Preventing infections in immunosuppressed patients

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

I'm Dhineli Perera, your host for this episode, and it's genuinely exciting to be chatting to Dr Aadith Ashok and Dr Bradley Gardiner today about the strategies to prevent infections in immunosuppressed patients. Together with their team, Aadith and Brad aim to demystify and summarise what can be a pretty complex area of infection prevention in the immunocompromised host. A warm welcome to you both.

BG: Thanks very much for having us, Dhineli.

No problems at all. So Aadith, I'll start off with you. Maybe give us a little bit of a refresher explaining to listeners what we mean by an immunocompromised host. This really has expanded from what we historically have always siloed to the chemotherapy patients, but it's much bigger than that now. Is that right?

AA: Yeah, you're absolutely right, Dhineli. And I think if you asked a lot of people about this term of what constitutes an immunocompromised host, most people would probably think about conditions such as transplant recipients or those undergoing chemotherapy, or on the other hand, conditions where you may have had an acquired immunodeficiency, for instance, patients with asplenia or those living with HIV [human immunodeficiency virus]. But clearly there's been an explosion over the last 2 decades of new therapeutic options such as biologics and small-molecule inhibitors.

And of course, there's ever-increasing complexity of cancer therapeutics, including things like very novel CAR [chimeric antigen receptor] T-cell treatment. And all of this expansion has revolutionised the treatment of conditions like inflammatory arthritis and inflammatory bowel disease, and has improved overall survival in what were previously poor prognosis malignancies. So as a result, this is really great because people are living longer and the average patient age of those who are having access to these therapies is also increasing. And this cohort is not only expanding in terms of the percentage of the population that are immunosuppressed, but it also comes with a significant economic impact with these therapeutics accounting for over 7 billion in annual PBS [Pharmaceutical Benefits Scheme] expenditure.

And of course, this means that the number of patients that physicians and general practitioners are seeing that are immunosuppressed is also rising. And the problem we run into, of course, is that these patients are intrinsically susceptible to infection and infections are the primary driver of morbidity and mortality in a lot of these patients because their underlying disease is so well managed by these new agents. And herein lies the incentive for this article because so many of these infectious complications can be predicted and many are so easily preventable and we want to offer readers a rough toolkit to follow when they're seeing immunocompromised patients.

And that's exactly what it is. I really enjoyed seeing all the summary tables. I think that when you are not well versed in all of these conditions, having a table to refer to is incredibly useful. So I'd strongly encourage readers to go and check out the article because we'll be touching on it throughout the podcast, but the tables are really well put together and easy to follow. Thank you for that, Aadith.

Brad, I wanted to check in with you and get your take on what it's like to obtain a detailed medical history to really assess that individual risk for a patient's infection risk. And it sounds simpler than what it is.

BG: Yeah, thanks, Dhineli. It's true. It is complicated understanding someone's individual risk. And we've tried to outline some of the key components of assessment and patients even don't always realise that actually, some of the things they've done at any point in their lives could be relevant to their future infection risk when they're immunosuppressed. It starts from basic medical history, what are some of the details of the comorbidities they have and the medical journey they've been on thus far? What immunosuppression are they currently on, planned for in the future, but also have been on in the past because many of these agents have a legacy effect, which is cumulative over time.

Any infections they've had previously, I always ask patients, 'Have you ever had any serious infections before?' And they usually say, 'No, not really.' And then they said, 'Well, there was that one time that I was admitted to hospital with staph bacteraemia.' It sort of takes a bit of digging to draw some of this information out. And then having a good look through their medical records to see are there any particular bugs that they've had in the past, bacteria, mycobacteria, viruses that could be relevant in the setting of future immunosuppression. Things like what antimicrobials they've both had before and tolerated fine and can't have because of allergies or intolerances. They're some of the key medical aspects.

And then in terms of epidemiologic exposures, people can come into contact with different infections at many different points in their lives. So I always start from the beginning. I ask patients, 'Have you ever travelled overseas before?' And they think I mean recently, but then I have to explain, 'No, no, no. I mean, have you ever travelled overseas at any point in your life and where have you been? What have you done?' The answers you get range from, 'Oh, I went to Bali for a week in 2003,' to some people who had really high-risk origins in areas of the world where there are a lot of endemic infections. And so understanding someone's journey to where they've got to where they are today helps you understand what their future infection risk might be and what we could do to look into that in a bit more detail.

Excellent. And so, Aadith, Table 1 in your article also beautifully summarises the targeted screening investigations required for this individual risk assessment that Brad has just taken us through. Now I'll be honest and say that it's not always reported in a way that's intuitive to clinicians that are not working regularly in ID [infectious diseases]. So could you walk us through this list and provide any recommended tips and tricks on interpretation?

