Cytomegalovirus, splenomegaly

Donna Chriss-Price, RT, RDMS, Sandra K. Lawrence, MD^¶, Philippe Jeanty, MD, PhD^#

Address correspondence to Donna Chriss-Price, RT, RDMS, Dept. of Ultrasound/OB-GYN, Centennial Hospital of Nashville. ¶Dept. of Radiology, Vanderbilt University, # ^{Women’s Health Alliance, Nashville, TN}

Synonyms: Cytomegalovirus (CMV) disease, cytomegalic inclusion disease, "blue muffin" syndrome, TORCH syndrome.

Definition: Cytomegalic inclusion disease is caused by a species-specific double-stranded DNA herpes group virus, which causes an inapparent infection or a "mononucleosis-type" illness in young healthy adults, a chronic disease in older adults, and mild to severe congenital infections.

Incidence: An estimated 0.2-2.4% of worldwide live-born infants acquire the virus perinatally¹. Only 10% of these will demonstrate classic signs of illness at birth².

Pathogenesis: Cytomegalovirus preferentially invades the salivary glands and, in infants, the germinal matrix, but can infect other organ cells with development of characteristic cytoplasmic or nuclear inclusion bodies. Timing of the maternal infection and fetal development with hematogenous transplacental transmission is felt to play a critical role in the pathogenesis³, as disruption from the inclusion viral material may cause cell damage versus cell death and subsequent sequelae.

Differential diagnosis: Many viral prenatal infections including mumps, Ebstein-Barr virus, varicella, or TORCH etiologies (toxoplasmosis, rubella, cytomegalovirus, herpes virus) can clinically mimic congenital cytomegalic inclusion disease. Erythroblastosis fetalis due to Rh incompatibility or ABO incompatibility may present similar findings clinically. Extensive differential diagnoses of splenomegaly are in Table 1.

Prognosis: Neonatal symptomatology of microcephaly, intracranial abnormalities, and seizures are poor prognostic signs². Previous longitudinal studies have indicated that the majority of symptomatic infants have permanent visual, motor, or intellectual disabilities^4-7.

Associated anomalies: Hepatomegaly, splenomegaly, microcephaly, hydrocephaly, hydrops fetalis, intracranial calcifications, cardiovascular defects, gastrointestinal and musculoskeletal defects, ocular lesions, petechiae, neurosensory hearing loss, poor intellectual development, IUGR, and ascites.

MESH Cytomegalovirus inclusion disease BDE 0381 POS 3220 ICD9 771.1 CDC 771.100 

Introduction

There are rare case reports^8-12 and one small series of antenatal sonographic findings with confirmed fetal cytomegalovirus infection. Only one case report has described both hepatomegaly and splenomegaly in a cytomegalovirus infected fetus with intrauterine growth retardation (IUGR). We describe a case of isolated splenomegaly detected by sonography in a 36-week gestation fetus, which had antenatal laboratory confirmation of prenatal cytomegalovirus infection.

Case report

A 23-year-old G₂P₁ Caucasian woman (0 negative, Rh+) was referred for prenatal ultrasound at 22 weeks gestation by EGA for a routine anomaly screen. Her last menstrual periods were unknown. The patient had a normal triple screen at 16-17 weeks gestation. At this time, the amniotic fluid was considered low-normal and the fetus presented no evidence of anomaly. The measurements were consistent with a 20-week size. Three weeks later, a follow-up scan was performed. The biometry and measurements were consistent with 3 weeks growth. The fluid volume had increased to the 50^th percentile. The stomach was not seen at this time, and it was thought to be empty. Two weeks later, the ultrasound demonstrated a normal fetal stomach position and amniotic fluid. Seven weeks later, growth retardation was suspected, as the maternal abdomen size failed to increase appropriately. The ultrasound examination now revealed a small fetal chest with a normal heart. The amniotic fluid was low-normal (AFI: 25^th percentile) for 36/37 week gestation.

