Herpes simplex virus hepatitis: An analysis of the published literature and institutional cases

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DOI: 10.1002/lt.21250 · Source: PubMed
Abstract
Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.
ORIGINAL ARTICLE
Herpes Simplex Virus Hepatitis: An Analysis of
the Published Literature and Institutional Cases
John P. Norvell,
1
Andres T. Blei,
1
Borko D. Jovanovic,
2
and Josh Levitsky
1
1
Department of Internal Medicine, Division of Hepatology, Northwestern University Feinberg School of
Medicine, Chicago, IL;
2
Department of Preventive Medicine, Northwestern University Feinberg School of
Medicine, Chicago, IL
Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation
(LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an
analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were
identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash
was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected
clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-
treated patients as compared to 88% in the untreated subjects (P 0.03). Variables on presentation associated with death or
need for LT compared to spontaneous survival: male gender, age 40 yr, immunocompromised state, ALT 5,000 U/L,
platelet count 75 10
3
/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has
a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with
significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the
frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for
patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded. Liver Transpl 13:
1428-1434, 2007.
© 2007 AASLD.
Received March 11, 2007; accepted May 24, 2007.
First described in adults in 1969,
1
herpes simplex
virus (HSV) hepatitis is an uncommon complication of
HSV infection often leading to acute liver failure (ALF).
2
It is thought to represent less than 1% of all ALF cases
and less than 2% of all viral causes of ALF.
3
The most
commonly affected individuals are immunosuppressed
patients and females in the third trimester of preg-
nancy, although HSV hepatitis can occur in immuno-
competent patients. HSV hepatitis is characterized by
fulminant hepatic necrosis with serum aminotransfer-
ase levels 100 to 1,000-fold above normal. The diagno-
sis is frequently made at postmortem examination due
to the nonspecific clinical presentation and lack of
awareness. In one series, the diagnosis of HSV hepatitis
was considered antemortem in only 33% of pregnant
patients and 26% of nonpregnant patients.
4
Not all
patients with HSV hepatitis have mucocutaneous le-
sions that provide clinical clues to the diagnosis.
2,5
Despite the high morbidity and mortality, HSV hepa-
titis is a potentially treatable disorder if recognized and
treated expeditiously. A high degree of suspicion, even
in the absence of skin lesions, combined with early
diagnostic modalities (serology, polymerase chain reac-
tion, liver biopsy) may dramatically improve survival.
Treatment with parenteral acyclovir may reverse the
disease process if instituted early.
5
Prognostic markers
on presentation and during the course of disease would
be of great use to clinicians in determining the likeli-
hood of clinical progression, need for liver transplanta-
tion (LT), or spontaneous recovery.
6
Given previous
data and knowledge on HSV hepatitis has originated
from multiple case reports, this article represents a
Abbreviations: HSV, herpes simplex virus; ALF, acute liver failure; LT, liver transplantation; OR, odds ratio; CI, confidence interval;.
Address reprint requests to Josh Levitsky, M.D., Assistant Professor of Medicine, Northwestern University Feinberg School of Medicine,
Department of Medicine, Division of Hepatology, 675 N. St. Clair St. Suite 15-250, Chicago, IL 60611. Telephone: 312-695-4413; FAX:
312-695-5998; E-mail: j-levitsky@northwestern.edu
DOI 10.1002/lt.21250
Published online in Wiley InterScience (www.interscience.wiley.com).
LIVER TRANSPLANTATION 13:1428-1434, 2007
© 2007 American Association for the Study of Liver Diseases.
comprehensive analysis of all the documented adult
cases of HSV hepatitis from our center and in the liter-
ature to determine patient characteristics and prognos-
tic factors associated with important outcomes.
EXPERIMENTAL PROCEDURES
A retrospective review of our institution’s electronic
chart and pathology databases (established in 1995)
revealed 5 previously unreported cases of HSV hepati-
tis. A comprehensive search of the National Library of
Medicine PubMed database (1969-2006) revealed 89
publications involving 132 additional case reports of
HSV hepatitis. The following National Library of Medi-
cine MEDLINE subject heading (MeSH) terms were
matched to search for cases in PubMed: “herpes sim-
plex virus,” “hepatitis virus,” “hepatitis,” “acute hepatic
failure,” and “fulminant liver failure.” The criteria for
inclusion of cases were patients aged 18 yr or older,
evidence of hepatocellular injury, and histological evi-
dence of HSV hepatitis. If no liver histology was ob-
tained by biopsy or autopsy, the case was included only
if the article provided evidence of HSV hepatitis by all of
the following 3 clinical criteria: 1) serology or biopsy of
nonhepatic tissue consistent with active HSV infection;
2) peak aminotransferase 500 U/L; and 3) no other
attributable cause of ALF. A total of 6 articles with case
reports were excluded due to insufficient evidence of
HSV hepatitis. This study was approved by the North-
western University Institutional Review Board.
