Posts Tagged ‘bronchiectasis’
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
keeping it simple, for now
Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine.
Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects.
Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.
Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out.
Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…
Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…
Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.
Canto: Amazing. Why aren’t they using this all the time? Everywhere?
Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:
One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.
Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.
Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it:
… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice.
Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break.
Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…
Canto: As have I, from time to time. At least I think it was corticosteroid…
Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.
Canto: That sounds great. Let’s leave it there before I hear any bad news…
References
Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain
Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?
How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others
Coronavirus Treatment and Prevention with Monoclonal Antibodies
bronchiectasis once more – resistance, viruses, treatment
Having fallen ill again, for the first time really in a few years, with debilitating dry coughing, breathing problems and fatigue, and having had no great relief from a first course of broad-spectrum antibiotics, I think it’s a good time to review the condition I suffer from – bronchiectasis.
I’ve tried to put it in the back of mind and have been mostly successful, except now and then to marvel that it hasn’t come roaring back for a year, then two years, then three years. Still, I’ve never quite gotten rid of a niggling cough, and every time I have a sneezing fit my mind turns, however briefly to what might finally await me…
Bronchiectasis literally means ‘widened or widening airways’. The airways leading to the lungs have become permanently distended and develop ‘cul de sacs’ in which bacteria gather as in a stagnant backwater. The increased bacterial load means that those with the condition are easier prey for bacterial and viral pathogens. The causes of this condition are various, including genetic conditions such as cystic fibrosis, or a general immunodeficiency. In my case it was most likely an early childhood infection, the cause in about a third of all adult cases. The sad thing is that with each new flare-up the damage to the airways is increased, the condition worsens, and there’s no cure, but it can be contained through specific exercises designed to clear the airways, postural drainage and other techniques. Above all (he adonishes himself) always get regular flu and pneumococcal jabs. I was diagnosed with this condition about four and a half years ago, but I think I’ve been suffering from it for much longer. Like many stupid men I’ve tended not to go to the doctor till I’m at death’s door. I’ve improved a little in that area in recent years, but not enough.
The recent flare-up has been traced to a relatively common virus, called respiratory syncytial virus (RSV). My doctor sent me for a virology swab after my second visit. On my first visit I presented with my severe cough, and I explained my bronchiectasis, which he knew something about as I’d had my records transferred to him from a previous establishment. Although I expressed concern about antibiotics, having experienced what I presumed to be resistance to erythromycin previously, I was prescribed a broad-spectrum antibiotic called roxithromycin GH. Desperately wanting to get rid of this debilitating and spirit-weakening cough, I got the set of ten tablets – a five-day dose – together with a repeat dosage. I’m currently two tablets away from finishing the repeat. It was also recommended that I get a bottle of Bisolvon®, which ‘thins, loosens, clears mucus from the chest’ and ‘helps clear stubborn chest congestion’.
This first consultation was on a Friday. I was contracted for a two-day work week at Eynesbury College starting the following Thursday, and I really wanted to be fit by then. However, by Monday-Tuesday I was worried. The antibiotics, I felt, had been initially successful but then my condition seemed to deteriorate. On Wednesday I had my second consultation. I explained my amateur theory that the antibiotics had an immediate impact, but then the resistant strain of the bacteria continued to multiply, took over the territory of the non-resistants, and the illness came sweeping back. Classic evolution, in a sense: from random variation the environment of my body selects the stronger, resistant strain. The doctor agreed, or said he did, but pointed out that the problem was that my infection was probably viral rather than bacterial. In my enthusiasm for my own cleverness I hadn’t thought of this. And this probably explained the ineffectiveness of the erithromycin in the past. Maybe I’m not resistant at all.
So I was sent to the nearest Clinical Labs testing centre for a swab. I was also advised to continue with the antibiotics. The swab is applied by means of a long needle-like instrument wrapped in something like cotton wool at one end. This material is soaked in a virus-detecting solution and inserted fairly deeply into the nasal cavity. I visited the testing centre more or less immediately after the consultation, and received word the next day that the results were out. On Friday, I think, I attended my third consultation and was given the read-out. Ten viruses tested for were presented, including influenza A and B, and types 1 to 4 paraainfluenza, all undetected. The other undetected viruses were adenovirus, rhinovirus and metapneumovirus. RSV, an RNA virus (as are most viruses), was the only one detected.