The biometry of the fetus confirmed growth retardation with measurements of 32/33 week size and splenomegaly. The spleen measured 6x5x2 cm, reaching the fetal umbilicus (fig. 1). A viral infection was suggested.

Figure 1: Scan at 33 weeks demonstrates splenomegaly and oligohydramnios.

Blood analysis was negative for HIV. A TORCH profile verified an acute maternal cytomegalovirus infection. The lab values were as follows: toxo IGM: 0.2 Index (Negative results < 0.5 Index), toxo IGG: 0.1 IU/ml (Negative < 6 IU/ml), cytomegalovirus IGM: 1.0 Index (Negative < 0.500 Index), cytomegalovirus IGG: 250 AU/ml (Negative < 15 AU/ml), rubella: 57 (Negative >10 IU/ml). The patient spontaneously went into labor 4 days later.

The male newborn had an Apgar of 8 at 1 minute and 9 at 5 minutes. He weighed 2220g (5^th percentile). The neonate presented with congenital deafness, splenomegaly, microcephaly, and petechiae: culture and TORCH titers were positive for cytomegalovirus. The cord blood typed A-negative. A Coombs test was negative, which ruled out ABO incompatibility. The normal antenatal intracranial findings were confirmed with a normal study of neonatal head. The infant was fitted with bilateral hearing aids and will be monitored closely over the next few developing years.

Discussion

Incidence

Cytomegalovirus antibodies are identified in 44% to 100% of the adult population². In the United States, pregnancy is often complicated by infection with cytomegalovirus¹³. The occurrence of maternal cytomegalovirus differs with maternal age, parity, socioeconomic status, and stage of gestation. Day care workers, dialysis technicians, and nursery hospital personnel are at the highest risk. Most primary and nearly all recurrent maternal cytomegalovirus infections are asymptomatic in the mother.

With the change in society lifestyle and more children in day-care, there is an increasing incidence of cytomegalovirus infection in the United States¹⁷ . More than 9000 infants demonstrate sequelae from the 30,000 to 40,000 cytomegalovirus congenitally infected infants born in the United States each year¹⁸. Cytomegalovirus has become the most frequent cause of perinatal viral infection and is responsible for 3000 new cases of mental retardation each year¹⁹. Cytomegalovirus is the primary cause of congenital viral deafness²⁰.

Prenatal infection

Congenital infection usually occurs in a fetus of a mother with primary infection, with timing of the maternal infection and fetal stage of development considered a critical factor¹⁴, as there is a 40-50% risk of giving birth to a clinically symptomatic infected neonate¹⁵. Cytomegalovirus transmission has been occasionally reported in consecutive pregnancies in women who are seropositive, but such infants are rarely adversely affected¹⁵ , as maternal antibody prior to conception provides substantial protection¹⁵. Worldwide estimates that 0.2-2.4% of liveborn infants acquire the virus perinatally¹; of these, only 10% will demonstrate classic signs of illness at birth². An additional 5-15% of asymptomatic congenitally infected infants will demonstrate late sequelae of deafness, neurodevelopmental delay, and/or chorioretinitis.

