Congenital CMV associated with diaphragm dysfunction: a rare cause of tachypnoea
- 1 Pediatrics, UC San Diego, La Jolla, California, USA
- 2 Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, California, USA
- 3 Pediatrics, Division of Pediatric Pulmonary Medicine, Rady Children's Hospital San Diego, San Diego, California, USA
- 4 Pediatrics, Division of Neonatology, Rady Children's Hospital San Diego, San Diego, California, USA
- Correspondence to Dr Rebecca Carter; rebecca.carter@ucsf.edu
Abstract
A late preterm infant with intrauterine growth restriction developed respiratory distress, tachypnoea and hypoxia after birth, requiring supplemental oxygen. Chest radiographs demonstrated persistent elevation of the right hemidiaphragm. Chest ultrasound initially demonstrated symmetrical bilateral diaphragm motion, but subsequent ultrasounds showed asymmetrical excursion with weaker movement of the right hemidiaphragm. Placental pathology demonstrated chronic infectious villitis secondary to cytomegalovirus (CMV), and subsequent CMV testing on the infant was positive. The infant was microcephalic and head imaging revealed intracranial calcifications, consistent with congenital CMV infection.
CMV is the most common congenital infection and has a wide array of clinical manifestations. This report highlights the rarely described association between congenital CMV infection and respiratory distress due to underlying diaphragm dysfunction. In neonates with respiratory distress and features of congenital CMV infection, clinicians should have a high index of suspicion for diaphragm dysfunction.
Background
Cytomegalovirus (CMV) is the most common congenital viral infection in the USA, with a prevalence of 0.6% in developed countries.1 2 It is the leading cause of non-hereditary sensorineural hearing loss (SNHL) and a significant cause of neurodevelopmental delay. Though pneumonitis is a well-known respiratory manifestation of CMV infection, there are few reports in the literature of respiratory distress associated with diaphragm dysfunction in congenital CMV.3–6 Here, we present a neonate with symptomatic congenital CMV infection and respiratory distress associated with diaphragm dysfunction.
Case presentation
A female infant was born by caesarean section for non-reassuring fetal status at 34 weeks and 5 days to a G3P3 woman in her 40s. Prenatal testing demonstrated fetal growth restriction with estimated fetal weight <1st percentile with resistive umbilical artery Doppler. Maternal evaluation for Toxoplasma, rubella, CMV and herpes simplex virus (TORCH) infections revealed a positive CMV IgG and negative CMV IgM. IgG avidity was not performed. The mother received a complete course of betamethasone prior to delivery. Rupture of membranes occurred at delivery with meconium-stained fluid. Delivery of the infant by caesarean section was atraumatic. Apgar scores were 8, 7, and 9, at 1, 5, and 10 min of life, respectively. Arterial and venous cord gases were reassuring. The infant required initiation of positive pressure ventilation at 5 min of life for transient bradycardia, after which she stabilised on mask continuous positive airway pressure (CPAP) and was admitted to the neonatal intensive care unit. The infant’s birth weight was at the third percentile (1615 g), length was 10% and head circumference was 3% per Fenton preterm girls growth chart. Physical examination demonstrated a vigorous infant with no grunting or increased work of breathing, a respiratory rate of 51 and lungs clear to auscultation. She moved all four extremities well and tone was appropriate for gestational age. The abdomen was non-distended with no hepatosplenomegaly. The skin was mottled without petechiae. Chest radiograph was obtained on admission due to the infant’s need for CPAP beyond the delivery room, and demonstrated an elevated right hemidiaphragm (figure 1). The infant was weaned to room air at 6 hours of life but subsequently developed tachypnoea and hypoxia without significant retractions or distress. Supplemental oxygen with fractional inspired oxygen 0.3 on 1 L/min nasal cannula was initiated with resolution of hypoxia, and further evaluation was pursued.
Chest radiograph. Admission chest radiograph on the first day of life demonstrated an elevated right hemidiaphragm.
Investigations
The infant remained stable on supplemental oxygen via nasal cannula. She remained tachypnoeic but without increased work of breathing or retractions, and blood gases revealed adequate gas exchange. Four serial chest radiographs over the first week of life demonstrated persistent elevation of the right hemidiaphragm. Chest ultrasound on day of life (DOL) 2 showed symmetric bilateral diaphragm movement. Echocardiogram and ECG were reassuring. Laboratory evaluation revealed thrombocytopenia to 73×109/L, which normalised without intervention. Total and direct serum bilirubin and transaminases were within normal limits. Head ultrasound (HUS) was recommended due to intrauterine growth restriction but was initially declined.
