Bloodstream Infections and Herpesvirus Activation Following Intensive Chemother- Apy of Adult Oncohematological Patients
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CLINICAL ARTICLES Cellular Therapy and Transplantation (CTT). Vol.5, No.4 (17), 2016 doi: 10.18620/ctt-1866-8836-2016-5-4-21-31 Submitted: 17 June 2016, accepted: 25 November 2016 Bloodstream infections and herpesvirus activation following intensive chemother- apy of adult oncohematological patients Vitaly N. Chebotkevich, Stanislav S. Bessmeltsev, Ekaterina E. Kiseleva, Natalya P. Stizhak, Elena I. Kaytandzhan, Vitaly V. Burylev Russian Research Institute of Hematology and Transfusiology, St. Petersburg; 2nd Sovetskaya St.16, 191024 St. Petersburg, Russia. Professor Vitaly N. Chebotkevich, Russian Research Insti- Phone: +7 (812) 717-29-58 tute of Hematology and Transfusiology, St. Petersburg; 2nd Fax: +7 (812) 717-25-50 Sovetskaya St. 16, 191024 St. Petersburg, Russia. E-mail: [email protected] Our group of 33 clinical cases with proven sepsis ob- Summary served among 64 patients. Generally, Gram-posi- tive species prevailed over Gram-negative bacteria Intensive cytostatic chemotherapy is a standard strate- (69.2% versus 30.8%). However, the ratio of detectable gy for leukemia treatment. Meanwhile, such treatment Gram-negative flora was found to be increased from causes negative effects, i.e., including lymphopenia, 23.1% to 40.2% between 2002 and 2013 (p<0.05). Coag- granulocytopenia and damage to tissue barriers associ- ulase-negative staphylococci (CoNS) prevailed among ated with significant risks of infectious complications, Gram-positive microorganisms, in particular, S. epi- especially, bacterial sepsis and viremia. Our study was dermidis and S. aureus), whereas Enterobacteriaceae, aimed for identification of bacteremia and fungemia in especially, E.coli, dominated among the Gram-negative oncohematological patients following intensive chemo- bacteria. therapy, and assessment of potential modifying role of herpesvirus infections. Interestingly, 4 of 11 patients with coagulase-negative bacteremia had a concomitant herpesvirus infection: We assessed frequency of infectious complications 2 cases were associated with EBV; 1, with CMV, and 1, and their etiological agents in two groups of oncohe- with HHV6/EBV coinfection. Therefore, a high ratio of matological patients treated at the Russian Institute of viral and bacterial co-infections may be revealed in a Hematology and Transfusion, especially focusing on number of patients with proven sepsis. Moreover, com- mixed infections. Throat smears, venous blood, as well mon reactivation of herpesviruses may cause immuno- as urine and sputum specimens were taken for routine suppression, or represent additional immunodeficiency bacteriological cultures. Whole blood leukocytes were markers predictive for bacterial infections at later terms. virologically tested by PCR, using standard examination Therefore, one should take into account their predispos- protocol. al for severe infectious complications when planning he- matopoietic stem cell transplantation (HSCT) for these Our first virological study was performed for respirato- patients. ry infections and included 85 randomly chosen patients. Influenza and parainfluenza viruses, respiratory syncyt- ial virus, rhinovirus, adenovirus were detected in blood Keywords of single patients. Meanwhile, herpesviruses were de- tectable in 42% proportion of cases, i.e., HSV, EBV, and Leukemia, lymphoma, intensive chemotherapy, sepsis, CMV DNA in blood cells were revealed in 5.2%, 26.3%, viremia, coinfection and 10.5%, respectively. Viral infections were not associ- ated with positive bacteriological findings in this group. CTT JOURNAL | VOLUME 5 | NUMBER 4 | DECEMBER 2016 21 CLINICAL ARTICLES Before implementation of pre-emptive antiviral therapies in Introduction oncohematology, CMV infection was associated with severe organ affection and high mortality rates among recipients of Implementation of modern treatment strategies in leuke- hematopoietic stem cells (HSCs). In our previous experience mia patients, e.g., extensive usage of novel targeted drugs [11], mortality of the patients with clinical CMV disease was have resulted into sufficient increase of complete remission 32% (7/22). Most cases of CMV disease were registered fol- rates and higher survival rates. However, introduction of the lowing allogeneic HSCT. Noteworthy, the CMV disease was new-generation treatment is associated with additional ad- accompanied by different aggravating conditions (bacterial verse effects including granulocytopenia and injuries of tis- sepsis, graft rejection, multi-organ failure, GvHD (graft ver- sue barriers (skin and mucosae). These side effects cause sig- sus host diseases), thus presuming severity of the condition nificant risks for infectious