A case of the very rare condition Macrophage Activation Syndrome

It is often difficult to identify and diagnose a rare medical condition in a patient and make sure they receive appropriate treatment. It is sometimes the case that a number of working diagnoses have to be made and all of them treated, to cover all bases, until the correct diagnosis is eventually established. Establishing that correct diagnosis and ensuring the right treatment path often requires the involvement of appropriate medical specialists early on, otherwise a wrong diagnosis or incorrect treatment may prove to be disastrous. This is exactly what happened with a clinical negligence case of mine involving an incredibly rare condition. The diagnosis was understandably difficult and, whilst the treating team rightly tried to cover all bases, the correct diagnosis remained elusive, probably because no appropriate specialist was involved until too late in the day. As such, although the initial treatment that was implemented was appropriate and, indeed, was extremely effective, there was a subsequent simple fatal error in failing to treat the patient sufficiently aggressively and for sufficient duration with a key treatment. This undertreatment led to the death of a young man in the prime of his life. Had an appropriate specialist been involved early on, it is likely this very sad outcome would have been avoided.

The History

The claim centred around the death of a young man in his early thirties (‘the deceased’). In early winter, he developed some general ‘flu-like symptoms of a sore throat, aching muscles (myalgia) and a high temperature of 38.0°C (pyrexia). He was no better three days later, so he began to take some oral Penicillin V antibiotics given to him by his GP. He almost immediately developed a rash over his trunk and chest and he also developed joint pains (arthralgia). The next day, his GP diagnosed a viral infection. A further two days later and he was still no better, so the GP took some bloods. Just over a week from the initial symptoms, he was still no better and so he attended A&E. The bloods taken by the GP were on the hospital system: his white cell count (WCC) was at the very upper limit of normal (10.6; normal <11) and he had a high neutrophil count (neutrophilia) and a low lymphocyte count (lymphopenia), possibly suggesting an infection. The Casualty doctor diagnosed ‘flu and/or a penicillin allergy and stopped the penicillin.

However, over the next few days, the deceased deteriorated to the point that he could not get out of bed. His GP referred him to the Acute Medical Unit at his local District General Hospital. The clerking history noted the history of a ‘flu-like illness, rash, arthralgia, sore throat, temperature and recent rapid weight loss. His temperature on admission was high at 38.4°C. On investigation, his WCC was by now very elevated at 24.2, again with a neutrophilia. He also had deranged liver function tests (LFTs), with an AST (aspartate transaminase) of 62 (normal 10-35) and an ALP (alkaline phosphatase) of 227 (normal 30-130). He had a very high C-reactive protein (CRP) of 281 (normal <5). The working diagnosis was an infective process, such as Streptococcus or Mycoplasma, or possibly an antibiotic allergy. The deceased was treated with the intravenous steroid hydrocortisone 200mg three times daily (tds) and the intravenous antibiotics clarithromycin and teicoplanin. Within 3½ hours of his first dose of iv hydrocortisone, his temperature had dropped to 35.4°C.

The next day (Day 1 after admission) brought a very rapid response. The deceased was feeling much better and his temperature had fallen to normal. An abdominal ultrasound scan revealed a slightly enlarged spleen. By the subsequent day (Day 2), the CRP had fallen to 93 but the WCC had increased yet further to 28.2. Another day on (Day 3) and the CRP had fallen further to 57 and the WCC now also began to fall at 25.2. His temperature remained normal.

Such was the rapid response to treatment, a locum consultant respiratory physician on her ward round diagnosed an allergy to penicillin and ordered a rapid reduction of the high dose intravenous steroids and replacement with the oral steroid prednisolone 20mg once a day (od). Accordingly, on Day 4, only a single dose of iv hydrocortisone was given and the following day (Day 5) the hydrocortisone was stopped and the lower dose of oral prednisolone was started.

However, the next day (Day 6) the deceased reported that he had begun to feel unwell again. His CRP had started to climb at 80. His blood film showed immature white cell precursors (usually a marker of infection or inflammation). His rash had disappeared but there remained concern about Scarlet Fever. There was a note about possible discharge in two days. He continued his reducing oral steroids such that a further day later (Day 7) he was taking only 10mg oral prednisolone od. He was seen by an Infectious Disease consultant, who added in metronidazole to the teicoplanin because of concern about a retropharyngeal abscess. The deceased’s CRP increased to 133, platelets increased to 538 (normal <450) and temperature increased to 38.6°C. Matters continued to worsen: by the next day (Day 8), CRP was 152 and temperature in the evening was 41.1°C; the deceased felt absolutely terrible. The working diagnosis remained as Scarlet Fever.

