Chapter 13 – Immunocompromised Patients




Chapter 13 Immunocompromised Patients


Enjarn Lin and Stuart Hastings



Key Points





  • Immunocompromised patients may present with multi-systemic disease and are at risk for increased perioperative morbidity and mortality.



  • Perioperative care of the immunocompromised patient requires an understanding of the immune system and an understanding of the pharmacological therapies used to treat the underlying disease.



  • Hereditary and acquired defects in the immune system may result in either an inadequate or a misdirected immune response or an excessive immune response that may all lead to disease.



  • Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) remains a global health issue. Antiretroviral therapy has significantly improved the morbidity and mortality associated with HIV infection. The perioperative physician must be cognisant of the complications associated with the use of antiretroviral therapy and the potential for drug interactions with anaesthetic medications.



  • Immunosuppression is essential for successful organ transplantation, but the balance between under- and over-immunosuppression is difficult. Rejection and organ dysfunction are the hallmarks of under-immunosuppression, while the undesired consequences of immunodeficiency are infection in the short term and cancer in the long term.



  • Many patients with cancer will display little physiological derangement, while some may have widespread multisystem disease due to the disease process or its treatment with anti-neoplastic agents. The rapid pace of change in oncological treatments and availability and the use of novel agents has resulted in a lag in awareness in the anaesthetic literature.




Introduction


Perioperative care of the immunocompromised patient requires an understanding of the immune system and an understanding of the pharmacological therapies used to treat the underlying disease. This section will discuss the perioperative management of patients with cancer, patients infected with the human immunodeficiency virus (HIV) and recipients of solid organ transplantation.



The Immune System


The immune system is a complex, layered biological defence system that has evolved over time to protect animals from invading microorganisms, foreign or non-self-antigens and allergens and even cancer. In simplistic terms, the immune system can be separated into the innate and adaptive immune systems. The innate immune system provides an immediate but non-specific immunological response, while the adaptive immune system, which is present only in higher life forms, provides a specific pathogen and antigen response that can result in immunological memory. Both innate and adaptive immune systems possess cell-mediated and humoral components. Cell-mediated components of innate immunity include neutrophils, macrophages, monocytes and natural killer cells. Humoral or non-cellular elements include the complement system of 18 proteins, acute-phase proteins and proteins of the contact activation pathway. The humoral component of adaptive immunity is primarily composed of antibodies or immunoglobulins, comprised of five protein subclasses named IgM, IgA, IgG, IgD and IgE, produced by B-lymphocytes. T-lymphocytes that include killer T-cells and helper T-cells dominate the cellular component of adaptive immunity and play a significant role in the recognition of ‘non-self’ targets such as foreign cells, pathogens and cancers. Cells activated by the immune system release various cytokines, resulting in the biological amplification of the immune system and a coordinated response. Hereditary or acquired defects in the immune system may result in either an inadequate or misdirected immune response or an excessive immune response that may all lead to disease. It is beyond the scope of this chapter to discuss all of these disorders in detail; however, they are listed in Tables 13.1a and 13.2b (Littlewood, 2008).




Table 13.1a Congenital immunodeficiency disorders.

































Category Examples
Defects of phagocytic cells Chronic granulomatous disease, leukocyte adhesion deficiency, Schwachman’s syndrome, Che´diak-Higashi syndrome, Hyperimmunoglobulinemia E syndrome,
Leukocyte adhesion defects, leukocyte glucose-6 phosphate dehydrogenase deficiency,
Myeloperoxidase deficiency, IL-12 deficiency
Complement abnormalities C1-esterase inhibitor deficiency, C3 deficiency,
C6 deficiency, C7 deficiency, C8 deficiency
T-cell abnormalities DiGeorge anomaly, chronic mucocutaneous candidiasis,
X-linked lymphoproliferative syndrome
Combined T-cell and B-cell immunodeficiencies Ataxia-telangiectasia, severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome
Antibody defects (B-cell abnormalities) X-linked agammaglobulinemia, common variable immunodeficiency, IgA deficiency, IgG subclass deficiency


(Littlewood, 2008)

Legend: IL =interleukin, Ig=immunoglobulin




Table 13.2b Acquired immunodeficiency disorders.








































Category Examples
Endocrine Diabetes mellitus
Gastrointestinal Hepatic failure, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy
Haematologic Aplastic anaemia, cancer, graft-vs-host disease, sickle cell disease
Iatrogenic Anticonvulsants (causing IgA deficiency), general anaesthesia, immunosuppressants (e.g., antithymocyte globulin, chemotherapeutic drugs, corticosteroids), radiation therapy, splenectomy
Infectious Cytomegalovirus, Epstein-Barr virus, HIV infection, measles, varicella
Nutritional Malnutrition, alcoholism
Physiologic Physiologic immunodeficiency, pregnancy
Renal Nephrotic syndrome, renal failure and uraemia
Rheumatologic Rheumatoid arthritis, systemic lupus erythematosus
Other Burns, chromosomal abnormalities (e.g., Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis


