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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 1 Hi. I'm John Perfect from Duke University. It's my privilege today to talk about the host and the impact of the host on fungal infections. I'm going to try to do this over a 30-minute period of time, starting with, "The Host is the Most". We will start specifically with cases. These cases illustrate the principles that we have to deal with when we treat fungal infections.

Patient Case # 1

· 22-year-old female with rejection of a 4-year-old kidney transplant, which was treated with highdose steroids and muromonab-CD3; given more steroids for acute pericarditis · 3 months after treatment of acute rejection while receiving tacrolimus, mycophenolate, and prednisone, she presented with 1-week history of headaches, nausea, and vomiting; temperature 37.2ºC ­ Neurologic exam: bilateral clonus and papilledema; mental status normal

Slide 2 The first case is a 22-year-old who had rejection of a 4-year-old kidney transplant, which was treated with high-dose steroids, antibodies, and steroids later on for acute pericarditis. With that immune suppression, 3 months later after the treatment, she was receiving various other immunosuppressive agents. She presented with a 1-week history of headaches, nausea, vomiting, and a slight temperature. Her neurological exam was significant in that she had bilateral clonus and papilledema, and her mental status was normal. In summary, a patient who received a lot of immunosuppression trying to protect a kidney from rejecting

Lab Studies

CBC LP WBCs Glucose Protein OP MRA Cr Normal 100 cells/mm3 43 mg/dL 79 mg/dL 400 mm H2O Basilar meningitis 4.0

Slide 3 These were the lab studies for this patient. She had a normal white count. Her lumbar puncture had 100 cells/mm 3 . She had a moderately low glucose, a mildly elevated protein, and a high opening pressure. Her magnetic resonance angiogram (MRA) showed a basilar meningitis, and she had a creatinine of 4.0.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 4 Her lumbar puncture also had cultures for Cryptococcus. The India ink was positive. It's important to realize her cerebrospinal fluid (CSF) antigen titer was 1:256, which is moderately high, and the serum antigen titer was greater than 1024. After 2 weeks, the cultures in the CSF were negative, India ink was negative, CSF antigen titer had not changed, and the cell count had come down significantly, down to 28/ mm 3 . The opening pressure had normalized. She had a very decent response to this particular regimen.

Lab Studies

Initial LP

Culture for C. neoformans India ink CSF antigen Serum antigen Positive Positive 1.256 >1:1024

2-Week LP

Culture for C. neoformans India ink CSF antigen Cell count OP Negative Negative 1.256 28/mm3 140 mm/H2O

Treatment Schedule

· Liposomal AmpB, 5mg/kg/d for 20 days · Flucytosine for 14 days ­ Then, fluconazole 200 mg/d · Continue immunosuppressants but less aggressive dosing

Slide 5 She had liposomal amphotericin B at 5 mg/kg for 20 days along with flucytosine at 14 days. This is the classic approach that the guidelines suggest we use in patients with cryptococcal meningitis who are transplants to protect the kidneys: a liposomal product, flucytosine, and induction therapy for 2 weeks. Then she was put on fluconazole. She had a continuation of her immunosuppressants, but these were less aggressively dosed. She had the mycophenolate mofetil removed, she had the steroids reduced, and the tacrolimus reduced, trying to protect her and trying to clear this infection.

Clinical Course

· 4 months after diagnosis on fluconazole · New-onset severe headaches · MRI scan shows diffuse supra- and infratentorial leptomeningeal enhancement · CSF crypto antigen 1:16 · CSF WBC 100/mm3

Slide 6 What happened with her after this very smooth initial course? Four months later after the diagnosis on fluconazole, she developed new-onset severe headaches. She had an MRI scan that showed diffuse supra- and infratentorial leptomeningeal enhancement. Her CSF cryptococcal antigen, as you see here, has actually come down, although we can never use that precisely in the management of cryptococcal disease. It did suggest that we were on the right track. Her CSF white blood cell count had risen over this time.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 7 There is concern about relapse of infection, and she received 2 weeks of liposomal amphotericin B with no improvement in her headaches. Her CSF cultures were negative; they were negative after 2 weeks, they were negative at this period of time. She then, after not improving, was continued on fluconazole and was started on dexamethasone, which was tapered over 6 weeks. Her various other immunosuppressants were eliminated. After the discontinuation of the dexamethasone, her severe headaches returned. She had a lumbar puncture done and the cultures were negative; the antigen titer was negative right now. She did have some improvement of the MRI scan, although she still had inflammation. We then gave her another taper of steroids, this time over a 4-month period, and she became asymptomatic, went on for the next 2 to 3 years to do quite fine, and is ready to get another transplant.

