Transcript

MIC CAVAZZINI:        Welcome to Pomegranate Case Report, from the Royal Australasian College of Physicians. I’m Mic Cavazzini, but your chief detective today will be Associate Professor Stephen Bacchi. He’s just been awarded his FRACP letters and is currently undertaking a Fulbright Fellowship in Boston. That’s where he has rustled up two guest speakers to talk through a startling case from 20 years ago. I will share a link to the article published in the journal Transplantation in the show notes, but no spoilers just yet. You’ll get drip fed the exam results and clinical findings just as a trainee presenting a long case would be. See how you go narrowing down the diagnosis.

STEPHEN BACCHI:   Hi, I'm Stephen. I'm a neurology Fellow at the Massachusetts General Hospital, and Christina Gao is a medical student at the University of Adelaide. And today, we'll be discussing a fascinating case with Associate Professor Camille Kotton, who is an infectious disease physician at the Massachusetts General Hospital. She's the Director of Transplant and Immunocompromised Host Infectious Diseases, and her interests include vaccination, travel medicine for transplant recipients and reducing the infectious risk of immunocompromising medications. And Dr Simran Gupta, who is a transplant and oncology infectious disease Fellow at the Brigham and Women's Hospital with an interest in invasive fungal disease and sepsis in immunocompromised hosts. Thank you both for joining us.

CAMILLE KOTTON:   Thanks for having us.

SIMRAN GUPTA:         Yeah, great to be here.

STEPHEN BACCHI:   So as usual, we'll be discussing a previously published case report in a step by step manner, with a focus on content that's relevant to trainees and a generalist audience. Would you like to take it away with the case, Christina?

CHRISTINA GAO:       Yeah, absolutely. So today we have a 42-year-old male who has fevers in the first nine days following an orthotopic liver transplant. The patient has a past medical history of cirrhosis. Specifically, this cirrhosis was in association with hepatitis C infection, genotype 2b haemochromatosis, C282Y heterozygous and alcoholism. He also had a history of diabetes mellitus. There's clearly a lot more detail that's required here, but could you please talk us through how you think about and also approach fever in a post-transplant patient

CAMILLE KOTTON:   Well, thanks a lot for starting us off. So, you know, fevers in any patient, we always look for specific signs and symptoms and where we think the aetiology of the fever might be. So, this patient is very close to transplant. So, we would think about, you know, nosocomial issues. We would think about donor-derived infections. Is this a surgical site infection? You know, is this something related to the recent surgery which all of which seem most likely. We would also want to dip back and look at their pre-transplant exposures. You know, do they have a history of latent tuberculosis, other latent infections, that type of thing. But I think first and foremost, go with signs and symptoms of various types of infection.

And there is this timetable of various infections that can happen after transplant, which was initially published in the New England Journal of Medicine by doctors Robert Rubin and Jay Fishman in the late 1990s but sort of divides people into the first one month after transplant. And then months two through six, and then month six and beyond, with that first month of infection, predominantly relating to many of many of the things that I mentioned. And then, months one through one through six; more of the classic opportunistic infections, the risk of which can be greatly mitigated by various forms of prophylaxis. And then more than six months out, tends to be more community acquired later on, when the net state of immunosuppression is lower.

CHRISTINA GAO:       So, that was really helpful. Applying some of those things specifically to this case patient. There were no focal features on history or examination or Initial investigations, computer tomography or CT of the chest, performed on day nine after the liver transplant for fevers, revealed multiple bilateral, small pulmonary nodules. A previous chest X ray at the time of transplant had demonstrated no such abnormalities. Bronchoscopy with bronchoalveolar lavage was subsequently undertaken, and the results of this investigation were negative for bacterial, fungal and viral studies. So just to recap, we have a patient who is within two weeks post liver transplant with fevers and new multiple bilateral, small pulmonary nodules with a negative bronchoscopy and bronchoalveolar lavage. How do these results help you, and what are the strengths and limitations of bronchoscopy and bronchoalveolar lavage in transplant patients?

