Infectious Complications in the Hematopoietic Stem Cell Transplant Patient, by Leslie Lehmann. Today, I would like to review infectious complications in hematopoietic stem cell transplant, or HSCT, patients, who, in general, have a very compromised immune system and, thus, are very vulnerable to a variety of other infections. So the immune system following hematopoietic stem cell transplant is affected by very, very many factors.

And some of these factors are understood, and some of these factors still remain to be elucidated. But we absolutely know that the immune system is abnormal for a period of weeks to months, to perhaps even years, following stem cell transplantation. The things that impact the immune system’s function most seem to be the type of the transplant, and by that we mean the donor source, whether the donor is yourself, or someone related to you, or someone unrelated to you. Very, very significantly, the time from stem cell transplantation, and the longer you are from the actual process of transplant, in general, the more your immune system is able to recover and approach, and even, perhaps, reach normal levels at some point in time. And then also what happens to you individually on the transplant road. And so what infections you had prior to coming into transplant and what infections you get following transplant.

And so, in general, there are group-specific things such as donor source and time from transplant, and then patient-specific things, such as what happens to you individually. And both of those impact both immune reconstitution after transplant and the infectious risks that you have. Introduction and Types of HSCT. So starting with the type of transplant and how that impacts immune reconstitution and the risk of infections following transplant. The way that transplanters divide up transplant is the following– autologous transplants, where you actually get your own cells back; matched sibling allogeneic transplants, and allogeneic means that the transplant comes from someone else; unrelated donor transplants, and those can be both matched on the HLA loci that we know are most important or mismatched on some of those loci; umbilical cord blood transplant from an unrelated source; and then haploidentical transplant.

And haploidentical transplant means that you use someone else who is a half-match. And the advantage of haploidentical transplantation is that most children have a donor, because a parent can serve as a donor. But the disadvantage is that, in order to make this transplant feasible, the T-cells in the graft need to be removed, and that T-cell depletion affects immune reconstitution profoundly. Autologous transplant is basically when you give high-dose chemotherapy, and you rescue patients with previously collected and frozen autologous stem cells. And for matched sibling, unrelated, cord blood and haploidentical transplants, you need to identify a different donor who has their own infectious history and immune system function. And we use those after high-dose chemotherapy and/or radiation therapy for the patient. Timeline Post-Transplant. So the second thing that affects immune reconstitution post-transplant is the time from the transplant itself. And as many of you probably know, we label day zero as the day that the stem cells are infused back into the patient. And there’s a variable period of conditioning before that that usually lasts between 5 and 10 days.

But to set the clock the same for everyone, we call day zero the day that the stem cells are actually infused. So following that day zero, the immune function absolutely recovers in stages. And not all markers, or not all sets of the immune system, are equally important. So the first thing that we see recover are neutrophils, and those actually return within weeks. And we actually define engraftment as the period in time when the absolute neutrophil count has been greater than 500 for three days. And that in autologous transplants will happen around day 12 to 15 and allogeneic transplants happen around day 20.

But as most of you know, neutrophils are only a very small part of the immune system. And while they’re very important for protecting patients from bacterial infections, they are not the long-lived or sort of clever part of the immune system. And that’s why patients are still very profoundly vulnerable, even after they have the return of neutrophil counts and return of neutrophil function. Within weeks to months after transplant, the NK cells return, and NK cells are a type of cell that come from the innate immune system, so aren’t very sophisticated, but can provide some protection against viral and fungal infections.

And then T-cell function, which you really need to have a sophisticated, intact immune system that can respond to new bombardments, that returns in a staggering manner. And, really, if you do functional testing, it takes many months until it is normal. A problem for us is when we try to say, when is someone’s immune function back to normal, so that they can return to a normal life or be treated as a normal patient? It is very, very difficult to ascertain because the immune system is clinically good enough before it actually becomes normal by testing. So many patients say, can’t you just test my immune system? And then, if it looks normal, I can go back to school.