Management

2 weeks of liposomal AmpB

· No improvement with headaches · CSF cultures: negative

Continue fluconazole and add dexamethasone taper over 6 Weeks Tacrolimus/mycophenolate D/C and dialysis started After D/C dexamethasone; 1 wk severe headaches returned

(LPs: cultures/antigen negative; MRI: improvement but still meningeal enhancement)

Four-month steroid taper and now off steroids and asymptomatic for 2 years

The Damage-Response Framework of Microbial Pathogenesis*

· Simplistic but accurate ­ we, as clinicians, deal with disease that can be caused by the invading fungus or through protecting the host · Goldilocks paradigm of immunity ­ not too much or not too little, but just right

*Casadevall A, Pirofski LA. Nat Rev Microbiol. 2003;1:17-23.

Slide 8 Important case. Important case of what? I think that an important issue that we need to talk about here is that we as clinicians deal with disease. There is infection there, there is a host there, but we deal with disease that changes the homeostatic forces within the patient. This is important because a lot of times we deal with trying to kill the organism and eliminate it, but in fact the host himself or herself may actually overshoot their immunity and cause a disease by the inflammatory reaction of their own host cells. This is eloquently described in a very simplistic manner by Casadevall and Pirofski, and I would recommend reading about this kind of damage response framework of microbial pathogenesis. What I call it in simplistic terms is a "Goldilocks" paradigm of immunity, and we talk about this significantly. Not too much, not too little; you need to get it just right. We work with these severely immunosuppressed patients with fungal infections, trying to get the immunity just right.

Definition/Diagnostic Criteria for IRS or IRIS in Mycoses*

a) New appearance or worsening of any of the following: clinical or radiographic manifestations consistent with an inflammatory process such as contrast-enhancing lesions on imaging studies (CT/MRI); CSF pleocytosis > 5 WBCs; increased ICP; histopathology showing granulomatous lesions; unexplained hypercalcemia and b) Symptoms occurred during receipt of appropriate antifungal therapy* and could not be explained by a newly acquired infection and c) Negative results for cultures or stable/reduced biomarkers for the initial fungal pathogen during diagnostic work-up for the inflammatory process

*An attempt should be made to exclude intrinsic and de novo drug resistance and suboptimal drug levels. Singh N, Perfect JR. Lancet Infect Dis. 2007;7:395-401.

Slide 9 What if we don't get it just right? What if it overshoots? In this particular case, we believe it did. This is a definition that Singh and I reported on, and it's one that many people have of the immune reconstitution inflammatory syndrome (IRIS) in mycoses. The important ingredients to this are that it's a worsening or continuing inflammatory reaction, and that's determined by various radiographs and by various biological markers. Important to this is the symptoms that the patient had, that they received appropriate antifungal therapy, that they could not explain it by a newly acquired infection, and that, in fact, all the negative cultures, biomarkers, etc, suggested that the infection was actually under control, but the patient continued to have symptoms. This is classic IRIS and it's a nice definition. Therefore, it needs to be placed in the clinical management of the patient. Many times, this is not that easy.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 10 The series of host immune responses to the pathophysiology around Host Immune Responses the IRIS: it's cell-mediated immunity; it's a fluctuation between the T-helper 1 (TH1) cells or the aggressive part of the immune system, Pathogen-Mediated to the downgrading part, which is TH2. There are various iatrogenic Pathophysiology Immunosuppression immune suppressants, as in the patient who we reported on, that · Cell-mediated immunity · Cryptococcal may downgrade the immunosuppression and allow the immunity TH1 vs TH2 response polysaccharide to increase, as in this particular patient; that is, a fluctuation that occurs. There is also an influx of inflammatory cells at the site of · Iatrogenic immuno· Antifungal therapy suppressive agents infection. Classically, bone marrow transplants in neutropenic · Specific antibodies patients get inflammatory cells back and can worsen radiographically · Influx of inflammatory before they get better. The pathogen itself can do this. Cryptococcus cells with bone marrow recovery has a polysaccharide capsule that can immune modulate locally at the site of infection. Antifungal therapy, like amphotericin B, can affect the immune system, both lymphocytes and macrophages, and may modulate the immunity. Finally, antibodies that are made by the host can help modulate this. Therefore, there's a series of immune reactions that occur. This is a dynamic situation; we are trying to deal with both an immunosuppressed patient and, maybe later, one that overshoots itself and causes disease.

Immune Reconstitution Syndrome in HIV Patients

· 30% of patients with HAART and cryptococcosis have IRS1 · Risk factors: increased CSF opening pressure, increased CSF glucose levels, and WBC and: ­ Antiretroviral drug-naïve patients ­ HAART in close proximity to opportunistic infection diagnosis and ­ Rapid decline in HIV RNA levels2

1. Shelburne SA et al. Clin Infect Dis. 2005;40:1049-1052. 2. Shelburne SA et al. AIDS. 2005;19:399-406.

Slide 11 This has been seen classically in several different disease processes. It was brought to light significantly in the era of the AIDS epidemic with HAART therapies, and here is a review of this by Shelburne, et al. The immune reconstitution syndrome (IRS) in HIV patients can occur in up to 30% of patients who are started on HAART therapy, and they are starting to immune reconstitute with cryptococcosis. You can see the risk factors of: high burden to organism, starting on HAART therapies, rapid decline in HIV viral loads, and the immune system revving itself up and attacking the organism and causing inflammatory reactions. Particularly in the central nervous system, this can be detrimental to the host.

