Use of cidofovir in pediatric patients with adenovirus infection

Lakshmi Ganapathi; Alana Arnold; Sarah Jones; Al Patterson; Dionne Graham; Marvin Harper; Ofer Levy

doi:10.12688/f1000research.8374.1

Home Browse Use of cidofovir in pediatric patients with adenovirus infection

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Research Note

Use of cidofovir in pediatric patients with adenovirus infection

[version 1; peer review: 2 approved, 1 approved with reservations]

Lakshmi Ganapathi^1,2, Alana Arnold³, Sarah Jones³, [...] Al Patterson³, Dionne Graham⁴, Marvin Harper^1,2, Ofer Levy^1,2

Lakshmi Ganapathi^1,2, Alana Arnold³, [...] Sarah Jones³, Al Patterson³, Dionne Graham⁴, Marvin Harper^1,2, Ofer Levy^1,2

PUBLISHED 26 Apr 2016

Author details Author details

¹ Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA
² Harvard Medical School, Boston, MA, USA
³ Division of Pharmacy, Boston Children’s Hospital, Boston, MA, USA
⁴ Program for Patient Quality and Safety, Boston Children’s Hospital, Boston, MA, USA

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity.
Methods: We conducted a retrospective 5-year review at Boston Children’s Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction.
Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV.
Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.

Keywords

cidofovir, anti-viral, pediatric, adenovirus, stem-cell, solid organ, immunocompromised

Corresponding author: Ofer Levy

Competing interests: No competing interests were disclosed.

Grant information: OL’s laboratory is supported by a Boston Children’s Hospital Department of Medicine award to the Precision Vaccines Program as well as Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation and by NIH grants 1R01AI100135-01 and 3R01AI067353- 05S1 and National Institute of Allergy & Infectious Diseases Adjuvant Discovery Program, Contract No. HHSN272201400052C. The Levy Laboratory has received sponsored research support from VentiRx Pharmaceuticals, 3M Drug Delivery Systems, MedImmune, and Crucell (Johnson & Johnson)- companies that develop adjuvants and vaccines.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2016 Ganapathi L et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

How to cite: Ganapathi L, Arnold A, Jones S et al. Use of cidofovir in pediatric patients with adenovirus infection [version 1; peer review: 2 approved, 1 approved with reservations]. F1000Research 2016, 5:758 (https://doi.org/10.12688/f1000research.8374.1) First published: 26 Apr 2016, 5:758 (https://doi.org/10.12688/f1000research.8374.1) Latest published: 16 Dec 2016, 5:758 (https://doi.org/10.12688/f1000research.8374.2)

Introduction

Adenovirus (ADV) is a common cause of respiratory infection in childhood. ADV infections are usually self-limited and asymptomatic in the immunocompetent host but have been recognized as a cause of significant morbidity and mortality in immunocompromised pediatric patients such as recipients of hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT)¹. In these patients, ADV is an opportunistic pathogen that may lead to severe localized disease including pneumonia/pneumonitis, hepatitis, hemorrhagic cystitis or disseminated disease with multiorgan failure^2–4. Case fatality rates in immunocompromised patients with ADV pneumonia have been reported to be as high as 60%⁵. Currently, there is no FDA-labeled product available for treatment of ADV infection though several agents have been administered for this indication including ribavirin^6,7, ganciclovir⁸, vidarabine^9,10, immune globulin¹¹ and cidofovir^12–21.

Cidofovir (CDV), a nucleoside and phosphonate analogue is a broad-spectrum antiviral agent that inhibits viral DNA polymerase and has broad activity in vitro against multiple viruses including all serotypes of ADV^22,23. CDV has an FDA indication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Although this drug does not have an FDA indication for treating ADV, there is evidence of in vivo efficacy of CDV against ADV^12,14. While CDV at a standard dose of 5mg/kg has been reported as primary therapy for treatment of ADV infection in pediatric and adult hematopoietic stem cell transplantation (HSCT) patients^12,21, concern exists regarding potential nephrotoxicity. These associated adverse effects have limited the use of CDV for treatment of ADV infections in pediatric patients. To minimize potential toxicity of CDV, modified dosing regimens such as the use of 1 mg/kg three times have been utilized¹⁴.

Limited information regarding safety and efficacy of CDV in pediatric patients prompted us to review prior published studies in the literature and conduct a retrospective review of our inpatient use of CDV at Boston Children’s Hospital (BCH).

Methods

Following Institutional Review Board (IRB) approval (IRB-P00015576), a retrospective chart review was conducted for all hospitalized patients at Boston Children’s Hospital (BCH), who were prescribed CDV for adenovirus infection from January 2006 through December 2010. The following data were collected: (1) demographic information, (2) underlying disease state, (3) type of transplant, (4) duration of cidofovir therapy, (6) serum creatinine (SCr) (baseline, peak during therapy, and level up to 2 weeks post last dose), (7) concomitant nephrotoxins prescribed (acyclovir, amikacin, cyclosporine, foscarnet, gentamicin, liposomal amphotericin B, tacrolimus, tobramycin, vancomycin, and intravenous contrast media), (8) sites of ADV detection by viral direct fluorescent antibody (DFA), nucleic acid test, and/or culture, (9) viral quantitative PCR surveillance in blood and other sites of infection (all specimens were tested at least weekly before, during and to two weeks post last dose of CDV to evaluate for changes in viral load with a minimum three serial values being obtained before, during and at end of therapy); (10) symptoms of infection, and clinical course including response to therapy, (11) concomitant reduction of immunosuppression and (12) mortality and cause(s) of mortality. All blood sample testing for adenovirus quantitative PCR in blood was performed at the Boston Children’s Hospital Virology Laboratory using our laboratory developed test, the Argene adenovirus assay (bioMerieux, Cambridge, MA). The Argene adenovirus assay contains primers and probes selective for a 138 base pair (bp) sequence in the Hexon gene of the adenovirus. Using a 5’ nuclease assay, viral DNA is detected using the primers and fluorescent probes from the Argene assay kit by means of real time PCR in a Cepheid SmartCycler (Cepheid, Sunnyvale, CA).

Definitions

As there is no accepted definition for ADV infection or disease, we adopted definitions used in prior studies¹³. Specifically, definite adenovirus disease as follows: Non-gastrointestinal locations: Symptoms and signs from the appropriate organ combined with histopathological documentation of adenovirus and/or adenovirus detection by culture, antigen test, or nucleic acid test from biopsy specimens (liver or lung), BAL fluid, or cerebrospinal fluid and without another identifiable cause; Gastrointestinal location: Symptoms together with detection of adenovirus from biopsy material by culture, antigen test, or nucleic acid test.

Probable adenovirus disease as follows: Gastrointestinal tract: Detection of adenovirus in stool by culture, antigen test, or nucleic acid test together with symptoms; Urinary tract: Symptoms of dysuria or hematuria combined with detection of adenovirus by culture, antigen test, or nucleic acid test without another identifiable cause; and Respiratory tract: Symptoms and signs of pneumonia/pneumonitis combined with detection of adenovirus by culture, antigen test, or nucleic acid test without another identifiable cause.

Asymptomatic adenovirus infection as follows: any detection of adenovirus in an asymptomatic patient from stool, blood, urine, or upper airway specimens by viral culture, antigen tests, or PCR.

Adenoviremia was defined as the detection of >100 copies of ADV/mL of blood (this being the lower limit of detection of the assay). Viral clearance was defined as an ADV viral load of <100 copies in blood by quantitative PCR at the end of therapy. Viral response was defined as decrease in viremia by at least one log-fold. Clinical resolution was defined as resolution of symptoms and/or signs of infection. Renal dysfunction was defined as a ≥50% increase in SCr from baseline during the course of CDV therapy. The peak SCr during therapy was used to calculate the number of patients that experienced renal dysfunction.

Statistical analysis

Statistical analyses employed Prism 5 for Windows Version 5.04 (GraphPad Software Inc, CA). The Mann-Whitney test was used to assess risk of renal dysfunction. Trends in adenoviremia including pre-treatment viral load, changes in viral load during therapy, and post-treatment viral load were graphed.

