Journals | Policy | Permission

Journal of Hematology

Short Communication

Volume 10, Number 3, June 2021, pages 123-129

A Description of the Type, Frequency and Severity of Infections Among Sixteen Patients Treated for T-Cell Lymphoma

Mature T-cell non-Hodgkin’s lymphomas (T-NHLs) are a rare and heterogeneous group of lymphoid malignancies that pose an infectious risk to patients both from direct perturbations of T-cell functionality, immune dysregulation and treatment related toxicities. Few studies exist that describe the types of infections in patients with T-cell lymphomas (Table 1) [1-24]. Identifying the types, timing and risks for infection may help guide clinicians deliver timely prophylaxis to protect against bacterial, fungal and viral infections.

Click to view

Table 1. Case Reports of Infections in Patients With T-Cell Lymphoma

The aim of this study was to describe the pattern of infectious episodes in patients with T-NHL in an Australian tertiary center to help inform infection prevention guidelines for patients undergoing treatment for T-cell lymphoma.

We performed a retrospective cohort study at Monash Health, a 1,500-bed health service in Melbourne, Australia that treats approximately 150 patients with newly diagnosed lymphoma per year. All adult patients with a diagnosis of T-NHL by WHO 2008 criteria between January 1, 2011 and January 1, 2016 were included. Patients were identified through a search of hospital admission coding entries at Monash Health. Demographic data, details of lymphoma treatment and outcomes, and infectious outcomes were collected from medical record review.

Patients were identified from hospital coding and clinical databases and included if they had a hospital admission code for T-NHL first appearing during the study period. Patients were excluded if they were less than 18 years at time of diagnosis or the majority if their lymphoma care was not performed at the study institution.

Demographic data collected at diagnosis of T-NHL included age, sex, country of birth, and comorbidities according to Charlson Comorbidity Index [25]. T-NHL specific staging and prognostic parameters included subtype of T-NHL, Ann-Arbor stage, International Prognostic Index (IPI) presence and sites of extranodal involvement, and date of first lymphoma admission [26]. Treatment received was recorded including type of chemotherapy (regimen type and duration), radiotherapy or observation for indolent T-NHL. Lymphoma specific treatment outcomes were recorded by standard response criteria, incorporating positron emission tomography (PET) where appropriate [27]. Supportive care was also recorded including use of prophylactic antibiotics, antiviral and antifungal agents, as well as use of granulocyte colony-stimulating factor (G-CSF).

Severe infection was defined as any infection that required hospital admission and fulfilled the Common Terminology Criteria for Adverse Events (CTCAE) grade category 3, 4, or 5 [28]. For each episode of infection grade 3 or worse, data were collected regarding onset relative to last chemotherapy, dates and length of hospital admission. Method of acquisition of the specific infectious episode was recorded as community-acquired, hospital-acquired, or hospital-associated.

Data for microbiology isolates were extracted from the hospital laboratory information system. Infections were classified as “microbiologically proven” if microbiological organisms were isolated. If a site of infection was clinically evident but no microbiological organism isolated, the infectious episode was classified as “clinically defined infection”. If no organism was isolated and there was no clear clinical source of infection, the infectious episode was classified as “fever without source”. Details of each severe infection were recorded including presence of fevers or neutropenia. The absolute neutrophil count within 48 h of first day of the infectious episode was obtained from the laboratory information system. Neutropenia was defined as an absolute neutrophil count less than 1.0 × 10⁹/L [29]. Each severe infection was classified according to body site and these sites were not considered to be mutually exclusive. Sepsis was defined as the presence of systemic inflammatory response syndrome (SIRS) [30] with confirmed or presumed infection. Fungal infection was classified according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) [31]. Death due to infection or other causes at 30 days was recorded.

Descriptive statistics were used for incidence of infection, types of infection and changes over time. Categorical variables were summarized using frequency and percentage. Continuous variables were summarized using median and standard deviation (SD) or median and interquartile range (IQR) as appropriate.

This study was approved by the Human Research Ethics Committee at Monash Health as a quality improvement project (number 13085A). This study was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.

Over the 6-year period, 16 patients were diagnosed with T-NHL and received their lymphoma management at the study institution. Sixteen patients were excluded (one patient was <18 years and the remaining 15 received their lymphoma care at another institution).