Prenatal diagnosis

In a study in Brussels, Belgium (1985 to 1992), 52 women at risk for congenital cytomegalovirus infection were investigated using ultrasound examinations, amniocentesis, and fetal blood sampling. Other nonspecific blood testing was done such as white blood cell count, hemoglobin, hematocrit, platelets, and gamma-glutamyl transferase determination. With results of all testing, antenatal diagnosis of cytomegalovirus was made in 13 of 16 fetuses¹⁷. The ultrasound findings in the literature are isolated case reports, and a few small series of cytomegalovirus infected fetuses were reviewed. Drose et al reported the largest series of ten fetal cytomegalovirus confirmed-infection patients⁸. The amniotic fluid was normal in one, decreased in six, and increased in three⁸. The placenta was enlarged in only 50%⁸. Antenatal ultrasound findings included (Table 1) hydrocephalus (3), periventricular calcifications (2), inhomogeneous brain parenchyma (2), microcephaly (1), ascites (3), bilateral pleural effusions (1), growth retardation (2), cardiomegaly (2), septal abnormalities (2), and multiple cystic areas in the pelvis (1)⁸. Microcephaly, periventricular calcifications, cerebral ventriculomegaly, and IUGR have been noted in other reports^{3,8,9,10, 16,21,22}. Polyhydramnios and placental enlargement were previously described by Price et al²⁴. A fetal abdominal echogenic mass has been described in several separate case reports^{8,11,12,16,21, 24,25,26,}. A single case report had previously noted splenomegaly and IUGR but with associated microcephaly and hepatomegaly⁹. Antenatal ascites^8,11,21,24 and/or hydrops fetalis^19,20 is a poor prognostic indicator with 100% fetal demise.

Table 1: Prenatal findings in cytomegalovirus infection.

Amniotic fluid: normal, decreased or increased Placenta enlarged (50%)8 Hydrocephalus Periventicular calcifications Inhomogeneous brain parenchyma Microcephaly Ascites Bilateral pleural effusions Growth retardation Cardiomegaly Septal abnormalities Cystic areas in the pelvis Echogenic abdominal mass Splenomegaly Hepatomegaly Hydrops Fetal demise

Differential diagnosis

The differential diagnosis of splenomegaly in an infant or fetus presents a puzzling diagnostic dilemma. The differential diagnosis of splenomegaly in a fetus has not been established. However, the differential for an enlarged spleen in an infant is similar to an adult (Table 2), with the exception of no reported cases of lymphoma, multiple myeloma, rheumatoid arthritis, or Felty"s syndrome. With most etiologies presenting as a neonate or infant, it is conceivable that a very early presentation of some of the disorders could occur in the fetus.

Table 2: Disorders associated with splenomegaly in children.
Infections	Nonspecific splenitis of blood-borne infections Infective endocarditis Infectious mononucleosis Tuberculosis33,34 Typhoid fever Brucellosis35 Cytomegalovirus Syphilis Malaria36,37 Histoplasmosis Toxoplasmosis Kala-azar39,40 Trypanosomiasis Schistosomiasis41,42 Leishmaniasis40 Echinococcosis Human immunodeficiency virus Mumps46 Mononucleosis Rubella virus47
Congestive states related to portal hypertension (Bantis disease)	Liver cirrhosis44 Portal or splenic vein thrombosis48 Right-sided cardiac failure
Lymphohematogenous disorders	Hodgkin"s disease Non-Hodgkin"s lymphoma Histiocytoses (Gaucher"s, Niemann Pick, ) (Langerhans cell histocytosis)44,49,50 Multiple myeloma Myeloproliferative syndromes51,52 Hemolytic anemias Thalasemia44 Leukemia Hereditary spherocytosis53 Acquired hemolytic disease of the newborn54 Sickle-cell anemia55,56 Thrombocytopenic purpura Collagen diseases Systemic lupus erythematosus Felty"s syndrome Rheumatoid Arthritis
Miscellaneous	Sarcoidosis Amyloidosis Gargoylism hemochromatosis (Wilson"s disease) Morquio-Brailsford syndrome57 Turner syndrome
Splenic tumors	Hemangioma Lymphangioma Lymphangiosarcoma

Splenomegaly is usually secondary to systemic illness, signifying an abnormality of the lymphoid, reticuloendothelial, or vascular components of the spleen. The most common cause of splenomegaly is infection, but other categories include hematologic, metabolic, vascular, neoplastic, congestive states and miscellaneous disorders.

In our case, without evidence of splenic infarction, mass lesion, portal or splenic vein thrombosis, cavernous transformation of the portal vein, or other organ abnormalities, the suspected etiology was primarily splenic lymphoid hyperplasia from an infectious agent, hemolytic disease of the newborn with compensatory hematopoietic recruitment, or leukemia.