AA: Yeah, sure. And to be honest, this is not really done in a very standardised manner, even in those within ID. And part of the reason for this, of course, is that we don't want to perform the barrage of tests or outlandish tests on a patient who, for instance, is only getting sulfasalazine for the inflammatory arthritis, where the overall infection risk is low. But on the other hand, we also don't want to miss the potential for TB [tuberculosis] reactivation in someone who's proceeding to a solid organ transplant. So I think a lot of this links really closely to that risk stratification and individualisation that Brad has just talked about.

Specifically, what we've tried to do here is to highlight the most relevant tests that we would perform when we see these patients when Brad and I are doing a pre-immunosuppression evaluation, and we've tried to separate these tests into a few categories. So the first one is tests that we would routinely perform in all patients, and these include things like HIV and the viral hepatitides, where clearly the diagnosis and treatment has significant impacts both at an individual level as well as from a public health perspective. We've also included MMR [measles, mumps and rubella] testing here, given the waning population immunity and the increasing outbreaks, as well as serology for zoster, given the availability of an effective vaccine.

There are, of course, some tests that we try to reserve only for patients who are planned for solid organ or bone marrow transplantation. And the haematologists and the specialist transplant physicians in this space are really great at ensuring that these are done in the pre-transplant workup. And we encourage listeners to lean away from sending these on a routine basis, and these include tests like CMV [cytomegalovirus] and EBV [Epstein-Barr virus] serology. But then of course, there are tests such as Strongyloides serology, syphilis serology, and TB testing, which are really, really important to consider in primary practice because if these tests are done prior to sending off that referral to the rheumatologist or the gastroenterologist for their autoimmune disease, we can firstly pick up patients who require intervention quickly and to streamline the process of the referral so the patients aren't waiting for the screening to be done prior to starting effective treatment for their underlying disease.

And from a pragmatic use perspective, we kind of want physicians to try and individualise the use of this table as much as possible and involve the patient in this process. And the most important thing we want to generate from this is to educate the patients about their potential infectious risks. And of course, there are so many tests that you can order that aren't explicitly stated in this table, and of course can be sent based on individual risk factors in terms of their travel or epidemiological or environmental exposures. And of course, if there are any questions or concerns on this front, please don't hesitate to call your local ID physician or to email or call us.

Yeah. Excellent. Thank you for that. Would you suggest that primary practitioners do refer to an ID physician if they're unclear on interpretation or potentially the pathology itself?

AA: Yeah, absolutely. And we've tried to make interpretation available in the paper so that primary practitioners can at least enact a response based on serology. But of course, if there's any concerns around interpretation or if you're worried that the epidemiological risk and the serology are not matching up, that would absolutely be a indication to call us. And we have a section within the paper about when to pick up the phone and call for help because this is not something that people routinely do on an everyday basis.

Excellent. Thank you for that. So Brad, moving on to the antimicrobial prophylaxis options that are listed in Table 2, would it be fair to say that there is not perfect consensus on the optimal duration and choice for all patients? What goes into determining these factors?

BG: It's always a tricky one, right? On the one hand, we don't want to overuse antibiotics. Reserving them for where they're really needed is really important, especially with growing antimicrobial resistance. But on the other hand, there's really good evidence that giving certain patients targeted prophylaxis can really reduce the risk of some serious infections. Probably the best example of this is pneumocystis pneumonia, where Bactrim (trimethoprim+sulfamethoxazole) is very effective at preventing this potentially serious infection that can land people in hospital and one pill 3 times a week can keep people well.

Now there's a spectrum of risk here, right? And this is where it can get a bit complicated and you're always trying to balance out the benefits of antibiotic prophylaxis with potential risks. And so the more immunosuppressed the patient is, the more they're going to benefit from prophylaxis. And then there are certain types of immunosuppression where there's specific infection risks. And so it does get a little complicated sometimes, but probably the main 2 drugs to consider are trimethoprim+sulfamethoxazole for PJP [Pneumocystis jirovecii pneumonia] risk. There's some really helpful advice in Therapeutic Guidelines that sort of says, 'Okay, well, how much prednisone is enough to warrant PJP prophylaxis?' And it works out to be about 25 mg a day for more than about 4 weeks.

And the herpes virus is the other one. And the agents that we're talking about there really are valaciclovir or for CMV, valganciclovir. There's a few antimicrobials, which it's a bit semantic. Is it prophylaxis to prevent an infection or is it treatment of a latent infection? We've sort of included those in the table. Things like ivermectin to treat Strongyloides or isoniazid to treat latent TB. They're kind of not exactly prophylaxis, but we thought we'd group them all together just because it's sort of prophylaxis against disease.

Kind of keeping it at bay, right?

BG: Yeah.

