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Drug-induced depression of immunity in the critically ill 

Drug-induced depression of immunity in the critically ill
Drug-induced depression of immunity in the critically ill

Russell J. McCulloh

and Steven M. Opal

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date: 01 December 2020

Key points

  • Glucocorticoids are the most commonly-used immunosuppressive drugs today and affect gene transcription, leukocyte distribution, and clearance of microbial pathogens.

  • Calcineurin and MTOR inhibitors are commonly used in autoimmune diseases and organ transplantation, but require close monitoring for drug-related toxicities and interaction with other medications metabolized by the liver.

  • Cytotoxic and antimetabolite medications used in the treatment of various cancers can be associated with bone marrow suppression and pancytopenia.

  • Newer biological agents such as monoclonal antibodies target specific immunomodulatory chemokines or chemokine receptors which can result in profound immunosuppression, particularly of cell-mediated immunity.

  • Clinicians should use data on infectious complications commonly associated with specific immunosuppressive drugs to help guide their evaluation of immunosuppressed patients suspected to have an opportunistic infection.


The use of immunosuppressive drugs is now commonplace in multiple disciplines of medicine and surgery from organ transplantation, neurosurgery, neoplastic diseases, autoimmune diseases and an array of inflammatory diseases affecting many organ systems. These agents have greatly benefitted patients, but come at the price of induction of specific and at times generalized immunosuppression with all the associated risk of infections and even some neoplasms with long-term use of these agents [1]. This chapter will summarize the major categories of immunosuppressive agents now in common use to which critical care specialists need to maintain a working familiarity with their indications, major risks, and side effects. The list of biological agents and monoclonal antibody therapies entering clinical usage is rapidly expanding to fulfil the need for new therapeutic indications and safer immunomodulation than existing agents. We will discuss corticosteroids, transplant regimens and common agents used for neoplastic diseases and inflammatory disorders, and provide a summary of the newer biological agents entering clinical practice.

Glucocorticoids remain the mainstay for anti-inflammatory therapy needs and have proven their worth over the past 75 years of clinical use. The mechanisms of action that account for their anti-inflammatory effects are complex, but increasingly well understood as summarized in Fig. 290.1 [2]. Glucocorticoids are lipid soluble and freely diffuse across cell membranes where they bind to their specific receptors. Glucocorticoid receptors disassociate from Heat Shock Protein 90 when glucocorticoids enter the cell; they dimerize and translocate to the nucleus and markedly alter cellular and transcriptional activity of the cell. Anti-inflammatory genes are upregulated as they have GRE (Glucocorticoid response element) sequences near promoter sites. A prominent effect of steroids is upregulation of Iκ‎B-α‎, a potent inhibitor of the capacity of NFκ‎B to translocate across the nuclear membrane and activate pro-inflammatory genes. Another major impact of glucocorticoids is their capacity to block transcription of inflammatory gene programs at the level of the essential co-activator complex of the transcriptional machinery of the cell. Steroids also block the actions of other transcriptional activators including a number of mitogen activated protein kinases and activator protein 1. Stability of mRNA is impaired by glucocorticoids limiting the translation of mRNA into protein products such as pro-inflammatory cytokines, chemokines, and enzymes that generate prostaglandins and other inflammatory mediators.

Fig. 290.1 Molecular mechanisms of glucocorticoid anti-inflammatory actions. Glucocorticoids have multiple ant-inflammatory actions including: (1) binding to glucocorticoid response elements at promoter sites for upregulation of anti-inflammatory gene transcription; (2) upregulation of I kappa B levels that block NFκ‎B (nuclear factor from kappa B cell) nuclear translocation; (3) inhibition of AP-1 (activator protein 1) and 4) inhibition of NFκ‎B activation of pro-inflammatory gene transcription by blocking coactivators of transcription; (5) inhibition of MAPK (mitogen activated protein kinase) activated transcriptional factors; (6) activation of MAPK phosphatase-1 that degrades MAPKs and induces mRNA instability with reduced translation of pro-inflammatory mediators and enzymes.