(Littlewood, 2008)

Legend: Ig=immunoglobulin, HIV=human immunodeficiency virus



Human Immunodeficiency Virus



Introduction


Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) causes a spectrum of diseases that continues to be a global health issue. It is described as a global pandemic, and it is estimated that more than 35 million people are living with HIV worldwide (Anon, n.d.). Effective antiretroviral therapy (ART) has made significant inroads, particularly in Western societies with greater healthcare access, into improving the morbidity and mortality associated with HIV infection (Antiretroviral Therapy Cohort Collaboration, 2008; Nieuwkerk et al., 2007). With improved survival and quality of life, it has been estimated that up to a quarter of patients living with HIV will require surgery at some time during their illness (Eichler, Eiden and Kessler, 2000).



Pathophysiology and Natural History


HIV is an enveloped RNA retrovirus in the genus of lentiviruses, in the family of retroviridae. It primarily infects components of the immune system, including CD4 T-cells, macrophages and dendritic cells, by integrating with the host DNA via its reverse transcriptase (Cohen et al., 2011). HIV infection is characterised by a long latency, chronic infection, persistent viremia and destruction and depletion of CD4 T-cells (Alimonti, Ball and Fowke, 2003). There is subsequent impairment of cellular immunity and the host becomes susceptible to microorganisms and cancer (Evron et al., 2004). In the era prior to ART, AIDS-related illnesses, including opportunistic infections such as pneumocystic carinii pneumonia (PCP) and rare cancers such as Kaposi’s sarcoma, developed within 10 years of infection (Cohen et al., 2011). However, modern treatment with antiretroviral therapy has seen the clinical characteristics of HIV/AIDS changed dramatically. The clinical sequelae of HIV infection, with multisystem involvement (Table 13.3), is now less common, while the clinical consequences of ART have become more prominent (see Antiretroviral Agents on p.180).




Table 13.3 Clinical manifestations of Human Immunodeficiency Virus /Acquired Immunodeficiency Syndrome.








































Nervous system Meningoencephalitis
Peripheral neuropathy
Myopathy
Dementia
Cardiovascular Myocarditis/cardiomyopathy
Pericardial effusion
Pulmonary Severe pneumonias including PCP
Tuberculosis
Gastrointestinal Oesophagitis, dysphagia, odynophagia, GORD (related to candida, cytomegalovirus, herpes)
Hepatitis
Biliary stasis and cholangitis
Genitourinary Nephrotic syndrome
Haematological Anaemia or bone marrow suppression with pancytopenia
Lymphomas


Legend: PCP= pneumocystis carinii pneumonia, GORD= gastro oesophageal reflux disease



Diagnosis


HIV diagnosis can be made using serological tests, viral culture or the detection of viral RNA or proviral DNA (Cohen et al., 2011). Specific antibodies to HIV glycoproteins (p24 core protein) can be detected within 3 weeks of infection, while polymerase chain reaction amplification of viral RNA and proviral DNA can aid in earlier detection. Determination of viral load and CD4 counts is important in defining disease stage and for the monitoring of antiretroviral treatment. Successful treatment with ART aims to suppress viral load to undetectable levels (Antiretroviral Therapy Cohort Collaboration, 2008).



Antiretroviral Agents


Modern ART includes the use of five classes of antiviral agents, which are differentiated by their target within the retroviral life cycle (Table 13.4). They include the reverse transcriptase inhibitors, which can be divided into nucleoside/nucleotide and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI, respectively), the protease inhibitors, entry/fusion inhibitors and the integrase inhibitors. They are commonly used in combination, and the treatment is termed highly active antiretroviral therapy (HAART) (Anon, 2015). Combination therapy increases the efficacy while reducing the risk for antiviral resistance. In recent times, a number of fixed-dose combinations have also been introduced.




Table 13.4 Classes of Human Immunodeficiency Virus antiviral agents.









































































Class Drug
Reverse transcriptase inhibitors: Zidovudine (AZT)
Nucleoside reverse transcriptase inhibitors (NRTIs) Lamivudine (3TC)
Non-nucleotide reverse transcriptase inhibitors (NNRTIs) Abacavir
Kivexa (abacavir/lamivudine)
Trizivir (abacavir/lamivudine/zidovudine)
Didanosine (DDI)
Emtricitabine (FTC)
Tenofovir
Truvada (tenofovir/emtricitabine)
Nevirapine
Evavirenz
Etravirine
Rilpivirine
Protease inhibitors Indinavir
Saquinavir
Lopinavir/ritonavir
Fosamprenavir
Atazanavir
Tipranavir
Darunavir
Ritonavir
Entry/fusion inhibitors Enfuvertide
Maraviroc
Integrase inhibitors Raltegravir
Elvitegravir
Dolutegravir
Fixed-dose combinations Atripla (tenofovir/emtricitabine/efavirenz)
Eviplera (tenofovir/emtricitabine/rilpivirine)

Modern treatment regimens typically involve the use of two NRTIs in combination with an NNRTI, a protease inhibitor or an integrase inhibitor (Anon, 2015).




