Virus World

Background

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) in ~ 30% of all infected individuals. Here, we present a case of PASC in a patient with rheumatoid arthritis characterized by viral persistence in the nasopharynx for 6 months after acute infection. We demonstrate transient disappearance of antigen persistence and decreased antiviral and autoimmune T cell responses after nirmatrelvir/ritonavir and tocilizumab treatment.

Case Presentation

A 37-year-old female with a 7-year history of rheumatoid arthritis enrolled in a COVID-19 research study was found to continuously test SARS-CoV-2 antigen positive in the nasopharynx for 6 months after acute infection. She simultaneously presented with new-onset PASC symptoms including chronic occipital headache and periods of intense fatigue 8 weeks after acute infection. The patient was prescribed nirmatrelvir/ritonavir to treat SARS-CoV-2 persistence at 3.5 months post-acute infection and observed a reduction in PASC symptoms 3 weeks after completing antiviral treatment. After resurgence of PASC symptoms, she stopped treatment with tocilizumab for rheumatoid arthritis to attempt complete SARS-CoV-2 viral clearance. The severity of the patient’s PASC symptoms subsequently increased, and she developed new-onset brain fog in addition to previous symptoms, which resolved after resumption of tocilizumab treatment. Assessment of adaptive immune responses demonstrated that nirmatrelvir/ritonavir and tocilizumab treatment decreased antiviral and autoreactive T cell activation. After resuming tocilizumab treatment, the patient’s PASC symptoms were significantly reduced, but nasopharyngeal antigen positivity remained.

Conclusions

These data suggest that nirmatrelvir/ritonavir should be considered in the treatment of PASC in patients who have SARS-CoV-2 antigen persistence, though care must be taken to monitor the patient for symptom resurgence or viral reactivation. In addition, the IL-6 inhibitor tocilizumab may ameliorate PASC symptoms in patients with persistent headache, fatigue, and brain fog.

Preprint available ( July 22, 2022):

https://www.researchsquare.com/article/rs-1879380/v1 

It isn’t often that an investigation of a single patient who has a devastating, unrecognized disease leads to finding an existing drug that works, but also reveals something entirely new about gene function. A study from Dusan Bogunovic, PhD, Director of the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai and colleagues just published in the journal Immunity, tells such a tale. The young woman was only 18 when the investigation began. Her death from COVID-19 tragically juxtaposes the challenges of treating an ultrarare genetic disease with those of a pandemic infectious disease. “We were so so sad when she passed. She was doing so well for the first time in her life for full 2 years. She was very happy, and her family was very happy to see her that way,” said Dr. Bogunovic.

An Immune Response in Overdrive - Problems started right away.

The patient was born with an oozing rash that striped the left side of her body – which would turn out to be a clue. At a year of age she developed persistent diarrhea and vomiting, and tests showed massive inflammation along her digestive tract. At age three she ballooned with sudden water weight as protein seeped into her urine from damaged kidney tubules. But her overactive immune system rejected a transplant, anti-rejection drugs weakened her, and she went on dialysis. Then asthma and food and environmental allergies kicked in. Her growth slowed. Although her condition didn’t have a name, it was clearly autoinflammatory. The innate immune response, the part that controls the signals that release cytokines, was always in overdrive, inflaming her own tissues. The researchers found the patient in an “undiagnosed disease program” at Mt. Sinai, one of several that the National Institutes of Health sponsors, where patients with unusual collections of signs and symptoms, many of them children who’ve been through grueling “diagnostic odysseys,” have their genomes searched for causative mutations. The programs help connect patients and researchers. The young woman had a previously unknown mutation in a well-studied gene called JAK1. Matching a mutation in a single gene to a disease is valuable because it can identify a specific glitch in a protein, and that can suggest therapeutic strategies – including existing treatments. In this case, a drug already available to treat two other autoimmune conditions, rheumatoid arthritis and psoriatic arthritis, made sense: tofacitinib, known from drug ads as Xeljanz. It’s a daily pill, a “JAK inhibitor.”

The researchers nailed down the mechanism using a powerful and increasingly prevalent technique, “custom single-cell RNA sequencing.” Scrutinizing one cell at a time better reflects molecular happenings than analyzing all the RNAs that fall out of a mashed up tissue sample consisting of more than one cell type. It’s a signal-to-noise issue. The four types of JAK genes – that stands for “Janus kinase” – encode enzymes (kinases) that turn on other genes. The JAK genes control production of cytokines, and the gene that was mutant in the young woman – JAK1 – controls more than 25 of them. Cytokines must be in precise, dynamic balance to prevent infections while not raging out of control and backfiring, which happens in the “cytokine storms” that kill during COVID.  The young woman’s mutation was unusual in several ways. First, instead of abolishing a gene’s function, it not only ramps it up, but affects cytokine types that JAK enzymes usually don’t. In genetics we call this a “toxic gain-of-function.” A second peculiarity is that the mutation was only in some of the young woman’s cells, making her a genetic mosaic. Perhaps the mutation had never been identified before because having it in every cell is unsurvivable. There’s precedent for a mosaic being a milder case. Jesse Gelsinger, the young man who died in a gene therapy trial in 1999, was a mosaic for a metabolic disorder; infants with the mutation in every cell die without treatment...

Original study published in Immunity (August 3, 2020):

https://doi.org/10.1016/j.immuni.2020.07.006

BACKGROUND

The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear.

METHODS

We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.

RESULTS

A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group.

CONCLUSIONS

Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114. opens in new tab.)

Published in NEJM (June 16, 2021):

https://doi.org/10.1056/NEJMoa2101643 

Researchers develop way to ID cells infected with chikungunya. Since chikungunya virus emerged in the Americas in 2013, it has infected millions of people, causing fever, headache, rash, and muscle and joint pain. For some people, painful, debilitating arthritis lasts long after the other symptoms. Now, researchers at Washington University School of Medicine in St. Louis have figured out a way to detect cells infected with chikungunya virus that survive the infection. They genetically modified the virus such that it activated a fluorescent tag within cells during infection. Months after the initial infection, the researchers could detect glowing red cells still harboring viral RNA. The study, in mice, opens up new ways to understand the cause of – and find therapies for – chronic viral arthritis. The findings are published August 29, 2019 in PLOS Pathogens.

Senior author Deborah Lenschow, MD, PhD, an associate professor of medicine and of pathology and immunology, and co-first author and graduate student Marissa Locke answered questions about the research, which was conducted in collaboration with co-first author Alissa Young, PhD, co-author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, and others.

How common is chronic arthritis caused by chikungunya infection?

Lenschow: Between 30% and 60% of people infected with chikungunya virus go on to develop chronic arthritis that can last up to three or four years after infection. Researchers had found viral RNA in joint fluid from people with chronic arthritis, but they didn’t know whether the virus had gone dormant or whether it was still multiplying and infecting new cells at an undetectably low level.

Locke: Nobody had located the cells that harbored the viral RNA. This matters because if we can’t find the infected cells, we can’t study them.

Where did you find the virus, and what does that tell you about the cause of chronic arthritis?

Locke: We found the virus in muscle cells and in connective tissue cells in the skin and muscle. These cells likely had become infected within the first week of the virus invading the body, yet managed to survive. They were still there in the muscles and joints up to 114 days after infection, and they still had viral RNA inside them.....

Findings published  August 29 on PLOS Pathogens (Open Access):

https://doi.org/10.1371/journal.ppat.1007993