Cryptococcosis/Immune Syndrome Reconstitution/Organ Transplant

· IRS 5.6% (3/54)1 · Worsening symptoms despite negative cultures · Etiology: effective antifungal treatment and/or cessation of immunosuppressive therapy (tacrolimus, mycophenolate, and prednisone) · Temporal association of graft loss2

Slide 12 It's not just seen in HIV-infected patients; this is very typical with the drugs being started. But on the other side of this, is the stopping of the drugs, the reducing of the drugs, and solid-organ transplants. Singh has reported up to 5%-6% of patients with cryptococcosis will have an immune reconstitution-type syndrome with worsening symptoms despite negative cultures. This is also temporally a lot of times associated with the graft being lost as the immune system is revved up. This is another site that one clinically has to understand in the patient.

1. Singh N et al. Clin Infect Dis. 2005;40:1756-1761. 2. Singh N et al. Transplantation. 2005;80:1131-1133.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 13 Remember, immune reconstitution, everything is not always bad; Immune Reconstitution it's necessary to treat these fungal infections. If you do not have an immune system, it will not be successful. This is the good part of this Cryptococcal meningitis: use of two doses of recombinant gamma interferon. Trend toward faster thing. In fact, we try to rev them up and we've even tried to rev them Good CSF yeast count drop (not statistically significant)1 up with cytokinins. An example of that is cryptococcal meningitis, where there was some suggestion that giving gamma interferon could Aspergillosis Treatment With G-CSF 04500 WBC Immediate Death Rate increase the immunity and inprove the killing of Cryptococcus in the Rapid <5 days 4/8 (50%) CSF. This was the Pappas study that was done a couple of years ago; Bad Slow >5 days 2/12 (17%) it was the trend and not statistically significant. But Harrison et al Increased volume of lesion by CT not correlated have a paper that will soon come out that shows that it does increase with outcome3 the ability of Cryptococcus to be treated in the central nervous system, and killing of the organism is much faster by adding an HAART: when to start it? Ugly ­2 wks vs 10 wks after crypto treatment immune stimulant. It's bad in the sense that the inflammatory actions, particularly in areas like the lung and the brain, can cause significant disease. Here's a small study from Italy that suggests that when the white count went up very fast, within 5 days from neutropenia up to a normal white count, the mortality rate was a little bit higher than if it took a longer period of time for the organism and the host to adjust. This was a small study, but it suggests that when the inflammatory system comes back too fast, the host will develop disease from the inflammatory situation, and it becomes a very tricky issue for the clinician to manage, particularly if they go into acute respiratory distress syndrome. Finally, the ugly part of this is in HAART therapies and conditions like cryptococcal disease. When do we start therapy? Do we start it 2 weeks after we've started antifungal therapy or 10 weeks? Again, we don't know precisely. We do not need the inflammatory action too vigorous in the central nervous system in the early stages with increased intracranial pressure. There are studies that are starting to try to determine early versus late HAART therapies, to see what the impact is on IRS.

2 1. Pappas PG et al. J Infect Dis. 2004;189:2185-2191. 2. Todeschini G et al. Eur J Clin Invest. 1999;29:453-457. 3. Caillot D et al. J Clin Oncol. 2001;19:253-259.

Pulmonary Aspergillosis With IRS During Neutrophil Recovery

Definite clinical/radiographic worsening with infiltrates, temporally related to neutrophil recovery, decrease in GMI 50%, and no change in therapy · 6/37 (16%) · One week after ANC recovery (rapid) · No change in therapy--all survived (two received steroids)

Slide 14 As I mentioned, in pulmonary aspergillosis with neutrophil recovery, there is no question you can get patients who may get worse before they get better in terms of infiltrates. This is a study by Anaissie et al. In 6/37 of their patients with invasive aspergillosis, as their neutrophil count recovered, they developed increasing infiltrates, and yet their galactomannan decreased over time. There was no change in therapy; a couple of patients got some steroids, but the patients all eventually did fine. Therefore, be careful of using the x-rays to be the determination of whether you have failure or not and that, in fact, this may be just simply the immunity itself.