Reverse Transcriptase Inhibitors

NRTIs are nucleoside or nucleotide analogues that inhibit viral reverse transcription by acting as competitive substrates for viral DNA. Reverse transcription of RNA to DNA is unique to retroviridae and therefore reverse transcriptase is a selective target for viral inhibition. Despite their selectivity, a number of side effects exist, including the exacerbation of existing HIV-related peripheral neuropathy (Deeks, Lewin and Havlir, 2013).


NNRTIs inhibit viral replication by direct non-competitive binding to the viral reverse transcriptase. The major limitation to the use of NNRTIs is the rapid development of viral resistance when used as a single agent. Side effects include skin rashes and Stevens-Johnson syndrome. NNRTIs cause cytochrome P450 (CYP3A4) enzyme induction and may decrease levels of sedative drugs such as midazolam and fentanyl (Evron et al., 2004).



Protease Inhibitors

Protease inhibitors block the HIV protease enzyme that is a key step in virus maturation, resulting in dysfunctional, non-infectious viral particles. Viral resistance to protease inhibitors is also a feature, though newer-generation drugs appear to have greater efficacy and lower risk of resistance (Wensing, Van Maarseveen and Nijhuis, 2010). Side effects include gastrointestinal disturbances, hyperglycaemia, hyperlipidaemia, lipodystrophy, elevation of liver enzymes, peripheral neuropathy and obstructive uropathy (Evron et al., 2004). The protease inhibitors cause competitive inhibition of cytochrome P450 (CYP3A4) and therefore may increase levels of sedative drugs, including fentanyl (Olkkola, Palkama and Neuvonen, 1999).



Entry/fusion inhibitors

A relatively new class of antiviral agents includes the entry or fusion inhibitors, which interfere with the binding, fusion or entry of HIV to the host cell. They include agents such as maraviroc that target the CCR5 co-receptor on human T-helper cells and block viral binding (Pugach et al., 2008). Enfuvirtide binds to the gp41 protein of HIV itself and prevents viral entry into cells (Flexner and Saag, 2013).



Integrase inhibitors

The latest class of antiviral drugs approved for the treatment of HIV is the integrase inhibitors. They work by blocking the viral integrase enzyme that facilitates the integration of viral DNA into host DNA. As a group, they appear to have considerable efficacy and tolerability, and are increasingly a key component of HAART (Blanco et al., 2015).



Perioperative Implications


The literature has been inconclusive regarding the mortality risk associated with HIV infection. HIV infection without significant immunodeficiency does not appear to be a significant independent risk factor for poor outcome in patients undergoing major surgery. However, low CD4+ count, presence of AIDS-defining illnesses and opportunistic infections have been associated with worse perioperative outcomes (Horberg et al., 2006). More recently, in a study of more than 1000 patients with HIV/AIDS undergoing surgery, multivariate analysis revealed that in addition to urgent surgery and older age, a CD4+ cell count of <50/mL, anaemia with a haemoglobin level <120g/L and a white blood cell count >11g/L within 90 days before the surgical procedure were strong predictors of increased 30-day post-operative mortality (Wiseman et al., 2012).



Preoperative Assessment and the Impact of Highly Active Antiretroviral Therapy


Patients with HIV infection presenting for surgery may range in their disease severity from asymptomatic to those with advanced symptoms. Preoperative evaluation should follow established perioperative guidelines; however, particular attention should be placed on assessing the severity of HIV infection and the severity of complications related to HAART. While asymptomatic patients present a minimal anaesthetic challenge, patients with advanced disease have multisystem disorders and a cautious approach is necessary. Consultation with the treating physician is a crucial component of the preoperative assessment, and allows for the exchange of important management decisions.


Effective antiretroviral therapy has changed HIV infection from a disease of inevitable early death to a potentially manageable chronic disease. However, combination antiviral therapy is associated with a number of long-term complications that should be recognised during the perioperative period. They can be broadly classified as mitochondrial dysfunction, metabolic abnormalities, bone marrow suppression, allergic reactions and immune recovery syndrome (Hannaman and Ertl, 2013).


HAART is associated with mitochondrial dysfunction that may lead to varying degrees of lactic acidosis, hepatic toxicity, pancreatitis, peripheral neuropathy, cardiomyopathy, myopathy, polymyositis, peripheral neuropathy and lipoatrophy. Metabolic abnormalities include glucose intolerance, insulin resistance, dyslipidaemia, osteopenia and osteoporosis. Importantly, lipodystrophy causes changes to body habitus due to fat maldistribution. There is fat loss from the face, limbs and buttocks, but fat accumulation around the abdomen, breasts and particularly over the posterior cervical spine and upper back, leading to a humpback appearance on occasion. Bone marrow suppression may lead to anaemia or even pancytopenia, while hypersensitivity reactions may lead to rashes and loss of skin integrity to life-threatening Stevens-Johnson syndrome. Immune recovery syndrome, characterised by a marked local and systemic inflammatory response that may result in severe autoimmune disorders, arises as a consequence of rapid and acute increase in CD4+ lymphocytes associated with HAART (Hoffman and Currier, 2007).


