Invasive virus infections during chemotherapy: an underestimated factor

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(Vienna, 29.04.2021) While the importance of virus infections as a leading cause of morbidity and mortality is well documented in patients undergoing allogeneic stem cell transplantation, their impact in cancer patients receiving chemotherapy is less well studied. A new publication reveals that invasive viral infections can be clinically relevant in this setting both in pediatric and adult patients. Routine screening for viremia at the onset of neutropenic fever is therefore warranted and could prevent unnecessary use of antibacterial or antifungal agents.

Cancer chemotherapy can induce neutropenia, defined by pronounced reduction of specific white blood cells called “neutrophilic granulocytes”. In this weakened state of the immune system, patients are more susceptible to infections and commonly develop fever referred to as febrile neutropenia. Owing to the clear predominance of bacterial and fungal infections in this setting, screening for systemic viral infections is rarely part of current routine diagnostic surveillance. According to a recent study led by scientists from the St. Anna Children’s Cancer Research Institute, invasive viral infections are an underestimated cause of febrile complications in cancer patients receiving chemotherapy. Routine screening for viremia could therefore prevent overtreatment with antibiotic or antifungal agents in some instances.

Dormant viruses can be re-activated

Highly immunosuppressive treatment approaches favor opportunistic infections, in which viruses can take advantage of the weakened immune system. This includes virus reactivation, a process by which latent viruses persisting from earlier infections switch back into an active replication mode. Persistent viral infections that are commonly reactivated during states of impaired immune function include various members of the herpes virus family (HHV), for example Epstein-Barr virus (EBV) or cytomegalovirus (CMV), and different other viral pathogens, such as human adenoviruses (HAdV).

Invasive viral infections can play a role during cancer chemotherapy

To shed more light on the incidence and potential role of viral infection or reactivation, the authors of this multinational study have prospectively screened 237 febrile neutropenic episodes in pediatric and adult patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia, and tested for the presence and quantity of select clinically relevant viruses.

Viremia was documented in 35 cases, including 27 pediatric (18%), and eight adult (9%) patients, representing 15% of all febrile neutropenic episodes studied. In adult patients, EBV was detected most frequently, while in pediatric patients HHV6 (human herpes virus 6) showed the highest prevalence, followed by EBV and CMV. The detectability of viremia already at first onset of fever correlated with the virus concentration, and fever persisting for more than 24 hours correlated with increasing virus copy numbers (see Figure). Most importantly, high virus copy numbers exceeding 104 copies/ml blood were generally observed in absence of detectable bacterial or fungal pathogens, indicating that the virus identified was a probable cause of the febrile episode, and the patients affected may therefore not have required antibacterial or antifungal therapy in these instances.

Prevention of overtreatment with inappropriate medication

“While low or intermediate levels of viremia were commonly associated with bacterial or fungal co-infection, viremia at higher levels was documented in patients without evidence for other infections”, informs Dr. Klara Obrova, the first author on the paper, “Our findings highlight the role of viruses as potentially important and currently underdiagnosed pathogens in patients with malignant neoplasms undergoing chemotherapy.” The corresponding author, Prof. Thomas Lion, further explains: “patients with febrile neutropenia not responding to antibiotic treatment for 72-96 hours commonly receive systemic antimycotic therapy without any evidence for the presence of fungal infection. This empirical treatment strategy can be associated with considerable toxicity and costs. It is therefore desirable to reduce or prevent overtreatment by antifungal agents.”

“Our study indicates that viral infection or reactivation are probably responsible for a proportion of febrile episodes in the clinical setting studied. Screening for viral infections might therefore be warranted to elucidate their potential role in patients undergoing intensive chemotherapy for malignant disorders”, emphasizes Obrova. “Detection of high-level viremia in the absence of evidence for other microbial infections might serve as a basis for more judicious administration of antimicrobial treatment.”

Publication: Presence of viremia during febrile neutropenic episodes in patients undergoing chemotherapy for malignant neoplasms.

Klára Obrová, Silke Grumaz, Marlene Remely, Stefan Czurda, Isabella Krickl, Susanne Herndlhofer, Karoline V Gleixner, Wolfgang R Sperr, Lisa Größlinger, Tijana Frank, Nuno Andrade, Teresa Egger-Matiqi, Christina Peters, Gernot Engstler, Michael Dworzak, Andishe Attarbaschi, Martine van Grotel, Marry M van den Heuvel-Eibrink, Ivan S Moiseev, Yuliya Rogacheva, Ludmilla Zubarovskaya, Natalia Zubarovskaya, Herbert Pichler, Anita Lawitschka, Elisabeth Koller, Felix Keil, Peter Valent, Kai Sohn, Thomas Lion; Am J Hematol. 2021 Mar 30. doi: 10.1002/ajh.26177. Online ahead of print.