The Health Sciences Authority (HSA) is Singapore’s national authority regulating health products. Apart from approval of new drugs and indications, every few months, HSA releases a bulletin summarising the various adverse drug reactions (ADRs) that were collated over the past few months. The bulletins can be found on the HSA’s website.
A summary of the key points from the issue in December 2021 may be found below:
ADR #1: Severe Cutaneous Adverse Reactions Associated with Allopurinol and Considerations for Patient Genotyping
Allopurinol-induced severe cutaneous adverse reactions (SCAR) are rare but known undesirable events related to the drug. They include:
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
- Drug reaction with eosinophilia and systemic symptoms (DRESS)
Advanced age, renal impairment, and higher starting doses of allopurinol are some of the risk factors for SCAR. Patients who possess the HLA-B*5801 gene also have a greater probability of developing the adverse event.
Since March 2016, there have been at least 80 local cases of SCAR linked to allopurinol that were reported, some of which were fatal.
Investigations revealed that most of the affected patients had pre-existing risk factors for allopurinol-induced SCAR. Out of those who also underwent an HLA-B*5801 genotyping test subsequently, majority of them obtained a positive result.
Checking for the HLA-B*5801 allele is not mandatory before initiating a patient on allopurinol. However, it should be considered when patients are deemed to have a higher risk for allopurinol associated SCAR.
There are 3 places offering the HLA-B*5801 genotyping test in Singapore:
- DNA Diagnostic & Research Laboratory at KK Women’s and Children’s Hospital
- Tan Tock Seng Hospital Molecular Diagnostic Laboratory
- Tissue Typing Laboratory at HSA
Results can generally be obtained within 1 to 7 working days.
Although, patients negative for HLA-B*5801 are at a lower risk of developing allopurinol-induced SCAR, there are still non-genetic elements that can increase a patient’s likelihood for it. Thus, clinical vigilance must be exercised.
Takeaway Message #1:
- Be mindful of risk factors for allopurinol-induced SCAR before commencing therapy, and to consider HLA-B*5801 genotyping, especially in patient groups with added risks for SCAR.
- Educate patients on recognition of symptoms of SCAR, for prompt drug withdrawal and medical consultation at the first sign of rash. Provide supplementary patient education material.
References:
- Allopurinol-induced serious cutaneous adverse reactions and the role of genotyping. (2016). Retrieved 4 January 2022, from https://www.hsa.gov.sg/announcements/safety-alert/allopurinol-induced-serious-cutaneous-adverse-reactions-and-the-role-of-genotyping.
- Gout: Achieving the Management Goal. (2019). Retrieved 4 January 2022, from https://www.ace-hta.gov.sg/docs/default-source/acgs/gout—achieving-the-management-goal-(dec-2019).pdf.
- Safe use of allopurinol (gout medicine). 2019). Retrieved 4 January 2022, from https://www.hsa.gov.sg/consumer-safety/articles/safe-use-of-allupurinol.
ADR #2: Risk of Myocarditis and Pericarditis with mRNA COVID-19 Vaccines
mRNA COVID-19 vaccinations have been found to be associated with a greater risk for myocarditis and pericarditis. Occurrence of the rare adverse event (AE) after the immunisation was reported both internationally, and in Singapore.
Locally, as of 30 November 2021, the HSA has received 94 AE reports of myocarditis and pericarditis linked to the mRNA COVID-19 vaccine, all of whom have either recovered, or were still recuperating.
Majority of the cases developed in younger aged males below 30 years old without significant past medical history. In females, the risk was found to be higher in those between 20 to 49 years old. Most of the cases also developed following the second dose of the vaccine. For myocarditis and pericarditis arising after the first dose, patients should be assessed for any previous SARS-CoV-2 infection.
The AE is postulated to be immune-mediated. Symptoms often manifest about 3 to 5 days after the second dose.
Common clinical presentations include:
- Chest pain (100%): May be pleuritic or positional in nature
- Muscle aches, fatigue, or fever (63%)
- Abnormal ECG results (87%)
- Increased levels of troponins (100%)
- Raised inflammatory biomarkers (e.g., C-reactive protein)
Initial investigations recommended to aid in diagnosis of mRNA COVID-19 vaccine related myocarditis and pericarditis are:
- Comprehensive medical history-taking (e.g., recent infection, strenuous activity) and clinical examination
- 12-lead electrocardiogram (ECG)
- Blood biomarkers (e.g., troponin T/I)
- Imaging tests, if necessary (e.g., in patients with pre-existing cardiovascular risk factors, or for more in-depth workup)
Depending on the patient’s condition, they may be treated as follows:
- Chest pain: Analgesia (e.g., paracetamol, non-steroidal anti-inflammatory drugs [NSAIDs])
- Ventricular contractile dysfunction: Medications used in heart failure (e.g., angiotensin converting enzyme [ACE] inhibitors, beta-blockers)
- Presumed pericardial inflammation: Immunomodulatory therapy (e.g., colchicine)
- Other severe cases: Parenteral agents (e.g., globulins, corticosteroids)
Most of the time, patients will make a quick and complete recovery spontaneously and without any complications.
A recently published study has also shown that the potential for severe AEs, including myocarditis, following infection by SARS-CoV-2 was significantly increased in comparison to after receiving the mRNA COVID-19 vaccine.
Hence, the benefits of getting the mRNA COVID-19 vaccination still outweighs the risk for immunization related myocarditis and pericarditis.