SIMRAN GUPTA:         Thanks, Christina. Well, as you know, bronchoscopy is a really highly valuable tool in this population, in patients with suspected pulmonary infections, it's particularly useful in those who can't produce sputum samples, because it allows us to really get a good lower respiratory tract sample, and we can investigate a wide range of pulmonary infections; bacterial, fungal, viral, mycobacterial aetiologies. There are, of course, risks associated with all interventions like bronchs, and particularly in our immunocompromised haem-onc patients, there can be a risk of bleeding, but they really allow us to get valuable information. So, if it's felt that the benefits outweigh the risks, they're really important to pursue.

Something to keep in mind, the diagnostic rate of the bronch and BAL is pretty variable. Overall, most studies have reported about a 50 percent or so microbiologic yield from bronchs in the stem cell population. That ranges from 40 to 65 and that yield is improved when transbronchial biopsies are also performed. And that's similar to solid organ transplant patients, although the diagnostic rate that's been published in prior studies is anywhere from 27 to 70 percent so that's very wide. Again, transbronchial biopsies can increase the diagnostic yield, particularly in fungal and viral infections.

And then something else to keep in mind is that each specific infectious test has its own characteristics. For example, the BAL-galactamanin, which can assist with a diagnosis of pulmonary Aspergillus, has a sensitivity in the 60s, but a specificity about 90 percent. But that's less in the liver transplant patients, 56 percent sensitivity and 87 percent specificity. You can also send PCR—multiplex PCR—from the Bal, but that's got a low sensitivity as well specificity of only about 80 percent for both bacterial and fungal infections.

So, all of this to say, the recap is that it can be a really valuable tool in this population to investigate the aetiology of pulmonary infections, but it's not perfect. It's dependent on many factors, like the test, the host and even sometimes the clinician performing the bronch, whether they're able to get a really good sample. And so in this particular patient, where all the Bal studies are negative, it actually doesn't change my suspicion that this is probably or likely infection.

STEPHEN BACCHI:   Brilliant. That's, really helpful. So, in this case, he was treated empirically with eight days of oral fluconazole, and the fevers resolved. And now we're going to jump down the track in terms of the case. So, for six weeks following this time, he was on itraconazole to maintain his serum cyclosporine level, and this was then stopped because of elevated cyclosporine levels. Now three weeks after stopping the itraconazole, now nine weeks after his original course of fluconazole, he presents again with a recurrence of fever to 38.1 degrees Celsius, and this is accompanied by a headache, neck stiffness and altered mental status, and he's admitted.

Now here's an MRI, and the first MRI shows multiple subcortical, non-enhancing T2 lesions, a CT chest showed reduction in the size of the pulmonary nodules, and he had multiple lumbar punctures. To summarize, essentially, there was over 100 white cells on these with approximately a 60:40 split between neutrophils and lymphocytes and markedly low glucose. And now he's worsening despite being on ceftriaxone, ampicillin and vancomycin. So, Prof Kotton, we've clearly got some sort of unusual central nervous system infection in an immunocompromised host here. What sorts of tests and treatment might you think about next?

CAMILLE KOTTON:   This was a very interesting turn of events. So he had fluconazole at therapeutic levels, and then was on itraconazole to maintain his cyclosporine levels. And I will say this is an older case, and we used to use itraconazole when itraconazole was very inexpensive and cyclosporine was expensive. So, to keep the cyclosporine levels up, so it was purely being used for that reason.

But it sounds as though the patient may have—assuming that we lump together the fevers with his current syndrome, which may or may not be right—it sounds as though he may have had a response to the fluconazole, the fevers went away, the lung nodules are getting smaller, and then perhaps the itraconazole as well. And then was when that was stopped, now he has worsening of CNS symptoms.