Less likely considerations included other lymphohematogenous disorders, storage diseases, reticuloendithelioses, and lupus erythematous syndrome. Initial blood analysis demonstrated no lymphohematogenous disorders or erythroblastosis fetalis. Seronegative titers to HIV, toxoplasmosis, herpes simplex virus, rubella, hepatitis with seropositive confirmation of cytomegalovirus from urine and blood established the diagnosis.

Associated anomalies

The associated anomalies with cytomegalovirus cover a wide range of systems. Congenital cytomegalic inclusion disease is classically associated with periventricular calcifications, petechiae, splenomegaly, hepatomegaly, prematurity, hydrocephaly, intrauterine growth retardation, jaundice, microcephaly, chorioretinitis, deafness, and intellectual developmental delay^2,18.

Presentation in the newborn

Clinical presentation of petechiae, jaundice, splenomegaly, and neurosensory hearing loss are typical congenital cytomegalovirus sequelae.

Comments

Early detection of IUGR with subsequent sonographic follow-up evaluation allowed detection of the isolated splenomegaly in our case. Ultrasound abnormalities in isolation may not suggest a definitive diagnosis but does alert the physician to the possibility of a prenatal congenital disease or disorder and the need for further evaluation. As more information is accrued, detection of fetal splenomegaly in utero may represent a sign of early infection and provide predictive value of multi-organ involvement. From review of previous case reports, antenatal ascites and/or hydrops fetalis is a poor prognostic indicator. Since prenatal diagnosis of fetal cytomegalovirus infection has been reported using amniotic fluid analysis, cordocentesis, and fetal blood analysis^{16,20,22,28,29,30,31,32} after an active maternal infection is documented, sonographic evaluation of the fetus is an important fetal screen modality21. If further trials with dosage and administration of ganciclovir in neonates is successful in ameliorating the sequelae of cytomegalovirus infection, early sonographic detection of abnormalities and appropriate follow-up studies will play a role in fetal management.

References

1. Berge P, Stagno S, Federer W, et al. Impact of asymptomatic congenital cytomegalovirus infection on size at birth and gestational duration. Pediatr Infect Dis J 1990; 9:170-175.

2. Bale JF Jr. Human cytomegalovirus infection and disorders of the nervous system. Arch Neurol 1984; 41:310-320.

3. Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus infection in pregnancy: incidence transmission to fetus, and clinical outcome. JAMA 1986; 256:1904-1908.

 4. McCracken GH Jr, Shinefield HR, Cobb K, et al. Congenital cytomegalic inclusion disease. A longitudinal study of 20 patients. Am Dis Child 1969; 117:522-539.

 5. Williamson WD, Desmond MM, Lafevers N, et al. Symptomatic congenital cytomegalovirus: disorders of language, learning, and hearing. Am J Dis Child 1982; 136:902-905.

 6. Conboy TJ, Pass RF, Stagno S, et al. Early clinical manifestations and intellectual outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 1987; 14:343-348.

 7. Berenburg W, Nankervis G. Long-term follow-up of cytomegalic inclusion disease of infancy. Pediatrics 1970; 46:403-410.

 8. Drose JA, Dennis MA, Thickman D. Infection in utero: US findings in 19 cases. Radiology 1991; 33:239-242.

9. Eliezer S, Feldman E, Ehud W, et al. Fetal splenomegaly, ultrasound diagnosis of cytomegalovirus infection: a case report. JCU 1984; 12:520-521.

10. Twickler DM, Perlman J, Maberry MC. Congenital cytomegalovirus infection presenting as cerebral ventriculomegaly or antenatal sonography. Am J Perinatol 1993; 10:404-406.

11. Szeifert G, Csecsei K, Toth Z, et al. Prenatal diagnosis of ascites caused by cytomegalovirus hepatitis. Acta Paediatr Hung 1985; 26:311-316.