And the problem is that if we waited until the immune system was normal by our most sophisticated testing, it may perhaps be years. But, still, it is good enough for patients to be out in the community. And an analogy is, if we tested everyone’s immune function here, people who were stressed, people were pregnant, people who are recovering from a viral illness, would perhaps not have a normal immune function by the most sophisticated measures of testing.

Yet, obviously they can be out and about, and they aren’t acquiring bizarre infections that we usually see in immunocompromised patients. The second thing is that many patients do return to a normal immune system at some point after transplant. And, sadly, those are the patients that you tend not to see, or happily, because they rarely need to come to the ICU. But unlike solid organ transplant recipients, or recipients of kidney, lung, small bowel transplants, our BMT patients, or stem cell transplant patients, are actually off all immunosuppression at sometime following transplant.

And that can happen months or years after transplant. But at some point, there are no immunosuppressive medications, and at that point, really do have a normal immune system. The problem is that the average journey can be delayed or derailed by other issues that I will talk about. And so while some patients do end up with a very normal immune system, some patients don’t because of individual difficulties they encounter. Pre-Transplant Patient Factors. Some of the assessment of the immune system can be predicted by pre-transplant factors. And the saying we have in transplant is, things that happen to you pre-transplant end up really affecting you post-transplant, which is why we try to keep people as safe and sort of clean as possible in the times leading up to transplant.

So these can be broken into many different factors. One is the indication for transplant itself. So if you are transplanting a baby for a severe combined immunodeficiency versus AML versus thalassemia versus aplastic anemia, all those patients will come to day zero having a different amount of infectious burden beforehand. So severe combined immunodeficiency babies may have had many infections, such as PCP, or polio, from live polio vaccines, because they never had an immune system. That’s changing a bit with neonatal screening and diagnosis of SCID. So it depends on the age, and the way, and the manner in which the child was diagnosed. Patients with AML, in order to come to transplant, receive very, very strong immunosuppressive chemotherapy, and often had been normal before that, but then acquired a lot of infections in the time leading up to transplant from their other chemotherapy.

Thalassemic patients, for example, basically are normal except for iron overload and transfusions prior to transplant, and have a normal immune system, but iron overload can make some infections more likely. And then patients with aplastic anemia have been neutropenic for a period of weeks to months prior to transplant, and, thus, again come to transplant with perhaps undiagnosed bacterial infections, although their T-cell function and innate immunity are usually normal. So that’s just looking at them as a group and saying, why did they come to transplant? The second thing to look at are the actual infections that they had prior to transplant. And, most often, infections that are acquired in the weeks to months before transplant still remain a risk factor for patients after transplant because of ongoing chemotherapy or abnormalities in the immune system pre-transplant, and then the strong conditioning regimen peritransplant. They weren’t able to adequately clear these infections before the transplant process starts. These can be bacterial infections that remain at some low level, either on central lines, and we often ask for central lines to be changed if there’s ever been a positive culture prior to transplant, or in abscesses like perirectal abscesses or other deep-seated infections.

If patients had fungal infections, particularly with aspergillus, within the weeks and months prior to transplant, it almost certainly has been held at bay, but not completely eradicated. And they’re at risk for that for months following transplant. And, again, viral infections. Any chemotherapy or process that effected their lymphocyte function would mean that they, while perhaps holding the viral infection at bay, weren’t able to completely clear it. And then there’s patient-specific issues. And all of these, we look at very closely when someone has an infection post-transplant to make sure that we’ve understood the history and the way it can impact current issues. So patients who are obese are known to do worse after transplant.

And no one completely understands it, but the thought is that it’s perhaps related to immobility and skin issues, in terms of, you know, folds of skin being more prone to cellulitis or skin breakdown. There are definitely psychologic issues, and it’s also known that patients with significant psychologic burden, or problems, don’t do as well in transplant. And the thought is that may be related to compliance or tics and behavioral aspects that can impact transplant. And then, prior surgical interventions. So if people had had abdominal surgery in close proximity to transplant, their bowel may not be intact or any anastomoses may not be firmly healed. If they had other wounds, they probably aren’t firmly healed by the time of transplant.

