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Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis

BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b5106 (Published 08 December 2009) Cite this as: BMJ 2009;339:b5106

Rapid Response:

Toxic epidermal necrolysis associated with an influenza-like illness and oseltamivir phosphate

Dear Editor,

In December 2009, an 18-year-old girl, with a past medical history of

occasional migraines and a low body mass index (BMI), experienced new
onset symptoms of headache, sore throat, coryzal symptoms, myalgia and
fever. Within 24 hours of the onset, she had telephoned her GP practice.
The
practice advised she contact the National Pandemic Flu Service who made a
presumptive diagnosis of Swine-Origin Influenza A (H1N1) 2009 infection.
She was prescribed oral oseltamivir (Tamiflu®) 75mg twice daily for five
days.

After 24 hours and three doses of oseltamivir she noticed a rash over her
abdomen. Her mother then contacted the GP who visited the patient and
noted a widespread maculopapular rash over the trunk and upper limbs,
associated tachycardia, pyrexia (temperature 39.4°C), significant cervical

lymphadenopathy, bilateral conjunctivitis and pharyngitis. He prescribed
oral
penicillin V because of a concern about scarlet fever and advised the
patient to
stop oseltamivir. The next day the GP reviewed the patient noting blisters
and
erosions, particularly in the mouth and lips and referred the patient to
the
local dermatology team.

On examination at the department of dermatology she was alert and
orientated but noted to have an extensive macular rash on the trunk and
limbs with lesions forming a confluent sheet of erythema on the abdomen.
Scattered targetoid lesions were present over the periphery of the trunk
and
proximal limbs. There were initially small discrete areas of blistering on
the
face and lower abdomen (Figure 1). Crusted erosions were visible on the
lips
and there was conjunctival suffusion. The rash was subjectively described
as
itchy but not painful. She was pyrexial (temperature 39.5 °C) and
tachycardic
but normotensive, normoxyaemic with a normal respiratory examination. Her
initial blood tests showed a thrombocytopenia, elevated serum C-reactive
protein, mildly deranged electrolytes and liver function and normal renal
function (Table 1). Blood film showed toxic granulation. She was admitted
to
hospital, a skin biopsy was taken from the thigh and nasal and pharyngeal
swabs were sent to HPA Southampton laboratory for H1N1 PCR. Initial
treatment of the skin lesions consisted of emollients and non-adherent,
soft
silicone dressings. Topical chloramphenicol, prednisolone and lubricants
were
applied to the eyes. Regular paracetamol, cyclizine and intravenous fluids

were administered. She remained stable initially but deteriorated rapidly
overnight with significant breathing difficulties, hypotension and
hypoxaemia
due to worsening toxic epidermal necrolysis (TEN; SCORTEN score 1,
mortality 3.2%[1]). She was transferred to ITU where she required
inotropic
support and invasive ventilation. Intravenous immunoglobulin (IV Ig) was
administered for TEN and intravenous co-amoxiclav was started for a
suspected lower respiratory tract infection. She was noted to be
pancytopenic
and treated with lenograstim (GCSF). Intravenous vitamins B and C
(Pabrinex®) were added because of concern over malnutrition (BMI 16 kg/m2
at presentation). By the third hospital day approximately half the body
surface area was denuded of epithelium. On the fourth day the patient was

transferred to the Burns Unit at the Chelsea and Westminster Hospital,
London, where her treatment is continuing. At bronchoscopy there was
evidence of mucosal erythema and necrosis extending into right and left
segments. Follow up bronchoscopy at day 6 revealed early reepithelisation
of
the mucosa. She was treated according to the local protocol: IV Ig, GCSF
and
cyclosporine.[2] The initial biopsy of the skin showed evidence of
interface
dermatitis with an erythema multiforme like picture in keeping with the
spectrum of TEN and a second biopsy taken in London was diagnostic of TEN.

Human immunodeficiency virus serology was negative. The swabs taken for
Swine-Origin Influenza A (H1N1) 2009 were negative.

Severe skin reactions (including Stevens-Johnson syndrome and toxic
epidermal necrolysis) following oseltamivir are listed as undesirable
effects in
the Summary of Product Characteristics.[3] There has been much recent
concern about the safety profile of neuraminidase inhibitors in adults and

children with influenza.[4,5] Between 1st April and 24th November 2009,
966
adverse reactions to oseltamivir were reported to the Medicines and
Healthcare Products Regulatory Agency (MHRA) of which 329 (34%) involved
the skin or subcutaneous tissues. Of the 10 fatalities reported, none were

related to the skin. Two cases of TEN have been reported to the UK’s MHRA
but neither appear in the literature.[6]

