188 Pictorial Essay
Herpes Simplex Virus Reactivation and Disease during Treatment for Childhood Acute Lymphoblastic Leukemia Herpes-simplex-Reaktivierung und HSV-Primärinfektion während der Behandlung der akuten lymphoblastischen Leukämie im Kindesalter Authors
M. Lauten1, C. Güttel2, C. Härtel1, B. Erdlenbruch3
Affiliations
1
Key words ▶ childhood ● ▶ acute lymphoblastic ● leukemia ▶ disseminated herpes ● simplex infection ▶ induction ● ▶ re-induction ● ▶ herpes encephalitis ●
Introduction
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1354387 Published online: October 24, 2013 Klin Padiatr 2014; 226: 188–189 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Melchior Lauten Department of Pediatrics UKSH, Campus Lübeck Ratzeburger Allee 160 23538 Lübeck Germany Tel.: + 49/451/500 2956 Fax: + 49/451/500 3767 [email protected]
▼
Treatment related mucositis is known as a risk factor for systemic bacterial, fungal and viral infections in childhood acute lymphoblastic leukemia (ALL). Childhood ALL-BFM treatment related mortality (TRM) is reported to be up to 4 % [14] and infectious agents are the main cause. Recently, Pichler et al. showed that the inferior prognosis of 15–18 years old ALL patients is mainly due to an infection related higher TRM [10]. Prucker et al. described 31 patients with TRM during induction therapy due to non-leukemic reasons and 21/31 patients died of infections. In ten of these an infectious agent was detectable, only 2 of these 10 were viral agents (CMV) [11]. Latent infections and reactivation of herpes simplex (HSV) are of importance in immuocompromised patients [4]. However, HSV reactivation or disease has not been reported as a cause of TRM in childhood ALL without allogeneic stem cell transplantation (SCT). Nevertheless, oral mucositis is a major risk factor for systemic bacterial infections following chemotherapy and the severity of oral mucositis is associated with detection of HSV-DNA in oral swabs [3]. Therefore, HSV may facilitate fatal disseminated bacterial infections as reported in a 69 year old relapsed ALL patient with fatal systemic Enterococcus faecalis infection and post mortem detection of HSV in an esophageal erosion by histopathologic examination [5]. Here we report on 3 patients treated according to the ALL-BFM 2009 and EsPhALL studies with severe HSV reactivation and/or infection during (re-)induction treatment. 2 of them died due to multiorgan dysfunction syndrome.
Case reports
▼
Patient 1: An 18 months old girl presented with BCR/ABL positive precursor B-cell ALL. She devel-
Lauten M et al. Herpes Simplex Virus Reactivation … Klin Padiatr 2014; 226: 188–189
oped severe mucositis with neutropenic fever during protocol I (prednisone good response, PGR). As cause of the mucositis, candida was clinically suspected and treatment with local amphotericin suspension and intravenous liposomal amphotericin was initiated. Protocol I was completed without significant delay. During HR-1 (grade 4) and HR-2 (grade 2–3) cycles, the girl presented with recurrent episodes of mucositis. Initially and after HR-3, HSV titres were negative. On day 17 of protocol II fever, elevation of CrP (11 mg/l) and grade 1 mucositis occurred. From day 22 on mucositis worsened, while CrP decreased. Antibiotic therapy had been intensified using piperacillin, tazobactam, aminoglycoside, metronidazole and liposomal amphotericin, but the girl deterioated clinically demanding tracheal intubation and cardio-pulmonary resuscitation. On day 25 the girl died. Retrospectively, herpes DNA was detected in blood samples on day 21 and in a buccal swab, which was misinterpreted as negative before.
Patient 2: During protocol IA (ALL-BFM 2009) a 13 year old boy with T- ALL and mediastinal mass presented with grade 4 mucositis and neutropenia. In addition to the standard antibiotic regimen, aciclovir was given for suspected HSV reactivation despite a negative HSV PCR (HSV serum titres at diagnosis: IgG 1:19 000, IgM negative). During protocol M mucositis grade 2 occurred and resolved spontaneously. On day 16 of protocol IIa mucositis grade 1 re-occured. The patient was hospitalised for oral pain and fatigue 6 days later. Another 6 days later rapid elevation of CrP (147 mg/l) with concomitant disequilibrium of electrolytes occurred. After extension of the antibiotic regimen (piperacillin, vancomycin, tobramycin, liposomal amphotericin) and addition of hydrocortison CrP (max. 394 mg/l) started to decrease. However, on day 33 of protocol IIa arterial hypotension and pulmonary failure required catecholamines and non-invasive ventilation. On the same day aciclovir was started due to a
Downloaded by: Karolinska Institutet. Copyrighted material.
