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HIV-1 Drug Resistance by Ultra-Deep Sequencing Following Short Course Zidovudine, Single-Dose Nevirapine, and Single-Dose Tenofovir with Emtricitabine for Prevention of Mother-to-Child Transmission. | Antiretroviral drug resistance following pMTCT strategies remains a significant problem. With rapid advancements in next generation sequencing technologies, there is more focus on HIV drug-resistant variants of low frequency, or the so-called minority variants. In South Africa, AZT monotherapy for pMTCT, similar to World Health Organization option A, has been used since 2008. In 2010, a single dose of co-formulated TDF/FTC was included in the strategy for prevention of resistance conferred by single-dose nevirapine (sd NVP). The study was conducted in KwaZulu-Natal, South Africa, among pMTCT participants who received AZT monotherapy from 14 weeks of gestation, intrapartum AZT and sd NVP, and postpartum sd TDF/FTC. Twenty-six specimens collected at 6 weeks post-delivery were successfully sequenced using 454 ultra-deep sequencing. Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was detected in 17 of 26 (65%) patients, 2 (7%) had Thymidine analogue mutations, and 3 (11%) had K65R. Of the 17 patients with NNRTI resistance, 11 (65%) had high-level NNRTI resistance, whereas 6 (35%) had intermediate NNRTI resistance. The levels of NNRTI resistance are much higher than would be expected, given the inclusion of antepartum AZT and postpartum TDF/FTC. This high level of NNRTI resistance could impact future NNRTI-containing treatment for a large proportion of pMTCT-exposed women. The detection of Thymidine analogue mutations highlights the need to understand the clinical impact of these on AZT-containing antiretroviral treatment in women exposed to AZT monotherapy. |
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J Acquir Immune Defic SyndrJ. Acquir. Immune Defic. SyndrqaiJournal of Acquired Immune Deficiency Syndromes (1999)1525-41351944-7884JAIDS Journal of Acquired Immune Deficiency Syndromes QAIV1639610.1097/QAI.000000000000111600003Basic and Translational ScienceHIV-1 Drug Resistance by Ultra-Deep Sequencing Following Short Course Zidovudine, Single-Dose Nevirapine, and Single-Dose Tenofovir with Emtricitabine for Prevention of Mother-to-Child Transmission Samuel Reshmi MD*Julian Marc Noguera PhD†‡Paredes Roger MD, PhD†‡§‖Parboosing Raveen MD*Moodley Pravi MD*Singh Lavanya MSc*Naidoo Anneta MSc*Gordon Michelle PhD¶* Department of Virology, National Health Laboratory Service, University of KwaZulu-Natal, Durban, South Africa;† IrsiCaixa AIDS Research Institute, Badalona, Catalonia, Spain;‡ Universitat de Vic, Vic, Catalonia, Spain;§ HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain;ǁ Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain; and¶ Department of Virology, HIV Pathogenesis Laboratory, Nelson R Mandela Medical School, University of KwaZulu-Natal, Durban, South Africa.Correspondence to: Reshmi Samuel, MD, Department of Virology, National Health Laboratory service, Inkosi Albert Luthuli Hospital, University of KwaZulu-Natal, Durban 4001, South Africa (e-mail: maharajr3@ukzn.ac.za).1 12 2016 27 10 2016 73 4 384 389 23 11 2015 23 5 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Supplemental Digital Content is Available in the Text.
Abstract:
Antiretroviral drug resistance following pMTCT strategies remains a significant problem. With rapid advancements in next generation sequencing technologies, there is more focus on HIV drug-resistant variants of low frequency, or the so-called minority variants. In South Africa, AZT monotherapy for pMTCT, similar to World Health Organization option A, has been used since 2008. In 2010, a single dose of co-formulated TDF/FTC was included in the strategy for prevention of resistance conferred by single-dose nevirapine (sd NVP). The study was conducted in KwaZulu-Natal, South Africa, among pMTCT participants who received AZT monotherapy from 14 weeks of gestation, intrapartum AZT and sd NVP, and postpartum sd TDF/FTC. Twenty-six specimens collected at 6 weeks post-delivery were successfully sequenced using 454 ultra-deep sequencing. Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was detected in 17 of 26 (65%) patients, 2 (7%) had Thymidine analogue mutations, and 3 (11%) had K65R. Of the 17 patients with NNRTI resistance, 11 (65%) had high-level NNRTI resistance, whereas 6 (35%) had intermediate NNRTI resistance. The levels of NNRTI resistance are much higher than would be expected, given the inclusion of antepartum AZT and postpartum TDF/FTC. This high level of NNRTI resistance could impact future NNRTI-containing treatment for a large proportion of pMTCT-exposed women. The detection of Thymidine analogue mutations highlights the need to understand the clinical impact of these on AZT-containing antiretroviral treatment in women exposed to AZT monotherapy.
Key Words:
HIV vertical transmissionPMTCTHIV drug resistanceOPEN-ACCESSTRUESDCT
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INTRODUCTION
Although prevention of mother-to-child transmission (pMTCT) strategies have recently improved with the implementation of World Health Organization (WHO) options B and B plus,1 antiretroviral (ARV) drug resistance remains a significant problem in the wake of single-dose nevirapine (sd NVP)2,3 monotherapy and dual-therapy use in resource-limited settings. The current standard method for resistance testing is Sanger sequencing, or so-called population sequencing, and although widely used, it is limited since the sensitivity relies on mutations being present in 15%–20% of the HIV quasispecies.4,5 Thus, resistance conferring mutations present at low frequencies, or drug-resistant minority variants (DRMVs) will be missed by Sanger sequencing. The more sensitive technologies, commonly known as next-generation sequencing, include the Miseq and HiScan (Illumina, San Diego, CA), 454 GS-FLX and Junior (Roche Daignostics, Basel, Switzerland), Pac-Bio RS II (Pacific Biosciences, CA), and Ion-Torrent PGM (Life Technologies, Thermo Fischer Scientific, NY). Resistance testing performed using these technologies can detect DRMVs present at low frequencies.6 These DRMVs were shown to be clinically significant in studies investigating non-nucleoside reverse transcriptase inhibitor–based ART.7,8 DRMVs doubled the risk of virological failure to first-line NNRTI-containing antiretroviral treatment (ART).9
Following pMTCT exposure, DRMVs that develop may impact negatively on future ART, leading to virological failure.10 In South Africa, zidovudine (AZT) administered from the 14th week of pregnancy and intrapartum, together with sd NVP and a stat postpartum dose of co-formulated tenofovir (TDF) with emtricitabine (FTC) was used as the pMTCT strategy from 2010 to 2013.11 Using Sanger sequencing, high-level NVP resistance was detected in 34% of women in this context.12 This study therefore further aims to determine the patterns and frequency of DRMVs in this group of women, using ultra-deep sequencing (UDS).
METHODS
This study was conducted at Lwazi Clinic, Addington Hospital in Durban, South Africa. Ethical approval (BF069-09) was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee. Ninety-seven pregnant women who did not qualify for ART as per National Guidelines,11 ie, CD4 count >350 cells per cubic millimeter were recruited for the study from August 2010 until December 2011. Data on adherence were captured at the 6-week post-delivery visit and limited to “Yes,” “No,” or “Unsure” with regard to receiving intrapartum AZT, sd NVP, and postpartum TDF/FTC. Furthermore, an EDTA whole-blood specimen for HIV-1 viral load testing was collected at recruitment and at 6 weeks post-delivery. A specimen for HIV-1 drug resistance testing was also collected at 6 weeks post-delivery.
HIV-1 Viral Load
The viral loads were performed using an automated Nuclisens EasyQ (bioMerieux) HIV-1 assay, which was later replaced by the Abbot m2000sp and Abbot m2000rt systems of extraction and real-time amplification, respectively. UDS was performed on 26 specimens which had an HIV-1 viral load of >5000 RNA copies per milliliter, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter.
Amplicon Design
Four sets of overlapping amplicons were designed to cover the Reverse Transcriptase region of HIV-1 such that each significant codon position was interrogated by 2 separate amplicons. Primers were based on a subtype C isolate, Genbank accession no AY772699 (http://www.ncbi.nlm.nih.gov/nuccore/AY772699). Primer sequences are listed in Table 1.
TABLE 1. Primer Sequences
RNA Preparation, Conventional Reverse Transcription Polymerase Chain Reaction, and Polymerase Chain Reaction
Two milliliter of plasma was ultracentrifuged at 14,000 rpm for 3 hours. RNA was extracted from 1 ml of plasma using the Nuclisens EasyMag HIV-1(bioMerieux, France) extraction system.
One-step reverse transcription (RT)-polymerase chain reactions (PCRs) using the SuperScript III One-Step RT-PCR System (with Platinum Taq High Fidelity; Invitrogen, Carlsbad, CA) were performed in triplicate per specimen. The triplicate RT-PCR products were then pooled and used for a second round of PCR that amplified overlapping amplicons which were also performed in triplicate per amplicon. The PCR products were pooled, purified, and sequenced.
A volume of 3.75 μl of extracted RNA was added to the RT-PCR reaction mix which had a final volume of 12.5 μl. Reagents included 2x buffer, Mg2SO4 (5 mM, final concentration of 0.6 mM), RNAse out, sterile water, SuperScript III (Invitrogen, Carlsbad, CA), and primers 1855-F1 and 2745-R2 (final concentration of 0.2mM).
A reverse transcription step at 55°C for 25 minutes was performed. Thermocycling was performed using an initial denaturation of 94°C for 2 minutes, followed by 25 cycles of 94°C for 30 seconds, 57°C for 30 seconds, 68°C for 30 seconds and a final extension step at 68°C for 1 minute. After the first round of PCR, 1 μL of the pooled PCR product was added to the second round PCR reaction mix (final volume of 50 μL) containing 10× buffer, dNTPs (200 mM), Platinum Taq High Fidelity enzyme (Invitrogen), MgS04 (50 mM, final concentration 2 mM), and DNase free water. The reaction mix was aliquoted equally into 4 separate tubes so that the relevant primers for the individual amplicons were added (F1, R1 to tube 1; F2, R2 to tube 2, etc). Conditions of cycling were the same as for the first round with omission of the RT step of 55°C for 55 minutes. After pooling, 150 μL of product was available for ultra-deep 454 sequencing. Samples were purified using the Qiagen min Elute spin columns.
To limit random sampling error caused by the sampling of only a few viral variants in patients with low viral loads, only patient samples with viral loads >5000 copies per milliliter were used, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter. Primers were designed to target conserved regions to limit primer induced selection bias, where particular templates are amplified earlier than others, and these become overrepresented in the final amplicon pool; each sample was amplified in 3 independent PCRs, and the PCR products were pooled before sequencing to compensate for biased priming and random sampling error during the PCR; multiplex identifier adapters were added after the amplification step to avoid the selection bias induced by using fusion primers.
Ultra-Deep 454 Sequencing
UDS was performed using the Roche 454 GS-FLX at the Technology Innovation Agency, National Genomics Platform in Durban. Twenty-six samples were successfully sequenced. Amplicon lengths varied in size (Amplicon 1: 459 bases, Amplicon 2: 376 bases, Amplicon 3: 436 bases, Amplicon 4: 344 bases). Samples had to meet standard requirements for library preparation after passing quality control. Samples were tagged with multiplex identifier adapters during library preparation. After emulsion PCR, sequencing was performed fulfilling all quality criteria and using a 4-lane divider on the picotiter plate. Four standard flowgram format files were generated and used for data analysis.
Data Analysis
For statistical analysis, nonparametric methods in SPSS version 23.0 (IBM Corp, Armonk, NY), including the Mann–Whitney U test, were used.
For bioinformatics analysis, Amplicon Variant Analyzer software v2.7 (Roche Diagnostics, Basel, Switzerland) was used to analyze and obtain sequence alignments against HIV-1 subtype C reference sequence (Genbank ID: AY772699). A short sequence length filter was applied based on the amplicon design and the corresponding sequence length. Short sequences (<90% of expected sequence length) were discarded. Error-corrected consensus sequences, as obtained from Amplicon Variant Analyzer, were used for amino acid variant calling. Variants were considered valid when present in both forward and reverse directions in a balanced manner as reported elsewhere.13 To control for sample cross-contamination, phylogenetic trees were built for all amplicons and samples with evidence of interfering cross-contamination were discarded. A minimum 500×/300× depth of coverage was required to call a minor variant (≤20%) and a major variant (>20%), respectively. Depth of coverage is provided in Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A854. A 1% conservative minimum threshold was defined based on internal sequencing controls and on published literature.13–16
To estimate whether sufficient viral templates were sampled, we used the formula pVL = NRNA(λ)/(VfeERNAXEcDNA) to calculate the minimal viral load required to detect minor variants at 1%, where pVL is the minimum viral load required; NRNA(λ) is the number of RNA copies that according to the Poisson distribution should be tested to detect at least 1 minor variant with a likelihood of > 99%; V, the volume of plasma (milliliter); fe, the fraction of the RNA eluent used for DNA synthesis; ERNAX, the extraction yield and EcDNA, the RT efficiency.17 Based on the following V = 1 mL, ERNAX = 0.96 and EcDNA = 0.7, using 0.5 as the fraction of the RNA eluent used for DNA synthesis, the minimum viral load required to reliably detect minor variants at 1% is 1488 copies per milliliter. Viral loads of all samples that underwent 454 sequencing were in excess of 5000 copies per milliliter, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter. Ensuring that an acceptable number of templates were sampled (Table 2).
TABLE 2. Viral Loads and Mutations Detected in Each Patient (provided as the Percentage of the Variant Within the Quasispecies)
RESULTS
There was no statistical difference in the CD4 cell count or HIV-1 viral load (at recruitment and at 6 weeks postdelivery) between those patients who developed NNRTI resistance and those who did not using the Mann–Whitney U test in SPSS version 23.0 (IBM Corp).
The median overall viral load was 17,269 copies per milliliter, with an interquartile range of 17,307 copies per milliliter (Table 2). The median viral load among patients where no Thymidine analogue mutations (TAMs) were detected was 14,921 copies per milliliter (interquartile range of 15262 copies/ml) compared with the median viral load of 93886 copies/ml in patients where TAMs were detected (P value 0.042).
The mean duration of AZT exposure overall was 16 weeks. The median duration of AZT exposure in those who developed TAMs was 20 weeks and 18 weeks (interquartile range of 8 weeks) in those who did not develop TAMs (P value 0.318).
Mutations conferring resistance to NRTIs and NNRTIs were detected at variable frequencies (Table 2). Of 26 patients, 20 patients (77%) had mutations conferring resistance. NNRTI resistance was detected in 17 of 26 (65%) patients, 2 (7%) patients had TAMs, and 3 (11%) patients had K65R. Of the 17 patients with NNRTI resistance, 11 (65%) had high-level resistance to NVP and EFV, whereas 6 (35%) had intermediate NNRTI resistance. One patient had both high-level NNRTI resistance and high-level resistance to TDF and 1 patient had both low to intermediate NNRTI resistance and K70R.
Of all mutations conferring resistance to NNRTIs, the most common were those conferring high-level NNRTI resistance such as K103N in 8 of 26 (30%), V106M in 8 of 26 (30%), Y188C in 6 of 26 (23%), G190A in 4 of 26 (15%), Y181C in 3 of 26 (11%), and V106A in 3 of 26 (11%) patients. K103N and V106M were the most common mutations detected. In patients who had K103N, it was also the predominant variant within the viral population compared to the other mutations detected as minor variants only. Mutations conferring low to intermediate NNRTI resistance included K101E in 7 of 26 (27%), A98G 5 of 26 (19%), L100V 4 of 26 (15%), V108I in 1 of 26 (3%) and F227L in 1 of 26 (3%) of patients. V90I which is associated with minimal, if any, detectable reduction in NNRTI susceptibility was found in 5 of 26 (19%) of patients.
Mutations conferring NRTI resistance included K70R in 2 of 26 (7%) patients and T69S which was detected in 1 of 26 (3%) patients. Resistance to TDF (K65R) was found in 3/26 (11%) patients. No other TAMs were detected. There was a 100% correlation between the mutations detected by Sanger sequencing12 and those detected by 454 UDS in samples that underwent both methods of sequencing. In addition, 454 UDS was able to detect a significant number of mutations that were missed by Sanger sequencing as indicated in bold in Table 2.
Regarding adherence, among the patients with high-level NNRTI resistance, 1 of 11 patients said that she was unsure about receiving antepartum AZT and intrapartum TDF/FTC and 1 said that she did not receive intrapartum TDF/FTC. Among the patients where no resistance was detected, 4 of 5 patients answered “unsure” or “no” to receiving prophylactic ARVs.
DISCUSSION
Using UDS, higher rates of NNRTI resistance were detected as compared to Sanger sequencing.12 More than two-third of patients had NNRTI resistance, the majority having high-level NNRTI resistance. The most common mutations (30%) detected were K103N and V106M, which are associated with high-level NNRTI resistance. Most of the K103N mutations were detected between frequencies of 17% and 59%, making it the predominant variant in the quasispecies for those specimens (Table 2).