Results

time	Pat. 1a	Pat. 2	Pat. 3	Pat. 4	Pat. 6	Pat. 7	Pat. 8	Pat. 9	Pat. 10	Pat. 11	Pat. 12	Pat. 13	Pat. 14	Pat. 15	Pat. 16	Pat. 5
-37								600
-36
-35
-34
-33
-32
-31
-30
-29								1200
-28								3600
-27
-26
-25
-24
-23
-22								10100
-21
-20
-19
-18
-17
-16								38500
-15
-14
-13															10
-12
-11
-10							10200								10
-9		500
-8														700
-7	10							4900
-6		2600
-5				376000								1800000			10	10
-4													981000
-3										2600000	6100000
-2		26700					90200	30800	10
-1			10					17800				783000		10100	100	100
0	10				33000	5600000				766000
1		25200		134000				4600
2											1300000	107000	600		600
3			200				2700000						700	40900
4	10									40000						200
5		83400		1700	1400000				10
6						65000000		200		28000					100 and 300
7										37700	29800		400
8		57000								37400
9	400						2200000	100				79000			400
10						8000					10400			43900		100
11	1100								10	2600
12		269000	397000	10		200		600
13								300	100						500
14											15500
15		253000						500	10
16	43700		1100000					600		4100					3300
17							589000		100					4700		10
18			782000
19		744000	74500	10				100
20															9700
21									300		1600
22	12200	842000
23							7600	10							23600
24									100		1100			1000
25
26	700	2000000
27								10							29600
28			1400							100	400
29
30	100							100							15500
31
32
33	200	2400000
34							10	300		100					7100
35											6400
36
37		1500000													900
38	10
39
40								200
41		1900000
42											200				10
43
44
45			10												100
46
47		147000						10
48
49															10
50
51
52														10	10
53
54		3400						200
55
56
57
58
59
60
61		100
62
63
64
65
66
67
68
69
70
71
72		10
73
74
75		10
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90		10
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
This is a portion of the data; to view all the data, please download the file.

Dataset 1.Raw data for Figure 1.

Adenovirus blood viral load is represented in each column at each particular time in days (before or after onset of cidofovir treatment) for each patient.

Pt	Pre -Cr	Peak Cr	Post Cr
1a	0.3	1.2	0.6
1b	0.6	1	0.6
2	0.6	0.6	0.5
3	0.3	0.6	0.2
4	0.3	0.3	0.2
5	0.4	0.7	0.5
6	0.2	0.4	0.6
7	0.2	0.5	0.7
8a	1	1.7	0.4
8b	0.4	2.6	1.3
9	0.3	2.7	0.6
10	0.2	0.2	0.2
11	0.4	1.6	0.6
12	0.5	1.6	0.6
13	0.2	0.2	0.2
14	0.2	0.2	0.2
15a	0.3	0.3	0.3
15b	0.2	0.3	0.2

Dataset 2.Raw data for Figure 2.

Nephrotoxicity - pre, peak and post serum creatinine levels in mg/dL are represented in each column for each patient.

From January 1, 2006 to December 31, 2010, a total of 16 pediatric patients received CDV for adenovirus infection at our hospital. These 16 patients received 19 courses (three patients received two separate CDV courses). The standard CDV dose of 5mg/kg weekly was used in all courses unless there was concern for renal dysfunction at the start of therapy in which case a dosing regimen of 1mg/kg three times a week was used. Patient demographics, primary diagnosis, clinical symptoms and course, and sites of adenovirus detection appear in Table 1. Patient age ranged from 0.75–20 years (mean 6.5 years). Seven (44%) patients were male. Underlying primary diagnosis included 8 (50%) HSCT (1 autologous), 4 (25%) SOT, 2 (12.5%) leukemia, and 2 (6.5%) defined as other. Duration of CDV therapy ranged from 5–82 days (median 33.5 days).

Table 1. Demographics, primary diagnosis, sites of ADV detection, clinical symptoms and course of patients included in the study.

The age and gender distribution, primary diagnosis, sites of adenovirus detection, symptoms and clinical course of the patients included in the study are shown.

Pt #	Age (yrs)	Gender	Diagnosis	Site(s) of ADV detection	Clinical symptoms
1a	12	F	AML - Mismatched UD Cord SCT	Sp, S, R	Pneumonia
1b	12	F	AML - Mismatched UD Cord SCT	Sp	Fever and Respiratory symptoms
2	12	M	Severe Idiosyncratic Immunodeficiency - MRD SCT	B, S	Prolonged fever
3	3	M	AML - Chemotherapy	B, S, U	Pneumonia
4	4	F	Neuroblastoma - Autologous SCT	B, S, PF	Prolonged fever, pericardial effusion
5	19	F	Cystic Fibrosis - Lung Transplant	B, BAL	Asymptomatic
*6	1	F	Familial HLH - MUD SCT	B, Sp	Pneumonia, sepsis. Other co-infections including Enterococcus bacteremia, EBV viremia
*7	0.83	M	Persistent pulmonary hypertension, cardiomyopathy	B	Fever, sepsis, pneumonia. Other co-infections including stenotrophomonas bacteremia
8a	20	M	ALL - MRD SCT and MUD SCT	BAL, B, U	Pneumonia
8b	20	M	ALL - MRD SCT and MUD SCT	S	Asymptomatic
9	1	F	Congenital Nephrotic Syndrome & Hepatoblastoma - Combined Liver & Kidney Transplant	B,Sp	Respiratory symptoms
*10	0.75	M	HLH - SCT	S, B, U	Fever, sepsis, diarrhea
*11	5	F	CID and Lymphoproliferative Disorder - Mismatched UD Cord SCT	B	Fever, respiratory symptoms, diarrhea, hemorrhagic cystitis
12	2	F	Congenital Cardiac Defect - Heart Transplant	B	Fever, sepsis
13	2	F	ALL - Chemotherapy	B, S	Fever, respiratory symptoms
14	2	F	Cerebral Palsy	B	Pneumonia
15a	1.8	M	Hepatoblastoma - Multiviseral Transplant	B, S	Increased stoma output, rejection, biopsy proven ADV In stoma mucosa
15b	1.8	M	Hepatoblastoma - Multiviseral Transplant	B, S	Increased stoma output
*16	17	M	AML - MUD SCT	B, U	Hemorrhagic cystitis. Other co-infections including BK viruria and EBV viremia

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CID, congenital immunodeficiency; CML, chronic myelogenous leukemia; HLH, hemophagocytic lymphohistiocytosis; MRD, matched related donor; MUD, matched unrelated donor; Pt #, patient number; SCID, severe combined immunodeficiency disorder; SCT, stem cell transplant; UD, unrelated donor; Yrs, years; Site of adenovirus detection: S, stool, Sp, sputum, B, blood, BAL, bronchoalveolar lavage, R, respiratory DFA, CSF, cerebrospinal fluid, U, Urine, PF, Pericardial Fluid; *indicates patient expired

Of the 19 courses prescribed (Table 1), two courses were prescribed in a patient with definite adenovirus disease of the gastrointestinal tract, 15 courses were prescribed in patients with probable disease and two courses were prescribed in patients with asymptomatic infection. Sixteen courses (84%) were in patients who had a positive blood ADV PCR either in whole blood only or in combination with positive ADV PCR of sputum, stool, urine, broncho-alveolar lavage (BAL) fluid, pericardial fluid or positive sputum adenoviral DFA sample. Respiratory symptoms were the most common presentation in 10 courses (53%) of which six courses were prescribed for patients with respiratory symptoms and radiological evidence of pneumonia. Two courses were prescribed in patients who presented with prolonged fevers; four courses were prescribed in patients who had worsening diarrhea and colitis, two of which were biopsy proven adenovirus infection; four courses were prescribed in patients with viral sepsis with or without pneumonia; and two courses were administered in patients with severe hemorrhagic cystitis. Two courses were prescribed in patients with asymptomatic respiratory tract infection and asymptomatic gastrointestinal infection respectively.

We further examined the 16 blood-positive courses to assess trends in ADV viral load pre-, during and post- CDV therapy (Figure 1). A quantitative reduction in viral load was seen in 15 blood positive courses (94%) with viral clearance achieved in 14 (88%). Of note, all solid organ transplant recipients treated with CDV also had concomitant decrease in their immunosuppression. A single patient (Patient 6) did not demonstrate viral response to therapy and expired. The majority of adenovirus blood-positive CDV courses (10/16, 63%) were associated with clinical improvement with viral clearance, however this was not the case in four courses. Patients 7, 10, 11 and 16 expired despite demonstrating viral clearance. Patients 6, 7 and 16 had multiple other co-infections. Patients 11 and 16 developed severe hemorrhagic cystitis. Patient 11 experienced significant complications of hemorrhagic cystitis including urinary tract obstruction, renal failure and bladder perforation. Patient 16 also had concomitant BK Polyoma virus detected in the urine.

Figure 1. Kinetics of Adenovirus blood viral load under cidofovir treatment.

Viral loads of 16 patients with quantitative blood adenovirus PCR treated with cidofovir, are shown. Day of therapy ≤0 denotes pre-treatment viral loads. Up to two post-treatment values are shown where available and informative. Each patient’s individual treatment duration is shown in the legend. + denotes patient expired.

Each patient’s medication profile was assessed to determine the number of additional nephrotoxic agents concomitantly prescribed during CDV therapy (from Day 1 to 7 days post last CDV dose). All 19 courses prescribed had at least one additional nephrotoxic agent prescribed during CDV therapy (Table 2). Four courses (21%) had only one additional nephrotoxic medication prescribed, five courses (26%) had two such medications prescribed, six courses (32%) had three prescribed, two courses (11%) had four prescribed, and two courses (11%) had five prescribed.

Table 2. Additional nephrotoxic agents prescribed and changes in serum creatinine during cidofovir therapy.

Absolute values for serum creatinine in mg/dL for each patient are represented pre-treatment, during treatment (peak serum creatinine), and post-treatment. Additional nephrotoxic agents that each patient received are also represented.

