Five years after the pandemic hit, questions remain about how and why millions of Americans are still struggling with long-term disease.<\/p>\n\n\n\n
Michele G. Sullivan, Health Central<\/p>\n\n\n\n
According to a June 2024 report<\/a> by the Centers for Disease Control and Prevention (CDC), about 20% of adults with long COVID report health problems that significantly limit their daily activities. Children, too, can and do develop long COVID; an estimated 5.8 million<\/a> American school-age kids have been diagnosed with it since 2021. And, as with adults, long COVID in children can affect virtually every body system, including the brain, gut, muscles, and even behavior.<\/p>\n\n\n\n It\u2019s true that COVID hospital admissions and deaths<\/a> are way down since the pandemic peaks of 2020 and 2021, due in large part to the 80% vaccine coverage rate<\/a> in the U.S. But long COVID remains a real and ongoing concern, says David Hill, M.D.<\/a>, the chairman of the American Lung Association<\/a>\u2018s board of directors and a pulmonologist based in Waterbury, CT. \u201cWhile many people who get COVID have mild symptoms, some experience severe respiratory distress, chest pain, organ failure, and other significant complications from the disease,\u201d Dr. Hill says. \u201cThis is especially concerning for older adults, people with chronic lung disease<\/a>, people with a weakened immune system, and people who smoke or used to smoke.\u201d What\u2019s more, \u201ca substantial number will have persistent respiratory symptoms,\u201d he adds. \u201cEspecially, cough or shortness of breath, lasting months after infection\u2014more likely in those with severe disease and the unvaccinated.\u201d<\/p>\n\n\n\n Despite their enormous numbers, people with long COVID have struggled to carve out a legitimate niche in the world of research and clinical medicine, notes Lisa Sanders, M.D.<\/a>, the medical director of the Long COVID Multidisciplinary Care Center at Yale Medical Center in New Haven, CT. \u201cWhen I first started seeing patients three years ago, a lot of people came to me saying, \u2018Nobody believes in long COVID \u2026 I can\u2019t get any help because people just think I\u2019m nuts or lazy,\u2019\u201d she reports. \u201cNow, I hear that less often. Long COVID has been around long enough to get greater buy-in from the medical community.\u201d<\/p>\n\n\n\n On the five-year anniversary of a pandemic<\/a> that so profoundly disrupted our lives and health, we asked leading experts to unpack the current state of long COVID, including the latest scientific findings on distinguishing these symptoms into four categories that reflect distinct disease outcomes\u2014the first step, researchers hope, toward developing targeted diagnostics and treatments.<\/p>\n\n\n\n Many Experiences<\/p>\n\n\n\n These days, most of us recover fairly uneventfully from a bout of COVID. But recent research shows that 22% of cases<\/a> do not resolve within 90 days. In fact, the average duration of long COVID symptoms<\/a> is about nine months in those who\u2019d been hospitalized for acute infection, and four months among the nonhospitalized. Roughly 15% of people report symptoms a year later.<\/p>\n\n\n\n Meaning, such lingering disease outcomes meet the official, clinical long COVID timeline<\/a>, first outlined by experts in 2024. The disorder, the same experts note, can be continuous, progressive, or relapse and recur. Long COVID can wreak havoc throughout the body. It can make existing health problems worse or create multiple new ones.<\/p>\n\n\n\n Get the latest long COVID research and recovery tips \u2014delivered right to your inbox. Your Email…Your\u00a0privacy<\/a>\u00a0is important to us.<\/p>\n\n\n\n Admittedly, this covers a lot of ground. \u201cLong COVID is a condition that is known to have over 200 manifestations that can affect virtually every system in the body,\u201d explains Dr. Sanders. Some can be seen and measured\u2014like irregular heartbeat<\/a> and fluctuating blood pressure. \u201cOthers\u2014such as brain fog, fatigue, and depression<\/a>\u2014are invisible but still seriously impair quality of life,\u201d she adds. \u201cThe sheer diversity of symptoms is overwhelming.