 12. Pletcher BA, Williams MK, Mulivor RA, et al. Intrauterine cytomegalovirus infection presenting as fetal meconium peritonitis. Obstet Gynecol 1991; 78:903-905.

13.Kumar ML, Nankeruis GA, Cooper AR, et al. Postnatally acquired cystomegalovirus in infants of cytomegalovirus-excreting mother. J Pediatr 1984; 104:669-73.

14.Stern H, Tucker SM. Prospective study of cytomegalovirus infection in pregnancy. Br Med J 1973;2:268-272.

15. Rudolphs pediatrics. 19th edition. Rudolph AM, ed. East Norwalk, CT: Appleton & Lange, 1991.

 16. Donnor C, Liesnord C, Content J, et al. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol 1993; 82:481-6.

 17. Dobbins JG, Stewart JA, Demmler GJ. Surveillance of congenital cytomegalovirus disease, 1990-91. Collaborating Registry Group. MMWR CDC Surveillance Summaries, 1992; 42:35-39.

18. Demmler GJ. Infectious diseases of America and centers for disease control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991; 13:315-329.

19. Mostoufi-Zadech M, Driscoll SG, Biano SA, et al. Placental evidence of cytomegalovirus infection of the fetus and neonate. Arch Pathol Lab Med 1984; 108:403-6.

20. Strauss M. A clinical pathologic study of hearing loss in congenital cytomegalovirus infection. Laryngoscope 1985; 95:951-62.

21. Hogge WA, Buffone GJ, Hogge JS. Prenatal diagnosis of cytomegalovirus infection: a preliminary report. Prenat Diagn 1993; 13:131-136.

22. Lynch L, Daffos F, Emanuel D, et al. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 1991; 165:714-718.

23.Williamson WD, Perry AK, Yow MD, et al. Asympotomatic congenital cytomegalovirus infection. Am J Dis Child 1990; 144:1365-1368.

24. Price JM, Fisch AE, Jacobsen J. Ultrasonic findings in fetal cytomegalovirus infection. JCU 1978; 6:268-300.

25. Dechelotte PJ, Mulliez NM, Bouvier RJ, et al. Pseudo-meconium ileus due to cytomegalovirus infection: a report of three cases. Pediatr Pathol 1992; 12:73-82.

26. Foronzan I. Fetal abdominal echogenic mass: an early sign of intrauterine cytomegalovirus infection. Obstet Gynecol 1992; 80:535-537.

27. Etches PC, Lemous JA. Nonimmune hydrops fetalis: report of 22 cases including three siblings. Pediatrics 1979; 64:326-332.

28. Meisel RL, Alvarez M, Lynch L, et al. Fetal cytomegalovirus infections: a case report. Am J Obstet Gynecol 1990; 162:663-664.

29. Weiner CP, Grose C. Prenatal diagnosis of congenital cytomegalovirus infection by virus isolation of amniotic fluid. Obstet Gynecol 1990; 163:1253-1255.

30. Hohlfeld P, Vial Y, Maillard-Brignon C, et al. Cytomegalovirus fetal infection: prenatal diagnosis. Obstet Gynecol 1991; 78:615-618.

31. Lamy ME, Mulongo KN, Gadisseux JF, et al. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 1992; 166:91-94.

32. Dinsmoor JM, Grossman JH. Perinatal viral and parasitic infections. ACOG Technical Bulletin 177, February 1993.

33. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991; 10:832.

34. Schaaf HS, Gie RP, Beyers N, et al. Tuberculosis in infants less than 3 months of age. Arch Dis Child 1993; 69:371-374.

35. Benjamin B, Annobil SH. Childhood brucellosis in southwestern Saudi Arabia: a 5 year experience. J Trop Pediatr 1992; 38:167-172

36. Hulbert TV. Congenital malaria in the United States: report of a case and review. Clin Infect Dis 1992; 14:922-926.

37.Emanuel B, Aronson N, Schulman S. Malaria in children in Chicago. Pediatrics 1993; 92:83.

