Dasatinib-Induced CMV Hepatitis in an Immunocompetent Patient: A Rare Complication of a Common Drug

Davalos, Fidencio; Chaucer, Benjamin; Zafar, Wahib; Salman, S.K.; Nfonoyim, Jay

doi:10.1016/j.tranon.2015.12.004

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…Considering the diverse functions controlled by Abl/Src kinases it is unexpected, that severe infections related to TKI‐treatment are exceptional . Case reports describe sporadic viral (cytomegalovirus, hepatitis B) or fungal ( Pneumocystis jiroveci ) infections . This provides strong clinical evidence that the inhibition of T‐cell function by TKIs is compensated by protective effects on the microbial host cells.…”

Section: Discussionmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Discussionmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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“…In this study, three samples were detected as positive for HCMV. This virus has been reported in cases of liver transplantation in addition to being associated with induction of hepatitis (20,21). The association of HCMV replication with ALF suggests a condition that increases the occurrence of HCMV infection after transplantation (21), leading to a requirement for prophylactic antiviral treatment to prevent HCMV infection in transplant recipients (22).…”

Section: Detection Via Pan Herpesvirus Pcr and Sequencingmentioning

confidence: 99%

Multiplex qPCR Facilitates Identification of Betaherpesviruses in Patients With Acute Liver Failure of Unknown Etiology

Raposo

Alves

Silva

et al. 2019

Preprint

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Background: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods: Liver and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results: Betaherpesviruses infection was effectively detected using multiplex qPCR. Seven (26%), two (7%) and three (11%) cases were positive for HHV-6, HHV-7 and HCMV, respectively. Two cases of dual infection (HHV-7/HHV-6 and HHV-7/HCMV) were additionally identified. Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values>1.4 were determined in all betaherpesvirus-positive patients. Conclusions: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver and serum samples were positive for some betaherpesviruses, suggesting an association with ALF. Coinfection of HHV-7 with HHV-6 or HCMV was additionally detected, suggesting that the precursor betaherpesviruses infection can trigger HHV-7 infection. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.

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“…This virus has been reported in cases of liver transplantation in addition to being associated with induction of hepatitis [23, 24]. The association of HCMV replication with ALF suggests a condition that increases the occurrence of HCMV infection after transplantation [24], leading to a requirement for prophylactic antiviral treatment to prevent HCMV infection in transplant recipients [25]. To date, studies have revealed that HCMV is not the main cause of ALF but rather the most common hepatic manifestation in immunocompromised patients [26].…”

Section: Discussionmentioning

confidence: 99%

Multiplex qPCR facilitates identification of betaherpesviruses in patients with acute liver failure of unknown etiology

et al. 2019

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Background The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods Liver explant and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results Betaherpesviruses infection was effectively detected using multiplex qPCR. Six (22%) HHV-6, one (3%) HCMV and two (7%) dual infections (one with HHV-7/HHV-6, and the other with HHV-7/ HCMV). Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values> 1.5 were determined in all betaherpesvirus-positive patients. Conclusions Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver explant and serum samples were positive for some betaherpesviruses, and coinfection of HHV-7 with HHV-6 and HCMV was additionally detected. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.

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Dasatinib-Induced CMV Hepatitis in an Immunocompetent Patient: A Rare Complication of a Common Drug

Cited by 16 publications

References 11 publications

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

Multiplex qPCR Facilitates Identification of Betaherpesviruses in Patients With Acute Liver Failure of Unknown Etiology

Multiplex qPCR facilitates identification of betaherpesviruses in patients with acute liver failure of unknown etiology

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