Case presentation Thalassemia Center

1. Case presentationThalassemia Center

2. A 14-year old Omani girl • Known case of Beta-Thalassemia Major • Diagnosed at the age of 6 months. • On regular transfusion every 4 weeks since that time. • First visit to Thalassemia centre at the age of 9 years old.

3. Findings on 1st presentation: • Mild thalassemic features. • Severe growth retardation (below 3rd centile). • Liver: 8cm. • Spleen: 14 cm. • Hb: 6.8 g/dl. • S. Ferritin: 8600 ug/l • HCV RNA +ve

4. Chelation history: • Not on any chelation therapy till the age of 9 years. • Desfral started at the age of 9 years • On Exjade since November 2006 ( 500mg, 20 mg/kg daily )

5. Family History: 23 y 22 y 16 y 16 y 14 y 9 y 6 y

6. On Examination: • Good general condition • Vital signs are stable • Growth parameters are below 3rd centile • Pallor: ++ • No jaundice • Abdomen: spleen 4 cm and liver 3 cm BCM. • CVS: normal. • Chest: clear • CNS: grossly intact.

7. Investigations: • B gene: IVS 1-5 (G C) /CD 30 (G C) • One Alpha gene deletion. • HCV RNA turned –ve in Nov 2007 (no treatment). • EF was 60% in 2006. • Euglycemic, normal thyroid & parathyroid functions.

8. Baseline investigations done before starting Exjade: • Serum ferritin: 2992 ug/l • Serum creatinine: 0.4 mg/dl • SGPT: 168 IU/L / SGOT: 91 IU/L • IGG: 30.3/ IGA: 3.2/ IGM: 3.5 (in 2004) • Anti ds DNA: -ve (in 2004) • ANF: +ve 1/1000 speckled (in 2004) • RF: +ve (in 2004) • Anti smooth muscle Ab: +ve (in 2004)

13. Exjade started HCV RNA –ve

14. Drug fever

15. Definition • A disorder characterized by fever coinciding with the administration of the drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful physical examination and laboratory investigation

16. Mechanisms • Hypersensitivity reactions • Altered thermoregulatory mechanisms • Directly related to administration of the drug • Direct extension of the pharmacologic action of the drug • Idiosyncratic reactions

17. 1. Hypersensitivity reactions: • Due to: 1. Ab-Ag complexes 2. T-cell immune responce • Fever appears several days to three weeks after the drug has been started, but the lag time can be as long as several years. • Fever can arise within hours of a rechallenge, in a previously sensitized patient.

18. Fever may the sole manifestation of a hypersensitivity reaction. • Hepatic, renal or pulmonary involvement, rash, mucosal ulceration, and hematologic abnormalities are not uncommon. • Withdrawal of the offending drug usually results in disappearance of the fever within 72 to 96 hours which helps to confirm the diagnosis.

19. Five drug-classes deserve special mention: • Anticonvulsants (e.g: phenytoin) • Minocycline • Other antimicrobial agents (e.g: beta lactams) • Allopurinol • Heparin

20. 2. Altered thermoregulatory mechanisms: • Regulated by the anterior hypothalamus. • Fever is caused by releasing “Endogenous Pyrogens” (e.g: IL alpha & beta, TNF and Interferon alpha). • Drugs that can alter these Thermoregulatory mechanisms: • Exogenous thyroid hormone • Anticholinergics (e.g: TCA) • Sympathomimetics (e.g: amphetamines)

21. 3. Directly related to administration of the drugs: • Contamination of the administrated drug with endotoxin or other exogenous pyrogens. • Phlebitis, local inflammation and/or sterile abscesses can occur at sites of injection.

22. 4. Fever as an extension of the pharmacologic effect of a drug: • Fever observed following chemotherapy for various solid tumors, lymphomas, and leukemias due to release of different cytokines from cell necrosis and lysis.

23. Fever starts two to three days after chemotherapy and may last for one week or more. • This early febrile response usually can be distinguished from febrile neutropenia which rarely develops before the second week after chemotherapy.

24. 5. Fever due to an idiosyncratic reaction: • These reactions include unpredictable syndromes and genetic disorders, and there is some overlap with hypersensitivity phenomena. • Malignant hyperthermia • Neuroleptic malignant syndrome (NMS) • Serotonin syndrome • Glucose-6-phosphate dehydrogenase deficiency:

25. GENERAL CLINICAL ISSUES • Drug fever is usually a diagnosis of exclusion. • The first assumption of most clinicians is that fever is due to infection, which may not always be easy to exclude. • Connective tissue diseases or malignancy are also often difficult to exclude. • Absence of the rash does not exclude Drug Fever as it is only present in 18% of cases.

26. Fever patterns: • The onset is in about eight days, but varies from less than 24 hours to many months. • fever may vary from a low-grade fever to high grade “hectic” fever with chills and rigors. • Patient’s condition may vary from severely ill to surprisingly well. • Relative bradycardia occurs in only about 10% of cases.

27. Laboratory investigations: • WBC can be elevated with eosinophilia and occurs in less than 20% of cases. • ESR is usually increased but this is a nonspecific finding. • Unexplained disturbance of liver function and/or renal impairment can provide clues to the diagnosis (e.g: interstitial nephritis caused by beta lactams).

28. Cessation of the drug(s): • The only real way to know if a patient has a drug fever in the majority of patients is by stopping the drug(s). • The usual clinical approach is to discontinue the most probable offending drug first, followed by cessation of other drugs if fever persists. • In most cases, resolution of drug fever will occur within 72 to 96 hours of discontinuing the offending drug.

29. Rechallenge: • Rechallenge with the offending drug can confirm the diagnosis if fever recurs. • Rechallenge is usually safe, particularly when the initial febrile illness is mild, but unexpected events can arise. • In clinical practice, rechallenge is not often performed.

30. Thank you