Another day on (Day 9) and the deceased’s CRP had increased to 327, his WCC was 30.4 with a high neutrophilia (29.8) and he still had a very high temperature of 40.3°C. It was apparent that he was by now developing “shock”, with a falling blood pressure and rising pulse and his oxygen saturations were also falling. The Critical Care Outreach Team visited him on the ward and escalated him to the High Dependency Unit (HDU). He was only on 5mg oral prednisolone. He was admitted to HDU and a central line inserted. His renal function began rapidly to deteriorate.

On Day 10 post-admission, the deceased’s blood tests continued to deteriorate. A ferritin was >10,000. A CT chest was consistent with Adult Respiratory Distress Syndrome (ARDS). Eventually, a consultant rheumatologist was asked to review the deceased, with a haematologist, and they concluded that there was a good chance of the diagnosis being Haemophagocytic Lympho-Histiocytosis (HLH) probably secondary to Adult Onset Still’s Disease (AOSD). The rheumatologist prescribed 1g iv methylprednisolone. A lumbar puncture was normal. The following day, Day 11, the deceased had a bone marrow biopsy which revealed a marrow that was failing with a 3-cell lineage relative cytopenia (reduction in all cell lines). The trephine was indeed consistent with HLH. The deceased continued to deteriorate despite the treatment with iv methylprednisolone and organ support. Such treatment was too little too late and he arrested and, despite resuscitation attempts, died on Day 12, witnessed by his partner.

The Medical Background

Adult Onset Still’s Disease

Epidemiology: Adult Onset Still’s Disease (AOSD) is a rare inflammatory arthritis. Still’s Disease is Juvenile Chronic Arthritis and AOSD is its adult form, although it is most common in young adults aged under 35 years, as in this case.

Aetiology: Its cause is unknown but it is thought to be usually due to either genetic and/or an infectious cause e.g. Epstein Barr Virus (EBV), Parvovirus B19, Coxsackie virus, although many other infectious agents have been implicated.

Pathology: The underlying pathological mechanisms of disease are not properly understood.

Clinical and diagnostic: Criteria known as the Yamaguchi criteria are still widely accepted as being the primary diagnostic criteria. Yamaguchi identified “major”, “minor” and “exclusion” criteria, with the requirement for a diagnosis of a minimum of five criteria and at least two of them being major. The major criteria are: arthralgia >2 weeks; fever >39°C and intermittent >1 week; maculopapular non-pruritic rash; WCC >10,000 with >80% granulocytosis. The minor criteria are: sore throat; lymphadenopathy and/or splenomegaly; abnormal liver function tests; rheumatoid factor and anti-nuclear antibody (ANA) negative. The exclusion criteria are: infection (including sepsis); EBV infection; malignancy; and inflammatory disease. The deceased had six, possibly seven, criteria, with three being major, so he fulfilled the Yamaguchi criteria from relatively early on in his history. It is, however, in essence, a diagnosis of exclusion.

Investigations: The typical investigations will include a high WCC, CRP and ESR (Erythrocyte Sedimentation Rate), abnormal LFTs and a very high serum ferritin, often>3,000 (normal <300), indicative of a hyperacute inflammatory process.

Treatment: The treatment includes non-steroidal anti-inflammatory drugs (NSAIDs) and/or immune suppressants: high dose steroids are the mainstay of management. It is critical to monitor regularly during treatment and taper the steroids slowly once remission has been achieved.

Natural history and prognosis: There are three forms of the disease: (a) monocyclic: a single, acute, severe flare of the disease with complete remission with treatment (which is what the deceased had) and a very good prognosis; (b) polycyclic: intermittent, recurrent flares with periods of remission of 2 weeks to 2 years; and (c) chronic: which is the articular rather than systemic form of the disease, and this is the most common form.

Haemophagocytic Lymphohistiocytosis (HLH)

Epidemiology: HLH is an incredibly rare “hyper-inflammatory syndrome” and an uncommon complication of AOSD.

Aetiology: It exists in a primary familial form (about 25% of cases) or a secondary reactive form due to autoimmune diseases, infections or malignancy. HLH due to AOSD is known as Macrophage Activation Syndrome (MAS). MAS is what the deceased had.

Pathology: HLH’s hallmark is the presence of autoimmune hyperactivity, such that macrophages and histiocytes (the body’s immune cell “scavengers”) auto-digest the reticuloendothelial system (known as macrophagocytosis and histiophagocytosis respectively), including blood and immune cells and tissues such as bone marrow, liver and lymph nodes.

Clinical: HLH presents with hyperpyrexia, hepatosplenomegaly, cytopenia in 2-3 cell lines in the peripheral blood, an extremely elevated ferritin, coagulopathy/disseminated intravascular coagulation (DIC) and neurological abnormalities.

Diagnosis: The diagnosis is made essentially by bone marrow biopsy showing increased macrophages and lymphocytes with macrophagocytosis and histiophagocytosis.

