return to: Hearing Loss Clinic or Congenital CMV Hearing Loss

GENERAL CONSIDERATIONS

• Complete history and physical as per instructions in Hearing Loss Clinic
• Document NBHS information as well as most recent hearing test

INDICATIONS FOR TREATMENT

• Positive cCMV diagnosis
  • Saliva rapid culture, saliva or urine PCR within the 21 first days of life or DBS CMV PCR assay
  • If a patient has signs and symptoms of symptomatic cCMV they should be referred to infectious disease for further workup
• Confirmed hearing loss through aABR on confirmatory testing after NBHS
• Exclude other causes of hearing loss: syndromic or non-syndromic genetic causes, other TORCH infections, drug induced, meningitis, etc.
• < 30 do
  • No child in the study group had therapy started after 29 days of life. There is no evidence for treatment efficacy after this time period, though treatment may still be offered depending on the child circumstance after discussion with parents. Infectious disease consultation may also be appropriate for those children outside of this window.

EVIDENCE FOR TREATMENT BENEFIT

• In patients with symptomatic CMV the most comprehensive study showed statistically significant maintenance or improvement at 6 months in the best hearing ear. For 6 months of Valganciclovir this was maintained in 73% of patients at 12 and 24 months. Children in the Valganciclovir group also showed better neurodevelopmental assessments at 24 months (Kimerlin 2015)
• Consensus guidelines suggest that therapy should NOT routinely be recommended for children with congenital CMV with isolated sensorineural hearing loss (SNHL) (Rawlinson 2017).
• After this consensus statement was published a retrospective study of children with isolated SNHL who had antiviral therapy was conducted showing 69% improvement in affected ears (Pasternak 2018).
• Our local pediatric infectious disease group has reviewed current literature and has occasionally recommend treatment in these cases because of the significant potential benefit of improved hearing and developmental outcomes. This should be a shared decision between parents and practitioner after adequate discussion.

POTENTIAL COMPLICATIONS

• Leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia and bone marrow failure (including aplastic anemia) are possible. In the most comprehensive trial of valgancyclovir for symptomatic cCMV hearing loss 19% of patients in the valgancyclovir treatment group had neutropenia in the first 6 weeks and 21% when measured at 4.5 months (Kimerlin 2015).
  • Cell counts usually return to baseline 3-7 days after discontinuing the drug (Lexicomp).
• Animal studies have generated reports of gonadal toxicity and carcinogenicity. These have not been seen in humans

TREATMENT

• Valganciclovir 16 mg/kg/dose, oral BID for 6 months
  • Our UIHC pharmacy uses a 50mg/ml solution
  • Valganciclovir should be given with meals
  • Renal dosing may be used using the formula: 7*BSA*(creatinine clearance) = mg/dose
  • There is no data on hepatic dosing
  • Containdications: hypersensitivity to valganciclovir, ganciclovir or any ingredient in the formulation, patients with ANC <500/mm³, platelet count <25,000/mm³, or a hemoglobin concentration < 8g/dL.
  • Generally we would not start treatment in a patient with asymptomatic cCMV unless the ANC >1000/mm³
• Weight based monthly re-dosing will be required. Expected follow up in hearing loss clinic at 1 month. Subsequent follow up can be performed with the child's pediatrician for weights. If the pediatrician is comfortable writing for Valganciclovir this is acceptable, otherwise they will need to inform us of monthly weight changes so that we may adjust dosing accordingly.
• The patient should follow up in clinic and receive a repeat hearing test after completion of treatment.
• Referral to Ophthalomology and CDD for initial evaluation for risks secondary to congenital CMV

LABWORK

• Obtain baseline labwork at or before the first visit including: CBC with Diff, Liver function panel (Bilirubin, ALP, AST, ALT, GGT, Total Protein, Albumin)
• Obtain CBC and creatinine weekly for 6 weeks, then at 8 weeks, then monthly for the duration of antiviral treatment
• Monthly ALT monitoring
• If done locally, labwork must be faxed to our clinic. This may be done by writing an external lab order including our fax number (319-356-4547) with ATTN: Hearing Loss Clinic. Cassie will then deliver to the Otolaryngology Pediatric Fellow or R5 on Pediatrics.
• For the purpost of following up labwork:
  • ​Hemoglobin:
    • If Hemoglobin drops <9 g/dL the child will be considered anemic. Re-discuss with the parents about risks and continuing treatment (between weeks 8-12 of life there is a physiologic nadir: Hb 9-11)
    • If the patient has a subsequent drop on the next weeks Hemoglobin, or Hemoglobin <8 g/dL referral to infectious disease. If stable, continue monitoring.
    • If Hemoglobin is <7 g/dL discontinue treament, admission, discuss with pediatrics the need for blood transfuction.
  • ANC​
    • Calculating ANC from UIHC labwork
      • WBC*%Neutrophils = ANC
      • If WBC 8.6 with 55.8% Neurophils; 8.6*55.8 = 4799 ANC
    • If ANC <1000 discontinue treatment, referral to infectious disease, do not recontinue treatment until ANC >1000. 
  • Referral to Infectious disease if Creatinine or ALT Grade 1 (see below) or greater, or Platelets Grade 2 or greater

Grading the severity of adverse events:

Table based of data from DAIDS AE Grading Table referenced below

COMMON PATIENT QUESTIONS

Many answers to questions can be found in this CDC fact sheet (in both English and Spanish) here: English or Spanish

What else should we be looking out for?