So, progress has been made, and I was prescribed one more medication, a Turbuhaler® called Symbicort®, often used for symptomatic treatment of asthma. Instructions are to inhale two doses a day of the oral powder, which consists of budesonide and eformoterol fumarate dihydrate. There are 120 doses in my inhaler.
Budesonide is a corticosteroid, commonly used in this inhaled form for long-term treatment or management of asthma and COPD. It’s been around for a while, having been patented in 1973, and in commercial use as an asthma medication since 1981. It’s also on the WHO list of essential medicines. According to Wikipedia, ‘common side effects with the inhaled form include respiratory infections, cough, and headaches’, and at the moment I have a headache, and have suffered from severe coughing fits. I’m also producing quite a lot of mostly clear mucus, through the nose. I’ve attributed these symptoms to the virus, not the medication, but who knows?
Eformoterol is a more recent addition to the arsenal of anti-asthma type medications. This 1997 article in Australian Prescriber describes it as ‘a long-acting beta2 adrenoceptor agonist’ – a type of beta-blocker. Here’s some further interesting info from this site:
After inhalation of eformoterol powder, bronchodilatation begins within 3 minutes. This effect lasts for 12 hours with a peak effect within two hours of inhalation. These properties make eformoterol suitable for twice daily inhalation in patients who require regular, long-term treatment of reversible airways obstruction. It is not recommended for use in acute asthma. Patients should have a short-acting agonist, such as salbutamol, available to help deal with acute attacks.
Unfortunately my airways problems aren’t reversible, though particular obstructions and their causes may be treated effectively.
So what I have in my little Turbuhaler is a combo of a corticosteroid and a long-acting beta2 agonist (i.e. a bronchodilator). According to Wikipedia ‘combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread’.
It doesn’t seem as if there’s much I can do but wait for my condition to slowly improve. It’s been nine days since my first consultation, and I’ll be revisiting my doctor in a day or two. Mucus still flows freely and the distinctive, whistling wheeze I developed about a week ago is still present (I’ve never experienced this before). Physical exertion quickly makes me exhausted, but I’m hoping I can soon be sufficiently recovered to consider specific exercises to improve my condition and support me against further setbacks. Don’t want to end up slowly drowning in my own phlegm.
bronchiectasis updated
A lot has happened regarding my bronchiectasis recently, so I need to write about it here to learn more about the medication I’m on and what it might be doing to me.
I posted on this a couple of weeks ago, and that was an update on my first important post on the subject. But last time I wrote about an ‘acute exacerbation’, as the literature has it, of my condition, and what I believed was its cause. As it turned out, I was completely wrong. My doctor thought it might be viral, while I was privately convinced it wasn’t. I was given a doctor’s certificate and told to take a couple of days off, because I could benefit from the rest and because I might be infectious. I reluctantly did so, but was back at work the next day when I noticed a missed private call on my phone. It took me another day to respond, and it turned out to be my doctor telling me that my sputum tested positively for two viruses, influenza A and a human rhinovirus. Oh dear. I had to take more time off work, and my doctor told me not to worry about the antibiotics (it was a small course and I’d finished them anyway) and gave me a puffer with 60 doses of Alvesco®, which is ciclesonide, a synthetic corticosteroid which ‘prevents the release of substances in the body that cause inflammation’, according to this website. This was on top of the ingestible steroids, the subject of my previous post, though I didn’t go into detail about those pills, which I’ll rectify shortly. He also gave me a nasal spray for my rhinovirus, and arranged for me to have a consultation with a professor of Chesty Things at the RAH Chest Clinic.
So I’d like to look more carefully now at the medication I’ve been prescribed, apart from the antibiotics.
Firstly, Panafcortelone®, 30 white tablets each containing 25mg of prednisolone, an anti-inflammatory steroid much like ciclesonide. The worry about steroids is that they can interact with other medications to our detriment. They can also weaken our immune systems under some circumstances. I must say, though, that I’ve never yet had an adverse reaction to any medication I’ve taken. There’s quite a list of ailments that can be adversely affected by steroid use, no matter whether it’s prednisolone, ciclesonide or any other steroid, it seems. However, they shouldn’t be confused with anabolic steroids, notoriously misused by athletes.
Secondly, the nasal spray, Avamys®. Its active ingredient is Fluticasone furoate, yet another corticosteroid. According to the accompanying leaflet:
Avamys is used to treat symptoms of allergic rhinitis including stuffy, runny or itchy nose, sneezing, and watery, itchy or red eyes. The effects are usually felt within the first day, although some people will not feel the effects until several days after first taking it.
