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Immune system diseases

Infectious diseases Consensus statement 4 April 2022 Free

COVID‐19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non‐malignant haematological conditions: Australian and New Zealand Children’s Haematology/Oncology Group consensus statement

Recommendations are based on evidence-based knowledge of safety, immunogenicity and efficacy of the vaccines in the general population, plus emerging data regarding COVID-19 vaccination in immunocompromised individuals

Eliska Furlong · Rishi S Kotecha · Rachel Conyers · Tracey A O'Brien · Jordan R Hansford · Leanne Super · Peter Downie · David D Eisenstat · Gabrielle Haeusler · Brendan McMullan · Marianne B Phillips · Bhavna Padhye · Luciano Dalla‐Pozza · Frank Alvaro · Christopher J Fraser · Wayne Nicholls · Julia E Clark · Matthew O'Connor · Benjamin R Saxon · Heather Tapp · John Heath · Sarah E Hunter · Karen Tsui · Mark Winstanley · Amanda Lyver · Emma J Best · Ushma Wadia · Daniel Yeoh · Christopher C Blyth · Nicholas G Gottardo

Mja2 51444
Infectious diseases Letters 7 February 2022 Free

An Australian case of multisystem inflammatory syndrome in an adult during the 2021 SARS‐CoV‐2 Delta outbreak

TO THE EDITOR: Multisystem inflammatory syndrome in children (MIS‐C) or adults (MIS‐A) is a rare but severe systemic inflammatory syndrome,1 with an epidemiological peak occurring 4–6 weeks after severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) outbreaks.2 Also known as paediatric inflammatory multisystem syndrome temporally associated with SARS‐CoV‐2, MIS‐C is the subject of active surveillance across paediatric centres.3 The peak age for the syndrome is 9 years,1 although cases have been reported in adults.4 We report, to our knowledge, the first Australian case of MIS‐A, diagnosed 2 months into the SARS‐CoV‐2 Delta outbreak in New South Wales, with 60 075 coronavirus disease 2019 (COVID‐19) notifications in the period 29 June to 4 October 2021.5 A 42‐year‐old woman presented with 7 days of subjective fevers, myalgia, light‐headedness, abdominal pain, nausea, palpitations and non‐pleuritic chest pain. Presentation occurred 27 days after acute COVID‐19 pneumonitis, confirmed by polymerase chain reaction and serology testing. The acute illness was mild, requiring neither oxygen nor hospitalisation, and the patient recovered fully 72 hours before onset of this new symptom complex. She was unimmunised against SARS‐CoV‐2. The patient was febrile (38.2°C), with tachycardia (114 beats per minute) and hypotension (79/56 mmHg) but no respiratory distress. She had bilateral conjunctival injection, a widespread blanching macular rash (Box), and oedema of the hands bilaterally. There was no lymphadenopathy or oral mucosal change. Investigations revealed significant inflammation, with a raised C‐reactive protein level (119 mg/L; reference interval [RI], ≤ 4 mg/L), lymphopenia (0.5 × 109/L; RI, 1.0–4.0 × 109/L), thrombocytopenia (74 × 109/L; RI, 150‐400 × 109/L), neutrophilia (12.2 × 109/L; RI, 2.0–8.0 × 109/L), deranged liver function tests (alanine transaminase, 160 U/L; RI, 10–35 U/L), and hypoalbuminemia (20 g/L; RI, 35–50 g/L). Her D‐dimer level was raised (2.34 mg/L; RI, < 0.5 mg/L), as was her brain natriuretic peptide level (1660 ng/L; RI, ≤ 125 ng/L); troponin and creatine kinase levels were normal. Blood and urine cultures were negative, and anti‐streptolysin O and anti‐DNase B titres were not raised. No echocardiographic evidence of myocarditis was seen, and there was no coronary artery dilatation. The patient responded to two doses of intravenous immunoglobulin (2 g/kg each) following 48 hours of inotropic support (metaraminol infusion then low dose noradrenaline). Aspirin (3 mg/kg daily) was administered, as well as intravenous antibiotics for 72 hours while cultures were pending. MIS‐A was diagnosed on the basis of current case definitions,6,7 although the patient also fulfilled criteria for probable toxic shock syndrome, as described in other case series.8 Adults and adolescents with MIS‐A typically present with multisystem involvement, often incorporating myocarditis, shock and gastrointestinal features,4,9 whereas younger children present more commonly with a Kawasaki disease‐like illness.9 Given the absence of specific diagnostic markers, the overlapping phenotype with toxic shock syndrome and the poor sensitivity of cultures and serological markers for these alternative diagnoses, such differentials must be carefully considered in the early phase of illness. Nonetheless, clinicians should be aware of MIS‐C or MIS‐A in patients presenting with shock, mucocutaneous changes and/or gastrointestinal symptoms, even without preceding symptomatic SARS‐CoV‐2 infection. Prompt treatment with intravenous immunoglobulin and/or steroids is essential to minimise long term morbidity from coronary artery dilatation.1 Although rare, further cases of MIS‐C and MIS‐A are anticipated following increasing COVID‐19 case notifications in NSW and Victoria. This letter was published as a peer‐reviewed Accepted Article (prior to structural editing and typesetting) on 14 October 2021. Box – Bilateral conjunctival injection (A) and diffuse blanching macular rash (B) in an adult with multisystem inflammatory syndrome