On the other hand, it's possible—it's always Occam's Razor versus what we call Hickam’s dictum—you know, do we lump these together, or do we just say this is something entirely different from the initial fever? But he now has what's clearly, you know, a meningoencephalitis, meningitis type picture. He's not getting better with standard Ceftrex, ampicillin and vancomycin. So, this does sound as though it could be either fungal or perhaps mycobacterial. And I would probably initiate—given how sick he is—probably initiate treatment for those things and then try to send additional testing.

So, I would look to see what kinds of stains have been done on his CSF. I would make sure we've done fungal stains, especially including cryptococcal antigen. And I would do that on both blood and the CSF. And then I would make sure he’s had AFB stains and culture fungal stain and perhaps save some CSF—this is an older case—but I would probably save some CSF for potential additional studies such as deep sequencing. But we're sort of not, not there yet, necessarily.

And then whenever I see these challenging cases, I might go back and just review all of his prior culture data. Is there anything deep in the chart? Deep in the microbiology results? Does he have anything in another record? Does he have any unusual exposures? And then I would always be how the other recipients are doing, recipients of organs from the same donor, and is this a donor-derived infection? And I would report to my local organ procurement organization, and then they usually go out and ask all the other recipient centers how their recipients are doing, because this is sort of one of these staggered clinical presentations, and certainly could be a donor-derived infection. But in the meantime, I'd start some type of therapy for fungal—I'd probably use ambazone until I know what's going on, and then I might even start mycobacterial treatment until we have a little better handle on what's happening.

CHRISTINA GAO:       Yeah, thank you for that. So, in line with some of those mentioned and also suggested treatment options, the case patient was started empirically on fluconazole and also anti-TB treatment, cyclosporine was then reduced and interferon alpha was also reduced, while CSF parameters were improved. Tests that were negative included fungal smears, acid fast smears, VDRL and PCR for HSV, VZV, CMV, Bartonella, mycobacteria, toxoplasma, bacterial, fungal, mycobacterial cultures and also cryptococcal antigen.

On day, 13 repeat MRI showed likely granulomatous changes and retinal examination showed lesions that were suggestive of fungal disease. In the context of the patient having previously lived in Arizona, ultimately, his repeat coccidioidomycosis serology returned positive. The patient responded well to fluconazole therapy, with resultant improvement in both mental status and good liver function. I imagine a lot of Australian clinicians might not have encountered coccidioidomycosis. So, could you please tell us a bit about it?

SIMRAN GUPTA:         Yeah, absolutely. Coccidioidomycosis is an infection near and dear to me, so I'm excited to talk about it today. So cocci, for short, is known more colloquially as Valley Fever, and it's caused by Coccidioides immitis and C. posadasii, which are dimorphic fungi that are endemic to the southwestern United States, Mexico and select areas of Central and South America. Although with some changing climates and more intense dust storms, the geographic distribution of cocci is spreading, so it's important to keep it on the differential for a lot of these patients.

Infection with cocci is typically caused by inhalation of spores from the soil. And in patients who are immunocompetent, it typically just causes sort of a self-limited, moderate respiratory illness, fevers, malaise, cough, et cetera. And a lot of papers have published that it can be asymptomatic and up to about 60 percent of people. But it can become a very serious disease and cause really substantial morbidity and mortality in immunocompromised patients, like this solid organ transplant patient. And then there's also risk for dissemination to other sites of the body in these patients, like the CNS bone and joints and skin and soft tissue.

The way you diagnose cozy begins with suggestive clinical symptoms, radiographic changes like pulmonary nodules or tree and bud. And then typically confirmed via serologic testing, IgM and IgG antibodies for enzyme immunoassay, immunodiffusion and complement fixation, antibody titres. There's a couple of other tests that you can use, though they’re used less frequently. There's a urine coccidioides antigen, but the sensitivity is pretty low, at about 50 pecent, so it misses a lot of true cases. And so, we don't often order it. And then histopath and cytology can be useful to aid in the diagnosis, but again, the sensitivity can range pretty widely. So ultimately, we generally use serologic testing to make the diagnosis.

