Download Reactivation of cytomegalovirus in a patient with Stevens

Case Study
Reactivation of cytomegalovirus in a
patient with Stevens-Johnson syndrome/
toxic epidermal necrolysis
Mohamed Tagajdid,a Hicham El Annaz,a Bouchra Belefequih,a Yahia Mekki,b Taoufik Doblali,a Saâd Mrania
Laboratory of Virology, Mohamed V Military Teaching Hospital, Rabat, Morocco; Mohamed V Souissi University, Morocco
b
Hospices Civils de Lyon, National Influenza Centre, Medical Virology Department, Lyon, France
a
Correspondence to: Mohamed Tagajdid, e-mail: [email protected]
Keywords: cytomegalovirus, Stevens-Johnson syndrome, toxic epidermal necrolysis, pneumonia
Abstract
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions to drugs. We describe
a 19-year-old patient with SJS/TEN overlap syndrome who had been treated with antiepileptic drugs and subsequently developed
severe interstitial pneumonia. A cytomegalovirus (CMV) infection was diagnosed by real-time PCR detection during bronchoalveolar
lavage. If our observations are based on biological data, temporal relationship and clinical features, it is possible to infer that the
reactivation of CMV with viral replication can predispose a person to SJS/TEN. In the light of the current literature, the probable
association that links drug-induced SJS/TEN to the fulminant reactivation of CMV is discussed.
S Afr Pharm J 2012;79(10):43-44
Peer reviewed. (Submitted: 2011-07-18. Accepted: 2012-10-29.)
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN) are variants of acute, rapidly progressive mucocutaneous
reactions which differ only in the amount of body surface area
(BSA) that is affected. SJS is the less severe condition, in which
skin sloughing is limited to less than 10% of the BSA. With TEN,
there is sloughing of more than 30% of the BSA. In the case of
SJS/TEN overlap syndrome, patients have been described to have
greater than 10%, but less than 30%, affected BSA.1 SJS/TEN is a
life-threatening condition, where extensive detachment of the
skin is characterised by full-thickness necrosis of the epidermis.
Most cases of SJS/TEN are drug induced. In patients who have
not taken drugs, SJS/TEN is induced by chemicals, Mycoplasma
pneumoniae, immunisation and viral infections. 2,3 We describe
a patient with SJS/TEN overlap syndrome who had been treated
with antiepileptic drugs and who developed severe interstitial
pneumonia caused by cytomegalovirus (CMV) in parallel.
Case history
A 19-year-old Moroccan woman, with no history of a drug or
food allergy, followed-up for a month for epilepsy, was treated with phenobarbital (100 mg/day) and valproate (1 000 mg/day)
and was admitted for erythroderma. She had a fever of 39.8°C and
dyspnoea.
On admission, the patient reported having experienced chills,
a cough and rhinorrhoea two days earlier. A rash developed
on her face days after starting epilepsy treatment and rapidly
progressed to her trunk, limbs, neck and chest over the next four
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43
days. Subsequently, the facial rash evolved into pustules. She had
multiple erosions on the mouth and vulva and her conjunctiva
was inflamed. Nikolsky’s sign was positive. The total extent of the
erythematous rash was 55% BSA. Histological investigation of the
damaged skin revealed evidence of a drug eruption (extensive
epidermal necrosis, focal subepidermal necrotic blisters, melanin
incontinence and moderate perivascular lymphocytic infiltrate in
the absence of eosinophils, neutrophils and viral inclusions). Direct
immune fluorescence staining was performed [immunoglobulin
M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA)] and
complement component 3. No immunoglobulin or complement
deposition in the epidermis or the epidermal-dermal zone was
detected. The diagnosis of SJS/TEN, caused by antiepileptic drugs,
was made.
Laboratory testing revealed anaemia, eosinophilia, increased
inflammatory markers and a white blood cell count of 10x109/µl. A
chest X-ray showed multifocal patch consolidations with groundglass opacity in both lungs. No bacterial pathogen was isolated
in the respiratory tract, urine and blood. Viral serology (human
immunodeficiency virus and hepatitis B and C) was negative. Realtime PCT detection (R-gene® kits) during bronchoalveolar lavage
(BAL) revealed and confirmed (by cell culture of the MRC-5 cells)
that the cause of the respiratory symptom was CMV. Prior serology
data showed that this patient had had a primary CMV infection at
the age of six years, which could explain the current reactivation.