Of the included cases, univariate logistic regression
was performed to determine which of the following vari-
ables on presentation were associated with either sur-
vival or death/LT: age, gender, immunosuppression,
liver/renal function, coagulopathy, hepatic encepha-
lopathy, and subsequent antiviral therapy. Multivariate
analysis was performed, but due to missing values in
the data from the retrospective collection of literature
cases, the joint estimators of risk were judged to be not
reliable. A univariate analysis was also performed to
determine differences in clinical characteristics among
acyclovir treated and untreated patients. Chi-squared
and Mann-Whitney 2-sample rank sum tests were used
in this analysis for categorical and continuous vari-
ables, respectively. All P values are 2-sided and were
considered significant if less than 0.05. Statistical anal-
ysis was performed using the Intercooled STATA system
for Windows, version 9.2 (StataCorpLP, College Station,
TX)
RESULTS
Clinical Presentation (Northwestern and
PubMed Cases)
Table 1 displays the clinical presentation and outcome
of previously unreported cases presenting at our hos-
pital with HSV hepatitis. Table 2 shows the combined
clinical characteristics, when reported, of all patients in
the literature and our hospital presenting with HSV
hepatitis.
1,2,4-95
Of note, 24% were considered immu
-
nocompetent. The remaining patients were either preg-
nant (23%) or immunocompromised from a previous
solid organ or hematopoietic cell transplantation (30%)
or immunosuppressive agent (23%). Of the immuno-
compromised patients from prior transplantation, the
average time of disease onset after transplantation was
205 days (526). 98% of the patients had fever. Her-
petic rash was detected in only 44% of patients, of
which 61% were mucocutaneous and 39% were dis-
seminated. The majority developed coagulopathy
(96.5%), encephalopathy (80%), and acute renal failure
(65.3%).
Diagnosis
Table 3 demonstrates the method of diagnosis for the
137 cases. The majority was first diagnosed after death
on autopsy (57.6%); 31.4% were diagnosed by liver bi-
opsy. Of the patients first diagnosed by autopsy, only 8
TABLE 1. Characteristics of Northwestern HSV Hepatitis Cases
Age (yr),
gender Predisposing factors
ALT/AST
(U/L) INR
TB
(mg/dL) Rash Treatment
Diagnosis
method Outcome
1: 44, female None 6,000 7.1 24.4 Disseminated ACV 11 days
prior to LKT
Liver biopsy,
explant
Died
2: 31, male PNH, stem cell
transplant on
steroids
13,955 2.5 2.5 None ACV 6 days Liver biopsy,
autopsy
Died
3: 29, female UC, steroids after
colectomy
2,097 3 8.1 None ACV ? duration Liver biopsy Survived
4: 59, female Multiple myeloma,
chemotherapy
4,531 3.5 7.7 None None Autopsy Died
5: 43, male CML, bone marrow
transplant
3,349 1.8 34.5 None GCV 5 days Liver biopsy Died
Abbreviations: ACV, acyclovir; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CML, chronic myelogenous
leukemia; GCV, ganciclovir; INR, international normalized ratio; LKT, liver-kidney transplantation; PNH, paroxysmal
nocturnal hemoglobinuria; TB, total bilirubin; UC, ulcerative colitis.
HERPES SIMPLEX VIRUS HEPATITIS 1429
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
were suspected clinically prior to death. A total of 11
patients (8%) included in this series never had HSV
hepatitis confirmed by liver biopsy or autopsy but met
our 3 clinical criteria.
6,29,34,37,49,54,60,65,70,76,80
Only
31 (22.6%) of the 137 cases were first suspected clini-
cally by the patient’s history and presentation. Of these
cases, the diagnosis was confirmed by autopsy in 8,
liver biopsy in 10, and explanted liver in 2.
Treatment and Outcomes
A total of 49 (36.6%) of 134 patients were given paren-
teral acyclovir. It was unclear whether acyclovir was
administered or not in 3 patients. As a result, they were
removed from the analysis. Table 4 displays the com-
parison of clinical characteristics and outcome (when
reported) of acyclovir-treated and untreated patients.