Pt #	Pre-treatment Serum Cr	Peak Serum Cr	Post-treatment Serum Cr	Additional nephrotoxic agents
1a	0.3	1.2	0.6	ambisome, cyclosporine, gentamicin
1b	0.6	1	0.6	cyclosporine
2	0.6	0.6	0.5	cyclosporine, ganciclovir, pentamidine
3	0.3	0.6	0.2	vancomycin, ambisome, gentamicin
4	0.3	0.3	0.2	acyclovir
5	0.4	0.7	0.5	tacrolimus
6	0.2	0.4	0.6	ambisome, ganciclovir, pentamidine, tacrolimus, vancomycin
7	0.2	0.5	0.7	gentamicin, tobramycin
8a	1	1.7	0.4	ambisome, vancomycin
8b	0.4	2.6	1.3	ganciclovir, tacrolimus, vancomycin
9	0.3	2.7	0.6	chemotherapy
10	0.2	0.2	0.2	acyclovir, ambisome, cyclosporine, vancomycin
11	0.4	1.6	0.6	gentamicin, acyclovir, ambisome, cyclosporine, foscarnet, ganciclovir
12	0.5	1.6	0.6	gentamicin, ganciclovir, tacrolimus
13	0.2	0.2	0.2	ambisome,foscarnet,ganciclovir
14	0.2	0.2	0.2	vancomycin
15a	0.3	0.3	0.3	tacrolimus, vancomycin
15b	0.2	0.3	0.2	tacrolimus, vancomycin
16	0.3	0.5	0.3	cyclosporine, gentamicin, vancomycin, contrast

Pt #, patient number; Cr, creatinine; all creatinine values are in mg/dL.

Administration of CDV was significantly associated with occurrence of renal dysfunction when comparing the peak Cr measured during CDV therapy to the baseline serum Cr (p=0.0016). Eleven courses (58%) were associated with development of renal dysfunction. Cr increased by a mean of ~50% from baseline during CDV therapy (Figure 2). Of the courses with elevation in serum creatinine, 64% demonstrated return to pre-treatment creatinine levels following cessation of CDV therapy. There was no statistically significant difference when assessing for increased risk of renal dysfunction if patients received ≤ 1 additional nephrotoxic agent or ≥ 2 additional nephrotoxic agents.

Figure 2. Change in serum creatinine during, and at the end of cidofovir therapy compared to pre-treatment serum creatinine.

The y axis represents change in serum creatinine (in percentage) compared to pre-treatment serum creatinine. During therapy, serum creatinine increased by a mean of 50%. *** indicates p<0.01; NS indicates change is not significant.

Discussion

In this retrospective review of patients treated with CDV for adenovirus infection at our hospital during a 5-year period, we assessed the safety and potential efficacy of the medication in pediatric patients. Our review yielded a case series of 16 patients. While the number of patients is modest, this series adds to the existing literature describing the use of CDV in pediatric recipients of HSCT, SOT and chemotherapy for oncologic diagnoses (Table 3).

Table 3. Summary of studies describing use of cidofovir in pediatric HSCT and SOT recipient.

Published studies in the literature describing use of cidofovir in pediatric HSCT and SOT recipients are summarized. Toxicities, and clinical outcomes reported in each study are highlighted.

Study	# Patients (N)	Clinical Setting	Median Age	Cidofovir dosage	Duration of cidofovir use	Potential Toxicity	Outcome
Hoffman¹⁴	8	HSCT	7 yrs	1 mg/kg/dose three times weekly × 9 doses or until clearance	3 weeks–8 months	Well tolerated; no toxicity reported	100% viral suppression 3 recurrences 4 expired (2 ADV- related)
Muller¹²	10	HSCT	Not reported	5 mg/kg/dose weekly up to 6 weeks, then every other week for 3 more doses	3 weeks–6 months	30% nephrotoxicity (50% increase Cr)	9 virologic clearance 5 recurrences 1 expired (interstitial pneumonitis)
Anderson¹⁹	7	HSCT	1.5 yrs	Preemptive therapy: 1 mg/kg/dose three times weekly × 3 weeks	3 weeks	Well tolerated without significant toxicity reported	No patient developed ADV viremia 2 expired (non-ADV related)
Bhadri¹⁵	23	87% HSCT 13% oncologic receiving chemotherapy	5.7 yrs	5 mg/kg/dose weekly, 3 mg/kg/dose weekly or 1 mg/kg/dose three times weekly	Median 6 weeks (1–26 weeks)	9% Grade 1 nephrotoxicity defined by increase of creatinine up to 1.5 times upper limit of normal	85% of 20 evaluable patients considered successful by Ljungman criteria¹³ 17 expired
Yusuf¹⁷	57	90% HSCT 10% oncologic receiving chemotherapy	8 yrs	5 mg/kg/dose weekly × 2 weeks, then every other week until 3 negative ADV samples	Median 60 days (1 week–9 months)	No toxicity reported	98% successful viral clearance 14% recurrence 29 expired (1 ADV- related death)
Legrand¹⁸	7	HSCT	6.4 yrs	5 mg/kg/dose weekly × 3 wks then every other wk or 10 days	25–330 days	43% nephrotoxicity	71% deemed recovered 2 expired (1 ADV related death)
Sivaprakasam²⁶	8	HSCT	11 yrs	1 mg/kg/dose 3 times weekly (4 patients also received IV ribavirin 5 mg/kg 3 times daily)	Not reported	2 cases marrow failure, 1 case nephropathy	3 expired (attributed to ADV and GVHD)
Williams²⁷	9	HSCT	3 yrs	5 mg/kg/dose once weekly until 3 weeks of negative results or pt no longer high risk; if underlying renal dysfunction 1 mg/kg/ dose 3 times weekly	Median 8 doses (3–32 doses)	22% renal failure (compared to 80% untreated comparator group)	89% ADV clearance 3 expired (1 ADV related)
Engelmann¹⁶	1	Liver transplant	7 months	6 mg/kg/dose × 1 with 1 repeat dose 6 days later	2 weeks	No toxicity reported	Liver rejection; reported to have slow recovery
Wallot²⁰	2	Liver transplant	8 months and 14 months	1 mg/kg/dose three times weekly	5–8 weeks	1 moderate neutropenia, 1 transient rise in creatinine	Blood PCR ADV clearance in both patients No deaths
Carter²⁴	1	Liver transplant	7 months	1 mg/kg/dose three times weekly	7 weeks	Transient acidosis and proteinuria	ADV viral culture and blood PCR became negative
Doan²⁵	4	Lung transplant	<3 yrs	1 mg/kg/dose every other day to three times weekly plus IVIG (1 pt increased dose to 2 mg/kg/dose; 1 pt increased frequency to daily therapy × 2 weeks)	4 weeks	No toxicity reported	75% negative blood ADV PCR 1 death

Similar to other studies the majority of our patients had received a HSCT or had an oncologic diagnosis and received chemotherapy. We identified eight publications describing the use of CDV for adenovirus infection in the setting of HSCT or oncologic diagnoses treated with chemotherapy (Table 3). Three of these studies^14,17,27 reported viral clearance in 89–100% of their patients. We observed similar rates of viral clearance (88%) but this was not consistently associated with clinical improvement.

There are very few reports on the use of CDV for adenovirus infection in pediatric SOT recipients, which have largely been restricted to reports of children receiving liver or lung transplants^16,20,24,25. We identified four publications reporting the use of CDV for adenovirus infection in pediatric SOT recipients limited to one to four per report and all of these children having received liver or lung transplants^16,20,24,25. Doan et al.²⁵ described children who had received lung transplants with reported viral clearance in three of their four patients. Our case series contributes patients who received several types of SOT including lung, heart, combined kidney and liver, and multi-visceral transplants. All patients with SOT in our series demonstrated viral clearance as well as resolution of symptoms, which may have reflected a combination of both the antiviral effect of CDV coupled with reduced immunosuppression.

Two-thirds of our patients experienced resolution of their symptoms and had an overall favorable clinical course with recovery. However, one-third died all of which were stem cell transplant recipients. With the exception of one patient it is unclear whether adenovirus was the direct cause of mortality in these patients. Our observations are consistent with what has been reported in the literature pertaining to outcomes in stem cell transplant recipients with adenovirus infections who have been treated with CDV^{9,12,14,18,23,27}. Among SCT patients mortality remains high (10%–70%) even when clearance from blood is seen.

In our case series, renal dysfunction was common during CDV therapy with patients experiencing an average 50% increase of serum creatinine from their baseline. However, renal dysfunction was transient in the majority of patients with serum creatinine returning to baseline after cessation of CDV therapy. While some studies have reported no toxicities related to the use of CDV^{14,16,17,19,25}, the transient nature of nephrotoxicity observed has been reported by other studies^20,24. We were unable to detect any increased risk of nephrotoxicity associated with concomitant administration of additional nephrotoxic agents but this may reflect our small number of study participants.

Our study has several limitations. Most notably, the small number of patients precluded evaluation of other factors that may impact infection resolution such as immunosuppressive regimens, and additional factors that may impact degree of renal dysfunction. Nevertheless, our study adds to the limited reported literature of pediatric ADV patients treated with CDV.