Resistance to sd NVP is documented to occur at an average rate of 37.5%.18 The addition of peripartum AZT19 and postpartum TDF/FTC20 was shown to reduce the rate of resistance conferred by sd NVP. An open-labeled randomized control trial in Zambia found that the addition of sd TDF/FTC reduced NNRTI resistance by half at 6 weeks post-delivery.21 However, in our study, despite the use of AZT and TDF/FTC, there was no reduction in NNRTI resistance and the rate of NNRTI resistance of 65% is significantly higher than in earlier pMTCT strategies where only sd NVP was used.18 The high rate of NVP resistance could be explained by poor adherence to the complicated overall pMTCT strategy, exposure to NVP in successive pregnancies,22 and the higher rates of transmitted NNRTI drug resistance in KZN as reported by the WHO drug resistance report of 2012.23
The clinical impact of minority NNRTI drug-resistant variants has recently become topical following advances in the next-generation sequencing technologies. Studies investigating this show that minority NNRTI-resistant variants are clinically significant and can lead to treatment failure when these patients are initiated on NNRTI-containing ARVs,7,8,13,16,24,25 Furthermore, even with 95% adherence, these variants are associated with up to 3 times the risk of virological failure.7 In addition, preexisting minority Y181C variants were associated with a risk of virological failure in patients initiated on first-line efavirenz (EFV)-containing ART24 and in EFV exposed treatment experienced patients.26 In our study, Y188C and Y181C were detected in 23% and 11%, respectively, of patients as minority variants.
The added clinical benefit of using next-generation sequencing has been demonstrated in many studies.7,26–28 Although the sensitivity is significantly better with such technologies, its inclusion for routine use faces many challenges some being the large cost factor as well as the sophisticated bioinformatics support required.
Two (7%) patients harbored the K70R mutation while no other TAMs were found. Although the rate of AZT resistance is much lower than that detected by Olson et al,29 it is possible that AZT resistant mutants may have faded by the time of sample collection in our study, ie, 6 weeks postdelivery and may also be reflective of a smaller sample size. A study in Tanzania among pMTCT recipients where a similar pMTCT strategy was used, found AZT resistance in 18% of patients by Allele-specific PCR. The higher sensitivity of Allele-specific PCR compared to deep sequencing may explain the higher rates of TAMs.30 The clinical impact of these minority AZT-resistant variants when patients initiate ART requires further investigations.
K65R was detected in 11% of patients at low frequencies (1%–2.6%). There are reports of higher levels of K65R detection in HIV-1 subtype C among patients failing first-line TDF-based ART31,32 and in ART-naive patients.33 This highlights the need to explore the impact of minority TDF drug-resistant variants in HIV-1 subtype C. The mechanism for higher levels of K65R in subtype C seems to be template specific, where a preferential pause in subtype C reverse transcription at position 65 AAG-AGG is seen.34 It is therefore important to interpret low abundance K65R mutations in subtype C with caution. In addition, PCR-induced error is an important consideration when interpreting very low-abundance variants. Varghese et al35 showed that using UDS which is PCR dependent for the sequencing of subtype C, RT KKK template may result in spurious detection of K65R.
The limitations of this study include the lack of baseline genotyping, limited adherence information and lack of knowledge of previous exposure to sd NVP. Owing to the increasing rates of transmitted NNRTI resistance,23 it is possible that the high levels of NNRTI resistance detected in this study is partially reflective of the transmitted NNRTI resistance. However for AZT, resistance most likely developed while on short course AZT since these patients were not exposed to ART regimens, had high HIV-1 viral loads and prolonged AZT exposure.36,37
We have demonstrated a high level of NNRTI resistance (65%), which may have serious impact on the national ART programme in South Africa. Since this regimen was part of the South African pMTCT prophylaxis from 2008 to 2013,11,38,39 approximately 1.5 million women may have been exposed to this regimen, given that about 300,000 HIV-infected women require pMTCT annually in South Africa.40 If this figure is adjusted for the average uptake of pMTCT prophylaxis in South Africa at 58.7%,41,880,000 women would have been exposed to this regimen. Therefore, more than half a million women may fail first-line NNRTI-containing ART and require a switch to a protease inhibitor–based ART regimen.
Furthermore, our extrapolation does not consider, first, the women exposed to sd NVP before 2008 who subsequently may have developed NNRTI resistance when initiated on ART. Second, the WHO reported in 2012 that transmitted NNRTI resistance is increasing in Africa. The prevalence of transmitted NNRTI resistance in KwaZulu-Natal has increased from below 5% in 2007 to 5%–15% in 2010 with the most commonly detected mutation being the K103NS.23 Third, the number of patients with NNRTI mutations among those failing NNRTI-based ART is high in rural South Africa, ie, 82% in both adults42 and children,43 with K103NS again being the most commonly detected NNRTI mutation. Finally, the underestimation of ART resistance using conventional sequencing and the rising evidence of the clinical impact of minority NNRTI mutations remains an important consideration.
These factors may consequently contribute to a higher than expected ART failure rate among patients on first-line NNRTI-containing ART. Therefore, it may be prudent to consider more rigorous monitoring for virological failure in these women to ensure good future treatment outcomes.
Supplementary Material
SUPPLEMENTARY MATERIAL
ACKNOWLEDGMENTS
The authors thank Columbia University-South Africa Fogarty Aids and TB Training and Research Program (AITRP); Professor Daniel Kuritzkes, Dr Jonathan Li, and Dr Athe Tsibris for their kind assistance during my AITRP traineeship at the HIV Research lab, Harvard Medical School; Technology Innovation Agency, Dawn Stephens.
Supported by the Medical Research Council of South Africa and the National Health Laboratory Service Research Trust (NHLSRT).
The authors have no conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).
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29. Olson SC Ngo-Giang-Huong N Beck I
Resistance detected by pyrosequencing following zidovudine monotherapy for prevention of HIV-1 mother-to-child-transmission . AIDS . 2015 ;29 :1467 –1471 .26244386
30. Hauser A Sewangi J Mbezi P
Emergence of minor drug-resistant HIV-1 variants after Triple antiretroviral prophylaxis for prevention of vertical HIV-1 transmission . PLoS One . 2012 ;7 :e32055 .22384138
31. Sunpath H Wu B Gordon M
High rate of K65R for antiretroviral therapy-naive patients with subtype C HIV infection failing a tenofovir-containing first-line regimen . AIDS . 2012 ;26 :1679 –1684 .22739389
32. Van Zyl GU Liu TF Claassen M
Trends in genotypic HIV-1 antiretroviral resistance between 2006 and 2012 in South African patients receiving first- and second-line antiretroviral treatment regimens . PLoS One . 2013 ;8 :e67188 .23840622
33. Li JF Lipscomb JT Wei X
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34. Coutsinos D Invernizzi CF Xu H
Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1 . J Virol.
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37. Welles SL Pitt J Colgrove R
HIV-1 genotypic zidovudine drug resistance and the risk of maternal–infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group . AIDS . 2000 ;14 :263 –271 .10716502
38. Policy and Guidelines for the Implementation of the PMTCT Programme . Pretoria, South Africa : National Department of Health ; 2008 .
39. Updates on Revised Antiretroviral Treatment Guidelines 2013 . South Africa : National Department of Health ; 2013 Available at: http://www.sahivsoc.org/upload/documents/FDC%20Training%20Manual%2014%20March%202013(1).pdf.
40. Unicef . Available at: http://www.unicef.org/southafrica/survival_devlop_343.html. Accessed September 7, 2015.
41. MRC . Evaluation of the Effectiveness of the National Prevention of Mother-to-Child Transmission (PMTCT) Programme on Infant HIV Measured at Six Weeks Postpartum in South Africa . 2010 Available at: http://www.mrc.ac.za/healthsystems/SAPMTCTE2010.pdf. Accessed July 11, 2016.
42. Manasa J Lessells RJ Skingsley A
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43. Pillay S Bland RM Lessells RJ
Drug resistance in children at virological failure in a rural KwaZulu-Natal, South Africa, cohort . AIDS Res Ther.
2014 ;11 :3 .24444369
| Drug resistance, Exposure during pregnancy, Viral mutation identified | [
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"Drug resistance, Exposure during pregnancy, Viral mutation identified",
"Drug resistance, Exposure during pregnancy, Viral mutation identified",
"Drug resistance, Exposure during pregnancy, Viral mutation identified",
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] | 27327263 | CC BY-NC-ND | hiv 1 drug resistance by ultra deep sequencing following short course zidovudine single dose nevirapine and single dose tenofovir with emtricitabine for prevention of mother to child transmission | 73(4) | 384-389 | Journal of acquired immune deficiency syndromes (1999) | Samuel|Reshmi|R|;Julian|Marc Noguera|MN|;Paredes|Roger|R|;Parboosing|Raveen|R|;Moodley|Pravi|P|;Singh|Lavanya|L|;Naidoo|Anneta|A|;Gordon|Michelle|M| | 2016-12-01 | 10.1097/QAI.0000000000001116 | *Department of Virology, National Health Laboratory Service, University of KwaZulu-Natal, Durban, South Africa; †IrsiCaixa AIDS Research Institute, Badalona, Catalonia, Spain; ‡Universitat de Vic, Vic, Catalonia, Spain; §HIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain; ∥Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain; and ¶Department of Virology, HIV Pathogenesis Laboratory, Nelson R Mandela Medical School, University of KwaZulu-Natal, Durban, South Africa. | J Acquir Immune Defic Syndr | 100892005 | 1525-4135 | United States | D019380:Anti-HIV Agents; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D009154:Mutation; D019829:Nevirapine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000068698:Tenofovir; D019562:Viral Load; D015215:Zidovudine | D016428:Journal Article | D019380:Anti-HIV Agents; D015215:Zidovudine; D019829:Nevirapine; D000068698:Tenofovir; D000068679:Emtricitabine | 22179227;25336166;17885298;21576473;25755001;19073730;21257741;21467286;23991055;20102271;10716502;20169113;25940687;17662474;25614045;17215531;20672451;19886836;22739389;17533166;18666824;20539818;1358026;20160635;22384138;24444369;23840622;26244389;20649427;25300623;21632754;20102272;26244386;24879788;17997151;19210162 | false | [
13864684,
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HIV-1 Drug Resistance by Ultra-Deep Sequencing Following Short Course Zidovudine, Single-Dose Nevirapine, and Single-Dose Tenofovir with Emtricitabine for Prevention of Mother-to-Child Transmission.
ABSTRACT:
Antiretroviral drug resistance following pMTCT strategies remains a significant problem. With rapid advancements in next generation sequencing technologies, there is more focus on HIV drug-resistant variants of low frequency, or the so-called minority variants. In South Africa, AZT monotherapy for pMTCT, similar to World Health Organization option A, has been used since 2008. In 2010, a single dose of co-formulated TDF/FTC was included in the strategy for prevention of resistance conferred by single-dose nevirapine (sd NVP). The study was conducted in KwaZulu-Natal, South Africa, among pMTCT participants who received AZT monotherapy from 14 weeks of gestation, intrapartum AZT and sd NVP, and postpartum sd TDF/FTC. Twenty-six specimens collected at 6 weeks post-delivery were successfully sequenced using 454 ultra-deep sequencing. Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was detected in 17 of 26 (65%) patients, 2 (7%) had Thymidine analogue mutations, and 3 (11%) had K65R. Of the 17 patients with NNRTI resistance, 11 (65%) had high-level NNRTI resistance, whereas 6 (35%) had intermediate NNRTI resistance. The levels of NNRTI resistance are much higher than would be expected, given the inclusion of antepartum AZT and postpartum TDF/FTC. This high level of NNRTI resistance could impact future NNRTI-containing treatment for a large proportion of pMTCT-exposed women. The detection of Thymidine analogue mutations highlights the need to understand the clinical impact of these on AZT-containing antiretroviral treatment in women exposed to AZT monotherapy.
TEXT:
INTRODUCTION
Although prevention of mother-to-child transmission (pMTCT) strategies have recently improved with the implementation of World Health Organization (WHO) options B and B plus,1 antiretroviral (ARV) drug resistance remains a significant problem in the wake of single-dose nevirapine (sd NVP)2,3 monotherapy and dual-therapy use in resource-limited settings. The current standard method for resistance testing is Sanger sequencing, or so-called population sequencing, and although widely used, it is limited since the sensitivity relies on mutations being present in 15%–20% of the HIV quasispecies.4,5 Thus, resistance conferring mutations present at low frequencies, or drug-resistant minority variants (DRMVs) will be missed by Sanger sequencing. The more sensitive technologies, commonly known as next-generation sequencing, include the Miseq and HiScan (Illumina, San Diego, CA), 454 GS-FLX and Junior (Roche Daignostics, Basel, Switzerland), Pac-Bio RS II (Pacific Biosciences, CA), and Ion-Torrent PGM (Life Technologies, Thermo Fischer Scientific, NY). Resistance testing performed using these technologies can detect DRMVs present at low frequencies.6 These DRMVs were shown to be clinically significant in studies investigating non-nucleoside reverse transcriptase inhibitor–based ART.7,8 DRMVs doubled the risk of virological failure to first-line NNRTI-containing antiretroviral treatment (ART).9
Following pMTCT exposure, DRMVs that develop may impact negatively on future ART, leading to virological failure.10 In South Africa, zidovudine (AZT) administered from the 14th week of pregnancy and intrapartum, together with sd NVP and a stat postpartum dose of co-formulated tenofovir (TDF) with emtricitabine (FTC) was used as the pMTCT strategy from 2010 to 2013.11 Using Sanger sequencing, high-level NVP resistance was detected in 34% of women in this context.12 This study therefore further aims to determine the patterns and frequency of DRMVs in this group of women, using ultra-deep sequencing (UDS).
METHODS
This study was conducted at Lwazi Clinic, Addington Hospital in Durban, South Africa. Ethical approval (BF069-09) was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee. Ninety-seven pregnant women who did not qualify for ART as per National Guidelines,11 ie, CD4 count >350 cells per cubic millimeter were recruited for the study from August 2010 until December 2011. Data on adherence were captured at the 6-week post-delivery visit and limited to “Yes,” “No,” or “Unsure” with regard to receiving intrapartum AZT, sd NVP, and postpartum TDF/FTC. Furthermore, an EDTA whole-blood specimen for HIV-1 viral load testing was collected at recruitment and at 6 weeks post-delivery. A specimen for HIV-1 drug resistance testing was also collected at 6 weeks post-delivery.
HIV-1 Viral Load
The viral loads were performed using an automated Nuclisens EasyQ (bioMerieux) HIV-1 assay, which was later replaced by the Abbot m2000sp and Abbot m2000rt systems of extraction and real-time amplification, respectively. UDS was performed on 26 specimens which had an HIV-1 viral load of >5000 RNA copies per milliliter, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter.
Amplicon Design
Four sets of overlapping amplicons were designed to cover the Reverse Transcriptase region of HIV-1 such that each significant codon position was interrogated by 2 separate amplicons. Primers were based on a subtype C isolate, Genbank accession no AY772699 (http://www.ncbi.nlm.nih.gov/nuccore/AY772699). Primer sequences are listed in Table 1.
TABLE 1. Primer Sequences
RNA Preparation, Conventional Reverse Transcription Polymerase Chain Reaction, and Polymerase Chain Reaction
Two milliliter of plasma was ultracentrifuged at 14,000 rpm for 3 hours. RNA was extracted from 1 ml of plasma using the Nuclisens EasyMag HIV-1(bioMerieux, France) extraction system.
One-step reverse transcription (RT)-polymerase chain reactions (PCRs) using the SuperScript III One-Step RT-PCR System (with Platinum Taq High Fidelity; Invitrogen, Carlsbad, CA) were performed in triplicate per specimen. The triplicate RT-PCR products were then pooled and used for a second round of PCR that amplified overlapping amplicons which were also performed in triplicate per amplicon. The PCR products were pooled, purified, and sequenced.
A volume of 3.75 μl of extracted RNA was added to the RT-PCR reaction mix which had a final volume of 12.5 μl. Reagents included 2x buffer, Mg2SO4 (5 mM, final concentration of 0.6 mM), RNAse out, sterile water, SuperScript III (Invitrogen, Carlsbad, CA), and primers 1855-F1 and 2745-R2 (final concentration of 0.2mM).
A reverse transcription step at 55°C for 25 minutes was performed. Thermocycling was performed using an initial denaturation of 94°C for 2 minutes, followed by 25 cycles of 94°C for 30 seconds, 57°C for 30 seconds, 68°C for 30 seconds and a final extension step at 68°C for 1 minute. After the first round of PCR, 1 μL of the pooled PCR product was added to the second round PCR reaction mix (final volume of 50 μL) containing 10× buffer, dNTPs (200 mM), Platinum Taq High Fidelity enzyme (Invitrogen), MgS04 (50 mM, final concentration 2 mM), and DNase free water. The reaction mix was aliquoted equally into 4 separate tubes so that the relevant primers for the individual amplicons were added (F1, R1 to tube 1; F2, R2 to tube 2, etc). Conditions of cycling were the same as for the first round with omission of the RT step of 55°C for 55 minutes. After pooling, 150 μL of product was available for ultra-deep 454 sequencing. Samples were purified using the Qiagen min Elute spin columns.
To limit random sampling error caused by the sampling of only a few viral variants in patients with low viral loads, only patient samples with viral loads >5000 copies per milliliter were used, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter. Primers were designed to target conserved regions to limit primer induced selection bias, where particular templates are amplified earlier than others, and these become overrepresented in the final amplicon pool; each sample was amplified in 3 independent PCRs, and the PCR products were pooled before sequencing to compensate for biased priming and random sampling error during the PCR; multiplex identifier adapters were added after the amplification step to avoid the selection bias induced by using fusion primers.