Schlüsselwörter ▶ Kind ● ▶ akute lymphoblastische ● Leukämie ▶ disseminierte Herpes● simplex-Infektion ▶ Induktion ● ▶ Reinduktion ● ▶ Herpes encephalitis ●
Department of Pediatrics, UKSH, Campus Lübeck, Germany Department of Pediatrics, HELIOS Kliniken Schwerin, Germany 3 Department of Pediatrics, Mühlenkreiskliniken, Minden, Germany 2
Pictorial Essay 189
Patient 3: After good response to prednisone a 5 years old girl with TEL/AML1 positive common ALL developed neutropenic fever and abdominal pain on day 18 of protocol I. She was treated with cefotaxim, tobramycin and vancomycin. CrP was 53 mg/l and reached its maximum on day 26 (107 mg/l). On day 23 the antibiotic regimen was extended because of positive clostridium difficile toxine detection and finally changed to meropenem, metronidazole and vancomycin for positive blood and stool cultures of Pseudomonas aeruginosa (day 27). 1 week later she developed focal seizures of the right arm and anisocoria. CSF examination showed pleocytosis, elevated lactate and a positive HSV PCR in the CSF. Magnetic resonance imaging (MRI) of her head showed left temporal encephalitis. HSV IgG was positive and IgM negative (HSV PCR in serum was not done). Intravenous aciclovir (60 mg/kg) led to clinical resolution of the focal seizures by day 45. Paralytic ileus required partial resection of the ileum with end-to-end anastomosis. After 21 days aciclovir was stopped. During protocol M and protocol IIa no problems occurred. During protocol IIb mucositis grade 2 associated with HSV (positive PCR from saliva) re-occurred. Aciclovir was restarted and given orally until the end of maintenance treatment.
Discussion
▼
Prognosis of childhood ALL is very good [9, 14], but hampered by TRM due to severe infections. HSV infection as a cause of febrile episodes seems to account for 10 % of proven infections [2] and can be detected in blood cultures of non-febrile patients as well [15]. In patients with chemotherapy induced severe mucositis the prevalence of HSV in oral swabs is 50 % [2]. Risk factors for HSV reactivation in immunocompromised patients are age and history of cold sores as well as lymphopenia
Herpes Simplex Virus Reactivation and Disease during Treatment for Childhood Acute Lymphoblastic Leukemia Herpes-simplex-Reaktivierung und HSV-Primärinfektion während der Behandlung der akuten lymphoblastischen Leukämie im Kindesalter Authors
M. Lauten1, C. Güttel2, C. Härtel1, B. Erdlenbruch3
Affiliations
1
Key words ▶ childhood ● ▶ acute lymphoblastic ● leukemia ▶ disseminated herpes ● simplex infection ▶ induction ● ▶ re-induction ● ▶ herpes encephalitis ●
Introduction
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1354387 Published online: October 24, 2013 Klin Padiatr 2014; 226: 188–189 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Melchior Lauten Department of Pediatrics UKSH, Campus Lübeck Ratzeburger Allee 160 23538 Lübeck Germany Tel.: + 49/451/500 2956 Fax: + 49/451/500 3767 [email protected]
▼
Treatment related mucositis is known as a risk factor for systemic bacterial, fungal and viral infections in childhood acute lymphoblastic leukemia (ALL). Childhood ALL-BFM treatment related mortality (TRM) is reported to be up to 4 % [14] and infectious agents are the main cause. Recently, Pichler et al. showed that the inferior prognosis of 15–18 years old ALL patients is mainly due to an infection related higher TRM [10]. Prucker et al. described 31 patients with TRM during induction therapy due to non-leukemic reasons and 21/31 patients died of infections. In ten of these an infectious agent was detectable, only 2 of these 10 were viral agents (CMV) [11]. Latent infections and reactivation of herpes simplex (HSV) are of importance in immuocompromised patients [4]. However, HSV reactivation or disease has not been reported as a cause of TRM in childhood ALL without allogeneic stem cell transplantation (SCT). Nevertheless, oral mucositis is a major risk factor for systemic bacterial infections following chemotherapy and the severity of oral mucositis is associated with detection of HSV-DNA in oral swabs [3]. Therefore, HSV may facilitate fatal disseminated bacterial infections as reported in a 69 year old relapsed ALL patient with fatal systemic Enterococcus faecalis infection and post mortem detection of HSV in an esophageal erosion by histopathologic examination [5]. Here we report on 3 patients treated according to the ALL-BFM 2009 and EsPhALL studies with severe HSV reactivation and/or infection during (re-)induction treatment. 2 of them died due to multiorgan dysfunction syndrome.