CMV infection is associated with a variety of birth defects and developmental disabilities. Generally, children are classified as symptomatic or asymptomatic at birth. Children with isolated hearing loss was included in the asymptomatic group historically and this has continued. These children will often will have additional communication and learning issues or mild vision disorders. They can also have other signs and symptoms of cCMV as every child is unique.

In symptomatic CMV there can be more significant cognitive delays, feeding and sleep issues, cerebral palsy, vision loss, seizures, microcephaly, intracranial calcifications, lack of coordination, jaundice, enlarged liver, enlarged spleen, skin rashes, low platelet and blood counts and in some cases death.

What could have been done differently during pregnancy?

Congenital CMV is transferred from mother to child during pregnancy. This is sometimes the result of a primary infection of the mother (her first exposure to the virus) but can also be the result of reactivation or reinfection. Routine maternal screening is not recommended based on a variety of economic and diagnostic factors. Targeted screening often takes place for women with influenza like symptoms not attributable to another infection or when ultrasound findings are concerning. Ultimately parents and especially mothers may feel guilt related to congenital diagnoses. While this guilt feels legitimate to the parent, they do not share blame for the condition and should be reassured. 0.5% of the U.S. population is born with congenital CMV and only a small portion are symptomatic through mechanisms we do not yet fully understand.

Are further children at risk?

As far as we understand, any subsequent child would have risk of cCMV similar to any other child in the surrounding demographic. Having one child with cCMV does not convey increased risk to subsequent children. Good hygiene practices should be exercised for all pregnant women, avoid sharing food/drink and thorough hand washing.

Expectations for CMV related hearing loss

Ultimately, we do not have data on the long term efficacy of anti-viral treatment in patients with asymptomatic cCMV though preliminary results are encouraging. The natural history of CMV related hearing loss is extremely variable. In children with asymptomatic cCMV hearing loss ~20% have progressive loss and ~24% have fluctuating hearing. Approximately 78% have severe to profound hearing loss and for 42% this hearing loss is bilateral. In 9% of these patients hearing loss is delayed. Some patients with CMV do well with hearing aids for amplification. Others will require cochlear implantation as the most appropriate treatment. If hearing loss appears to be progressive or fluctuating, more frequent hearing testing will be indicated.

REFERENCES/SUGGESTED READING

• Valgancyclovir dosing information based on Lexicomp
• CMV Hearing loss profile:

Goderis, J., et al. “Hearing Loss and Congenital CMV Infection: A Systematic Review.” Pediatrics, vol. 134, no. 5, 2014, pp. 972–982., doi:10.1542/peds.2014-1173.

• CMV consensus recommendations:

Rawlinson, William D, et al. “Congenital Cytomegalovirus Infection in Pregnancy and the Neonate: Consensus Recommendations for Prevention, Diagnosis, and Therapy.” The Lancet Infectious Diseases, vol. 17, no. 6, 2017, doi:10.1016/s1473-3099(17)30143-3.

• Anti-viral treatment:

Kimberlin, David W., et al. “Valganciclovir for Symptomatic Congenital Cytomegalovirus Disease.” New England Journal of Medicine, vol. 372, no. 10, 2015, pp. 933–943., doi:10.1056/nejmoa1404599.

Kimberlin, David W., et al. “Pharmacokinetic and Pharmacodynamic Assessment of Oral Valganciclovir in the Treatment of Symptomatic Congenital Cytomegalovirus Disease.” The Journal of Infectious Diseases, vol. 197, no. 6, 2008, pp. 836–845., doi:10.1086/528376.

Kimberlin, David W., et al. “Effect of Ganciclovir Therapy on Hearing in Symptomatic Congenital Cytomegalovirus Disease Involving the Central Nervous System: a Randomized, Controlled Trial.” The Journal of Pediatrics, vol. 143, no. 1, 2003, pp. 16–25., doi:10.1016/s0022-3476(03)00192-6.

Pasternak, Yehonatan, et al. “Valganciclovir Is Beneficial in Children with Congenital Cytomegalovirus and Isolated Hearing Loss.” The Journal of Pediatrics, vol. 199, 2018, pp. 166–170., doi:10.1016/j.jpeds.2018.02.028.

• Labwork:

National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table) 2004.

Boppana SB. Dried Blood Spot Real-time Polymerase Chain Reaction Assays to Screen Newborns for Congenital Cytomegalovirus Infection. Jama. 2010;303(14):1375. doi:10.1001/jama.2010.423.

Leruez-Ville M, Magny J-F, Couderc S, et al. Risk Factors for Congenital Cytomegalovirus Infection Following Primary and Nonprimary Maternal Infection. Clinical Infectious Diseases. 2017;65(3):398-404. doi:10.1093/cid/cix337.