Ultra-Deep 454 Sequencing
UDS was performed using the Roche 454 GS-FLX at the Technology Innovation Agency, National Genomics Platform in Durban. Twenty-six samples were successfully sequenced. Amplicon lengths varied in size (Amplicon 1: 459 bases, Amplicon 2: 376 bases, Amplicon 3: 436 bases, Amplicon 4: 344 bases). Samples had to meet standard requirements for library preparation after passing quality control. Samples were tagged with multiplex identifier adapters during library preparation. After emulsion PCR, sequencing was performed fulfilling all quality criteria and using a 4-lane divider on the picotiter plate. Four standard flowgram format files were generated and used for data analysis.
Data Analysis
For statistical analysis, nonparametric methods in SPSS version 23.0 (IBM Corp, Armonk, NY), including the Mann–Whitney U test, were used.
For bioinformatics analysis, Amplicon Variant Analyzer software v2.7 (Roche Diagnostics, Basel, Switzerland) was used to analyze and obtain sequence alignments against HIV-1 subtype C reference sequence (Genbank ID: AY772699). A short sequence length filter was applied based on the amplicon design and the corresponding sequence length. Short sequences (<90% of expected sequence length) were discarded. Error-corrected consensus sequences, as obtained from Amplicon Variant Analyzer, were used for amino acid variant calling. Variants were considered valid when present in both forward and reverse directions in a balanced manner as reported elsewhere.13 To control for sample cross-contamination, phylogenetic trees were built for all amplicons and samples with evidence of interfering cross-contamination were discarded. A minimum 500×/300× depth of coverage was required to call a minor variant (≤20%) and a major variant (>20%), respectively. Depth of coverage is provided in Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A854. A 1% conservative minimum threshold was defined based on internal sequencing controls and on published literature.13–16
To estimate whether sufficient viral templates were sampled, we used the formula pVL = NRNA(λ)/(VfeERNAXEcDNA) to calculate the minimal viral load required to detect minor variants at 1%, where pVL is the minimum viral load required; NRNA(λ) is the number of RNA copies that according to the Poisson distribution should be tested to detect at least 1 minor variant with a likelihood of > 99%; V, the volume of plasma (milliliter); fe, the fraction of the RNA eluent used for DNA synthesis; ERNAX, the extraction yield and EcDNA, the RT efficiency.17 Based on the following V = 1 mL, ERNAX = 0.96 and EcDNA = 0.7, using 0.5 as the fraction of the RNA eluent used for DNA synthesis, the minimum viral load required to reliably detect minor variants at 1% is 1488 copies per milliliter. Viral loads of all samples that underwent 454 sequencing were in excess of 5000 copies per milliliter, with the exception of sample 3, where the viral load was 4604 RNA copies per milliliter. Ensuring that an acceptable number of templates were sampled (Table 2).
TABLE 2. Viral Loads and Mutations Detected in Each Patient (provided as the Percentage of the Variant Within the Quasispecies)
RESULTS
There was no statistical difference in the CD4 cell count or HIV-1 viral load (at recruitment and at 6 weeks postdelivery) between those patients who developed NNRTI resistance and those who did not using the Mann–Whitney U test in SPSS version 23.0 (IBM Corp).
The median overall viral load was 17,269 copies per milliliter, with an interquartile range of 17,307 copies per milliliter (Table 2). The median viral load among patients where no Thymidine analogue mutations (TAMs) were detected was 14,921 copies per milliliter (interquartile range of 15262 copies/ml) compared with the median viral load of 93886 copies/ml in patients where TAMs were detected (P value 0.042).
The mean duration of AZT exposure overall was 16 weeks. The median duration of AZT exposure in those who developed TAMs was 20 weeks and 18 weeks (interquartile range of 8 weeks) in those who did not develop TAMs (P value 0.318).
Mutations conferring resistance to NRTIs and NNRTIs were detected at variable frequencies (Table 2). Of 26 patients, 20 patients (77%) had mutations conferring resistance. NNRTI resistance was detected in 17 of 26 (65%) patients, 2 (7%) patients had TAMs, and 3 (11%) patients had K65R. Of the 17 patients with NNRTI resistance, 11 (65%) had high-level resistance to NVP and EFV, whereas 6 (35%) had intermediate NNRTI resistance. One patient had both high-level NNRTI resistance and high-level resistance to TDF and 1 patient had both low to intermediate NNRTI resistance and K70R.
Of all mutations conferring resistance to NNRTIs, the most common were those conferring high-level NNRTI resistance such as K103N in 8 of 26 (30%), V106M in 8 of 26 (30%), Y188C in 6 of 26 (23%), G190A in 4 of 26 (15%), Y181C in 3 of 26 (11%), and V106A in 3 of 26 (11%) patients. K103N and V106M were the most common mutations detected. In patients who had K103N, it was also the predominant variant within the viral population compared to the other mutations detected as minor variants only. Mutations conferring low to intermediate NNRTI resistance included K101E in 7 of 26 (27%), A98G 5 of 26 (19%), L100V 4 of 26 (15%), V108I in 1 of 26 (3%) and F227L in 1 of 26 (3%) of patients. V90I which is associated with minimal, if any, detectable reduction in NNRTI susceptibility was found in 5 of 26 (19%) of patients.
Mutations conferring NRTI resistance included K70R in 2 of 26 (7%) patients and T69S which was detected in 1 of 26 (3%) patients. Resistance to TDF (K65R) was found in 3/26 (11%) patients. No other TAMs were detected. There was a 100% correlation between the mutations detected by Sanger sequencing12 and those detected by 454 UDS in samples that underwent both methods of sequencing. In addition, 454 UDS was able to detect a significant number of mutations that were missed by Sanger sequencing as indicated in bold in Table 2.
Regarding adherence, among the patients with high-level NNRTI resistance, 1 of 11 patients said that she was unsure about receiving antepartum AZT and intrapartum TDF/FTC and 1 said that she did not receive intrapartum TDF/FTC. Among the patients where no resistance was detected, 4 of 5 patients answered “unsure” or “no” to receiving prophylactic ARVs.
DISCUSSION
Using UDS, higher rates of NNRTI resistance were detected as compared to Sanger sequencing.12 More than two-third of patients had NNRTI resistance, the majority having high-level NNRTI resistance. The most common mutations (30%) detected were K103N and V106M, which are associated with high-level NNRTI resistance. Most of the K103N mutations were detected between frequencies of 17% and 59%, making it the predominant variant in the quasispecies for those specimens (Table 2).
Resistance to sd NVP is documented to occur at an average rate of 37.5%.18 The addition of peripartum AZT19 and postpartum TDF/FTC20 was shown to reduce the rate of resistance conferred by sd NVP. An open-labeled randomized control trial in Zambia found that the addition of sd TDF/FTC reduced NNRTI resistance by half at 6 weeks post-delivery.21 However, in our study, despite the use of AZT and TDF/FTC, there was no reduction in NNRTI resistance and the rate of NNRTI resistance of 65% is significantly higher than in earlier pMTCT strategies where only sd NVP was used.18 The high rate of NVP resistance could be explained by poor adherence to the complicated overall pMTCT strategy, exposure to NVP in successive pregnancies,22 and the higher rates of transmitted NNRTI drug resistance in KZN as reported by the WHO drug resistance report of 2012.23
The clinical impact of minority NNRTI drug-resistant variants has recently become topical following advances in the next-generation sequencing technologies. Studies investigating this show that minority NNRTI-resistant variants are clinically significant and can lead to treatment failure when these patients are initiated on NNRTI-containing ARVs,7,8,13,16,24,25 Furthermore, even with 95% adherence, these variants are associated with up to 3 times the risk of virological failure.7 In addition, preexisting minority Y181C variants were associated with a risk of virological failure in patients initiated on first-line efavirenz (EFV)-containing ART24 and in EFV exposed treatment experienced patients.26 In our study, Y188C and Y181C were detected in 23% and 11%, respectively, of patients as minority variants.
The added clinical benefit of using next-generation sequencing has been demonstrated in many studies.7,26–28 Although the sensitivity is significantly better with such technologies, its inclusion for routine use faces many challenges some being the large cost factor as well as the sophisticated bioinformatics support required.
Two (7%) patients harbored the K70R mutation while no other TAMs were found. Although the rate of AZT resistance is much lower than that detected by Olson et al,29 it is possible that AZT resistant mutants may have faded by the time of sample collection in our study, ie, 6 weeks postdelivery and may also be reflective of a smaller sample size. A study in Tanzania among pMTCT recipients where a similar pMTCT strategy was used, found AZT resistance in 18% of patients by Allele-specific PCR. The higher sensitivity of Allele-specific PCR compared to deep sequencing may explain the higher rates of TAMs.30 The clinical impact of these minority AZT-resistant variants when patients initiate ART requires further investigations.
K65R was detected in 11% of patients at low frequencies (1%–2.6%). There are reports of higher levels of K65R detection in HIV-1 subtype C among patients failing first-line TDF-based ART31,32 and in ART-naive patients.33 This highlights the need to explore the impact of minority TDF drug-resistant variants in HIV-1 subtype C. The mechanism for higher levels of K65R in subtype C seems to be template specific, where a preferential pause in subtype C reverse transcription at position 65 AAG-AGG is seen.34 It is therefore important to interpret low abundance K65R mutations in subtype C with caution. In addition, PCR-induced error is an important consideration when interpreting very low-abundance variants. Varghese et al35 showed that using UDS which is PCR dependent for the sequencing of subtype C, RT KKK template may result in spurious detection of K65R.
The limitations of this study include the lack of baseline genotyping, limited adherence information and lack of knowledge of previous exposure to sd NVP. Owing to the increasing rates of transmitted NNRTI resistance,23 it is possible that the high levels of NNRTI resistance detected in this study is partially reflective of the transmitted NNRTI resistance. However for AZT, resistance most likely developed while on short course AZT since these patients were not exposed to ART regimens, had high HIV-1 viral loads and prolonged AZT exposure.36,37
We have demonstrated a high level of NNRTI resistance (65%), which may have serious impact on the national ART programme in South Africa. Since this regimen was part of the South African pMTCT prophylaxis from 2008 to 2013,11,38,39 approximately 1.5 million women may have been exposed to this regimen, given that about 300,000 HIV-infected women require pMTCT annually in South Africa.40 If this figure is adjusted for the average uptake of pMTCT prophylaxis in South Africa at 58.7%,41,880,000 women would have been exposed to this regimen. Therefore, more than half a million women may fail first-line NNRTI-containing ART and require a switch to a protease inhibitor–based ART regimen.
Furthermore, our extrapolation does not consider, first, the women exposed to sd NVP before 2008 who subsequently may have developed NNRTI resistance when initiated on ART. Second, the WHO reported in 2012 that transmitted NNRTI resistance is increasing in Africa. The prevalence of transmitted NNRTI resistance in KwaZulu-Natal has increased from below 5% in 2007 to 5%–15% in 2010 with the most commonly detected mutation being the K103NS.23 Third, the number of patients with NNRTI mutations among those failing NNRTI-based ART is high in rural South Africa, ie, 82% in both adults42 and children,43 with K103NS again being the most commonly detected NNRTI mutation. Finally, the underestimation of ART resistance using conventional sequencing and the rising evidence of the clinical impact of minority NNRTI mutations remains an important consideration.
These factors may consequently contribute to a higher than expected ART failure rate among patients on first-line NNRTI-containing ART. Therefore, it may be prudent to consider more rigorous monitoring for virological failure in these women to ensure good future treatment outcomes.
Supplementary Material
SUPPLEMENTARY MATERIAL
ACKNOWLEDGMENTS
The authors thank Columbia University-South Africa Fogarty Aids and TB Training and Research Program (AITRP); Professor Daniel Kuritzkes, Dr Jonathan Li, and Dr Athe Tsibris for their kind assistance during my AITRP traineeship at the HIV Research lab, Harvard Medical School; Technology Innovation Agency, Dawn Stephens.
Supported by the Medical Research Council of South Africa and the National Health Laboratory Service Research Trust (NHLSRT).
The authors have no conflicts of interest to disclose.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com). |
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Neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol. | A 39-year-old female with a 20-year history of bipolar disorder was admitted due to a recurrence of a manic episode with psychotic symptoms. She was treated with standard doses of lithium carbonate and clozapine. Three days after admission, she showed aggressive behavior and refused to take her medications so her oral clozapine was switched to intramuscular haloperidol. Three days later she developed a high temperature and exhibited symptoms of neuroleptic malignant syndrome (NMS) including excessive sweating, cramps and tremors in limb muscles, muscle rigidity, and impaired consciousness. The haloperidol and lithium were stopped immediately, symptomatic treatment was provided, and she was administered the dopamine agonist bromocriptine. The NMS symptoms resolved within three days but she continued to have severe psychotic symptoms. She was subsequently re-challenged with valproate and olanzapine but the NMS did not re-occur. After one month of this treatment she recovered and was discharged. Several case histories similar to this one suggest - but do not prove - that individuals concurrently receiving lithium and antipsychotic medications may be at higher risk of developing NMS than those receiving monotherapy with antipsychotic medication. |
==== Front
Shanghai Arch PsychiatryShanghai Arch PsychiatrySAPShanghai Archives of Psychiatry1002-0829Shanghai Municipal Bureau of Publishing Shanghai, China 25642114sap-26-06-36810.11919/j.issn.1002-0829.214099Case ReportNeuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol 碳酸锂结合氟哌啶醇致恶性综合征 YANG Yanfen *GUO Yahui ZHANG Aiguo Rongjun Kangning Psychiatric Hospital, Shanxi Province, China* correspondence: luluyang0@163.com(Yanfen YANG);
12 2014 26 6 368 370 25 7 2014 28 10 2014 Copyright © 2014 by Shanghai Municipal Bureau of Publishing2014This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Summary
A 39-year-old female with a 20-year history of bipolar disorder was admitted due to a recurrence of a manic episode with psychotic symptoms. She was treated with standard doses of lithium carbonate and clozapine. Three days after admission, she showed aggressive behavior and refused to take her medications so her oral clozapine was switched to intramuscular haloperidol. Three days later she developed a high temperature and exhibited symptoms of neuroleptic malignant syndrome (NMS) including excessive sweating, cramps and tremors in limb muscles, muscle rigidity, and impaired consciousness. The haloperidol and lithium were stopped immediately, symptomatic treatment was provided, and she was administered the dopamine agonist bromocriptine. The NMS symptoms resolved within three days but she continued to have severe psychotic symptoms. She was subsequently re-challenged with valproate and olanzapine but the NMS did not re-occur. After one month of this treatment she recovered and was discharged. Several case histories similar to this one suggest – but do not prove – that individuals concurrently receiving lithium and antipsychotic medications may be at higher risk of developing NMS than those receiving monotherapy with antipsychotic medication.
概述
一名39岁的女性双相障碍患者因再次出现伴精神病性症状的躁狂发作而住院，总病程20年。用常规剂量的碳酸锂和氯氮平治疗。入院3 天后，患者出现攻击行为，并拒绝服药，因而停用氯氮平口服，予氟哌啶醇肌注。3天后，患者出现高热以及其他恶性综合征的表现，如大量出汗，肢体肌肉痉挛、震颤，肌强直以及意识障碍。立刻停用氟哌啶醇和锂盐，对症支持治疗，同时用多巴胺激动剂溴隐亭治疗。恶性综合征的症状在3天内缓解，但精神病性症状依然很严重。继而使用丙戊酸钠和奥氮平治疗，未再出现恶性综合征。又治疗1个月后，患者康复出院。过去有若干个病例也与此类似，这些病例提示抗精神病药物合并锂盐治疗引起恶性综合征的风险可能比单用一种抗精神病药物要高。当然病例报告本身无法证实这一点。
lithium carbonatehaloperidolneuroleptic malignant syndromeChina
==== Body
1. Case history
A 39 year-old female was admitted to our hospital on 18 February 2014 with a three-day history of agitation, elevated mood, and paranoia. She had a 20-year history of manic and depressive episodes that included four previous psychiatric admissions. During the previous admission at our hospital, she was treated with clozapine, risperidone, and lithium carbonate (maximum dosage 1.0g/day) and given a one-time injection of haloperidol 5mg. After discharge, her dosage of lithium carbonate was gradually reduced to 0.25g/day. In September of 2013, she vomited repeatedly and was diagnosed with ‘sinus thrombosis’ at a local hospital where she recovered after inpatient treatment. No other physical condition or family history of mental disorders was reported.
Routine physical and neurological examinations at admission found no abnormalities. Her routine blood tests, biochemical tests, electrocardiogram, and electroencephalogram were also normal. She was diagnosed with bipolar disorder, current manic episode with psychotic symptoms, based on criteria specified in the International Classification of Diseases, 10th edition (ICD-10).[1]
During the first three days of admission, she was treated with lithium carbonate 0.75g/day and clozapine 150mg /day (starting at 50mg/day and gradually increasing). On the third day of admission she became more agitated, argued with nurses, refused to take her medication, and became aggressive. Based on this change, her antipsychotic medication was changed from oral clozapine to intramuscular haloperidol (5mg bid) and scopolamine (0.3mg bid). Three days later she became disoriented and experienced cramps and tremors in her limb muscles, increased muscle tone, excessive sweating, and intermittent visual hallucinations. She had a fever of 38.5 - 39.6℃ but there was no evidence of infection. Her white blood count was 15.6×109/L with 86.1% neutrophilic granulocytes. Electrolyte levels were normal and serum lithium level was 0.61mmol/L. Chest X-ray showed no abnormalities. Electrocardiogram showed a nodal tachycardia of 106 beats per minute.
