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BMJ Case Rep. 2010; 2010: bcr11.2009.2439.
Published online Apr 9, 2010. doi:  10.1136/bcr.11.2009.2439
PMCID: PMC3047523
Unexpected outcome (positive or negative) including adverse drug reactions
The national pandemic flu service, oseltamivir, and a case of pancreatitis
Richard Newton,1 Dominic King,2 Henry Lee,2 Mike Anderson,3 and John Lynn4
1Imperial College, Institute of Biomedical Engineering, South Kensington Campus, London W2 1NY, UK
2Imperial College, Department of Biosurgery and Surgical Technology, St Mary’s Hospital, Praed Street, London W2 1NY, UK
3Chelsea and Westminster Hospital, Gastrointestinal Unit, Fulham Road, London SW10 9NH, UK
4BUPA Cromwell Hospital, Cromwell Road, London SW5 0TU, UK
Correspondence to Richard Newton, r.newton/at/imperial.ac.uk
The recent outbreak of the influenza virus H1N1 continues to pose a serious public health threat at a population wide level. In response to this, the UK National Health Service has made antiviral medication available to the general public in a unique way. Individuals can receive treatment without having to consult a medical practitioner, by simply answering a set of questions online or over the telephone. We present the case of a 65-year-old woman who developed a case of acute pancreatitis shortly after taking oseltamivir. Extensive investigation revealed that she had no risk factors or other identifiable cause for developing pancreatitis, and the possible adverse drug reaction has been reported to the Medicines and Healthcare Products Regulatory Agency. Concerns regarding the strategy to provide antiviral medication to the population using this novel approach are discussed in light of patient safety and implications for health policy.
Beginning in March 2009 North America experienced an outbreak of a new strain of influenza A virus, designated influenza H1N1 2009, which represents a reassortment of swine, avian and human influenza viruses.1 On 11 June 2009, the World Health Organization (WHO) signalled that a global pandemic of novel influenza A/H1N1 (swine flu) was underway by raising the worldwide pandemic alert level to phase 6,2 the highest level.
In the UK, cases of influenza A/H1N1 have spread from hotspots where it first started to affect at times nearly every local community. The Department of Health reported on the 23 July 2009 that there had been approximately 100 000 new cases of H1N1 reported in the preceding week in England.3 While the majority of cases had been mild, there had been 840 hospitalisations and an estimated 26 deaths in England at this stage of the pandemic.4 Since then the case incidence has generally decreased with 9000 new cases per week estimated on the Health Protection Agency report of the 17 December 2009, with 203 swine flu related deaths since the pandemic started.4
The death toll of this, as any, pandemic depends not only on the virulence of the virus in question but also on the rapidity with which we are able to introduce effective preventative and therapeutic measures.5 During the current pandemic of swine influenza, neuraminidase inhibitors such as oseltamivir phosphate (Tamiflu) and zanamivir (Relenza) have been extensively used. In studies, oseltamivir has been found to be effective at reducing the duration and severity of illness6,7 and providing prophylaxis for close contacts of influenza infected persons against illness.8 In adults, the most commonly reported adverse drug reactions (ADRs) are moderate nausea and vomiting9; however, recent reports suggest there may be more serious ADRs associated with the use of oseltamivir,10 including hepatitis, gastrointestinal bleeding and neuropsychiatric side effects.1113
On 23 July 2009 the National Health Service (NHS) launched the National Pandemic Flu Service in order to deal with the increasing number of H1N1 cases in the UK. The service (through the telephone or internet) assesses the patient’s symptoms and, if required, provides an authorisation number which can be used to pick up antivirals from a local antiviral collection point.14 To receive antivirals, individuals do not need to see or speak to a doctor or other health professional and do not require a prescription. Medical leaders and charities have already given a warning that diagnosing all cases of flu remotely could lead to other serious infections and conditions being missed, or the ‘worried well’ applying for and receiving medication inappropriately.15
We present a case of acute pancreatitis that was diagnosed in a previously well patient who had received oseltamivir through the National Pandemic Flue Service. The patient was found to be negative for H1N1 on subsequent polymerase chain reaction (PCR). We discuss some of the issues surrounding current policies regarding the prevention and treatment of H1N1 in the UK.
A 65-year-old retired Caucasian female nurse developed a headache and arthralgia. She had previously been completely fit and well, took no medications, and had not been in recent close contact with anyone displaying symptoms of influenza. Concerned that her symptoms may have been related to the onset of H1N1 she visited the National Pandemic Flu website where she filled in the ‘Flu assessment’. She was asked to confirm if she had a high temperature and at least two of the following symptoms: widespread muscle and joint aches, a cough, headache, blocked or runny nose, sore throat, vomiting, or watery diarrhoea. After, confirming her symptoms the website recommended that she receive a course of antivirals (fig 1). Her husband subsequently picked up oseltamivir from their local antiviral collection point.