I took this medication regularly as prescribed for 5 or 6 days, then dropped off, as I obviously felt a lot better. It contains 30 sprays, and I wasn’t told to keep taking it to the end, as far as I can recall. The leaflet says that ‘once symptoms are controlled you may be able to decrease your dose to one spray in each nostril per day [down from 2]’. However it says elsewhere: ‘Do not stop using Amavys or change the dose without first checking with your doctor’. So I’ll try to keep taking it, though I don’t feel that I need it. My symptoms have always been mild compared to the description above.
Thirdly, the first medication prescribed by the Professor. Spiriva® is the brand name for capsules containing 18 micrograms of tiotropium (equivalent to 22.5 micrograms of tiotropium bromide, monohydrate), which are punctured and inhaled rather than orally ingested. It’s an anticholinergic bronchodilator used generally to manage COPD (chronic obstructive pulmonary disease), but not for acute exacerbations. Here’s what Wikipedia has to say on anticholinergics:
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. Anticholinergics inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, etc. Anticholinergics are divided into three categories in accordance with their specific targets in the central and/or peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.
Tiotropium is described as a muscarinic receptor antagonist (MRA), which means that it blocks the muscarinic acetylcholine receptor, found in the cell membranes of some neurons and other cells. Muscarinic receptors are divided into types, and the one I’m concerned with is the M3 receptor, which plays a role in bronchoconstriction.
Finally, the second medication prescribed by the professor is Nuelin™, aka theophylline (200mg in a sustained release form), which causes the muscle lining of the airways to relax, according to the leaflet. It is used to treat asthma and other conditions where breathing is difficult. According to the netdoctor site,
Theophylline is a type of medicine called a xanthine bronchodilator. It is used to open the airways.
Theophylline causes the muscles surrounding the airways to relax by a mechanism that is not fully understood. This allows the airways in the lungs to open.
In conditions where the airways tighten, such as asthma or chronic obstructive pulmonary disease (COPD, eg emphysema and chronic bronchitis), it is difficult for air to get in and out of the lungs. By opening the airways, theophylline makes it easier to breathe.
So all these medications are to help me breathe easier, but of course I’m hoping to be cured, and the professor, a lively and interesting gentleman, informed me that my lung function test, like the previous one earlier this year, came up very positively. That’s to say, my lung functionality is above average even for a normal person, so I’m really not having any difficulty breathing at all, I think… In fact, the professor mentioned a lung capacity of 106%, which doesn’t make much sense to me, and I forgot to ask for clarification (I’ve never given a student more than 100% for any test I’ve given them).
In any case I’m to go back to him around April for another consultation, by which time all these medicaments will be consumed. I think the hope is that some of the blocked areas as revealed on my CT scan will be a little less blocked. So maybe there’ll be another CT scan in the pipeline. The professor took me on a tour of my lungs via the previous scan, pointing out that because the whole of the right lung is affected by little blockages all through it, no operation would be possible, as might be the case if it was one localised very badly blocked region. presumably he was talking about an operation to remove a section of the lung. The left lung is not affected at all, which is apparently quite unusual.
Anyway, I’m always the optimist, and I’m hoping that maybe I can yet be cleared of all this gunk, and so cured.
bronchiectasis and steroids
My bronchiectasis has just ‘acutely exacerbated’.
Today I’m off work because I’ve got another infection, the first since I finished the course of broad-spectrum antibiotics back in May. The symptoms are an increase in phlegm, a slightly sore throat, a nasty cough and a scratchy voice, not good for teaching. And generally I feel rundown and a little depressed. This morning I visited the doctor for the first time since February. It was a new doctor, as my usual doctor apparently doesn’t work in the mornings. I didn’t want to take any time off work as I’m saving my pennies for an overseas trip, so I was planning to go to work straight afterwards because I didn’t start teaching until 1 o’clock. However the doc put the kibosh on that by giving me a sick certificate for Thursday and Friday, telling me I needed the rest and that I might be infectious. He also prescribed steroids along with the usual antibiotics, in this case Augmentin forte – though I bought the cheapie alternative called Curam Duo Forte – tablets containing a mix of amoxycillin (875mgs) and clavulanic acid (125mgs).