\u201d<\/p>\n\n\n\n A 2024 review<\/a> outlines long COVID\u2019s shapeshifting personality. Examining the findings of 47 prior studies, the paper confirmed that long COVID can cause\u2014among dozens of other health woes\u2014impaired smell and taste; neurocognitive issues; chronic respiratory problems; migraine<\/a>; muscle aches and weakness; and damage to the heart, kidneys, joints, and gastrointestinal (GI) tract. According to the paper, the most common symptoms were fatigue (23%), memory problems (14%), breathing difficulty (13%), sleep problems (11%), and joint pain (10%.)<\/p>\n\n\n\n While this study didn\u2019t home in on cardiovascular complications, other research has, including a 2022 Veterans Administration study<\/a> that found a 60% increase in the risk of heart complications among long COVID patients. Another recent study <\/a>determined that those who developed COVID early in the pandemic faced double the risk for cardiovascular events, including heart attack<\/a> and stroke<\/a>, for up to three years post-infection, compared to those without a COVID infection history.<\/p>\n\n\n\n Emerging evidence also suggests that a COVID infection (especially one that led to hospitalization) may increase the risk of new-onset diabetes<\/a>. In some people, the strong immune response associated with COVID can destroy<\/a> the pancreatic cells that produce insulin (a.k.a., beta cells). Several studies<\/a> have found up to a 5% increase in new type 2 diabetes<\/a> after COVID infection, compared to people who never had the virus.<\/p>\n\n\n\n No Definitive Diagnostics<\/p>\n\n\n\n Unfortunately, while some of those symptoms can be individually measured, there\u2019s still no way to prove that any of them are long COVID, specifically. That\u2019s because no blood or imaging test for COVID fallout yet exists\u2014\u201dnothing that is reliable and universal enough for me to say, \u2018OK, you have long COVID,\u2019\u201d says Dr. Sanders. \u201cIn a very practical sense, it\u2019s a clinical diagnosis. You have to go with the symptoms people are experiencing.\u201d<\/p>\n\n\n\n A recent study<\/a> by the National Institutes of Health (NIH) illustrates this frustrating problem. Of the 10,000 people in the study, about 9,000 had a history of COVID infection and 1,880 had a clinical diagnosis of long COVID. Every participant was given 25 standard diagnostic lab tests\u2014and not a single test differentiated those with long COVID from those without it.<\/p>\n\n\n\n Even more confusing? While a COVID infection is at the root of all long COVID cases, the virus affects different bodies differently, Dr. Sanders adds\u2014and likely for varying reasons. \u201cSome symptoms, like respiratory and heart problems, may be because the virus actually damaged the organs,\u201d she explains. \u201cOthers are caused by viral reservoirs<\/a>\u2014populations of the SARS-CoV-2 virus that are still hanging around in the body. Some are because the body\u2019s inflammatory response is still hyperactive, and some seem to be [due to] autoimmune responses.\u201d<\/p>\n\n\n\n Meaning, each case is clinically different, making it difficult to classify long COVID patients, Dr. Sanders says. But a novel approach is attempting to do just that, one that offers the potential of definitive tests and effective treatments.<\/p>\n\n\n\n Phenotypes<\/p>\n\n\n\n For any medicine to be effective, it has to be given under the right circumstances and to the right person. So, scientists are trying to distinguish long COVID phenotypes\u2014meaning, the physical and biochemical characteristics that mark common presentations of the disorder. This is the beginning of creating specific long COVID tests and treatments, says Michael Peluso, M.D.<\/a>, an assistant professor of medicine and infectious disease clinician at the University of California, San Francisco.