Keywords

Transplantation remains a pioneering scientific innovation that has a significant impact on restoring well-being for patients and benefit society as a whole. Blood and marrow hematopoietic stem cells have become accepted and, in some instances, established approach to treat incurable neoplastic diseases and congenital disorders of immune system [1]. Similarly, use of allografts in patients with end-stage organ disease involving the liver, kidneys, intestines, heart, and lungs has provided a possibility for continuation of life and a potential for patients to integrate and resume participation in their communities [2]. Recent advances in limb, integument, and face transplantation underscore the substantial leap forward in restoring normalcy for individuals with devastating and often catastrophic physical encumbrance [3, 4].

In patients undergoing solid organ transplantation, advancement in understanding the complex interplay within various facets of immune response against the transplanted allogeneic tissue that recipients’ immune system fails to recognize as “self” has resulted in encouraging long-term outcomes [5]. These achievements in decoding higher mammalian immunity underscore the recent progress made in development and implementation of refined strategies to harness potentially devastating immune rejection of the implanted solid organ allograft [6]. The antirejection strategies , as expected, involve a delicate balance that favors preservation of a functioning allograft and aims at limit severity of drug-induced suppression of recipients’ immune function, which is crucial for the surveillance against various neoplastic processes; conventional and opportunistic infections.

A similar, albeit an opposing role of undesired immune response comes into play in patients undergoing hematopoietic blood and marrow stem cell transplantation from a foreign donor. The conflict arises from aforementioned disconnect between immune recognition of self versus nonself [7, 8]. These transplanted stem cells install foreign effector immune cells in the recipient, and if remain unabated, the resulting graft-versus-host disease is capable of unleashing potentially ruinous systemic inflammation resulting in irreversible tissue damage and death [7]. The stem cell graft restores immunity and functional marrow in patients in need for myeloablative antineoplastic therapy . Furthermore, it is the foreign, graft-mediated, adaptive cancer immune surveillance that has now been widely recognized as the pivotal feature that sustains cancer in remission following successful allogeneic hematopoietic stem cell transplantation. This feature of stem cell graft-assisted antitumor response is recognized as “graft-versus-leukemia or graft-versus-tumor effect.” Donor-derived adaptive antitumor immunity is an important objective of allogeneic stem cell transplantation, especially in patients with hematologic malignancies, and forms the bases for donor lymphocyte infusions to treat cancer recurrences during posttransplant period [9]. As in patients following solid organ transplants, in recipients of allogeneic HSCT , anti-GVHD therapy is assessed and continuously refined to achieve the lowest possible cumulative iatrogenic immune suppression required to prevent or treat GVHD, whereas an earnest attempt is made for preservation of recipients’ immune function such that the risk of conventional and opportunistic infections and malignancies do not overwhelm the projected efficacy and feasibility of these lifesaving procedures.

A number of agents have been successfully used for prevention and treatment of graft-versus-host disease and solid organ allograft rejection [8, 10]. Severity of immune dysfunction is in most instance a direct consequence of treatment with these agents that are commonly prescribed as combination drug regimens. Cyclosporine was the first major breakthrough in this regard; subsequent generation calcineurin inhibitors (CNI) have improved therapeutic index although resultant severe immune suppression and the risk for opportunistic infection like CMV, BK virus, and certain posttransplant cancers question the therapeutic feasibility for agents such as tacrolimus, especially in patients with low risk for allograft-related complications. Serious infections due to cytomegalovirus including viremia and end-organ disease, BK virus viremia, viruria, and BK virus allograft nephropathy with risk for potential graft compromise, rare progressive multifocal leukoencephalopathy due to polyomavirus, higher potential for opportunist cancers such as Kaposi’s sarcoma, EBV lymphoproliferative disorders among others, are well-recognized limitations in individuals given tacrolimus for extended duration with doses leading to prolong high serum drug concentration [11]. Experience with sirolimus, a macrolide xenobiotic that induces potent immune suppression via inhibition of mechanistic target of rapamycin (mTOR; a conserved threonine and serine protein kinase) was associated with lower incidence of CMV infection in solid organ transplant recipients. This protective antiviral effect of mTOR inhibitors against BK virus nephropathy after renal transplantation has not been noted consistently. Additionally, antitumor properties of mTOR inhibitors may favorably influence the lower incidence and risk for posttransplant malignancies in recipients of solid organ allografts, especially those with a profile that indicates low risk for graft rejection [12].

Monoclonal antibodies against T- and B-cell pathways have also gained prominence, as potential treatment options. Alemtuzumab (Campath) is a monoclonal antibody that targets C52 antigen expressed on all lymphocytes. Treatment with Campath results in profound lymphocyte depletion. The drug-induced immune suppression may last for up to 9 months, although maximum degree of lymphopenia is noted between 8 and 9 weeks after therapy. As part of HSCT preparatory condition regimen, treatment with alemtuzumab was associated with reduced risk for GVHD following allogeneic hematopoietic stem cell transplantation [13].

