New antifungal therapy for fungal meningitis
med.umn.edu
med.umn.edu
The problem, though, wasn't treating it. His neurosurgeon told me they treated it with the same medication they give women for yeast infections. The problem was diagnosing it. He's not HIV positive nor has he had a transplant. Apparently, in a small percentage of the population, the fungus makes it way to a non-immunocompromised brain. It's so small that, according to his neurosurgeon, they have to treat patients like him as if they were HIV positive/transplant recipients because they don't have enough data otherwise.
I'm glad to hear about this new therapy but, with my father at least, they weren't able to properly diagnose until they did a biopsy on his brain. So, it seems like improvements in diagnosis may be in order as well.
Couple weeks later several of my joints got really swollen which led to them testing me for a human Parvovirus-B6 infection, and indeed, that's what it was - but it was just a lucky guess by the doctor there, he said they don't normally test people in my age group for it because it's incredibly rare for adults to get infected or show any symptoms, but lucky me, I was in that 0.000001% group that not only got infected by also had severe symptoms. But even then it was just "ok, we know what it is but there is nothing we can do to help, it should go away, oh and btw there is a 5% chance you will continue getting symptoms for years if not forever". Well it's been 4 years and I'm still fighting it, so...........
I have the same thing, and I also caught mine in 2019!!!! For me the treatment is one steroid shot a year, I've seen various rheumatologists and they all said it's postviral reactive arthritis, but with the recurrence of symptoms being so rare(once a year) they wouldn't recommend treatment with any of the typical medicines like methotrexate(which is probably a good thing tbh). None of them predict this is going to go away any time soon though, apparently the average time for post-reactive arthritis to resolve itself is 8-10 years.
It's incredibly interesting to find someone else with the same symptoms as me though, most doctors I speak to say this is the first time they've seen a case like mine(after parvovirus that is, reactive arthritis after viral infections is unfortunately somewhat common).
>>I'm surprised to hear that it's considered so rare
I've been treated at one of England's largest infectious diseases unit and they said it's incredibly rare for them to see an adult with an active parvo B19 infection, they literally had a handful over the last 10 years. That's not to say that the infection itself is rare, just that it rarely gets diagnosed properly.
Your white cell counts were indicative of viral infection?
PCR was positive, indicating infection?
Do you supplement zinc, C, B6, magnesium?
For example, as a poor absorber of Vitamin D3 I require 12k IU / day (with all of its cofactors) to stay within the established blood range. It would be inadvisable and reckless for anyone to consume this amount of a fat soluble vitamin without monitoring blood levels. I'm also prone to iron deficiency anemia of unknown etiology (cause), but that's another problem suggesting either poor absorption (most likely), cancer, or unexplained bleeding.
Or undiagnosed parasitic infection. They scavenge iron and some hide from the immune system by changing their protein markers.
I don't know where you are, but American doctors tend to not test for them. "Third World Problem. Nothing we need to worry about."
And we don't keep stats on them because "Third World Problem. Nothing we need to worry about." so we don't actually know how prevalent they are.
That said, these "third-world problems" - by which I think you mean things like parasites, curable / preventable / vaccinatable diseases, "tropical" diseases, and mosquito-borne diseases - are becoming more and more prevalent in the US and Europe because of climate change and other factors - I'm thinking poor health care, aging infrastructure (think Flint), shortcuts (think the UK dumping sewage into the sea because their infrastructure can't handle processing), but also evolution, things like parasites being able to survive better.
And yes I do, all of those + vitamin D.
https://virologyj.biomedcentral.com/articles/10.1186/s12985-...
Note that the attached figure describes pathogenicity as affecting any animal host, not just humans.
And yes it's very common in children with mild symptoms, and in adults it's extremely rare to have any symptoms at all(from what I understand it's actually not well studied how common it is as an infection because the symptoms either don't exist or are the same as normal cold so no one gets tested for it). At the hospital at the specialized infectious diseases unit they told me they have only seen 5 adults with it in the last 10 years and I've been the worst case they had.
>>Are you immunocompromised?
No
>>Has any radical treatment such as convalescent plasma been considered?
Not that I know. I did eventually start recovering so I guess they didn't want to go nuclear.
I hope they publish a case study article as a clinical treatment guide for the next cases.