Placental pathology demonstrated extensive chronic villitis and plasma cells, suggestive of TORCH infection. Special stains and immunohistochemistry were negative for Treponema pallidum, Toxoplasma gondii and herpes simplex virus. Immunohistochemistry for CMV resulted positive on DOL 27 for minute foci, consistent with infectious villitis secondary to CMV.
Given the placental findings of infectious villitis secondary to CMV and fetal growth restriction, we sent urine and serum CMV DNA PCR qualitative and quantitative studies on DOL 28, which resulted positive (plasma CMV 7370 IU/mL). Because these tests were sent after 3 weeks of age, we obtained retrospective testing of newborn screen dried blood spots, which were positive for CMV, and supported the diagnosis of congenital CMV infection.
We obtained an HUS on DOL 28, which revealed intracranial calcifications (figure 2), consistent with congenital CMV infection and cystic changes with ventricular enlargement, thought to represent either cerebral atrophy related to CMV disease or subacute intraventricular haemorrhage with secondary hydrocephalus. Brain MRI confirmed HUS findings, redemonstrating periventricular calcifications consistent with congenital CMV infection and ventricular dilation. Ophthalmology evaluation was negative for chorioretinitis, and auditory brainstem response hearing screen was passed at 3 and 6 weeks of life.
Head ultrasound. Head ultrasound demonstrated periventricular intracranial calcifications consistent with congenital cytomegalovirus (CMV) infection and cystic changes with ventricular enlargement, thought to represent either cerebral atrophy related to CMV disease or subacute intraventricular haemorrhage with secondary hydrocephalus. Curved arrows indicate cystic changes from subacute intraventricular haemorrhages. Stars indicate ventricular enlargement. Straight arrows indicate intracranial calcifications.
Differential diagnosis
We considered phrenic nerve injury, CMV pneumonitis and meconium aspiration as contributors to respiratory distress. However, phrenic nerve injury was thought to be unlikely given the infant’s atraumatic delivery. CMV pneumonitis was thought to be unlikely given the patient’s mild respiratory symptoms and the radiographic absence of diffuse ground-glass infiltrates that are typical of this condition. Meconium aspiration was thought to be unlikely given the radiographic absence of diffuse bilateral patchy opacities and hyperinflation that are typical of this condition. Genetic testing was not pursued.
Treatment
The infant started valganciclovir treatment on DOL 29. She was discharged home at 6 weeks of age on 0.25 L/min nasal cannula flow with 100% oxygen after several failed attempts to wean to room air.
Outcome and follow-up
Repeat chest ultrasound at 2 months of age showed asymmetric excursion with weaker movement of the right hemidiaphragm compared with the left but no paradoxical motion. She was successfully weaned off supplemental oxygen at 4 months of age. Outpatient audiology evaluation demonstrated moderate-to-severe asymmetric SNHL on brainstem auditory evoked response at 4 months of age, and she was referred to otolaryngology for cochlear implant evaluation. At 5 months, she achieved appropriate developmental milestones for her corrected gestational age. She remains under the supervision of many outpatient subspecialists including neurology, audiology, pulmonology, otolaryngology and developmental paediatrics. Repeat diaphragm ultrasound at 6 months of age showed persistent asymmetric excursion with decreased movement of the right hemidiaphragm.
Discussion
This report describes a preterm neonate with fetal growth restriction, intracranial calcifications, thrombocytopenia and mild respiratory distress with associated diaphragm dysfunction in the setting of congenital CMV infection. Four prior reports in the literature describe cases of congenital CMV infection and associated diaphragm dysfunction, with clinical courses ranging from early neonatal death3 4 to survival into infancy with or without need for prolonged mechanical ventilation.5 6 Our report describes a mild clinical course with supplemental oxygen requirement for the first 4 months of life.