Miceli MH, Anaissie EJ. Presentation at focus on fungal infection (personal communication). Miceli MH et al. Clin Infect Dis. 2008;46:1412-1422. Woods G et al. Cancer. 2007;110:830-834.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 15 I think even in hepatosplenic candidiasis, these are a unique syndrome of patients with fever, alkaline phosphatases that are elevated, and patients who feel bad for long periods of time. But some of this is directly related to the organism in the liver/spleen and the reaction of the host himself or herself to it. In fact, a group from France has actually used steroids in these type of patients and have done very well in controlling the symptoms of these patients. In fact, I wonder today whether the echinocandins that affect beta-glucans synthesis, and the glucan being a major immune modulator, might be better drugs for these types of patients. They eliminate the glucan or reduce the glucan, so that there isn't as much immunological reaction to this. Surely, the success rates with the echinocandins have been very good in hepatosplenic candidiasis.

Candida IRS

· 10 patients with hepatosplenic candidiasis (HSC) (amphotericin B treatment without response)1 · Time from HSC diagnosis to steroids (40 d) · Rapid improvement on steroids (all improved) · Prednisone 0.5 mg/kg for at least 3 weeks · Does echinocandin treatment suppress the known beta 1-3 glucan-induced proinflammatory signals? ­ High success rate of echinocandin in HSC2

1. Legrand F et al. Clin Infect Dis. 2008;46:696-702. 2. Cornely OA et al. J Antimicrob Chemother. 2007;60:363-369.

Cryptococcus, Pregnancy, and IRS

· Anti-inflammatory responses in pregnancy through IL-10 and TGF- and inhibition of Th1 cytokines · Case of 15 years of cryptococcal meningitis with deterioration after pregnancy1 · Dramatic case report with rapid reversal of immunologic repertoire leads to IRS with cryptococcal meningitis2

Slide 16 Even in pregnancy--pregnancy is an event that is a little bit immune suppressive, and one has to pay attention to organisms like Cryptococcus that may occur during pregnancy and then after the pregnancy, where the woman has to readjust to a nonforeign body, and the immune system will change over time. The postpartum situations can be bad for these types of patients, as inflammatory IRS actually takes place. I caution patients that it's not just in cryptococcal infections but other types of infections that the postpartum period might be a time of a dysregulation with a change in the immunity as it comes off having a child, and the infections can be worsened with the damage of the host.

1. Beeson PB. Arch Intern Med. 1952;89:453-457. 2. Einsiedel L et al. Clin Infect Dis. 2004;39:e78-e82.

Tumor Necrosis Alpha Blockage Therapy

Fungal Infections and IRIS · Infliximab > etanercept and adalimumab1 · 3 months to a year on treatment with other immunosuppressants; histoplasmosis most common · Since TNF- blockade is stopped during therapy IRIS must be considered (such as increasing symptoms or radiograph abnormalities)

1. Tsiodras S et al. Mayo Clin Proc. 2008;83:181-194. 2. Salmon-Ceron et al. Ann Rheum Dis. 2011;70:616-623. 3. Osawa R, Singh N. Int J Infect Dis. 2010;14:e436-e440.

Slide 17 I also would say that, over time, we've seen changes in the immunity with various monoclonal antibodies. You can see here the anti-tumor necrosis factor (TNF) therapies that are used for a series of disease processes today. They have very potent abilities to control the immunity, and they have increased instances of fungal infections.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 18 But on the other side of that, once you get that infection and you start treatment, and then you start taking them off the anti-TNF therapies, be careful or you'll end up with patients with a lot of inflammatory reactions. There will be a kind of IRIS situation that occurs with that, with the infiltrates getting worse before they get better. Also, with all the disseminated cryptococcosis that I see, the hardest thing today is not to treat an HIV-infected patient with Cryptococcus or treat a transplant patient with Cryptococcus, and it turns out to be an apparently normal host. It's a "tale of two states". There's a tale of a prolonged diagnosis because it's missed, and second of all, the IRIS is also associated with the inflammatory reactions that these hosts can get. They have fairly good immunity, for some reason, either a high inoculum or some immune suppression. It would be very difficult to manage some of these patients, both because of the prolonged ability not to diagnose and high burden of organisms, but also the immune system that impacts on these patients. Again, IRIS, even in the normal host, can be quite important. Slide 19 Specific issues around IRS include Cryptococcus in renal transplants; as I mentioned, IRS can be associated with allograft rejection, where the immunity has gone up so high. histoplasmosis lymphadenitis can cause obstruction/compression associated with these large granulomas that occur as the immune system fights off these infections. Even in pneumocystis, about 5% of the patients will develop symptoms after stopping steroids and are started on HAART therapy. Even that fungus can be associated with a relapse of disease associated with the immune system coming back. Finally, there may be even little tricks of the macrophage activation that you see in IRS in patients who present with hypercalcemia that's endogenously related to activation of macrophages and vitamin D metabolism.