Data availability

F1000Research: Dataset 1. Raw data for Figure 1, 10.5256/f1000research.8374.d117321²⁸

F1000Research: Dataset 2. Raw data for Figure 2, 10.5256/f1000research.8374.d117322²⁹

Author contributions

OL conceived the study. LG, AA and SJ collected data and prepared the first draft of the manuscript. LG, AP and DG performed data analysis. MH contributed to the preparation of the manuscript. All authors were involved in the revision of the draft manuscript and have agreed to the final content.

Competing interests

No competing interests were disclosed.

Grant information

OL’s laboratory is supported by a Boston Children’s Hospital Department of Medicine award to the Precision Vaccines Program as well as Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation and by NIH grants 1R01AI100135-01 and 3R01AI067353- 05S1 and National Institute of Allergy & Infectious Diseases Adjuvant Discovery Program, Contract No. HHSN272201400052C. The Levy Laboratory has received sponsored research support from VentiRx Pharmaceuticals, 3M Drug Delivery Systems, MedImmune, and Crucell (Johnson & Johnson)- companies that develop adjuvants and vaccines.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Faculty Opinions recommended

References

1. Ison MG: Adenovirus infections in transplant recipients. Clin Infect Dis. 2006; 43(3): 331–339. PubMed Abstract | Publisher Full Text
2. Carrigan DR: Adenovirus infections in immunocompromised patients. Am J Med. 1997; 102(3A): 71–74. PubMed Abstract
3. Howard DS, Phillips II GL, Reece DE, et al.: Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999; 29(6): 1494–1501. PubMed Abstract | Publisher Full Text
4. Hale GA, Heslop HE, Krance RA, et al.: Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant. 1999; 23(3): 277–282. PubMed Abstract
5. Hierholzer JC: Adenoviruses in the immunocompromised host. Clin Microbiol Rev. 1992; 5(3): 262–274. PubMed Abstract | Free Full Text
6. Gavin PJ, Katz BZ: Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics. 2002; 110(1 Pt 1): e9. PubMed Abstract
7. McCarthy AJ, Bergin M, De Silva LM, et al.: Intravenous ribavirin therapy for disseminated adenovirus infection. Pediatr Infect Dis J. 1995; 14(11): 1003–1004. PubMed Abstract | Publisher Full Text
8. Chen FE, Liang RH, Lo JY, et al.: Treatment of adenovirus-associated haemorrhagic cystitis with ganciclovir. Bone Marrow Transplant. 1997; 20(11): 997–999. PubMed Abstract | Publisher Full Text
9. Kawakami M, Ueda S, Maeda T, et al.: Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997; 20(6): 485–490. PubMed Abstract | Publisher Full Text
10. Kitabayashi A, Hirokawa M, Kuroki J, et al.: Successful vidarabine therapy for adenovirus type 11-associated acute hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994; 14(5): 853–854. PubMed Abstract
11. Saquib R, Melton LB, Chandrakantan A, et al.: Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin. Transpl Infect Dis. 2010; 12(1): 77–83. PubMed Abstract | Publisher Full Text
12. Muller WJ, Levin MJ, Shin YK, et al.: Clinical and in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic stem cell transplant recipients. Clin Infect Dis. 2005; 41(12): 1812–1816. PubMed Abstract | Publisher Full Text
13. Ljungman P, Ribaud P, Eyrich M, et al.: Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2003; 31(6): 481–486. PubMed Abstract | Publisher Full Text
14. Hoffman JA, Shah AJ, Ross LA, et al.: Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001; 7(7): 388–394. PubMed Abstract | Publisher Full Text
15. Bhadri VA, Lee-Horn L, Shaw PJ: Safety and tolerability of cidofovir in high-risk pediatric patients. Transpl Infect Dis. 2009; 11(4): 373–379. PubMed Abstract | Publisher Full Text
16. Engelmann G, Heim A, Greil J, et al.: Adenovirus infection and treatment with cidofovir in children after liver transplantation. Pediatr Transplant. 2009; 13(4): 421–428. PubMed Abstract | Publisher Full Text
17. Yusuf U, Hale GA, Carr J, et al.: Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation. 2006; 81(10): 1398–1404. PubMed Abstract | Publisher Full Text
18. Legrand F, Berrebi D, Houhou N, et al.: Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children. Bone Marrow Transplant. 2001; 27(6): 621–626. PubMed Abstract
19. Anderson EJ, Guzman-Cottrill JA, Kletzel M, et al.: High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant. 2008; 12(2): 219–227. PubMed Abstract | Publisher Full Text
20. Wallot MA, Dohna-Schwake C, Auth M, et al.: Disseminated adenovirus infection with respiratory failure in pediatric liver transplant recipients: impact of intravenous cidofovir and inhaled nitric oxide. Pediatr Transplant. 2006; 10(1): 121–127. PubMed Abstract | Publisher Full Text
21. Ribaud P, Scieux C, Freymuth F, et al.: Successful treatment of adenovirus disease with intravenous cidofovir in an unrelated stem-cell transplant recipient. Clin Infect Dis. 1999; 28(3): 690–691. PubMed Abstract | Publisher Full Text
22. Naesens L, Lenaerts L, Andrei G, et al.: Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob Agents Chemother. 2005; 49(3): 1010–1016. PubMed Abstract | Publisher Full Text | Free Full Text
23. Morfin F, Dupuis-Girod S, Mundweiler S, et al.: In vitro susceptibility of adenovirus to antiviral drugs is species-dependent. Antivir Ther. 2005; 10(2): 225–229. PubMed Abstract
24. Carter BA, Karpen SJ, Quiros-Tejeira RE, et al.: Intravenous Cidofovir therapy for disseminated adenovirus in a pediatric liver transplant recipient. Transplantation. 2002; 74(7): 1050–1052. PubMed Abstract
25. Doan ML, Mallory GB, Kaplan SL, et al.: Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients. J Heart Lung Transplant. 2007; 26(9): 883–889. PubMed Abstract | Publisher Full Text
26. Sivaprakasam P, Carr TF, Coussons M, et al.: Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention. J Pediatr Hematol Oncol. 2007; 29(2): 81–85. PubMed Abstract | Publisher Full Text
27. Williams KM, Agwu AL, Dabb AA, et al.: A clinical algorithm identifies high risk pediatric oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral infection. J Pediatr Hematol Oncol. 2009; 31(11): 825–831. PubMed Abstract | Publisher Full Text | Free Full Text
28. Ganapathi L, Arnold A, Jones S, et al.: Dataset 1 in: Use of cidofovir in pediatric patients with adenovirus infection. F1000Research. 2016. Data Source
29. Ganapathi L, Arnold A, Jones S, et al.: Dataset 2 in: Use of cidofovir in pediatric patients with adenovirus infection. F1000Research. 2016. Data Source

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 16 Dec 2016

Revised

Comment

Version 1

VERSION 1 PUBLISHED 26 Apr 2016

Discussion is closed on this version, please comment on the latest version above.

Reader Comment 08 Dec 2016

Karoly Toth, Saint Louis University Health Sciences Center, USA

08 Dec 2016

Reader Comment

The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are ... Continue reading The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are already approved for other indications, while others are undergoing clinical trials. The references to these publications are provided below.

Toth et al. 2008. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A 105:7293-7297.
Diaconu et al. 2010. Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir. Journal of Gene Medicine 12:435-445.
Ying et al. 2014. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother 58:7171-7181.
Tollefson et al. 2014. Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res 112:38-46.
Toth et al. 2015. Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters. Viruses 7:1409-1428.

The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are already approved for other indications, while others are undergoing clinical trials. The references to these publications are provided below.

Toth et al. 2008. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A 105:7293-7297.
Diaconu et al. 2010. Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir. Journal of Gene Medicine 12:435-445.
Ying et al. 2014. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother 58:7171-7181.
Tollefson et al. 2014. Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res 112:38-46.
Toth et al. 2015. Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters. Viruses 7:1409-1428.

Competing Interests: No competing interests were disclosed. Close
Report a concern
Discussion is closed on this version, please comment on the latest version above.

Author details Author details

Competing interests

No competing interests were disclosed.

Grant information

OL’s laboratory is supported by a Boston Children’s Hospital Department of Medicine award to the Precision Vaccines Program as well as Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation and by NIH grants 1R01AI100135-01 and 3R01AI067353- 05S1 and National Institute of Allergy & Infectious Diseases Adjuvant Discovery Program, Contract No. HHSN272201400052C. The Levy Laboratory has received sponsored research support from VentiRx Pharmaceuticals, 3M Drug Delivery Systems, MedImmune, and Crucell (Johnson & Johnson)- companies that develop adjuvants and vaccines.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (2)

version 2

Revised

Published: 16 Dec 2016, 5:758

https://doi.org/10.12688/f1000research.8374.2

version 1

Published: 26 Apr 2016, 5:758

https://doi.org/10.12688/f1000research.8374.1

© 2016 Ganapathi L et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

SEE MORE DETAILS

CITE

how to cite this article

Ganapathi L, Arnold A, Jones S et al. Use of cidofovir in pediatric patients with adenovirus infection [version 1; peer review: 2 approved, 1 approved with reservations] F1000Research 2016, 5:758 (https://doi.org/10.12688/f1000research.8374.1)

NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?