Case reports
▼
Patient 1: An 18 months old girl presented with BCR/ABL positive precursor B-cell ALL. She devel-
Lauten M et al. Herpes Simplex Virus Reactivation … Klin Padiatr 2014; 226: 188–189
oped severe mucositis with neutropenic fever during protocol I (prednisone good response, PGR). As cause of the mucositis, candida was clinically suspected and treatment with local amphotericin suspension and intravenous liposomal amphotericin was initiated. Protocol I was completed without significant delay. During HR-1 (grade 4) and HR-2 (grade 2–3) cycles, the girl presented with recurrent episodes of mucositis. Initially and after HR-3, HSV titres were negative. On day 17 of protocol II fever, elevation of CrP (11 mg/l) and grade 1 mucositis occurred. From day 22 on mucositis worsened, while CrP decreased. Antibiotic therapy had been intensified using piperacillin, tazobactam, aminoglycoside, metronidazole and liposomal amphotericin, but the girl deterioated clinically demanding tracheal intubation and cardio-pulmonary resuscitation. On day 25 the girl died. Retrospectively, herpes DNA was detected in blood samples on day 21 and in a buccal swab, which was misinterpreted as negative before.
Patient 2: During protocol IA (ALL-BFM 2009) a 13 year old boy with T- ALL and mediastinal mass presented with grade 4 mucositis and neutropenia. In addition to the standard antibiotic regimen, aciclovir was given for suspected HSV reactivation despite a negative HSV PCR (HSV serum titres at diagnosis: IgG 1:19 000, IgM negative). During protocol M mucositis grade 2 occurred and resolved spontaneously. On day 16 of protocol IIa mucositis grade 1 re-occured. The patient was hospitalised for oral pain and fatigue 6 days later. Another 6 days later rapid elevation of CrP (147 mg/l) with concomitant disequilibrium of electrolytes occurred. After extension of the antibiotic regimen (piperacillin, vancomycin, tobramycin, liposomal amphotericin) and addition of hydrocortison CrP (max. 394 mg/l) started to decrease. However, on day 33 of protocol IIa arterial hypotension and pulmonary failure required catecholamines and non-invasive ventilation. On the same day aciclovir was started due to a
Downloaded by: Karolinska Institutet. Copyrighted material.
Schlüsselwörter ▶ Kind ● ▶ akute lymphoblastische ● Leukämie ▶ disseminierte Herpes● simplex-Infektion ▶ Induktion ● ▶ Reinduktion ● ▶ Herpes encephalitis ●
Department of Pediatrics, UKSH, Campus Lübeck, Germany Department of Pediatrics, HELIOS Kliniken Schwerin, Germany 3 Department of Pediatrics, Mühlenkreiskliniken, Minden, Germany 2
Pictorial Essay 189
Patient 3: After good response to prednisone a 5 years old girl with TEL/AML1 positive common ALL developed neutropenic fever and abdominal pain on day 18 of protocol I. She was treated with cefotaxim, tobramycin and vancomycin. CrP was 53 mg/l and reached its maximum on day 26 (107 mg/l). On day 23 the antibiotic regimen was extended because of positive clostridium difficile toxine detection and finally changed to meropenem, metronidazole and vancomycin for positive blood and stool cultures of Pseudomonas aeruginosa (day 27). 1 week later she developed focal seizures of the right arm and anisocoria. CSF examination showed pleocytosis, elevated lactate and a positive HSV PCR in the CSF. Magnetic resonance imaging (MRI) of her head showed left temporal encephalitis. HSV IgG was positive and IgM negative (HSV PCR in serum was not done). Intravenous aciclovir (60 mg/kg) led to clinical resolution of the focal seizures by day 45. Paralytic ileus required partial resection of the ileum with end-to-end anastomosis. After 21 days aciclovir was stopped. During protocol M and protocol IIa no problems occurred. During protocol IIb mucositis grade 2 associated with HSV (positive PCR from saliva) re-occurred. Aciclovir was restarted and given orally until the end of maintenance treatment.
Discussion
▼
Prognosis of childhood ALL is very good [9, 14], but hampered by TRM due to severe infections. HSV infection as a cause of febrile episodes seems to account for 10 % of proven infections [2] and can be detected in blood cultures of non-febrile patients as well [15]. In patients with chemotherapy induced severe mucositis the prevalence of HSV in oral swabs is 50 % [2]. Risk factors for HSV reactivation in immunocompromised patients are age and history of cold sores as well as lymphopenia