And then, in regards to treatment, it's different in immunocompetent and immunocompromised patients. So as I mentioned before, not all immunocompetent patients even need treatment, even if they're mildly symptomatic. If treatment is pursued, which is typically recommended in patients who have persistent or prolonged symptoms, then the initial treatment is an oral azole like fluconazole, and it's usually continued for three to six months, driven by the illness course and patient improvement.

But all immunocompromised patients should be treated because of the risk of disease progression, and that is the case in this patient like solid organ transplant patients. Treatment of choice, again, is typically an oral azole like fluconazole, usually starting at a dose of about 400 milligrams daily, but can go up to as high as 1200 milligrams daily. And IV Amphotericin b can be used as initial therapy for severe or rapidly progressive infections.

The duration of treatment is very long, anywhere from six to twelve months or even more, sometimes, depending on resolution of the illness. And then in these patients because of their immunosuppressed status and the risk of reactivation, we typically recommend secondary prophylaxis. So, after they finish their treatment course, they'll then go on a lower dose for prevention.

I actually wanted to highlight a couple of specific points about this patient, in general. So, transplant patients who have lived in endemic areas in the past should undergo pre-transplant screening for cocci, and this is done with serologic testing—the same antibodies as I mentioned before. And if any of those antibody tests are positive, that the patient should be started on azole prophylaxis at the time of transplant to prevent post-transplant reactivation. The duration of prophylaxis is really highly variable and pretty controversial, and it depends on if patients continue to reside in their endemic area, or if they move to a non-endemic area, since that's a factor that affects the chance of reactivation.

And then finally, in like all, the last point I wanted to make in relation to this case is, it's not unique in only that this was a transplant patient who developed de novo, or maybe reactivated, cocci. But this patient also developed cocci-meningitis, as evidenced by the CNS symptoms and MRI changes, and meningitis is actually the most lethal form of disseminated coccyx, and due to the high risk of recurrence, it's typically recommended for patients to be on lifelong therapy.

STEPHEN BACCHI:   Thanks, Dr Gupta, that's really interesting. Us encountering this organism in Australia would be very uncommon, but with international travel occurring again after COVID , I guess, anything's possible, and travelers can present with diverse previous exposures. Now, in our training, and our BPT long cases, at times, we'll have patients with a previous transplant who express a strong desire for future travel. So Prof Kotton, how do you counsel patients who've had a transplant about travel and what types of additional precautions can they employ to improve their safety while traveling?

CAMILLE KOTTON:   That's a great question. I have a real love for the topic of travel after transplant or travel for the immunocompromised host. And actually, if people want to read more about that, the US Centers for Disease Control, CDC yellow book for travel medicine has a whole chapter that we update every two years on travel medicine for the immunocompromised, where we talk about a whole variety of topics.

One of the biggest issues is finding a destination and type of travel that sort of limits the risk of infection. I will say that overall, I've had an amazingly good experience with travel—I call it travel after transplant—but travel for the immunocompromised, where as long as they pick a destination that's reasonable risk—which is most areas of the world—and the type of travel, you know, if it's staying in reasonable level hotels and that type of thing, in general, people do pretty well. They need to be careful about making good food and water choices, or making sure that they would be in a place where they can do that. You know, I think spending months in a tent in areas where it's very hard to get treated water would be high risk. But areas where they have, access to clean food and water, lower risk of mosquito bites, tick bites, that type of thing, and then ready access to health care in a setting that could manage an immunocompromised patient. are all good tips.

I have not advised people to avoid areas with coccidiomycosis, and I have not had cases myself with patients developing coccidiomycosis. There was an interesting case report in Clinical Infectious Disease several years ago in a patient from the Chicago area who went to the coccidioides area and developed a really unusual lip lesion, that almost if you looked at it, you might think the patient had some type of malignancy. But when they biopsied it, it was all coccidioides. You know, it's all about the travel history. This is why infectious disease specialists love asking about travel and exposures and whatnot.

