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Research Summary: Possible Diagnostic Tests for Long COVID

Research Summary: Possible Diagnostic Tests for Long COVID

Nearly every day, new research is published that describes abnormal findings in people with long COVID. However, few discuss diagnostic tests that are part of usual medical practice.  

In this article, I'll describe some of these tests and give my view of their usefulness in day-to-day care for long COVID.  

Blood tests for long COVID 

Healthcare professionals were surprised that most people with long COVID have a normal set of routine blood tests. This even applies to the most used test to detect ongoing inflammation, called C- reactive protein (CRP). 

But no test is infallible, and we need to look further. The following are some of the blood tests which are abnormal in studies of people with long COVID. 

Cortisol 

A few weeks ago, I discussed a study that found that people with long COVID have lower than normal cortisol levels, the steroid hormone that goes up with stress and illness. This hit the headlines at the time, but I’m not aware that more work has yet been done to discover why.  

Blood cortisol is a space worth watching and a test worth asking for, and it can be measured randomly or following an injection to stimulate the adrenal glands. It may open the gateway to treatments in the future, but for now, it is too early to say. 

Interleukins  

Interleukins are produced by white blood cells in response to any bodily disturbance. There are over 50 of them, and we’re still finding out what they do and how they do it.  

Modern detection methods can scan blood for the entire range of interleukins, though this is a research-only procedure. Interleukins in clinical practice are only measured to help diagnose and guide treatment.  

The abovementioned study published in MedRxiv found that most people with long COVID have increased interleukin 8 (IL-8). They also show increased levels of galectin. Galectin is another immune agent involved in processes that protect the body from invaders, and there are many different types of galectin.  

It's quite possible that before long, a “signature” pattern of interleukins and galectins will emerge that's diagnostic of long COVID, but it's too early to say. Different studies agree on some measurements but not others. IL-8 and interferon-gamma are good examples. We must resolve these differences before arriving standard set of blood tests to define long COVID.   

Clots and platelets  

Since the middle of last year, a phenomenon called “microclotting” has been proposed as a major cause of long COVID symptoms. Resia Pretorius and her team in Stellenbosch, South Africa reported seeing abnormal debris in the circulation of people with long COVID, and have published several descriptions of this. 

In their work, Resia and her team used fluorescent imaging which isn't standard in hematology practice, and other researchers have been slow to follow their lead. They also went on to treat their patients with combinations of anti-clotting agents. But no one has yet carried out a full randomized clinical trial to see if the benefits of such treatment outweigh the risk of increased major bleeding.  

Despite the promise of this work, we still can't assess the place of microclotting in long COVID, or safely use treatments in the hope of preventing it. Frustrating though it is, we must wait for the findings of the Pretorius team to be replicated by others—a common problem in long COVID research, but the only way to avoid harm.  

CT, MRI, and ultrasound  scans for long COVID 

In the last 50 years, new kinds of imaging have revolutionized our ability to see inside the body. Computerized tomography (CT) scanning, magnetic resonance imaging (MRI), and ultrasound are so effective that people often think that anything abnormal can be detected if you scan hard enough.  

Here, I’m focusing on people who develop long COVID after a mild infection of COVID-19 followed by worsening symptoms. Many are told that medical scans, usually of the lungs or heart, show nothing abnormal. This is meant to be reassuring but often has the opposite effect by leaving people without an explanation. They might think the disease is their fault, and it also implies that their providers don’t know how to help them.   

One important scan abnormality which doesn’t seem to have been confirmed by further studies is the swelling of the vagus nerve. The vagus links many common symptoms of long COVID, such as: 

  •  heart rate disturbances 
  • dizziness on standing 
  • pounding feelings in the chest 
  • nausea 

So, I got pretty excited when earlier this year, in a report presented at the European Congress of Clinical Microbiology and Infectious Diseases, Italian researchers discussed swelling of this nerve on ultrasound scans of a small group of people with long COVID. But here again, I can’t find any indication that this work has been replicated in more extensive studies.  

Long COVID and  body function

One of the simplest tests you can carry out is to ask someone to stand with their feet together and shut their eyes. If they begin to falter, you know something is wrong with their balance system, which is located in the inner ear. This is often the case in long COVID.   