complications, up to bloodstream and worse prognosis. CMV disease following auto-HSCT, infections and generalized septic conditions. Spectrum of was associated with retarded engraftment. Meanwhile, only detectable microbial pathogens in the hematooncologi- 5% (3/66) of leukemia patients who received intensive che- cal patients was sufficiently changed over last decades. I.e., motherapy have developed CMV disease (hemorrhagic Gram-positive microflora predominated in the 90’s, making cystitis, cytopenic fever, interstitial pneumonia). Anyway, up to 70% of the microbial findings [13]. More recently, how- clinically sound CMV reactivation may prevent a full-scale ever, an increasing proportion of Gram-negative infections chemotherapy, thus suggesting worse prognosis for primary was registered in the immunocompromised patients [4]. malignancy. Potential role of viral pathogens, especially, herpesviruses, in development of bloodstream infections is also poorly un- Modern approaches to management of CMV infection al- derstood, despite their common reactivation during mixed lowed to decrease risk of fatalities in this cohort. There exist, infections in hemato-oncological patients. [5]. however, some open questions concerning pathogenesis of CMV infections and their role as an underlying factor for At present time, a septic state is determined as a generalized development of other viral and microbial infections, e.g., re- inflammatory response to infectious pathogens of different spiratory conditions. origin, either bacterial, fungal, parasitic, or viral etiology. Clinical criteria of the sepsis diagnostics first approved in The aim of our study was to assess some features of emerging 1992, are well known and applicable worldwide [6]. In ac- infectious complications in immunocompromised oncohe- cordance with these criteria, sepsis is considered a systemic matological patients and possible role of herpesviruses in inflammation syndrome in response to infectious factor(s). their genesis. Viral infections are widely known to play a significant role in genesis of infectious complications in patients with he- Patients and methods mato-oncological disorders. In most cases, the virus-relat- ed conditions are caused by reactivation of latent virus(es), The first case series included eighty-five randomly chosen whereas reinfections seems to be more rare. Viral reactiva- adult patients with oncohematological disorders (Table 1). tion is most commonly detected for herperviruses, e.g., cy- We assessed general frequency of infectious complications tomegalovirus (CMV), Herpes Simplex types 1 and 2 (HSV and their etiological agents focusing, mainly, on mixed in- 1/2), Varicella Zoster virus (VZV). CMV is considered a fections of bacterial, fungal and viral origin. Throat smears, most common risk factor for life-threatening infections in venous blood, as well as urine and sputum specimens were hemato-oncology patients However, some other viruses (ad- taken for bacteriology and virological testing under standard enovirus, hepatitis B virus) may also undergo reactivation in examination protocol at the Hematology Clinics. immunocompromised patients. In particular, respiratory vi- ral infections are common to this cohort. Table 1. Clinical and demographic characteristics of the patients in group 1 Clinical diagnosis Number of patients Males Females Median age, years Multiple myeloma 15 5 10 26 – 70 Acute leukemia: Acute lymphoblastic leu- 2 1 1 18 – 52 kemia (ALL) Acute myeloid leukemia 10 5 5 28 – 73 (AML) Total: 12 22 CTT JOURNAL | VOLUME 5 | NUMBER 4 | DECEMBER 2016 cttjournal.com CLINICAL ARTICLES Clinical diagnosis Number of patients Males Females Median age, years chronic lymphocytic leu- 33 19 14 46 – 81 kemia (CLL): Chronic myeloid leukemia 4 3 1 34 – 52 (CML), chronic phase Primary myelofibrosis 1 1 - 60 Essential thrombocythemia 1 1 - 44 Total: 39 Malignant lymphomas 19 9 10 27 – 66 Total 85 44 41 As seen from Table 1, 80% of the patients were admitted with therapy was corrected according to in vitro antibiotic sensi- CLL (n=33), malignant lymphomas (n=19), multiple myelo- tivity testing. ma (n=15). Acute leukemias made only 12% of the group. To assess rates of clinical conditions and outcomes of the All the patients received specific cytostatic therapy accord- bloodstream infections, as well as to specify possible com- ing to their primary diagnosis, i.e., cytostatic drugs, mono- plicating role of herpesviruses, we carried out an additional clonal antibodies, proteasome inhibitors, immunomodu- retrospective analysis of 64 clinical cases of different oncohe- latory drugs, tyrosine kinase inhibitors, hypomethylating matological disorders treated at the Department of Hematol- drugs. Appropriate treatment protocols were as follows: 7+3 ogy of our Institute within 2005-2013 (Series 2, Table 2). The for AML; 7+3+ATRA for acute