Key to Reviewer Statuses VIEW HIDE

ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions

Version 1

VERSION 1

PUBLISHED 26 Apr 2016

Views

Reviewer Report 09 May 2016

David A Hunstad, Division of Pediatric Infectious Diseases, Washington University in St Louis, St Louis, MO, USA

Andrew Janowski, Department of Pediatrics, Washington University in St Louis, St Louis, MO, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.9007.r13746

Ganapathi et al describe a case series of 16 patients who received a total of 19 courses of cidofovir for adenovirus infection. The authors provide virological data to demonstrate a response to cidofovir therapy, and provide additional data regarding renal function and co-administration of renal toxic medications. Ganapathi et al. provides unique data regarding the peak creatinine level during therapy with cidofovir, though this value is difficult to interpret given the confounding factors of other nephrotoxic agents.

This case series is an incremental addition to the number of published cases of pediatric patients infected by adenoviruses who were treated with cidofovir. The manuscript follows a similar format to the case series reported by Bhadri et al. (2009), with presentation of the effects on renal function, and a summarization of the literature.

The authors should summarize outcomes from all other case series to provide updated overall mortality and nephrotoxicity of CDV-treated adenovirus infections in hematopoietic stem cell transplants, solid organ transplants, or other patients. Such analyses may enhance the timeliness and utility of this manuscript.

In the discussion, the authors describe the potential benefit of cidofovir in solid organ transplant patients, in conjunction with reduced immunosuppression. However, without a comparative cohort of children who did not receive cidofovir or reduced immunosuppression, it would be difficult to draw this conclusion from the data presented. In addition, the authors do not discuss two interesting published papers. Humar et al. (2005) described a cohort of adult SOT patients with adenovirus viremia who did not receive cidofovir; all had spontaneous resolution of viremia with no deaths. In contrast, Seidemann et al. (2004) reported that 3 out of 5 pediatric SOT with adenoviremia (one also had a HSCT) died despite receiving cidofovir. The authors should absolutely cite these studies, especially Seidemann as it included pediatric SOT patients. In addition, the authors should highlight whether the positive outcomes in their SOT population are aligned with the adult study by Humar et al. (and the conclusion in that paper that treatment may not be necessary for adenoviremia in SOT patients); and contrast their results with those of Seidemann et al.

Specific comments

Methods: The authors should report their study site’s protocol for testing for adenoviruses, specifically, whether testing for adenoviruses was only performed on symptomatic patients, or if high-risk patients were routinely screened for adenovirus.
Methods: Probenecid is often co-administered with cidofovir. The authors should report if this drug was used in any of the courses of cidofovir, and what dosages. If probenecid was not used in all courses, the authors should analyze their data to investigate the role of probenecid in reducing nephrotoxicity.
Methods: It is not clear if adenovirus testing is completed on whole blood or serum. Later in the results, the authors state whole blood, but this should be explained in the methodology.
Methods: The authors should define pre-treatment/peak/post-treatment creatinine levels in their methodology. In addition, what defines pre-treatment creatinine? Is that the creatinine on the day of initiation of cidofovir? One week prior? Baseline from months prior? Defining this value is essential to the author’s statistical analysis.
Table 1: Patients should be ordered by diagnosis for better organization (as opposed to patient number); for example, the hematopoietic stem cell transplant patients should be grouped together, then the solid organ transplant patients should be grouped together. A column of outcomes should be added for greater clarity of which cases resulted in mortality, instead of the usage of an asterisk.
Results: Much of the information stated in the paragraph starting “Of the 19 courses prescribed” is redundant with the data presented in table 1, including the number of courses involving viremia, pneumonia, and GI symptoms. This paragraph can be consolidated, and the case characteristics presented as already implemented in Table 1.
Results: The authors should include a description of the patient’s response to cidofovir in Table 1. This would provide better organization and clarity in interpreting which characteristics were associated with response (or lack thereof) to therapy. It also would make the paragraph “We further examined the 16 blood-positive…” redundant, and this could be consolidated.
Figure 1: This figure might be easier to interpret if it were separated, for example, into two graphs of HSCT and SOT/other patients. It is difficult to follow 16 distinct virological lines in the current graph. In addition, the color choices for patients 4, 9, and 13 are too similar.
The statistical analysis of increased risk of renal dysfunction when receiving 1 vs >2 renal toxic medications should be omitted as currently presented. The authors do not describe whether the additional nephrotoxic agents were co-administered at the same time or for what duration. These are critical confounding variables that are necessary for interpretation of whether nephrotoxicity was associated with increased administration of additional nephrotoxic agents. Given that this review is retrospective, such information may or may not be available.
Figure 2 is a somewhat awkward way to describe SCr before and after CDV therapy. In addition, it is unclear how, if only 64% of patients with elevated SCr returned to baseline, the mean SCr after CDV was equal to baseline (in the right bar of Figure 2). The table describes the SCr data adequately, and Figure 2 could therefore be omitted.
The publication search criteria used to generate Table 3 should be explained in the methods. In their literature review, the authors should incorporate other pediatric adenovirus-cidofovir case reports and series that were not reviewed in this manuscript, including: Seidemann et al. (2004), Leruez-Ville et al. (2004), Nagafuji et al. (2004).
At least brief mention of the advent of brincidofovir for treatment of these patients with much reduced nephrotoxicity would be warranted.

References

1. Bhadri VA, Lee-Horn L, Shaw PJ: Safety and tolerability of cidofovir in high-risk pediatric patients.Transpl Infect Dis. 2009; 11 (4): 373-9 PubMed Abstract | Publisher Full Text
2. Humar A, Kumar D, Mazzulli T, Razonable RR, et al.: A surveillance study of adenovirus infection in adult solid organ transplant recipients.Am J Transplant. 2005; 5 (10): 2555-9 PubMed Abstract | Publisher Full Text
3. Seidemann K, Heim A, Pfister ED, Köditz H, et al.: Monitoring of adenovirus infection in pediatric transplant recipients by quantitative PCR: report of six cases and review of the literature.Am J Transplant. 2004; 4 (12): 2102-8 PubMed Abstract | Publisher Full Text
4. Leruez-Ville M, Minard V, Lacaille F, Buzyn A, et al.: Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection.Clin Infect Dis. 2004; 38 (1): 45-52 PubMed Abstract | Publisher Full Text
5. Nagafuji K, Aoki K, Henzan H, Kato K, et al.: Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients.Bone Marrow Transplant. 2004; 34 (10): 909-14 PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

CITE

Report a concern

Author Response 16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

16 Dec 2016

Author Response

Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus ... Continue reading Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus infection, 2) Usage of probenecid and dose (it was used in all patients who received cidofovir), 3) how we defined pre-treatment creatinine and 4) the publication search criteria. While we mention the use of concomitant medications that are known to render nephrotoxicity, we agree that the analysis is confounded by several factors and hence have omitted the statistical analysis of increased risk of renal dysfunction when receiving 1 versus >1 nephrotoxic medications.

In the discussion section, we have expanded our discussion on the potential benefit of cidofovir in solid organ transplant recipients, and compare the findings of Humar et al (a study in which patients were all adults) with the findings reported by Seidemann et al and Leruez-Ville et al. As such, we added the latter two studies to table 3 for an updated literature review. However, we did opt to leave out the study by Nagafuji et al as recommended by the reviewers. The study by Nagafuji et al focused primarily on adult HSCT recipients and included only one pediatric patient. We feel that given much larger pediatric specific case series of HSCT recipients with adenovirus infection, this one case reported adds little. On the other hand, we did include case reports in the solid-organ patient literature review given the paucity of data in this population. We have also made a brief mention regarding the advent of brincidofovir.

We updated table 1 to include include a column of outcomes. While we recognize that other changes as recommended by the reviewers may contribute to better organization of text and data, we did not make too many other changes to table 1 or figure 1 given that these changes are stylistic and not necessarily content relevant.

Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus infection, 2) Usage of probenecid and dose (it was used in all patients who received cidofovir), 3) how we defined pre-treatment creatinine and 4) the publication search criteria. While we mention the use of concomitant medications that are known to render nephrotoxicity, we agree that the analysis is confounded by several factors and hence have omitted the statistical analysis of increased risk of renal dysfunction when receiving 1 versus >1 nephrotoxic medications.

In the discussion section, we have expanded our discussion on the potential benefit of cidofovir in solid organ transplant recipients, and compare the findings of Humar et al (a study in which patients were all adults) with the findings reported by Seidemann et al and Leruez-Ville et al. As such, we added the latter two studies to table 3 for an updated literature review. However, we did opt to leave out the study by Nagafuji et al as recommended by the reviewers. The study by Nagafuji et al focused primarily on adult HSCT recipients and included only one pediatric patient. We feel that given much larger pediatric specific case series of HSCT recipients with adenovirus infection, this one case reported adds little. On the other hand, we did include case reports in the solid-organ patient literature review given the paucity of data in this population. We have also made a brief mention regarding the advent of brincidofovir.