Like preventing that reactivation. And so then what would be your advice to primary care providers who are asked to continue supplying scripts for these indications if we're not clear on duration plans, given that as you've just said, there are so many factors to determine how long they should be on it for.

BG: Well, this is also one of the challenges, right? Because infection risk is not static. It's dynamic over time, and so patients will go through periods of higher and lower immunosuppression. It really depends on the details. And this is why the individual approach is really important. So for example, if a patient who's had MDA5 [melanoma differentiation-associated protein 5] dermatomyositis receives big doses of cyclophosphamide and high-dose methylprednisolone and then gradually weans down over the following years, their infection risks should decline in parallel with that.

And they may reach a point where the need to continue prophylaxis can be reassessed. Then similarly, other patients will have say a flare of their interstitial lung disease and need re-initiation of high-dose immunosuppression. Along with that, it's really important to remember to re-implement that prophylaxis at that time.

Yes. So would you then suggest they reach out to the specialists managing that disease management for the hospital sector? What would be your recommendation to find out the duration plans that need to be implemented?

BG: Yeah, it's a shared responsibility, I guess. Patient's been on these drugs before and they've just been forgotten about or need re-initiation, then be reasonable to just do that. But working collaboratively in primary care, with the primary treating medical specialties and with infectious diseases as needed is probably the best approach.

Yeah, absolutely. So then when it comes to vaccination, Aadith, this also needs to be quite bespoke for patients. And outside of the hospital sector, where can clinicians go to find out these plans and assist with their implementation?

AA: Yeah, absolutely, Dhineli. Vaccination's obviously a very hot topic at the moment. In terms of resources, hopefully this paper helps close some of the gaps for clinicians, but there are some other resources which I would point to, including the Australian Immunisation Handbook, the CDC [Centre for Disease Control] Yellow Book and ATAGI [Australian Technical Advisory Group on Immunisation] for most up-to-date guidance, because this is a really difficult space to keep abreast of because it's constantly evolving.

What I will say though is that vaccination is such an effective and relatively cheap measure of reducing your risk of infection. And given we're talking about patients who are immunocompromised, whose normal mechanisms for fighting these infections are so impaired, it's a really, really important point for physicians to at least have the conversation with patients about and to start unpacking patients' opinions and thoughts on vaccination and vaccination practices.

And then your Table 3 lists quite a few of them. How would you suggest we delineate between which vaccinations need to be reviewed and considered for the patient sitting in front of you?

AA: What I might start with is maybe just stating the obvious that vaccines aren't perfect. A small percentage of vaccinated patients will still contract the disease and a much smaller number will have adverse effects from vaccination. We know from current research that vaccine response and efficacy is impaired in immunocompromised hosts. So there is a bit of incentive to try and get these done prior to the commencement of immunosuppression wherever possible. And most importantly, what we do know is that many of these vaccines, regardless of the net state of immunosuppression, they can significantly reduce the severity of an infection if a person was to actually contract it.

From a primary practice perspective, it's really important that the vaccine list be reviewed on a regular basis so that patients don't miss out on their booster dose or their follow-up dose. And in terms of Table 3 itself, my practice has often been to offer nearly all of these vaccines to every immunocompromised patient I see. And a big reason for this is that evolving nature. The first time you see them, they might be on the lower end of the immunocompromised spectrum, but things have a tendency to change quickly in this space and they may become heavily immunosuppressed rather quickly. My focus has always been to have a very open discussion with patients and to talk to them about which vaccines are highly important, such as influenza, pneumococcal vaccines, hepatitis and zoster, then talk about which ones carry an additional cost as they may not routinely be funded by the NIP [National Immunisation Program], and then which ones they would benefit from in terms of their current and future plans, such as the travel-related vaccines or the live attenuated vaccines.

And my last point on this from a pragmatic perspective is particularly for those in general practices to kind of strike while the iron is hot, because the most effective vaccine is the one that, 1, the patient wants to have, and 2, then actually goes on to receive it. So if you can stock some of these vaccines in your practice, administer them yourself if you have to, and have effective recall or reminder systems, and use the time intervals between vaccines as a guide rather than a strict rule, that's all going to be very beneficial for these patients. And of course, whatever you do administer, if we can document it on the Australian Immunisation Registry, it's a great national system and a really effective way of ensuring that patients are not only up to date, but they're not given any unnecessary doses of vaccines.

Yeah, 100%. I can't emphatically support that any more. And so Brad, who would you say are the patients that warrant a more detailed evaluation and potentially a consultation with an ID physician?