Based on a probable diagnosis of Neuroleptic Malignant Syndrome, her lithium, haloperidol, and scopolamine were stopped. She was given intravenous penicillin and supportive care to maintain her fluid and electrolyte balance. After consultation with senior clinicians her diagnosis was confirmed as NMS and she was treated with the dopamine agonist bromocriptine (2.5mg tid). Over the next two days her temperature dropped to normal and her physical symptoms subsided, though her psychotic symptoms remained. Given the severity of her psychosis, she was cautiously re-introduced to medications using 1.0g/day valproate as the mood stabilizer, olanzapine as the antipsychotic (up to a maximum of 20mg/d), and a variety of nighttime sleep medications (lorazepam, alprazolam, clonazepam, and clonazepam). Her symptoms gradually resolved and she was discharged on 28 March 2014, after six weeks of inpatient treatment.
2. Discussion
The diagnostic criteria for neuroleptic malignant syndrome (NMS) provided in the fourth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)[2] specify that the individual must exhibit severe muscle rigidity and elevated temperature associated with the use of antipsychotic medication and have at least two of the following associated symptoms: (a) diaphoresis, (b) dysphagia, (c) tremor, (d) incontinence, (e) changes in level of consciousness ranging from confusion to coma, (f) mutism, (g) tachycardia, (h) elevated or labile blood pressure, (i) leukocytosis, or (j) laboratory evidence of muscle injury (e.g., elevated CPK). NMS is usually seen at the beginning of antipsychotic treatment (within a week). In our case a patient who was already taking clozapine and lithium developed muscle rigidity, fever, tremor, sweating, altered consciousness, and leukocytosis 3 days after changing the clozapine to haloperidol. Despite our inability to confirm the diagnosis by assessing muscle enzyme levels (due to lack of the required laboratory facilities), the history and symptomatology were sufficient to meet the DSM-IV criteria of NMS.
First described by Delay in 1960, [3] NMS is considered the most severe side effect of antipsychotic medications. It is uncommon, currently occurring in only 0.01 to 0.02% of patients treated with antipsychotic medications, but it has a high case-fatality rate of 10%.[4] Almost all dopamine antagonists have been associated with NMS, but the risk of NMS appears to be greater when using high-potency conventional antipsychotics (such as haloperidol) than when using low-potency or atypical antipsychotics.[4] NMS has also been reported in patients taking lithium[5] and antidepressants.[6]
Lithium, particularly in high doses, is also associated with neurotoxicity[7],[8] so it is reasonable to suggest that individuals concurrently taking lithium and neuroleptic medications - a substantial minority of individuals with manic phase bipolar disorder - are at greater risk of developing NMS than those taking antipsychotic medications without lithium.[9] There are multiple case reports of NMS occurring in individuals simultaneously receiving antipsychotic medication and lithium.[10],[11] The case described in this report is an example in which a person already taking clozapine and lithium developed NMS after the clozapine was changed to haloperidol, a high-potency traditional antipsychotic medication. The case supports the contention that lithium may increase the risk of NMS associated with the use of high-potency antipsychotics, but in the absence of a comparison group (e.g., lithium + haloperidol versus monotherapy haloperidol) no definitive conclusion can be drawn. Such case reports are not sufficient to prove the case that individuals taking lithium plus antipsychotic combinations are at greater risk of NMS that those on monotherapy antipsychotic medication; the outcome event (NMS) is so rare and the potential confounding factors (age, physical health, dosage, rate of change of dosage, etc.) so many, that impossibly large sample sizes would be needed to definitively resolve this issue.
The mechanism of NMS is entirely unclear. Most researchers[12],[13] believe that the non-infectious hyperthermia seen in NMS is related to disruption of dopamine receptors in the hypothalamus; that hyperfunction of the sympathetic nervous system (manifested as tachycardia, polypnea, hypertension, sweating, etc.) is the result of the dopamine antagonists’ effects on the function of the autonomic nervous system; and that obstruction of dopamine receptors in the striatum results in muscle rigidity, tremor, and the catabolism of voluntary muscles (leading to myoglobinuria and increased serum creatine kinase).
The outcome of NMS is related to age, the physical condition of the patient, and on whether or not NMS is detected early.[4] Fatalities are more likely to occur in cases where the individual is elderly or physically frail, and where the condition was not recognized early (so the medications were continued even while the symptoms worsened). The overall principle for the treatment of NMS is the immediate cessation of antipsychotic medication, provision of supportive treatment (i.e., maintaining fluid balance, cooling, and prevention of infections), and, if necessary, administration of dopamine agonists such as admantadine, L-dopa, or bromocriptine. Recurrence of NMS in patients re-challenged with antipsychotic medications occurs in about 30% of cases. It is generally recommended that clinicians wait for at least 20 days prior to re-challenging a patient who has experienced NMS, [4] but in some cases where the psychiatric symptoms are severe - as in this case - it may be necessary to shorten this re-challenge interval.
Conflict of interest: The authors report no conflict of interest related to this manuscript.
Informed consent: The patient provided written informed consent for publication of this report.
Yanfen Yang graduated from Shanxi Changzhi Medical College in 2005. She is currently an attending psychiatrist at Rongjun Kangning Psychiatric Hospital in Shanxi province. She is also the vice director of the Department of Mood Disorders. Her research interests are the clinical treatment of mood disorders and psychotherapy.
==== Refs
1 World Health Organization International Classification of Diseases, 10th Edition 2010
2 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders the Fourth Edition 1994
3 Delay J Pichot P Lemperiere T Elissalde B Peigne F [A nonphenothiazine and non-reserpine major neuroleptic haloperidol in the treatment of psychosis] Ann Med Psychol (Paris) 1960 118 1 145 152 French 13815606
4 Strawn JR Keck PE Jr Caroff SN Neuroleptic malignant syndrome Am J Psychiatry 2007 164 6 870 876 17541044
5 Rai S Arun P Lithium-induced neuroleptic malignant syndrome: a case report Hong Kong Journal of Psychiatry 2007 17 3 101 102
6 Uguz F Sonmez EÖ Neuroleptic malignant syndrome following combination of sertraline and paroxetine: a case report Gen Hosp Psychiatry 2013 35 3 327.e7 327.e8 Epub 2013 Jan 9 10.1016/j.genhosppsych.2012.11.004 23312145
7 Gill J Singh H Nugent K Acute lithium intoxication and neuroleptic malignant syndrome Pharmacotherapy 2003 23 6 811 815 10.1592/phco.23.6.811.32179 12820823
8 Edokpolo O Fyyaz M Lthium toxicity and neurologic effects: probable neuroleptic malignant syndrome resulting from lithium toxicity Case Reports in Psychiatry 2012 271858 10.1155/2012/271858
9 Alexander PJ Thomas RM Increased risk of occurrence of neuroleptic malignant syndrome on combined treatment with lithium and neuroleptic Indian J Psychiatry 1997 39 3 251 255 21584083
10 Bourgeois JA Kahn DR Neuroleptic malignant syndrome following administration of risperidone and lithium J Clin Psychopharmacol 2003 23 3 315?17 12826996
11 Borovicka MC Bond LC Gaughan KM Ziprasidone- and lithium-induced neuroleptic malignant syndrome Ann Pharmacother 2006 40 1 139 142 Epub 2005 Dec 13 10.1345/aph.1G470 16352776
12 Shen YC [Psychiatry, 5th Edition] Beijing: People's Health Publishing House 2009 Chinese
13 Yu X Si TM [Prescription Guide of Psychopharmacology, 2nd Edition] Beijing: Peking University Medical Press 2009 Chinese
| Neuroleptic malignant syndrome | [
"Neuroleptic malignant syndrome",
"Neuroleptic malignant syndrome"
] | 25642114 | CC BY-NC-SA | neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol | 26(6) | 368-70 | Shanghai archives of psychiatry | Yang|Yanfen|Y|;Guo|Yahui|Y|;Zhang|Aiguo|A| | 2014-12 | 10.11919/j.issn.1002-0829.214099 | Rongjun Kangning Psychiatric Hospital, Shanxi Province, China.;Rongjun Kangning Psychiatric Hospital, Shanxi Province, China.;Rongjun Kangning Psychiatric Hospital, Shanxi Province, China. | Shanghai Arch Psychiatry | 9891453 | 1002-0829 | China | D002363:Case Reports | China; haloperidol; lithium carbonate; neuroleptic malignant syndrome | 21584083;22953147;16352776;12820823;13815606;23312145;17541044;12826996 | false | [
13557219,
12391452
] | TITLE:
Neuroleptic malignant syndrome in a patient treated with lithium carbonate and haloperidol.
ABSTRACT:
A 39-year-old female with a 20-year history of bipolar disorder was admitted due to a recurrence of a manic episode with psychotic symptoms. She was treated with standard doses of lithium carbonate and clozapine. Three days after admission, she showed aggressive behavior and refused to take her medications so her oral clozapine was switched to intramuscular haloperidol. Three days later she developed a high temperature and exhibited symptoms of neuroleptic malignant syndrome (NMS) including excessive sweating, cramps and tremors in limb muscles, muscle rigidity, and impaired consciousness. The haloperidol and lithium were stopped immediately, symptomatic treatment was provided, and she was administered the dopamine agonist bromocriptine. The NMS symptoms resolved within three days but she continued to have severe psychotic symptoms. She was subsequently re-challenged with valproate and olanzapine but the NMS did not re-occur. After one month of this treatment she recovered and was discharged. Several case histories similar to this one suggest - but do not prove - that individuals concurrently receiving lithium and antipsychotic medications may be at higher risk of developing NMS than those receiving monotherapy with antipsychotic medication.
TEXT:
1. Case history
A 39 year-old female was admitted to our hospital on 18 February 2014 with a three-day history of agitation, elevated mood, and paranoia. She had a 20-year history of manic and depressive episodes that included four previous psychiatric admissions. During the previous admission at our hospital, she was treated with clozapine, risperidone, and lithium carbonate (maximum dosage 1.0g/day) and given a one-time injection of haloperidol 5mg. After discharge, her dosage of lithium carbonate was gradually reduced to 0.25g/day. In September of 2013, she vomited repeatedly and was diagnosed with ‘sinus thrombosis’ at a local hospital where she recovered after inpatient treatment. No other physical condition or family history of mental disorders was reported.
Routine physical and neurological examinations at admission found no abnormalities. Her routine blood tests, biochemical tests, electrocardiogram, and electroencephalogram were also normal. She was diagnosed with bipolar disorder, current manic episode with psychotic symptoms, based on criteria specified in the International Classification of Diseases, 10th edition (ICD-10).[1]
During the first three days of admission, she was treated with lithium carbonate 0.75g/day and clozapine 150mg /day (starting at 50mg/day and gradually increasing). On the third day of admission she became more agitated, argued with nurses, refused to take her medication, and became aggressive. Based on this change, her antipsychotic medication was changed from oral clozapine to intramuscular haloperidol (5mg bid) and scopolamine (0.3mg bid). Three days later she became disoriented and experienced cramps and tremors in her limb muscles, increased muscle tone, excessive sweating, and intermittent visual hallucinations. She had a fever of 38.5 - 39.6℃ but there was no evidence of infection. Her white blood count was 15.6×109/L with 86.1% neutrophilic granulocytes. Electrolyte levels were normal and serum lithium level was 0.61mmol/L. Chest X-ray showed no abnormalities. Electrocardiogram showed a nodal tachycardia of 106 beats per minute.
Based on a probable diagnosis of Neuroleptic Malignant Syndrome, her lithium, haloperidol, and scopolamine were stopped. She was given intravenous penicillin and supportive care to maintain her fluid and electrolyte balance. After consultation with senior clinicians her diagnosis was confirmed as NMS and she was treated with the dopamine agonist bromocriptine (2.5mg tid). Over the next two days her temperature dropped to normal and her physical symptoms subsided, though her psychotic symptoms remained. Given the severity of her psychosis, she was cautiously re-introduced to medications using 1.0g/day valproate as the mood stabilizer, olanzapine as the antipsychotic (up to a maximum of 20mg/d), and a variety of nighttime sleep medications (lorazepam, alprazolam, clonazepam, and clonazepam). Her symptoms gradually resolved and she was discharged on 28 March 2014, after six weeks of inpatient treatment.
2. Discussion
The diagnostic criteria for neuroleptic malignant syndrome (NMS) provided in the fourth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)[2] specify that the individual must exhibit severe muscle rigidity and elevated temperature associated with the use of antipsychotic medication and have at least two of the following associated symptoms: (a) diaphoresis, (b) dysphagia, (c) tremor, (d) incontinence, (e) changes in level of consciousness ranging from confusion to coma, (f) mutism, (g) tachycardia, (h) elevated or labile blood pressure, (i) leukocytosis, or (j) laboratory evidence of muscle injury (e.g., elevated CPK). NMS is usually seen at the beginning of antipsychotic treatment (within a week). In our case a patient who was already taking clozapine and lithium developed muscle rigidity, fever, tremor, sweating, altered consciousness, and leukocytosis 3 days after changing the clozapine to haloperidol. Despite our inability to confirm the diagnosis by assessing muscle enzyme levels (due to lack of the required laboratory facilities), the history and symptomatology were sufficient to meet the DSM-IV criteria of NMS.
First described by Delay in 1960, [3] NMS is considered the most severe side effect of antipsychotic medications. It is uncommon, currently occurring in only 0.01 to 0.02% of patients treated with antipsychotic medications, but it has a high case-fatality rate of 10%.[4] Almost all dopamine antagonists have been associated with NMS, but the risk of NMS appears to be greater when using high-potency conventional antipsychotics (such as haloperidol) than when using low-potency or atypical antipsychotics.[4] NMS has also been reported in patients taking lithium[5] and antidepressants.[6]
Lithium, particularly in high doses, is also associated with neurotoxicity[7],[8] so it is reasonable to suggest that individuals concurrently taking lithium and neuroleptic medications - a substantial minority of individuals with manic phase bipolar disorder - are at greater risk of developing NMS than those taking antipsychotic medications without lithium.[9] There are multiple case reports of NMS occurring in individuals simultaneously receiving antipsychotic medication and lithium.[10],[11] The case described in this report is an example in which a person already taking clozapine and lithium developed NMS after the clozapine was changed to haloperidol, a high-potency traditional antipsychotic medication. The case supports the contention that lithium may increase the risk of NMS associated with the use of high-potency antipsychotics, but in the absence of a comparison group (e.g., lithium + haloperidol versus monotherapy haloperidol) no definitive conclusion can be drawn. Such case reports are not sufficient to prove the case that individuals taking lithium plus antipsychotic combinations are at greater risk of NMS that those on monotherapy antipsychotic medication; the outcome event (NMS) is so rare and the potential confounding factors (age, physical health, dosage, rate of change of dosage, etc.) so many, that impossibly large sample sizes would be needed to definitively resolve this issue.
The mechanism of NMS is entirely unclear. Most researchers[12],[13] believe that the non-infectious hyperthermia seen in NMS is related to disruption of dopamine receptors in the hypothalamus; that hyperfunction of the sympathetic nervous system (manifested as tachycardia, polypnea, hypertension, sweating, etc.) is the result of the dopamine antagonists’ effects on the function of the autonomic nervous system; and that obstruction of dopamine receptors in the striatum results in muscle rigidity, tremor, and the catabolism of voluntary muscles (leading to myoglobinuria and increased serum creatine kinase).
The outcome of NMS is related to age, the physical condition of the patient, and on whether or not NMS is detected early.[4] Fatalities are more likely to occur in cases where the individual is elderly or physically frail, and where the condition was not recognized early (so the medications were continued even while the symptoms worsened). The overall principle for the treatment of NMS is the immediate cessation of antipsychotic medication, provision of supportive treatment (i.e., maintaining fluid balance, cooling, and prevention of infections), and, if necessary, administration of dopamine agonists such as admantadine, L-dopa, or bromocriptine. Recurrence of NMS in patients re-challenged with antipsychotic medications occurs in about 30% of cases. It is generally recommended that clinicians wait for at least 20 days prior to re-challenging a patient who has experienced NMS, [4] but in some cases where the psychiatric symptoms are severe - as in this case - it may be necessary to shorten this re-challenge interval.
Conflict of interest: The authors report no conflict of interest related to this manuscript.
Informed consent: The patient provided written informed consent for publication of this report.
Yanfen Yang graduated from Shanxi Changzhi Medical College in 2005. She is currently an attending psychiatrist at Rongjun Kangning Psychiatric Hospital in Shanxi province. She is also the vice director of the Department of Mood Disorders. Her research interests are the clinical treatment of mood disorders and psychotherapy. |
||||
Aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension. | Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography. |
==== Front
Korean Circ JKorean Circ JKCJKorean Circulation Journal1738-55201738-5555The Korean Society of Cardiology 10.4070/kcj.2015.45.1.77Case ReportAggravation of Hepatopulmonary Syndrome after Sildenafil Treatment in a Patient with Coexisting Portopulmonary Hypertension Chung Seungmin MD1Lee Kyungho MD2Chang Sung-A MD1Kim Duk-Kyung MD11 Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Correspondence: Duk-Kyung Kim, MD, Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: 82-2-3410-3419, Fax: 82-2-3410-3849, dukkyung.kim@samsung.com1 2015 26 1 2015 45 1 77 80 25 3 2014 16 5 2014 12 6 2014 Copyright © 2015 The Korean Society of Cardiology2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography.