The demographic details of the patients are described in Table 2. The median age was 59 years and 10 (62%) were male. Fourteen (87%) received chemotherapy, and two patients died prior to commencement of chemotherapy.

Click to view

Table 2. Demographics and Clinical Features at Study Entry (n = 16)

Of the 16 patients, 13 (81%) experienced one or more severe infectious events. Six (37%) patients had one severe infection, three (19%) patients had two severe infections, one (6%) patient had three severe infections, and three (19%) patients had greater than four severe infections. There were 42 discrete episodes of severe infection in total. The median follow-up time was 1.93 years, and there was a median of 0.77 infections/year of follow-up.

Fifteen (36%) infectious episodes occurred during first line chemotherapy and two (5%) occurred during second line chemotherapy. Twenty-six episodes of infection (62%) occurred during progressive disease, 13 (31%) occurred during lymphoma remission, and three (7%) occurred during stable disease.

Of the 42 severe infections, 21 (50%) episodes were microbiologically proven infections, eight (19%) were clinically defined infections, and 13 (31%) episodes were classified as fever without source. Seven (17%) episodes were community-acquired, 11 (26%) episodes were hospital-acquired, and 24 (57%) were hospital-associated. Thirty-four (81%) severe infections were characterized by fever. Twenty-three episodes of infection were defined from a clear source. The most common source of infection was skin with 10 episodes (24%), followed by lower respiratory tract with seven episodes (17%), upper respiratory tract with two episodes (5%), gastrointestinal with two episodes (5%), and urinary with two episodes (5%).

Twenty-one (50%) episodes had neutropenia associated with their infectious episode.

Of the microbiologically proven severe infections, 13 (62%) were bacterial, three (14%) were viral, and five (24%) were fungal (Table 3).

Click to view

Table 3. Microbiologically Proven Infections in a Case Series of Patients With T-Cell Lymphoma (n = 16)

Of the bacterial isolates, Gram-positive organisms accounted for seven (54%) and Gram-negative accounted for six (46%). Staphylococcus aureus and Pseudomonas aeruginosa were the most common Gram-positive and negative isolates, respectively. Six (46%) of the bacterial isolates were grown from blood cultures, of which two were taken from a peripherally inserted central catheter line.

There were three (14.3%) viral isolates. CMV was isolated in one patient who was receiving valaciclovir anti-viral prophylaxis. The five episodes of fungal infection were found in three patients and included two episodes of hepatosplenic candidiasis, one episode of candidemia and two episodes of invasive pulmonary aspergillosis. Four of the five fungal isolates were classified as proven, and one was classified as possible according to EORTC guidelines [31]. Antifungal prophylaxis was not administered to these patients prior to diagnosis of fungal infection. There were no cases of Pneumocystis jirovecii pneumonia.

Of the 16 patients, six were receiving viral prophylaxis (valaciclovir), three were receiving bacterial prophylaxis (two on trimethoprim-sulfamethoxazole and one on dapsone), and one patient was on fungal prophylaxis (fluconazole). The relationship between prophylaxis and severe infection is illustrated in Supplementary Material 1 (www.thejh.org).

The median length of hospital stay was 13 days (IQR 6.2 - 38). Fourteen (33%) episodes required intensive care unit (ICU) admission.

Of the 42 episodes of infection, 22 (52%) were classified as severe, and 14 (33%) life-threatening.

Within 30 days of the incident infection, eight (19%) patients had died, with four of these events attributed to complications from infection, and four events attributed to progressive lymphoma.

This study demonstrated high rates of infection in patients with T-cell lymphoma with over 80% of patients experiencing severe infective episodes, and over 40% having multiple episodes of severe infection. A number of these infections were opportunistic and resulted in lengthy hospital admissions and/or death. The data indicate that further research could be directed towards infections prevention strategies in these patients.

There are few dedicated studies examining the type and severity of infections in patients with T-cell lymphoma. A list of case reports can be seen in Table 1, showing some common infections such as enterococcus, streptococcus and viral infections, but also a variety of atypical mycobacterial, fungal and parasitic infections.

In comparison to existing data, our cohort appears to have a higher rate of infective episodes [1] [1, 2]. In addition, the burden of fungal disease was high in our cohort at 24%, with only 2.4% of infective episodes being associated with fungal prophylaxis. No previous studies have specifically looked at clinical rates of fungal infections in T-cell lymphomas, although a high rate has been described post mortem in patients with T-cell lymphoma by Suzumiya et al [3]. Additionally, local guidelines have identified these patients as low risk for invasive fungal infection [32]. According to our data, antifungal prophylaxis may be considered in some patients with T-cell lymphoma.