Preoperative evaluation should encompass careful cardiovascular assessment, as cardiac dysfunction is a potential complication of HIV infection or treatment with HAART. Myocarditis and cardiomyopathy are associated with acute HIV infection and opportunistic infections, especially in developing countries with limited access to HAART. Coronary artery disease appears to be accelerated in HIV‐infected patients and it is now an important cause of death. A number of factors contribute to this increased risk, including HIV infection itself and the dyslipidaemia associated with HAART (Pham and Torres, 2015). Cardiovascular investigations should proceed according to established guidelines, and preoperative stress testing and echocardiography may be warranted.


HIV infection increases the risk of chronic pulmonary disease due to an increased risk of bacterial pneumonia and opportunistic infection. Chest radiography and pulmonary function testing may be warranted. There is also evidence to suggest that post-operative pulmonary complications are more common in HIV-infected patients (Horberg et al., 2006). Patients with HIV may have hepatic dysfunction due to HAART or co-infection with hepatitis B or hepatitis C. Renal dysfunction is more prevalent in the HIV-infected population and is an important consideration for drug clearance irrespective of impending anaesthesia and surgery.


The risk of impaired glucose tolerance and hyperglycaemia in patients on HAART is increased and is an important consideration during the perioperative period. Unstable glycaemic control should warrant referral to endocrinology specialists.


Routine baseline assessment should include full blood examination, electrolytes and renal function, liver function tests, blood sugar level and clotting profile in patients undergoing major surgery. Assessment of disease severity and recent CD4+ cell count and HIV viral load determination may help define perioperative risk.



Perioperative Management


In consultation with treating specialists, antiretroviral therapy should be continued where possible. If it is necessary to cease oral medications, all antiretroviral drugs should be discontinued to minimise the risk of development of drug resistance. It is important to note that the majority of antiviral agents are only available in oral formulation. In patients co-infected with hepatitis B, the cessation of ART may cause a flare of hepatitis.


There is currently no published literature to guide the choice of anaesthetic technique in patients with HIV. The potential risk for toxicity, side effects or drug interaction must be considered before embarking upon a particular anaesthetic technique or medication used during the perioperative period. Midazolam and fentanyl are relatively contra-indicated due to the variable effects on hepatic metabolism by ARTs. Though HIV patients may suffer from myopathy and neuropathy, there is little evidence to suggest suxamethonium is a contra-indication, and there have been no reports of hyperkalaemia associated with its use in these patients (Evron et al., 2004). There is a theoretical risk of lactic acidosis related to the use of propofol infusion and mitochondrial toxicity; however, this has not been borne out in the anaesthetic literature (Leelanukrom, 2009).


Regional anaesthesia may offer the avoidance of significant drug interactions, but significant concerns remain regarding the safety of neuroaxial blockade in patients with HIV-associated neuromuscular disease. However, a number of studies have demonstrated the safety of neuroaxial anaesthesia in HIV-infected patients (Avidan et al., 2002; Kuczkowski, 2003). Furthermore, epidural blood patch also appears to be safe in the obstetric population (Tom et al., 1992).


The immunomodulation that occurs during the perioperative period as a result of anaesthesia, surgery and the stress response is a concern for the HIV-infected individual. While there is some evidence that perioperative immunomodulation may increase the risk of cancer recurrence (Kurosawa and Kato, 2008), and the immunosuppressive effects of blood transfusion have been shown to increase viral load (Mudido et al., 1996), it remains unclear whether surgery and anaesthesia is an independent risk factor for adverse outcome in HIV-infected patients.



Organ Transplantation


Immunosuppression is essential for successful solid organ transplantation and can be achieved by depleting lymphocytes, diverting lymphocyte traffic or blocking lymphocyte response pathways. Immunosuppressive drugs have three effects: the therapeutic effect (suppressing rejection), undesired consequences of immunodeficiency (infection or cancer) and non-immune toxicity to other tissues. Immunodeficiency leads to characteristic infections and cancers, such as post-transplantation lymphoproliferative disease (Halloran, 2004).


Though subtle differences exist in approach, the aims of immunosuppression are the same in thoracic, hepatic or renal transplantation. The overarching aim is to produce sufficient suppression of the immune system to prevent rejection of the transplanted organ while limiting toxicity. In general, combinations of immunosuppressive agents are used to reduce the side effects of each individual agent (Halloran, 2004). This section will have a predominant bias towards the perioperative care of the patient with a history of heart or lung transplant; however, the principles of management in reality apply to the majority of transplant recipients



