The relatively low titres of the corresponding antibodies in serum from the first blood sample taken from the infant is characteristic, in our experience, of severe congenital viral infection. This discrepancy in CMV and EBV IgG titres between the infant's and the mother's serum at the time of the infant's birth was observed by two different means - immunofluorescence and complement fixation. A tentative explanation could be that specific IgG antibodies transferred from the mother are used up in the neutralization of virus and that at the same time, by a feedback mechanism, they limit the active synthesis of specific IgG antibodies by the infant. This phenomenon, observed in our case for both CMV and EBV antibodies, also suggests a mixed congenital infection. This work was supported in part by research grants from the National Cancer Institute of Canada and the Department of Education (programme de formation de chercheurs et d'action concert.e) of Quebec. References 1. CHANG RS, BLANKENSHIP W: Spontaneous in vitro transformation of leukocytes from a neonate. Proc Soc Exp Biol Med 144: 337. 1973

1418 CMA JOURNAL/DECEMBER 17, 1977/VOL 117

2. VIsINTINE AM, GERBER P, NANMIAS AJ: Leukocyte transforming agent (Epstein-Barr virus) in newborn infants and older individuals. I Pediatr 89: 571, 1976 3. Jo.c.s J, GRANOER-JULIEN M, GERvAIs F: Improved Epstein-Barr virus immunoglobin M antibody test. I Clin Microbiol 1: 192, 1975 4. JONCAS J, MENEZES J, HUANG ES: Persistence of the CMV genome in lymphoid cells after congenital infection. Nature 258: 432, 1975 5. JoNc#s J: Viral attributes and host factors in carcinogenesis: EBV and CMV. Rev Can Biol 36: 17, 1977 6. Idem: Laboratory diagnosis of infectious mononucleosis: Epstein-Barr virus and the heterophil test, in Proceedings of an ASM Symposium on Modern Methods in Medical Microbiology, Systems and Trends, Nov. 14is, 1974, Baltimore, Md, Univ Park, 1975, pp 105-25 7. Tsni TH, KLEIN G, LANGENHUYSEN MMAC: Antibody reactions to virus-specific early antigens (EA) in patients with cytomegalovirus (CMV) infection. Clin Exp Immunol 16: 1, 1974 8. GEDER L: Evidence for early nuclear antigens in cytomegalovirus-infected cells. .f Gen Virol 32: 315, 1976

9. HANsHAw JB, NIEDERMAN JC, CHEssIN LN: Cytomegalovirus macroglobulin in cell-associated herpesvirus infections. .! Infect Dis 125: 304, 1972 10. SCHMJTZ H, VOLZ D, RIECHERT-KRAINIcK C, et at: Acute Epstein-Barr virus infections in children. Med Microblol Immunol 158: 58, 1972

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