In kidney transplant recipients, the risk for organ rejection was low in patients given alemtuzumab; however, this benefit was mainly observed in patients that were at a low risk for allograft rejection [14]. Other trials are underway with the aim to explore regimen(s) that may spare CNI (tacrolimus) for the prevention of allograft rejection.

Humanized monoclonal antibody rituximab that targets CD20 antigen expressed prominently and selectively on B lymphocytes forms the cornerstone for treatment of solid organ antibody-mediated renal allograft rejection. It is also considered the standard of care for the treatment of posttransplant B-cell lymphoproliferative disorders [15].

Systemic glucocorticoids have maintained relevance in drug cocktails given to prevent and treat solid organ graft rejection and GVHD . Since the early observation enabled addition of corticosteroids to successfully reduce cyclosporine dose that was traditionally needed to prevent rejection of transplanted allograft, this observation was regarded as a major breakthrough and forged the path for preservation of transplanted organs without serious, life-threatening CNI toxicity. Detailed discussion regarding immunosuppressive agents for prevention and treatment of allograft rejection is provided in chapters throughout this book.

A keen understanding of patients’ underlying immune defect(s) is the knowledge cornerstone, essential for optimizing infection risk stratification, assessing need for preventive, preemptive or empiric antimicrobial therapy. This information serves as an imperative in establishing meaningful patient-centered management and infection prevention paradigm [16, 17]. Table 1.1 provides an outline for such a relationship between underlying immune defects and susceptibility for particular group of pathogens. It is also important to note that a combination of unrelated immune defects may overlap. Furthermore, such patients may present with multiple infections concurrently, sequentially, or in close proximity to a primary infection episode, with a variety of conventional and opportunistic microorganisms.

Table 1.1 Infections in transplant patients in relationship with the underlying immune defects
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An extensive exposure to hospital environment poses risk for transplant recipients to acquire infections that may not respond to conventional antimicrobial drugs. The recent interest in exploring the potential influence of perturbation and reorganization of hosts’ microbial flora or microbiota resulting from extensive exposure to healthcare environment, broad-spectrum antimicrobial drugs among other factors, has yielded greater insight into a field that was largely underappreciated for decades. Altered orointestinal microbiota has been proposed in limited observational studies to influence the risk for acquiring infection, recurrence of previously resolved infection, suboptimum response to antimicrobial therapy, and importantly, long-term viability of the transplanted allograft [18,19,20]. The possibility of noninfectious complications and their potential relationship with altered hosts’ microbiota are currently under investigation.

An important approach in the assessment of transplant patients lends from the understanding and knowledge of temporal relationship for the risk of infection that may occur during various clinical phases after transplantation procedure (Table 1.2, with Figs. 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6). For example, patients with long-standing chronic GVHD are at an additional risk for infections that are often seen in asplenic patients or those with functional hyposplenism. Patients with chronic GVHD are not only at an increased risk for systemic fungal disease like invasive aspergillosis or herpes virus reactivation herald by CMV viremia; additionally, encapsulated bacteria such as outlined in Table 1.1 may also be included in the risk profile during evaluation of such patients.

Patients receiving treatment for acute GVHD after allogeneic HSCT have heightened risk for invasive aspergillosis and infections due to other filamentous molds. Unlike the first risk period for invasive mold disease in allogeneic stem cell recipients, which coincides with the period of pre-engraftment severe neutropenia, patients with acute and chronic GVHD are seldom neutropenic.

Table 1.2 Infections in recipients of allogeneic hematopoietic stem cell transplantation
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Fig. 1.1
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CT scan of lungs without intravenous contrast showing necrotizing left lung Pseudomonas infection in a patient following HSCT. The differential for this thick-walled irregular cavitary lesion is broad and includes other bacterial infection such as Klebsiella spp., Stenotrophomonas maltophilia, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Nocardia spp.; Mycobacterium tuberculosis and nontuberculous mycobacterial infections. Cavitary rapidly growing cancers may have similar presentation, whereas viral infections including cytomegalovirus and adenovirus seldom present with such features. Other than suppurative necrosis of the lung, ischemic necrosis, i.e. pulmonary infarction, should also be considered. Tissue invasive mold lung disease may also have comparable radiographic presentation

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Fig. 1.2
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CT scan of lungs without intravenous contrast showing tree-in-bud appearance due to pulmonary Mycobacterium avium complex disease mostly involving the right lung demonstrating multiple areas of centrilobular nodules with a linear branching pattern. Endobronchial tuberculosis may present with such a radiographic finding, wherein patients with acutely developed tree-in-bud infiltrates bacterial or viral (CMV) etiology may also be entertained. It is important to note that bronchiectasis is the prominent radiographic presentation of Mycobacterium avium complex infection in patients undergoing transplantation. Rarely carcinomatous endarteritis due to breast or gastric cancer; bronchovascular interstitial infiltration due to lymphoma, leukemia, and sarcoidosis may have similar presentation. Scedosporium lung disease and pulmonary fusariosis may occassionally have nodular peribrochovascular distribution