And some of our immunosuppressive drugs, such as rapamycin, are known to interfere with wound healing, and that can be a factor as well. There are many, many other considerations that impact on how much at risk the patient is for infections post-transplant. The age of the patient. It is clear, clear, clear through many studies that the younger the patient, the better the immune reconstitution, perhaps partly because there’s still thymic tissue available to sort of reset the new cells, partly because young patients have had fewer infections coming into transplant, just because they haven’t lived as long, they tend to be less likely exposed to CMV and other herpes infections.

But a young patient, in general, is going to be less at risk than an older patient. The age of the donor also matters. When you use an old donor, those new T-cells aren’t as plastic and aren’t as able to be re-educated and learn how to fight infection. For unrelated donors, the cutoff age is 60, we don’t take donors older than 60, but we still really try to use young donors when it’s possible. Point of clarification. One exception to this is cord blood transplant. Umbilical cord blood is mostly comprised of naive T-cells and lacks transfer of T-cell memory.

Thus, transplant recipients of umbilical cord blood are more vulnerable to viral infections during the first phase of T-cell reconstitution. Where the patient comes from matters. And patients from Mexico or other Latin American countries are more often exposed to toxoplasmosis, and that can reactivate after transplant. Whereas the incidence here is quite low. Patients that come from Egypt and the Middle East have a huge incidence of hepatitis C exposure prior to transplant, and that can reactivate after transplant. So you need to look for things that are linked to the geography of where the patient grew up. Compliance, we talked about briefly before. If patients don’t take their immunosuppressive or anti-infectious medications, they may have infections that you would think they wouldn’t have.

For example, we almost only see PCP or PJP, now, in the setting of non-compliance because medicines are so good. But it still can be seen in patients who aren’t taking the medications, or have GI issues, so they aren’t absorbing the medications. There’s been a huge literature on polymorphisms in both patient and donor in immunoregulatory genes, such as TNF Alpha and IL-10, that may impact the ability to fight actions post-transplant.

Malnutrition can be significant post-transplant, both for psychologic and medical reasons, such as GI GVHD. And it is absolutely clear that, although we don’t assess this as much as we should, the significant malnutrition is a risk factor for infections because your immune system really just doesn’t work well when you are significantly malnourished. And then, finally, hardware that you have in, whether it be central access, as we talked about before, a VP shunt that can become infected, dialysis catheters, artificial valves. Anything that is where it shouldn’t be naturally can be a source of infection. Post-Transplant Patient Factors. So now you’ve got the patient through transplant and you want to know what their risk for infection is. Well, what has happened to them post-transplant, and how does that impact on their risk of specific infections? The biggest impact in the allogeneic setting is Graft Versus Host Disease. Graft Versus Host Disease occurs when donor T-cells, which are the graft, attack the patient, or host. These donor T-cells recognize tissues in the host as foreign. They mount an immune response, which can lead to tissue damage and cell death.

This, in turn, creates further immunocompromise in the patient, with an increased risk for opportunistic infection. The organs that Graft Versus Host Disease attack also contribute to infectious risk. So bad Graft Versus Host Disease of the skin can cause skin sloughing, and similar to burn patients, the skin barrier is lost, and there’s many opportunities for infection there. And more commonly, Graft Versus Host Disease of the gut actually affects the integrity of the GI mucosal boundary. And so there is a lot of translocation of bacteria and infectious opportunities from that stance. Also, because of the complexity of significant Graft Versus Host Disease treatment, most of our patients have prolonged central access with CVLs and sometimes other lines as well, and that also is a risk for infection. Every patient, except an identical twin, receives Graft Versus Host Disease prophylaxis with immunosuppressive agents, the backbone of which are usually calcineurin inhibitors such as cyclosporine and tacrolimus.

