45: A Disrespectful Bug

He is a chief resident at Jacobi Medical Center and Albert Einstein College of Medicine, but as now an incoming ID fellow at the combined Massachusetts General and Brigham and Women's Hospital ID fellowship program. Joining us as our discussant is Dr. Shweta Anjan. Dr. Anjan is a transplant ID physician at the Miami Transplant Institute.

She is an Assistant Professor in Clinical Medicine and the associate Program Director of the Transplant ID Fellowship program at the University of Miami Miller School of Medicine. I'm so glad you guys are here. We always start with our one question as a cultured podcast. We'd love to hear about a little piece of culture that you enjoyed recently or brought you some happiness.

Her current medications includes triple immunosuppressive therapy -- tacrolimus, mycophenolate, and prednisone. And in terms of prophylaxis, she is on valganciclovir and atovaquone. Her social history, um, remarkable is that she lives in Las Vegas, Nevada. She is currently retired. She spends her weekends hiking. She does not have any pets or no recent travels. The physical exam of this patient um, shows, uh, tachycardic patient with decreased breath sounds in the right lower lobe.

Uh, and additionally, on the physical exam, we're able to find, uh, tender one by one centimeter ulcerated lesion of the left ankle without any purulent secretions. Um, the CT scan of this patient shows a right lower lobe consolidation with a two centimeter lesion, um, with peripheral cavitation. So, how would you approach to this patient who's presented with lung and skin findings?

that would put her at risk for different endemic fungi, which is just the first little bell that went off in my head when you said skin lesion and cavitary lung lesion, you know, Um, and then some more information about her underlying condition that led up to the transplant. Like she has emphysema, but why would, um, a female have emphysema? Is there a history of smoking, you know, any other medical history we need to think about? Auto-immune conditions, for example.

Also, um, you didn't cover drug use or marijuana use, you know. Sure, like most transplant patients are very careful with regards to marijuana smoking, but it's still, um, something I would like to know. So coming up with a more broad differential diagnosis, and then we can narrow it down to specific features of our patients. The way I think through things is consider infections and noninfectious causes also. So you have like a table with one side that says infections.

And the other side that has non-infectious causes. When you go through infectious causes, you look at the big four -- bacterial, viral, fungal, parasitic, and try to see which one would fit this picture. So we're looking at an immunocompromised host so, if you had to think of bacterial causes here, can, you can say like Staph aureus and MRSA can cause cavitary lesions.

And if there's bacteremia and an hematogenous spread, you know, they could also be some skin lesions or cutaneous abscesses resulting from that. And then other, um, other bacteria like Rhodococcus, which is not very common. And she doesn't have a history of contact with animals, but it's still possible in transplant patients. And consider gram negative bacteria like Pseudomonas and Klebsiella, that can also cause more of a, um, echythma when it comes to a skin lesion.

Um, and rarely cavitary lesion. The big thing to also consider is mycobacteria, non TB mycobacteria (NTM) especially, um, I'm assuming this patient would have had screening for TB pre-transplant. Hopefully there was a Quantiferon that was checked and negative, but it is still possible for her to either have donor derived TB or have, um, new TB infection. So keep, you know, tuberculosis, non TB mycobacteria also on top of the list.

And in a different part of the country, I would say consider zoonoses like tularemia. You know, she obviously has had no contact with rabbits. So I wouldn't put that high on my list, but it's usually the board question where you have pulmonary symptoms and this ulcerative glandular lesion somewhere on the hand or leg. Um, and you have to consider rabbits and tularemia. All right. So that's bacterial. I think my favorite out of this will be working through the fungal etiology.

So she is a lung transplant patient. Um, a question I would have is, was she on any antifungal prophylaxis? Because some centers choose to put their lung transplant patients on prophylaxis for six to 12 months. I know we do that here in Miami. They're on voriconazole prophylaxis for 12 months. That being said, just because they're on prophylaxis does not mean that they cannot have breakthrough infections or fungal infections in general because of sub-therapeutic antifungal levels.

So when you think about fungal infections in these patients, I would consider aspergillosis as my number 1. And then other molds. Mucor would be rare and she should be a lot more sicker if she had that and it was disseminated. Um, Fusarium also causes a skin rash, another board question. One of the few that actually grows in blood culture, um, and the other endemic fungi, for example, Cryptococcus can definitely cause pulmonary cryptococcosis with the cavitary lesion and skin rashes.