As of 3rd December 2009, the UK’s Health Protection Agency estimates
that
the cumulative total number of cases of Swine-Origin Influenza A (H1N1)
2009 is 790,000 since the pandemic began with 22,000 new cases in England
in the last week.[7] The estimated case fatality rate is 26 (range 11–66)
per
100,000.[8] Between 23rd July and 17th November 2009, 941,890 courses of
oseltamivir have been collected via the National Pandemic Flu Service in
England.[6] It is unclear whether the trial data for oseltamivir can be
generalised to a pandemic scenario; however, Jefferson and colleagues
found
evidence of benefit for oseltamivir if taken within 48 hours of the onset
of
symptoms in shortening the duration of influenza-like illness. Data on the

effectiveness of oseltamivir against complications of influenza remains
controversial and a paucity of good data has undermined previous findings
for oseltamivir’s effectiveness.[5]

Toxic epidermal necrolysis can present with a prodromal influenza-
like
illness similar to that experienced by our patient prior to the first dose
of
oseltamivir. Although infection or other agents have been reported to
trigger
TEN, there is a consensus amongst dermatologists that idiosyncratic drug
reactions account for the majority of cases. Our patient and her mother
told
us that she had not taken any medications other than oseltamivir before
the
onset of her rash. Therefore we have significant concern that this
represents
the first case of TEN following oseltamivir, administered empirically for
an
influenza-like illness by the UK’s National Pandemic Flu Service. Defining
the
aetiology of serious adverse events may be difficult; information about
the
patient's setting, symptoms, and timing of the event is often
insufficiently
precise, missing or absent.[9] Nevertheless, the risks and benefits of
oseltamivir remain uncertain.[4] Therefore life-threatening adverse
events,
however rare, must be carefully considered when the distribution of
oseltamivir is planned for future pandemics.

Tom Parks (1,2) academic foundation year 1 doctor
(thomas.parks@medsci.ox.ac.uk)

Iaisha Ali (1) specialist registrar in dermatology
(iaisha.ali@orh.nhs.uk)

Kamal R. Mahtani (1,3) specialist trainee in general practice and
academic
clinical fellow (kamal.mahtani@dphpc.ox.ac.uk)

Hanif Esmail (4) specialty registrar in infectious diseases
(hanifesmail@gmail.com)

Arani Chandrakumar (5) specialist registrar in dermatology
(arani.chandrakumar@chelwest.nhs.uk)

Suveer Singh (6) consultant intensivist (suveer.singh@imperial.ac.uk)

Jorge Leon-Villapalos (7) consultant plastic surgeon (jorge.leon-
villapalos@chelwest.nhs.uk)

Ruth Asher (8) consultant dermatopathologist (ruth.asher@orh.nhs.uk)

Chris Bunker (5) consultant dermatologist
(christopher.bunker@chelwest.nhs.uk)

Carl Heneghan (3) clinical lecturer (carl.heneghan@dphpc.ox.ac.uk)

Vanessa Venning (1)* consultant dermatologist
(vanessa.venning@orh.nhs.uk)

(1) Department of Dermatology, Churchill Hospital, Old Road,
Headington,
Oxford OX3 7JL

(2) Oxford University Clinical Academic Graduate School, Medical
Sciences
Division, Level 3, John Radcliffe Hospital, Oxford OX3 9DU

(3) Department of Primary Health Care, University of Oxford, Rosemary
Rue
Building, Old Road Campus, Headington, Oxford OX3 7LF

(4) Department of Microbiology and Infectious Diseases, Level 7, John

Radcliffe Hospital, Oxford OX3 9DU

(5) Department of Dermatology, Chelsea and Westminister Hospital, 369

Fulham Road, London SW10 9NH

(6) Department of Anaesthesia and Intensive Care, Chelsea and
Westminster
Hospital, 369 Fulham Road, London SW10 9NH

(7) Department of Plastic Surgery, Chelsea and Westminster Hospital,
369
Fulham Road, London SW10 9NH

(8) Department of Cellular Pathology, Level 1, John Radcliffe
Hospital, Oxford
OX3 9DU

*Correspondence to: Dr Vanessa Venning (vanessa.venning@orh.nhs.uk)

Author contribution: TP and KRM conceived the idea of rapid
submission as a
case report. TP wrote the first draft which was edited by KRM, VV and CH.
TP,
IA, HE, AC, SS, JLV, RA, CB and VV were responsible for the clinical care
of the
patient. Funding: No external funding was sought prior to submission of
this
article.

Competing interests: All authors have completed the Unified Competing

Interest form at www.icmje.org/coi_disclosure.pdf (available on request
from
the corresponding author) (URL) and declare that all authors had: (1) No
financial support for the submitted work from anyone other than their
employer; (2) No financial relationships with commercial entities that
might
have an interest in the submitted work; (3) No spouses, partners, or
children
with relationships with commercial entities that might have an interest in
the
submitted work; (4) No Non-financial interests that may be relevant to the

submitted workPatient consent: A signed consent form has been received
from the patient and submitted to The BMJ.

