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Cold agglutinin disease (CAD) secondary to Mycoplasma pneumoniae (M. pneumoniae) infection in adults is linked to severe illness, including a high risk of complications related to blood clots and intensive care admissions, according to a national study in France.

Still, data showed that most patients recover within weeks with antibiotics and supportive care, while no clear benefit is seen with glucocorticoids — anti-inflammatory and immunosuppressive medications commonly used to manage autoimmune conditions such as CAD.

“GC [glucocorticoid] use can probably be avoided in most patients, although the benefit/risk balance has to be carefully evaluated in the most severe cases,” researchers wrote.

The study, “Cold Agglutinin Syndrome Secondary to Mycoplasma pneumoniae Infection in Adults: Results From a Large French Observational Study (MyCOLD Study),” was published in the American Journal of Hematology.

CAD classified as secondary when triggered by an underlying condition

CAD is an autoimmune disease in which self-reactive antibodies, known as cold agglutinins, wrongly bind to red blood cells at low temperatures, causing them to clump together and marking them for destruction, or hemolysis.

This can lead to the formation of blood clots that can block vessels and reduce the number of circulating red blood cells, leading to anemia, impaired oxygen delivery throughout the body, fatigue, and other CAD symptoms.

CAD is classified as primary when it occurs for an unknown reason, and secondary — this is also known as cold agglutinin syndrome or CAS — when triggered by an underlying condition, such as certain cancers or infections.

The M. pneumoniae bacterium is mostly known for causing mild respiratory infections, but it is increasingly recognized for its ability to provoke serious complications beyond the lungs, among them, CAS.

While cold agglutinins are commonly seen during M. pneumoniae infections, clinically significant CAS “in this setting is rare and its optimal management is not consensual,” the researchers wrote.

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Nearly all participants received antibiotics to treat M. pneumoniae infection

To learn more, a team of researchers in France launched MyCOLD, a national, multicenter observational study aimed at investigating CAD secondary to M. pneumoniae infection in adults. The goal was to describe the clinical features, identify risk factors, and assess whether treatments like glucocorticoids improve outcomes.

A total of 60 adults with M. pneumoniae-related CAS seen at 38 hospitals across France were included in the study. All had been hospitalized for M. pneumoniae infection between September 2023 and September 2024.

Slightly more than half were female, and the median age at CAS diagnosis was 48.5 years. Participants were diagnosed with CAS at a median of 10 days after the first infection symptoms.

Nearly all adults (96.7%) had respiratory symptoms, including shortness of breath, and 71.7% had fever. Nearly 35% had dark-colored urine, a common sign of hemolysis.

Participants’ median level of hemoglobin, the oxygen-carrying protein in red blood cells, indicated moderate to severe anemia, and cold agglutinins were detected in all 29 tested adults.

Nearly half (45%) of thes patients were admitted to intensive care, and 16.7% experienced blood vessel blockage due to blood clots, mostly in the first 72 hours after admission.

All but one adult (98.3%) received antibiotics to treat the underlying M. pneumoniae infection. Nearly 72% received blood transfusions, often using warmed blood products to prevent further hemolysis, and 41.7% received at least one treatment for CAD, most commonly glucocorticoids (28.3%).

After a median follow-up of 56 days, or nearly two months, 90% of adults had recovered from CAS. The remaining participants were either lost to follow-up or had other blood disorders.

Patients receiving glucocorticoids did not recover faster

Despite having more severe CAS at diagnosis, including lower hemoglobin levels and higher hemolysis markers, adults who received glucocorticoids did not recover faster or at a higher rate than those who did not.

“Patients recovered within weeks, irrespective of the treatments received, suggesting that cold agglutinins disappear [quickly] and that the long-term prognosis of CAS following MP [M. pneumoniae] infection is good,” the researchers wrote. “While it is difficult to firmly conclude on the usefulness of GC for [M. pneumoniae-related CAS], our data suggest that most patients recover only with supportive care and that a prolonged GC course is probably not useful.”

The team then compared data from the 60 adults with M. pneumoniae-related CAS to that of 1,267 people from the national MYCADO study who were hospitalized with the same infection, but did not develop CAS.

Overall, the prognosis of CAD is good, and glucocorticoids do not appear to influence outcomes.

They found no demographic or clinical features significantly associated with the risk of CAS. However, CAS patients were significantly more likely to show anemia-related symptoms and to develop pulmonary embolism, or blood clots blocking lung arteries. They were also significantly more likely to be admitted to intensive care (45% vs. 31%).

“Overall, based on these data, the main messages for the clinician are that [shortness of breath] worsening and/or the occurrence of anemia in the context of a [lung infection] should prompt measuring markers of hemolysis … and a search for cold agglutinin, especially if MP infection is confirmed,” the researchers wrote.

In addition to specific antibiotics, adults with M. pneumoniae-related CAS should receive supportive care, including preventive treatment for blood clots and warmed blood transfusions in cases of severe anemia, the team noted.