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Fig. 1.3
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CT scan of lungs without intravenous contrast showing right lung Mycobacterium kansasii pneumonia with peribronchial thickening that could be mistaken for CMV pneumonitis and Mycobacterium tuberculosis, among other lung infections in a patients following allogeneic HSCT

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Fig. 1.4
figure 4

CT scan of lungs without intravenous contrast showing bilateral nodular zygomycosis in a patient following allogeneic HSCT while receiving voriconazole prophylaxis. The right lung nodule with a central cavity cannot be radiographically excluded from other causes of nodular pneumonia such as invasive pulmonary aspergillosis, Fusarium spp., and other mold lung disease. Among bacteria, Nocardia spp. is a concern in allograft transplant recipients with such radiographic presentation. Primary lung lymphoma may have similar presentation. Rarely, patients with relapse acute leukemia in the post HSCT period may present with atypical pulmonary infiltrates

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Fig. 1.5
figure 5

CT scan of lungs without intravenous contrast showing cavitary pneumonia with dense consolidation involving both lower lobes in a patient with GVHD, who developed infection due to dematiaceous mold following allogeneic HSCT. In the differential diagnosis, necrotizing bacterial, clear (hyaline) and black (melanin pigmented) mold infections should also be considered along with multifocal pulmonary nocardiosis

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Fig. 1.6
figure 6

CT scan of lungs without intravenous contrast showing cryptogenic organising pneumonia in a patient following allogeneic HSCT that may be mistaken for fibrosing subacute infection due to endemic mycosis among other causes of subacute lung infection

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Table 1.3 illustrates the salient features of infection risk and their association with the type of stem cell graft, pretransplant conditioning preparatory regimens, and drugs commonly used in the prevention of GVHD. Cord blood stem cells are regarded as a major breakthrough for source that yields a steady supply of hematopoietic stem cells, especially among patients with difficult to find, immunologically (HLA-matched) compatible hematopoietic stem cell graft [18]. Cord blood stem cells have a limited number of nucleated cells that are adequate for children. In adults due to larger body surface area, transplantation with less than optimum number of stem cells complicate posttransplant period with issues such as inadequate and delayed neutrophil engraftment and peripheral blood cell count recovery, precarious graft stability, and, similar to recipients of T-cell-depleted grafts, a higher risk for infections associated with severe and prolonged neutropenia or those observed during GVHD (Tables 1.1 and 1.2). Various strategies are being explored to assuage this limitation including transplantation with cord blood grafts from more than one donor and ex vivo expansion of a single donor cord blood graft to increase the yield of nucleated cells [21]. In a review of 100 cord blood transplants at a comprehensive cancer center in Houston, Texas, the infection incidence rate ratio, which was total infection episodes per days at risk (survival after CBT) Ă— 100, was 2.4 times higher in adult patients compared with children [22]. It was important to note that risk of infection was even greater (three times higher) in adults with neutropenia and was 1.9 times higher in patients with GVHD when compared with children undergoing CBT procedure [22].

Table 1.3 Relationship between infection risk and HSCT variables
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It is considered essential to create a comprehensive infection assessment strategy that takes into account and recognizes the local issues at a particular transplant unit and its unique patient population. Such an approach requires cognizance of existing influences that may promote risk for infection including local and regional infection trends, patterns in pathogen prevalence and drug susceptibility profiles. Continued vigilance regarding emergent pathogens and ever-changing infection risk profile with advances in transplant procedures and drug-induced immune suppression are of paramount importance in providing care for the highly vulnerable transplant population.

A variety of noninfectious conditions may clinically and radiographically emulate an infectious process. Among these noninfectious maladies, those involving the skin and the lungs are the great imitators; when present, they are difficult to clinically distinguish from infections such as cellulitis or pneumonia. Two chapters in this volume are dedicated to provide an in-depth discussion on these topics.

An approach for establishing correct diagnosis for opportunistic infections is based on the maxim “when uncertain, obtain a tissue sample.” A diligent adjudication is the central tenet in establishing accurate diagnosis for the immunologically vulnerable patients, in whom proclivity for atypical disease presentation further complicates ascertaining correct and timely diagnosis. Inaccurate diagnosis under the old dispensation of serologic and culture-based system may lead to inappropriate and ineffective treatment, worsening patients’ morbidity, risk for further complications, and death. Therefore, focused yet comprehensive differential diagnoses, which encompasses etiology of infections and noninfectious causes that may mimic an infectious process including but not limited to drug toxicity; de novo malignancies or post transplant cancer recurrence; typical or atypical presentation of lymphoproliferative disorders; immune-inflammatory diseases like GVHD; and tissue infiltrative processes such as solid allograft rejection among others may greatly improve the guidance for an optimized management approach in patients undergoing lifesaving, stem cell and solid organ allograft transplantation.