Licensing agreement: The Corresponding Author has the right to grant
on
behalf of all authors and does grant on behalf of all authors, an
exclusive
licence (or non exclusive for government employees) on a worldwide basis
to
the BMJ Publishing Group Ltd and its licensees, to permit this article (if

accepted) to be published in BMJ editions and any other BMJPG products and

to exploit all subsidiary rights, as set out in our licence
(http://bmj.bmjjournals.com/advice/copyright.shtml)

1. Bastuji-Garin S FN, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein
P.
SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J
Invest
Dermatol. 2000;115:149-153.

2. de Sica-Chapman A, Williams G, Soni N, Bunker CB. Granulocyte
colony-
stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea &
Westminster TEN protocol. Br J Dermatol. 2009 Nov 11. [Epub ahead of
print]

3. Roche. Tamiflu 75mg hard capsule – Summary of Product
Characteristics.
Available from: http://emc.medicines.org.uk/ Accessed on: 9th December

4. Godlee F CM. Why don’t we have all the evidence on oseltamivir?
BMJ.
2009;339:b5351.

5. Jefferson T JM, Doshi P, Del Mar C. Neuraminidase inhibitors for
preventing and treating influenza in healthy adults: systematic review and

meta- analysis. BMJ. 2009;339:b5106.

6. Medicines and Healthcare Products Regulatory Agency. UK Suspected
Adverse Drug Reaction (ADR) Analysis: Influenza antivirals - oseltamivir
(Tamiflu) and zanamivir (Relenza): 3rd December 2009. London: Medicines
and Healthcare Products Regulatory Agency; 2009

7. Health Protection Agency. Weekly pandemic flu media update 3
December 2009. London: Health Protection Agency; 2009

8. Donaldson LJ, Rutter PD, Ellis BM, Greaves FEC, Mytton OT, Pebody
RG et
al. Mortality from pandemic A/H1N1 2009 influenza in England: public
health
surveillance study. BMJ 2009;339:b5213

9. Jefferson T JM, Doshi P, Del Mar C. Possible harms of
oseltamivir—a call
for urgent action. Lancet. 2009;374:1312-1313.

Acknowledgements

The authors would like to thank Dr George Moncrieff, the patient’s
GP, and
the Department of Plastic Surgery, Department of Anaesthesia and Intensive

Care and the Burns Unit at the Chelsea and Westminster Hospital, London,
for
their help in reporting the case and their care of the patient. Thanks
also go
to Dr Chris Conlon, Infectious Diseases, Churchill Hospital, Oxford, and
Dr
Duncan Young, Intensive Care Unit, Churchill Hospital, Oxford who cared
for
the patient while she was at the Churchill Hospital.

Figure 1. The patient’s face soon after admission
See: Oseltamivir Figure 1.jpg

  Table 1. Blood results on admission
Sodium 135 mmol/L
Potassium 3.4 mmol/L
Urea 5.2 mmol/L
CRP 135 mg/L
Creatinine 54 mmol/L
Bilirubin 25 mmol/L
ALT 58 IU/L
ALP 79 IU/L
Albumin 30 g/L
Adj. Calcium 2.25 mmol/L
Phosphate 0.48 mmol/L
Magnesium 0.71 mmol/L
Haemoglobin 13.5 g/dL
WCC 6.55 x 109/L
Platelets 74 x 109/L
Neutrophils 1.77 x 109/L
Lymphocytes 0.46 x 109/L
Band forms 3.93 x 109/L
Metamyelocytes 0.39 x 109/L

Competing interests:
None declared

Editorial note: Patient consent obtained.

Competing interests: Table 1. Blood results on admissionSodium 135 mmol/LPotassium 3.4 mmol/LUrea 5.2 mmol/LCRP 135 mg/LCreatinine 54 mmol/LBilirubin 25 mmol/LALT 58 IU/LALP 79 IU/LAlbumin 30 g/LAdj. Calcium 2.25 mmol/LPhosphate 0.48 mmol/LMagnesium 0.71 mmol/LHaemoglobin 13.5 g/dLWCC 6.55 x 109/LPlatelets 74 x 109/LNeutrophils 1.77 x 109/LLymphocytes 0.46 x 109/LBand forms 3.93 x 109/LMetamyelocytes 0.39 x 109/L

18 December 2009
Tom Parks
academic foundation year 1 doctor
Iaisha Ali, Kamal R. Mahtani, Hanif Esmail, Arani Chandrakumar, Suveer Singh, Jorge Leon-Villapalos, Ruth Asher, Chris Bunker, Carl Heneghan, Vanessa Venning
Department of Dermatology, Churchill Hospital, Old Road, Headington, Oxford OX3 7JL, UK