Your kind of situation exposes one of the current inadequacies of the clinical medical profession: falling through the epidemiological cracks of rare diseases and syndromes. There is a finite amount of evidence-based medical knowledge and an inability to rapidly test and adapt to infinite presentations that don't fit neatly into an "average" common case. Perhaps we need both cheaper lab tests/diagnostic procedures (not Theranos in execution but close to it) and tens of thousands more "detective" MD researchers meeting up with clinical side of the healthcare industry to elucidate the unknowns and the unexplained rather than shrug of patient concerns lacking clear explanations. Lastly, clinical MDs should aim to never forget their roots by publishing more.
Note that last year the WHO released a list of "fungal priority pathogens" based on criteria related to "unmet research and development needs and perceived public health importance." Cryptococcus is at the top of this list.
https://www.who.int/publications/i/item/9789240060241
General resources on fungal meningitis:
https://www.cdc.gov/meningitis/fungal.html
CDC resources specific to Cryptococcus:
https://www.cdc.gov/fungal/diseases/cryptococcosis-neoforman...
Do you know if they did testing of easier material like cerebral spinal fluid first?
Normally, intact cell-mediated immunity prevents harmless airway colonization of these types of organisms from entering the blood stream or causing clinical infection hence why they're called opportunistic infections. Rare in immunocompetent patients.
Something I'm looking at the moment is the role zinc plays in things like membranes and blood brain barrier.
When looking at how much zinc is used through out the body which combined with one of these, cysteine, histidine, aspartic acid, glutamic acid, with the first two largely involved in structural applications ranging from zinc fingers to organelle stability, cell stability and membrane health, it looks like the RDA is woefully inadequate.
The problem is a blood test wont show zinc status as its so tightly controlled in serum, so if its measured and it shows a problem, its going to be an extreme problem. However if you suffer a head injury, the damaged brain cells will dump zinc straight away into the blood so that the neurons take up glutamate which then become neuro toxic leading to cell death.
For example, if you take vitamin D3 supps, it needs a zinc finger, so taking VitD3 with zinc, is useful other wise you could be wasting your time taking VitD3 if there is simply not enough zinc in the body, which can explain why some people dont respond to vit D3 supps.
If the zinc status is low, there are so many vitamins and minerals that are just not worth doing.
But mega dosing so many vitamins and minerals can create a zinc deficiency, like mega dosing vit A or D, or even nicotinic acid (b3) to compound things.
Its not been unheard of taking a few hundred mg's a day, with documented therapeutic doses at 2grams a day! There is also disputes over whether an increased zinc intake even causes copper deficiency's. Studies are mixed, so typical medical caution is order of the day with regard to high doses of zinc, but that caution can contribute to medical conditions.
The digestive system has no restriction on the uptake of zinc, unlike iron which uses hepcidin, but things like fibre, phytates, tannins, found in vegetables, will all bind to zinc in the gut very easily reducing its effectiveness, and then there is calcium, iron which is known to compete, with phosphate also looking like a similar competitor of zinc.
B6 is recommended for any high intakes of minerals, it can be used to reduce the incidence of sideroblastic anemia and peripheral neuropathy amongst many things.
The Nicotinic Acid form of B3 works with every enzyme in the body via Nicotinamide Adenine Dinucleotide (NAD) and Adenosine triphosphate (ATP).
But as there is no reliable way to measure zinc status, things like an enlarged spleen (splenomegaly), cancer, diabetes, and numerous more disease states and illness could indicate an inadequate zinc status. Put another way, Zinc deficiency is found in so many illnesses including depression.
> > weren't able to properly diagnose until they did a biopsy on his brain.
Did they measure the surrounding tissue around the brain and bone mineral density, to check if the blood brain barrier was intact, and immune response optimal?
If its any consolation, fungi can be sniffed as a smell and end up in the sinuses where they can contribute to mental health issues, but these only show up in autopsy's, and biopsy's!
When zinc acetate at 75mg was used to shorten the common cold, its typically portrayed that it shortened the cold duration by a couple of days and its not really worth taking.
When looking at the studies, the common cold had a typical 8.3day duration but with a total 75mg of zinc acetate spread over a day, reduced it to a 4.5day duration. Take into account the time it takes for the immune cells to respond, with or with out supplement, and that zinc duration could be reduced to under 4 days, even fewer days if there was adequate zinc status before infection, making it much more significant and effective than its currently portrayed!