38. Vogt M, Burghard R, Ruschoff J. Congenital malaria- a rare neonatal infection. Monatsschr Kinderheilkd 1990; 138:224-226.

39. Barclay AJ, Coulter JB. Tickborne relapsing fever in central Tanzania. Trans R Soc Trop Med Hyg 1990; 84:852-856.

40. Zijlstra EE Alims K, el-Hassan AM, et al. Clinical aspects of Kala-Azar in children from the Sudan: a comparison with the disease in adults. 1992; 38:17-21.

41. Wiest PM, Wu G, Zhong S, et al. Schistosomiasis japonica on Jishan Island, Jiangxi Province, Peoples Republic of China: persistent hepatic fibrosis after reduction of the prevalence of infection with age. Trans R Soc Trop Med Hyg 1993; 87:290-294.

42. Gryseels B. The epidemiology of schistosomiasis in Burundi and its consequences for control. Trans R Soc Trop Med Hyg 1991; 85:626-633.

43. Desinor-Mompoint OI, Gonzalez-Saldana N, Palacios-Saucedo G, et al. AIDS in children. Experience at the National Institute of Pediatrics. Bol Med Hosp Infant Mex 1992; 49:566-572.

44. Shah R, Mahour GH, Ford EG, et al. Partial splenic embolization. An effective alternative to splenectomy for hypersplenism. Am Surg 1990; 56:774-777.

45. Ades AE, Newell ML,Peckham CS, eds. Children born to women with HIV-1 infection: natural history and risk of transmission. European collaborative study. Lancet 1991; 337:253-260.

46. Lacour M, Maherzi M, Vienny H, et al. Thrombocytopemia in a case of neonatal mumps infection: evidence for further clinical presentations [Review]. Eur J Pediatr 1993; 152:139-141.

47. Sugita K, Ando M, Makino M, et al. Magnetic resonance imaging of the brain in congenital rubella virus and cytomegalovirus infections. Neuroradiology 1991; 33:239-242.

48. Glassman MS, Klein SA, Spivak W. Evaluation of cavernous transformation of the portal vein by magnetic resonance imaging [Review]. Clin Pediatr 1993; 32:77-80.

49. Henter JI, Elinder G, Soder O, et al. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistocytosis. Acta Paediatr Scand 1991; 80:428-430.

50. Kelly DA, Portman B, Mowat AP, et al. Pick disease type C: diagnosis and outcome in children. J Pediatr 1993; 123:242-247.

51. Hickman MP, Lucas D, Novak Z, et al. Preoperative embolization of the spleen in children with hypersplenism. J Vasc Radiol 1992; 3:647-652.

52. Mallouh AA, Sadi AR. Agnogenic myeloid metaplasia in children. Am J Dis Child 1992; 146:965-967.

53. Koh MT, Ng SC. Hereditary spherocytosis: a study of 16 patients from University Hospital, Kuala Lumpar. Singapore Med J 1991; 32:67-69.

54. al-Awami SM, al-Salem AH, Knox-Macaulay H, et al. Splenectomy for hematological disorders in the eastern province of Saudi Arabia. Int Surg 1992; 77:60-63.

55. Christakis J, Vavatsi N, Hassapopoulou H, et al. A comparison of sickle cell syndrome in northern Greece. Br J Hematol 1991; 77:386-391.

56. Adekile AD, McKie KM, Adeodu OO, et al. Spleen in sickle cell anemia: comparative studies of Nigerian and US patients. Am J Hematol 1993; 42:316-321.

57. Tzanova I, Schwarz M, Jantzen JP. Securing the airway in children with the Morquio-Brailsford syndrome. Anaesthesia 1993; 42:477-481.

58. George CD, Patton MA, el Sawi M, et al. Abdominal ultrasound in Noonan syndrome: a study of 44 patients. Pediatr Radiol 1993; 23:316-318.

Originally published in The Fetus in 1994, posted 6/1999