Immunocompromised hosts with Delta/Omicron co-infections

A recent study published on the website of the medRxiv*preprint server reviewed clinical cases of co-infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta/Omicron variants and Omicron BA.1/BA.2 sublines in immunocompromised patients ( CI).

Various studies have reported the prolongation of virus survival in immunocompromised patients, which creates an environment conducive to additional viral mutations. It is therefore necessary to assess the impact of an underlying immunodeficiency or an immunosuppressive treatment on the co-infection of viral variants which result in the formation of recombinant variants.

Study: Delta/Omicron and BA.1/BA.2 co-infections occurring in immunocompromised hosts. Image credit: ktsdesign / Shutterstock

Delta/Omicron co-infection case description

Investigators in the present study evaluated two clinical cases of co-infection with the Delta/Omicron variants of SARS-CoV-2 (B.1.617.2/B.1.1.529) and two cases of co-infection with the sub – Omicron BA.1/ BA.2 lines in patients with IC.

The first clinical case was a 70-year-old man with a history of lung transplantation. He reported fever and respiratory symptoms related to coronavirus disease 2019 (COVID-19) before testing positive by polymerase chain reaction (PCR) for SARS-CoV-2. Virus genotyping showed that the patient was infected with the Delta variant of SARS-CoV-2. The patient received three doses of the Pfizer/BioNTech SARS-CoV-2 vaccine before the onset of symptoms. Initial treatment with casirivimab/imdevimab followed by administration of dexamethasone and remdesivir to the patient was undertaken for five and ten days, respectively. He was then discharged from the hospital without mechanical oxygen; however, he reported reduced forced expiratory volume (FEV1) from baseline and exertional dyspnea.

Six weeks after discharge, the patient returned to the hospital with fever, productive cough and shortness of breath. The patient again tested positive for SARS-CoV-2 by PCR, with viral genotyping showing the presence of both the Delta variant, presumably from the initial infection, and the Omicron variant, indicating secondary infection. He was treated with dexamethasone and remdesivir for active SARS-CoV-2 infection and with tixagevimab and cilgavimab for additional prophylaxis.

The researchers found that the patient had undetectable IgG and IgM antibodies against the SARS-CoV-2 nucleocapsid (N) protein of the Delta and Omicron variants. These results made it possible to differentiate an immune response associated with an infection or a vaccine. The patient was treated with a monoclonal antibody composed of casirivimab and imdevimab for both infections, which resulted in increased levels of IgG antibodies against SARS-CoV-2 spike (S).

Variant analysis was performed at the points marked with a red triangle (SARS-CoV-2 test positive) and the dotted line above intersects the hypothetical viral loads of a Delta (Δ) and Omicron (O) variant in each sample.  Black triangles represent negative SARS-CoV-2 PCR tests.  V1-V3 represent the vaccine doses.  Rem: remdesivir.  Green lines indicate immunosuppressants and the height of the shape reflects the dose level.  Monoclonal antibody treatment and administration time are indicated by the blue triangles.  C/I: casirivimab/imdevimab, C/T: tixagevimab and cilgavimab.  COVID serology indicates when specific antibody tests were performed.  IgMSP: anti-spike IgM, IgGSP: anti-spike IgG, IgGNC: anti-nucleocapsid IgG, ND: not detected, AU: arbitrary units.

Variant analysis was performed at the points marked with a red triangle (SARS-CoV-2 test positive) and the dotted line above intersects the hypothetical viral loads of a Delta (Δ) and Omicron (O) variant in each sample. The black triangles correspond to negative SARS-CoV-2 PCR tests. V1-V3 represents the vaccine doses. Rem: remdesivir. Green lines indicate immunosuppressants and the height of the shape reflects the dose level. Monoclonal antibody treatment and administration time are indicated by the blue triangles. C/I: casirivimab/imdevimab, C/T: tixagevimab and cilgavimab. COVID serology indicates when specific antibody tests were performed. IgMPS: Anti-spike IgM, IgGPS: anti-spike IgG, IgGCN: Anti-nucleocapsid IgG, ND: not detected, AU: arbitrary units.