Dysfunction of the neonatal diaphragm can be due to a variety of causes, including impaired innervation, contractile function or mechanical coupling to the chest wall, and may be a result of congenital or acquired abnormalities. Congenital abnormalities include aplasia, hypoplasia and hernias. Acquired abnormalities are generally the result of traumatic injury to the phrenic nerve due to birth injury or during cardiothoracic surgery.7 Diaphragm paralysis is poorly tolerated in the neonate due to high compliance of the chest wall and weakness of accessory respiratory muscles. It may present with tachypnoea, atelectasis, respiratory failure, pneumonia or difficulty weaning from respiratory support, even in unilateral cases. Eventration, or elevation of part or all of the diaphragm into the thoracic cavity, was present in this case as evidenced by persistent elevation of the right hemidiaphragm on chest radiographs. Acquired abnormality, or phrenic nerve injury, was felt to be unlikely given the infant’s atraumatic delivery. Rather, congenital eventration related to aplasia or hypoplasia of the diaphragm was felt to be more likely. The majority of congenital eventrations involve muscle replacement by fibroelastic tissue in partial segments of the diaphragm and most commonly affect the right hemidiaphragm, as in our case. Causes have been related to both genetic and infectious conditions, including CMV.8 Two case reports describing postmortem findings in infants with congenital CMV demonstrated muscular hypoplasia of the diaphragm.3 4 One report of several infants with diaphragm dysfunction and congenital CMV proposed a mechanism of disrupted diaphragm myocyte differentiation or migration due to CMV infection.5
The presence of an elevated hemidiaphragm on chest radiograph may be suggestive of diaphragm paralysis but has poor sensitivity. Diaphragm ultrasound and fluoroscopy can assess for absent, reduced, asymmetric or paradoxical diaphragm movement during spontaneous respiration.9 10 Diaphragm ultrasound has been identified as a highly sensitive and specific tool for diagnosis of neuromuscular diaphragm dysfunction.11 In this report, the infant’s initial chest ultrasound on DOL 2 demonstrated bilateral symmetric diaphragm excursion; however, repeat ultrasound at 2 months of life showed asymmetric excursion with weakness of the right hemidiaphragm. Negative initial findings may have reflected inadequate optimisation of images and the operator dependence of ultrasound. The presence of asymmetric diaphragm motion on two subsequent ultrasounds at 2 and 6 months of age is suggestive of diaphragm paresis or eventration and is consistent with chest radiograph findings of persistent right hemidiaphragm elevation. We are unable to distinguish between diaphragm paralysis and muscle hypoplasia in this case because phrenic nerve conduction studies and electromyography were unable to be performed.
Primary maternal CMV infection confers the highest risk of vertical transmission, with approximately one-third of cases resulting in vertical transmission.1 However, the majority of congenital CMV infections in the USA are a result of non-primary maternal infection, either due to reactivation of latent infection or reinfection with a different strain.12 The frequency of congenital CMV and spectrum of disease after non-primary CMV infection is unclear due to challenges in the diagnosis of non-primary CMV.13 CMV IgG avidity may help identify pregnant women at increased risk of vertical CMV transmission,14 as in the case described here, when maternal CMV IgG is positive and CMV IgM is negative.
Detection of CMV in urine or saliva by viral culture or PCR in the first 3 weeks of life is diagnostic of congenital CMV infection. After 3 weeks, detection of CMV in body fluids cannot discriminate between congenital and postnatal infection, the latter of which is often benign and self-limited. PCR analysis of dried blood samples obtained for newborn screening indicates CMV viraemia and can be performed retrospectively to support a diagnosis of congenital CMV.15 16 In the case described here, positive CMV testing of the placenta resulted in the fourth week of life. The infant’s positive urine and serum CMV testing confirmed CMV infection; retrospective CMV PCR testing of the infant’s dried blood samples from newborn screening confirmed congenital CMV. Initiation of valganciclovir is recommended in infants with symptomatic congenital CMV infection as soon as virological testing is confirmed. Among infants with symptomatic congenital CMV, randomised clinical trials have demonstrated that a 6-month treatment course of oral valganciclovir initiated in the first month of life has favourable effects on long-term hearing and neurodevelopmental outcomes.17 As in the case described, infants with congenital CMV disease are at risk of SNHL but may not be identified on newborn hearing screen. They require continued surveillance of hearing status during early childhood.
In conclusion, we report a case of symptomatic congenital CMV infection due to maternal non-primary infection in a preterm newborn with respiratory insufficiency and diaphragm dysfunction. Though a causal link between congenital CMV and diaphragm dysfunction has not been established, this case adds to the existing literature describing the association of congenital CMV infection and diaphragm dysfunction. Evaluation of newborns with features of congenital CMV and respiratory insufficiency should include diaphragmatic evaluation. Successful medical management of diaphragm dysfunction with supplemental oxygen and adequate growth can avoid surgical intervention in these cases.
Learning points
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Cytomegalovirus (CMV) is the most common congenital infection worldwide and is the leading cause of sensorineural hearing loss.
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Most infants are asymptomatic at birth, but 10% will have symptoms including growth restriction, petechiae, hepatosplenomegaly and respiratory insufficiency.
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Primary maternal CMV infection confers the greatest risk of transmission, but most CMV cases are from reinfection or reactivation.
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Congenital CMV can be diagnosed at >3 weeks of life with a PCR analysis of dried blood samples obtained for newborn screening.
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Newborns with congenital CMV and respiratory insufficiency should undergo diaphragmatic evaluation.
Ethics statements
Patient consent for publication
Footnotes
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Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content—RC, MY, JR and KW. The following authors gave final approval of the manuscript—RC, MY, JR and KW.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
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