Disseminated Cryptococcosis in the Apparently Normal Host

"Tale of Two States" · Prolonged diagnosis and IRIS = very difficult disease and management

Ecevit IZ et al. Clin Infect Dis. 2006;42:1443-1447. Nguyen MH et al. J Infect. 2010;61:419-426.

Specific Issues Around IRS

· Cryptococcosis in renal transplant patients with IRS have reduced allograft survival1 · Histoplasmosis lymphadenitis with obstructive or compressive lesions, histopath well-formed epitheloid and giant cell granulomas2 · Pneumocystosis (5% develop symptoms after D/C steroids or start of HAART)3 · Hypercalcemia (endogenous vitamin D)4

1. 2. 3. 4. Singh N et al. Transplantation. 2005;80:1131-1133. Koval et al. Clin Infect Dis. 2002;35:491-493. Breton G et al. AIDS. 2006;20:119-121. Jenny-Avital ER, Abadi M. Clin Infect Dis. 2002;35:e128-e133.

Slide 20 Is there a genetic predisposition to IRS in the mycosis? We Issues to Consider in IRS don't really know that today. There is some suggestion with cytomegalovirus (CMV) and mycobacterial disease that there may · Is there a genetic predisposition to IRS in mycoses (has be certain patients who are more predisposed to overreacting, but been suggested in CMV and mycobacterial disease)? we simply don't have it in the fungal infections yet. Hopefully that's · No precise test for IRS diagnosis in mycoses (DTH skin an area for research. What is quite clear, and one of the important testing, lymphoproliferative assays, and ELI spot assays messages and principles of this talk, is that there is no precise for mycobacterial disease) test for IRS in mycosis. There are various types of skin testing, · Immunomodulators: lymphoproliferative testing, enzyme-linked immunospots (ELI spots) for mycobacterial disease, but there is nothing at this stage that can ­ Gamma interferon for cryptococcosis identify whether you have IRS. It is an art; it is not a science. It's ­ Colony stimulating factors for invasive fungal looking at the clinical case. It looks at where the patient's at, how infections they are doing in terms of biological control of the organism, and what · Refractory fungal infections are not always easy to define is happening with the inflammatory reaction. Unfortunately, there is no lab test to indicate that this patient is over-stimulated versus not. Hopefully the future will be able to allow us immunologically to study this much better. That's why it is very difficult to diagnose the refractory fungal infections. They are not easy to define. Is it the organism still doing it, or has now the host overshot?

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 21 In terms of treatment, if you do have to treat them (not all IRS needs to be treated), in the central nervous system, these can be problems. There is a series of approaches, from various anti-inflammatories, probably the most common is prednisone if you're in the central nervous system, probably dexamethasone.

Use of Anti-inflammatory Therapy in IRS Associated With Opportunistic Mycoses

· Most cryptococcus/histoplasma · Lymphadenitis to hepatitis to CNS disease · Successful regimens include: ­ Naprosyn ­ Prednisone (1-2 mg/kg/d) ­ Thalidomide · Length of treatment variable

1. Blanche P et al. Scand J Infect Dis. 1998;30:615-616. 2. Lortholary O et al. AIDS.2005;19:1043-1049. 3. King MD et al. Int J STD AIDS. 2002;13:724-726. 4. Breton G et al. AIDS. 2006;20:119-121. 5. Boelaert JR et al. AIDS. 2004;18:1223-1224.

Steroids in Tuberculous Meningitis

· Regimen dexamethasone (8 wk) ­ 0.4 mg/kg/d X 7 days ­ 0.3 mg/kg/d X 7 days ­ 0.2 mg/kg/d X 7 days ­ 0.1 mg/kg/d X 7 days ­ Then, 4 mg per week and decreasing 1 mg per week · Improved survival but not disability

Thwaites GE et al. N Engl J Med. 2004;351:1741-1751.

Slide 22 As the case described, there was not a clear length of time these patients needed to be treated. I would suggest that probably in very tough cases and in the central nervous system, you might use the guidelines for steroids and tuberculosis meningitis that were published several years ago, using dexamethasone in a taperingtype situation. Again, there is nothing yet in Cryptococcus, although those studies are getting started. But at least maybe there are some guidelines, and in serious cases where patients are having lifethreatening problems with increased intracranial pressure, you might want to use this type of steroid taper. But again, it's empiric; it needs to be identified.

