Hematological complications
Fifty percent of episodes were associated with at least one new cytopenia. Among patients with a decrease in their hemoglobin values, 86% had a value in the range for anemia. Regarding the drop in the platelet level, 35% achieved levels below 100.000 platelets/μL. About the decrease in the neutrophil count, 96% were in the range for neutropenia, being severe in 23% of them.
To rule out confusion factors, type of maintenance and co-infection were analyzed in relation with cytopenia incidence. No statistically differences were found, neither with chemotherapy regimen (M1 46% vs. M2 54%, p value 0.157) nor co-infection (co-infection 58.3%, no co-infection 48.9%, p value 0.560).
A delay in chemotherapy occurred in 32.7% with a median duration of the treatment withdrawal of 7 days (IQR 4). Bone marrow aspiration (BMA) was performed in 8.1% due to prolonged cytopenia, and immunophenotype ruled out relapse. There were two relapses, both in patients without treatment withdrawal. No microbiological studies were performed. No deaths were recorded.
Complete data is summarized in table II .
DISCUSSION
In our study, children with ALL and RV infection presented with a mild disease, but cytopenia were common and led to increased chemotherapy delays. Nonetheless, no relapses were detected in these patients
Many publications report the impact of viral infections in hematological patients3,5, but little is known concerning the association between RV infection and aplasia. The few previous reports showed a similar rate of RV laboratory-confirmation, ranging from 30% to 76%5. Data on co-infection is consistent with previously published studies (19-20%)3,5.
In our study, cytopenia were detected in 52.4% of cases, and 44.2% presented with a low neutrophil count. This was in line with Aydın Köker et al study³, which reported a 42% rate of neutropenia associated with RV infection and a 33% rate of chemotherapy delays compared to our 32.7%.
Other causes of aplasia (asparaginase use and co-infections3) were not related to its incidence, suggesting that RV infection may be an independent risk factor for aplasia.
Treatment continuity during maintenance has a significant impact on its response, so delays should be avoided8. Despite this, we did not find any relapse events during the follow-up of patients in whom chemotherapy was discontinued in relation to RV- related cytopenia.
This study has some limitations. It is a retrospective, single-center study that may limit data collection, but our electronic medical record minimizes potential loss of information. The use of a single-point PCR RV detection may incorrectly preclude RV as the cause of infection in a population with prolonged viral shedding. To minimize this, we excluded those with a recent detection. The fact that the study ends in December 2021 could cause some detection bias since NPAs were more commonly performed from March 2020 due to the COVID-19 pandemic. Lastly, RV testing was not performed in BMA to rule out a direct cytopathic virus effect.
In conclusion, in our series, RV infection during maintenance treatment was frequent, causing cytopenia in half of the patients and delays in chemotherapy in one out of three, without increasing the risk of relapse. Thus, screening for rhinovirus infection should be considered as part of the investigation in cases of unexpected pancytopenia during maintenance treatment, particularly during the colder months.
CONFLICT OF INTEREST STATEMENT
The authors declare that they have no conflict of interest.
AKNOWLEDGEMENTS
We would like to thank all our colleagues from the Oncology and Hematology, Infectious Diseases, and Microbiology departments involved in the care of the patients featured in this study. We also want to express our special gratitude to Dr. Ángela Menárguez and Dr. Eva Castilla, who spearheaded the creation of the pediatric database for patients with acute lymphoblastic leukemia, without which this project would not have been possible.
Lastly, we extend our heartfelt appreciation to all the patients and their families for contributing to the advancement of knowledge about childhood cancer.
REFERENCES
  1. Hijano DR, Maron G, Hayden RT. Respiratory Viral Infections in Patients With Cancer or Undergoing Hematopoietic Cell Transplant. Front Microbiol. 2018;9. doi:10.3389/fmicb.2018.03097
  2. Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology/Oncology. 2014;36(7):503-517. doi:10.1097/mph.0000000000000206
  3. Aydin Köker S, Demirağ B, Tahta N, et al. A 3-Year Retrospective Study of the Epidemiology of Acute Respiratory Viral Infections in Pediatric Patients With Cancer Undergoing Chemotherapy. Journal of Pediatric Hematology/Oncology. 2019;41(4):e242-e246. doi:10.1097/mph.0000000000001418
  4. Bozkurt Turhan A. Assessment of respiratory tract viruses in febrile neutropenic etiology in children and comparison with healthy children with upper / lower respiratory tract infection. North Clin Istanbul. Published online 2020. doi:10.14744/nci.2020.99896
  5. Fontana L, Strasfeld L. Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient. Infectious Disease Clinics of North America. 2019;33(2):523-544. doi:10.1016/j.idc.2019.02.004
  6. Cerdeira Barreiro N, Santiago-García B, Casas I, et al. Detection of Respiratory Viruses in the Clinical Outcome of Children With Fever and Neutropenia. Pediatric Infectious Disease Journal. 2020;39(6):533-538. doi:10.1097/inf.0000000000002611
  7. Torres JP, Castro-Moraga ME, Catalán P, et al. Infecciones respiratorias virales en episodios de fiebre en niños con trasplante de precursores hematopoyéticos. Rev chil infectol. 2020;37(4):371-382. doi:10.4067/s0716-10182020000400371
  8. Yeoh A, Collins A, Fox K, et al. Treatment delay and the risk of relapse in pediatric acute lymphoblastic leukemia. Pediatric Hematology and Oncology. 2017;34(1):38-42. doi:10.1080/08880018.2016.1276235