<\/p>\n\n\n\n The goal is to group long COVID patients by their physical symptoms and find chemical signals in their blood, called biomarkers, which are common and specific to those groups, Dr. Peluso explains. To that end, the NIH\u2019s Researching COVID to Enhance Recovery (RECOVER) initiative<\/a> has identified four different physical clusters,<\/a> each with a distinct patient profile. They are:<\/p>\n\n\n\n Protein Signatures<\/p>\n\n\n\n Currently, researchers are further distinguishing these four phenotypes into subtypes by identifying specific molecular patterns<\/a> in the blood of people with different disease outcomes. The study found that people with long COVID with heart and lung problems had a completely different biomarker profile than those with GI symptoms. Those with cognitive impairment showed changes in markers of nerve tissue repair, while those with GI issues tested positive for proteins that are associated with an autoimmune response.<\/p>\n\n\n\n These \u201cprotein signatures\u201d\u2014biochemical patterns that are associated with specific symptoms\u2014could eventually become the basis of two desperately needed long COVID innovations, says Zyad Al-Aly, M.D.<\/a>, the senior clinical epidemiologist at Washington University in St. Louis. They include long COVID lab tests that predict risk and confirm diagnosis, as well as treatments that are tailored to each specific phenotype. Because they are complementary, the two areas should proceed in tandem.<\/p>\n\n\n\n \u201cThis is important because it will allow us to classify people into these categories, based on the type of long COVID they have, as well as the underlying mechanism,\u201d says Dr. Al-Aly. \u201cThen we\u2019ll be able to figure out who is most likely to respond to specific agents, which will allow us to make advances in trials.\u201d<\/p>\n\n\n\n Dr. Al-Aly likens this scientific push to the successful development of targeted cancer treatments. \u201cWe don\u2019t treat skin cancer<\/a>, breast cancer<\/a>, and colon cancer all the same way,\u201d he notes. \u201cWe identify clear diagnostic biomarkers, objective measures of disease activity and underlying mechanisms, and then develop promising therapeutics to try on them.\u201d<\/p>\n\n\n\n Research<\/p>\n\n\n\n Five years in, we are still without a universal treatment for long COVID. Doctors manage symptoms based on the person\u2019s individual array of symptoms, and the physician\u2019s clinical experience with what works and what doesn\u2019t, says Albert Rizzo, M.D.<\/a>, the chief medical officer of the American Lung Association and a pulmonologist at ChristianaCare Pulmonary Associates in Newark, DE.<\/p>\n\n\n\n \u201cBecause there are several possible mechanisms [behind] the development and persistence of long COVID symptoms, a universal treatment is hard to identify,\u201d Dr. Rizzo says. \u201cFor now, long COVID treatments will need to target different mechanisms, such as abnormal immune responses, abnormalities in the blood-clotting mechanism, the persistence of viral particles, the development of autoimmunity, and related ongoing inflammation<\/a>\u2014and these may all be intertwined.\u201d<\/p>\n\n\n\n Enter the Yale Paxlovid for Long COVID trial<\/a> (PAX LC)\u2014a highly anticipated study of extended Paxlovid treatment in people with long COVID. PAX LC has now wrapped up, with its results due to be published this summer. This research randomized 100 people with long COVID to 15 days of Paxlovid treatment (a combination of nirmatrelvir and ritonavir) or to placebo plus ritonavir. The aim: To eliminate any residual SARS-CoV-2 virus that might be lingering within cells and causing long-term problems.<\/p>\n\n\n\n Like many formal studies of existing drugs, this one was sparked by doctors who, lacking any other options, treated long COVID with an antiviral drug already known to knock down the virus. \u201cThe first foray into the arena of treating viral persistence was really the case reports that came out as far back as 2022, in which some people with long COVID took Paxlovid and said that their symptoms improved,\u201d Dr. Peluso explains. \u201cThis led to a massive push toward clinical trials targeting viral persistence.