Other than age being lower in treated patients, no other
variables on clinical presentation were different be-
tween the groups. For outcomes, the percentage of
treated patients progressing to death or LT was signif-
icantly lower (51%) compared to untreated patients
(88.1%) (P 0.001). Of the 34 cases with sufficient
clinical information, the mean time from overt symp-
toms of HSV hepatitis to treatment with acyclovir was
4.2 days (standard deviation 1.8). A significantly
longer time from symptom onset to treatment initiation
(mean 4.7 .48 vs. 3.5 .27 days) was seen in patients
who died or required LT compared to those who sur-
vived (P 0.03).
A total of 7 patients underwent orthotopic LT for ful-
minant liver failure with 3 ultimately surviving. The
causes of death in the 4 patients are the following:
hemothorax (29 days after LT),
92
acute respiratory dis
-
tress syndrome (11 days after LT),
92
unknown (365
days after LT, Northwestern patient #1, no autopsy),
and recurrent HSV and multiorgan failure despite con-
tinuous parenteral acyclovir (42 days after LT).
93
The 3
remaining patients survived long-term (mean reported
follow-up 989 days, standard deviation 1,448
days). Two patients developed HSV rash within 2 weeks
of discontinuing acyclovir but neither developed dis-
seminated HSV (Northwestern patient #1).
95
Both re
-
sponded to intravenous acyclovir. Two patients devel-
TABLE 2. Demographics and Clinical Presentation of
HSV Hepatitis
Number (%)
Mean age (yr) 34 15
Gender
Male 51/137 (38)
Female 82/137 (62)
Immune status
Immunocompetent 33/137 (24)
Immunosuppressed, total 73/137 (53)
Immunosuppressed, transplant 41/137 (30)
Immunosuppressed, nontransplant 32/137 (23)
Pregnant 32/137 (23)
Fever 98/100 (98)
Herpetic lesions (initial or during
hospitalization)
None 69/123 (56)
Mucocutaneous 33/123 (27)
Disseminated 21/123 (17)
Mean peak ALT or AST (U/L) 4927 4099
Mean peak total bilirubin (mg/dL) 6.0 8.1
Leukopenia 50/70 (71.4)
Thrombocytopenia 59/63 (93.6)
Coagulopathy 93/111(83.7)
Acute renal failure 34/52 (65.3)
Hepatic encephalopathy 57/71 (80)
HSV serotype
Type I 36/93 (38.7)
Type II 57/93 (61.3)
Abbreviations: ALT, alanine aminotransferase; AST,
aspartate aminotransferase.
TABLE 3. Diagnosis and Outcomes of HSV Hepatitis
Number (%)
Method of initial diagnosis
Autopsy 79/137 (57.6)
Liver biopsy 43/137 (31.4)
Explanted liver 4/137 (2.9)
Clinical criteria 11/137 (8.0)
Clinical suspicion on initial
presentation 31/137 (22.6)
Confirmed by liver biopsy 10/137 (7.3)
Confirmed by explanted liver 2/137 (1.5)
Confirmed by autopsy 8/137 (5.8)
Confirmed by clinical criteria 11/137 (8.0)
Acyclovir treatment 49/134 (36.6)
Reason for acyclovir treatment
Clinical suspicion 23/49 (46.9)
Serological confirmation 4/49 (8.2)
Liver biopsy confirmation 22/49 (44.9)
Death
Overall 99/133 (74.4)
Liver transplant 4/7 (57.1)
TABLE 4. Acyclovir-Treated and Untreated Group
Comparison
Acyclovir No acyclovir
Mean age (yr)* 32.9 11.3 40 18.1
Male gender (%) 15/49 (30.1) 35/84 (41.6)
Coagulopathy (%) 35/44 (79.5) 57/66 (86.4)
Immunocompromised (%) 25/49 (51) 45/84 (53.6)
Encephalopathy (%) 21/25 (84) 36/46 (78.3)
Rash (%) 19/44 (43.2) 35/78 (44.8)
Mean ALT or AST (U/L) 4398 3668 5263 4375
Mean bilirubin (mg/dL) 7.8 10.8 3.7 4.1
Mean platelet (10
3
/L)
68 62 5239
Death/LT
(%)
25/49 (51) 74/84 (88.1)
Abbreviations: ALT, alanine aminotransferase; AST,
aspartate aminotransferase.
*P 0.03.
P 0.001.
1430 NORVELL ET AL.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
oped acute cellular rejection within 2 weeks of LT,
68,95
1 required retransplantation
68
and both survived.