Figure 1
Figure 1
Online authorisation screenshot for antiviral treatment.
Two hours following her first dose of oral oseltamivir (75 mg) she developed abdominal pain. She remained at home, but after taking a further dose of oseltamivir the following day she attended hospital as her abdominal pain had become more severe. A consultant general surgeon examined her and recommended she be admitted to hospital for further investigations for an acute abdomen.
Laboratory investigations found an elevated serum amylase of 1906 IU and a diagnosis of acute pancreatitis was made. An ultrasound scan showed a normal gallbladder and biliary tree with no gallstones, and a computed tomography scan of her abdomen showed increased peri-pancreatic attenuation that was in keeping with an inflammatory process involving her pancreas. No other abnormalities were noted on imaging.
Additional investigations showed a triglyceride concentration of 0.85 mmol/l, and a calcium concentration of 2.21 mmol/l. Although the cause of acute pancreatitis is not identified in a proportion of all cases,16 with negative tests for a number of potentially aetiological organisms (enteroviruses, Epstein–Barr virus, varicella zoster, measles, salmonella, leptospira, campylobacter, and mycobacterium), and normal titres of IgG4, no evidence of gallstone disease on imaging and no history of alcohol misuse (γ-glutamyl transferase 36 iU/l), oseltamivir was considered to be a possible aetiological agent. Acute pancreatitis triggered by parasite infection has been described,17,18 but with no relevant travel history this was not investigated.
Outcome and follow-up
The patient was managed expectantly with supportive treatment. She received intravenous crystalloid fluids to maintain a urine output above 0.5 ml/kg body weight/h, and oral analgesia for symptom relief. Initially she was kept nil by mouth and diet was reintroduced after 24 h. She made a good recovery, and was discharged 3 days following admission.
A literature search found only one report of a child (who subsequently died) where an association between acute pancreatitis and the use of oseltamivir has been described.19 This suspected drug reaction has been reported to the Medicines and Healthcare Products Regulatory Agency (MHRA), and the pharmaceutical company producing oseltamivir (Roche, Basel) was informed of our concerns.
There are a number of challenges facing us in reducing the impact of H1N1, and for future virulent influenza strains or severe respiratory viral infections. These include the provision of sufficient diagnostic services, the logistics of antiviral drug delivery, epidemiological monitoring of viral evolution as well as the ongoing priority setting for treatment plus plans for vaccination.20 It appears that the UK is better placed than many countries for meeting such challenges, with considerable pre-pandemic planning, large stocks of antivirals and pre-ordering of vaccine.21
The current response by the NHS is unprecedented. While infectious diseases in the past have been countered by mass vaccination, they have never before been treated by mass distribution of a prescription only drug in the current manner.22 While features of the process are novel and admirable it should be remembered that a drug has been made available to the general public without the usual safeguards of health professionals policing its distribution. This case highlights a possible new ADR relating to oseltamivir, and with a huge new population likely to take this antiviral in the coming months, we must consider the impact of known side effects and new ADRs on our communities. All policy decisions entail risk and benefits: risks and benefits for the decision maker alongside risks and benefits to those affected by the decision. Though the rapidity of transmission of influenza virus during pandemics necessitates immediate action, we must balance this by continuous reflection on whether the fix is better than the problem.
Alongside concerns regarding the methods in which the NHS has seen fit to distribute oseltamivir, the widespread use of such antiviral treatment may also lead to new resistance patterns. The obvious parallel is to the emergence of highly virulent and resistant bacterial pathogens following the unchecked use of broad spectrum antibiotics over the last decade. With numerous reports of oseltamivir resistant H1N1 already published,23,24 a more selective approach to the use of antiviral treatment could be considered as better clinical management.
Decisions have been taken about how we face the challenge of H1N1. It remains to be seen whether they will be regarded as innovative and appropriate, or over reactive and impulsive.
It is essential that we make best use of evolving information and that policymakers are provided with a comprehensive picture of what is happening at a micro as well as a macro level. This will involve ongoing feedback from frontline health professionals and we encourage continued efforts, despite the many obvious challenges, of providing this. Doctors should remain vigilant about the potential for individuals to present with complications of oseltamivir treatment—both known and unknown. Where suspicion exists these should be reported immediately to the relevant authorities to ensure that in our efforts to tackle a major health challenge, patient safety is not compromised.
Learning points
  • Optimal pandemic disease management strategies may require approaches that most practising doctors are not familiar with but these policies may save lives.
  • Clinicians in all specialties must keep up to date with current initiatives in public health and primary care that may impact on their practice.
  • Mass distribution of prescription drugs by non-clinicians on the basis of subjective symptoms does raise concerns for patient safety that have yet to be fully addressed.
Footnotes
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.
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