Lung disease and antibody levels contribute to long COVID, Stanford researchers find

People recovering from COVID-19 with a history of lung disease, including asthma or chronic obstructive pulmonary disorder, or who had lower levels of a particular antibody in the first week of diagnosis, took longer than their peers to experience a complete resolution of their symptoms, according to a new Stanford Medicine study.

The likelihood of experiencing sustained symptoms was unaffected by the severity of the initial disease; the ethnicity, age or sex of the patient; or whether the patient had been treated with the drug remdesivir.

The yearlong study is one of the first to evaluate the incidence of what has come to be known as long COVID in an ethnically diverse population and for a range of disease severities. The findings may help doctors predict who is likely to develop long COVID, as well as guide future vaccine development.

“Our finding that the levels of antibody to a specific viral protein within one week of diagnosis correlate with the time to complete resolution of symptoms is one of the first to identify a possible biomarker that can be assessed early to predict the course of the disease,” said Kari Nadeau, MD, PhD, who directs the Sean N. Parker Center for Allergy and Asthma Research at Stanford Medicine.

Nadeau, the Naddisy Foundation Professor in Pediatric Food Allergy, Immunology, and Asthma, is the senior author of the study, which was published online July 8 in JCI Insight. The lead authors of the study are Xiaolin Jia, MD, assistant professor of medicine; biostatistician Shu Cao; undergraduate Alexandra Lee; Samuel Yang, MD, associate professor of emergency medicine; Scott Boyd, MD, PhD, associate professor of pathology; Benjamin Pinsky, MD, PhD, associate professor of pathology and of medicine; and Sharon Chinthrajah, MD, associate professor of medicine and of pediatrics.

Yearlong study

The study followed 617 people diagnosed with COVID-19 at Stanford Health Care between March 2020 and February 2021. Monitoring began at their initial infection and included evaluations every one to three months thereafter for up to a year. Forty-two of the 105 people who remained in the study six months after their initial diagnosis reported at least one lingering symptom — most commonly fatigue, headaches or body aches — and four of the 21 people who remained in the study for a full year reported continuing symptoms including cough, nasal congestion, a loss of taste or smell, headache, fatigue, body aches, chills and fever 12 months after diagnosis.

Due to the time frame of the study, most participants were not vaccinated against the disease.

“When we began the study, we didn’t know much about the existence of long COVID,” Jia said. “We began by asking infected people about their symptoms and looked for any correlation with the initial severity of their disease; pre-existing health conditions including high blood pressure, diabetes and lung disease; and their ethnicity, age and sex.”

Of the 617 study participants, 39 never had any symptoms throughout the course of their infection and were excluded from further analysis. The disease severity of the remaining 578 ranged from mild to critical, and 351 were hospitalized as a result of their infection. Sixteen patients died during the study period. Thirty of the participants had received two doses of the mRNA vaccines available at the time. Nearly 44% of the participants were Hispanic or Latino; about 31% were white, 16% were Asian American or Pacific Islander, and 2% were Black.

Participants were asked to fill out a survey about their symptoms three, five, seven and 30 days after their diagnosis, and during subsequent follow-up visits that occurred at one- to three-month intervals. The researchers also collected nasal swabs and blood draws during the visits to assess the levels of antibodies to viral proteins.

The most common symptoms reported by the participants at the time of their diagnosis were cough, shortness of breath, fever, and nausea or vomiting. The most common lasting symptoms reported by the participants one month after diagnosis included a loss of taste or smell, fatigue, headache, and body aches. By six months, the most common symptoms were fatigue, headache and body aches.

Sustained symptoms

The researchers found that, among symptomatic people, the median time to the first resolution of all their symptoms was 44 days after diagnosis. But symptoms recurred in a significant number of people, most often in those who had moderate to severe initial disease. The median time for the sustained resolution of all symptoms — defined as being free from any symptom for one month or longer — was 214 days.

Infection by the virus that causes COVID-19 causes an immune response that includes antibodies that target viral proteins. One antibody recognizes a viral protein, called the nucleocapsid, or N protein, that surrounds the virus’s genetic material.

“We found that high levels of antibody to the viral N protein during the first week of infection were associated with a shorter time to sustained resolution of symptoms,” Jia said. “Conversely, people with a history of lung disease took longer to see their symptoms resolve completely.”

After three months, about 57% of the 179 people who filled out questionnaires reported persistent symptoms, including some people who had been asymptomatic at diagnosis but developed symptoms later.

“As has been shown in other studies, our results confirm that a person’s risk of long-term symptoms from COVID-19 is the same regardless of the severity of their initial infection, including those with no symptoms or very mild disease,” Nadeau said. “Therefore, it is better to avoid infection through vaccination, masking and avoiding crowded indoor areas when case levels are high.”

In May of 2021, Stanford launched the Post-Acute COVD-19 Syndrome Clinic to care for people struggling with long-term effects of the infection and to facilitate research into the disorder.

The findings from the study could facilitate the development of vaccines that could lower the risk of lasting effects of infection, the researchers said.

“Current vaccines primarily target the spike protein antigen,” Jia said. “However, other studies have shown that vaccines targeting the nucleocapsid antigen can elicit immune responses against the virus. Our study suggests that future vaccines targeting the N protein may result in higher anti-nucleocapsid antibody levels and may have additional benefits for the prevention of long COVID.”

Researchers from the Chan Zuckerberg Biohub are also coauthors of the study.

The study was supported by the National Institutes of Health (grants UL1TR003142, U5CA260517 and R21ES03304901), the Sean N. Parker Center for Allergy and Asthma Research, the Chan Zuckerberg Biohub, the Chan Zuckerberg Initiative, the Sunshine Foundation, the Crown Foundation, and the Parker Foundation.

See the study for additional support and possible conflicts of interest.