Hepatopulmonary syndromePulmonary arterial hypertensionSildenafil
==== Body
Introduction
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation in the presence of liver disease.1)2) In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure, but is rarely associated with hypoxia.1) We reported a case in which a patient had both HPS and PPHTN at the time of presentation with aggravated HPS subsequent to sildenafil administration for the treatment of PPHTN.
Case
A 58-year-old man with increasing shortness of breath on exertion was referred to our hospital. He had a 13-year history of hepatitis B virus-induced cirrhosis. The patient had suffered from esophageal variceal bleeding in 1999, and was treated by endoscopic variceal ligation. Progressive exertional dyspnea had developed over the past 5 years. On admittance to another hospital a plain chest radiograph (Fig. 1A) was normal and cardiac magnetic resonance image (CMR) (Fig. 1B) exhibited no evidence of pulmonary thromboembolism or intra- and extra-cardiac shunt disease. A right-heart catheterization showed a mean pulmonary artery pressure (PAP) of 35 mm Hg, capillary wedge pressure of 8 mm Hg, cardiac index of 3.63 L/min/m2 and pulmonary vascular resistance (PVR) of 313 dyne · sec/cm5. The patient was diagnosed as PPHTN and was started on diuretics and sildenafil 25 mg thrice daily. However dyspnea worsened despite treatment. The patient stopped taking sildenafil at his own discretion. Ten days later he was referred to our center. At admission, the patient was in World Health Organization (WHO) functional class (FC) III. His respiratory rate was 20/min, pulse rate 41/min, and blood pressure 127/49 mm Hg. Physical examination revealed spider angiomata, palmar erythema, shifting dullness, positive hepatojugular reflux and bilateral pretibial pitting edema. Heart and lung sounds were normal. Serum total bilirubin was elevated (3.3 mg/dL) and serum albumin level was decreased at 3.3 g/dL. Prothrombin time was 16.9 seconds (international normalized ratio 1.37). Liver cirrhosis was staged as Child-Pugh class B. N-terminal pro-B-type natriuretic peptide was 535.3 pg/mL. Arterial blood gas analysis (ABGA) obtained at room air in supine position revealed a resting PaO2 of 84.4 mm Hg and an alveolar-arterial (A-a) oxygen gradient of 22.9 mm Hg. Initial transthoracic echocardiography (TTE) demonstrated normal left-ventricular and right-ventricular function and mild tricuspid regurgitation (Fig. 1C), with an increased right ventricular systolic pressure of 53 mm Hg (Fig. 1D). Albumin macroaggregate lung perfusion scan showed normal perfusion without significant intrapulmonary shunt (IPS). A saline-contrast TTE (SC-TTE) showed delayed appearance of bubbles in the left atrium following five heart cycles, suggestive of IPS (Fig. 2A). Thirty minutes after a challenge dose of 50 mg sildenafil orally, SC-TTE showed IPS aggravation (Fig. 2B) with a PaO2 drop to 56.1 mm Hg. Four hours after the sildenafil challenge, SC-TTE showed IPS improvement with a PaO2 rise to 71.1 mm Hg (Fig. 3). On the next day, the symptoms and PaO2 did not improve after a challenge dose of 5 mcg iloprost inhalation (PaO2 values were obtained from two ABGAs, performed just before and 15 minutes after the start of iloprost inhalation: 89.8 mm Hg and 86.3 mm Hg, respectively). After administration of furosemide and permanent discontinuation of sildenafil, the patient had significant clinical improvement. The patient remained in WHO FC II without further hospitalization at the 7 months follow-up. Living donor liver transplantation was eventually performed due to advanced liver cirrhosis.
Discussion
The patient had longstanding liver cirrhosis and portal hypertension before he presented with exertional dyspnea. Additionally, a right-heart catheterization showed an elevated mean PAP at rest (35 mm Hg). There was no evidence of an alternative cause of the pulmonary arterial hypertension (PAH)3) such as collagen vascular disease, congenital heart disease, and pulmonary thromboembolism. Thus the patient was diagnosed as PPHTN. However, dyspnea worsened after sildenafil treatment. The lack of decompensating factors led to the consideration of IPS as the predominant cause of worsening dyspnea, after sildenafil administration. After admission to our hospital, ABGA revealed an oxygenation defect (alveolar-arterial oxygen gradient >15 mm Hg) and SC-TTE showed positive findings, i.e., microbubble opacification of the left heart chambers 5 cycles after right atrial passage. Therefore, coexisting HPS was diagnosed. Significant clinical improvement occurred on administration of diuretics and discontinuation of sildenafil. We recognize that our case had several limitations. Firstly, we do not know the exact reason for CMR at the other hospital, rather than pulmonary CT angiography, prior admission to our institution. We speculated that CMR was performed for assessment of structure and function of the right ventricle, via the measurement of right ventricular volumes and ejection fractions. We did not perform pulmonary CT angiography because pulmonary thromboembolism was excluded based on the CMR. Secondly, we did not perform any functional test.
Pathophysiologically, HPS is almost exactly the opposite of PPHTN.1) While abnormal intrapulmonary vascular dilatation is the hallmark of the HPS, PPHTN results from excessive pulmonary vasoconstriction and vascular remodeling. It was interesting that these two independent and opposite processes could occur in the same patient.
There have been 10 other documented cases of coexisting HPS and PPHTN in the same adult patient.4)5) Sequential development was suspected in 8 of the 10 cases, with HPS developing first, followed by PPHTN; and in the other 2 cases, HPS and PPHTN coexisted at the time of presentation. Our case was unique in that a patient with both HPS and PPHTN at the time of presentation developed aggravation of HPS on sildenafil therapy for the treatment of PPHTN. We demonstrated increased amount of IPS after sildenafil administration by SC-TTE.
Sildenafil is an oral phosphodiesterase-5 inhibitor with proven benefits to patients with PAH via enhanced nitric oxide (NO) availability in pulmonary vasculature.6) Patients with PPHTN showed sustained improvement in a 6 minutes walking distance and a decrease in B-type natriuretic peptide in response to sildenafil alone or in combination with prostanoid.7) Additionally, sildenafil effectively reduced PVR in patients prior to liver transplantation.8) However, in theory any vasodilator can exacerbate hypoxemia by reduction of PVR and aggravation of ventilation-perfusion mismatch. A high dose of sildenafil resulted in a dose-dependent fall in PVR associated with a marked increase in ventilation-perfusion heterogeneity in a porcine model.9) A patient with a history of PAH and treated with sildenafil, was reported with IPS and severe hypoxemia.10) Accurate diagnosis by SC-TTE and drug discontinuation allowed rapid symptomatic recovery and improvement of hypoxemia in the presented case.
Interestingly, inhaled iloprost neither improved nor aggravated the symptoms and hypoxemia. The mechanism by which sildenafil but not iloprost, aggravated IPS in this case, might be related to differential expression of the endothelin-1 (ET-1) receptor between HPS and PPHTN, as well as different mechanisms of the two drugs.5)6)11) ET-1 bound to receptor A leads to vasoconstriction and increased PVR.12) In contrast, as seen in rat models of HPS, binding of ET-1 to receptor B leads to upregulation of endogenous nitric oxide synthetase and increased nitric oxide production, resulting in pulmonary vasodilation.13)14) This results in pulmonary vasodilatation, shunting, and hypoxemia characteristic of HPS.15) Sildenafil is an oral phosphodiesterase-5 inhibitor that enhances NO-mediated vasodilation,6) while iloprost is a synthetic analog of prostacyclin that causes cyclic adenosine monophosphate mediated smooth muscle relaxation and vasodilation.11) Therefore, different mechanisms of the two drugs may have resulted in a different clinical course in this patient.
The diagnosis of HPS requires confirmation of pulmonary vascular dilatation and SC-TTE is considered the most practical method to do so.2) Under normal circumstances, only right heart chambers are opacified and the microbubbles are trapped in the pulmonary capillaries. The presence of microbubbles in the left chamber is suggestive of an arteriovenous connection. Late arrival of microbubbles in the left atrium after a time delay of 4-8 cardiac cycles is diagnostic of IPS.2)16) SC-TTE may be performed to exclude HPS before initiation of vasodilator therapy for the treatment of PPHTN.
In conclusion, HPS and PPHTN can occur in the same patient and sildenafil may be associated with aggravation of HPS in patients with coexisting HPS and PPHTN. In such cases, SC-TTE may be helpful to demonstrate IPS.
The authors have no financial conflicts of interest.
Fig. 1 A plain chest radiograph, cardiac magnetic resonance image (CMR) and transthoracic echocardiography (TTE). Plain chest radiograph (A) was normal and CMR (B) exhibited no evidence of pulmonary thromboembolism. TTE demonstrated mild tricuspid regurgitation (C) with an increased right ventricular systolic pressure of 53 mm Hg (D).
Fig. 2 Saline-contrast transthoracic echocardiogram (SC-TTE). SC-TTE showed right-to-left shunt (A). Thirty minutes after a challenge dose of 50 mg sildenafil orally, SC-TTE showed intrapulmonary shunt aggravation (B). LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle.
Fig. 3 Arterial blood gas analysis (ABGA) results before and after sildenafil challenge. ABGA was obtained just before (0 minute) and 30, 60, 90, 240 minute after sildenafil administration; PaO2 was 80.1 mm Hg, 56.1 mm Hg, 72.8 mm Hg, 61.1 mm Hg, and 71.7 mm Hg, respectively.
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1 Hoeper MM Krowka MJ Strassburg CP Portopulmonary hypertension and hepatopulmonary syndrome Lancet 2004 363 1461 1468 15121411
2 Rodríguez-Roisin R Krowka MJ Hepatopulmonary syndrome--a liver-induced lung vascular disorder N Engl J Med 2008 358 2378 2387 18509123
3 Rodríguez-Roisin R Krowka MJ Hervé P Pulmonary-Hepatic vascular Disorders (PHD) Eur Respir J 2004 24 861 880 15516683
4 Pham DM Subramanian R Parekh S Coexisting hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation J Clin Gastroenterol 2010 44 e136 e140 20463591
5 Zopey R Susanto I Barjaktarevic I Wang T Transition from hepatopulmonary syndrome to portopulmonary hypertension: a case series of 3 patients Case Rep Pulmonol 2013 2013 561870 24324910
6 Schwartz BG Levine LA Comstock G Stecher VJ Kloner RA Cardiac uses of phosphodiesterase-5 inhibitors J Am Coll Cardiol 2012 59 9 15 22192662
7 Reichenberger F Voswinckel R Steveling E Sildenafil treatment for portopulmonary hypertension Eur Respir J 2006 28 563 567 16807265
8 Gough MS White RJ Sildenafil therapy is associated with improved hemodynamics in liver transplantation candidates with pulmonary arterial hypertension Liver Transpl 2009 15 30 36 19109844
9 Kleinsasser A Loeckinger A Hoermann C Sildenafil modulates hemodynamics and pulmonary gas exchange Am J Respir Crit Care Med 2001 163 339 343 11179103
10 Castro PF Greig D Verdejo HE Intrapulmonary shunting associated with sildenafil treatment in a patient with idiopathic pulmonary arterial hypertension Thorax 2011 66 1097 1098 21289023
11 Olschewski H Rose F Schermuly R Prostacyclin and its analogues in the treatment of pulmonary hypertension Pharmacol Ther 2004 102 139 153 15163595
12 Shao D Park JE Wort SJ The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension Pharmacol Res 2011 63 504 511 21419223
13 Ling Y Zhang J Luo B The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the rat Hepatology 2004 39 1593 1602 15185300
14 Zhang J Ling Y Tang L Luo B Pollock DM Fallon MB Attenuation of experimental hepatopulmonary syndrome in endothelin B receptor-deficient rats Am J Physiol Gastrointest Liver Physiol 2009 296 G704 G708 19196949
15 Fallon MB Mechanisms of pulmonary vascular complications of liver disease: hepatopulmonary syndrome J Clin Gastroenterol 2005 39 4 Suppl 2 S138 S142 15758649
16 Gudavalli A Kalaria VG Chen X Schwarz KQ Intrapulmonary arteriovenous shunt: diagnosis by saline contrast bubbles in the pulmonary veins J Am Soc Echocardiogr 2002 15 1012 1014 12221424
| Condition aggravated, Hepatopulmonary syndrome, Product use issue, Ventilation perfusion mismatch | [
"Condition aggravated, Hepatopulmonary syndrome, Product use issue, Ventilation perfusion mismatch"
] | 25653708 | CC BY-NC | aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension | 45(1) | 77-80 | Korean circulation journal | Chung|Seungmin|S|;Lee|Kyungho|K|;Chang|Sung-A|SA|;Kim|Duk-Kyung|DK| | 2015-01 | 10.4070/kcj.2015.45.1.77 | Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Division of Cardiology, Heart, Vascular and Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. | Korean Circ J | 101247141 | 1738-5520 | Korea (South) | D016428:Journal Article | Hepatopulmonary syndrome; Pulmonary arterial hypertension; Sildenafil | 15163595;21289023;15516683;19109844;12221424;16807265;21419223;19196949;15121411;11179103;15758649;24324910;22192662;18509123;15185300;20463591 | false | [
10802321
] | TITLE:
Aggravation of hepatopulmonary syndrome after sildenafil treatment in a patient with coexisting portopulmonary hypertension.
ABSTRACT:
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. Their pathophysiological mechanisms clearly differ. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation. In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling, but is rarely associated with hypoxia. We report a case of a patient who had both HPS and PPHTN at the time of presentation. HPS was aggravated after sildenafil administration for the treatment of PPHTN. We demonstrated increased amount of intrapulmonay shunt after sildenafil challenge by using agitated saline contrast transthoracic echocardiography.
TEXT:
Introduction
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPHTN) are complications of portal hypertension and cirrhosis. HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilatation in the presence of liver disease.1)2) In contrast, PPHTN is predominantly due to excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure, but is rarely associated with hypoxia.1) We reported a case in which a patient had both HPS and PPHTN at the time of presentation with aggravated HPS subsequent to sildenafil administration for the treatment of PPHTN.
Case
A 58-year-old man with increasing shortness of breath on exertion was referred to our hospital. He had a 13-year history of hepatitis B virus-induced cirrhosis. The patient had suffered from esophageal variceal bleeding in 1999, and was treated by endoscopic variceal ligation. Progressive exertional dyspnea had developed over the past 5 years. On admittance to another hospital a plain chest radiograph (Fig. 1A) was normal and cardiac magnetic resonance image (CMR) (Fig. 1B) exhibited no evidence of pulmonary thromboembolism or intra- and extra-cardiac shunt disease. A right-heart catheterization showed a mean pulmonary artery pressure (PAP) of 35 mm Hg, capillary wedge pressure of 8 mm Hg, cardiac index of 3.63 L/min/m2 and pulmonary vascular resistance (PVR) of 313 dyne · sec/cm5. The patient was diagnosed as PPHTN and was started on diuretics and sildenafil 25 mg thrice daily. However dyspnea worsened despite treatment. The patient stopped taking sildenafil at his own discretion. Ten days later he was referred to our center. At admission, the patient was in World Health Organization (WHO) functional class (FC) III. His respiratory rate was 20/min, pulse rate 41/min, and blood pressure 127/49 mm Hg. Physical examination revealed spider angiomata, palmar erythema, shifting dullness, positive hepatojugular reflux and bilateral pretibial pitting edema. Heart and lung sounds were normal. Serum total bilirubin was elevated (3.3 mg/dL) and serum albumin level was decreased at 3.3 g/dL. Prothrombin time was 16.9 seconds (international normalized ratio 1.37). Liver cirrhosis was staged as Child-Pugh class B. N-terminal pro-B-type natriuretic peptide was 535.3 pg/mL. Arterial blood gas analysis (ABGA) obtained at room air in supine position revealed a resting PaO2 of 84.4 mm Hg and an alveolar-arterial (A-a) oxygen gradient of 22.9 mm Hg. Initial transthoracic echocardiography (TTE) demonstrated normal left-ventricular and right-ventricular function and mild tricuspid regurgitation (Fig. 1C), with an increased right ventricular systolic pressure of 53 mm Hg (Fig. 1D). Albumin macroaggregate lung perfusion scan showed normal perfusion without significant intrapulmonary shunt (IPS). A saline-contrast TTE (SC-TTE) showed delayed appearance of bubbles in the left atrium following five heart cycles, suggestive of IPS (Fig. 2A). Thirty minutes after a challenge dose of 50 mg sildenafil orally, SC-TTE showed IPS aggravation (Fig. 2B) with a PaO2 drop to 56.1 mm Hg. Four hours after the sildenafil challenge, SC-TTE showed IPS improvement with a PaO2 rise to 71.1 mm Hg (Fig. 3). On the next day, the symptoms and PaO2 did not improve after a challenge dose of 5 mcg iloprost inhalation (PaO2 values were obtained from two ABGAs, performed just before and 15 minutes after the start of iloprost inhalation: 89.8 mm Hg and 86.3 mm Hg, respectively). After administration of furosemide and permanent discontinuation of sildenafil, the patient had significant clinical improvement. The patient remained in WHO FC II without further hospitalization at the 7 months follow-up. Living donor liver transplantation was eventually performed due to advanced liver cirrhosis.