Fig. 290.1 Molecular mechanisms of glucocorticoid anti-inflammatory actions. Glucocorticoids have multiple ant-inflammatory actions including: (1) binding to glucocorticoid response elements at promoter sites for upregulation of anti-inflammatory gene transcription; (2) upregulation of I kappa B levels that block NFκ‎B (nuclear factor from kappa B cell) nuclear translocation; (3) inhibition of AP-1 (activator protein 1) and 4) inhibition of NFκ‎B activation of pro-inflammatory gene transcription by blocking coactivators of transcription; (5) inhibition of MAPK (mitogen activated protein kinase) activated transcriptional factors; (6) activation of MAPK phosphatase-1 that degrades MAPKs and induces mRNA instability with reduced translation of pro-inflammatory mediators and enzymes.

HSP, heat shock protein; GR, glucocorticoid receptor; COX2, cyclooxygenase 2; JNK, janus N terminal kinase; ERK, extracellular receptor activated kinase; GRE, glucocorticoid response element; RNA pol, RNA polymerase; MKK, MAPK kinases; Iκ‎K, inhibitor kappa B kinase; TAK, transforming factor beta associated kinase; TAB, TAK binding protein; TRAF6, TNF receptor associated factor 6; IRAK, interleukin-1 receptor associated kinase; MyD88, myeloid differentiation 88; Mal, Myd88 adaptor like; LPS, lipopolysaccharide; TLR4, Toll-like receptor.

Reproduced from Drugs, 66(1), 2006, pp. 15–29, 'Role of Toll-like receptors in infection and immunity: Clinical implications', Cristofaro P and Opal SM. With kind permission from Springer Science and Business Media.

Clinical experience has clearly delineated the importance of escalating doses of glucocorticoids and most importantly the duration of steroid use as major determinants of the risk of infectious and metabolic complications of glucocorticoids. High doses of these immunosuppressive agents are remarkably well tolerated for the first 14–21 days of therapy before major complications associated with their use become clinically manifest [3]. Similarly, the administration of low doses of glucocorticoids (<10 mg prednisone or equivalent agents) are tolerated with minimal to no excess infection risk for years of therapy. Numerous functional consequences affecting the cellular constituents of both the innate and adaptive immune systems occur and account for the increase risk of infection from steroids. Neutrophilia with initial use is commonplace as a consequence of decreased egress out of the circulation and increased release from bone marrow stores. Conversely T lymphocytes, NK cells, and eosinophils redistribute to extravascular sites with glucocorticoid use. Of greater functional consequence is steroid-induced reduction in surface expression of Fc receptors, complement receptors (CR3 receptor) and reduced expression of class II molecules and co-stimulatory signals by macrophages, eosinophils, and monocytes. Chemotaxis of monocytes and intracellular killing and cytokine and chemokine signalling are all reduced by corticosteroids resulting in poor microbial clearance and excess infection risk.

Lymphocyte populations, particularly T-cells (both CD4 and CD8 cells) are also affected with reduced proliferative capacity and cytokine generation after exposure to steroids with 2 weeks of starting these drugs. Reduced IL-2 generation associated with steroid use primarily accounts for impaired proliferative capacity of T-cells to respond to intracellular pathogens. B cell and plasma cell populations are only mildly affected by high dose steroids and antibody synthesis is well preserved to recall antigens. NK cell function is well preserved even after long term exposure to glucocorticoids. It should be remembered that therapeutic doses of steroids impair fever generation by the upregulation of lipocortins that block phospholipase A2. Blockade of fever occurs from reduced arachidonic acid synthesis and thereby loss of prostaglandin E2 alpha levels in the hypothalamic thermoregulatory centre of the brain. Steroid-induced blockade of fever generation not only removes this cardinal sign of inflammation from the clinician’s attention, it also likely impairs the capacity to clear pathogens.

An array of well-known opportunistic pathogens and a host of routine pathogens remain a constant concern with the long- term use of glucocorticoids [3,4,5]. Isoniazid preventive therapy is indicated in steroid-treated patients with evidence of latent tuberculosis. Special concern should be paid to opportunistic fungi and endemic mycoses in specific geographic regions where coccidioidomyocosis and histoplasmosis are prevalent in the environment. The hyperinfection syndrome with strongyloidasis is a real risk in steroid treated patients and should be screened for in endemic regions of the world.