And then other immunosuppressive medications such as steroids are often added. The therapy to treat Graft Versus Host Disease are all based on anti T-cell function, whether they be high dose steroids, antibodies such as ATG or Campath, or immunomodulatory drugs that affect metabolic pathways of T-cell development, such as mycophenolic acid. All of them have profound effects on the immune system. Other post-transplant factors include relapse. And I think this is something that people who don’t live in our world often are not aware of is that if a patient relapses with a malignant disease following transplant, they are perhaps at the greatest risk of infectious complications. Because now, they have donor cells that weren’t working sufficiently and they have overgrowth of their own cells that are malignant and not working well. And also are getting, usually, induction chemotherapy on top of that. And they really have no protection against significant infections. And if you look at the treatment of patients who relapse with malignant diseases following transplant, often, their death is from infectious complications as well as from recurrent disease.

Other post-transplant factors, there’s veno-occlusive disease of the liver, which has recently been renamed sinusoidal obstruction syndrome, or SLS. This is usually a complication that occurs quite proximal to transplant in the first weeks to months following transplant, and acts as an hepatic obstructive process in the small veins of the liver. It causes ascites, and liver insufficiency, or liver failure. And the treatment of it often requires abdominal drains, occasionally, there’s pleural effusions or pericardial effusions as well, and those together can increase the risk of infection somewhat. And then, finally, graft failure is a very, very significant risk for infection, similar to relapse or Graft Versus Host Disease.

Graft failure is when the donor cells don’t take, and it can happen in the acute transplant period in the first weeks to months, or the graph can take for a while and then be rejected due to immunologic mechanisms months to years following transplant. And when that happens in a malignant setting, it’s usually associated with relapse, but it can happen in nonmalignant conditions as well. And then the patient either has recurrence of their initial disease such as thalassemia or sickle cell disease, or they become aplastic and have no count. Regardless, that usually requires ongoing transfusions and a setting of iron overload. And when one moves up into thinking about a second transplant, that iron overload and period of immune dysregulation makes patients more susceptible to infections. Approach to Fever in a Hematopoietic Stem Cell Transplant Patient. Switching gears– then how would you approach a fever in a stem cell transplant patient who was in the ICU or even in your hospital? So first is taking a very good history.

You need to know who the donor is– if it’s a matched sibling donor versus a mismatched, unrelated donor? How far out are they from transplant? What things are still in them in terms of central venous lines and other plastic? Have they had surgical interventions recently? What is their viral status of them and their donor? What immunosuppressive and other medications are they on? What infections have they had recently? What are the sensitivities of any documented infections? What have they had for prior therapies? Next, you go to a very thorough exam.

You have to look at their skin very, very carefully. There are lots of undetected paronychia, for example, that could be a problem. The GU area has to be examined very carefully. And that’s something I think we don’t always do well and particularly, perhaps, in obese patients. But there can be perirectal breakdown. There can be other GU issues. And then you need to look at the CVL exit sites. We also do weekly surveillance cultures on our patients of the nose, of the nares, throat, and stool.

And while we don’t treat things found on surveillance cultures, if the patient is sick, it’s good to know what is growing in them, at least as a way to potentially direct therapy. Everybody should receive a blood cultures very quickly after presenting with the fever. And if there are any respiratory symptoms, an NP aspirate for a full viral panel would be useful. If there are specific symptoms such as abdominal pain or dysemia or hypoxia, you could image the appropriate areas. And then you need to quickly start broad coverage with antibiotics– ideally double coverage for gram negative rods while you’re sort of sorting out the patient. And then, if there’s something in the patient’s history, or if they’re very sick, you may want to add vancomycin quickly and more antifungals than the antifungal prophylaxis they are probably on. Common Infections Post-Transplant. What are some of the common infections post-transplant? And I wanted to start with some, what I call, stem cell transplant oddities. These are things that, in general, most transplant physicians across all programs would do, even though there really are not good data to support them.