Takeaway message #2:
- Consider potential mRNA COVID-19 vaccine induced myocarditis and pericarditis in patients with similar clinical features and immunization history.
- Educate patients on recognising symptoms of myocarditis and pericarditis post vaccination. Advise vaccinated people, especially adolescents and younger men, to avoid strenuous physical activity for one week after their second dose to minimise risk of developing these complications.
References:
- COVID-19 Vaccination – Myocarditis and Pericarditis After mRNA COVID-19 Vaccination. Centers for Disease Control and Prevention. (2021). Retrieved 4 January 2022, from https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/myocarditis.html.
- Bozkurt, B., Kamat, I., & Hotez, P. (2021). Myocarditis With COVID-19 mRNA Vaccines. Circulation, 144(6), 471-484. https://doi.org/10.1161/circulationaha.121.056135
- Stone, C., Rukasin, C., Beachkofsky, T., & Phillips, E. (2019). Immune‐mediated adverse reactions to vaccines. British Journal Of Clinical Pharmacology, 85(12), 2694-2706. https://doi.org/10.1111/bcp.14112
- Shay, D., Shimabukuro, T., & DeStefano, F. (2021). Myocarditis Occurring After Immunization With mRNA-Based COVID-19 Vaccines. JAMA Cardiology, 6(10), 1115. https://doi.org/10.1001/jamacardio.2021.2821
- Haaf, P., Kuster, G., Mueller, C., Berger, C., Monney, P., & Burger, P. et al. (2021). The very low risk of myocarditis and pericarditis after mRNA COVID-19 vaccination should not discourage vaccination. Swiss Medical Weekly. https://doi.org/10.4414/smw.2021.w30087
- Collet, J., Thiele, H., Barbato, E., Barthélémy, O., Bauersachs, J., & Bhatt, D. et al. (2021). 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal, 42(14), 1289-1367. https://doi.org/10.1093/eurheartj/ehaa575
- Ferreira, V., Schulz-Menger, J., Holmvang, G., Kramer, C., Carbone, I., & Sechtem, U. et al. (2018). Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation. Journal Of The American College Of Cardiology, 72(24), 3158-3176. https://doi.org/10.1016/j.jacc.2018.09.072
- Ammirati, E., Frigerio, M., Adler, E., Basso, C., Birnie, D., & Brambatti, M. et al. (2020). Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy. Circulation: Heart Failure, 13(11). https://doi.org/10.1161/circheartfailure.120.007405
- Barda, N., Dagan, N., Ben-Shlomo, Y., Kepten, E., Waxman, J., & Ohana, R. et al. (2021). Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. New England Journal Of Medicine, 385(12), 1078-1090. https://doi.org/10.1056/nejmoa2110475
ADR #3: E-cigarette or Vaping Product Use Associated Lung Injury (EVALI)
E-cigarettes and other forms of electronic vaporisers can cause EVALI, an acute lung injury. It is a result of pulmonary inflammation, that may have the following pathological features:
- Acute fibrinous pneumonitis,
- Diffuse alveolar damage, or
- Organising pneumonitis.
Oftentimes, they are bronchiolocentric and with bronchiolitis.
EVALI is defined by the United States Centre for Disease Control and Prevention as “the utilisation of an e-cigarette 90 days prior to symptom onset, pulmonary infiltrates on chest imaging, absence of viral, bacterial, or fungal infection, and no evidence of a cardiac or rheumatologic cause”.
The pathogenesis of EVALI is unknown, but use of e-cigarettes and similar devices within the last 90 days is a major risk factor for the condition.
Patients who develop EVALI usually present with these symptoms after a week of vaping:
- Respiratory: Dyspnoea, chest congestions, cough
- Gastrointestinal symptoms
- Fever
Haemoptysis is an uncommon manifestation of EVALI.
There is no one particular test to identify EVALI. Diagnosis is typically determined based on the patient’s history, and through ruling out other potential illnesses (e.g., infection, neoplasm, autoimmune, vascular, or pulmonary conditions).
Supportive treatment and abstinence from vaping is the mainstay of therapy in most cases. For more severe cases, a trial of steroids may be considered as well. Ultimately, complete cessation of vaping is needed to attain the best clinical results.
Takeaway message #3:
- Consider EVALI as a potential diagnosis in patients with associated symptoms and background.
References:
- Butt, Y., Smith, M., Tazelaar, H., Vaszar, L., Swanson, K., & Cecchini, M. et al. (2019). Pathology of Vaping-Associated Lung Injury. New England Journal Of Medicine, 381(18), 1780-1781. https://doi.org/10.1056/nejmc1913069
- Jonas, A., & Raj, R. (2020). Vaping-Related Acute Parenchymal Lung Injury. Chest, 158(4), 1555-1565. https://doi.org/10.1016/j.chest.2020.03.085
- Layden, J., Ghinai, I., Pray, I., Kimball, A., Layer, M., & Tenforde, M. et al. (2020). Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin — Final Report. New England Journal Of Medicine, 382(10), 903-916. https://doi.org/10.1056/nejmoa1911614
- Siegel, D., Jatlaoui, T., Koumans, E., Kiernan, E., Layer, M., & Cates, J. et al. (2019). Update: Interim guidance for health care providers evaluating and caring for patients with suspected e‐cigarette, or vaping, product use associated lung Injury — United States, October 2019. American Journal Of Transplantation, 19(12), 3420-3428. https://doi.org/10.1111/ajt.15690
