Improving outcomes: Medical monitoring matters

Case notes: Miss B, 25 years old  

‘Miss B’ had felt unwell for several months, but now her urine had turned dark and her boyfriend noticed her eyes looked yellow. She tried to book a GP appointment. This was difficult, but when she was seen, her GP arranged blood tests at the local hospital. This was a palaver in itself, but bloods were eventually taken the following week and showed severe hepatitis with jaundice.

Miss B was urgently referred to the local gastroenterologist. An appointment was sent out for an appointment within three weeks, but it was never received. By now, the yellowness of Miss B’s eyes had become worse and she went to A&E. Seen after six hours, Miss B was referred to the medical team who admitted her overnight. Blood tests were organised, but excluded liver failure, as well as ultrasound scan to exclude biliary obstruction. Two days later. Miss B was discharged with no diagnosis, with arrangements to see her two weeks later. At that subsequent appointment, the young doctor thought she might have autoimmune hepatitis and arranged more blood tests and a liver biopsy. The liver biopsy came through four weeks later with the jaundice seemingly getting worse by the day. No treatment had yet been started. The liver biopsy was straightforward and Miss B went home the same day, with an appointment set for six weeks later. At that review, the consultant confirmed Miss B had autoimmune hepatitis; she needed to start treatment with steroids, followed by azathioprine. The steroids were taken and Miss B immediately started to feel better. Within four weeks, when she next saw the consultant, her jaundice was visibly resolving. All good so far, but it had taken a long time to get here. Later tests would show that, in the 18-week delay from onset of jaundice to beginning treatment, Miss B had developed early cirrhosis.

At this point, the consultant advised that Miss B take some extra tablets but would need some blood tests beforehand to make sure this was safe. TPMT (an enzyme that metabolises the drug) was measured and found to be normal. But Miss B’s immunity to chicken pox or other common infections wasn’t included. While technically okay, when Miss B saw the consultant four weeks later, she was prescribed azathioprine; this is a drug known to cause bone marrow suppression in some susceptible patients. Miss B was given three blood forms for a full blood count at two weeks, four weeks and eight weeks, plus a blood test form for several blood tests at four weeks and two months. Additionally, there was a repeat appointment for two months later.

Miss B was not the most assertive character. If someone said no, they meant no. She tried to book the blood tests one week after starting the azathioprine, but there were no appointments. She also tried turning up, but was refused. Phlebotomy was overwhelmed, since Covid and the almost overnight closure of all Primary Care phlebotomy services. All of this time, Miss B was taking the newly prescribed drug that needed monitoring for safety. Miss B eventually got an appointment. This was two weeks after starting the drug. Unfortunately, bus delays meant she was 30 minutes late and the clinic refused to take the tests.

Four weeks after starting the azathioprine, and with no blood tests yet taken, Miss B started to feel unwell. This was just shivery at first. Then, her urine smelt odd; she was clearly not right. When Miss B started shaking uncontrollably, her partner rushed her to A&E. She was diagnosed with neutropenic sepsis and a urinary tract infection. Since her blood pressure was so low, Miss B was admitted to intensive care, began taking antibiotics and, luckily, survived.

Miss B had developed severe bone marrow suppression with neutropenic sepsis secondary to azathioprine. This was entirely preventable with proper monitoring. NICE guidelines suggest more weekly monitoring for four weeks, but this was ignored by her treating doctors. Miss B was unable to get the tests requested done because of the long waiting list, and the fact that the tests had not been marked as ‘Urgent’. But even the tests requested were too few and too late.

Many new medicines require safety monitoring in the form of blood tests. If the regulators (MHRA in the UK, EMA in Europe and FDA in the US), could be confident that drug safety monitoring would be undertaken regularly, then the regulators would approve more drugs with a marginal safety record, confident that safety monitoring would occur. However, we know from audits undertaken that such monitoring only occurs <40% of the time.

With our Medicines Monitor software

Before starting on azathioprine, Miss B would be registered on Salutare’s Medicines Monitor. This immediately lists all of the baseline tests needed before beginning treatment, including TPMT and measurement of antibodies to chickenpox, HIV and so forth. Once the start date of azathioprine is entered, the software generates an email with a list of such test requests and the date for blood test appointments, including a weekly full blood count. The first four weeks of tests are automatically marked as ‘Urgent’, so Miss B bypasses the long waiting time for blood test appointments.  

There is also a link to make an appointment through Swiftqueue for the blood tests. Miss B attends for her blood tests but misses the week three full blood count. An automated alert is sent by text and email to Miss B, reminding her that it is vital that she gets this test done urgently. Her doctor is also informed. Miss B re-presents with the urgent blood form the next day. Later that day, Medicines Monitor, which has been ingesting the weekly blood results, flags up that her white blood count and the neutrophil count specifically were low at 2.2 and 0.7 respectively. An alert text message and email are sent to Miss B and her doctor, stating that her white blood count is low and she must stop the medication until she speaks with her doctor. The doctor receives Miss B’s phone number and blood results and can log into the system to get the full picture. It is clear that Miss B’s white blood count had dropped significantly. Phoning Miss B, her doctor advises her to stop taking the azathioprine completely and that alternative drugs will be considered.

Miss B takes this advice. Monitoring continues and the next week her full blood count shows that the white blood count had stabilised or increased at 2.6. Miss B is safe once more. Four weeks later, Miss B’s blood tests appear normal, and she starts on mycophenolate (a drug similar to azathioprine, but with less side effects). Miss B remains well to this day, while her liver fibroscan shows an elevated liver stiffness at 16.8kPa, suggestive of early cirrhosis or advanced fibrosis.

Better outcomes are possible with software created by clinicians, for clinicians.