Other SARS-CoV-2 co-infections

The researchers also looked at another case of SARS-CoV-2 co-infection in a woman in her 70s with uncontrolled diabetes. She tested positive by PCR for SARS-CoV-2 after being vaccinated with three doses of the messenger ribonucleic acid (mRNA) vaccine.

The team also identified three separate cases of BA.1/BA.2 co-infection.

The first case was that of a woman aged approximately 60, with a history of hematological malignancy after five cycles of chemotherapy. Notably, she had not received any COVID-19 vaccine. She tested positive for SARS-CoV-2 with a predominantly BA.1 infection. Initial treatment with monoclonal antibody of sotrovimab was given to him. She returned to the hospital two months later with persistent symptoms of COVID-19. A co-infection was subsequently detected.

The second case was of a man in his 50s who had a history of stroke. He had BA.1/BA.2 co-infection and was vaccinated with all three doses of mRNA.

The third patient was an approximately 80-year-old woman with a history of chronic lymphocytic leukemia. She was initially treated with anti-B cell therapy with obinutuzumab and venetoclax and received three doses of mRNA vaccine.

RNA re-extraction of patient samples showed multiple amplified peaks for RNA polymerase 1 (RDR1), RDR2, and RDR3-4. Additionally, the team observed the co-occurrence of amplicons characteristic of the BA.1 and BA.2 variants, indicating that co-infection occurred in the samples, rather than variant recombination.

A) Electrophoretogram of ORF1A, Spike 1 region, Spike 2 region and Spike 3-4 region sites where different sized amplicons indicating Omicron (red) and BA.2 (green) co-infection ) are here.  B) Schematic illustrating expected fragment location for variants under normal, mixed, or recombinant conditions.  C) Next-generation sequencing reads were visualized in the built-in genome viewer, with the direction of the reads colored in red or blue.  Deletions are indicated by a bar, single nucleotide variants show the variant nucleotide, and insertions are highlighted by a purple box.

A) Electrophoretogram of sites of ORF1A, Spike 1 region, Spike 2 region and Spike 3-4 region where amplicons of different sizes indicating co-infection with Omicron (red) and BA.2 ( green) are present. B) Schematic illustrating expected fragment location for variants under normal, mixed, or recombinant conditions. C) Next-generation sequencing reads were visualized in the built-in genome viewer, with the direction of the reads colored in red or blue. Deletions are indicated by a bar, single nucleotide variants show the variant nucleotide, and insertions are highlighted by a purple box.

Laboratory results of case studies of co-infections

The team detected the variants present in the PCR-positive SARS-CoV-2 samples by combining whole genome sequencing (WGS) and a genotyping PCR performed by fragment analysis. Mutation hotspots present on the SARS-CoV-2 genome were amplified, and the resulting fragments, called amplicons, were separated by capillary electrophoresis. The assessed size differences were then used to determine any characteristic deletions. The initial sample from the patient co-infected with the Omicron/Delta variants contained only the Delta variant sequences, while subsequent samples exhibited the mutational signatures of the initial Delta infection and subsequent Omicron infection.

Conclusion

The results of the study showed the comorbidities and symptoms that are responsible for the weakening of the immune system in patients with IC, making them more susceptible to co-infections of the SARS-CoV-2 variant.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health behavior or be treated as established information.

Journal reference:

  • Delta/Omicron and Omicron/BA.2 co-infections occurring in immunocompromised hosts, Richard Leuking, Madhusudhanan Narasimhan, Lenin Mahimainathan, Alag mut, Yan Liu, Chao Xing, Christian Larsen, Andrew E Clark, Jeffrey A SoRelle, medRxiv preprint 2022 , DOI: https://doi.org/10.1101/2022.04.04.22273058, https://www.medrxiv.org/content/10.1101/2022.04.04.22273058v1

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