Discussion
The patient had longstanding liver cirrhosis and portal hypertension before he presented with exertional dyspnea. Additionally, a right-heart catheterization showed an elevated mean PAP at rest (35 mm Hg). There was no evidence of an alternative cause of the pulmonary arterial hypertension (PAH)3) such as collagen vascular disease, congenital heart disease, and pulmonary thromboembolism. Thus the patient was diagnosed as PPHTN. However, dyspnea worsened after sildenafil treatment. The lack of decompensating factors led to the consideration of IPS as the predominant cause of worsening dyspnea, after sildenafil administration. After admission to our hospital, ABGA revealed an oxygenation defect (alveolar-arterial oxygen gradient >15 mm Hg) and SC-TTE showed positive findings, i.e., microbubble opacification of the left heart chambers 5 cycles after right atrial passage. Therefore, coexisting HPS was diagnosed. Significant clinical improvement occurred on administration of diuretics and discontinuation of sildenafil. We recognize that our case had several limitations. Firstly, we do not know the exact reason for CMR at the other hospital, rather than pulmonary CT angiography, prior admission to our institution. We speculated that CMR was performed for assessment of structure and function of the right ventricle, via the measurement of right ventricular volumes and ejection fractions. We did not perform pulmonary CT angiography because pulmonary thromboembolism was excluded based on the CMR. Secondly, we did not perform any functional test.
Pathophysiologically, HPS is almost exactly the opposite of PPHTN.1) While abnormal intrapulmonary vascular dilatation is the hallmark of the HPS, PPHTN results from excessive pulmonary vasoconstriction and vascular remodeling. It was interesting that these two independent and opposite processes could occur in the same patient.
There have been 10 other documented cases of coexisting HPS and PPHTN in the same adult patient.4)5) Sequential development was suspected in 8 of the 10 cases, with HPS developing first, followed by PPHTN; and in the other 2 cases, HPS and PPHTN coexisted at the time of presentation. Our case was unique in that a patient with both HPS and PPHTN at the time of presentation developed aggravation of HPS on sildenafil therapy for the treatment of PPHTN. We demonstrated increased amount of IPS after sildenafil administration by SC-TTE.
Sildenafil is an oral phosphodiesterase-5 inhibitor with proven benefits to patients with PAH via enhanced nitric oxide (NO) availability in pulmonary vasculature.6) Patients with PPHTN showed sustained improvement in a 6 minutes walking distance and a decrease in B-type natriuretic peptide in response to sildenafil alone or in combination with prostanoid.7) Additionally, sildenafil effectively reduced PVR in patients prior to liver transplantation.8) However, in theory any vasodilator can exacerbate hypoxemia by reduction of PVR and aggravation of ventilation-perfusion mismatch. A high dose of sildenafil resulted in a dose-dependent fall in PVR associated with a marked increase in ventilation-perfusion heterogeneity in a porcine model.9) A patient with a history of PAH and treated with sildenafil, was reported with IPS and severe hypoxemia.10) Accurate diagnosis by SC-TTE and drug discontinuation allowed rapid symptomatic recovery and improvement of hypoxemia in the presented case.
Interestingly, inhaled iloprost neither improved nor aggravated the symptoms and hypoxemia. The mechanism by which sildenafil but not iloprost, aggravated IPS in this case, might be related to differential expression of the endothelin-1 (ET-1) receptor between HPS and PPHTN, as well as different mechanisms of the two drugs.5)6)11) ET-1 bound to receptor A leads to vasoconstriction and increased PVR.12) In contrast, as seen in rat models of HPS, binding of ET-1 to receptor B leads to upregulation of endogenous nitric oxide synthetase and increased nitric oxide production, resulting in pulmonary vasodilation.13)14) This results in pulmonary vasodilatation, shunting, and hypoxemia characteristic of HPS.15) Sildenafil is an oral phosphodiesterase-5 inhibitor that enhances NO-mediated vasodilation,6) while iloprost is a synthetic analog of prostacyclin that causes cyclic adenosine monophosphate mediated smooth muscle relaxation and vasodilation.11) Therefore, different mechanisms of the two drugs may have resulted in a different clinical course in this patient.
The diagnosis of HPS requires confirmation of pulmonary vascular dilatation and SC-TTE is considered the most practical method to do so.2) Under normal circumstances, only right heart chambers are opacified and the microbubbles are trapped in the pulmonary capillaries. The presence of microbubbles in the left chamber is suggestive of an arteriovenous connection. Late arrival of microbubbles in the left atrium after a time delay of 4-8 cardiac cycles is diagnostic of IPS.2)16) SC-TTE may be performed to exclude HPS before initiation of vasodilator therapy for the treatment of PPHTN.
In conclusion, HPS and PPHTN can occur in the same patient and sildenafil may be associated with aggravation of HPS in patients with coexisting HPS and PPHTN. In such cases, SC-TTE may be helpful to demonstrate IPS.
The authors have no financial conflicts of interest.
Fig. 1 A plain chest radiograph, cardiac magnetic resonance image (CMR) and transthoracic echocardiography (TTE). Plain chest radiograph (A) was normal and CMR (B) exhibited no evidence of pulmonary thromboembolism. TTE demonstrated mild tricuspid regurgitation (C) with an increased right ventricular systolic pressure of 53 mm Hg (D).
Fig. 2 Saline-contrast transthoracic echocardiogram (SC-TTE). SC-TTE showed right-to-left shunt (A). Thirty minutes after a challenge dose of 50 mg sildenafil orally, SC-TTE showed intrapulmonary shunt aggravation (B). LA: left atrium, LV: left ventricle, RA: right atrium, RV: right ventricle.
Fig. 3 Arterial blood gas analysis (ABGA) results before and after sildenafil challenge. ABGA was obtained just before (0 minute) and 30, 60, 90, 240 minute after sildenafil administration; PaO2 was 80.1 mm Hg, 56.1 mm Hg, 72.8 mm Hg, 61.1 mm Hg, and 71.7 mm Hg, respectively. |
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Gemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report. | Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure. |
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Oncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2017.5576OL-0-0-5576ArticlesGemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report Lai-Tiong Florence 1*Duval Yann 1*Krabansky Francois 21 Jean Godinot Institute, 51100 Reims, France2 Department of Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, 51100 Reims, FranceCorrespondence to: Miss. Florence Lai-Tiong, Jean Godinot Institute, 1 Rue du Général Kœnig, 51100 Reims, France, florence.lai-tiongfofo@laposte.net* Contributed equally
3 2017 05 1 2017 05 1 2017 13 3 1201 1203 01 4 2015 16 5 2016 Copyright: © Lai-Tiong et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure.
gemcitabinethrombotic microangiopathylung cancer
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Case report
A 63-year-old Caucasian male without a previous medical history was diagnosed with metastatic non small cell lung cancer (NSCLC) in March 2013 at Jean Godinot Cancer Center Institute (Reims, France). The patient received first-line treatment with gemcitabine (1,250 mg/m2) plus carboplatin (700 mg/m2; area under the curve, 5) every 3 weeks for 3 cycles (overall ~2 months), followed by 7 cycles of gemcitabine alone (1,000 mg/m2; day 1 and day 8; overall ~2 months). Following the seventh cycle, the patient developed high blood pressure (180/100 mmHg) and was subsequently intravenously administered with enalapril-hydrochlorothiazide (1,000 mg/m2; 1,075 mg/30 min).
A week later the patient was admitted to Jean Godinot Cancer Center due to acute renal failure. The patient's serum creatinine level had reached 199 µmol/l (normal range, 65–120 µmol/l), the platelet level was decreased to 17×109/l (normal range, 150–400×109/l) and the hemoglobin level was decreased to 8.3 g/dl (normal range, 129–167 g/l). Ultrasound of the urinary tract did not show any signs of obstruction and a urine test did not reveal a functional profile.
Further investigations revealed a normal coagulation pattern, with a bilirubin level of 47 µmol/l (normal range, 3.4–17 µmol/l), a lactose dehydrogenase (LDH) level of 2,374 IU/l (normal range, 200–450 IU/l), reticulocytes at 7.5% (normal range, 1–2.5%) and an undetectable haptoglobin level (<0.10 g/l; normal range, 0.5–2.5 g/l). Schiztocytes were found on the peripheral blood smear. Albuminemia (35.4 g/l; normal range, 35–50 g/l) and proteinuria (4.21 g per day; 3.51 g/l; normal range, <150 mg per day ot <0.20 g/l) were noted, in association with macroscopic hematuria. Complement factors were within normal ranges. A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity was also normal.
Thrombotic microangiopathy (TMA) was suspected and this diagnosis of hemolytic uremic syndrome (HUS) TMA was later confirmed by renal biopsy.
The patient received two infusions of three units each of freshly frozen plasma. Also, patient stabilization required three units of packed red cells. Blood pressure was controlled using multiple antihypertensive medications (80 mg furosemide, intravenous nicardipine and 5 mg beta blockers twice a day). At day 16 post-presentation, hemodialysis was started.
The patient recovered quickly from the thrombopenia and anemia. However, renal failure persisted and the patient required hemodialysis until he succumbed ~3 months subsequent to the diagnosis of TMA.
Discussion
TMA is a disorder characterized by microvascular occlusion due to platelet aggregation, thrombocytopenia and organ damage, such as renal failure (1). The main subtypes of TMA are HUS and thrombotic thrombocytopenic purpura (TTP). Thrombocytopenia, schistocytosis and elevated levels of LDH are enough to form a diagnosis in clinical practice. The majority of cases are idiopathic, but several etiologies have been recognized, among which are the use of cytotoxic chemotherapies, including mitomycin C, bleomycin, cisplatin and 5-fluorouracil (2). TMA may also be caused by the underlying malignancy itself (3,4). Indeed, TMA associated with metastatic adenocarcinomas, such as those of the stomach, colorectum, breasts, lungs and prostate, have been reported (5–7). It can be difficult to distinguish between HUS caused by the cancer itself and that caused by the chemotherapy. Certain studies have suggested that malignancy-associated HUS typically occurs during widespread metastatic disease, whereas the chemotherapy-associated type occurs more frequently when the patient is in disease remission. In the present study, the patient had minimal tumor burden.
The physiopathology of this disease remains unclear. Several mechanisms have been suggested, including an immune-mediated response or a direct toxic effect. Endothelial injury is the main event (8). HUS does not appear to be associated with a deficiency in ADAMTS13 activity; indeed, even if ADAMTS13 activity is absent or deficient in familial TTP, this condition it is not sufficient to cause the syndrome. Also, no specific correlation has been found between TMA and gender or age (9).
ADAMTS13 has been shown to be of major pathophysiological importance TMA in the setting of TTP when either lacking antibodies against ADAMTS13 (inherited TTP) or if antibodies against ADAMTS13 are present (acquired TTP). A severe deficiency of <5% ADAMTS-1 activity, with clinical symptoms of an acute thrombocytopenia and evidence of a microangiopathic hemolytic anemia, appropriately defines a diagnosis of TTP (10,11).
Gemcitabine is an important chemotherapeutic agent and its indications in oncology and hematology are wide. It is used in the therapy of pancreatic, ovarian, breast and bladder cancers, and NSCLC. Gemcitabine is associated with side effects that can lead to patient mortality (9).
First-line gemcitabine combined with cisplatin is indicated in patients with inoperable NSCLC (locally advanced or metastatic). In 1994, the first case of gemcitabine-associated TMA occurred during a phase II trial in pancreatic metastatic adenocarcinoma (12). To the best of our knowledge, there have been only 3 cases of gemcitabine-associated microangiopathy in patients treated for NSCLC to date (6).
The incidence of gemcitabine-attributed TMA is between 0.015 and 1.4% (13). However, the true incidence is difficult establish due to its underreported nature, the poor recognition of the condition or the failure to diagnose mild symptoms (14). A TMA diagnosis is more difficult in patients treated for cancer compared with otherwise healthy individuals, as certain symptoms may be adverse effects of chemotherapy agents. Clinically, TTP presents with hemolytic anemia, thrombocytopenia and renal insufficiency. Neurological symptoms and a fever are often present. However, anemia and thrombocytopenia are also common side-effects associated with chemotherapy due to myelotoxicity. Data on the incidence of TMA associated with gemcitabine use are conflicting. In 2004, in a study by Humphreys et al (15), the incidence of gemcitabine-associated TMA was shown to be 0.31%. This was in contrast with the estimated incidence of only 0.015% described by Fung et al in 1999 (16). In Boston, a review was performed between 1997 and 2002, and among 2,586 patients, 9 were identified with gemcitabine-associated TMA (15). New or exacerbated hypertension preceded the diagnosis of TMA by 0.5–10 weeks. The study concluded that this could represent an early clinical marker for the presence of a TMA syndrome (8). In the present study, the blood pressure of the patient remained high at 200/110 mmHg for several days.
The risk for gemcitabine-associated TMA appears to increase with a cumulative drug dose of >20,000 mg/m2 or administration for >18 cycles (14). The condition rarely occurs prior to 7 months of therapy. In the present case, the patient received only 10,750 mg/m2 (cumulative dose) of gemcitabine during 8 months. In the majority of reported cases, gemcitabine has been administered as a single-agent treatment, but in other cases, such as the present study, the condition has been reported during combination therapy (16). Screening for TMA has been proposed for after 10 cycles of gemcitabine. However, the development of TTP has been also reported after a single dose of gemcitabine (17).
A number of different treatments types have been previously suggested for patients with HUS (7,18). Glucocorticoids and plasma infusion may be used, but the interruption of chemotherapy and plasma exchange are the mainstays of treatment, and these therapies are quite effective. Management also involves the control of hypertension. Although these treatments are readily available, HUS remains a highly fatal disease.
The estimated mortality rate for HUS is 10–40% in the majority of case series (19,20), but has been reported to be as high as 60–70% in others (7,21,22).
Humphreys et al (15) recommend that for patients receiving gemcitabine for >3 months, the creatinine, schistocyte and haptoglobin levels should be checked monthly. Desramé et al (23) proposed that systematic screening should be performed for HUS during gemcitabine therapy. In this series, the frequency of HUS was 2.2%.
In conclusion, even if TMA is a rare adverse effect of cancer therapy, clinicians should be aware of it due to its potentially lethal evolution. Chemotherapy-induced TMA and that caused by the cancer itself are difficult to differentiate between, but the patient's clinical data can aid the clinician in making the right diagnosis. The precise and regular reporting of chemotherapeutic adverse events may assist in evaluating the frequency of TMA. Although no precise recommendation exists for the diagnosis and treatment of TMA, we suggest that chemotherapy should be halted and a glucocorticoid therapy or a plasma infusion should be introduced. Any worsening of anemia, thrombocytopenia or serum creatinine level with high blood pressure should lead to a prompt examination.
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11 Tsai HM The molecular biology of thrombotic microangiopathy Kidney Int 70 16 2006 10.1038/sj.ki.5001535 16760911
12 Casper ES Green MR Kelsen DP Heelan RT Brown TD Flombaum CD Trochanowski B Tarassoff PG Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas Invest New Drugs 12 29 34 1994 10.1007/BF00873232 7960602
13 Oberic L Buffet M Schwarzinger M Veyradier A Clabault K Malot S Schleinitz N Valla D Galicier L Bengrine-Lefèvre L Cancer awareness in atypical thrombotic microangiopathies Oncologist 14 769 779 2009 10.1634/theoncologist.2009-0067 19684072
14 Walter RB Joerger M Pestalozzi BC Gemcitabine-associated hemolytic-uremic syndrome Am J Kidney Dis 40 E16 2002 10.1053/ajkd.2002.35758 12324937
15 Humphreys BD Sharman JP Henderson JM Clark JW Marks PW Rennke HG Zhu AX Magee CC Gemcitabine-associated thrombotic microangiopathy Cancer 100 2664 2670 2004 10.1002/cncr.20290 15197810
16 Fung MC Storniolo AM Nguyen B Arning M Brookfield W Vigil J A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy Cancer 85 2023 2032 1999 10.1002/(SICI)1097-0142(19990501)85:9%3C2023::AID-CNCR21%3E3.0.CO;2-2 10223245
17 De Smet D Jochmans K Neyns B Development of thrombotic thrombocytopenic purpura after a single dose of gemcitabine Ann Hematol 87 495 496 2008 10.1007/s00277-007-0429-9 18097666
18 Sedlacek SM First-line and salvage therapy of metastatic breast cancer with mitomycin/vinblastine Oncology 50 (Suppl 1) S16 S21 1993 10.1159/000227243
19 Hollenbeck M Kutkuhn B Aul C Leschke M Willers R Grabensee B Haemolytic-uraemic syndrome and thrombotic-thrombocytopenic purpura in adults: Clinical findings and prognostic factors for death and end-stage renal disease Nephrol Dial Transplant 13 76 81 1998 10.1093/ndt/13.1.76 9481719
20 Sens YA Miorin LA Silva HG Malheiros DM Filho DM Jabur P Acute renal failure due to hemolytic uremic syndrome in adult patients Ren Fail 19 279 282 1997 10.3109/08860229709026289 9101604
21 Sheldon R Slaughter D A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma Cancer 58 1428 1436 1986 10.1002/1097-0142(19861001)58:7<1428::AID-CNCR2820580709>3.0.CO;2-J 3091244
22 Mergenthaler HG Binsack T Wilmanns W Carcinoma-associated hemolytic-uremic syndrome in a patient receiving 5-fluorouracil-adriamycin-mitomycin C combination chemotherapy Oncology 45 11 14 1988 10.1159/000226521 3124028
23 Desramé J Duvic C Bredin C Béchade D Artru P Brézault C Defuentes G Poirier JM Dourthe LM Coutant G Hemolytic uremic syndrome as a complication of gemcitabine treatment: Report of six cases and review of the literature Rev Med Interne 26 179 188 2005 (In French) 10.1016/j.revmed.2004.11.016 15777580
| Acute kidney injury, Death, Haemolytic uraemic syndrome, Thrombotic microangiopathy | [
"Acute kidney injury, Death, Haemolytic uraemic syndrome, Thrombotic microangiopathy",
"Thrombotic microangiopathy",
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] | 28454234 | CC BY-NC-ND | gemcitabine associated thrombotic microangiopathy in a patient with lung cancer a case report | 13(3) | 1201-1203 | Oncology letters | Lai-Tiong|Florence|F|;Duval|Yann|Y|;Krabansky|Francois|F| | 2017-03 | 10.3892/ol.2017.5576 | Jean Godinot Institute, 51100 Reims, France.;Jean Godinot Institute, 51100 Reims, France.;Department of Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, 51100 Reims, France. | Oncol Lett | 101531236 | 1792-1074 | Greece | D016428:Journal Article | gemcitabine; lung cancer; thrombotic microangiopathy | 11444722;3091244;8613975;20551375;12324937;10223245;7993594;7960602;16760911;18097666;7491579;2120375;9101604;15197810;12978378;15777580;8483557;9481719;3124028;19684072;2497229 | false | [
14250884,
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Gemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report.