We updated table 1 to include include a column of outcomes. While we recognize that other changes as recommended by the reviewers may contribute to better organization of text and data, we did not make too many other changes to table 1 or figure 1 given that these changes are stylistic and not necessarily content relevant.

Competing Interests: None Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

16 Dec 2016

Author Response

Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus ... Continue reading Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus infection, 2) Usage of probenecid and dose (it was used in all patients who received cidofovir), 3) how we defined pre-treatment creatinine and 4) the publication search criteria. While we mention the use of concomitant medications that are known to render nephrotoxicity, we agree that the analysis is confounded by several factors and hence have omitted the statistical analysis of increased risk of renal dysfunction when receiving 1 versus >1 nephrotoxic medications.

In the discussion section, we have expanded our discussion on the potential benefit of cidofovir in solid organ transplant recipients, and compare the findings of Humar et al (a study in which patients were all adults) with the findings reported by Seidemann et al and Leruez-Ville et al. As such, we added the latter two studies to table 3 for an updated literature review. However, we did opt to leave out the study by Nagafuji et al as recommended by the reviewers. The study by Nagafuji et al focused primarily on adult HSCT recipients and included only one pediatric patient. We feel that given much larger pediatric specific case series of HSCT recipients with adenovirus infection, this one case reported adds little. On the other hand, we did include case reports in the solid-organ patient literature review given the paucity of data in this population. We have also made a brief mention regarding the advent of brincidofovir.

We updated table 1 to include include a column of outcomes. While we recognize that other changes as recommended by the reviewers may contribute to better organization of text and data, we did not make too many other changes to table 1 or figure 1 given that these changes are stylistic and not necessarily content relevant.

Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus infection, 2) Usage of probenecid and dose (it was used in all patients who received cidofovir), 3) how we defined pre-treatment creatinine and 4) the publication search criteria. While we mention the use of concomitant medications that are known to render nephrotoxicity, we agree that the analysis is confounded by several factors and hence have omitted the statistical analysis of increased risk of renal dysfunction when receiving 1 versus >1 nephrotoxic medications.

In the discussion section, we have expanded our discussion on the potential benefit of cidofovir in solid organ transplant recipients, and compare the findings of Humar et al (a study in which patients were all adults) with the findings reported by Seidemann et al and Leruez-Ville et al. As such, we added the latter two studies to table 3 for an updated literature review. However, we did opt to leave out the study by Nagafuji et al as recommended by the reviewers. The study by Nagafuji et al focused primarily on adult HSCT recipients and included only one pediatric patient. We feel that given much larger pediatric specific case series of HSCT recipients with adenovirus infection, this one case reported adds little. On the other hand, we did include case reports in the solid-organ patient literature review given the paucity of data in this population. We have also made a brief mention regarding the advent of brincidofovir.

We updated table 1 to include include a column of outcomes. While we recognize that other changes as recommended by the reviewers may contribute to better organization of text and data, we did not make too many other changes to table 1 or figure 1 given that these changes are stylistic and not necessarily content relevant.

Competing Interests: None Close
Report a concern

Views

Reviewer Report 04 May 2016

Jeffrey Bergelson, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Approved

https://doi.org/10.5256/f1000research.9007.r13587

This paper reports the use of cidofovir for treatment of adenovirus infection in 16 pediatric patients, and provides detailed information about the patients’ clinical status, blood viral loads, and renal function throughout the treatment course.

I have only one major point for the authors to consider. Most patients survived, and a number had decreases in viral load within several weeks of the start of cidofovir therapy. However, the patient group was quite heterogeneous (one case had cerebral palsy, but no apparent immune dysfunction); in some cases the viral loads rose for a long time before they began to fall; and 4 of the 7 patients who had undergone allogeneic stem cell transplant died. I think the discussion should point out explicitly that it is difficult to conclude from these data whether or not cidofovir provided any clinical benefit.

Minor points:

Clarify the assay used for viral loads. Is it the Argene assay, or an in-house assay using some components of the Argene kit?
Clarify the definition of “viral response”. Is it a 10-fold decrease in titer?
Perhaps mention briefly why the asymptomatic patients were treated with cidofovir. It appears that one was a lung transplant patient (considered to be at high risk) and one a SCT patient with recurrent viremia.
Figure 2 adds little.

Typos, spelling, glitches:

Page 3. “These associated adverse effects”; THIS adverse EFFECT.
Page 3.   “1 mg/kg three times” WEEKLY
Page 3.   “Respiratory tract”; italicize
Page 3.   “The peak SCr during therapy was used to calculate the number…” should be deleted.
Table 1. “multivisCeral”
Page 5.   “Respiratory symptoms were the most common presentation in 10 courses”; should be “… most common presentation (10 courses)..”
Page 5. “Two courses were prescribed… respectively” ; should be One course was prescribed in asymjptomatic x, and one in y.
Page 5. “improvement with viral clearance, however”; comma should be a semicolon.
Page 6. “.. one third died all of which”; ? …died, all of WHOM..”

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Reviewer Response 06 May 2016

Jeffrey Bergelson, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, USA

06 May 2016

Reviewer Response

Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Competing Interests: None
Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Competing Interests: None Close
Report a concern
Author Response 16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

16 Dec 2016

Author Response

Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we ... Continue reading Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we did observe clearance of viremia in several patients overall clinical benefit was somewhat harder to conclude. We have also mentioned the rationale behind treating asymptomatic patients (both treated patients were considered to be at high risk for complications).

In the methods section, we have clarified the following: 1) The assay used to determine viral load, 2) What we defined as viral response.

We have also corrected the minor spelling and punctuation issues.

We agree with both Dr Bergelson and Dr Hundstad that Figure 2 adds little and have removed it from this version of the manuscript

Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we did observe clearance of viremia in several patients overall clinical benefit was somewhat harder to conclude. We have also mentioned the rationale behind treating asymptomatic patients (both treated patients were considered to be at high risk for complications).

In the methods section, we have clarified the following: 1) The assay used to determine viral load, 2) What we defined as viral response.

We have also corrected the minor spelling and punctuation issues.

We agree with both Dr Bergelson and Dr Hundstad that Figure 2 adds little and have removed it from this version of the manuscript
Competing Interests: none Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Reviewer Response 06 May 2016

Jeffrey Bergelson, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, USA

06 May 2016

Reviewer Response

Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Competing Interests: None
Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.
Competing Interests: None Close
Report a concern
Author Response 16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

16 Dec 2016

Author Response

Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we ... Continue reading Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we did observe clearance of viremia in several patients overall clinical benefit was somewhat harder to conclude. We have also mentioned the rationale behind treating asymptomatic patients (both treated patients were considered to be at high risk for complications).

In the methods section, we have clarified the following: 1) The assay used to determine viral load, 2) What we defined as viral response.

We have also corrected the minor spelling and punctuation issues.

We agree with both Dr Bergelson and Dr Hundstad that Figure 2 adds little and have removed it from this version of the manuscript

Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we did observe clearance of viremia in several patients overall clinical benefit was somewhat harder to conclude. We have also mentioned the rationale behind treating asymptomatic patients (both treated patients were considered to be at high risk for complications).

In the methods section, we have clarified the following: 1) The assay used to determine viral load, 2) What we defined as viral response.

We have also corrected the minor spelling and punctuation issues.

We agree with both Dr Bergelson and Dr Hundstad that Figure 2 adds little and have removed it from this version of the manuscript
Competing Interests: none Close
Report a concern

Views

Reviewer Report 03 May 2016

Miguel O’Ryan, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile

Approved

https://doi.org/10.5256/f1000research.9007.r13586

This is a well written descriptive, retrospective study of a case series of immunocompromised children receiving cidofovir for treatment of mostly probable, few definite or asymptomatic adenovirus infections. Children had different underlying diseases including a few with solid organ transplantation. The series review is transparent, showing viral and clinical evolution as well as renal compromise in association with treatment. Most children cleared adenovirus with treatment but as the authors point out, also in association with improved immunity. Most but not all children clearing the virus improved clinically, a few died despite clearing the virus. Transient nephrotoxicity occurred in near 50% of children, but this occurred in association with other nephrotoxic treatments and was not a major problem. This review adds to the rather limited number of currently available series and although not providing any definite conclusion (clinicians will still have to balance several variables before deciding to use cidofovir or not) it adds helpful information for treating physicians that have to make these hard decisions.

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Respond or Comment

Comments on this article Comments (1)

Version 2

VERSION 2 PUBLISHED 16 Dec 2016

Revised

Comment

Version 1

VERSION 1 PUBLISHED 26 Apr 2016

Discussion is closed on this version, please comment on the latest version above.

Reader Comment 08 Dec 2016

Karoly Toth, Saint Louis University Health Sciences Center, USA

08 Dec 2016

Reader Comment

The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are ... Continue reading The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are already approved for other indications, while others are undergoing clinical trials. The references to these publications are provided below.

