Cytomegalovirus (CMV) is the most common cause of congenital viral infection, affecting 0.2 to 2.3% of all live births in developed countries;1-12 it is also estimated as the leading infectious cause of non-genetic hearing loss, mental retardation1,2,13-15 and non-genetic congenital malformations.16 Very low birth weight and extremely low birth weight newborns are at higher risk of symptomatic CMV infection, most commonly secondary, acquired through breast milk.17
Maternal primary CMV infection or reinfection during pregnancy are the cause of neonatal congenital infection, with a mean risk of transmission of 40% (24-75%),3,18 lower in the first three months (36%) than in the last three months of gestation (78%).3,19
Considering all the infected newborns, only 5 to 10% are symptomatic at birth, in particular with neurodevelopmental delay signs and sensorial hearing loss. Among asymptomatic patients, 10% to 15% will show developmental disorders, mainly sensory hearing loss.1,2,8,10,11,13,14,20-22 Most of congenital infections (85-90%) remain asymptomatic:3,16,23 among them, 8 to 15% will show developmental disorders or sensorial hearing loss.1-3,13,14
Possible signs and symptoms of congenital CMV infection with onset at birth are the following:3,16,24 unilateral or bilateral sensorial hearing loss, visual loss, microcephaly, hepatomegaly and/or hepatitis, splenomegaly, thrombocytopenia, jaundice, petechiae, motor defects, mental disability, chorioretinitis, strabismus, optic atrophy, dental defects. Rarely it could present as a severe multi organ dysfunction with polyserositis.
Gastrointestinal involvement is considered very rare in congenital and acquired CMV infection.7,8,10,11,20 On the other hand, CMV gastrointestinal symptoms could be an important manifestation of postnatal infection in patients admitted to neonatal intensive care units25 or a manifestation of CMV intestinal disease in immunocompromised patients or patients affected by inflammatory bowel disease.22,26-33 A rare presentation with intestinal polyps in immunocompetent healthy patients has also been described.34
A 2330-g female was born at 37 weeks of gestational age through urgent cesarean delivery, necessary due to alterations in foetal cardiac pulse, decline of growth and ultrasound finding of abnormal bowel distension. During pregnancy, serologic conversion for CMV was documented in the third trimester. APGAR score was 2 after the first minute, and 7 at the 5th minute of life.
Due to an important abdominal distension observed immediately after birth, an underlying abdominal pathology was suspected: the patient was promptly transferred to a third level neonatal centre, the neonatal intensive care unit of Niguarda Hospital (Milan, Italy).
Since birth, the baby had passed liquid meconium with subsequent mucus and liquid stools. Radiologic examinations performed immediately after admission showed small-intestinal distension with a widespread intestinal wall thickening. Through thoracic and abdominal Xray, abdominal ultrasound and neonatal-surgery expert advice, surgical pathologies were excluded.
Oral feeding was started on the 3rd day of life, with good tolerance but persistence of liquid stools, suggesting colitis as cause of the symptoms.
Urine and blood were tested for CMV DNA through polymerase chain reaction, yielding positive results (1.296.341 and 2.322 copies/mL, respectively). All the other examinations carried out to exclude other CMV localizations (ophthalmologic examination, brain ultrasound) were normal. No specific analysis to confirm a possible relation between CMV and enteric symptoms, such as intestinal biopsy, were done, due to the rapid and progressive improvement of the patient. So we hypothesized a possible association between CMV and gastrointestinal involvement, but it was not proven with invasive tests.
On the 7th day of life, the patient was transferred back to our unit. During hospital stay, gastrointestinal symptoms progressively improved until normalization, with good oral feeding tolerance of both maternal and formula milk and a very good growth curve. Moreover, brain and abdominal ultrasonographies were normal. A follow-up brain magnetic resonance was negative. Neurologic development was normal, with a physiologic course. Any antiviral treatment was started.
Even though gastrointestinal involvement due to congenital or immediately post-natal CMV infection has been considered extremely rare, some case reports have been found in the literature. Table 1 summarizes all the case reports and articles found in a review of the literature. Using PubMed and OVID MEDLINE®, the following key words were searched in titles and abstracts: cytomegalovirus AND colitis or intestine or intestinal or bowel or colic or Hirschsprung AND infant or neonatal or neonate or newborn. Only reports regarding newborns and infants under 3 months of age were considered.
Thirty-eight articles were found up to July 2015. The first report dates back to 1979, when Gretillat et al.36 described a correlation between necrotizing enterocolitis (NEC) and CMV infection, based on inclusion bodies on pathologic examination of bowel specimens.
Most of the studies revealed a possible association between CMV infection and enteritis,22,37,38 enterocolitis,25,42,45-51,54-56,59-61,64 and NEC,17,25,33,36,37,39,40,44,63,65 often with finding of CMV inclusions in histological intestinal samples. It is debatable whether the virus has a role in the pathogenesis of the diseases, either directly or as a secondary super-infection after the acute phase of the enterocolitis.5,22,39,40,53
Four other reports11,38,50,51 described a possible association between CMV infection and intestinal perforation: two ileal perforations,11,43 one perforated appendicitis as a complication of CMV enterocolitis51 and one Merkel’s diverticulum perforation.50
Déchelotte et al.41 described 3 cases of pseudo-meconium ileus caused by a CMV infection, two of which with antenatal ultrasound detection of increased echogenicity of the lower foetal abdomen.
In a 5 year period, Cheong et al.,25 in the neonatal intensive care units of Queen Charlotte’s and Chelsea and Hammersmith Hospitals, identified 16 infants with postnatal CMV infection, eleven of whom with gastrointestinal signs.
Bonnard et al.,50 in a 5-year retrospective study involving neonates operated for gastrointestinal conditions, described the presence of CMV inclusions in five cases: two NEC, two complications of Meckel’s diverticulum (volvulus and perforation) and one distal ileal atresia.
A possible correlation between primary colonic stricture and CMV infection was described in three case reports,5,52,57 whereas two articles53,66 reported an association between ileal stricture and CMV enteritis. Post-necrotizing enterocolitis strictures have been described in three reports.39,40,65 Hendriks et al.62 described an association between CMV infection and intestinal obstruction without strictures.
When data was available, the onset of gastrointestinal symptoms in the first 24 hours of life20,43,50,62 or in the first 7 days of life49 was rarely reported and, respectively, in patients with: ileal ulceration,43 pseudo-Hirschsprung’s disease,20 Merkel’s diverticulum perforation,50 ileal atresia,50 intestinal obstruction62 and enterocolitis.49
The review of the literature suggests that is important to suspect CMV as possible etiologic cause of gastrointestinal symptoms with unknown origin in newborns. The diagnosis of congenital CMV can be done with urine analysis for CMV DNA, a non-invasive and accurate test.
The treatment of congenital CMV infection remains an open and debatable field. While there is agreement to treat CMV positive cases with neurological involvement, and avoiding treatment of CMV positive but asymptomatic patients, the necessity to treat CMV positive newborns with non-neurologic symptoms is controversial. It’s also debatable the real necessity to do the intestinal biopsy in suspected cases, since it is invasive and with uncertain utility on clinical practice.
Gastrointestinal involvement during congenital and post-natal CMV infection is uncommon, in particular in immunocompetent and physiologic newborns. Particularly rare is the onset of these manifestations in the first 24 h of life. The possible association between congenital infection and gastrointestinal involvement has to be suspected in newborns with specific symptoms and unknown origin. The role of invasive tests, such as the intestinal biopsy, and the necessity of a specific antiviral treatment should be considered accurately on each single case, basing also on the review of the literature and recent scientific evaluations.