But we know that the immune system is so broken in most of our patients, even though there is a normal neutrophil count, that we always err on the side of more instead of less antibiotics. And until there are studies to really try to figure out the risk/benefit ratio of that strategy, this is what transplanters will recommend. It will be very uncomfortable if that is not the practice being followed. So one is that all antibiotics started during the neutropenic phase continue to engraftment, even if there’s no documented infection found. So during the acute transplant period before neutrophil engraftment occurs, patients are at their most vulnerable. They have no neutrophils. The conditioning regimen has ablated both their innate immunity with their NK cells and their learned immunity with their T and B cells. And so they really have no protection. And so when they are febrile, we start double antibiotic coverage. And then we continue that coverage until engraftment, even if there are repeated negative blood cultures and even repeated imaging.

There are always exceptions. If a patient has a specific bad reaction to a specific antibiotic, we will switch the antibiotic out. But we almost never pull back on coverage until engraftment occurs and fever resolves. Secondly, any documented infection requires a period of treatment after neutrophil recovery occurs. And everyone agrees that this is true, but there really is very little data about it. Past infections are still lurking. So again, if you had aspergillus a month before coming into transplant, you will need prolonged treatment with anti-fungals post-transplant for weeks and weeks in order to finally eradicate that infection, particularly if you are still on in immunosuppressive agents during that time, as all allogeneic bone marrow transplant patients are.

And finally, lines are suspect. So when patients are persistently febrile and have many, many negative cultures, and we can’t find a source, often we’d like to pull the central line, because it may be subliminally, or at a low level, infected with some bacteria that we just aren’t able to detect. And this is a very hard concept and something that we don’t know is correct, and really requires discussions with the ICU team and the surgeons about the risk/benefit aspects to a particular patient about this. What are some of the common infections post-transplant? So gram-negative rod bacterial infections and the resulting sepsis that they can cause are much less frequent than they were in the past. And in the 90s, they were really the most common cause of bacterial infection post-transplant. But they still represent a real cause of morbidity and mortality, and are the thing that is most urgent to treat during the pre-engraftment period. Double coverage is still the standard. Though, as I alluded to before, data is really lacking, but double coverage for the potential pseudomonas. And I think we all need to be aware that resistant organisms are an emerging problem.

And it’s very helpful to know what the organism sensitivities are, either in the institution that you’re in with the patient, but also in the institution from which the patient came, if they received their treatment elsewhere before coming to your institution for a transplant. In terms of gram-positive organisms, those are also common due to the loss of GI integrity, oral and GI tract mucositis, and the loss of skin integrity because of chemotherapy agents such as thiotepa, because of prolonged bed rest, because of graft versus host disease. Point of clarification. One should consider the addition of broader gram positive coverage such as vancomycin if fever persists or if there are patient-specific risk factors Even if the patient is VRE positive on colonization, one can still add vancomycin in the setting of a fever because you don’t know yet that they’re bacteremic with the VRE.

However, if a patient were sick and had signs of sepsis, it may be better to start with a drug that would be suitable for VRE organisms, such as daptomycin or linezolid. Fungal infections are still a big problem as far as post-transplant. All patients are on fungal prophylaxis until engraftment– for everybody, autos and allos. And for allo patients, they remain on fungal prophylaxis through day 75 based on this study out of Seattle, showing that that had a better outcome. We here leave patients on some anti-fungal prophylaxis until they are off steroids. And that is common practice among most transplant centers, although, again, it’s not been specifically studied. Fungal infections are uncommon in the autologous transplants, because they recover neutrophil function relatively quickly. And their T-cell function is somewhat better. But allogeneic patients remain at risk, particularly if they’re on steroids and/or have ongoing GVHD, and if they had a history of fungal infection pre-transplant. Fungal infections are difficult to diagnose, and there’s now serum markers, such as Beta-D-glucan and galactomannan.

