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The Clinical Diagnosis of ADRs
Pia Caduff-Janosa MD
Annual Course 2013
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2 Pia Caduff-Janosa, Uppsala Monitoring Centre
Outline
• What is a medical diagnosis?
• How is it reached?
• The certainty of diagnosis
• ADR or ”natural illness”?
• Selected conditions often associated with the use of medicines
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3 Pia Caduff-Janosa, Uppsala Monitoring Centre
Medical diagnosis
• Medical diagnosis:
1. is the process of attempting to determine or identify a possible disease
2. the opinion reached by this process
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4 Pia Caduff-Janosa, Uppsala Monitoring Centre
Differential Diagnosis
• Many candidate conditions -> elimination process -> diagnosis of exclusion
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5 Pia Caduff-Janosa, Uppsala Monitoring Centre
Key elements
• Recognizing patterns
• Comparing observation with experience
• Settting priorities
• Investigating
• Accepting and communicating that a final opinion cannot always be reached
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6 Pia Caduff-Janosa, Uppsala Monitoring Centre
Diagnostic certainty
• 83 yr old lady feels dizzy and falls
• Unable to get up, pain in hip and leg
• At admission: – Patient in pain, unwell, unable to lift left leg
which shows a rotation to the left
• Suspected diagnosis?
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7 Pia Caduff-Janosa, Uppsala Monitoring Centre
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8 Pia Caduff-Janosa, Uppsala Monitoring Centre
Diagnosis
• Fractured neck of left femur due to trauma
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9 Pia Caduff-Janosa, Uppsala Monitoring Centre
Diagnostic certainty
• 25 yr old, middle european man with recurring abdominal pain
• No temporal pattern • No stool abnormalities • No fever • No history of travel • All investigations (physical examination, x-
ray, ultrasound, stool cultures etc. etc) bland
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10 Pia Caduff-Janosa, Uppsala Monitoring Centre
So?
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11 Pia Caduff-Janosa, Uppsala Monitoring Centre
ADRs...
• ... are drug induced disease: they present the same way as natural disease does and show a similar course
-> the questions asked and diagnostic procedures will be the same
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12 Pia Caduff-Janosa, Uppsala Monitoring Centre
Skin
• Most frequently targeted organ
• Drug ”eruptions” -> mostly benign
• Severe reaction may be fatal
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13 Pia Caduff-Janosa, Uppsala Monitoring Centre
Exanthemous Drug Eruption
• Common (≥ 1%)
• Higher risk with allopurinol, antiepileptics, antibiotics (sulpha, cephalosporins, aminopenicillins)
• Time to onset 4-14 d (also after discontinuation
• Trunk -> extremities
• Conservative treatment
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14 Pia Caduff-Janosa, Uppsala Monitoring Centre
Exanthemous Drug Eruption
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15 Pia Caduff-Janosa, Uppsala Monitoring Centre
SJS and TEN
• Stevens Johnson Syndrome and Toxic Epidermal Necrolysis are – Rare (TEN 0.4-1.2/mio py; SJS 1-6/mio py) – Life-threatening (mortality 10% SJS and >30% TEN) – Drug induced skin reactions (70%) – Blistering and skin detachment (SJS 10% body surface,
TEN >30% body surface) – Mucosal involvement – High fever – Hepatic, intestinal and pulmonary involvment possible
Roujeau et Stern 1994
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16 Pia Caduff-Janosa, Uppsala Monitoring Centre
Most commonly associated drugs
• Sulphonamides
• Anticonvulsants
• Allopurinol
• Oxicam and pyrazolone NSAIDs
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17 Pia Caduff-Janosa, Uppsala Monitoring Centre
SJS/TEN
• Time to onset <4 weeks – 7 to 21d when first exposed, faster if rechallenge
• Symptomatic treatment – Fluid/electrolyte balance
– Nutritional support
– Nursing care
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18 Pia Caduff-Janosa, Uppsala Monitoring Centre
TEN
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19 Pia Caduff-Janosa, Uppsala Monitoring Centre
SJS/TEN – mucosal involvement
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20 Pia Caduff-Janosa, Uppsala Monitoring Centre
Relevant elements in reporting dermatological ADRs
• Description, distribution, number of lesions • Mucosal involvement • Duration of eruption • Associated symptoms
– Fever
– Itching
– Lymph node enlargement
– Hepatic involvement
– Blood count (eosinophilia)
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21 Pia Caduff-Janosa, Uppsala Monitoring Centre
Reference
Roujeau JC et al
Medication use and the risk of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis
New Engl J Med 333: 1600-7 (December 14th 1995)
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22 Pia Caduff-Janosa, Uppsala Monitoring Centre
Haematological ADRs
• Myelosuppression – One or all cell lines
– Production and /or maturation of cells
• Shortened peripheral cell survival
• Effects on clotting (plasma factors)
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23 Pia Caduff-Janosa, Uppsala Monitoring Centre
Myelosuppression
• Cytotoxic Type A effects – Predictable based on pharmacology – Dose dependent – Common – ...