But I think, although coccidioides is reasonably common in those areas, it doesn't mean that we transplant patients shouldn't go there. And, in fact, as Dr Gupta knows quite well, they have very active and productive transplant programs in Southern California, Arizona, that entire region, with really good clinical outcomes. So, on the rare case that somebody actually gets coccidioides, they should be able to be diagnosed and treated.

There was a really interesting case of that was reported in France where a donor traveled to the American Southwest and went back to France and had a devastating accident and became a deceased donor. And they had a really curious fungus grow from the bronchoscopy specimens, and they actually had trouble initially identifying it. You know, it's France, it's not a cocci region, and so they had to do advanced studies and figured out that it was coccidioides. So I think no matter where we are in the world, we should be attuned to the idea that we can see unusual unexpected pathogens. And both as clinicians and also laboratorians, we should be ready to face those challenges, especially with the amount of travel going on in the world these days.

CHRISTINA GAO:       Thank you so much for all that that was both really interesting and also really helpful to wrap up the case for our listeners. Could you please outline a couple of key learning points or take-home messages that trainees could take from this case?

SIMRAN GUPTA:         Yeah, definitely. I think Dr Kotton made some really good points, but it's really important to take a good history from these patients. I think that's something that really draws us to infectious disease. But, you know, Dr Kotton clinched this diagnosis when this patient came in and she got more of a history, and found out that he'd lived in Arizona, and then even called the outside hospital in Arizona and was able to get some of those test results. So that's where kind of being a good clinician and taking a really good history comes into play, and it's so important in the care of our patients.

We learned a lot atoday, about different travel precautions to take, and just to keep a lot of different things on your mind where you're counseling these patients about travel, and I think that's really important. I never want to tell anybody to not go to Arizona, because that's where I grew up, and I love it. But, you know, something to keep in mind for those patients that come back from Arizona, if they might have an unusual clinical presentation. And then just being really mindful of screening and prophylaxis in these in these transplant patients, because there is a lot of infections that they're at risk for, and a lot of things that we can try and help prevent. So, we just want to make sure that they're getting all their appropriate screening tests and all their appropriate prophylaxis medications.

STEPHEN BACCHI:   Thank you again, Prof Kotton and Dr Gupta. It's been a fascinating discussion. I've certainly learned a lot. So ,for full details of the case, listeners can refer to the original article, which was titled, Coccidioidal Meningitis after Liver Transplantation in a Nonendemic Region: A Case Report. It was published in Transplantation in 2006 the first author was Prof Camille Kotton. The last author, Dr Martin Hertl, thank you again.

MIC CAVAZZINI:        And thanks Stephen Bacchi and Christine Gao for another great Case Report. And also to the students, Trainees and Fellows who helped tidy up drafts of this episode. This is a passion project to support peer development, so please don’t sue us if something wasn’t said quite right.  

For a more vetted reference modeled around the basic physician training curriculum go to the College Learning Series at elearning.racps.edu.au. There you’ll find dozens of lectures on infectious diseases and immunology, including one title “Fever in the returning traveler.”

There are also some good lectures on pharmacological interactions like the one we heard about today. Itraconazole boosts cyclosporin levels primarily through inhibition of cytochrome P450 enzymes which is responsible for the metabolism of cyclosporin. This results in increased systemic levels of cyclosporin, prolonging its half-life and increasing serum concentration.

Thank you for being one of the several thousand people who tune in regularly to the Pomegranate Health podcasts. But I’d really love to see those numbers increase, so please mention it to a colleague if you think you’ve learned something today. Or you can leave a review on Apple Podcasts or Spotify to help other people find the show.

You’re always welcome to send feedback or story ideas to podcast@racp.edu.au. This podcast was produced on the lands of the Gadigal clans of the Yura nation. I pay respect to their elders past and present. I’m Mic Cavazzini. Speak to you soon.