Haemophagocytic lymphohistiocytosis (HLH) and MAS

The trouble in HLH is a failed "off switch": the immune system cannot stand itself down. Some immune cells, a type known as macrophages among them, remain active and pour inflammatory signals into the bloodstream. Instead of the usual sequence, the threat cleared and calm restored, a storm that feeds on itself sets in, and healthy tissues and organs start to suffer.

It usually starts in response to a trigger, and when that trigger is an active autoimmune condition the same process is often called macrophage activation syndrome. Young children are the main group affected by a rarer form that is inherited, through faults in immune genes.

For adults the usual triggers are three: a serious infection, viral or otherwise; a blood cancer, lymphoma for instance; or an active autoimmune disease, adult-onset Still's disease and lupus among them. Less often it follows pregnancy or a treatment, such as some drugs, some cancer therapies and bone marrow transplants.

The whole body can be involved, and things can build fast. The features of HLH may take in:

• A high fever that persists rather than settling
• Marked tiredness or weakness, and feeling very unwell
• Swollen glands, or an enlarged liver or spleen
• A rash
• Easy bruising or bleeding
• Skin or eyes turning yellow (jaundice)
• Confusion or other effects on the brain in more severe cases

Since HLH can progress rapidly, a high fever that does not settle, in someone who also feels very unwell, is a 999 or A&E emergency, and the case is stronger still when an autoimmune condition is already known.

HLH has no single confirming test; the diagnosis is put together from the pattern of the illness and a set of urgent blood tests, which usually reveal intense inflammation. One important clue is a very high ferritin, a protein measured in the blood; low blood counts and altered liver tests sit beside it. Sampling the bone marrow is sometimes the step that completes the picture. Because HLH can closely resemble a severe infection it can be easy to miss, and it takes a high degree of suspicion and prompt specialist assessment to get the diagnosis made quickly and treatment started at once.

HLH is treated as a medical emergency, in hospital and often on an intensive care unit, and the treatment works on two fronts at once: damping down the runaway immune response, and dealing with whatever set it off. The immune response is usually damped with steroids first, and other medicines that quieten inflammation, anakinra, a biologic, among them, are added when steroids are not enough or would cloud the search for what set it off, with the choice guided by the cause and by how ill the person is. In parallel, the search is on for the trigger, be it an infection, a blood cancer or an active autoimmune condition, and it is treated when found. Care is shared between teams, and the plan is revisited again and again as things change. Even with treatment HLH can be life-threatening, but the best chance of bringing it under control comes from recognising it early and starting treatment quickly.

HLH is a whole-body illness that can change at speed, and it is almost always looked after by more than one specialty acting together. Dr Borukhson practises within a world-renowned tertiary centre, with ready access to consultant colleagues in the other specialties this condition may call on. Where it helps, she can bring those specialists in directly, and particularly complex cases can go to a multidisciplinary team meeting (MDT) with minimal delay. Whenever more than one kind of expertise is needed, the strands of your care can be drawn together and decisions reached promptly.

Recovering from HLH happens under your hospital team's direction, not on your own, and it can be slow. Tiredness can outlast the illness itself while the body and the blood counts recover.

For as long as treatment holds your immune system down, you are an easier target for infection. Three habits protect you: taking up the vaccinations you are advised to have; reporting a fever or any contact with measles, chickenpox or shingles the same day, and any new symptom, each by the route the next section gives it; and taking your medicines precisely as prescribed. Should you be on steroids, they are not to be stopped abruptly.

• Miss none of the follow-up appointments or blood tests: through them your recovery is charted and any return is spotted early
• Rest, and add to what you do gradually
• Eat properly and keep your fluids up; healing needs both
• A serious illness leaves its mark on the mind as well as the body, so let family, friends or a counsellor share the load

Where an underlying condition set off your HLH, treating and steadying that condition is part of treating the HLH, and you are followed closely afterwards, because HLH can come back.

HLH can move fast, and your instincts are worth trusting: a few things cannot wait at all.

Treat any of these as a 999 or A&E emergency: call 999 and do not drive yourself to A&E.

• A high fever that does not settle, in someone who also feels very unwell; uncontrollable shivering; breathing very fast; or feeling dramatically worse over hours, all the more if they have an autoimmune condition
• With a fever or feeling unwell, a rash that does not fade when you press it, a stiff neck with eyes that cannot bear bright light, or skin, lips or tongue turning blue, grey, pale or blotchy, since these can be signs of meningitis or sepsis; on black or brown skin the rash and the change of colour may be easier to see on the palms of the hands or the soles of the feet
• A seizure, a severe headache, or confusion or drowsiness that is new
• Sudden weakness or numbness on one side, a drooping face or difficulty speaking, a sudden severe headache, sudden confusion or a seizure, or sudden loss of vision, any of which can be a stroke, even if it stops after a short time
• An eye that suddenly and completely loses its sight
• Bruising easily, bleeding that is out of the ordinary, or blood in the urine or stools
• Breathlessness, or the skin or eyes turning yellow
• Chest pain that is crushing, tight or like a pressure, that spreads to an arm, the jaw, the neck, the stomach or the back, that comes with breathlessness, sweating, feeling sick or feeling light-headed, or that came on suddenly and does not go away
• Palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, since a heart whose muscle or rhythm is affected has to be checked at once
• A blackout, since a heart strained by the illness can be behind it
• Vomiting that will not let your tablets stay down, or, during an illness or after an injury, becoming very drowsy or confused, or fainting, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, since your body may be running short of cortisol and the steroid may need to be given by injection; have your NHS Steroid Emergency Card ready
• Sudden severe pain in the abdomen or back, since the pancreas can react to prednisolone
• Lips, mouth, throat or tongue that suddenly swell, a throat that feels tight, very fast breathing or a struggle to breathe or to swallow, skin, tongue or lips turning blue, grey or pale (on black or brown skin this may be easier to see on the palms of the hands or the soles of the feet), becoming suddenly very confused, drowsy or dizzy, or fainting and not being able to be woken, since this can be a severe allergic reaction, anaphylaxis, which can follow a dose of any medicine
• Vomiting blood, or bleeding from the back passage that is heavy or will not stop, most of all with faintness, confusion or pain in the abdomen, or vomit that is black or dark brown, since a stomach ulcer on prednisolone can bleed
• Serious harm you have already done to yourself, such as an overdose, or a feeling that you may be about to harm yourself, since you need help to keep you safe now