• Idiosyncratic effects – Not predictable – Dose independent – rare
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24 Pia Caduff-Janosa, Uppsala Monitoring Centre
Individual susceptibility
• Individual differences in absorption and metabolism can affect Type A reactions
• Genetic predisposition for some Type B reactions – Chloramphenicol – Clozapine – 6-Mercaptopurine – Methotrexate – ...
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25 Pia Caduff-Janosa, Uppsala Monitoring Centre
Aplastic Anaemia
• Hypocellular bone marrow
• Pancytopenia (all cell lines affected) – Haemoglobin < 100g/l
– Neutrophil granulocytes <1.5 x 10G/l
– Platelets <100 x 10G/l
• Associated with medicines, radiation, exposure to chemicals, infections, autoimmune disorders, ?
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26 Pia Caduff-Janosa, Uppsala Monitoring Centre
Died of AA
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27 Pia Caduff-Janosa, Uppsala Monitoring Centre
Examples
• Anticonvulsants – Phenytoin, carbamazepin
• Antimicrobials – Chloramphenicol, suphonamides, zidovudine,
amodiaquine, mebendazole....
• Antirheumatics – Indomethacin, phenylbutazone, piroxicam,
penicillamin...
• Other – Captopril, lisinopril, acetazolamide, alpha-
interferon....
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28 Pia Caduff-Janosa, Uppsala Monitoring Centre
Agranulocytosis
• Severe neutropenia (neutrophils <0.5 G/l)
• Drug induced agranulocytosis is immune mediated and involves myelosuppression as well as peripheral cell destruction
• Medicines involved as for AA, particularly well known are clozapine and antithyroid drugs
• Febrile neutropenia can be life threatening
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29 Pia Caduff-Janosa, Uppsala Monitoring Centre
Clozapine
• Antipsychotic indicated for therapy resistant schizophrenia approved in the 1960ies.
• No EPS as with other antipsychotics
• Intense monitoring program with regular white cell counts prescribed according to risk pattern: highest in the first 3 months of therapy (1:700)
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30 Pia Caduff-Janosa, Uppsala Monitoring Centre
Antithyroid drugs
• Carbimazole, propylthiouracil and methimazole
• Incidence highest in the first 3 months (3/100’000/year)
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31 Pia Caduff-Janosa, Uppsala Monitoring Centre
Hepatotoxicity
• Potential complication of every medicine
• Principal cause of termination of clinical trials (approx 30%)
• Leading cause of market withdrawal of approved drugs between 1975 and 2005 (Friedman et al 1999)
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32 Pia Caduff-Janosa, Uppsala Monitoring Centre
Classification
• Hepatocellular liver injury – ALT≥ 2 ULN alone OR ALT/AP ≥ 5
• Cholestatic liver injury – AP ≥ 2 ULN alone OR ALT/AP ≤ 2
• Mixed liver injury – ALT/AP between 2 and 5 CIOMS 1999
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33 Pia Caduff-Janosa, Uppsala Monitoring Centre
Evaluation
• Chronology
• Specificity of pattern
• Exclusion of alternate explanations within the same pattern
• CIOMS-RUCAM scale
• Maria+Victorino scale (underscoring!)
• Liver biopsy and histology
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34 Pia Caduff-Janosa, Uppsala Monitoring Centre
Mechanisms
• Metabolic – Metabolism into chemically reactive
intermediates -> large amounts cannot be neutralized -> liver injury
• Immunological – Ivolvement of other organs, slower onset with
acceleration if rechallenged
– Immune response targeted at primary drug or metabolite (-> mixed aetiology)
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35 Pia Caduff-Janosa, Uppsala Monitoring Centre
Hepatic Steatosis ( fatty liver)
• If mitochondiral oxydation process is impaired -> fatty acids accumulate in the liver – Ex tetracyclines, amiodarone, perhexiline....
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36 Pia Caduff-Janosa, Uppsala Monitoring Centre
Normal liver
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37 Pia Caduff-Janosa, Uppsala Monitoring Centre
Steatosis
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38 Pia Caduff-Janosa, Uppsala Monitoring Centre
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39 Pia Caduff-Janosa, Uppsala Monitoring Centre
Uppsala Monitoring CentreBox 1051SE-751 40 Uppsala, SwedenVisiting address: Bredgränd 7, Uppsala
tel +46 18 65 60 60fax +46 18 65 60 88website www.who-umc.org