3.5.2 Clinical Outcomes
Viral reactivation was shown to be significantly associated with higher
risk of outcomes of mortality in 1 year (OR, 3.9; 95% CI, 1.2-12.2;
p=0.02), dialysis initiation (OR, 3.4; 95% CI, 1.1-10.9; p=0.04),
increased length of hospital stay (IRR, 2.2; 95% CI, 1.4-3.3;
p<0.01), and recurrent flares in 1 year among DRESS patients
(OR, 3.1; 95% CI, 1.2-8.2; p=0.02) (Table 4). On sub-analysis with
respect to individual viruses, the association with mortality, ICU stay,
need for dialysis and length of stay (LOS) was significantly associated
with CMV reactivation. Similarly, when there were 2 or more viral
reactivations detected, the risk of inpatient mortality (OR, 5.8; 95%
CI, 1.7-20.7; p<0.01) as well as 1 year mortality was
significantly higher. (OR, 10.0, 95% CI, 2.9-34.9; p<0.01).
3.6 Impact of Anti-viral treatment in patients with viral
reactivation.
To explore the role of antiviral treatment in DRESS, a preliminary
comparative analysis was performed. Among the 39 patients with
reactivation, 13 received anti-viral therapy: 11 had serological
positive viral PCR, whereas 2 others had additional evidence of
pathology-proven clinical disease (CMV pneumonitis, CMV hepatitis).
Antivirals included ganciclovir (n=7,54%), acyclovir (n=5, 38%) and
valganciclovir (n=1,8%). Treatment decisions were made by the primary
physicians. There were no significant differences in outcomes
(Mortality, ICU, need for dialysis, LOS) between both groups
4. Discussion
This current study examines the impact of viral reactivation in a large
cohort of patients with DRESS syndrome. There were a few unique
observations. Firstly, herpes viral reactivation is a common but
non-universal phenomenon, occurring in 42% of patients. Secondly, viral
reactivation may not be detected at the onset of the rash (Figure 1) and
28% of patients with reactivation were detected on serial testing.
Thirdly, there were no baseline clinical, causative drug or treatment
factors that predicted reactivation. Lastly, our study suggests the
association of viral reactivation with a certain clinical phenotype –
such patients were more likely to have renal involvement as well as
poorer outcomes, namely recurrent flares, need for dialysis, length of
stay and death.
Identification of predictors of severe, life-threatening DRESS remains a
research gap. In a series of 15 patients with ICU stay and
death19, HHV6 reactivation was present in 6/7 tested
(No other herpes viruses were tested). Similarly, CMV reactivation has
been anecdotally reported with severe outcomes. Our current study
further clarifies this association. HHV6 in itself was not associated
with ICU stay or death. However, when it is associated with multiple
viral reactivation and / or CMV reactivation, poorer prognosis exists.
There were other significant negative findings that are of note.
Firstly, there were no baseline factors which predicted viral
reactivation. This proved that reactivation occurred independent of
systemic steroid treatment, type of culprit drug or baseline factors.
Nevertheless, valproic acid has been reported to increase replications
of HHV6,20 and
CMV.21 Secondly, in our
exploratory analysis of antiviral treatment in a small cohort of
viral-reactivated DRESS cases, there does not appear to be significant
difference in outcomes. This warrants further evaluation in a systematic
and controlled protocol.
The pathophysiology of DRESS and the role that herpes viruses play
remains poorly defined. Although viral reactivation is associated with
poorer outcomes, the cause versus effect conundrum remains unresolved. A
few possibilities exist: 1) Viral reactivation exist as a bystander
effect due to immunodysregulation – not dissimilar to an immune
reconstitution phenomenon in graft versus host disease or in critically
ill/immunosuppressed subjects. 2) Viral reactivation results in the
initiation of the drug allergy. 3) Direct reactivation of viruses from
drug / drug metabolites. 4) A combination of the above – with a primary
drug-specific immune response as the initiating event, then viral
reactivation in certain individuals with an associated secondary
anti-viral/self-response. The lack of universal reactivation in all
DRESS patients and reactivation occurring after the onset of DRESS
symptoms argues against it being the initial trigger or a necessity for
DRESS to occur. Furthermore, in-vitro and in-vivo evidence such as the
identification of drug-specific T cells in Allopurinol SCARs and
positivity on patch testing to the culprit drug in DRESS patients
supports the argument for a primary drug-mediated
response.11
There were various limitations in our study. These included the
retrospective design with its inherent flaws. Although viral studies
were performed in the acute phase of the disease, the timing of these
studies depended on various factors including time to hospital admission
and/or dermatological referral. This may have impacted on the proportion
of reactivation as well as the latency between onset of symptoms and
viral reactivation. This was partially ameliorated by repeated sampling
which was performed in 24% of our patients. In our cohort of 93
patients, 28% had HHV6 reactivation and these results are comparable to
other validated DRESS cohorts utilizing quantitative PCR viral studies.
In those cohorts, HHV6 reactivation varies between
39%-45%.13,
24 Moreover, the latency between
symptoms and reactivation in our cohort is similar to published
series.13,
23 Although we showed univariate
analysis for each outcome e.g. mortality, dialysis etc, these results
may be limited by the small sample size. A multivariable model for any
outcome was not possible due to the small sample and missing values. Our
analysis on anti-viral treatment, though novel, is not conclusive due to
the non-controlled nature, small cohort and risk of treatment bias.
Nevertheless, these preliminary data warrants further evaluation.
There were certain strengths in this study. This was a large cohort of
DRESS patients that was validated against standardized criteria.
Dermatological care was provided by the same clinical team within the
same care setting. This would reduce the bias introduced by care
variability and the “centre” effect.
In conclusion, our study suggests that herpes viral reactivation, when
present identifies patients at risk of poorer outcomes. Our work is
unable to prove a causal or pathogenic association and further work is
needed to understand the role of virus reactivation in DRESS disease
mechanism, identify patients at risk of reactivation as well as
potential impact of anti-viral treatment.