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Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.

ABSTRACT: BACKGROUND:Immune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration. CASE PRESENTATION:We report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed early-onset severe dyspnea associated with acute coronavirus HKU1 (non-COVID-19) infection, with diffuse pneumonitis evidenced by ground glass opacification on CT scan. He was treated with steroids leading to resolution of pneumonitis on repeat imaging, suggesting an exacerbated immune-mediated toxicity. CONCLUSION:We report the first case of a patient with melanoma with severe and reversible diffuse pneumonitis in association with coronavirus HKU1 following combined nivolumab and ipilimumab immunotherapy. Although we do not have data on the impact of ICI therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptomatology, a possible interaction should be considered when deciding on dosing in patients with possible SARS-CoV-2 exposure or when evaluating patients with presumed ICI-related pneumonitis during the COVID-19 pandemic.

SUBMITTER: Serzan MT

PROVIDER: S-EPMC7246106 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.

Serzan Michael T MT Kumar Princy N PN Atkins Michael B MB

Journal for immunotherapy of cancer 20200501 1

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration.<h4>Case presentation</h4>We report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed earl ...[more]

PMID: 32434789

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Project description:BACKGROUND:Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ?12 weeks of immunosuppression. METHODS:Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ?12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS:Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ?10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS:A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ?12 weeks, and has distinct clinicopathological features.

Project description:BackgroundPatients with non-small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies.Materials and methodsWe systematically compared computed tomography (CT) features of RT- versus ICI-pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics-based machine learning (ML) model to discern pneumonitis etiology.ResultsBetween 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI-pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT-pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI- from RT-pneumonitis with an area under the receiver-operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus.ConclusionRT- and ICI-pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision-making.Implications for practicePatients with non-small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI-pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.

Project description:We have recently described the discovery of a novel coronavirus, coronavirus HKU1 (CoV-HKU1), associated with community-acquired pneumonia. However, the clinical spectrum of disease and the epidemiology of CoV-HKU1 infections in relation to infections with other respiratory viruses are unknown. In this 12-month prospective study, 4,181 nasopharyngeal aspirates from patients with acute respiratory tract infections were subjected to reverse transcription-PCRs specific for CoV-HKU1 and human coronaviruses NL63 (HCoV-NL63), OC43 (HCoV-OC43), and 229E (HCoV-229E). Coronaviruses were detected in 87 (2.1%) patients, with 13 (0.3%) positive for CoV-HKU1, 17 (0.4%) positive for HCoV-NL63, 53 (1.3%) positive for HCoV-OC43, and 4 (0.1%) positive for HCoV-229E. Of the 13 patients with CoV-HKU1 infections, 11 were children and 8 had underlying diseases. Similar to the case for other coronaviruses, upper respiratory infection was the most common presentation of CoV-HKU1 infections, although pneumonia, acute bronchiolitis, and asthmatic exacerbation also occurred. Despite a shorter duration of fever (mean, 1.7 days) and no difference in maximum temperature in children with CoV-HKU1 infections compared to patients with most other respiratory virus infections, a high incidence of febrile seizures (50%) was noted, which was significantly higher than those for HCoV-OC43 (14%), adenovirus (9%), human parainfluenza virus 1 (0%), and respiratory syncytial virus (8%) infections. CoV-HKU1 and HCoV-OC43 infections peaked in winter, although cases of the former also occurred in spring to early summer. This is in contrast to HCoV-NL63 infections, which mainly occurred in early summer and autumn but were absent in winter. Two genotypes of CoV-HKU1 cocirculated during the study period. Continuous studies over a longer period are warranted to ascertain the seasonal variation and relative importance of the different coronaviruses. Similar studies in other countries are required to better determine the epidemiology and genetic diversity of CoV-HKU1.

Project description:We sequenced and compared the complete genomes of 22 strains of coronavirus HKU1 (CoV HKU1) obtained from nasopharyngeal aspirates of patients with respiratory tract infections over a 2-year period. Phylogenetic analysis of 24 putative proteins and polypeptides showed that the 22 CoV HKU1 strains fell into three clusters (genotype A, 13 strains; genotype B, 3 strains and genotype C, 6 strains). However, different phylogenetic relationships among the three clusters were observed in different regions of their genomes. From nsp4 to nsp6, the genotype A strains were clustered with the genotype B strains. For nsp7 and nsp8 and from nsp10 to nsp16, the genotype A strains were clustered with the genotype C strains. From hemagglutinin esterase (HE) to nucleocapsid (N), the genotype B strains were clustered closely with the genotype C strains. Bootscan analysis showed possible recombination between genotypes B and C from nucleotide positions 11,500 to 13,000, corresponding to the nsp6-nsp7 junction, giving rise to genotype A, and between genotypes A and B from nucleotide positions 21,500 to 22,500, corresponding to the nsp16-HE junction, giving rise to genotype C. Multiple alignments further narrowed the sites of crossover to a 143-bp region between nucleotide positions 11,750 and 11,892 and a 29-bp region between nucleotide positions 21,502 and 21,530. Genome analysis also revealed various numbers of tandem copies of a perfect 30-base acidic tandem repeat (ATR) which encodes NDDEDVVTGD and various numbers and sequences of imperfect repeats in the N terminus of nsp3 inside the acidic domain upstream of papain-like protease 1 among the 22 genomes. All 10 CoV HKU1 strains with incomplete imperfect repeats (1.4 and 4.4) belonged to genotype A. The present study represents the first evidence for natural recombination in coronavirus associated with human infection. Analysis of a single gene is not sufficient for the genotyping of CoV HKU1 strains but requires amplification and sequencing of at least two gene loci, one from nsp10 to nsp16 (e.g., pol or helicase) and another from HE to N (e.g., spike or N). Further studies will delineate whether the ATR is useful for the molecular typing of CoV HKU1.

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Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.

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Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.

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