Toth et al. 2008. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A 105:7293-7297.
Diaconu et al. 2010. Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir. Journal of Gene Medicine 12:435-445.
Ying et al. 2014. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother 58:7171-7181.
Tollefson et al. 2014. Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res 112:38-46.
Toth et al. 2015. Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters. Viruses 7:1409-1428.

The readers may be interested to note that several compounds were found to be efficacious against disseminated adenovirus infection in the permissive Syrian hamster animal model. Some of these compounds are already approved for other indications, while others are undergoing clinical trials. The references to these publications are provided below.

Toth et al. 2008. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci U S A 105:7293-7297.
Diaconu et al. 2010. Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir. Journal of Gene Medicine 12:435-445.
Ying et al. 2014. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother 58:7171-7181.
Tollefson et al. 2014. Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res 112:38-46.
Toth et al. 2015. Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters. Viruses 7:1409-1428.

Competing Interests: No competing interests were disclosed. Close
Report a concern
Discussion is closed on this version, please comment on the latest version above.

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2	3
Version 2 (revision) 16 Dec 16			read
Version 1 26 Apr 16	read	read	read

Miguel O’Ryan, Universidad de Chile, Santiago, Chile
Jeffrey Bergelson, University of Pennsylvania School of Medicine, Philadelphia, USA
David A Hunstad, Washington University in St Louis, St Louis, USA

Andrew Janowski, Washington University in St Louis, St Louis, USA

Comments on this article

All Comments(1)

Add a comment

Browse by related subjects

Back to all reports

Reviewer Report

7 Views

04 Jan 2017 | for Version 2

David A Hunstad, Division of Pediatric Infectious Diseases, Washington University in St Louis, St Louis, MO, USA

7 Views Cite this report Responses(0)

Approved

The authors have addressed my earlier critiques.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

28 Views

09 May 2016 | for Version 1

David A Hunstad, Division of Pediatric Infectious Diseases, Washington University in St Louis, St Louis, MO, USA

Andrew Janowski, Department of Pediatrics, Washington University in St Louis, St Louis, MO, USA

28 Views Cite this report Responses(1)

Approved With Reservations

Methods: The authors should report their study site’s protocol for testing for adenoviruses, specifically, whether testing for adenoviruses was only performed on symptomatic patients, or if high-risk patients were routinely screened for adenovirus.
Methods: Probenecid is often co-administered with cidofovir. The authors should report if this drug was used in any of the courses of cidofovir, and what dosages. If probenecid was not used in all courses, the authors should analyze their data to investigate the role of probenecid in reducing nephrotoxicity.
Methods: It is not clear if adenovirus testing is completed on whole blood or serum. Later in the results, the authors state whole blood, but this should be explained in the methodology.
Methods: The authors should define pre-treatment/peak/post-treatment creatinine levels in their methodology. In addition, what defines pre-treatment creatinine? Is that the creatinine on the day of initiation of cidofovir? One week prior? Baseline from months prior? Defining this value is essential to the author’s statistical analysis.
Table 1: Patients should be ordered by diagnosis for better organization (as opposed to patient number); for example, the hematopoietic stem cell transplant patients should be grouped together, then the solid organ transplant patients should be grouped together. A column of outcomes should be added for greater clarity of which cases resulted in mortality, instead of the usage of an asterisk.
Results: Much of the information stated in the paragraph starting “Of the 19 courses prescribed” is redundant with the data presented in table 1, including the number of courses involving viremia, pneumonia, and GI symptoms. This paragraph can be consolidated, and the case characteristics presented as already implemented in Table 1.
Results: The authors should include a description of the patient’s response to cidofovir in Table 1. This would provide better organization and clarity in interpreting which characteristics were associated with response (or lack thereof) to therapy. It also would make the paragraph “We further examined the 16 blood-positive…” redundant, and this could be consolidated.
Figure 1: This figure might be easier to interpret if it were separated, for example, into two graphs of HSCT and SOT/other patients. It is difficult to follow 16 distinct virological lines in the current graph. In addition, the color choices for patients 4, 9, and 13 are too similar.
The statistical analysis of increased risk of renal dysfunction when receiving 1 vs >2 renal toxic medications should be omitted as currently presented. The authors do not describe whether the additional nephrotoxic agents were co-administered at the same time or for what duration. These are critical confounding variables that are necessary for interpretation of whether nephrotoxicity was associated with increased administration of additional nephrotoxic agents. Given that this review is retrospective, such information may or may not be available.
Figure 2 is a somewhat awkward way to describe SCr before and after CDV therapy. In addition, it is unclear how, if only 64% of patients with elevated SCr returned to baseline, the mean SCr after CDV was equal to baseline (in the right bar of Figure 2). The table describes the SCr data adequately, and Figure 2 could therefore be omitted.
The publication search criteria used to generate Table 3 should be explained in the methods. In their literature review, the authors should incorporate other pediatric adenovirus-cidofovir case reports and series that were not reviewed in this manuscript, including: Seidemann et al. (2004), Leruez-Ville et al. (2004), Nagafuji et al. (2004).
At least brief mention of the advent of brincidofovir for treatment of these patients with much reduced nephrotoxicity would be warranted.

References

Competing Interests

No competing interests were disclosed.

Respond to this report

Responses (1)

Author Response

16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

Addressing Dr Hunstad’s and Dr Janowski’s report, in the new version of the manuscript we have clarified the following in the methods section: 1) The protocol for testing for adenovirus infection, 2) Usage of probenecid and dose (it was used in all patients who received cidofovir), 3) how we defined pre-treatment creatinine and 4) the publication search criteria. While we mention the use of concomitant medications that are known to render nephrotoxicity, we agree that the analysis is confounded by several factors and hence have omitted the statistical analysis of increased risk of renal dysfunction when receiving 1 versus >1 nephrotoxic medications.

In the discussion section, we have expanded our discussion on the potential benefit of cidofovir in solid organ transplant recipients, and compare the findings of Humar et al (a study in which patients were all adults) with the findings reported by Seidemann et al and Leruez-Ville et al. As such, we added the latter two studies to table 3 for an updated literature review. However, we did opt to leave out the study by Nagafuji et al as recommended by the reviewers. The study by Nagafuji et al focused primarily on adult HSCT recipients and included only one pediatric patient. We feel that given much larger pediatric specific case series of HSCT recipients with adenovirus infection, this one case reported adds little. On the other hand, we did include case reports in the solid-organ patient literature review given the paucity of data in this population. We have also made a brief mention regarding the advent of brincidofovir.

We updated table 1 to include include a column of outcomes. While we recognize that other changes as recommended by the reviewers may contribute to better organization of text and data, we did not make too many other changes to table 1 or figure 1 given that these changes are stylistic and not necessarily content relevant.

View more View less

Competing Interests

None

Back to all reports

Reviewer Report

27 Views

04 May 2016 | for Version 1

Jeffrey Bergelson, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

27 Views Cite this report Responses(2)

Approved

Clarify the assay used for viral loads. Is it the Argene assay, or an in-house assay using some components of the Argene kit?
Clarify the definition of “viral response”. Is it a 10-fold decrease in titer?
Perhaps mention briefly why the asymptomatic patients were treated with cidofovir. It appears that one was a lung transplant patient (considered to be at high risk) and one a SCT patient with recurrent viremia.
Figure 2 adds little.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (2)

Reviewer Response

06 May 2016

Jeffrey Bergelson, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, USA

Because the paper provides no evidence about efficacy, the abstract should be changed, as well as the discussion. "….was associated with viral response and clinical improvement" should be softened.

View more View less

Competing Interests

None

Author Response

16 Dec 2016

Lakshmi Ganapathi, Boston Children's Hospital, USA

Addressing Dr Bergelson’s report, in the new version of the manuscript we have expanded our discussion to point out more explicitly that at least based on our data, while we did observe clearance of viremia in several patients overall clinical benefit was somewhat harder to conclude. We have also mentioned the rationale behind treating asymptomatic patients (both treated patients were considered to be at high risk for complications).

In the methods section, we have clarified the following: 1) The assay used to determine viral load, 2) What we defined as viral response.

We have also corrected the minor spelling and punctuation issues.

We agree with both Dr Bergelson and Dr Hundstad that Figure 2 adds little and have removed it from this version of the manuscript

View more View less

Competing Interests

none

Back to all reports

Reviewer Report

16 Views

03 May 2016 | for Version 1

Miguel O’Ryan, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile

16 Views Cite this report Responses(0)

Approved

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

Click here to access the data.

Downloaded data do not display as expected? Download the data (4.73KB)

Click here to access the data.