“Overall, the prognosis of CAD is good, and glucocorticoids do not appear to influence outcomes,” the researchers wrote.

Neurosurgery Assistant Professor Frank Willett, PhD, and his teammates are using brain-computer interfaces, or BCIs, to help people whose paralysis renders them unable to speak clearly.

The brain’s motor cortex contains regions that control movement – including the muscular movements that produce speech. A BCI uses tiny arrays of microelectrodes (each array is smaller than a baby aspirin), surgically implanted in the brain’s surface layer, to record neural activity patterns directly from the brain. These signals are then fed via a cable hookup to a computer algorithm that translates them into actions such as speech or computer cursor movement.

To decode the neural activity picked up by the arrays into words the patient wants to say, the researchers use machine learning to train the computer to recognize repeatable patterns of neural activity associated with each “phoneme” – the tiniest units of speech – then stitch the phonemes into sentences.

Willett and his colleagues have previously demonstrated that, when people with paralysis try to make speaking or handwriting movements (even though they cannot, because their throat, lip, tongue and cheek muscles or the nerve connections to them are too weak), a BCI can pick up the resulting brain signals and translate them into words with high accuracy.

Recently, the scientists took another important step: They investigated brain signals related to “inner speech,” or language-based but silent, unuttered thought.

Willett is the senior author, and postdoctoral scholar Erin Kunz, PhD, and graduate student Benyamin Meschede-Krasa are the co-lead authors of a new study about this exploration, published Aug. 14 in Cell. (Researchers at Emory University; Georgia Institute of Technology; the University of California, Davis; Brown University; and Harvard Medical School were also involved in the study.)

Willett, the co-director of Stanford’s Neural Prosthetics Translational Laboratory, provided insight on the study’s findings and implications.

What is “inner” speech? And why would a BCI/thought-decoding system that could accurately interpret inner speech be better than one that decodes only attempted speech?

Inner speech (also called “inner monologue” or self-talk) is the imagination of speech in your mind – imagining the sounds of speech, the feeling of speaking, or both. We wanted to know whether a BCI could work based only on neural activity evoked by imagined speech, as opposed to attempts to physically produce speech. For people with paralysis, attempting to speak can be slow and fatiguing, and if the paralysis is partial, it can produce distracting sounds and breath control difficulties.  

What did you learn from your efforts to design and employ decoding systems that could discern inner speech?

We studied four people with severe speech and motor impairments who had microelectrode arrays placed in motor areas of their brain. We found that inner speech evoked clear and robust patterns of activity in these brain regions. These patterns appeared to be a similar, but smaller, version of the activity patterns evoked by attempted speech. We found that we could decode these signals well enough to demonstrate a proof of principle, although still not as well as we could with attempted speech. This gives us hope that future systems could restore fluent, rapid, and comfortable speech to people with paralysis via inner speech alone. 

Does the system’s potential ability to accurately decode unspoken, silent, inner speech raise issues that hadn’t accompanied previous advances in BCI/decoding software technology?

The existence of inner speech in motor regions of the brain raises the possibility that it could accidentally “leak out”; in other words, a BCI could end up decoding something the user intended only to think, not to say aloud. While this might cause errors in current BCI systems designed to decode attempted speech, BCIs do not yet have the resolution and fidelity needed to accurately decode rapid, unconstrained inner speech, so this would probably just result in garbled output. Nevertheless, we’re proactively addressing the possibility of accidental inner speech decoding, and we’ve come up with several promising solutions.

It’s worth pointing out that implanted BCIs are not yet a widely available technology and are still in the earliest phases of research and testing. They’re also regulated by federal and other agencies to help us to uphold the highest standards of medical ethics.

What are a couple of the steps that can address this privacy concern?

For current-generation BCIs, which are designed to decode neural activity evoked by attempts to physically produce speech, we demonstrated in our study a new way to train the BCI to more effectively ignore inner speech, preventing it from accidentally being picked up by the BCI. For next-generation BCIs that are intended to decode inner speech directly – which could enable higher speeds and greater comfort – we demonstrated a password-protection system that prevents any inner speech from being decoded unless the user first imagines the password (for example, a rare phrase that wouldn’t otherwise be accidentally imagined, such as “Orange you glad I didn’t say banana”). Both of these methods were extremely effective at preventing unintended inner speech from leaking out.

What lies ahead? How far off is practical realization of this approach? Your next steps?

Improved hardware will enable more neurons to be recorded and will be fully implantable and wireless, increasing BCIs’ accuracy, reliability, and ease of use. Several companies are working on the hardware part, which we expect to become available within the next few years. To improve the accuracy of inner speech decoding, we are also interested in exploring brain regions outside of the motor cortex, which might contain higher-fidelity information about imagined speech – for example, regions traditionally associated with language or with hearing.