Annaleise R Howard‐Jones · Sam R Orde · Zoe Jennings

Cardiovascular diseases Guideline summary 16 November 2020 Free

The 2020 Australian guideline for prevention, diagnosis and management of acute rheumatic fever and rheumatic heart disease

Introduction: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) cause significant morbidity and premature mortality among Australian Aboriginal and Torres Strait Islander peoples. RHDAustralia has produced a fully updated clinical guideline in response to new knowledge gained since the 2012 edition. The guideline aligns with major international ARF and RHD practice guidelines from the American Heart Association and World Heart Federation to ensure best practice. The GRADE system was used to assess the quality and strength of evidence where appropriate.Main recommendations: The 2020 Australian guideline details best practice care for people with or at risk of ARF and RHD. It provides up‐to‐date guidance on primordial, primary and secondary prevention, diagnosis and management, preconception and perinatal management of women with RHD, culturally safe practice, provision of a trained and supported Aboriginal and Torres Strait Islander workforce, disease burden, RHD screening, control programs and new technologies.Changes in management as a result of the guideline: Key changes include updating of ARF and RHD diagnostic criteria; change in secondary prophylaxis duration; improved pain management for intramuscular injections; and changes to antibiotic regimens for primary prevention. Other changes include an emphasis on provision of culturally appropriate care; updated burden of disease data using linked register and hospitalisations data; primordial prevention strategies to reduce streptococcal infection addressing household overcrowding and personal hygiene; recommendations for population‐based echocardiographic screening for RHD in select populations; expanded management guidance for women with RHD or ARF to cover contraception, antenatal, delivery and postnatal care, and to stratify pregnancy risks according to RHD severity; and a priority classification system for presence and severity of RHD to align with appropriate timing of follow‐up.

