An immunosuppressed patient with COVID-19 in England developed viral mutations last summer — including one included in the notorious B.1.1.7 or “U.K. variant” — after treatment with convalescent plasma, researchers found.
A man in his 70s, who had received immunotoxic chemotherapy in 2012 to treat lymphoma, was hospitalized with COVID-19 and treated with antibiotics, steroids, and remdesivir. However, following treatment with convalescent plasma in July, genomic sequencing revealed the patient acquired viral mutations, including a deletion present in the B.1.1.7 variant, reported Ravindra Gupta, MD, PhD, of University of Cambridge in England, and colleagues.
“We have documented a repeated evolutionary response by SARS-CoV-2 in the presence of antibody therapy during the course of a persistent infection in an immunocompromised host,” the authors wrote in an unedited but peer-reviewed manuscript published in Nature.
The man died in late August. Gupta’s group did not claim that he was the first to develop the B.1.1.7 mutation or that it spread from him to other people. Rather, they speculated that the plasma therapy had unleashed the resistant variants, and could do so in other immunosuppressed patients too.
In such patients, they wrote, “the antibodies administered [in plasma] have little support from cytotoxic T cells, thereby reducing chances of clearance and theoretically raising the potential for escape mutations.”
Consequently, they cautioned against using convalescent plasma in severe COVID-19 patients and especially in those with compromised immune function.
“The data from this single case report might warrant caution in use of convalescent plasma in patients with immune suppression of both T cell and B cell arms,” they wrote, suggesting it should only be used in immunosuppressed patients as part of observational studies with appropriate infection control precautions.
The FDA recently limited the scope of its emergency use authorization of convalescent plasma in COVID-19 patients to less severe patients, but did not suggest extra caution in immunosuppressed patients. In fact, the agency said, “The therapeutic window may be longer” when plasma is given to patients with “impaired humoral immunity.”
In the British case, the man was initially hospitalized in May with neutropenic sepsis, and tested positive for SARS-CoV-2 about a week later. He was discharged later that month, but readmitted in late June with cough and breathlessness.
His clinical condition deteriorated and he received dexamethasone and two 10-day courses of remdesivir with 5 days in between. Convalescent plasma was administered on two days around July 20; more remdesivir and convalescent plasma was administered about 4 weeks later. He died shortly afterward.
Gupta — who also documented the second case of HIV remission with the “London patient” in 2019 — and colleagues collected viral samples from this patient 23 times. During the first 57 days, they found little change in viral population following treatment with remdesivir, but following the July round of convalescent plasma, there was a shift in viral genotype.
Initially the patient’s viral serotype showed a mutation first reported in China (a D614G substitution in the spike protein). However, that changed in late July, when a variant with two alterations in the spike protein, including the deletion seen in the B.1.1.7 variant, became prevalent.
Experimental analyses found “two-fold reduced susceptibility of these viruses to convalescent plasma containing polyclonal antibodies,” though the researchers said it was not the reason for the ultimate treatment failure.
Gupta and colleagues said this viral evolution is unlikely to occur in immunocompetent patients, as “viral diversity is likely to be lower due to better immune control.”
However, they questioned CDC guidance recommending 20 days for afebrile immunocompromised patients as the upper limit of infection prevention, noting they detected “environmental contamination” in a single occupancy room, so the patient was moved to a negative-pressure isolation room.
Limitations to the study included that it was a single case, and samples were taken from the upper respiratory tract, not the lower tract.
The authors disclosed no conflicts of interest.