Immunosuppressive Drugs


Immunosuppressive drugs can be classified into small-molecule agents, depleting and non-depleting antibodies (polyclonal and monoclonal antibodies), intravenous immune globulin and glucocorticoids. Small-molecule immunosuppressive drugs include the calcineurin inhibitors (cyclosporine and tacrolimus), the mTOR (mammalian Target of Rapamycin) inhibitors (sirolimus and everolimus) and the inhibitors of DNA synthesis. Most small-molecule immunosuppressive agents are derived from microbial products and target proteins involved in intracellular immune pathways. Depleting immunosuppressive agents are antibodies that destroy T-cells, B-cells or both. This class includes polyclonal antibodies (horse or rabbit anti-thymocyte globulin), mouse monoclonal, humanised monoclonal antibodies against CD52 (alemtuzumab) and B-cell-depleting monoclonal antibody against CD20 (rituximab). T-cell depletion is often accompanied by the release of cytokines, which produces severe systemic symptoms, especially after the first dose. The use of depleting antibodies reduces early rejection but increases the risks of infection and post-transplantation lymphoproliferative disease and can be followed by late rejection as the immune system recovers. The depletion of antibody-producing B-cells is better tolerated than T-cell depletion, because it is not usually accompanied by cytokine release and immunoglobulin levels are usually maintained. Non-depleting are drugs such as humanised (daclizumab) or chimeric (basiliximab) monoclonal anti-CD25 antibody that reduce responsiveness without compromising lymphocyte populations. They have limited efficacy but are well tolerated without immunodeficiency complications. Furthermore, these drugs have low non-immune toxicity because they target proteins that are expressed only in immune cells and trigger little release of cytokines.



Calcineurin Inhibitors

Calcineurin catalyses important intracellular processes associated with the activation of T-cells. Calcineurin inhibitors bind to intracellular proteins called immunophilins, and the resultant complexes block the effect of calcineurin, decreasing the production of IL2 and therefore blocking the proliferation of T-cells. Nephrotoxicity is the major non-immune toxicity of calcineurin inhibitors and major limiting factor in their use (Table 13.5).




Table 13.5 Calcineurin inhibitors.



































Drug Description Mechanism Typical uses Side effects and comments
Cyclosporine 11-amino-acid cyclic peptide from Binds to cyclophilin; complex inhibits calcineurin phosphatase and T-cell activation Maintenance, especially for renal, hepatic, pulmonary and cardiac Nephrotoxicity, haemolytic-uremic syndrome, hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-transplantation diabetes mellitus, hyperlipidaemia.
Tolypocladium inflatum Trough monitoring or checking levels 2 hours after administration required
Tacrolimus Macrolide antibiotic from Binds to FKBP12; complex inhibits calcineurin phosphatase and T-cell activation Maintenance, especially for renal, hepatic, pulmonary and cardiac Effects similar to those of cyclosporine but with a lower incidence of hypertension, hyperlipidaemia, skin changes, hirsutism and gum hyperplasia and a higher incidence of post-transplantation diabetes mellitus and neurotoxicity; trough monitoring required
Streptomyces
tsukubaensis


Cyclosporine

Since the early 1980s, cyclosporine has been the primary immunosuppressant used in transplantation. It binds with cyclophilin to inhibit calcineurin. Cyclosporin has a narrow therapeutic range with large inter- and intra-subject pharmacokinetic variability. Cyclosporine is a substrate for cytochrome P450 (CYP3A4) and therefore is subject to a number of drug interactions. Concentration-related adverse effects include nephrotoxicity, hypertension, gingival hyperplasia, hirsutism, tremor and hyperlipidaemia. Haemolytic uremic syndrome and post-transplantation diabetes mellitus may also occur.



Tacrolimus

Tacrolimus is a macrolide antibiotic but is also a calcineurin inhibitor. It is more potent than cyclosporin and binds to a different immunophilin (FK-binding protein) to inhibit calcineurin. Adverse effects in common with cyclosporine include hypertension, nephrotoxicity and haemolytic uremic syndrome. Tacrolimus is less likely to cause hyperlipidaemia, hirsutism and gingival hypertrophy, but diabetes is more commonly associated. As with cyclosporine, tacrolimus is also a substrate of CYP3A4 and subject to the same interactions.



Mammalian Target of Rapamycin Inhibitors

Sirolimus (rapamycin) and everolimus are structurally very similar and have the same mechanism of action. Like tacrolimus, they bind to FK-binding protein, but they have no effect on calcineurin. Instead, the complex inhibits a protein kinase (mammalian target of rapamycin or mTOR) that is critical for cell cycle progression. Inhibition of mTOR suppresses cytokine-driven T-cell proliferation and activation, resulting in immunosuppression (Table 13.6).




Table 13.6 Mammalian target of rapamycin inhibitors.



