Our study identified that 50% of infective episodes were associated with neutropenia, while only 26% of infective episodes were associated with G-CSF use. This could perhaps suggest a role for increased monitoring and treatment of neutropenia to prevent infections; however, further information would be required to determine the true association and clinical benefit.

The episode of CMV raises the possibility that CMV monitoring may be indicated. Suzumiya et al performed a study on autopsy of patients with adult T-cell leukemia/lymphoma in 1993, and found the primary cause of death to be pulmonary infection, with CMV being the most common organism in 74.5% [3].

Study limitations include the retrospective nature of the study and the small number of T-cell lymphoma cases. We did not record the use of parenteral nutrition, which may influence infection rates.

Future research could focus on infection prevention through systematic screening and antimicrobial prophylaxis as a key strategy in the supportive care of patients diagnosed with T-cell lymphoma.

Our study, although small, demonstrates that there were high rates of proven fungal infection, and suggests that fungal prophylaxis may be indicated with T-cell lymphoma.

Suppl 1. The relationship between prophylaxis and severe infection.

Acknowledgments

None to declare.

Financial Disclosure

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

De-identified information was taken from medical records, therefore no informed consent was required.

Author Contributions

TK and CD devised the project and main conceptual ideas, developed the framework, and wrote the manuscript. TK and CS collected the data, TK analyzed the data. CD supervised the project. All authors discussed the results and contributed to the final manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