Anna P Ralph · Sara Noonan · Vicki Wade · Bart J Currie

Mja2 50851
Infectious diseases Perspectives 14 October 2020 Free

Considerations for cancer immunotherapy during the COVID‐19 pandemic

Cancer immunotherapy during the COVID‐19 pandemic presents management challenges from immune‐related toxicities, requiring careful patient selection The coronavirus disease 2019 (COVID‐19) pandemic has led to fundamental re‐evaluation of the benefits versus risks of treatment in oncology. Immunotherapy has had an expanding presence in oncology, becoming a primary systemic treatment option in diseases such as melanoma, lung, urothelial, renal, and head and neck cancers. Immune checkpoint inhibitor (ICI) therapy, namely anti‐programmed cell death protein 1 (anti‐PD‐1), anti‐programmed cell death ligand 1 (anti‐PD‐L1) and anti‐cytotoxic T‐lymphocyte‐associated protein 4 (anti‐CTLA‐4) antibodies, halt the negative regulatory checks of T lymphocytes, thus activating the immune response against tumours. Patients with cancer receiving these treatments are faced with a unique set of treatment‐related toxicities driven by an autoimmune mechanism. An association between immune‐related adverse events (irAEs) and severe COVID‐19 has been raised during the current outbreak. In particular, an overlap in the physiological insult from immunotherapy‐mediated pneumonitis and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐related interstitial pneumonia is hypothesised.1 Both conditions may present with lung parenchymal changes, and their coexistence may potentially aggravate the underlying interstitial inflammatory infiltrate and diffuse alveolar damage, leading to a common final pathway of respiratory failure. Pre‐existing lung pathology is expected to be a risk factor for COVID‐19 pneumonia, with higher incidence in patients with lung cancer and smokers.2 Whether prior thoracic radiation may have an impact on outcomes from COVID‐19 pneumonia is unknown. Parallels have been drawn between the cytokine storm driving COVID‐19‐associated acute respiratory distress syndrome and cytokine release syndrome as a complication following T cell‐engaging therapies, such as chimeric antigen receptor T cell and CD3‐based bispecific T cell engager therapies. It is known that interleukin (IL)‐6, IL‐10 and interferon (IFN)‐γ are key drivers behind cytokine release syndrome. Elevated circulating IL‐6 levels have been observed in patients with COVID‐19‐associated pneumonia.3 Patients with severe COVID‐19 have significantly higher circulating levels of pro‐inflammatory cytokines, including IL‐1B, IL‐6, IL‐8 and IL‐10, compared with milder cases of COVID‐19;3 and elevated IL‐6 has been shown to be a predictor of mortality risk. Patients with immune‐related toxicity have higher levels of 11 circulating cytokines, such as G‐CSF, GM‐CSF, IFN‐α‐2, IL‐1a, IL‐1B, IL‐2 and IL‐12,4 with some but incomplete overlap with the cytokine milieu seen in severe COVID‐19 cases.3 The outcomes of COVID‐19 in patients with cancer treated with immunotherapy remain under investigation, with some2,5 but not all6 studies suggesting a more severe outcome. In a multicentre study from China involving 105 patients with cancer infected with SARS‐CoV‐2, 6% received anti‐PD‐1 therapy within 40 days of COVID‐19 symptom onset and experienced increased risk of death and critical symptoms.2 Another series of 423 cancer patients with SARS‐CoV‐2 infection from New York City also reported that treatment with ICI therapy within 90 days was a predictor for admission to hospital and for severe respiratory illness, defined as the requirement for high flow oxygen supplementation or mechanical ventilation.5 Of interest, even after exclusion of patients with lung cancer, the ICI group experienced worse outcomes, inferring that the ICI therapy itself conferred inferior COVID‐19 outcomes without the confounding effect of lung cancer, which had been shown as an independent predictor of poor prognosis in COVID‐19. However, an interim analysis of the first 200 patients from the Thoracic Cancers International COVID‐19 Collaboration (TERAVOLT) registry of patients with thoracic malignancies did not observe a worse outcome among the 37% of patients receiving ICI therapy (23% ICI alone and 14% ICI plus chemotherapy), with data collection ongoing.6 Dual checkpoint inhibitor (anti‐CTLA4 with anti‐PD1 antibody) therapy has achieved high response rates in a number of cancer types,7,8 but is associated with greater incidence and severity of treatment‐related toxicity compared with monotherapy.7 This has several implications. Firstly, differentiating between immune‐mediated pneumonitis and COVID‐19‐associated pneumonia can be difficult due to similarities in clinical and radiological features. Earlier in the pandemic, there were concerns that this may cause delays in initiation of corticosteroids, which is the standard management of irAEs. However, emerging evidence for potential benefit of dexamethasone in severe cases of COVID‐199 reduces concerns for its empirical use in cases where immune‐mediated pneumonitis is a differential diagnosis. Secondly, patients with severe irAEs, such as immune‐mediated pneumonitis requiring intensive care support may face a health system already strained by demand from COVID‐19 cases. Finally, severe irAEs require treatment with high dose corticosteroid and, at times, additional immunosuppressive agents, such as infliximab and mycophenolate. To avoid rebound of the irAEs, corticosteroids are weaned over 6–8 weeks, subjecting patients to prolonged immunosuppression that can predispose them to opportunistic and nosocomial infections.10,11 This has the potential to add further burden to the health care system. The impact of cancer immunotherapy on microbial infection in general is not fully understood. A retrospective study of patients with metastatic melanoma receiving immunotherapy (mainly ipilimumab, an anti‐CTLA4 antibody) reported a 7.3% incidence of serious infections due to a variety of bacterial, viral, fungal or parasitic infections requiring hospitalisation or parenteral antimicrobials.10 Nonetheless, the study of this interaction is complex, with the receipt of corticosteroids for irAEs and having diabetes as a comorbidity10,12 associated with an increased risk of infection in patients with cancer receiving ICI therapy. Furthermore, immune checkpoint blockade can reactivate tuberculosis and viral infections. There are case reports of acute tuberculosis developing in patients with cancer receiving immunotherapy, without concurrent corticosteroid therapy.13 At least three of five cases were suspected to represent reactivation of latent tuberculosis, which may be directly mediated through PD‐1 inhibition driving an exaggerated immune response to tuberculosis infection. Another consideration for patients with cancer receiving