aHUS diagnosis: time is of the essence

Article No 360

22 July 2020

Whilst aHUS patients increasingly wonder whether It is possible to withdraw from eculizumab/Ravulizumab treatment,  many more are seeking to access the drugs in the first place. They cannot withdraw until they have benefited from treatment when they needed it.
All will first need to be diagnosed with aHUS or at least something that “ looks like it”.

The Global aHUS Patients Research Agenda lists a diagnosis topic relating to what they see as the key diagnosis challenge:

“Is there a diagnosis sweet spot which can be found before a developing thrombotic microangiopathy turns into a catastrophic episode of aHUS?”

A recent publication “Economic Impact of Early-in-Hospital Diagnosis and Initiation of Eculizumab in Atypical Haemolytic Uraemic Syndrome”   looks at the impact of a diagnosis timeline on 222 USA patients who were hospitalised with an episode of what looked like aHUS.

“ Looked like “ because the information source ,Premier Perspective® Hospital Database which the investigators were using for their research did not have a illness classification for “aHUS”, only “HUS” and “TMA” . No wonder it is difficult to answer the question “ How many aHUS patients are there?” when the disease has no separate classification in health records.

In the period Oct 2011 to March 2016 out of  about 29 million recorded hospital visits   there were 22908 hospital visits recorded as due to HUS or TMA. Of these 741 involved use of eculizumab and that was for 239 individual patients

So an investigator looked through the 239 records and eliminated those remaining whose HUS was down to e.coli infection or whose TMA was down to secondary reasons e.g. stem cell bone marrow transplant.

They were left with  222 patients to meet their criteria for inclusion i.e. with evidence of aHUS and eculizumab use in the database . This is from a database which claims to hold 350 million patients  records of  hospital visits.

This database used by the investigators was not set up for clinical research. It was more  for health insurance purposes and designed to track what happens to hospitalised patients and the cost of their hospitalisation.

Complex statistic models were set up to analyse the data held about the 222 aHUS patients and the results of their investigation can be read in the full article at this LINK.

The aim of the study was  to determine if there were incremental costs of treatment depending on whether eculizumab was initiated “early” or “late” . The cut off point for what was defined as early was 7 days or less from admission to hospital. The researchers used this cut off because that is the average time taken both to suspect a TMA and eliminate other causes of it  i.e HUS and TTP.

Of the 222 USA patients 72 had initiated eculizumab treatment early and 150 were late.

Although as stated the aim was to compare cost of hospitalisation between the two groups other measures were recorded including time from first eculizumab initiation to discharge, discharge status or death, days spent in the intensive care unit (ICU), readmission indicators, dialysis indicators, as well as total hospital costs.

The study also gave some rarely reported characteristics of the USA aHUS patients.

Compared with other age data seen the USA patient cohort studied was generally older. The average age of the two groups was 34 ( early ) and 46 ( late) respectively. Overall 20% of patients were over 65 years when expectation would be that it would be little more than 5%.

It was 1.5 times more likely that someone over 65 would be diagnosed later. Along with the data that it would be 3 times more likely for someone age 18 or less to be diagnosed early, age has a bearing on the speed of diagnosis.

Over 63% of the 222 patients were classified as white , 20 % black and 13% other races. This is a different mix of races to that reported by the aHUS Registry in 2015 which reported that nearly 87% of aHUS patients were Caucasian and 4% were black ( most Registry  participating centres are european).  A level of 63% white does however correspond  to proportion of non Hispanic white people in the USA population.  At 20% the black cohort with aHUS  is 50% higher than the 13% black  prevalent population in the general population. Black aHUS patients are more likely to be in the late initiator group. A new insight, perhaps, into aHUS in the USA.

58% of the early initiator group were female but that rose to 70% in the late initiator group.

So what is the impact of being in the late initiator group in the USA ?

The study says you are:

1 . three times more likely to need dialysis

2. likely  to stay almost twice as long in hospital  29 days v 16 days

3. twice as likely to need ICU care

4. likely to be discharged 1.5 days later, once eculizumab is initiated.

5. slightly more likely to be readmitted

5. to incur 20% more hospitalisation costs $103k v $ 86k

but you are also

1. likely to spend less time in ICU

2. slightly less likely to die in hospital

This research shows that there is a “sweeter spot“ for diagnosis once the patient is in hospital i.e. sometime less than 7 days after admission.

The first  barrier to overcome is recognising a TMA , and then eliminating HUS and TTP through testing as possible causes of  that TMA.  Before suspecting something which may respond to eculizumab treatment.

Recognition of a TMA ought to be regarded with the same priority  as recognising a heart attack or stroke. A “blue light” priority. Suspicion of aHUS , or a complement mediated TMA needs greater awareness among specialists. Some updating on what the spectrum of aHUS patients looks like may be needed.

Unusually the research group  proposes ideas for better diagnosis practice. These briefly are:

  1. education about the financial benefits of early diagnosis and eculizumab initiation:

  2. testing for ADAMTS13 activity and inhibitors as soon as TMA is suspected and moving to in-house testing  wherever possible to reduce the waiting times for results to one day.

  3. educating  plasmapheresis directors  to the need to obtain ADAMTS13 testing, as the results of this test informs the necessity for either plasma exchange or infusion and costs be saved:

  4. Establish cross speciality  TMA teams of physicians to pool knowledge.

By the time an aHUS patient is admitted to hospital, aHUS has probably reached  catastrophic levels  and so time is of the essence. Earlier intervention after admission reduces further harm. Days can be clipped from even the “early“  timeline of 7 days.

But aHUS patients’ stories always include tales of their  journey from feeling well to aware to getting admitted  to hospital.

That can take more time and may have much an impact on the severity of the illness on admission. That requires a different form of awareness.


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