In this model of aHUS onset and relapse the two key variables in it are patient genetic predisposition and the “second hit”- what triggers it. There may be more understanding about genetic mutation strength these days but what can be a trigger and how strong it may be, is much less understood and reported.
There is no comprehensive up to date list of triggers of the version of aHUS known as complement mediated TMA . Nor even the wider definition of aHUS which is everything else that triggers it except E.coli. Even though we know that E.coli can trigger aHUS.
So something different is needed something which specifies strength , longevity and also directness.
Directness is the most misunderstood by patients. A direct( or primary) trigger is what most patients talk about even believe there is. It is some thing that the body wants rid of and complement sets off to do that but because it cannot be controlled it starts damaging the lining of the small blood vessels leading directly to cTMA.
However in probably many more instances the linings of small blood vessels are already inflamed by another condition and a TMA has already begun and “messages” are picked up by complement which begins its own pile on secondary to whatever primarily started it. This is a secondary (indirect) trigger.
To confuse matters further some striggers can be either direct (primary) and secondary (indirect) triggers. They are in a grey zone.
What ever a trigger might be it is likely to be one from the following broad categories.
- Infections
- Pregnancy and childbirth
- Surgery and trauma
- Trnsplantation
- Certain medications
- Autoimmune disease flare
- Acute inflammatory diseases
- Malignant hypertension
Within each there are multiple individual triggering conditions, some direct and some secondary,
Now lets try to list them within this framework and bringing in
strength- weak /mild to strong/ robust,
and longevity -permanent/chronic/on going to transitory/acute/ transient/
and use of amplifier. Amplification from tick over is how the complement system reaches the point of loss of control.
This will be the first attempt at creating such a list, For each trigger the following abbreviation will be used: 1 for a direct cause, 2 for a secondary cause and O if the condition can be its own TMA.
| WEAK / MILD amplifier | STRONG / ROBUST amplifier | |
| PERMANENT / CHRONIC / ONGOING | -1. Milder or lower-intensity ongoing drug exposure -HRT (1) , -NSAIDS (1) , -Omeprazole (1) , -statins (1) , -EPO (1), -Interferons (1), -Allopurinol (1) , -oral contraceptives (1) , 2, Stable, controlled low-activity autoimmune conditions -SLE* (12) , -Rheumatoid Arthritis* (12) , -Sjogren’s Disease* (12) , – psoriasis * (12), -Crohn’s Disease * (12), -ulcerative colitis (1) , -thyroid disease (1) , -IBD (12), -vasculitis (12) * usually in addition to another stronger trigger 3, Chronic low-grade inflammatory or metabolic states that mildly stress endothelium: – Obesity (2), -Metabolic syndrome (2) , -Type 2 diabetes mellitus (2), – Prediabetes/insulin resistance (2). -Atherosclerotic cardiovascular disease (2) , -Non-alcoholic fatty liver disease (NAFLD) (2). -Obstructive sleep apnoea (2) | 1 Active malignancy cancer – metastatic solid tumours) (12O) -leukaemia -lymphomas. 2. Drugs : – calcineurin-inhibitor or TOR-inhibitor therapy (2O) -Tacrolimus (2O) -Ciclosporin (2O) -VEGF inhibitors (2O) -Campath (20) 3.Long-term chemotherapy agents strongly linked to TMA – mitomycin C (2O), – gemcitabine regimens) (2O) 4. 4.Active systemic autoimmune disease with complement involvement -SLE (12O) -APS (12O) |
| TRANSITORY / ACUTE / TRANSIENT | 1. Mild upper-respiratory or gastrointestinal infections -mild COVID (12O) -common cold (1) -pharyngitis (1) -sinusitis (1) – norovirus (1) rotavirus (1) -Sapovirus(1) -Astrovirus (1) -Salmonella (1) -Campylobacter enteritis (1) 2. Vaccinations (rarely reported) (12O) -COVID-19 (12O) -Influenza (12O) 3. Minor surgery or mild trauma (2) -caesarean procedure 4. Short-course or low-impact drug exposures that are quickly discontinued -Quinine (2O) -interferon alpha and beta (2O) -rifampicin (2O) -vancomycin (2O) -cocaine (12O) 5. Moderate physical stress (2) -heat exhaustion -dehydration | 1.Severe acute viral and bacterial infections : – Streptococcus pneumoniae (12O ), -influenza (1) , – severe COVID (12O) , -RSV (12O), -EBV (12O), -CMV (12O) , -E.coli (12O), -Hepatitis (12O) , -HIV (2O) , -Dengue (2O), -cellulitis (12) , -UTI (1) , -MRSA (12O) , 2.Pregnancy (1) -Childbirth/ postpartum period (1) , -HELLP (12O)* , -Pre-eclampsia (12O) * , 3. Acute malignant (severe) hypertension (12O)* 4. Major surgery (1) 5. Significant trauma (1) 6. Severe burns (10) 7. Solid-organ transplantation (12O) 8..Bone-marrow / stem cell transplantation event (12O) 9.. Snake venom (12O) 10 Excessive physical exercise (2O) |
As can be seen some of these triggers are sudden events bringing on an episode of aHUS/cTMA
Some of these chronic conditions may place a constant low level of stress on blood vessels and the complement system, lowering the threshold at which a stronger trigger can provoke a complement-mediated TMA episode. But the stronger trigger may not bring on an episode with without the weaker.
So when it comes precision medicine there is a need to identify and treat other conditions so that complement activity can be stopped with or without needing a complement inhibitor.
Also a constant low level sub clinical triggering needs to treated somehow maybe in those predisposed with one of the conditions. For example is someone who has not had full blown aHUS but has a condition like pre-diabetes been examined and counselled if it happening unseen,
For now anyone reading this can help by letting the author know of another trigger not captured in this inaugural patient driven categorisation of aHUS triggers.
Article No. 831