Patient Case #2

· 47-year-old male in good health presented with cough, fever, and SOB after cleaning out his attic with lots of bird droppings · Fine needle aspirate of nodule grew C. neoformans; serum antigen 1:256; CSF-negative · Treated with liposomal AmpB 10 days and then fluconazole daily; 5 months later SOB; from fine needle biopsy crypto seen, but not grown · Restarted on liposomal AmpB for 6 weeks (stopped because of line sepsis) · Serum crypto antigen negative; open lung biopsy; necroticizing granulomas with numerous yeasts; interstitial chronic inflammation with reactive mesothelial hyperphasia; all cultures are negative; PFTs mild restrictive lung disease with 02 desaturation

What do you do? IRS vs failed treatment

Slide 23 I want to finish with this case. This was a 47-year-old male in good health. He probably was in an attic and getting a lot of dust and dirt. There were a lot of pigeon droppings in there, and he probably inhaled Cryptococcus. He was diagnosed with Cryptococcus ; serum-antigen titer was positive, CSF was negative. He was treated with liposomal amphotericin B and fluconazole, but 5 months later, he had shortness of breath. They did a needle biopsy and they saw Cryptococcus but they did not grow it. He was restarted on liposomal amphotericin B for another 6 weeks, and had line sepsis from the amphotericin B being infused in the line. His serum cryptococcal antigen went negative, the lung biopsy showed necrotizing granulomas and numerous yeast, and he had various inflammatory reactions. Isn't this what this was? Probably a high burden of organisms, and then we treat it with antifungals when, in fact, it probably needed to downgrade the immune system that was actually fighting this organism. These are very typical cases we need to think about when we see these patients.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 24 In summary, IRS is elusive but very important clinically. We always realize that we have to deal with the disease caused by the fungus and the host response. How we deal with and eliminate the pathogen and control the dysregulation is going to be very important in the management of these patients. It's an art of medicine, but you have to realize you're dealing with the immune system moving back and forth.

Summary

· IRS or IRIS--it is elusive and important · We all must realize that we deal with disease (caused by fungus or host response) · How we deal with it is to eliminate the pathogen and attempt to correct a dysregulated immune system (the art of medicine)

Patient Case #3

Infection Mimics Host Immunity

· 60-year-old female with advanced CLL begins injections of her thighs with CAMPATH ­ neutrophil count rises/CD4 count drastically drops · Skin lesions ­ nonpainful, nodular, and slightly pruritic

Slide 25 What I'd like to do over the last 10 minutes or so is talk about the other side with the host--what the host himself or herself is and how it can be a human Petri dish. Do we make it from the underlying disease or the treatments that we give these patients? Sometimes, just looking at what the risk factors are, you see what organisms may actually be occurring and we can predict them. This is a 60-year-old female with advanced chronic lymphocytic leukemia (CLL), begins injections of her thighs with alemtuzumab. Her neutrophil count rises, but her CD4 counts drastically drop. She had skin lesions that are nonpainful, nodular, and slightly pruritic.

Slide 26 These are the skin lesions. Nondescript; the only way you would ever make the diagnosis of this is simply to biopsy them. But remember, she is almost like a chemical AIDS patient and, in fact, the biopsies showed microsporidium.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 27 Microsporidium is probably a fungus; it's classically seen in AIDS patients, particularly in the gastrointestinal tract, and it responds to albendazole.

Microsporidiosis

· 1,000 species in 144 genera · Multiple lines of evidence that microsporidian are fungi ­ -tubulin analysis suggest sister group to the Zygomycota* · Water contamination, zoonosis, and autoinfection · Immunosuppression: AIDS · Albendazole treatment

*Keeling PJ. Fungal Genet Biol. 2003;38:298-309.

The Rest of the Story!

· Treated with albendazole for 4 weeks; some improvement and eventually cleared · 3 months later diagnosed with invasive sinusitis/ osteomyelitis with Fusarium/Aspergillus treated with voriconazole · 3 months later presents with chronic pneumonia ­ Resected lesion in R lung and attempted to clean out pulmonary artery with Rhizopus

Slide 28 What's the rest of the story on this particular patient? She was treated with albendazole for 4 weeks, and she had improvement and eventually got better. But again, her white count goes down; it's chronically neutropenic. Three months later, she presents with invasive sinusitis and osteomyelitis with Fusarium and aspergillosis, where she is then treated with voriconazole. She did well from that. She controlled that type of infection, but 3 months later, she presented with chronic pneumonia, which was resected, and the right lung was cleaned out of a necrotic area with the pulmonary artery being completely blocked with a Rhizopus embolus. This is the classic stage of a patient with severe underlying disease--treatments that allow this organism to go from one organism to another organism to another organism-- the human Petri dish.

Alemtuzumab (Campath: anti CD52)

· Increased risk for invasive fungal infections1 · Studies are frequently complicated by underlying disease and other infections2 · Rapidly fatal cryptococcosis in CLL patient receiving alemtuzumab3 · CLL and alemtuzumab (aspergillosis, candidiasis, and PCP)4

1. 2. 3. 4. Safdar N et al. Diagn Microbiol Infect Dis. 2010;66:7-15. Maschmery G, Patterson TF. Curr Infect Dis Rep. 2009;11:435-438. Bassetti M et al. J Chemother. 2009;21:211-214. Elter T et al. Ann Hematol. 2009;88:121-132.