But they are not perfect either in terms of sensitivity or specificity. BALs are very non-helpful in diagnosing fungal infections in the lung, because they’re usually more peripheral. And the negative BAL should not be of reassurance at all. Currently, aspergillus is the most common infection that we see, but the mold infections are increasing and have variable sensitivities, and that’s why tissue is needed. In order to adequately treat a fungal infection, you really need tissue, because you need to know sensitivities and the specific subtype of the fungal infection. Also, except for candida, so for molds and aspergillus, curative therapy almost always requires excision of the primary lesion and central line removal. So the virus that we talk about most is cytomegalovirus (CMV). And that used to be the biggest killer of patients following allogeneic transplants. Most CMV infections occur because of re-activation of prior patient CMV, which means that the patient was CMV IgG positive prior to transplant. Occasionally, they will get CMV because of a donor who is CMV positive and transferred CMV, active CMV, with the marrow. It’s rarely a problem in autologous transplants because CMV is mostly controlled by your T-cells, and your T-cells are less hurt in autologous transplant.

But for all allogeneic transplants, the highest risk patients are those who are CMV positive pre-transplant, so they had a prior history of CMV, and then they receive a transplant from a CMV negative donor. And that means that the donor cells that are going in are CMV naive and are not going to be able to control very well when the patient reactivates the CMV that is still living in their body. All cord blood donors are CMV naive and are considered CMV negative, because those cord blood stem cells have not encountered CMV yet. All CMV patients receive prophylaxis during the first 30 days of transplant with acyclovir, even though that’s not a very good CMV drug. Historical literature has suggested that that’s helpful. And post-transplant, everyone needs weekly PCR screening, and that is a standard of care across all transplant centers. It’s very easy to forget, and it is crucial that weekly CMV PCRs be sent for the months following transplant. Low level PCR positivity may not be treated. You would have to consult with a transplant physician. But any blood load of over 500 copies is called reactivation and requires therapy with antivirals and IVIg.

You usually begin acyclovir, occasionally foscarnet. Also any CMV detected in a sterile site, pleural fluid, BALs, CSF, pericardial fluid is considered significant and requires CMV directed therapy, again, with an anti-viral and IVIg. The other virus that is becoming more common, perhaps because we’re able to detect it more, is adenovirus. We now can look for it by PCR, and we now have effective therapy, so it’s become much more on our radars. It is not clear whether patients who have adenovirus PCR detected post-transplant have reactivated prior adenoviral infections or whether they’ve acquired adenovirus newly, but PCR positivity in the blood at any level almost always requires intervention.

And PCR in other sites such as stool or urine requires thoughtful discussion. The current treatment is cidofovir. There is a lot of concern about nephrotoxicity, but in children, it has been our experience, as well as being reported more in the literature, that it actually is quite well tolerated. And when someone has adenovirus present and is sick, either with the fever or pulmonary complications, treatment delay, it can be very, very concerning, and we would rather start cidofovir while we sort it out than wait until the patient is too sick to have effective therapy. So in summary, while this is a huge talk, and these are just some of the highlights, I think these are the principles that can help you address fever and infections in this very vulnerable group of patients. One is while immune function can potentially return to normal following transplant, in the weeks to months around transplant, it is safest to consider patients as significantly immunocompromised, more than a patient with HIV or more than a patient after a solid organ transplant.

And whether or not they have a normal neutrophil count really is not a very important factor. It’s their T-cell function and their other, more sophisticated immune system that is broken for a long time after transplant. And two, while all patients are at risk, you can identify an extraordinarily high risk group where you need to act very quickly and where the right answer would almost always be more versus less therapy in terms of antibiotics, antivirals and anti-fungals. And this group primarily would be patients with ongoing GVHD on high immunosuppressive therapy, patients with graft failure, and patients who have previously been vulnerable, they had an immunodeficiency before transplant, so they never had a normal immune system.

They got intense therapy prior to transplant, such as for recurrent AML, or they now have had two transplants in close proximity to each other. And finally, the past always comes back to affect the present. So involving the team that has longitudinal knowledge of the patient is essential. And we will know things that seem trivial, whether it be that they’ve had a paronychia that we’ve never been able to clear, or whether their graft failure is associated with some specific organism, or whether they come from an area endemic for toxoplasmosis. But all of those things will help direct therapy and give the patient the, sort of, menu of antimicrobials that give them the best chance to contain the infection and to survive in the long term. Please help us improve the content by providing us with some feedback.