Death/Liver Transplantation vs. Survival
Analysis
On univariate logistic regression, the following vari-
ables were statistically associated with death or need
for LT compared to spontaneous recovery: age 40 yr
old (odds ratio [OR], 2.9; 95% confidence interval [CI],
1.2-7.5), male gender (OR, 6.9; 95% CI, 2.3-21.1), co-
agulopathy (OR, 21.5; 95% CI, 6.1-75.7), any immuno-
compromised state (OR, 2.3; 95% CI, 1.4-5.0), enceph-
alopathy (OR, 11.0; 95% CI, 2.9-41.5), ALT 5,000 U/L
(OR, 9.3; 95% CI, 2.6-33.6), platelet count 75,000 U
(OR, 15.5; 95% CI, 3.6-67.3), and acyclovir treatment
(OR, 0.14; 95% CI, 0.06-0.33).
DISCUSSION
We performed a retrospective analysis on the presenta-
tion and outcomes of all cases of HSV hepatitis reported
in the literature and at our institution. Common fea-
tures on presentation included fever, high amin-
otransferases, leukopenia, thrombocytopenia, en-
cephalopathy, coagulopathy, and acute renal failure.
On regression analysis, older age, male gender, immu-
nocompromised state, the degree of aminotransferase
elevation, and the presence of coagulopathy and en-
cephalopathy were significantly associated with pro-
gression of disease to death or need for LT. These clin-
ical predictors should highlight the need for early
treatment and immediate LT evaluation to increase sur-
vival.
Interestingly, almost 25% of the patients were con-
sidered immunocompetent prior to the onset of HSV
hepatitis. While multiple mechanisms of disseminated
infection have been proposed in immunocompromised
hosts, it remains unclear why a significant proportion is
seemingly immunocompetent. Theories include a high
inoculation of HSV viremia at initial infection that over-
comes immunological defenses, occult defects in T lym-
phocytes and/or macrophages processing HSV anti-
gen, reinfection by a second strain increasing HSV
virulence, or specific hepatovirulent strains of HSV.
55
This review highlights the challenge in diagnosing
HSV hepatitis. The characteristic rash occurred in less
than half of the cases. Most were not diagnosed until
after death and only 23% were clinically suspected to
have HSV hepatitis prior to histological confirmation.
Given the absence of clinical clues and need for rapid
diagnosis, HSV should be universally screened for
when a patient presents with acute hepatitis or liver
failure, particularly with fever on presentation. A pelvic
examination should be performed as many women have
vaginal and cervical involvement in the absence of more
obvious vulvar involvement.
96
Results of Tzanck smear
or direct fluorescent antibody staining can be available
quickly and guide management.
89
Serologic testing is
limited due to a high rate of false-positive and false-
negative tests. Recent attention has focused on quan-
titative HSV deoxyribonucleic acid by polymerase chain
reaction as a diagnostic modality, although this is only
performed in reference laboratories and the results may
not be available for real-time decision making pro-
cesses. Without a rapid polymerase chain reaction
available, liver biopsy should be considered early in the
course of hepatitis. It is the gold standard test but is
also underutilized, being performed in less than one-
third of patients in our study. The use of recombinant
factor VII, while expensive, may provide reversal of co-
agulopathy in ALF and safely allow such invasive pro-
cedures.
97,98
Despite a high mortality, HSV hepatitis is one of the
few treatable causes of ALF, reemphasizing the need for
early diagnosis. Our results show a significantly lower
rate of progression to death or LT in acyclovir-treated
patients compared to untreated. Other than being
somewhat younger, treated patients were similar to un-
treated patients in clinical characteristics and severity
of liver failure on presentation, suggesting that acyclo-
vir treatment was the major independent factor leading
to increased survival. In addition, an early diagnosis
with a shorter time delay from symptom onset to initi-
ation of treatment was significantly associated with
survival. It is clear that patients need to be diagnosed
and treated early to have an impact on recovery and
survival.
For progressive liver failure, LT may be a viable option
in the setting of pre- and posttransplantation acyclovir
therapy. Three of 7 patients survived long-term without
recurrent HSV hepatitis or dissemination. Of the 4 who
died post-LT, only 1 had recurrent HSV as a potential
contributor to death.