\u201d<\/p>\n\n\n\n The first results on this approach in 2024, from a trial called STOP-PASC<\/a>, were negative. But that doesn\u2019t necessarily mean that Paxlovid is a failure for treating long COVID, Dr. Al-Aly points out. Instead, it likely means that not everyone in the study had long COVID caused by viral persistence. \u201cThey may have had another biological mechanism instead,\u201d and for those people, Paxlovid would be useless. \u201cSo, this doesn\u2019t necessarily close the door on the idea that antivirals could be helpful [for some people with long COVID]. It just tells us we need to target the right patients for this treatment.\u201d<\/p>\n\n\n\n What\u2019s more, Dr. Peluso says that STOP-PASC may help provide valuable information by identifying specific protein biomarkers that are associated with a beneficial treatment response.<\/p>\n\n\n\n In addition, \u201cthe massive NIH RECOVER-VITAL trial<\/a>, with 900 participants randomized to either Paxlovid or placebo, will further build on both of these [findings],\u201d says Dr. Peluso, adding that the results are due later this year. \u201cVITAL also enrolled large numbers of individuals with specific phenotypes of long COVID, which will be really important in determining whether a particular subgroup benefits from this treatment approach.\u201d<\/p>\n\n\n\n RECOVER-VITAL is just one initiative from RECOVER, NIH\u2019s large-scale long COVID research program. In addition to the Paxlovid study, RECOVER is carrying out studies aimed at long COVID-related neurocognitive problems,<\/a> sleep issues<\/a>, autonomic dysfunction<\/a> (fast heart rate<\/a>, dizziness, and fatigue), and exercise intolerance.<\/a><\/p>\n\n\n\n Additional long COVID trials are proliferating, too, Dr. Peluso notes. They include a small study<\/a> of an antibody that binds to the SARS-CoV-2 spike protein so the virus can\u2019t enter human cells. Another is testing a new antiviral as a treatment for acute COVID infection. One is examining larazotide<\/a>, thought to \u201ctighten\u201d the gut barrier and keep persistent virus from re-entering circulation, while still another is looking at two anti-HIV drugs in the hopes that they\u2019ll knock out residual SARS-CoV-2.<\/p>\n\n\n\n Two larger studies are targeting the persistent inflammation and autoimmune reactions that can occur in long COVID. And the Department of Defense is exploring the use of bezisterim, a synthetic steroid that crosses into the brain and acts as an anti-inflammatory and insulin-sensitizer, in hopes of reducing long COVID\u2019s neurocognitive symptoms.<\/p>\n\n\n\n Vaccines<\/p>\n\n\n\n COVID vaccines have sparked debate, but these are the facts: If you get COVID after receiving the most up-to-date vaccine, you\u2019re much less likely to have a serious case or one that lands you in the hospital. And remember, serious COVID illness is one of the biggest risk factors for developing long COVID, says Dr. Hill. \u201cWe know vaccination reduces your risk of getting COVID at all, and your risk of getting a serious case of COVID,\u201d he says. \u201cAnd less COVID equals less long COVID.\u201d<\/p>\n\n\n\n The numbers say it all: A 2024 study<\/a> found that people who had two doses of a COVID vaccine on board were 40% less likely to develop long COVID post-infection. Other studies have similar conclusions. The largest so far, a European study of 20 million people<\/a> that was published in The Lancet Respiratory Medicine<\/em>, found that vaccination cut the risk by up to 52%. And a just-released pediatric study<\/a> concluded that the COVID vax reduced long COVID risk by up to 73% in kids aged 5 to 17.<\/p>\n\n\n\nOne Disease, Many Experiences<\/h2>\n\n\n\n
New Long COVID Newsletter Available!<\/h4>\n\n\n\n
No Definitive Long COVID Diagnostics\u2014Yet<\/h2>\n\n\n\n
Long COVID Phenotypes<\/h2>\n\n\n\n
\n
Protein Signatures May Hold the Key<\/h2>\n\n\n\n
Still Searching for Answers Through Research<\/h2>\n\n\n\n
New Thinking on Vaccines<\/h2>\n\n\n\n