1. Alonso JJ, Canovas A, Barreiro JG, Aguirre C. Infectious complications of chemotherapy in clinically aggressive mature B and T cell lymphomas. Eur J Intern Med. 2012;23(3):255-260.
   doi
2. Kawano N, Nagahiro Y, Yoshida S, Tahara Y, Himeji D, Kuriyama T, Tochigi T, et al. Clinical features and treatment outcomes of opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia-lymphoma (ATL) at a single institution from 2006 to 2016. J Clin Exp Hematop. 2019;59(4):156-167.
   doi
3. Suzumiya J, Marutsuka K, Nabeshima K, Nawa Y, Koono M, Tamura K, Kimura N, et al. Autopsy findings in 47 cases of adult T-cell leukemia/lymphoma in Miyazaki prefecture, Japan. Leuk Lymphoma. 1993;11(3-4):281-286.
   doi
4. Schein F, Fouillet L, Lutz MF, Daguenet E, Botelho-Nevers E, Cornillon J. Recurrent Enterococcus faecalis meningitis in a patient presenting with Strongyloides hyperinfection syndrome during HTLV-1-induced T-cell lymphoma. Med Mal Infect. 2018;48(6):428-430.
   doi
5. Oeser C, Andreas M, Rath C, Habertheuer A, Kocher A. Left ventricular thrombus in a patient with cutaneous T-cell lymphoma, hypereosinophilia and Mycoplasma pneumoniae infection - a challenging diagnosis: a case report. J Cardiothorac Surg. 2015;10:21.
   doi
6. Umeh OC, Kubak BM, Pegues DA, Leibowitz MR, Froch L. Corynebacterium jeikeium sepsis after 8-methoxypsolaren photopheresis for cutaneous T-cell lymphoma. Diagn Microbiol Infect Dis. 2004;50(1):71-72.
   doi
7. Tauro S, Dobie D, Richardson G, Hastings M, Mahendra P. Recurrent penicillin-resistant pneumococcal sepsis after matched unrelated donor (MUD) transplantation for refractory T cell lymphoma. Bone Marrow Transplant. 2000;26(9):1017-1019.
   doi
8. Holik H, Ljubicic IV, Coha B. Death caused by possible unrecognized (too Late Recognized) Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma. Int J Mycobacteriol. 2017;6(2):199-201.
   doi
9. van der Wekken L, Herbrink J, Snijders D, Chamuleau M, Griffioen A. Disseminated Mycobacterium chelonae infection in a patient with T-cell lymphoma. Hematol Oncol Stem Cell Ther. 2017;10(2):89-92.
   doi
10. Numbi N, Demeure F, Van Bleyenbergh P, De Visscher N. Disseminated Mycobacterium genavense infection in a patient with immunosuppressive therapy and lymphoproliferative malignancy. Acta Clin Belg. 2014;69(2):142-145.
    doi
11. Artacho-Reinoso MJ, Olbrich P, Solano-Paez P, Ybot-Gonzalez P, Lepe JA, Neth O, Aznar J. Catheter-related Mycobacterium fortuitum bloodstream infection: rapid identification using MALDI-TOF mass spectrometry. Klin Padiatr. 2014;226(2):68-71.
    doi
12. Nair AP, Al Shemmari S. T cell lymphoma with disseminated herpes zoster on presentation and subsequent recurrence leading to blindness—a case report. Ann Hematol. 2011;90(9):1119-1121.
    doi
13. Imafuku S, Yoshimura D, Moroi Y, Urabe K, Furue M. Systemic varicella zoster virus reinfection in a case of angioimmunoblastic T-cell lymphoma. J Dermatol. 2007;34(6):387-389.
    doi
14. Saito Y, Takenaka H, Chin T, Ueda E, Katoh N, Shimazaki C, Inaba R, et al. Cytomegalovirus in cutaneous ulcers in a patient with adult T-cell lymphoma. Acta Derm Venereol. 2006;86(2):181-182.
15. Np P, Tm A, Nambiar R, Puthusseri J, B S. Invasive Aspergillosis in Refractory Angioimmunoblastic T-Cell Lymphoma. Turk J Haematol. 2018;35(1):91.
    doi
16. Tisi MC, Giustiniani MC, D'Alo F, Sica S, Hohaus S, Pagano L. A T cell lymphoblastic lymphoma with mucormycosis as unusual etiology of acute cerebral ischemia. Ann Hematol. 2016;95(3):517-518.
    doi
17. Khan AA, Garg A, Dhawan S, Agarwal PK, Siraj F, Aggarwal S. T cell non-Hodgkin's lymphoma with colesional mucormycosis presenting as palatal perforation: a case report. J Indian Med Assoc. 2012;110(7):499-500.
18. Powel MS, Alizadeh AA, Budvytiene I, Schaenman JM, Banaei N. First isolation of Cryptococcus uzbekistanensis from an immunocompromised patient with Lymphoma. J Clin Microbiol. 2012;50(3):1125-1127.
    doi
19. Garcia-Noblejas A, Velasco A, Garcia-Leon N, Cananta-Ortiz J, Steegmann JL. Pneumocystis jirovecii pneumonia as first manifestation of late relapse angioimmunoblastic T-cell lymphoma. Leuk Res. 2011;35(9):e143-144.
    doi
20. Hsu CK, Hsu MM, Lee JY. Fusariosis occurring in an ulcerated cutaneous CD8+ T cell lymphoma tumor. Eur J Dermatol. 2006;16(3):297-301.
21. Poonawalla T, Diwan H, Duvic M. Mycosis fungoides with coccidioidomycosis. Clin Lymphoma Myeloma. 2006;7(2):148-150.
    doi
22. Abdelrahman MZ, Zeehaida M, Rahmah N, Norsyahida A, Madihah B, Azlan H, Nazlee WZ. Fatal septicemic shock associated with Strongyloides stercoralis infection in a patient with angioimmunoblastic T-cell lymphoma: a case report and literature review. Parasitol Int. 2012;61(3):508-511.
    doi
23. Stewart DM, Ramanathan R, Mahanty S, Fedorko DP, Janik JE, Morris JC. Disseminated Strongyloides stercoralis infection in HTLV-1-associated adult T-cell leukemia/lymphoma. Acta Haematol. 2011;126(2):63-67.
    doi
24. Isotalo PA, Toye B, Eidus L. Human T-lymphotropic virus 1 adult T-cell lymphoma with Giardia and Strongyloides parasitism. Arch Pathol Lab Med. 2000;124(8):1241.
    doi
25. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
    doi
26. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
    doi
27. Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP, Schwartz LH, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058.
    doi
28. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). 2010.
29. Naik JD, Sathiyaseelan SR, Vasudev NS. Febrile neutropenia. BMJ. 2010;341:c6981.
    doi
30. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644-1655.
    doi
31. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-1821.
    doi
32. Fleming S, Yannakou CK, Haeusler GM, Clark J, Grigg A, Heath CH, Bajel A, et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014;44(12b):1283-1297.
    doi

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Hematology is published by Elmer Press Inc.