immunotherapy is influenza vaccination during the COVID‐19 pandemic. While there is currently no vaccine specifically against COVID‐19, many health authorities encourage the uptake of influenza vaccination to reduce the concurrent burden from influenza illnesses, particularly for nations approaching winter facing the seasonal influenza period. Controversy surrounds whether influenza vaccination in patients receiving cancer immunotherapy heightens the risk of irAEs.14 Numerous retrospective series support the safety of inactivated influenza vaccine in recipients of anti‐PD‐1 monotherapy, with no increase in irAEs observed.15 Reassuringly, influenza vaccination had no adverse impact on the anticancer effect of ICI therapy.14,15 However, there may be heightened concerns for influenza vaccination in combination immunotherapy (anti‐PD‐1 with anti‐CTLA‐4) recipients, as they are more prone to irAEs, including rarer, but potentially fatal, complications such as immune‐mediated myocarditis. This potential concern for influenza vaccination in recipients of combination ICI can leave this patient population more vulnerable from influenza infection. For patients taking monotherapy ICI, current evidence supports the safety and efficacy for influenza vaccination. There are guidelines addressing the use of cancer immunotherapy in the COVID‐19 era.16,17 These call for careful considerations on the use of dual checkpoint inhibitor therapy depending on the local prevalence of community transmission and the capacity of the local health service to cope with demand.16 On a practical note, this requires individual patient risk–benefit assessment. Patient factors such as age, smoking and comorbidities (eg, diabetes and chronic obstructive pulmonary disease) may affect their recovery from irAEs and affect the outcomes from concomitant COVID‐19. Tumour factors for consideration include the burden and biology of disease. Combination immunotherapy may be justified, for example, in a young patient with metastatic melanoma with high disease burden and/or intracranial metastases. This is in contrast to a patient with underlying comorbidities who has low volume disease and/or disease characteristics, such as underlying B‐Raf proto‐oncogene (BRAF) V600K mutation or desmoplastic melanoma subtype, associated with higher likelihood of response to single‐agent anti‐PD‐1/anti‐PD‐L1 therapy. Current guidelines recommend ICI monotherapy to be delivered at increased dosing intervals, such as nivolumab four times per week and pembrolizumab six times per week.16 These approved alternate schedules have been shown to maintain therapeutic efficacy, while advantageous in reducing patient attendance at health care facilities, potentially reducing exposure and community transmission of COVID‐19. The timing of immunotherapy cessation in patients is another consideration. A number of trials in metastatic non‐small cell lung cancer had a 2‐year treatment duration for immunotherapy in responding patients.18 Data on metastatic melanoma support that cessation of anti‐PD‐1 after at least 6 months of therapy in patients achieving complete response can be feasible without adversely affecting outcome.19 Selection of patients with cancer suitable to stop immunotherapy may further reduce these patients’ hospital visits and may potentially reduce the chance of acquiring COVID‐19. There are international efforts to collate the clinical experience of COVID‐19 in patients receiving cancer immunotherapy.6 These registries will provide a valuable resource for further areas of research, such as assessing the impact of irAEs on COVID‐19. The data will also improve our understanding of the outcomes in this patient population to aid management decisions and counsel patients. Research on potential biomarkers of disease severity may also assist in patient triage. In this rapidly evolving area, it is helpful for practising clinicians to maintain current knowledge through regularly updated resources (Box). In summary, the increased role of ICI therapy in oncology calls for consideration of the impact of their use during the COVID‐19 pandemic. While these agents are not directly immunosuppressive, as with cytotoxic chemotherapy, ICI‐associated toxicities pose diagnostic and therapeutic challenges for management in the setting of a COVID‐19 outbreak. Overlapping clinical and radiographic features in immune‐mediated pneumonitis and COVID‐19‐associated pneumonia may cause diagnostic difficulties at initial presentation. Severe irAEs requiring corticosteroids and prolonged immunosuppression may predispose patients to opportunistic infections. Furthermore, there is a possibility of worse outcomes in the setting of COVID‐19 with underlying immune‐mediated pneumonitis and damaging inflammatory response from immune checkpoint blockade. Practical measures, namely prolonging treatment interval and careful patient selection for combination ICI therapy, may help minimise harm. Box – Practice points for cancer immunotherapy during the coronavirus disease 2019 (COVID‐19) pandemic Judicious use of combination anti‐CTLA-4 and anti‐PD-1/anti‐PD-L1 immunotherapy in patients requiring high tumour response rate with good organ functional reserve. Combination checkpoint therapy is associated with higher rate for immune‐related toxicities (eg, pneumonitis), which may potentially have an adverse impact on outcomes in patients with COVID‐19 Use of approved dosing schedule with longer duration between treatments (eg, nivolumab every 4 weeks, pembrolizumab every 6 weeks) Individualised assessment for pausing or cessation of immunotherapy in patients with controlled low disease burden Rapid assessment and COVID‐19 testing for patients receiving cancer immunotherapy who have clinical presentations with overlapping features for COVID‐19 and immune‐related adverse events Prevention of co‐infections: seasonal influenza vaccination for patients taking single‐agent immune checkpoint inhibitor (the use in combination checkpoint recipients should be individualised). Pneumocystis jirovecii prophylaxis for patients receiving prolonged corticosteroid therapy for immune‐mediated toxicities Maintain current knowledge through professional journals, dynamic resource links (examples below) and webinars sharing clinical knowledge and experience internationally: ▸ Clinical Oncology Society of Australia (https://www.cosa.org.au/publications/covid‐19-updates/articles/) ▸ American Society of Clinical Oncology (https://www.asco.org/asco-coronavirus‐information) ▸ European Society for Medical Oncology (https://www.esmo.org/covid‐19-and‐cancer/covid‐19-full‐coverage) ▸ Journal of Thoracic Oncology (https://www.jto.org/content/covid19) anti‐CTLA‐4 = anti‐cytotoxic T‐lymphocyte‐associated protein 4; anti‐PD‐1 = anti‐programmed cell death protein 1; anti‐PD‐L1 = anti‐programmed cell death ligand 1.