So, should we be re evaluating our zinc intake to see improvements in health, to avoid situations like this?
> Did they measure the surrounding tissue around the brain and bone mineral density, to check if the blood brain barrier was intact, and immune response optimal?
Not that they ever mentioned to me.
> If its any consolation, fungi can be sniffed as a smell and end up in the sinuses where they can contribute to mental health issues
The best theory we can come up with is that he contracted the fungus while crawling under a house.
As an example: I can do 250mg of zinc oxide a day and have minimal effect from it whatso ever, I just crave eating chicken and tomatoes. Add 100mg of manganese chloride alongside that intake and then I get an immune system response in the jaw, with aching around the bone where the teeth that have been filled are and the mandible. Ears discharge fluid which would suggest I have some sort of glue ear, ear infection or exposure to swimming pool chlorine. If I reduce those amounts, the ear discharge clears up and the jaw bone aches go, which would lead me to think everything is ok, when clearly its not. At that dose, I have a bit of tenderness in a tendon on each elbow and a little activity around the knees, so maybe its doing some good.
Its certainly not in the tens of mg/kg toxic dose ranges for these chemicals, but well above the rda amounts. However some chemicals have a toxic dose range in the 0.0X mg/kg range, making it highly toxic.
The manganese is normalising my blood sugars which help immune system responses. The doctors had been notified by the opticians a few years ago of possible diabetic implications, but the NHS GP has not been in touch about it, or anything from when I was at hospital for that matter, unless letters are going lost in the post, which isnt the first time that stuff has been done to me. So many criminals in the Royal Mail, it will be good to see their monopoly go.
So are vitamin RDA's high enough, or are just cautiously minimal in order to address the existence of said multi vitamin chemicals whilst not contributing to rude health?
Zinc chloride is an effective Lewis acid catalyst in the Diels–Alder reactions of the keto esters, but do these Diels–Alder reactions exist in the human body?
Oxide + gut hydrochloric acid = chlorine + water which is why I do zinc oxide, but might get some zinc chloride to dilute in deionised water. Dont want to chemically burn any holes in my guts now.
Re the fungus, so Bipolaris can be inhaled from compost bins, it seems a lot of fungus seems to get into the sinus from a variety of locations, and even I've smelt mould when doing manganese and beta alanine for no explicable reason other than it might have been in a sinus but the body hasn't been given the chemicals to respond until now. The manganese has seriously improved my sinuses. It also makes me think, forensic pathologists use these sinuses to work out if someone had snorted any drugs and other things that might contribute to an opinion on the cause of death.
From 1990 https://pubmed.ncbi.nlm.nih.gov/2312993/ Allergic Bipolaris sinusitis: clinical and immunopathologic characteristics
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC254347 Bipolaris spicifera Causes Fungus Balls of the Sinuses and Triggers Polypoid Chronic Rhinosinusitis in an Immunocompetent Patient
Usually a combination of clinical and MRI findings is enough for infectious diseases and neurology specialists to figure it out and start empiric treatment for something/a few somethings if the CSF doesn't give you the answer.
Rarely, at least at my institution, you could do a biopsy but you don't really want to be chopping up the brain if you can avoid it.
“An orally administered amphotericin that is effective against nearly all fungus and non-toxic sounds like the holy grail of antifungal medicines...
This is good news, though you can bet money that fungal infections will eventually adapt. They need to stop acting like we have solved it once and for all! It's an ongoing battle and as we change tactics, the invaders into our bodies change tactics too.
All observed resistance mechanisms (so far) work via active counter-measures, such as additional ion pumps, and they reduce the fitness of fungal cells as a result.
No, if it allows the organism to survive, it increases fitness by definition. "Survival of the fittest" does not mean "All those fungal cells who went to the gym and ate right and look like Arnold Schwarzenegger get to live because they are so beautiful." It often means the equivalent of drug addicts on skid row, so long as they live longer with the "bad" choice than without it.
Sickle Cell Anemia reduces fitness compared to people without the disorder -- unless you live someplace with malaria and no effective treatment for it, in which case you live longer if you have Sickle Cell Trait than if you don't and, gee, too bad, so sad that having two copies of the gene is so torturous and debilitating.