Real-time PCR in the blood showed fulminant viraemia with
459 copies/ml (a threshold of 350).
The antiepileptic drugs were withdrawn and anticoagulant
therapy, parenteral analgesia, eye drops and antiseptic mouth
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Case Study
drugs. This causes the deposition of toxic and immunogenic
metabolites on the epidermis.3
therapy were initiated. Ganciclovir intravenously (10 mg/kg/
day) was started. Oxygen therapy was initiated with parenteral
nutrition and adequate hydration. Six days after starting antiviral
therapy, the patient’s serial BAL assays were negative. Skin lesions
began to heal without the introduction of corticosteroids. The
patient had improved and was transferred to the general ward.
She was prescribed ganciclovir for a further two weeks.
The hypothesis is whether or not TEN is linked to fulminant CMV
infection, and also whether or not CMV triggers an interaction
between cytotoxic T lymphocytes, natural killer cells and
keratinocytes. Further observational studies are warranted.
Conclusion
Discussion
This case illustrates that possible CMV interstitial pneumonia,
secondary to CMV reactivation, may possibly predispose a patient
to SJS/TEN. Furthermore, flu-like symptoms that manifest prior
to the appearance of a rash may be prodromal symptoms which
could then progress to SJS/TEN. This might be indicative of a
CMV reactivation, and consequently, CMV-related pneumonia.
Pneumonia that is associated with SJS/TEN may be secondary
to alveolar sloughing, therefore not all pneumonia that occurs
in parallel with SJS/TEN is indicative of CMV reactivation. The
implications for clinical practice are that SJS/TEN is an adverse
condition that is caused by drugs and that patients at risk of
developing SJS/TEN could be identified by measuring their CMV
loads during the first few days after onset, even if the CMV IgM and
IgG levels are negative.
SJS and TEN are severe adverse cutaneous drug reactions that
predominantly involve the skin and mucous membranes.4,5 The
diagnosis relies on clinical symptoms and histological features.1
Treatment with corticosteroids is recommended, but is not
necessarily effective.5-7 Several drugs can induce SJS/TEN,1 and
M. pneumoniae and herpesvirus infections are believed to be
associated with these conditions. The aetiology is unknown in
many SJS/TEN cases.8
This case demonstrates a possible link between CMV replication
and SJS or TEN. The patient developed SJS/TEN in parallel with
pneumonia caused by CMV reactivation six days after initiation
of an antiepileptic drug. There have been rare cases in which
viral reactivation was accompanied by flu-like symptoms. It is
possible that the duration of reactivation was the six days before
the patient’s admission. The temporal relationship and the
clinical features strongly suggest that CMV with viral replication
predisposes to SJS/TEN.
Conflict of interest
We declare that we have no financial or personal relationships
which may have inappropriately influenced us in writing this
paper.
Without a full understanding of the underlying mechanisms
that were involved, it is difficult to establish a direct causal link
between CMV and drug hypersensitivity. However, a relationship
between viral infections and the simultaneous or subsequent
development of drug rashes has been observed in a number
of clinical situations. The full cascade of events that lead from
viral infections to the development of a drug allergy in humans
remains poorly understood. An ampicillin rash during infectious
mononucleosis, and an increased risk of developing drug rashes in
acquired immune deficiency syndrome, are well-known examples
of such a relationship.3 The herpesvirus family is the most likely
to significantly influence immune responses. This is because
herpesviruses can induce and maintain a potent memory T-cell
response. This property arises from their ubiquitous prevalence in
human populations and the capacity to grow in lymphoid cells.8
Specific viral infections had been shown to increase CD95 (Fas) or
Fas-ligand expression and increased sensitivity to Fas/Fas liganddependent apoptosis.3 Treatment strategies for SJS and TEN, when
these conditions are associated with CMV, include treatment with
ganciclovir, avoidance of possible offending drugs and abstention
from systemic steroids. The possible mechanism is the interaction
of CMV with some of the enzymes that detoxify the offending
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