Some side effect- Meningococcal infection!

The side effects of treatment and residual ailments of an  aHUS  onset featured highly by aHUS families in the contribution to the aHUS Patients Research Agenda. The topic is covered by this question for researchers in the Agenda.

Can the side effects of treatment using a complement inhibitor be distinguished from those temporary and permanent ongoing ailments which follow initial onset?

One such side effect rides higher than most i.e. the increased risk of a meningococcal infection.

aHUS is “bloody scary” but so too are meningitis and septicemia.

What is meningococcal infection? Why are those aHUS patients treated with eculizumab more susceptible to it?

Meningococcal infection is the result of the bacteria Neisseria meningitidis. The bacteria are divided into 12 groups distinguished by what the  capsule shell that they have is made from. Each type or serotype is given a different letter to identify it , These are A, B, C, E , H, I J, L, W ,Y, and Z.  Most infections  are caused by types A, B, C, W, X, and Y.

Most of the time the bacteria lives in the body , usually at the back of the nose, without doing any harm. Young people in particular are carriers and close contact can considerably increase invasion of the bacteria particularly in places that have a lot of people in a confined spaces.

The highest incidents are in babies less than 1 year old. Another spike occurs between 15 and 25 years.

JFrom being harmless to being deadly,  a lot depends on the individual’s immune system working properly.
The bacteria does take advantage if there is any deficiency in someone’s immune system. This is most striking in those with a deficiency in the innate immune system Complement .

It is the Complement System which is the first responder to invasion but if it  is overwhelmed by the bacteria the resulting uncontrolled  interplay with the coagulation system results in a varied response from mild to severe. Either meningitis or sepsis or both. can happen. Severe clotting can stop blood supply and limbs are lost through lack of blood flow.

aHUS patients treatment is to block the Complement System from working thus creating the environment in which the bacteria can thrive and switch from being harmless to deadly. Thus it is a side effect of the use of eculizumab making aHUS patients 1000 times more susceptible to meningococcal infection.

More at risk but not definite to get it.

For the general population in the USA  there may be between 1500 and  5000 incidents of meningococcal infection per year. Eculizumab has been in use for more than 10 years with thousands of aHUS and PNH patients at potential risk  and in that time only a handful of aHUS patients globally have onset with an infection.

Those incidents can be explained by :
-early risk management protocols for using eculizumab were not as stringent as in later years, a small number of incidents happened during trials which enormously benefited those yet to receive treatment.
– although vaccination for meningococcal infection is  compulsory as a condition of use , not all patients have accessed the vaccination for serotype B. Some patients not so vaccinated have experienced the infection.
-even when vaccinated it is advisable to have prophylactic antibiotics because breakthrough can occur in some vaccinated patients. It can take up to 14 days for a vaccination to take effect. So it is with meningococcal vaccination, it takes  time for body’s adaptive immune system to create the specific antibodies needed. This natural response varies between individuals and some may need a booster vaccination very soon after the initial one to be fully protected. All will need a booster vaccination every 3 to 5 years as the antibody protection depletes.

aHUS patients need to be VIGILANT:

  • vaccination for the most threatening types of meningococcal infection is essential , make sure you get at least one  for  A C W135 Y  and preferably for serotype B  too and those facing a potential transplant should get one  well before a transplant operation
  • booster vaccinations are needed in time , patients should ask their clinicians how they are monitoring their protected status;
  • if they are available to patients prophylactic use of antibiotics provide added protection and compliance with prescription by the patient is  very important;
  • Be aware of community outbreaks of meningococcal infections and keep a distance;
  • Know the symptoms* of an on set and get immediate medical attention if there are any concerns, as early treatment of aHUS patients with meningococcal infection has better outcomes than someone from the general population.
  • vigilance needs to be continued for a time after withdrawal from eculizumab treatment;
  • carry the Patient Safety Card  (see above)  given to patients when eculizumab is prescribed, bring it to clinicians attention if need be, and read it from time to time as a reminder.
*Symptoms   Septicaemia- S.  Meningitis- M    Both – B
Fever and/or Vomiting. B
Severe headache M
 Limb/joint/muscle pain (sometimes with stomach pain/diarrhoea) S
 Cold hand and feet/shivering. S
 Pale or mottled skin. S
 Breathing fast/breathless S
 Rash (anywhere on the body). B
 Stiff neck (less common in young children) M
 Dislike of bright lights (less common in young children). M
 Very sleepy /vacant /difficult to wake B
 Confused /delirious B
 Seizures (fits) may also be seen M
Further reading if viewer has more time
See a copy of Alexion’s leaflet about eculizumab click here.