Yada Kanjanapan · Desmond Yip

Mja2 50805
Environmental health Research 24 August 2020 Free

Respiratory and atopic conditions in children two to four years after the 2014 Hazelwood coalmine fire

Objective: To evaluate associations between exposure during early life to mine fire smoke and parent‐reported indicators of respiratory and atopic illness 2–4 years later. Design, setting: The Hazelwood coalmine fire exposed a regional Australian community to markedly increased air pollution during February – March 2014. During June 2016 – October 2018 we conducted a prospective cohort study of children from the Latrobe Valley. Participants: Seventy‐nine children exposed to smoke in utero, 81 exposed during early childhood (0–2 years of age), and 129 children conceived after the fire (ie, unexposed). Exposure: Individualised mean daily and peak 24‐hour fire‐attributable fine particulate matter (PM2.5) exposure during the fire period, based on modelled air quality and time‐activity data. Main outcome measures: Parent‐reported symptoms, medications use, and contacts with medical professionals, collected in monthly online diaries for 29 months, 2–4 years after the fire. Results: In the in utero exposure analysis (2678 monthly diaries for 160 children exposed in utero or unexposed), each 10 μg/m3 increase in mean daily PM2.5 exposure was associated with increased reports of runny nose/cough (relative risk [RR], 1.09; 95% CI, 1.02–1.17), wheeze (RR, 1.56; 95% CI, 1.18–2.07), seeking health professional advice (RR, 1.17; 95% CI 1.06–1.29), and doctor diagnoses of upper respiratory tract infections, cold or flu (RR, 1.35; 95% CI, 1.14–1.60). Associations with peak 24‐hour PM2.5 exposure were similar. In the early childhood exposure analysis (3290 diaries for 210 children exposed during early childhood, or unexposed), each 100 μg/m3 increase in peak 24‐hour PM2.5 exposure was associated with increased use of asthma inhalers (RR, 1.26; 95% CI, 1.01–1.58). Conclusions: Exposure to mine fire smoke in utero was associated with increased reports by parents of respiratory infections and wheeze in their children 2–4 years later.

Gabriela A Willis · Kate Chappell · Stephanie Williams · Shannon M Melody · Amanda Wheeler · Marita Dalton · Shyamali C Dharmage · Graeme R Zosky · Fay H Johnston

Mja2 50719

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