Slide 29 Here's alemtuzumab, well known to cause infections. It is like a chemical AIDS. Significant CD4 counts drop for long periods of time. There are multiple infections that have been associated with fungal infections, and with the doses we're using today, we have to pay attention to these patients, that they may have Aspergillus, Candida, pneumocystis, histoplasmosis, cryptococcosis; all these need to be very carefully watched, and we have to get these patients earlier rather than later.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 30 Remember also that there can be more than one infection. This is an example of dual infections at our own place. In candidemia patients, we've seen patients with more than one fungus. Wayne State has also seen these with more than one fungus in blood cultures, and the mortality rates are quite high here. You have to pay attention to these patients very carefully. We see mold infections where Fonsecaea pedrosoi was in the lung, but in the brain was Emericella nidulans. Every time things aren't going well, these are human Petri dishes; the host is where it's at. Therefore, we have to pay attention and we have to be diagnostically very aggressive. Even with endemic mycosis, I've had HIV-infected patients with low CD4 counts under 10 who have had both Cryptococcus and Histoplasma at the same time.

Dual Fungal Infections

· Best data in polymicrobial candidemia: ­ Wayne State 16/303 (5.2%) candidemia: sicker, nononcology with concomitant bacterial infection (43% mortality)1 ­ Duke University 28/1,000 (2.8%) candidemia (12/24 [50%] mortality)2 · Two mould infections3 (F. pedrosoi and E. nidulans) · Two endemic mycoses (Cryptococcus and Histoplasma)

1. Morris A et al. Clin Infect Dis. 1995;21:1346-1348. 2. Pulimood S et al. Diagn Microbiol Infect Dis. 2002;44:353-357. 3. Johnson et al 42th ICAAC. San Diego, California, September 27-30, 2002. Abstr. M881.

Zygomycosis Superinfections on Voriconazole

· More than 20 cases reported to date1-9 ­ Majority of patients · HSCT recipients receiving corticosteroids for GvHD and · Voriconazole prophylaxis · Is there a correlation? ­ Cancer patients10 · 27 patients with zygomycosis and 54 patients with invasive aspergillosis · Of 27 patients, only 15 received voriconazole · Only 15 met criteria for definite infection ­ Transplant patients11 · 393 transplant recipients · Voriconazole more frequently associated with breakthrough infections due to Zygomycetes or Fusarium rather than Aspergillus (OR=24.0)

1. 2. 3. 4. 5. 6. Chayakulkeeree M et al. Eur J Clin Microbiol Infect Dis. 2006;25:215-229. Ritz N et al. Eur J Pediatr. 2005;164:231-235. Kobayashi K et al. Haematologica. 2004;89:e140. Marty FM et al. N Engl J Med. 2004;350:950-952. Oren I et al. Clin Infect Dis. 2005;40:770-771. Vigoroux S et al. Clin Infect Dis. 2005;40:e35-e37. 7. Siwek GT et al. Clin Infect Dis. 2004;39:584-587. 8. Mattner F et al. Scand J Infect Dis. 2004;36:312-314. 9. Imhof A et al. Clin Infect Dis. 2004;39:743-746. 10. Kontoyiannis DP et al. J Infect Dis. 2005;191:1350-1360. 11. Park BJ, et al. 44th ICAAC [Abstract M-666-2004].

Slide 31 As clinicians, when you deal with this and you try to figure out what to do about it, you use all the tools you can. Where are the patients in their disease process? What's their potential immunity? They are human Petri dishes. The organism, the drugs themselves, can affect what fungus you may actually see. This is an example of superinfection zygomycetes. The organism potentially may protect against other organisms, causing disease to only allow the zygomycetes to be the final arbitrator. Or as Kontoyiannis has shown in his laboratory, exposure of voriconazole may impact on the virulence of the organism. But you have to use all these tools in this particular patient. The exposure of voriconazole may have been a factor to allow this patient to develop disseminated disease with zygomycetes.

Posaconazole for Zygomycosis: Salvage Therapy

Compassionate Use1 (n=24) Success Rates, %: Refractory to standard therapy Intolerant to standard therapy Overall survival, % 79 80 79 62.5 60 62 Retrospective Study2 (n=91)

Slide 32 Because not all azoles are the same, the zygomycetes do not do well against voriconazole. But posaconazole, although not the drug of choice for invasive zygomycetes infections, does have some activity in zygomycetes infections, and has been used in combination or as sequential for zygomycetes infections or refractory disease. You need to know which azole compound; they are not all created equal.

1. Greenberg RN et al. Antimicrob Agents Chemother. 2006;50:126-133. 2. Van Burik JA et al. Clin Infect Dis. 2006;42:e61-e65.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 33 Finally, think again about the host. This is the tale of two cases of fusariosis. The host is the most. This is a 60-year-old allogeneic bone marrow transplant with erythema around the catheter, positive blood cultures with Fusarium. Treatment was with voriconazole and liposomal amphotericin B, and the patient died 5 days later.