Drug Description Mechanism Typical uses Side effects and comments
Sirolimus (Rapamycin) Triene macrolide antibiotic Binds to FKBP12; complex inhibits target of rapamycin and IL2-driven T-cell proliferation Maintenance, especially for renal, hepatic, pulmonary and cardiac Hyperlipidaemia, increased toxicity of calcineurin inhibitors, thrombocytopenia, delayed wound healing, delayed graft function, mouth ulcers, pneumonitis, interstitial lung disease; lipid monitoring required; recipients whose risk of rejection is low to moderate can stop cyclosporine treatment 2 to 4 months after transplantation
From S. hygroscopicus from Easter May allow avoidance of calcineurin inhibitors
Island (Rapa Nui)
Everolimus Derivative of sirolimus Maintenance, especially for renal, hepatic, pulmonary and cardiac
May allow avoidance of calcineurin inhibitors


Legend: IL=interleukin


The main difference between sirolimus and everolimus is that the half-life of sirolimus (60 hours) is approximately double that of everolimus (30 hours). Both drugs are also substrates for cytochrome P450 3A4, and monitoring is required due to its narrow therapeutic window, large inter-individual variations in pharmacokinetics and the potential for drug-drug interactions and therefore toxicity.



Antimetabolites


Azathioprine

Azathioprine was the first widely used immunosuppressant. Although its use in transplantation has declined, azathioprine is still widely used as an immunosuppressant or corticosteroid-sparing drug in immune disorders. It is a prodrug which is converted to 6-mercaptopurine and metabolised to cytotoxic thioguanine nucleotides which cause immunosuppression via inhibition of DNA synthesis. Both cell-mediated and antibody-mediated immune reactions are depressed. The main toxicities are bone marrow suppression (particularly agranulocytosis) and hepatotoxicity. For further details and a summary of the side effects of Azathioprine and Mycophenolate please refer to Table 13.7.



Mycophenolate

Mycophenolate is the prodrug of mycophenolic acid, which inhibits purine synthesis by inhibiting inosine monophosphate dehydrogenase, preventing the proliferation of T- and B-cells. Mycophenolic acid is highly protein bound and it is the unbound or free mycophenolic acid that is pharmacologically active.




Table 13.7 Anti-proliferative agents/anti-metabolites.






























Drug Description Mechanism Typical uses Side effects and comments
Mycophenolate mofetil Mycophenolic acid from penicillium moulds Inhibits synthesis of guanosine monophosphate nucleotides; blocks purine synthesis, preventing proliferation of T- and B-cells Maintenance Gastrointestinal symptoms (mainly diarrhoea), neutropenia, mild anaemia; blood-level monitoring not required but may improve efficacy; absorption reduced by cyclosporine
Azathioprine Prodrug that releases 6-mercaptopurine 6-mercaptopurine converted to thioguanine nucleotides that interfere with DNA synthesis Maintenance Leukopenia, bone marrow depression, macrocytosis, liver toxicity (uncommon); blood-count monitoring required
Use with xanthine oxidase inhibitor such as allopurinol may result in severe myelotoxicity


Legend: DNA= deoxyribonucleic acid



Immunosuppressant Antibodies


Anti-thymocyte globulin

Anti-thymocyte globulin (ATG) is a polyclonal IgG antibody from horses or rabbits immunised with human thymocytes. Infusions of anti-thymocyte globulin cause profound T-cell depletion and the lymphopenia typically persists beyond 1 year. Cell lysis results in the release of cytokines and may lead to ‘cytokine release syndrome’ characterised by fever, rigours and hypotension.



Antibodies against CD25

Basiliximab and daclizumab are monoclonal antibodies against CD25 on the surface of T-lymphocytes. The antibodies bind to and block the IL2 receptor α-chain (CD25 antigen) on activated T-cells, resulting in the inhibition of IL2-induced T-cell activation. These antibodies appear to be relatively well tolerated and hypersensitivity reactions are uncommon. No monitoring is required.



Muromonab-CD3

Muromonab-CD3 is a mouse-derived monoclonal antibody that binds to the CD3 component of the T-cell receptor complex leading to T-cell depletion. Muromonab is also associated with cytokine release syndrome. Neutralising antibodies can develop which block the effect and limit the reuse of muromonab-CD3. A longer-term concern is the increased incidence of lymphoma. Muromonab-CD3 and other commonly used immunosuppressant antibodies are compared in Table 13.8.




Table 13.8 Immunosuppressant antibodies.
































































Drug Description Mechanism Typical uses Side effects and comments
Polyclonal antithymocyte globulin Polyclonal IgG from horses or rabbits immunised with human thymocytes Blocks T-cell membrane proteins causing altered function, lysis and prolonged T-cell depletion Induction Cytokine release syndrome (fever, chills, hypotension), thrombocytopenia, leukopenia, serum sickness
Acute rejection
Muromonab-CD3 Murine monoclonal antibody against CD3 component of T-cell–receptor signal-transduction complex Binds to CD3 associated with T-cell receptor, leading to initial activation and cytokine release, followed by blockade of function, lysis and T-cell depletion Induction Severe cytokine release syndrome, pulmonary oedema, acute renal failure, gastrointestinal disturbances, changes in central nervous system
Acute rejection
Alemtuzumab Humanised monoclonal antibody against CD52 Binds to CD52 on all B- and T-cells, most monocytes, macrophages and natural killer cells, causing cell lysis and prolonged depletion Induction Mild cytokine release syndrome, neutropenia, anaemia, pancytopenia, autoimmune thrombocytopenia, thyroid disease
Acute rejection
Rituximab Chimeric monoclonal antibody against membrane-spanning four-domain protein CD20 Binds to CD20 on B cells and mediates B-cell lysis Induction Infusion reactions, hypersensitivity reactions (uncommon)
Acute rejection
Basiliximab Chimeric monoclonal antibody against CD25 (IL2–receptor α chain) Binds to and blocks the IL2–receptor α chain (CD25 antigen) on activated T cells, depleting them and inhibiting IL2–induced T-cell activation Induction Hypersensitivity reactions (uncommon); no monitoring required
Acute rejection
Daclizumab Humanised monoclonal antibody against CD25 (IL2–receptor α chain) Similar to that of basiliximab Induction Hypersensitivity reactions (uncommon); no monitoring required. No longer available
Acute rejection