Also the following table from Alexion’s literature about all side effects reported and the likelihood of incidence
Table 1: Adverse Reactions reported in 1,407 patients included in overall eculizumab clinical trials, including patients with PNH, aHUS, and refractory gMG as well as from postmarketing experience

MedDRA System Organ Class Very Common
(≥1/100 to <1/10)
(≥1/1,000 to <1/100)
(≥1/10,000 to <1/1,000)
Infection and infestations Pneumonia, Upper respiratory tract infection, Nasopharyngitis, Urinary tract infection, Oral Herpes Meningococcal infectiona, Sepsis, Septic shock, Peritonitis, Lower respiratory tract infection, Fungal infection, Viral infection, Bronchitis, Abscess, Cellulitis, Influenza, Gastrointestinal infection, Cystitis, Infection, Sinusitis, Tooth infection Aspergillus infectionb, Arthritis bacterialb, Genitourinary tract gonococcal infection, Haemophilus influenzae infection, Impetigo, Gingivitis
Neoplasms benign, malignant and unspecified (including cysts and polyps) Malignant melanoma, Myelodysplastic syndrome
Blood and lymphatic system disorders Leukopenia, Anaemia Thrombocytopenia, Lymphopenia Haemolysis*, Abnormal clotting factor, Red blood cell agglutination, Coagulopathy
Immune system disorders Anaphylactic reaction, Hypersensitivity
Endocrine disorders Basedow’s disease
Metabolism and nutrition disorders Decreased appetite
Psychiatric disorders Insomnia Depression, Anxiety, Mood swings Abnormal dreams, Sleep disorder
Nervous system disorders Headache Dizziness, Dysgeusia, Tremor Paraesthesia Syncope
Eye disorders Vision blurred Conjunctival irritation
Ear and labyrinth disorders Tinnitus, Vertigo
Cardiac disorders Palpitation
Vascular disorders Hypertension Accelerated hypertension, Hypotension, Hot flush, Vein disorder Haematoma
Respiratory, thoracic and mediastinal disorders Cough, Oropharyngeal pain Dyspnoea, Epistaxis, Throat irritation, Nasal congestion, Rhinorrhoea
Gastrointestinal disorders Diarrhoea, Vomiting, Nausea, Abdominal pain Constipation, Dyspepsia, Abdominal distension Gastroesophageal reflux disease, Gingival pain
Hepatobiliary disorders Jaundice
Skin and subcutaneous tissue disorders Rash, Pruritus, Alopecia Urticaria, Erythema, Petechiae, Hyperhidrosis, Dry skin Dermatitis, Skin depigmentation
Musculoskeletal and connective tissue disorders Arthralgia, Myalgia, Pain in extremity Muscle spasms, Bone pain, Back pain, Neck pain, Joint swelling Trismus
Renal and urinary disorders Renal impairment, Dysuria Haematuria
Reproductive system and breast disorders Spontaneous penile erection, Menstrual disorder
General disorders and administration site conditions Pyrexia, Chills, Fatigue, Influenza like illness Oedema, Chest discomfort, Asthenia, Chest pain, Infusion site pain Extravasation, Infusion site paraesthesia, Feeling hot
Investigations Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Haematocrit decreased, Haemoglobin decreased Coombs test positiveb
Injury, poisoning and procedural complication Infusion related reaction

Also an in-depth clinical publication by Lewis and Ram about Meningococcal DIsease and the Complement System click here 

This article is for information and awareness  only and not clinical advice ,which should be sought from those medically qualified to give it.

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