And, um, specific to where she is in the Southwest, I would say even Coccidioidomycosis. She's, she is in Nevada, which puts her at risk. She's out hiking. Um, she's definitely had exposure to, um, air and soil, I would say. So. And, uh, coming to endemic fungi. So you think about Histoplasma and blastomycosis also that has similar presentations with pulmonary and skin involvement. The map for the geographic burden of Histoplasma has been changing.

So initially, while we classically learned that it's mostly like the Midwest and Ohio and Mississippi valley, now it is also seen in the South. So it's also there in the Southeast and Florida and Texas. And it seems to be moving more to the West, that new geographic distribution map for Histoplasma. So that's it. But the fungal.

Um, viral etiologies, it's uncommon for any of the viruses to cause a cavitary lesion and skin lesions, and sometimes they rarely, maybe a herpes virus can do that, but that's unlikely. Parasites. So one of the parasites I respect is Strongyloides, just because of what it's capable of doing. So it can cause pulmonary lesions like a consolidation and can cause a skin rash. But the skin rash, it's not generally, usually not a nodule. It's more of a diffuse rash, or it looks like purpura really.

And other pulmonary parasites like schistosomiasis, you know, the lung flukes. You can see um, pulmonary hydatid cysts, unlikely in this lady. I think that's it with the parasites. Um, and then coming to the noninfectious causes with her being a recent lung transplant and being out in the sun, I would say there's a high chance of skin cancer or melanoma, which could present with a lung lesion and a skin lesion.

Also think about primary, um, pulmonary adenocarcinoma with lung mets [metastases] and the malignancy section. Possibility of auto immune diseases like sarcoid or granulomatosis with polyangiitis. Though auto-immune conditions would be subdued because she's already on immunosuppressants. So I'd be surprised if it was auto immune because she's already on tacrolimus and prednisone, but should, um, you know, dial down the symptoms from that. So to narrow it down to our patient.

So you're presented lung transplant patient who is six months from transplant. She lives in Nevada, which is this dry climate with occasional winds. She likes hiking and spending time outdoors. So I would say our patient is at risk for bacterial or a fungal infection she could have inhaled. So my top three in her would be a non TB mycobacteria, so it could be M abscessus or M.avium or M.kansasii. Um, a fungal infection like Aspergillus, Cocci, or Cryptococcus and, um, Nocardia.

Malignancy is still a possibility, and of course we will know more as we start to work this patient up. Now approach to like the early steps of approach to getting to a diagnosis, start with blood cultures. That will definitely help us. Um, and noninvasive fungal markers. You can learn a lot from the serum Aspergillus galactomannan and Cryptococcal antigen, Coccidioides antibody. And, um, the best part about having skin lesions in transplant patients is that you can get them biopsied.

So it's like the one thing I tell every fellow and every medical student, I can catch hold of. If there's a rash, you biopsy that. It'll give us so many answers and fast answers that, um, even cultures cannot get back to you that quickly. So I would say push for invasive testing, call dermatology, biopsy the rash, send it for culture and for pathology. Let both the micro lab and pathology know what you're looking for, what you're considering in your patients.

Um, especially so Pathology can work on special stains for AFB and uh fungal staining. And then after the skin, I would say, um, go after the pulmonary nodule. Consider invasive testing for the pulmonary nodule and the cavitary lesion. Request for bronchoscopy and BAL.

She was started empirically on vancomycin and cefepime. And then as you said, a skin biopsy was pursued. We got the result of the skin biopsy and it shows a Gram positive branching and beaded rods surrounded by extensive inflammation. Cultures of the biopsy were also sent and they were in progress. While waiting on these cultures, what do you think should be the best antibiotic regimen and how do these change your differential?

So if we narrow it down from all of the broad differential diagnosis to, there is a 99% chance, this is Nocardia. The 1% we still have to wait for the culture. In transplant patients, I have come to learn that you should expect curveballs and plan ahead for them. So I would say, okay, I'm comfortable knowing that this is Nocardia, so we can plan our treatment around. So in solid organ transplant and immunocompromised patients, honestly, Nocardia is not that common. The incidence is less than 4%.

Um, our patient lives in the United States, Southwest, where the incidence of Nocardia is higher. So, which is why this makes it more likely in her. And there are other risk factors that you need to consider. She's a lung transplant patient, and heart and lung transplant patients are at higher risk of compared to liver and kidney for Nocardia infections. She is six months post transplant.

