Secondary Logo

Journal Logo

Congenital Cytomegalovirus Infection and Antiviral Therapy

How to Manage Neutropenia Properly?

Ronchi, Andrea MD; Pietrasanta, Carlo MD; Binda, Sandro DSc, PhD; Mosca, Fabio MD; Pugni, Lorenza MD

The Pediatric Infectious Disease Journal: August 2019 - Volume 38 - Issue 8 - p e190
doi: 10.1097/INF.0000000000002266
Letters to the Editor
Free

NICU Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

NICU Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

NICU Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

NICU Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

The authors have no funding or conflicts of interest to disclose.

Back to Top | Article Outline

To the Editors:

Ziv et al1 in their article emphasize the hematologic adverse effects among infants with congenital cytomegalovirus infection treated with valganciclovir.

We have cared over 12 years for 156 infants with congenital cytomegalovirus infection. Nineteen of them (12.2%) were treated with antiviral therapy (6 ganciclovir/6 weeks, 9 valganciclovir/6 weeks, 4 valganciclovir/6 months) starting at a median age of 6 days (interquartile range: 2–21).

Compared with Ziv et al, who had 28.8% of infants with any grade (Grade 1–4, according to National Institute of Allergy and Infectious Diseases division of AIDS Toxicity Tables, 2004) of neutropenia during the treatment, 52.6% (2/6 on ganciclovir, 8/13 on valganciclovir) of our patients had at least one episode of such adverse effect, 80% of whom had more than one episode (32 episodes of neutropenia overall). Interestingly, according to reference ranges for neutrophils count by Schmutz et al,2 100% of our patients were neutropenic. In our population, 88.8% of episodes occurred in the first 3 weeks of treatment. In Ziv’s population, 5.6% of infants had Grade 3–4 neutropenia, versus 26.3% (2/6 on ganciclovir, 3/13 on valganciclovir) of our patients, who had it mostly (80%) in the first 3 weeks of treatment. The drug was temporarily suspended in 40% of infants with Grade 3–4 neutropenia. Granulocyte colony-stimulating factor was administered to 3 infants. One neonate had a sepsis caused by Klebsiella pneumoniae, with a full recovery, during a Grade 4 neutropenia episode.

There are limited data in the literature about bone marrow toxicity caused by ganciclovir/valganciclovir in infants. Kimberlin et al3 reported Grade 3–4 neutropenia in 63% of infants treated with ganciclovir, 13.8% of whom had the drug permanently discontinued, while in the remaining the dosage was reduced. In 2015, Kimberlin et al4 reported neutropenia Grade 3–4 in 19–21% of patients, and antiviral therapy was interrupted in 2.8% of them.

Our data reinforce the concept that occurrence of neutropenia in infants on antiviral therapy for congenital cytomegalovirus infection is significant and could have serious consequences, such as bacterial sepsis. Nonetheless, little is known from the literature about its management and consequences. Rawlinson et al5 in their consensus suggest the timing to perform neutrophil count, but no recommendation is given about the management of neutropenic infants. Given that the incidence of neutropenia is nonnegligible and its recurrence in the same patient is high, at least considering our population, the absence of strong recommendations does not support the neonatologist/pediatrician in the daily clinical practice (Which reference ranges to use for neutrophils count? When to discontinue antiviral drug and how long? Which antiviral dosage should be used when the drug is resumed? Should granulocyte colony-stimulating factor be used?).

Certainly, multicenter studies gathering data from several treated infants could help to formulate recommendations for the correct management of adverse hematologic events, mainly neutropenia, thus standardizing the clinical management of these events and in some cases avoiding interruption or dose reduction of the drug, which are likely to expose the patient to a higher risk of viral replication and therefore to a greater risk of long-term adverse outcomes.

Andrea Ronchi, MD

NICU Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico

Milan, Italy

Carlo Pietrasanta, MD

NICU Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico

Milan, Italy

Department of Clinical Sciences and Community Health

University of Milan

Milan, Italy

Sandro Binda, DSc, PhD

Department of Biomedical Sciences for Health

University of Milan

Milan, Italy

Fabio Mosca, MD

NICU Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico

Milan, Italy

Department of Clinical Sciences and Community Health

University of Milan

Milan, Italy

Lorenza Pugni, MD

NICU Fondazione IRCCS Ca’ Granda

Ospedale Maggiore Policlinico

Milan, Italy

Back to Top | Article Outline

References

1. Ziv L, Yacobovich J, Pardo J, et al. Hematologic adverse events associated with prolonged valganciclovir treatment in congenital cytomegalovirus infection. Pediatr Infect Dis J. 2018.
2. Schmutz N, Henry E, Jopling J, et al. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J Perinatol. 2008;28:275–281.
3. Kimberlin DW, Lin CY, Sánchez PJ, et al; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143:16–25.
4. Kimberlin DW, Jester PM, Sánchez PJ, et al; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372:933–943.
5. Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis. 2017;17:e177–e188.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.