A team of scientists from the United Kingdom has recently revealed the therapeutic benefits of histamine receptor antagonists in reducing long-term symptoms of coronavirus disease 2019 (COVID-19). They have also indicated that T cell immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection vary between asymptomatic COVID-19 and long-COVID. The study is currently available on the medRxiv* preprint server.

Background

Studies characterizing clinical manifestation of COVID-19 have indicated that the disease is often associated with long-term consequences even after the resolution of acute SARS-CoV-2 infection. This is described as long-COVID. Patients with long-COVID may present with a variety of symptoms, including gastrointestinal, neurological, dermatological, cardiovascular, renal, and hepatic symptoms. In most cases, long-COVID symptoms develop after recovering from a mild or asymptomatic infection that does not require medical attention. Such symptoms may persist for more than 7 months.

In contrast to acute SARS-CoV-2 infection, a high prevalence of long-COVID has been observed among younger COVID-19 patients with few comorbidities. However, not enough information is available regarding the etiology of long-COVID and its therapeutic interventions.

In the current study, the scientists have analyzed the dynamics of cell-mediated immune responses in long-COVID, as well as exploring the therapeutic benefits of histamine receptor antagonists in reducing long-COVID symptoms.

Study design

The study was conducted on 49 patients with mild COVID-19 who eventually developed long-COVID symptoms following recovery from initial acute SARS-CoV-2 infection. The symptom persisted for more than 84 days following acute infection. During the acute infection phase, none of the patients required therapeutic interventions against the disease.

In addition, the study included 16 COVID-19 recovered patients who did not develop long-COVID. They were considered as asymptomatic controls. Blood samples were collected from all participants to measure hematological and biochemical parameters and for flow cytometric analysis of immune cells.

The participants were asked to complete a symptom questionnaire that was designed to gather information about possible long-COVID symptoms, including fatigue, fever, neurological and neuropsychological symptoms, post-exertional malaise, chest pain, gastrointestinal symptoms, and dermatological symptoms.

In the later phase of the study, combination treatment with histamine 1 (H1) and histamine 2 (H2) receptor antagonists was offered to all participants. Of 49 long-COVID patients, 25 agreed to receive the treatment, which was continued for a minimum of 4 weeks.

Important observations

Based on the study findings, about 96% of long-COVID patients presented with multiple symptoms, with an average of 5 typical symptoms. The average duration of symptoms was 269 days. Among long-COVID patients, the majority were relatively young (average age: 43 years) and female (60%).

Regarding hematological and biochemical measurements, of 49 long-COVID patients, only 2 and 4 had mildly increased C-reactive protein levels and erythrocyte sedimentation rates, respectively. Other parameters were within the normal range in all patients.

Regarding therapeutic intervention, almost 60% reduction in symptom burden was observed in long-COVID patients treated with histamine receptor antagonists. Specifically, of 25 patients in the treatment group, 5 reported complete resolution of all symptoms, 13 reported improvements, 6 reported no change, and 1 reported deterioration of symptoms.

Of 24 long-COVID patients who did not receive the treatment, 24% reported spontaneous improvement in symptoms and 67% reported no change. About 8% of untreated patients developed additional symptoms eventually. Importantly, no correlation was observed between the anti-SARS-CoV-2 level and symptom resolution in both treated and untreated patients.

T cell response in long-COVID

The flow cytometric analysis revealed a significant difference in the numbers of circulating effector memory T cells between long-COVID and asymptomatic patients.

Specifically, a significantly lower than normal level of CD4+ effector memory T cells was observed in 25 long-COVID and 3 asymptomatic patients. Further analysis of the findings revealed a significantly distinct status of CD4+ effector memory T cells in long-COVID and asymptomatic patients.

Regarding CD8+ effector memory T cells, a significantly lower level was observed in 43 long-COVID and 14 asymptomatic patients.

The analysis of antigen densities of T cell-related proteins revealed a significantly increased expression of program cell death protein 1 (PD-1) in both CD4+ and CD8+ central memory T cells in all patients. In contrast, a significantly higher expression of CD28 was observed in CD4+ central memory T cells in asymptomatic patients compared to that in long-COVID patients.

Importantly, although a distinguishable T cell profile was observed in asymptomatic and long-COVID patients, it failed to predict therapeutic responsiveness to histamine receptor antagonists.

Overall, the study findings indicate that treatment with histamine receptor antagonists might help reduce symptom intensity of long-COVID. Moreover, the study provides information about long-term (more than 400 days) abnormalities in T cell landscape in long-COVID, which are considerably different from that observed in asymptomatic infections.

*Important Notice

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

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.