ABSTRACT:
Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure.
TEXT:
Case report
A 63-year-old Caucasian male without a previous medical history was diagnosed with metastatic non small cell lung cancer (NSCLC) in March 2013 at Jean Godinot Cancer Center Institute (Reims, France). The patient received first-line treatment with gemcitabine (1,250 mg/m2) plus carboplatin (700 mg/m2; area under the curve, 5) every 3 weeks for 3 cycles (overall ~2 months), followed by 7 cycles of gemcitabine alone (1,000 mg/m2; day 1 and day 8; overall ~2 months). Following the seventh cycle, the patient developed high blood pressure (180/100 mmHg) and was subsequently intravenously administered with enalapril-hydrochlorothiazide (1,000 mg/m2; 1,075 mg/30 min).
A week later the patient was admitted to Jean Godinot Cancer Center due to acute renal failure. The patient's serum creatinine level had reached 199 µmol/l (normal range, 65–120 µmol/l), the platelet level was decreased to 17×109/l (normal range, 150–400×109/l) and the hemoglobin level was decreased to 8.3 g/dl (normal range, 129–167 g/l). Ultrasound of the urinary tract did not show any signs of obstruction and a urine test did not reveal a functional profile.
Further investigations revealed a normal coagulation pattern, with a bilirubin level of 47 µmol/l (normal range, 3.4–17 µmol/l), a lactose dehydrogenase (LDH) level of 2,374 IU/l (normal range, 200–450 IU/l), reticulocytes at 7.5% (normal range, 1–2.5%) and an undetectable haptoglobin level (<0.10 g/l; normal range, 0.5–2.5 g/l). Schiztocytes were found on the peripheral blood smear. Albuminemia (35.4 g/l; normal range, 35–50 g/l) and proteinuria (4.21 g per day; 3.51 g/l; normal range, <150 mg per day ot <0.20 g/l) were noted, in association with macroscopic hematuria. Complement factors were within normal ranges. A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity was also normal.
Thrombotic microangiopathy (TMA) was suspected and this diagnosis of hemolytic uremic syndrome (HUS) TMA was later confirmed by renal biopsy.
The patient received two infusions of three units each of freshly frozen plasma. Also, patient stabilization required three units of packed red cells. Blood pressure was controlled using multiple antihypertensive medications (80 mg furosemide, intravenous nicardipine and 5 mg beta blockers twice a day). At day 16 post-presentation, hemodialysis was started.
The patient recovered quickly from the thrombopenia and anemia. However, renal failure persisted and the patient required hemodialysis until he succumbed ~3 months subsequent to the diagnosis of TMA.
Discussion
TMA is a disorder characterized by microvascular occlusion due to platelet aggregation, thrombocytopenia and organ damage, such as renal failure (1). The main subtypes of TMA are HUS and thrombotic thrombocytopenic purpura (TTP). Thrombocytopenia, schistocytosis and elevated levels of LDH are enough to form a diagnosis in clinical practice. The majority of cases are idiopathic, but several etiologies have been recognized, among which are the use of cytotoxic chemotherapies, including mitomycin C, bleomycin, cisplatin and 5-fluorouracil (2). TMA may also be caused by the underlying malignancy itself (3,4). Indeed, TMA associated with metastatic adenocarcinomas, such as those of the stomach, colorectum, breasts, lungs and prostate, have been reported (5–7). It can be difficult to distinguish between HUS caused by the cancer itself and that caused by the chemotherapy. Certain studies have suggested that malignancy-associated HUS typically occurs during widespread metastatic disease, whereas the chemotherapy-associated type occurs more frequently when the patient is in disease remission. In the present study, the patient had minimal tumor burden.
The physiopathology of this disease remains unclear. Several mechanisms have been suggested, including an immune-mediated response or a direct toxic effect. Endothelial injury is the main event (8). HUS does not appear to be associated with a deficiency in ADAMTS13 activity; indeed, even if ADAMTS13 activity is absent or deficient in familial TTP, this condition it is not sufficient to cause the syndrome. Also, no specific correlation has been found between TMA and gender or age (9).
ADAMTS13 has been shown to be of major pathophysiological importance TMA in the setting of TTP when either lacking antibodies against ADAMTS13 (inherited TTP) or if antibodies against ADAMTS13 are present (acquired TTP). A severe deficiency of <5% ADAMTS-1 activity, with clinical symptoms of an acute thrombocytopenia and evidence of a microangiopathic hemolytic anemia, appropriately defines a diagnosis of TTP (10,11).
Gemcitabine is an important chemotherapeutic agent and its indications in oncology and hematology are wide. It is used in the therapy of pancreatic, ovarian, breast and bladder cancers, and NSCLC. Gemcitabine is associated with side effects that can lead to patient mortality (9).
First-line gemcitabine combined with cisplatin is indicated in patients with inoperable NSCLC (locally advanced or metastatic). In 1994, the first case of gemcitabine-associated TMA occurred during a phase II trial in pancreatic metastatic adenocarcinoma (12). To the best of our knowledge, there have been only 3 cases of gemcitabine-associated microangiopathy in patients treated for NSCLC to date (6).
The incidence of gemcitabine-attributed TMA is between 0.015 and 1.4% (13). However, the true incidence is difficult establish due to its underreported nature, the poor recognition of the condition or the failure to diagnose mild symptoms (14). A TMA diagnosis is more difficult in patients treated for cancer compared with otherwise healthy individuals, as certain symptoms may be adverse effects of chemotherapy agents. Clinically, TTP presents with hemolytic anemia, thrombocytopenia and renal insufficiency. Neurological symptoms and a fever are often present. However, anemia and thrombocytopenia are also common side-effects associated with chemotherapy due to myelotoxicity. Data on the incidence of TMA associated with gemcitabine use are conflicting. In 2004, in a study by Humphreys et al (15), the incidence of gemcitabine-associated TMA was shown to be 0.31%. This was in contrast with the estimated incidence of only 0.015% described by Fung et al in 1999 (16). In Boston, a review was performed between 1997 and 2002, and among 2,586 patients, 9 were identified with gemcitabine-associated TMA (15). New or exacerbated hypertension preceded the diagnosis of TMA by 0.5–10 weeks. The study concluded that this could represent an early clinical marker for the presence of a TMA syndrome (8). In the present study, the blood pressure of the patient remained high at 200/110 mmHg for several days.
The risk for gemcitabine-associated TMA appears to increase with a cumulative drug dose of >20,000 mg/m2 or administration for >18 cycles (14). The condition rarely occurs prior to 7 months of therapy. In the present case, the patient received only 10,750 mg/m2 (cumulative dose) of gemcitabine during 8 months. In the majority of reported cases, gemcitabine has been administered as a single-agent treatment, but in other cases, such as the present study, the condition has been reported during combination therapy (16). Screening for TMA has been proposed for after 10 cycles of gemcitabine. However, the development of TTP has been also reported after a single dose of gemcitabine (17).
A number of different treatments types have been previously suggested for patients with HUS (7,18). Glucocorticoids and plasma infusion may be used, but the interruption of chemotherapy and plasma exchange are the mainstays of treatment, and these therapies are quite effective. Management also involves the control of hypertension. Although these treatments are readily available, HUS remains a highly fatal disease.
The estimated mortality rate for HUS is 10–40% in the majority of case series (19,20), but has been reported to be as high as 60–70% in others (7,21,22).
Humphreys et al (15) recommend that for patients receiving gemcitabine for >3 months, the creatinine, schistocyte and haptoglobin levels should be checked monthly. Desramé et al (23) proposed that systematic screening should be performed for HUS during gemcitabine therapy. In this series, the frequency of HUS was 2.2%.
In conclusion, even if TMA is a rare adverse effect of cancer therapy, clinicians should be aware of it due to its potentially lethal evolution. Chemotherapy-induced TMA and that caused by the cancer itself are difficult to differentiate between, but the patient's clinical data can aid the clinician in making the right diagnosis. The precise and regular reporting of chemotherapeutic adverse events may assist in evaluating the frequency of TMA. Although no precise recommendation exists for the diagnosis and treatment of TMA, we suggest that chemotherapy should be halted and a glucocorticoid therapy or a plasma infusion should be introduced. Any worsening of anemia, thrombocytopenia or serum creatinine level with high blood pressure should lead to a prompt examination. |
||||
T wave oversensing in subcutaneous implantable cardioverter defibrillator secondary to hematoma formation: A potential cause of early postimplantation inappropriate shocks. | T wave oversensing (TWOS) is the most common cause of inappropriate shocks in subcutaneous cardioverter-defibrillators (S-ICD). We are presenting a patient with severe ischemic cardiomyopathy who received a S-ICD while on antiplatelets therapy. Pressure dressing was applied due to significant bleeding. On the first postoperative day, the device delivered 26 inappropriate shocks after removal of the pressure dressing. Interrogation revealed new TWOS, likely related to changes in the sensing vectors after hematoma formation. |
==== Front
J ArrhythmJ Arrhythm10.1002/(ISSN)1883-2148JOA3Journal of Arrhythmia1880-42761883-2148John Wiley and Sons Inc. Hoboken 10.1002/joa3.12132JOA312132Case ReportCase ReportsT wave oversensing in subcutaneous implantable cardioverter defibrillator secondary to hematoma formation: A potential cause of early postimplantation inappropriate shocks HALAWA and GAUTAMHalawa Ahmad MDhttp://orcid.org/0000-0001-5455-2378halawaa@health.missouri.edu
1
Gautam Sandeep MD, FHRS
1
1
Division of Cardiovascular Medicine
University of Missouri‐Columbia
Columbia
Missouri
* Correspondence
Ahmad Halawa, Division of Cardiovascular Medicine, University of Missouri‐Columbia, Columbia, MO.
Email: halawaa@health.missouri.edu
21 11 2018 2 2019 35 1 10.1002/joa3.2019.35.issue-1130 132 21 8 2018 24 9 2018 01 10 2018 © 2018 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract
T wave oversensing (TWOS) is the most common cause of inappropriate shocks in subcutaneous cardioverter‐defibrillators (S‐ICD). We are presenting a patient with severe ischemic cardiomyopathy who received a S‐ICD while on antiplatelets therapy. Pressure dressing was applied due to significant bleeding. On the first postoperative day, the device delivered 26 inappropriate shocks after removal of the pressure dressing. Interrogation revealed new TWOS, likely related to changes in the sensing vectors after hematoma formation.
inappropriate shockspocket hematomasubcutaneous implantable cardioverter defibrillator source-schema-version-number2.0component-idjoa312132cover-dateFebruary 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.5.8 mode:remove_FC converted:13.02.2019
Halawa
A
,
Gautam
S
. T wave oversensing in subcutaneous implantable cardioverter defibrillator secondary to hematoma formation: A potential cause of early postimplantation inappropriate shocks . J Arrhythmia . 2019 ;35 :130 –132 . 10.1002/joa3.12132
==== Body
1 INTRODUCTION
Subcutaneous cardioverter‐defibrillators (S‐ICD) have a growing role in primary and secondary prevention of sudden cardiac death.1 S‐ICD have many advantages over transvenous ICD (TV‐ICD) especially in young patients who do not require pacing, patients with difficult venous access or at high‐risk of systemic infection.1 However, S‐ICD and TV‐ICD share a major issue of inappropriate shocks (IAS). The rates of IAS in S‐ICD vary between 5% and 25%.2 In a recent study, the incidence of IAS with S‐ICD was approximately 8.1% at 1 year and 11.7% at 3 years follow‐up.3 We are reporting a unique case of S‐ICD inappropriate shock triggered by pocket hematoma in a patient on dual antiplatelets therapy (DAPT).
2 CASE REPORT
A 51‐year‐old female with severe ischemic cardiomyopathy, persistently depressed left ventricular ejection fraction (EF) of 30% following drug eluting stent (Promus Premier) placement in the right coronary artery and ramus intermedius, and end‐stage renal disease (ESRD) on maintenance hemodialysis, underwent S‐ICD placement for primary prevention of sudden cardiac death.
Patient also had multiple comorbidities including chronic obstructive pulmonary disease, chronic anemia, depression, hyperlipidemia, hypertension, diabetes mellitus, and below the knee amputation. Her medication list included dual antiplatelets therapy with Aspirin and Clopidogrel, in addition to optimal medical therapy for heart failure. Electrocardiogram showed nonspecific intraventricular conduction delay (QRS duration of 109 milliseconds).
Stents were placed about 3 months before the planned S‐ICD placement. Patient was considered as high‐risk for stent thrombosis so DAPT was not discontinued.
Preoperative manual screening showed adequate sensing in all three S‐ICD sensing vectors in supine and upright positions. Standard S‐ICD placement was performed using a dual incision technique, with appropriate sensing function and defibrillation threshold testing (Figure 1A). The primary sensing vector (distal electrode ring to can) was selected by the device for QRS sensing.
Figure 1 A, Proper R‐wave sensing at the day of S‐ICD implant. Sensing configuration is primary. B, TWOS on POD#1. Arrows indicate the over‐sensed T waves. Sensing configuration is primary. S‐ICD, subcutaneous implantable cardioverter defibrillator; TWOS, T wave over sensing; POD, postoperative day. C, Proper R wave sensing after changing the sensing configuration to secondary and applying SMART Pass
Patient had significant pocket bleeding during the procedure due to combination of dual antiplatelet therapy and renal failure, so we elected to apply a tight pressure dressing to prevent postoperative hematoma. She underwent hemodialysis the day of the procedure.
On the first postoperative day, the device delivered 26 inappropriate shocks right after removal of the pressure dressing. Device interrogation revealed smaller R wave amplitude compared to R wave after procedure, with new TWOS (T wave oversensing) leading to IAS, most likely related to a slight shift in the generator position (Figure 1B).
Follow‐up Chest‐X Ray showed proper position of the generator and both electrodes. (Figure 2).
Figure 2 Chest‐X Ray showing generator and both electrodes in position after implantation
TWOS resolved after switching the sensing vector to secondary and activating the SMART Pass filter (Figure 1C).
Patient was observed in the hospital for 1 day without any further sensing issues. She was discharged home in a stable condition without any IAS on outpatient follow up.
3 DISCUSSION
IAS is still a challenging problem in S‐ICD patients. T wave oversensing (TWOS) is the most common reason for inappropriate shocks suffered by S‐ICD patients.1 IAS can also result from supra‐ventricular tachycardia, atrial fibrillation or flutter.3
Soft tissue bleeding can happen during and after S‐ICD implantation and occasionally requires a pressure dressing, with unknown effect on the sensing vectors. Our patient suffered multiple IAS right after removal of the pressure dressing. We believe that release of the pressure dressing resulted in slight displacement of the generator, by the effect of small hematoma or soft tissue swelling under/above the device, which led to a significant change in the primary sensing vector and IAS. That will explain the small R waves on device interrogation after multiple IAS.
Hematoma after S‐ICD placement is a rare complication and it was reported in 0.9%‐5% of patients.3, 4 In a new study, out of 200 patients with S‐ICD, only 10 had hematoma that required surgical intervention. Three of these hematoma patients suffered IAS/TWOS.4
In our patient, DAPT and platelets dysfunction due to end‐stage renal disease both contributed to difficulty in achieving hemostasis. Applying pressure dressing to control hematoma formation is a known technique in TV‐ICD placement, but is unusual in S‐ICD.
We believe that our report is a unique presentation and pocket hematoma has never been reported as the cause of multiple IAS in S‐ICD patients.
To resolve this problem, we changed the sensing vector and applied SMART Pass filter. SMART Pass is an additional high pass filter that reduces the amplitude of lower frequency signals such as T waves, without altering higher frequency signals like R‐waves and ventricular arrhythmias. It is an additional safety mechanism in S‐ICDs to avoid TWOS, by activating a 9‐Hz high‐pass filter designed to prevent oversensing of relatively high‐amplitude T or P waves.5
Conclusion: To the best of our knowledge, this is the first case report of multiple inappropriate S‐ICD shocks due to delayed TWOS related to postoperative hematoma. To avoid this complication, we recommend programming the SMART pass filter on initial device programming, and to obtain device interrogation after removal of pressure dressing to reveal any changes in the sensing vectors.