Survival of the fittest is a war of attrition. It's last man standing no matter how awful he looks or terrible he feels.
It's not we can build a better organism if we plan this in advance, one that is stronger and faster and prettier.
Wrong. Or rather, needlessly obtuse in the clear context under discussion. The fitness function for human pathology is replication in excess of the body's capability to control/react adequately to maintain health. There's multiple counter factors going on. If an adapted resistant organism replicates 100x slower such that the immune system is then able to keep up and eliminate it, and/or the probalistic function drops below sustainment, then while yes it's successfully more fit vs the chemical compared to the vanilla organism from the perspective of patient health that's a huge win and the adapted organism has greatly reduced "fitness" (infectiousness/pathology) vs vanilla. The drug has done its job both destroying the vanilla and reducing danger of resistant, effectively driving evolution towards something more stable for humans.
We don't need to avoid all organisms in our bodies, we merely need to avoid harmful ones that damage/destroy the host vs live with it to an acceptable degree (or even have mutual benefit). Some adaptions to some drugs don't have any effect on the pathology of the infectious agent, so they can resist it "for free" from a health perspective. If others mean the resistant is less dangerous than wild type that's good.
I'm not really sure where the whole movie analogy stuff comes in.
In practice, the body is the battlefield and using very strong (toxic) drugs to pursue a scorched earth policy type health agenda tends to cost humans more than it costs pathogens.
If you successfully ruin this pathogen but also ruin the host, something steps in and that something tends to be something we cope with even less well, much like many Native tribes were decimated by "common" European diseases upon initial exposure because they had no immunity.
So any infectious agent that reaches the brain can easily become meningitis (if you are a thing that can reach the brain then if you cause inflammation you are definitionally meningitis).
So if there was a prion that caused inflammation you would have prion meningitis.
The thing that makes meningitises specifically a problem is that the inflammation itself will kill you, and the inflammation means onset is acute. Other pathogens that successfully reach the brain aren’t noticed until after they’ve caused enough direct damage to cause noticable symptoms (which is generally long after simply stopping the infection could correct the damage)
Fortunately, the patient made a full recovery, and nobody else (at the hospital) got infected, so at least there was a happy ending to that story.
There is a critical shortage of classes of antimycotics. For example, 3 medications of the echinocandin class remain useful in treating multi-drug resistant c. auris, the beastie that sometimes requires throwing out durable hospital equipment and tearing out the walls due to contamination.
https://slate.com/technology/2019/04/candida-auris-hospitals...
My teaching (in radiology) was HIV > toxoplasmosis > cryptococcosis for CNS infections in HIV+ but maybe we're out of date or this order is sepcific to the US/Canadian population.
Anecdotally I've definitely seen more toxo than crypto. I've also seen more white matter disease in HIV patients than either but the MRI findings aren't specific so I don't know what the final path was on those cases.
PO amphotericin B would be a huge boon in treating these patients and shortening hospital stays. Outpatient Ampho B is not a good option in most cases.
> In our HIV patients we see more more cryptococcal meningitis than CNS toxoplasmosis. Crypto is typically not going to have any significant radiologic abnormality unlike toxo in which imaging plays a large role in diagnosis. So I'm guessing, being a radiologist, you've got a sampling bias that favors toxo.
Agree crypto is much more subtle on imaging than either HIV encephalitis or toxo, the most common finding we see is dilated PVS which is nonspecific (particularly without priors). I only mentioned my anecdotal experience as it corresponds with what's taught to us but I agree it's highly susceptible to bias and I don't consider it evidence.
For example on StatDx (UpToDate for radiologists):
>[Cryptococcus is the] most common fungal infection in AIDS patients
>3rd most common [CNS] infection seen in AIDS patients (HIV > toxoplasmosis > Cryptococcus)
This could very well be out of date/incorrect, they don't give in-text citations like UpToDate so I'm not sure where these specific statements are coming from.
Do you have a reference handy? If so I can submit it as feedback on the article to get it updated/reviewed.
Thanks for taking the time to search and comment. Always appreciate learning from my clinical colleagues + now I can flex a new obscure fact to radiology trainees like a proper academic physician.