Even more common in long COVID is postural orthostatic tachycardia syndrome (POTS), which causes a rise in pulse rate when first standing up, often accompanied by feelings of dizziness and a need to sit down. It may or may not be accompanied by a drop in blood pressure, known as postural or orthostatic hypotension. Even if they can stand up without feeling faint, many people with long COVID have difficulty standing for more than a few minutes.   

Tests of exercise are more controversial because one of the prime features of long COVID is fatigue following physical exertion. In most situations, measuring how far a person can walk in 6 minutes is a harmless test that can provide helpful information about their fitness. But for people with long COVID, it can cause distress and exhaustion for hours or even days afterward.  

Many people with long COVID experience difficulty breathing, which can occur all the time or intermittently. Many kinds of lung function tests are often abnormal in people with severe initial COVID infection but normal in people with long COVID after mild infection. Highly specialized MRI scanning can show moment-by-moment deficiencies in oxygen uptake by the lungs, which would be impossible to detect by other means. Unfortunately, this requires using a rare and expensive isotope and is unlikely to be possible in routine clinical practice for the foreseeable future.   

Testing nerve function is mostly very straightforward by comparison. The most basic tests involve a needle, with or without a tiny electric current. In long COVID, these tests often show impaired function in the long nerves of the legs and the arms. When it comes to testing the brain, the simplest tests involve questions that reveal gaps in memory or word finding. These can sometimes be useful, but the problem of “brain fog” is hard to measure since it usually varies from one occasion to another and often depends on the mental effort made previously.   

Functional brain imaging by positron emission tomography (PET) or specialized MRI has revealed abnormalities in many people with long COVID. Still, these remain as research techniques used in a minority of specialized clinics instead of routine practice.    

Does long COVID affect the gut microbiome? 

One leading explanation of long COVID is the persistence of the SARS-CoV-2 virus anywhere in the body but especially in the intestines. Another theory is that the virus can disturb the normal balance of bacteria, fungi, and viruses in the large intestine (the gut microbiome) and create an inflammatory reaction that persists. The ideal way of testing such theories is to take samples from the wall of the intestine, but this involves biopsies carried out through endoscopes and would be a research procedure only for the time being.   

More straightforward, though not very appealing to many, is collecting waste samples (feces, often called stools) and looking at changes to the microbiome. However, the microbiome is highly complex and changeable, and we're still in the early stages of understanding what's significant and what's random variation.   

Other types of biopsies are possible, like skin sampling, to look for changes in the tiny blood vessels and nerves. Again, these have shown interesting results, but they're not part of routine clinical workup since they currently don’t help treat long COVID.  

The gist  

Healthcare providers do tests to confirm diagnoses and guide treatment.  

Two and a half years of research show that long COVID is a deep-seated condition affecting every system of the body, but more research is needed to find out how to treat it.  

This will happen most quickly if every person with long COVID is given a chance to participate in well-designed, large-scale research. Testing for the sake of testing is costly and won't provide enough helpful information to guide treatment.   

For this reason, I would recommend that people with long COVID should only undergo detailed testing in the context of good quality clinical research.       

Article resources:

  • Klein J, Wood J, Jaycox J, et al. Distinguishing features of Long COVID identified through immune profiling. medRxiv. Published online August 10, 2022:2022.08.09.22278592. DOI: 10.1101/2022.08.09.22278592
  • Williams ESCP, Martins TB, Hill HR, et al. Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID. medRxiv. Published online October 5, 2022:2022.10.03.22280661. DOI: 10.1101/2022.10.03.22280661
  • Pretorius E, Vlok M, Venter C, et al. Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (Pasc) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol. 2021;20(1):172. 
  • Allegretto A.(2022). Ultrasound finds link between long COVID, viral effect on vagus nerve. AuntMinnie.com.
  • Grist JT, Collier GJ, Walters H, et al. Lung abnormalities depicted with hyperpolarized xenon mri in patients with long covid. Radiology. Published online May 24, 2022:220069. DOI: 10.1148/radiol.220069
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Richard Lehman

Richard Lehman

Richard is a retired family doctor who lives in the UK. Until 2020 he was Professor of the Shared Understanding of Medicine at the University of Birmingham UK. For 20 years he produced weekly summaries of research articles from the main medical journals. Here we are giving you his personal comments on Long Covid research as it appears in the medical press. They are meant as pointers rather than complete summaries. Readers wanting more detail are advised to use the links provided to the original article. Richard welcomes feedback from readers but regrets that he cannot provide medical advice.

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