Patient Case #4

Tale of Two Cases of Fusariosis: The Host Is Most

· 60-year-old allogeneic BMT · Neutropenia (profound and prolonged <100 cells) · Erythema around a central line · Positive blood cultures for Fusarium solani · Treated with voriconazole, liposomal AmpB · Died 5 days after skin lesions appeared with pulmonary disease

Slide 34 You can see the lesions here; massive exposure of the organism throughout the bloodstream, probably from the catheter. The patient continues to stay neutropenic, was not recovering their bone marrow and, in fact, the patient did very poorly. We could not recover anything in the immune system; antifungal agents were not successful.

Patient Case #5

"Never give up if host/underlying disease under control."

· 2-year-old with BMT for Hurler's syndrome develops soft tissue infection at subcutaneous catheter site with Fusarium solani · Patient has immune reconstitution but infection spreads to fingers, elbow, skull, and tibia · CT scans of lung, brain, liver, and spleen were negative

Slide 35 On the other hand, never give up on these types of patients; pay attention to them. Surely the underlying disease can help you and the immunity can help you. This is a 2-year-old bone marrow transplant patient with a Fusarium infection that was extensive. However, the patient had the bone marrow back; they had it immune reconstituted. Although the infection had spread to his tibia, to his skull, to his fingers, and to his elbows, his CT scans of his major organs (lungs, brain, liver, and spleen) were negative.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 36 In the combination era of surgeries, you see in this young child who we had to do major surgery over their abdomen and chest.

Treatment

· Liposomal AmpB 10 mg/kg/d + voriconazole 12 mg/kg/d (drug level: 1.6 µg/mL); GM: CSF; surgical debridement; silver impregnated packing and daily packing of wound with 0.02% polyhexamethylene-biquanide · Over 7 months of this regimen with almost complete clearing of lesion and closure of wound · D/C liposomal AmpB within 3-4 wk soft tissue and bone recurrence in tibia and elbow · Surgery and liposomal AmpB restarted for another 2 months · Final outcome: healthy 6-year-old in first grade

Slide 37 We did a combination type of therapy where we ended up with liposomal amphotericin B and voriconazole, various types of local therapies, and granulocyte-macrophage colony stimulating factor (GM-CSF). A 7-month period of this regimen, and then patient had to go back again and do more surgery and more liposomal amphotericin B. But the final outcome of this patient was a success. The patient is now a 6-year-old in the first grade. The important component here is, be aggressive. Use every tool you have. But the immune system was actually good because the bone marrow had reconstituted

Aspergillosis Case-Fatality Rate by Underlying Disease or Conditions

Slide 38 Remember that you can predict the outcomes of these patients by their underlying diseases. This is a classic example from Lin et al from the 1990s, where Aspergillus outcomes were directly related not to the treatment per se, but to the underlying disease. It's important to stratify your patients and their underlying diseases.

Lin SW et al. Clin Infect Dis. 2001;32:358-366.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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The Impact of the Host on Fungal Infections

John R. Perfect, MD

Slide 39 For me, the worst underlying disease that you can have is disseminated Cryptococcus in cancer, because no one survived more than 2 years in the studies from Sloan-Kettering. I have not seen that myself because when you develop cryptococcal disease, you are probably at the end-stage of the underlying disease, which allows Cryptococcus to appear

Disseminated Cryptococcosis in Cancer Patients

No one survived longer than 2 years after diagnosis of fungal infection!

Kaplan MH et al. Cancer. 1977;39:2265-2274.

Summary

· Fungi attack us when we are at risk · Early, accurate diagnosis is essential ­"An ounce of prevention is worth a pound of cure" · The "host" is the most...in the final outcome (underlying disease control and ability to recover and modulate immunity are critical)

Slide 40 In summary, I hope I have helped you understand that "the host is the most", which is the inflammatory reaction, which sometimes can overburden the patient and cause disease. The second part is that these patients are severely immunosuppressed, and fungi attack when patients are at risk. We have to precisely identify what that risk is. Early, accurate diagnosis is absolutely essential. We have to get to a low burden of organism, and then control the underlying disease. Also, an ounce of prevention is worth a pound of cure; therefore, we need to protect these patients and in some high-risk patients, actually prophylax them. "The host is the most." In the final outcomes of these patients, the underlying disease controls what happens to the patient, and the ability to recover and modulate immunity are absolutely essential. Today, we have a lot of tools to modulate that immunity. But at times, we lose control of that because we do not have good markers to understand exactly where we're at.

Invasive Mycoses: Evolving Challenges and Opportunities in Antifungal Therapy · A Case-based Discussion

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