Legend: Ig=immunoglobulin, IL=interleukin



Glucocorticoids

Corticosteroids have been in clinical use for almost 80 years and have remained a cornerstone of immunosuppression in solid organ transplantation since its inception. Steroids exert a variety of anti-inflammatory and immunosuppressive effects (Table 13.9).




Table 13.9 Glucocorticoids.


































Drugs Mechanism Typical uses Side effects and comments
Prednisolone Multiple, broad effects on cellular immunity: Maintenance for most organs Hyperglycaemia
Methylprednisolone Decreased pro-inflammatory cytokines (e.g. IL1, IL6) High-dose pulses for acute rejection Increased infections
Hydrocortisone IL2 inhibition with depressed T-cell proliferation Hypertension Osteopenia
Decreased neutrophil chemotaxis and lysozyme release Cataracts


Legend: IL=interleukin


Cytosolic corticosteroid receptors are expressed ubiquitously, and their translocation to the nucleus results in the interruption of multiple steps in the presentation of antigen, the production of cytokines and the initiation of a proliferative response. Steroids also reduce the production of prostaglandins and other inflammatory mediators, which otherwise would enhance the recruitment of immune effector cells to the graft and upregulate the expression of alloantigen (Allan, 2004). Nearly all heart or lung transplant recipients are maintained on some level of steroid therapy. However, concomitant use of agents such as azathioprine can have a steroid-sparing effect.



Immunosuppressive Regimes in Transplantation


Immunosuppression can be divided into induction and maintenance therapies. Induction therapy is intensive immunosuppressant therapy given perioperatively to reduce the risk of acute rejection, but also serves to delay initiation of maintenance immunosuppression and to avoid the nephrotoxity associated with calcineurin inhibitors. These agents primarily target T lymphocytes, which are considered the effector cells in cell-mediated rejection (Scheffert and Raza, 2014; Söderlund and Rådegran, 2015). Maintenance immunosuppression is lifelong immunosuppressive therapy that is given to prevent both acute and chronic rejection. The goal is not only to prevent and minimise immune-mediated injury to the allograft, but also to minimise adverse effects associated with the medications used (Halloran, 2004).


Induction and maintenance immunosuppression in solid organ transplantation is very similar worldwide. According to the most recent registry report of the International Society for Heart and Lung Transplantation (ISHLT), approximately 50 per cent of the centres utilise induction, with the majority using non-depleting antibody immunosuppressants such as basilixmab. ATG is the second most commonly used induction agent (Lund et al., 2014; Yusen et al., 2014).


Conventional maintenance immunosuppressive regimens consist of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), an anti-proliferative agent (azathioprine, mycophenolate, sirolimus or everolimus) and a corticosteroid. Historically cyclosporine and azathioprine were used along with prednisone, but over time additional agents have emerged on the market, including tacrolimus, mycophenolate and the mTOR inhibitors sirolimus and everolimus allowing manipulation of regimes to reduce immune and non-immune toxicity (Scheffert and Raza, 2014; Söderlund and Rådegran, 2015). The choice of immunosuppressant and regime in the treatment of acute rejection and chronic allograft dysfunction is certainly beyond the scope of this chapter, but is summarised by Scheffert and Raza in lung transplantation (Scheffert and Raza, 2014) and Söderlund and Rådegran in heart transplantation (Söderlund and Rådegran, 2015).