So she kind of fits the timeline where the highest chances of having, um, Nocardia infections are one to two years post-transplant. Um, though, the bacteria doesn't read the guidelines and the timeline. So it's still possible that you can see it a little earlier, you can see it after two years, you can see to the later point in life, especially if they have recently been treated for rejection and they had, you know, augmentation in their immunosuppression.

So certain immunosuppressants also increase the risk factors for Nocardia, I would say. There have been various case control studies done. A large one here in the USA and another one from Europe that in solid organ transplant patients that identified that the risk factors include high doses of corticosteroids, um, a high serum concentration of calcineurin inhibitors and prior CMV infection, like in the past six months.

In addition, older age, prolonged ICU stay at also considered to be risk factors for nocardia infection. So this is specific to solid organ transplant, but remember like other stem cell transplants, leukemics, lymphoma, patients receiving monoclonal antibodies like rituximab and infliximab. They are also at risk for Nocardia. Especially I think with infliximab, they have, there have been reports where there, um, Nocardia infections in like patients being treated for rheumatoid arthritis.

So consider other immunosuppressants while you're at it. Typical clinical manifestations of Nocardia. Um, I would say the primary site of infection is the lung, you know, you inhale it. So that's why it's going straight to your lungs. Um, and in some cases there is cutaneous involvement, either alone, so the isolated cutaneous involvement.

If there is trauma, um, and you know, people who are into gardening and landscaping, where you just have a single nodule and hopefully it stays contained there, or it could be from hematogenous spread from the primary site to the skin. So you could have that, uh, pulmonary infection. And then of course, CNS infection.

Um, Nocardia seems to have affinity for the brain and, due to the tropism, there are a predominant number of cases in solid organ transplant that have disseminated nocardia infections. When it comes to diagnosis, I would say we absolutely need it on culture. Growth on culture is a must to help in diagnosis. In cases where it is not growing on culture, um, consider molecular testing like PCR testing, or like a 16 s RNA um, testing, where you can send it to a reference lab.

I actually honestly saw a similar case where the patient was initially diagnosed with organizing pneumonia, because it didn't grow on culture for weeks. And the treatment. The treatment is completely different because they get steroids for organizing pneumonia versus nocardia treatments. So it's something to think about.

While you're waiting for the culture, is first of all, get adequate samples, send the skin biopsy for cultures, send the BAL culture, whatever specimen you can find that's a source of infection. You send it for culture. Let the microlab know, communicate with the micro lab because they're your best friends. Tell him you're considering nocardia so they can do a modified acid fast stain. They can incubate it for longer.

Cause sometimes it might grow soon or sometime it might choose to grow 3-4 weeks later so they can hold your specimens and incubate them for longer. Also there's a role where they can consider certain selective media to help nocardia grow faster. So communicate with them about your potential diagnosis and that will help you. And then we're coming to imaging. Imaging for nocardia is important.

What you described, uh, in our patient's CT scan, where you said she had a right lower lobe consolidation with a two centimeter nodular lesion and peripheral cavity. So. Almost typical for, um, nocardia and other infections also unfortunately, but an irregular nodule, large mass, like a third of them have cavitation, can easily be considered to be malignancy. Um, that's what you typically see on a CT chest.

Remember, not just with nocardia infections, I would also say with fungal infections and non TB mycobacteria, remember to stage your infection. So, you know the severity. So staging of disease involves imaging of the chest, sinuses and brain to understand the extent of involvement. So in this case, you know, just to see if the patient has no CNS symptoms, no headaches, vision problems, we can start with a CT brain and, and then ask for an MRI brain. Um, or you could just get the MRI first.

with a typical ring enhancing lesion would mean, um, could also be toxoplasma but get neurosurgery involved. Is there any role for an intervention? Is there something to evacuate or drain? And is there anything to be done for the surrounding edema and inflammation? So starting there, I believe this patient is on vancomyvin and cefepime empirically?

And then in addition, the other first line options are the drugs you can add would be, you know, imipenem, Amikacin, linezolid, depending on the severity of disease. So, if it is just cutaneous, you can get away with monotherapy with Bactrim. If it was limited to the lung with imaging confirming that there's no brain or sinus involvement, you can also get away with monotherapy with Bactrim. In our patient, we actually know she has disseminated disease.