Downloaded data do not display as expected? Download the data (0.29KB)

[1] 1. Ison MG: Adenovirus infections in transplant recipients. Clin Infect Dis. 2006; 43(3): 331–339. PubMed Abstract | Publisher Full Text

[2] 2. Carrigan DR: Adenovirus infections in immunocompromised patients. Am J Med. 1997; 102(3A): 71–74. PubMed Abstract

[3] 3. Howard DS, Phillips II GL, Reece DE, et al.: Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 1999; 29(6): 1494–1501. PubMed Abstract | Publisher Full Text

[4] 4. Hale GA, Heslop HE, Krance RA, et al.: Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant. 1999; 23(3): 277–282. PubMed Abstract

[5] 5. Hierholzer JC: Adenoviruses in the immunocompromised host. Clin Microbiol Rev. 1992; 5(3): 262–274. PubMed Abstract | Free Full Text

[6] 6. Gavin PJ, Katz BZ: Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children. Pediatrics. 2002; 110(1 Pt 1): e9. PubMed Abstract

[7] 7. McCarthy AJ, Bergin M, De Silva LM, et al.: Intravenous ribavirin therapy for disseminated adenovirus infection. Pediatr Infect Dis J. 1995; 14(11): 1003–1004. PubMed Abstract | Publisher Full Text

[8] 8. Chen FE, Liang RH, Lo JY, et al.: Treatment of adenovirus-associated haemorrhagic cystitis with ganciclovir. Bone Marrow Transplant. 1997; 20(11): 997–999. PubMed Abstract | Publisher Full Text

[9] 9. Kawakami M, Ueda S, Maeda T, et al.: Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997; 20(6): 485–490. PubMed Abstract | Publisher Full Text

[10] 10. Kitabayashi A, Hirokawa M, Kuroki J, et al.: Successful vidarabine therapy for adenovirus type 11-associated acute hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994; 14(5): 853–854. PubMed Abstract

[11] 11. Saquib R, Melton LB, Chandrakantan A, et al.: Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin. Transpl Infect Dis. 2010; 12(1): 77–83. PubMed Abstract | Publisher Full Text

[12] 12. Muller WJ, Levin MJ, Shin YK, et al.: Clinical and in vitro evaluation of cidofovir for treatment of adenovirus infection in pediatric hematopoietic stem cell transplant recipients. Clin Infect Dis. 2005; 41(12): 1812–1816. PubMed Abstract | Publisher Full Text

[13] 13. Ljungman P, Ribaud P, Eyrich M, et al.: Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2003; 31(6): 481–486. PubMed Abstract | Publisher Full Text

[14] 14. Hoffman JA, Shah AJ, Ross LA, et al.: Adenoviral infections and a prospective trial of cidofovir in pediatric hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001; 7(7): 388–394. PubMed Abstract | Publisher Full Text

[15] 15. Bhadri VA, Lee-Horn L, Shaw PJ: Safety and tolerability of cidofovir in high-risk pediatric patients. Transpl Infect Dis. 2009; 11(4): 373–379. PubMed Abstract | Publisher Full Text

[16] 16. Engelmann G, Heim A, Greil J, et al.: Adenovirus infection and treatment with cidofovir in children after liver transplantation. Pediatr Transplant. 2009; 13(4): 421–428. PubMed Abstract | Publisher Full Text

[17] 17. Yusuf U, Hale GA, Carr J, et al.: Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation. 2006; 81(10): 1398–1404. PubMed Abstract | Publisher Full Text

[18] 18. Legrand F, Berrebi D, Houhou N, et al.: Early diagnosis of adenovirus infection and treatment with cidofovir after bone marrow transplantation in children. Bone Marrow Transplant. 2001; 27(6): 621–626. PubMed Abstract

[19] 19. Anderson EJ, Guzman-Cottrill JA, Kletzel M, et al.: High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy. Pediatr Transplant. 2008; 12(2): 219–227. PubMed Abstract | Publisher Full Text

[20] 20. Wallot MA, Dohna-Schwake C, Auth M, et al.: Disseminated adenovirus infection with respiratory failure in pediatric liver transplant recipients: impact of intravenous cidofovir and inhaled nitric oxide. Pediatr Transplant. 2006; 10(1): 121–127. PubMed Abstract | Publisher Full Text

[21] 21. Ribaud P, Scieux C, Freymuth F, et al.: Successful treatment of adenovirus disease with intravenous cidofovir in an unrelated stem-cell transplant recipient. Clin Infect Dis. 1999; 28(3): 690–691. PubMed Abstract | Publisher Full Text

[22] 22. Naesens L, Lenaerts L, Andrei G, et al.: Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob Agents Chemother. 2005; 49(3): 1010–1016. PubMed Abstract | Publisher Full Text | Free Full Text

[23] 23. Morfin F, Dupuis-Girod S, Mundweiler S, et al.: In vitro susceptibility of adenovirus to antiviral drugs is species-dependent. Antivir Ther. 2005; 10(2): 225–229. PubMed Abstract

[24] 24. Carter BA, Karpen SJ, Quiros-Tejeira RE, et al.: Intravenous Cidofovir therapy for disseminated adenovirus in a pediatric liver transplant recipient. Transplantation. 2002; 74(7): 1050–1052. PubMed Abstract

[25] 25. Doan ML, Mallory GB, Kaplan SL, et al.: Treatment of adenovirus pneumonia with cidofovir in pediatric lung transplant recipients. J Heart Lung Transplant. 2007; 26(9): 883–889. PubMed Abstract | Publisher Full Text

[26] 26. Sivaprakasam P, Carr TF, Coussons M, et al.: Improved outcome from invasive adenovirus infection in pediatric patients after hemopoietic stem cell transplantation using intensive clinical surveillance and early intervention. J Pediatr Hematol Oncol. 2007; 29(2): 81–85. PubMed Abstract | Publisher Full Text

[27] 27. Williams KM, Agwu AL, Dabb AA, et al.: A clinical algorithm identifies high risk pediatric oncology and bone marrow transplant patients likely to benefit from treatment of adenoviral infection. J Pediatr Hematol Oncol. 2009; 31(11): 825–831. PubMed Abstract | Publisher Full Text | Free Full Text

[28] 28. Ganapathi L, Arnold A, Jones S, et al.: Dataset 1 in: Use of cidofovir in pediatric patients with adenovirus infection. F1000Research. 2016. Data Source

[29] 29. Ganapathi L, Arnold A, Jones S, et al.: Dataset 2 in: Use of cidofovir in pediatric patients with adenovirus infection. F1000Research. 2016. Data Source

Pt	Pre -Cr	Peak Cr	Post Cr
1a	0.3	1.2	0.6
1b	0.6	1	0.6
2	0.6	0.6	0.5
3	0.3	0.6	0.2
4	0.3	0.3	0.2
5	0.4	0.7	0.5
6	0.2	0.4	0.6
7	0.2	0.5	0.7
8a	1	1.7	0.4
8b	0.4	2.6	1.3
9	0.3	2.7	0.6
10	0.2	0.2	0.2
11	0.4	1.6	0.6
12	0.5	1.6	0.6
13	0.2	0.2	0.2
14	0.2	0.2	0.2
15a	0.3	0.3	0.3
15b	0.2	0.3	0.2

Pt	Pre -Cr	Peak Cr	Post Cr
1a	0.3	1.2	0.6
1b	0.6	1	0.6
2	0.6	0.6	0.5
3	0.3	0.6	0.2
4	0.3	0.3	0.2
5	0.4	0.7	0.5
6	0.2	0.4	0.6
7	0.2	0.5	0.7
8a	1	1.7	0.4
8b	0.4	2.6	1.3
9	0.3	2.7	0.6
10	0.2	0.2	0.2
11	0.4	1.6	0.6
12	0.5	1.6	0.6
13	0.2	0.2	0.2
14	0.2	0.2	0.2
15a	0.3	0.3	0.3
15b	0.2	0.3	0.2

Use of cidofovir in pediatric patients with adenovirus infection

Abstract

Keywords

Introduction

Methods

Definitions

Statistical analysis

Results

Table 1. Demographics, primary diagnosis, sites of ADV detection, clinical symptoms and course of patients included in the study.

Figure 1. Kinetics of Adenovirus blood viral load under cidofovir treatment.

Table 2. Additional nephrotoxic agents prescribed and changes in serum creatinine during cidofovir therapy.

Figure 2. Change in serum creatinine during, and at the end of cidofovir therapy compared to pre-treatment serum creatinine.

Discussion

Table 3. Summary of studies describing use of cidofovir in pediatric HSCT and SOT recipient.

Data availability

Author contributions

Competing interests

Grant information

References

Comments on this article Comments (1)

Open Peer Review

Comments on this article Comments (1)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

The problem

How to fix it

The problem

How to fix it

Competing Interests Policy

Stay Updated

Pt	Pre -Cr	Peak Cr	Post Cr
1a	0.3	1.2	0.6
1b	0.6	1	0.6
2	0.6	0.6	0.5
3	0.3	0.6	0.2
4	0.3	0.3	0.2
5	0.4	0.7	0.5
6	0.2	0.4	0.6
7	0.2	0.5	0.7
8a	1	1.7	0.4
8b	0.4	2.6	1.3
9	0.3	2.7	0.6
10	0.2	0.2	0.2
11	0.4	1.6	0.6
12	0.5	1.6	0.6
13	0.2	0.2	0.2
14	0.2	0.2	0.2
15a	0.3	0.3	0.3
15b	0.2	0.3	0.2