Immune and Non-immune Complications of Immunosuppression


The long-term immune and non-immune toxicity associated with immunosuppression should be considered and complications identified. Complications may arise from under- or over-immunosuppression and from non-immune-related complications. Direct consequences of long-term immunosuppression include bone marrow suppression, increased risk of infections and lympho-proliferative disorders. Rejection of donor organs is usually a consequence of under-immunosuppression. Rejection can be acute or chronic in nature and contribute to allograft dysfunction. In heart transplantation, a type of chronic rejection called cardiac allograft vasculopathy is particularly clinically important and leads to a characteristic diffuse and concentric narrowing of the coronary arteries, giving rise to the symptoms of angina and even myocardial infarction (Söderlund and Rådegran, 2015). Though it may be difficult at times to differentiate immune from non-immune consequences of immunosuppression, non-immune complications include (Feltracco et al., 2011):




a. Post-transplant Diabetes

Immunosuppression with steroids and/or calcineurin inhibitors is associated with an increased incidence of diabetes and metabolic complications.



b. Arterial Hypertension

Corticosteroids and calcineurin inhibitors have pressor effects. The cardioprotective and nephroprotective angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are usually recommended to control blood pressure in transplant recipients.



c. Renal Insufficiency

Elevation of serum creatinine and urea values, as well as reduction of glomerular filtration rate and creatinine clearance, are almost always seen during long-term treatment with calcineurin inhibitors.



d. Steroid-Induced Osteoporosis

Rapid bone loss is common in all transplants and it markedly increases the risk of fracture. Avascular bone necrosis may affect any joint or bone, but it is particularly evident in the lumbar spine, ribs and femoral head.



e. Post-transplant Adrenal Suppression

Chronically suppressed adrenal glands may be incapable of mounting an adequate response to stress. Relative adrenal insufficiency must be considered in patients with symptoms such as hypotension and/or hyponatremia. Other symptoms of chronic adrenal insufficiency include fatigue, weakness, listlessness, orthostatic dizziness, weight loss, anorexia, abdominal cramping, nausea, vomiting and diarrhoea.



Perioperative Considerations in Transplant Recipients


The healthcare needs of patients after solid organ transplantation may be great. Transplant recipients may present for non-transplant-related surgery, sometimes many years after their transplant. Increased survival transplantation means that recipients may have indeed moved away from their transplant centre and it is necessary for non-transplant specialists to care for these patients when they present with new health problems. In fact, it has been reported that up to 40 per cent of heart transplant recipients will need non-cardiac surgery after their transplant (Marzoa et al., 2007).


The perioperative management of transplant recipients has been described in detail by a number of authors (Blasco, Parameshwar and Vuylsteke, 2009; Diaz and O’Connor, 2011; Feltracco et al., 2011; Kostopanagiotou et al., 1999; Kostopanagiotou et al., 2003; Valentine et al., 2013). However, it is important to note that despite significant experience in the care of these complicated patients, the anaesthetic and perioperative community has not published widely on this topic during recent times. The priorities of perioperative management are summarised in what follows.



Preoperative Evaluation and Management


It is vitally important to consult with the transplant team. Transplant physicians monitor their patients carefully and should be contacted whenever possible to seek information on the patient’s overall status. Importantly, the CMV status of the patient should be sought and the blood bank informed if there is significant potential for blood loss.


Preoperative assessment of transplant recipients does not differ greatly from what is required for the general population. It should include a thorough evaluation of allograft function, particularly if the surgery is to involve the allograft itself. Depending on the underlying diagnosis and indication for transplantation, it is important to remember that there may be systemic disease that is not treated by transplantation. Significant co-morbidities may coexist.


History should focus on the patient’s functional state and stability of symptoms, while clinical examination should target evidence of decompensation. Cardiovascular disease has emerged as a leading cause of mortality after solid organ transplantation, especially in those with chronic kidney disease or previous heart transplantation (Halloran, 2004; Hammel, Sebranek and Hevesi, 2010; Valentine et al., 2013). Heart transplant recipients should be investigated according to AHA/ACC published guidelines for patients with heart failure (Yancy et al., 2013) or guidelines published by the ISHLT (Costanzo et al., 2010). Recent echocardiography demonstrating ventricular function should be sought in patients with symptomatic heart failure. In the case of cardiac transplantation, cardiac biopsy results may help define the degree of rejection. Longer-term survivors may have had coronary angiography to delineate the degree of cardiac allograft vasculopathy. Though the predictive value of biomarkers in this population like BNP remains unclear, the trend in BNP values may help guide therapy and identify those patients who may need further optimisation (Shaw and Williams, 2006). Allograft function in lung transplant recipients formally assessed by serial spirometry may be helpful, though recent infective exacerbations with hospital admission may be the best indicator of decreasing pulmonary function. Laboratory tests should include measures of renal function, liver function, coagulation profile and a full blood examination to ensure the absence of bone marrow suppression. A preoperative ECG should be routinely performed where two p-waves may be seen in heart transplant recipients who have remnant left atrium. Furthermore, up to 5 per cent of heart transplant recipients will require internal pacemakers, which will require perioperative consideration (Blasco et al., 2009).


In addition to immunosuppressive therapy, these transplant recipients are likely to be receiving antiviral and antibacterial prophylaxis, anti-hypertensive agents, anti-failure therapy, insulin and oral hypoglycaemic agents and proton pump inhibitors. It is imperative that preoperative therapy be continued up to the day of surgery and resumed as soon as possible after surgery. Potential drug interactions with immunosuppressants must be considered (Table 13.10).


Sep 15, 2020 | Posted by in ANESTHESIA | Comments Off on Chapter 13 – Immunocompromised Patients
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