Investigations: As with AOSD, there are high inflammatory markers (e.g. WCC, CRP, etc.). Interestingly, there is usually a low ESR in MAS (although it was not performed in this case). There are abnormal LFTs and a very high serum ferritin, often>3,000 (normal <300). Of the more unusual tests, HLH shows low Natural Killer (NK) cells, high triglycerides and high CD25.

Natural history: HLH has a very poor prognosis generally and it is reported that c. 40% of MAS patients die (with a higher rate for those on ITU), although the data is limited because of the very low numbers of patients. To avoid mortality, it is imperative that MAS is detected and treated early and aggressively.

Treatment: Treatment is generally supportive. Immune suppressants such as methylprednisolone are the mainstay to try to reduce disease activity, but also cyclosporin. The Interleukin-1 receptor antagonist, Anakinra, has shown promise and there are many other disease activity modulation-related treatments that have been tried with varying degrees of success.

The legal claim

The liability case

It was claimed that there was, in breach of duty, an unacceptable delay in the defendant hospital recognising that the deceased’s deterioration was due to the rapid reduction in steroid dose by about Day 7 post-admission and, accordingly, in recognising that the deceased was likely suffering from an immune-related condition i.e. AOSD. It was further claimed that there was, in breach of duty, a consequential delay in managing the deceased with appropriate immunosuppression treatment for his immune-related illness, with such delay resulting in his death. In addition, it was claimed that, but for the breaches of duty, with appropriate treatment, the deceased would have: (a) survived intact; (b) been able to return to part-time work within two months of discharge and to full-time work after a further month; (c) been treated with steroids for a year but without any complications; and, (d) been cured of his MAS with no adverse effects on either his long-term morbidity or mortality.

Quantum case

With respect to quantum, the claim was based on the Law Reform (Miscellaneous Provisions) Act 1934 on behalf of the deceased’s Estate, the Fatal Accidents Act 1976 on behalf of the deceased’s dependents; and in common law for the psychiatric injury for his common law wife and partner. The deceased and his partner were living together with their young family and both were working up until the deceased’s death but the deceased was the primary earner.

Procedure

At first blush, the claim appeared very difficult. Not only was the underlying condition of HLH incredibly rare but some brief investigations into it revealed that it largely had a very poor prognosis. However, amazingly coincidentally, I had been involved with a case when I had been a medical SHO in the distant past and so knew a little about the condition; I had also done an SHO rheumatology rotation and had treated a number of cases of AOSD during that time, so was familiar with that condition, too. I was aware of the potential for a good response to high-dose steroids and the need for rapid, aggressive treatment, and a brief review of the chronology in the case ascertained the main likely criticism of the rapid steroid reduction. In investigating the claim there were the usual issues with missing medical records from the set supplied by the Trust, which took time to sort out. However, an expert rheumatologist was eventually instructed to report and he was critical along the lines set out above and these criticisms were reproduced in the Letter of Claim. He was also critical that no rheumatologist had been involved much earlier in the case. There were various non-rheumatological concerns but these were not investigated pending the outcome of the response to the rheumatological allegations.

A Letter of Claim was served on the Defendant Trust and a Letter of Response served by the Trust’s solicitors 9 months later admitted the breach of duty with respect to the rapid steroid reduction and the failure then to notice the consequential rapid deterioration post-reduction; causation of death was subsequently admitted a further three months later. However, the deceased’s hypothetical morbidity and mortality was not admitted. Following further expert rheumatological opinion on the point being obtained and subsequent correspondence between the parties, a full liability admission was made a further 13 months later, in essence on the basis referred to above, that the deceased would have made a full recovery with no long-term impact on either his morbidity or mortality, but with some minor timing differences with respect to returning to work.

The psychiatric element of the claim was also investigated with the claimant being a secondary victim having witnessed the horrific events surrounding the resuscitation of her long-term partner. It was apparent she suffered from resulting PTSD and depression and a claim was included. This was not formally admitted by the Trust but was included in the settlement negotiations and taken into account in the eventual apportionment of the damages.

Settlement

The parties attended mediation using NHS Resolution’s mediation scheme at which the action was compromised in the sum of £950,000. This was subsequently approved by the High Court and appropriate apportionment to the deceased’s partner and children was made.

Conclusion

The case was obviously very sad but substantively also very interesting and complex. Medically, it involved two rare conditions, one incredibly so, which presented a significant challenge, but more so given that MAS generally has a very poor prognosis. However, ultimately, the medical issues upon which the case turned were relatively simple: too rapid a reduction of intravenous steroid in a patient with an acute inflammatory condition and a delay in recognising the subsequent deterioration, which likely would have been avoided with involvement of the appropriate specialists early on in the management. It is hoped that such simple mistakes will be avoided in the future and that the Trust will learn from the fatal errors made in this case.