CONFLICT OF INTEREST
Authors declare no conflict of interests for this article.
==== Refs
REFERENCES
1
Priori
SG
,
Blomström‐Lundqvist
C
,
Mazzanti
A
, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death . Eur Heart J [Internet]. 2015 ;36 :2793 –867 .26320108
2
Aziz
S
,
Leon
AR
,
El‐Chami
MF
. The subcutaneous defibrillator: a review of the literature . J Am Coll Cardiol [Internet] Elsevier. 2014 ;63 :1473 –9 .24530663
3
Boersma
L
,
Barr
C
,
Knops
R
, et al. Implant and midterm outcomes of the subcutaneous implantable cardioverter‐defibrillator registry: the EFFORTLESS study . J Am Coll Cardiol . 2017 ;70 :830 –41 .28797351
4
Sheldon
SH
,
Cunnane
R
,
Lavu
M
, et al. Perioperative hematoma with subcutaneous ICD implantation: impact of anticoagulation and antiplatelet therapies . Pacing Clin Electrophysiol . 2018 ;41 :799 –806 . 10.1111/pace.13349
5
Theuns
DAMJ
,
Brouwer
TF
,
Jones
PW
, et al. A prospective, blinded evaluation of a novel sensing methodology designed to reduce inappropriate shocks by the subcutaneous implantable defibrillator . Heart Rhythm . 2018 ;15 :1515 –22 .29758404
| Device dislocation, Device inappropriate shock delivery, Electrocardiogram T wave abnormal, Haematoma, Haemorrhage, Implant site haematoma, Implant site haemorrhage, Labelled drug-drug interaction medication error, Oversensing, Post procedural haematoma, Procedural haemorrhage, Soft tissue haemorrhage | [
"Device inappropriate shock delivery, Post procedural haematoma, Soft tissue haemorrhage",
"Device inappropriate shock delivery, Post procedural haematoma, Soft tissue haemorrhage",
"Device dislocation, Device inappropriate shock delivery, Implant site haematoma, Implant site haemorrhage, Labelled drug-drug interaction medication error",
"Device inappropriate shock delivery, Electrocardiogram T wave abnormal, Haematoma, Haemorrhage, Oversensing",
"Procedural haemorrhage"
] | 30805053 | CC BY-NC | t wave oversensing in subcutaneous implantable cardioverter defibrillator secondary to hematoma formation a potential cause of early postimplantation inappropriate shocks | 35(1) | 130-132 | Journal of arrhythmia | Halawa|Ahmad|A|0000-0001-5455-2378;Gautam|Sandeep|S| | 2019-02 | 10.1002/joa3.12132 | Division of Cardiovascular Medicine University of Missouri-Columbia Columbia Missouri.;Division of Cardiovascular Medicine University of Missouri-Columbia Columbia Missouri. | J Arrhythm | 101263026 | 1880-4276 | Japan | D002363:Case Reports | inappropriate shocks; pocket hematoma; subcutaneous implantable cardioverter defibrillator | 24530663;26320108;28797351;29659027;29758404 | false | [
17589107,
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] | TITLE:
T wave oversensing in subcutaneous implantable cardioverter defibrillator secondary to hematoma formation: A potential cause of early postimplantation inappropriate shocks.
ABSTRACT:
T wave oversensing (TWOS) is the most common cause of inappropriate shocks in subcutaneous cardioverter-defibrillators (S-ICD). We are presenting a patient with severe ischemic cardiomyopathy who received a S-ICD while on antiplatelets therapy. Pressure dressing was applied due to significant bleeding. On the first postoperative day, the device delivered 26 inappropriate shocks after removal of the pressure dressing. Interrogation revealed new TWOS, likely related to changes in the sensing vectors after hematoma formation.
TEXT:
1 INTRODUCTION
Subcutaneous cardioverter‐defibrillators (S‐ICD) have a growing role in primary and secondary prevention of sudden cardiac death.1 S‐ICD have many advantages over transvenous ICD (TV‐ICD) especially in young patients who do not require pacing, patients with difficult venous access or at high‐risk of systemic infection.1 However, S‐ICD and TV‐ICD share a major issue of inappropriate shocks (IAS). The rates of IAS in S‐ICD vary between 5% and 25%.2 In a recent study, the incidence of IAS with S‐ICD was approximately 8.1% at 1 year and 11.7% at 3 years follow‐up.3 We are reporting a unique case of S‐ICD inappropriate shock triggered by pocket hematoma in a patient on dual antiplatelets therapy (DAPT).
2 CASE REPORT
A 51‐year‐old female with severe ischemic cardiomyopathy, persistently depressed left ventricular ejection fraction (EF) of 30% following drug eluting stent (Promus Premier) placement in the right coronary artery and ramus intermedius, and end‐stage renal disease (ESRD) on maintenance hemodialysis, underwent S‐ICD placement for primary prevention of sudden cardiac death.
Patient also had multiple comorbidities including chronic obstructive pulmonary disease, chronic anemia, depression, hyperlipidemia, hypertension, diabetes mellitus, and below the knee amputation. Her medication list included dual antiplatelets therapy with Aspirin and Clopidogrel, in addition to optimal medical therapy for heart failure. Electrocardiogram showed nonspecific intraventricular conduction delay (QRS duration of 109 milliseconds).
Stents were placed about 3 months before the planned S‐ICD placement. Patient was considered as high‐risk for stent thrombosis so DAPT was not discontinued.
Preoperative manual screening showed adequate sensing in all three S‐ICD sensing vectors in supine and upright positions. Standard S‐ICD placement was performed using a dual incision technique, with appropriate sensing function and defibrillation threshold testing (Figure 1A). The primary sensing vector (distal electrode ring to can) was selected by the device for QRS sensing.
Figure 1 A, Proper R‐wave sensing at the day of S‐ICD implant. Sensing configuration is primary. B, TWOS on POD#1. Arrows indicate the over‐sensed T waves. Sensing configuration is primary. S‐ICD, subcutaneous implantable cardioverter defibrillator; TWOS, T wave over sensing; POD, postoperative day. C, Proper R wave sensing after changing the sensing configuration to secondary and applying SMART Pass
Patient had significant pocket bleeding during the procedure due to combination of dual antiplatelet therapy and renal failure, so we elected to apply a tight pressure dressing to prevent postoperative hematoma. She underwent hemodialysis the day of the procedure.
On the first postoperative day, the device delivered 26 inappropriate shocks right after removal of the pressure dressing. Device interrogation revealed smaller R wave amplitude compared to R wave after procedure, with new TWOS (T wave oversensing) leading to IAS, most likely related to a slight shift in the generator position (Figure 1B).
Follow‐up Chest‐X Ray showed proper position of the generator and both electrodes. (Figure 2).
Figure 2 Chest‐X Ray showing generator and both electrodes in position after implantation
TWOS resolved after switching the sensing vector to secondary and activating the SMART Pass filter (Figure 1C).
Patient was observed in the hospital for 1 day without any further sensing issues. She was discharged home in a stable condition without any IAS on outpatient follow up.
3 DISCUSSION
IAS is still a challenging problem in S‐ICD patients. T wave oversensing (TWOS) is the most common reason for inappropriate shocks suffered by S‐ICD patients.1 IAS can also result from supra‐ventricular tachycardia, atrial fibrillation or flutter.3
Soft tissue bleeding can happen during and after S‐ICD implantation and occasionally requires a pressure dressing, with unknown effect on the sensing vectors. Our patient suffered multiple IAS right after removal of the pressure dressing. We believe that release of the pressure dressing resulted in slight displacement of the generator, by the effect of small hematoma or soft tissue swelling under/above the device, which led to a significant change in the primary sensing vector and IAS. That will explain the small R waves on device interrogation after multiple IAS.
Hematoma after S‐ICD placement is a rare complication and it was reported in 0.9%‐5% of patients.3, 4 In a new study, out of 200 patients with S‐ICD, only 10 had hematoma that required surgical intervention. Three of these hematoma patients suffered IAS/TWOS.4
In our patient, DAPT and platelets dysfunction due to end‐stage renal disease both contributed to difficulty in achieving hemostasis. Applying pressure dressing to control hematoma formation is a known technique in TV‐ICD placement, but is unusual in S‐ICD.
We believe that our report is a unique presentation and pocket hematoma has never been reported as the cause of multiple IAS in S‐ICD patients.
To resolve this problem, we changed the sensing vector and applied SMART Pass filter. SMART Pass is an additional high pass filter that reduces the amplitude of lower frequency signals such as T waves, without altering higher frequency signals like R‐waves and ventricular arrhythmias. It is an additional safety mechanism in S‐ICDs to avoid TWOS, by activating a 9‐Hz high‐pass filter designed to prevent oversensing of relatively high‐amplitude T or P waves.5
Conclusion: To the best of our knowledge, this is the first case report of multiple inappropriate S‐ICD shocks due to delayed TWOS related to postoperative hematoma. To avoid this complication, we recommend programming the SMART pass filter on initial device programming, and to obtain device interrogation after removal of pressure dressing to reveal any changes in the sensing vectors.
CONFLICT OF INTEREST
Authors declare no conflict of interests for this article. |
||||
"Hormone signaling via androgen receptor affects breast cancer and prostate cancer in a male patient(...TRUNCATED) | "BACKGROUND\nMale breast cancer (MBC) is rare, accounting for only around 1% of all breast cancers. (...TRUNCATED) | "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 521610.1186/s12885-018-5(...TRUNCATED) | Deep vein thrombosis | [
"Deep vein thrombosis"
] | 30577860 | CC BY | "hormone signaling via androgen receptor affects breast cancer and prostate cancer in a male patient(...TRUNCATED) | 18(1) | 1282 | BMC cancer | "Takuwa|Haruko|H|http://orcid.org/0000-0002-2897-8700;Tsuji|Wakako|W|;Shintaku|Masayuki|M|;Yotsumoto(...TRUNCATED) | 2018-12-22 | 10.1186/s12885-018-5216-6 | "Department of Breast Surgery, Shiga General Hospital, 5-4-30, Moriyama, Moriyama-City, Shiga, 524-8(...TRUNCATED) | BMC Cancer | 100967800 | 1471-2407 | England | "D000368:Aged; D019313:BRCA1 Protein; D018567:Breast Neoplasms, Male; D015972:Gene Expression Regula(...TRUNCATED) | D002363:Case Reports; D016428:Journal Article | "C410798:AR protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D011944:Receptors, (...TRUNCATED) | Androgen receptor; BRCA mutation; estrogen receptor; male breast cancer; prostate cancer | "10845281;11504305;11967536;14966099;15616218;16079314;16333030;18478326;19147544;19198621;19638585;(...TRUNCATED) | false | [
15884616
] | "TITLE:\nHormone signaling via androgen receptor affects breast cancer and prostate cancer in a male(...TRUNCATED) |
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"Reccurent thrombus in the gigantic left atrium during effective anticoagulant therapy: case report.(...TRUNCATED) | "Gigantic left atrium is defined in the current literature as an excessive dilatation of the left at(...TRUNCATED) | "\n==== Front\nBMC Cardiovasc Disord\nBMC Cardiovasc Disord\nBMC Cardiovascular Disorders\n1471-2261(...TRUNCATED) | "Atrial thrombosis, Chordae tendinae rupture, Dyspnoea exertional, Epistaxis, Left atrial enlargemen(...TRUNCATED) | ["Atrial thrombosis, Chordae tendinae rupture, Dyspnoea exertional, Epistaxis, Left atrial enlargeme(...TRUNCATED) | 32085730 | CC BY | reccurent thrombus in the gigantic left atrium during effective anticoagulant therapy case report | 20(1) | 86 | BMC cardiovascular disorders | "Masarova|Lucia|L|;Novak|Jan|J|0000-0001-5204-2067;Pesl|Martin|M|;Ondrasek|Jiri|J|;Semenka|Jiri|J|;S(...TRUNCATED) | 2020-02-21 | 10.1186/s12872-019-01279-1 | "First Department of Cardioangiology, St. Anne's University Hospital and Faculty of Medicine, Masary(...TRUNCATED) | BMC Cardiovasc Disord | 100968539 | 1471-2261 | England | "D000368:Aged; D000077144:Clopidogrel; D004359:Drug Therapy, Combination; D065427:Factor Xa Inhibito(...TRUNCATED) | D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't | "D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D000069552:Rivaroxaban; D000(...TRUNCATED) | "Anticoagulant therapy; Atrial fibrillation; Cardiac magnetic resonance; Echocardiography; Gigantic (...TRUNCATED) | "27614756;14734332;27826350;11888821;29374292;26729298;2144217;4254395;22767653;24725815;6237112;114(...TRUNCATED) | false | [
17548196,
17811329,
17691880
] | "TITLE:\nReccurent thrombus in the gigantic left atrium during effective anticoagulant therapy: case(...TRUNCATED) |
||
"Report of periprocedural oral anticoagulants in catheter ablation for atrial fibrillation: The Japa(...TRUNCATED) | "BACKGROUND\nTo obtain a perspective of the current status of catheter ablation for the cure of atri(...TRUNCATED) | "\n==== Front\nJ ArrhythmJ ArrhythmJournal of Arrhythmia1880-42761883-2148Elsevier S1880-4276(16)301(...TRUNCATED) | Ischaemic stroke | [
"Ischaemic stroke"
] | 28607611 | CC BY-NC-ND | "report of periprocedural oral anticoagulants in catheter ablation for atrial fibrillation the japan(...TRUNCATED) | 33(3) | 172-176 | Journal of arrhythmia | "Murakawa|Yuji|Y|;Nogami|Akihiko|A|;Shoda|Morio|M|;Inoue|Koichi|K|;Naito|Shigeto|S|;Kumagai|Koichiro(...TRUNCATED) | 2017-06 | 10.1016/j.joa.2016.10.002 | "Fourth Department of Internal Medicine, Teikyo University, School of Medicine, 3-8-3 Mizonokuchi, T(...TRUNCATED) | J Arrhythm | 101263026 | 1880-4276 | Japan | D016428:Journal Article | Atrial fibrillation; Catheter ablation; Direct oral anticoagulant; Warfarin | "27425183;24662400;25828523;17998456;26336520;23993352;19106199;20516376;26464027;22785434;25131666;(...TRUNCATED) | false | [
13727718
] | "TITLE:\nReport of periprocedural oral anticoagulants in catheter ablation for atrial fibrillation: (...TRUNCATED) |
||||
"Resonance metallic ureteric stent in a case of ketamine bladder induced bilateral ureteric obstruct(...TRUNCATED) | "BACKGROUND\nUpper urinary tract occlusion is well recognized in patients with chronic ketamine abus(...TRUNCATED) | "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports22(...TRUNCATED) | Acute kidney injury, Cystitis ulcerative, Drug abuse, Pyonephrosis, Sepsis, Ureteric obstruction | [
"Acute kidney injury, Cystitis ulcerative, Drug abuse, Pyonephrosis, Sepsis, Ureteric obstruction"
] | 25625490 | CC BY-NC-ND | "resonance metallic ureteric stent in a case of ketamine bladder induced bilateral ureteric obstruct(...TRUNCATED) | 8C() | 49-51 | International journal of surgery case reports | Yong|Guo Liang|GL|;Kong|Chia Yew|CY|;Ooi|Michelle Wei Xin|MW|;Lee|Eng Geap|EG| | 2015 | "University of Aberdeen,56C, Ashgrove Road, AB25 3AD Aberdeen, Scotland, UK. Electronic address: gl2(...TRUNCATED) | Int J Surg Case Rep | 101529872 | 2210-2612 | Netherlands | D016428:Journal Article | Ketamine induced uropathy; Management; Resonance stent | 24443558;18680495;23485505;20797465;7490898;22011000;9186322;17482909;9883213 | false | [
10947629
] | "TITLE:\nResonance metallic ureteric stent in a case of ketamine bladder induced bilateral ureteric (...TRUNCATED) |
|||||
"A Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Primary Sc(...TRUNCATED) | "Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and childre(...TRUNCATED) | "\n==== Front\nHepatol CommunHepatol Commun10.1002/(ISSN)2471-254XHEP4Hepatology Communications2471-(...TRUNCATED) | Cholangitis sclerosing, Hepatic enzyme increased, Inflammatory bowel disease, Off label use | ["Hepatic enzyme increased, Inflammatory bowel disease, Off label use","Cholangitis sclerosing, Hepa(...TRUNCATED) | 31701072 | CC BY-NC-ND | "a prospective trial of withdrawal and reinstitution of ursodeoxycholic acid in pediatric primary sc(...TRUNCATED) | 3(11) | 1482-1495 | Hepatology communications | "Black|Dennis D|DD|;Mack|Cara|C|;Kerkar|Nanda|N|;Miloh|Tamir|T|;Sundaram|Shikha S|SS|;Anand|Ravinder(...TRUNCATED) | 2019-11 | 10.1002/hep4.1421 | "Pediatrics University of Tennessee Health Science Center Memphis TN.;Pediatrics University of Color(...TRUNCATED) | Hepatol Commun | 101695860 | 2471-254X | United States | D016428:Journal Article | "27087822;30199272;28390159;11230733;10102223;28161472;20101749;24752961;22140074;18607270;10941964;(...TRUNCATED) | false | [
16818528,
16829950,
16812753
] | "TITLE:\nA Prospective Trial of Withdrawal and Reinstitution of Ursodeoxycholic Acid in Pediatric Pr(...TRUNCATED) |
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