I’m often overly passive and docile with doctors, as with everyone else, and I often don’t clarify my thoughts until after the consultation. So in my usual docile fashion I rang in sick for work straight afterwards, even though this would mean I would lose hundreds of dollars in pay when I could ill-afford it. It’s true that my voice can barely stand the strain at the moment but I enjoy the energy my work gives me. More importantly, I don’t think I’m infectious.
While I recognise of course that our brains often play tricks on us, or more accurately that our brains and our memories aren’t always reliable, that doesn’t always mean that the doctor knows better than we do.
During the consultation the doctor asked me what I thought had caused this latest infection. I said I thought it might be something I ate. He didn’t seem too impressed with that and thought it might be something I picked up from my students, something viral. Hence the idea that I might spread the infection. Here’s the rub though – I actually felt quite certain that it was something I ate, and I know what it was and when it was. And this is not the first time I’ve felt such certainty about one of my many infections. Once it was a glass of wine which gave me a furry tongue, followed by the usual full-blown symptoms, and on other occasions it was food that I’d left a day or so too long in the fridge. These were clearly bacterial not viral infections. On this occasion it was an odd concoction of tabouleh salad, tuna, beans and roast potato that I’d constructed and taken to work for lunch, but had forgotten to eat. I found it later in my bag and scoffed it, half-knowing that I was making a mistake. The first symptoms soon followed.
I wonder how the doctor would have reacted if I’d insisted that it was food and not people that had infected me. It’s not a major issue, but now I also wonder if he’d have given me steroids for a purely bacterial infection. Strangely I didn’t wonder about the steroids until I got home. My neighbour was suspicious of this, saying that steroids were pretty strong stuff. I’ve certainly never had them prescribed for me before and now I wonder why.
According to medicine-net:
Steroids are used to treat a variety of conditions in which the body’s defense system malfunctions and causes tissue damage. Steroids are used as the main treatment for certain inflammatory conditions, such as systemic vasculitis (inflammation of blood vessels) and myositis (inflammation of muscle). They may also be used selectively to treat inflammatory conditions such as rheumatoid arthritis, lupus, Sjögren’s syndrome, or gout.
Bronchiectasis would be classified as an inflammatory condition I suppose, but pertaining to the upper airways, and nothing is mentioned specifically about this. Bronchiectasis is, however, a relatively rare condition (though possibly under-diagnosed). I’ve found a really good, thorough account of the treatment and management of bronchiectasis on medscape, but it says nothing about using steroids. So now I’m just a bit concerned, though I’m sure I’ve been prescribed a low dosage.
Actually on closer inspection I have found a section on medscape, dealing with anti-inflammatory therapy for bronchiectasis, where corticosteroids and other anti-inflammatory drugs crop up. I note that I’ve been given prednisolone tablets by the pharmacist (unfortunately I didn’t check the doctor’s prescription before handing it in, and I wasn’t given it back, so I can’t be sure if this was what the doctor prescribed). Prednisolone, according to Wikipedia, is a corticosteroid commonly prescribed for liver failure, but also used for treating auto-immune conditions such as asthma – so now we’re in the ballpark, so to speak. There are known side-effects for up to 5% of users, but i’ve never suffered any side-effects from any drugs I’ve been prescribed, not that I’ve been prescribed many. And side-effects are more often associated with long-term usage – aren’t they?
Medscape reports the literature on inhaled and oral corticosteroids for use with the many varieties of bronchiectasis and finds it promising but not entirely conclusive. I noted this line in conclusion:
A practical approach is to use tapering oral corticosteroids and antibiotics for acute exacerbations..
It almost seems as if my doctor has memorised this line. I’m feeling a bit more reassured now, but I have no idea what ‘tapering’ oral corticosteroids are. Well, I suppose it’s pretty obvious that it means gradual reduction..
Anyway, here’s hoping for a speedy recovery, and I’ve really got to take more care over food.
A few last words – the doc sent me to Healthscope next door to give a sputum sample, which, astonishingly, is the first time i’ve been asked to give one. The trouble is, if the medication works, I might not revisit the doctor for months, and will never find out the results of the tests on my sputum, just as i haven’t received the result of the blood tests I requested at my last consultation. I wanted to know if my mild anaemia had righted itself, as well as all the other health indicators – HDL and LDL cholesterol, triglycerides, etc. But they never provide you with the results if you don’t persistently ask for them. This is something I might explore further in another post.