93
That being said, the high mor
-
bidity and mortality after LT is not insignificant. Life-
long antiviral therapy after LT is likely required to pre-
vent recurrences, as 2 of the patients had recurrent
rash within 2 weeks of acyclovir discontinuation. Point
mutations in the viral thymidine kinase, however, may
result in failure to clear viral replication, resulting in
acyclovir resistance. It is speculated that the relatively
high frequency of acyclovir resistant herpes viruses in
immunocompromised patients may be due to an im-
paired T-cell response.
93
There are limitations of this study. The retrospective
design is limited by the accuracy and completeness of
the data reported in the literature and from our hospital
records. Some of the data regarding the aspects of clin-
ical presentation and treatment were not presented in
the case series. This may have affected the ability to
determine other important variables associated with
progressive disease and perform a multivariate analy-
sis. In addition, only severe cases of herpes hepatitis
are likely to have been reported in the literature, leading
to selection bias. It is possible that cases of clinically
less severe HSV hepatitis have occurred and were not
reported, although all of the cases at our institution
presented with severe liver failure. Nevertheless, it is
likely that the included literature and institutional
cases represent the typical clinical spectrum. Finally,
this series includes 11 patients who met our clinical
inclusion criteria for HSV hepatitis without liver histol-
HERPES SIMPLEX VIRUS HEPATITIS 1431
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
ogy confirmation. While no other etiologies were identi-
fied and the presentations were highly suggestive of
HSV hepatitis, it is possible that another etiology was
responsible for ALF.
Given our findings, specific guidelines for the diagno-
sis and treatment of HSV hepatitis are recommended. It
is imperative that HSV is considered in the differential
diagnosis of a patient presenting with ALF, particularly
when fever is present. The absence of a vesicular rash
should not lower the physician’s index of suspicion for
HSV. Virological testing, such as quantitative HSV
deoxyribonucleic acid, should be sent immediately to
a laboratory providing a quick return of results. A
transjugular liver biopsy should be considered after
correction of coagulation disturbances. Based on the
low risk-benefit ratio and frequently-delayed diagnosis,
our data supports the practice of empiric treatment
with parenteral acyclovir for all patients presenting
with ALF of unknown etiology, until an alternative di-
agnosis is made or HSV is excluded. For those with risk
factors for progression on initial presentation, e.g.,
male gender, advanced age, immunosuppression, and
significant biochemical liver dysfunction, an urgent LT
evaluation should be considered early to maximize sur-
vival. While outcomes are not ideal, LT can be per-
formed successfully in select patients.
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LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
    • "L'aciclovir permet un taux de survie de l'ordre de 75 à 100 %. Le retard thérapeutique est le principal facteur de mortalité maternelle qui peut atteindre 80 % [65] . L'interruption de la grossesse est parfois envisagée et réalisée par césarienne compte tenu du risque de contamination herpétique du nouveau-né lors du passage de la filière génitale. "
    Article · Jun 2016 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
    • "Previous studies of HSV hepatitis cases reported that on clinical examination, most of HSV hepatitis presented with fever, severely elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), elevated bilirubin, leukopenia, coagulopathy, acute renal failure, and hepatic encephalopathy. In addition, the majority of patients (56%) did not have skin herpetic lesions [11,12] . Our patient was seronegative for HSV in preoperative period with specific kinetic of apparition of IgM and IgG antibodies (Fig. 2) that confirm herpes primary infection [13]. "
    [Show abstract] [Hide abstract] ABSTRACT: Herpes simplex Virus (HSV) hepatitis is a rare complication of HSV-1 primary infection, with a delayed diagnosis, affecting mainly immunocompromised patients. We describe a case of HSV-1 hepatitis after primary infection occurring in the postoperative days after a pancreas-kidney transplantation. The patient presented with an unusual evolution of a persistent severe hepatitis associated with a persistent viremia (Quantitative Polymerase Chain Reaction) despite an adequate intravenous (iv) antiviral treatment. Abdominal computed tomography scan showed a miliary hepatitis. The diagnosis of HSV-1 hepatitis was confirmed by immuno-chemistry on liver biopsy. The donor was negative for anti-HSV antibodies, excluding contamination by the graft. This case report emphasizes a rather seldom risk of care-associated viral infections, predominantly in immunocompromised patients.
    Full-text · Article · Apr 2016
    • "HSV hepatitis is rare and accounts for only 1% of all acute liver failure cases and only 2% of all viral causes of acute liver failure [4][5][6] . Several risk factors are associated with the development of HSV hepatitis, including burns, cancer, pregnancy, or immune-modulation drugs: the similarity in each of these conditions is that the host immune defenses are compromised [7]. "
    Full-text · Article · Jan 2016
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