BG: We love seeing patients, right? We do it a lot. However, there's a limited number of ID physicians out there. So we really want to try and get some of this happening in primary care as much as possible, but there are absolutely certain patients who are higher risk and who we would encourage a bit more of a specialised eye on. We've listed those in Box 2, and basically it's the more complex patients. Those who are clearly going to have a long journey of high degree, long-term immunosuppression. People who've got TB, for example, but also sarcoidosis or something. If there's sort of an urgency about it, if things need to be rushed, if there's not a lot of time, that's a good time to reach out and have a chat about a patient.

If people have been born or grew up overseas, they are definitely higher risk. Depends on the region and there's region-specific risk, but we're talking Asia, Africa, Latin America for 2 reasons. One is there are a lot of endemic infections in those regions that are more common. So the hit rate of a positive screening test is going to be much higher, but also they may not have had the opportunity for what we would consider here now a full childhood vaccination series. So many patients will be unaware of their childhood vaccination status if they've grown up overseas. And many of these countries were not routinely implementing the same vaccines that we have access to today. And other things like specific lifestyle risks, there's high risk occupations and things that put people at higher infection risk.

Thank you for that, Brad. Box 2 is a great resource, so I would definitely recommend checking that out. Aadith, your article also touches on safe living advice for patients. Some are pretty well understood, especially in the post-COVID era, but others are a bit more underappreciated. Could you talk us through the latter especially?

AA: Yeah, of course. I often refer to safe living advice to patients as a bit of a commonsense approach to reducing your risk of being exposed to or acquiring an infection. And most of the time, just having the conversation with the patients is all you need. So in terms of specifics, I talk to them firstly about effective hand hygiene. And whilst these patients, we don't necessarily tell them to wear a mask all the time, we do recommend them to wear masks in high-density areas. These are simple mechanisms of avoiding both gastrointestinal and circulating respiratory pathogens. This particularly applies to patients who have really young kids.

From a food perspective, I've asked patients to treat food similar to any pregnancy advice that they may have come across. So avoiding high-risk foods, including raw meat and seafood, avoiding soft cheeses and undercooked meat and poultry, and of course, staying away from things like unpasteurised milk and dairy products, all of which can harbour both bacterial and parasitic infections. Water's a specific problem for us because freshwater sources are often teaming with bugs. So if you're using things like a rainwater tank or consume well or bore water, it's really important to boil it before consuming it or using it on your body, or installing an in-line UV [ultraviolet] filter where practical. And the same goes for any exposures to freshwater from lakes, dams, and rivers for the same reason.

Sexual health always has a bit of taboo, but these patients, we want them to live full and healthy sexual lives. And in this setting, getting regular STI [sexually transmissible infection] checks and using barrier contraception reduces your risk of acquiring infection greatly. And from an ID perspective, we'd love if we can remove pets from the equation, but this is not really something that patients want to hear. So we encourage our patients to make sure that their pets are well cared for and that the pets get all the appropriate vaccinations and checks that they need. And of course, we try to tell them to not handle any of their bodily fluids or excrement and patients with birds specifically should avoid cleaning out any of the cages and things themselves. And if you do get those scratches or bites from your pet cat or dog, it's really important to tend to those immediately and to not let them fester into something bigger and turn into a nasty infection.

The biggest thing we spend time on is gardening or environmental exposure, specifically things like the garden, the wet areas of the house, the compost bins, sheds, or any area where you're doing some construction are really red flags for us. We see an unbelievable number of bacterial, fungal and mycobacterial infections from these exposures. And we strongly try and advise patients to minimise their contact with soil and disturbing the topsoil because whenever you do this, you actually aerosolise a lot of the spores and particles that are in the topsoil, and then you have exposures either on your skin or you inhale them into the lungs and eventually you get a targeted infection from a lot of these bugs.

And if you absolutely have to, please, please, please ensure you wear appropriate PPE [personal protective equipment], which includes appropriate gloves, as well as wearing an N95 or other respirator mask to essentially stop you from inhaling some of those spores that are aerosolised. And of course, we want patients to travel, but what we do ask patients to do is if they can let practitioners know about their travel plans at least 2 to 3 months prior to them going so that they can be counselled and have a discussion around appropriate advice for the place that they're going to, whether or not they need relevant prophylaxis. And of course, if they need any directed vaccines to be administered before they do head off.

Excellent. Well, that's unfortunately all the time we've got for this episode. It's such a broad topic and to summate it the way that you have in your paper is great. So thanks so much for joining us today, Aadith and Brad.

BG: Thanks very much for having us.

AA: Yeah, thanks, Dhineli. It's been great.

[Music]

Dr Ashok and Dr Gardiner's article, 'Preventing Infections in Immunosuppressed Patients', is available on the Australian Prescriber website. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Dr Gardiner has received travel support, speaker and advisory fees from Takeda and Biotest, and consulting fees from Qiagen. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber Podcast.

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