So I would say combination therapy, um, depending on what she can tolerate, I would say bactrim, imipenem and if the symptoms progress or don't improve within a week, also add amikacin IV and monitor her. Now, this is the best case scenario, but what do you do in terms of Bactrim allergies or, you know, patients who are intolerant to Bactrim?

Um, if they have a serious allergy to Bactrim consider desensitization, but even after that, if patients are intolerant to it, then you would have to consider treatments, such as linezolid. So you can try imipenem and linezolid, which has proven to be effective multiple times. In fact, linezolid is a great, great drug with the bioavailability being a hundred percent, ease of administration, there are both IV and PO options, you know, transitioning would be easy.

It achieves good CNS and lung tissue concentration. So it will be perfect. The only problem is the duration of treatment and toxicities, you'd have to factor in because when you're thinking about treating nocardia, you're thinking about prolonged treatment and with linezolid, you would have bone marrow suppression, thrombocytopenia, peripheral neuropathy, you know, serotonin syndrome to consider. It it's a good option, but a short-term option.

You would still need something else to complete the duration of treatment. So empirically, um, I would choose bactrim, imipenem, but without amikacin, depending on how the patient progresses. Imipenem would also cover some NTM. Um, and if there's a strong feeling that this is probably NTM, you could also add a macrolide, uh, while you wait for the final culture. So while we're managing this patient empirically.

You do need to emphasize on the cultures because a species identification and anti-microbial susceptibilities are absolutely necessary. The species of nocardia vary by geographical region. So the species that's predominant in Europe is not predominant in the U S and even within the U S every state has a predominant species. So you would have to know that. And every species differs in terms of pathogenicity and antibiotic susceptibility.

We have empiric treatment, but there are certain species of nocardia. I would say the dangerous ones are, um, N.farsinica, which almost always causes disseminated disease. It can be resistant to Bactrim, imipenem, third-generation cephalosporins. And there's also N.pseudobraziliensis that's also can be resistant to Bactrim and N.abscessus sometimes, um Nocardia abscessus has variable sensitivity to. Um, imipenem and Bactrim.

So like knowing these things, it's very important that we get down to the details. Like what is the species, what the antibiotic susceptibility, and then we can narrow our treatment from there.

Um, because this patient's going to be followed by you in clinic for the next 12 months. So for ease of communication, make sure you have emails and phone numbers, um, and a way to get ahold of labs. She's going to need clinical monitoring. I would say at least 1, 3, 6 months after diagnosis. Um, for both for drug toxicity, and also repeat imaging, you know, repeat the MRI of the brain, the CT chest. See where you're at with radiological resolution.

After completion of treatment, she may or may not need secondary prophylaxis. Um, but you would still need to follow up with imaging at least at six months and 12 months post stopping treatment.

And this has been an ongoing debate about, you know, is it because of the dosing, that the dosing for PJP prophylaxis is insufficient to ensure complete primary prevention of Nocardia? Um, and there are studies that show patients who have these breakthrough infections on Bactrim for PJP prophylaxis, the isolates can still be susceptible to Bactrim. And then there are a few instances where they're resistant to Bactrim, so that would explain the breakthrough infection.

Um, but I would say yes, when possible, and if the patient tolerates it, um, Bactrim for PJP prophylaxis is still preferred, um, and will definitely offer some protection against nocardia. Again, the data on, both dosing and duration of Bactrim for primary prevention and secondary prophylaxis for nocardia is, um, limited, I would say. We don't really have, you know, any head to head trials or prospective studies in this area.

Most of our information is from retrospective studies and case reports. In fact, there are, I think there's a study from Mayo clinic from a few years ago where they looked at recurrence rates in patients while they were on secondary prophylaxis and there was still a 5% recurrence rate on their secondary prophylaxis of Bactrim, single strength daily. And they identified the risk factor for those recurrences, mostly lung transplant, patients, chronic lung problems.

Um, and if for some reason they received less than six months of treatment. So even on the single strength daily, you know, they can still have recurrence, I think that might be why our AST guideline recommends Bactrim double strength daily for secondary prophylaxis in these patients. But there is no data to back that up.

And it's the same with fungal disease, that we use that as a piece of information, but can't really take something off the table.

Like it or not, it's going to become a big infectious disease problem with the rise of temperatures and providing this like favorable environment for all these bacteria, fungi and parasites to grow and multiply. Um, you're going to see a lot of these infections.

So please reach out if you have any suggestions for future shows or if you just want to be more involved with Febrile. Thanks for listening. Stay safe and we'll see you next time.