Any of these needs an assessment that is urgent, on the same day, from your GP, your rheumatology team or NHS 111:

• A fever, or feeling generally unwell, on immunosuppressant, biologic or steroid treatment, since an infection has to be treated early
• New chest pain or new palpitations, since the heart can be strained in HLH; palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, belong to the first list
• A new red, painful eye, or sight that has blurred, dimmed or changed, which needs an eye casualty or urgent eye clinic the same day, as does an eye that light hurts
• Thoughts of ending your life or of hurting yourself, or harm you have done to yourself that is not serious, short of the line in the first list, which steroids can bring on: ask your GP to see you that day or call NHS 111, and Samaritans answer at any hour on 116 123
• A marked change in mood or behaviour, confusion, or seeing or hearing things that are not there, on steroid treatment, since prednisolone can do this, the more so the higher the dose; confusion that is new or comes on suddenly is a 999 or A&E emergency, as the first list says, and so, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, is becoming very drowsy or confused during an illness or after an injury
• Unusual thirst or hunger, or passing urine more often, on steroids, or swelling of the arms or legs, severe stomach pain, severe back pain, a severe upset stomach, being sick, or very bad dizziness, since each can be a steroid effect that needs checking without delay; pain in the abdomen or back that comes on suddenly and severely is a 999 or A&E emergency, as the first list says, and so, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, is vomiting that will not let your tablets stay down, or, during an illness or after an injury, becoming very drowsy or confused, or fainting
• Contact with measles, chickenpox or shingles, since these infections can be severe on steroids and a medicine to protect you may be needed
• Being near someone with measles, chickenpox or shingles, while you take a medicine that weakens the immune system, since measles and chickenpox can be dangerous when the immune system is weakened, and you can catch chickenpox from someone with shingles if you have never had chickenpox; NHS 111 can tell you what to do that day

Contact your specialist team or GP within a day or two about a fever that keeps coming back once treatment has finished, swollen glands that are new or getting worse, marked tiredness, or anything that feels like a previous flare returning.

A routine appointment is the place for minor questions about your recovery or your medicines, once things have settled. If you take a steroid or a biologic, the warning signs that belong to each are set out in our guides to steroids and biologics and JAK inhibitors. If you are in any doubt, get checked; that is always the safer course.

HLH is rare, which makes it easy to miss, and dangerous, which means a missed diagnosis costs time that cannot be recovered. For anyone with an autoimmune condition such as adult-onset Still's disease or lupus, in whom it appears as macrophage activation syndrome, the rule is simple: a high fever that does not settle, in someone who also feels very unwell, is a 999 or A&E emergency; it is not something to wait on. The sooner a specialist is involved, the sooner what is happening is understood and the right treatment begins.

How is the diagnosis of HLH reached?

No single test settles HLH. The diagnosis comes from the pattern of the illness together with urgent blood tests, which usually show intense inflammation, a ferritin level far above normal, low blood counts and disturbed liver tests. A bone marrow sample sometimes adds the final piece. The difficulty is that all of this can look like a severe infection, which is why the diagnosis is easy to miss, why a specialist is brought in early, and why treatment is started on suspicion rather than after every result is back.

How is HLH treated?

In hospital, as an emergency, and often on an intensive care unit. Two things happen at once: the runaway immune response is damped down, usually with steroids first and then, if they are not enough, other medicines that quieten inflammation, anakinra among them, and the trigger is sought and treated, whether that is an infection, a blood cancer or an autoimmune condition in flare. More than one team is involved, and the plan is under constant review. It can still be life-threatening even when treated, and the odds are best when it is recognised early and treated quickly.

What is macrophage activation syndrome, and how does it relate to autoimmune conditions?

HLH that arises out of an autoimmune condition, the form rheumatologists see, often carries a different name: macrophage activation syndrome, or MAS. The immune system, activated by the underlying condition to begin with, gathers still more force and directs it against the body's own tissues. Conditions such as adult-onset Still's disease and lupus are where it arises most often, which is part of why regular specialist review, and acting fast when you become acutely unwell, by the routes the When to seek help section gives, count for so much.

I have an autoimmune condition. When should I seek urgent help?

If you have a condition such as adult-onset Still's disease or lupus, a high fever that does not settle, in someone who also feels very unwell, is a 999 or A&E emergency, not a routine appointment. The same goes for bruising or bleeding easily, the skin or eyes turning yellow, and confusion or drowsiness that is new, and the first list under When to seek help gives the rest, breathlessness, a seizure, a severe headache and the signs of a stroke among them. Call 999 and do not drive yourself to A&E. In HLH, catching it early genuinely alters the outcome. If you are in any doubt, get checked; that is always the safer course.

Why does HLH need several specialists working together?

Because HLH can involve the whole body and moves quickly, several specialties almost always share its care. Dr Borukhson works from a world-renowned tertiary centre, so whichever specialties a case needs, she has consultant colleagues there to call on. Where it helps, she can involve them directly, and a complex case can go to a multidisciplinary team meeting with minimal delay, so that decisions cover the whole of your care and are reached promptly.