Immunosuppressive agents used in oncology and transplant medication

Calcineurin inhibitors and MTOR inhibitors


Cyclosporine (cyclosporin A, CSA) is used for immunosuppression in a variety of circumstances, including human organ transplantation, treating graft-versus-host disease (GVHD) after haematopoietic stem cell transplantation (HSCT) [13], and in the treatment of autoimmune disorders including rheumatoid arthritis, psoriasis, and uveitis [16]. It is a peptide antibiotic that blocks activation of T-cells during antigen receptor-mediated induction of differentiation by binding to cyclophilin, an intracellular protein belonging to the immunophilin protein class. Together with cyclophilin, cyclosporin forms a complex that inhibits calcineurin, a cytoplasmic phosphatase crucial to activating NF-AT. This transcription factor is necessary for synthesis of several interleukins, including IL-2, IL-3, and IFN-gamma, by activated T-cells. Of note, cyclosporin does not block the effects of these cytokines on primed T-cells or interaction with antigen. Cyclosporin is metabolized by the CYP450 3A enzyme, which means it has multiple drug-drug interactions and requires monitoring of drug levels. Toxicities can include nephrotoxicity, hypertension, hyperglycaemia, liver dysfunction, hyperkalaemia, mental status chances, and seizures.


Tacrolimus (FK 506) is a macrolide antibiotic produced by Streptomyces tsukubaensis. It suppresses T-cell transcription of NF-AT by binding to the immunophilin FK-binding protein (FKBP). Its immunosuppressive activity is similar to cyclosporin but 10-100 times greater on a per-weight basis. It has been used in a similar array of conditions, including solid-organ transplant, HSCT, and treatment or prevention of GVHD. It is used topically to treat various dermatological conditions including atopic dermatitis and psoriasis. Tacrolimus is metabolized via the CYP450 pathway with similar drug interaction concerns as cyclosporin. Trough levels should be monitored in patients. Toxicities are also similar to cyclosporin, including nephrotoxicity, neurotoxicity, hyperglycaemia, hypertension, and hyperkalaemia, although gastrointestinal effects may be more common [16].


Sirolimus (rapamycin) is the prototype immunosuppressive macrolide antibiotic that inhibits the kinase activity of mammalian target of rapamycin (mTOR). Other ‘rapalogs’ in this group include everolimus and temsirolimus. Inhibition of the mTOR pathway has pleiotropic effects on various cellular processes including angiogenesis, metabolism, and cellular proliferation such as interleukin-mediated T-cell activation and proliferation. Sirolimus and the other rapalogs have potential applications in both targeted oncologic therapies as well as immunosuppression. Currently sirolimus is used in preventing solid organ allograft rejection, prevention, and treatment of GVHD, as well as in topical preparations for dermatological disorders. Sirolimus is metabolized by CYP450 3A and P-glycoprotein, with similar concerns for drug-drug interactions as the calcineurin inhibitors. Its half-life is 60 hours, resulting in prolonged toxicity even after drug cessation. Unlike cyclosporin and tacrolimus, sirolimus has no significant nephrotoxicity. However, use of the mTOR inhibitors has been associated with myelosuppression, thrombocytopenia, hepatic dysfunction, diarrhoea, headache, elevated serum triglycerides, and pneumonitis. Additionally, when combined with tacolimus for treatment of HSCT-related GVHD, sirolimus has been associated with increased incidence of haemolytic-uremic syndrome.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) inhibits several T- and B-lymphocyte actions, including mitogen and mixed lymphocyte responses, most likely via inhibition of purine synthesis. A semisynthetic derivative of mycophenolic acid, MMF can be given orally or intravenously. Unlike sirolimus and the calcineurin inhibitors, MMF is not metabolized via the CYP450 3A system. Mycophenolate mofetil is used in combination with prednisone as an alternative to cyclosporin or tacrolimus in patients intolerant to these medications. It also is used in refractory solid organ transplant rejection and GVHD [4]. Outside of transplant medicine, MMF is used to treat lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, and severe atopic dermatitis. Common side effects include headache, hypertension, gastrointestinal disturbances, and reversible myelosuppression.

Thalidomide and derivatives


Historically known as a sedative drug withdrawn from the market due to its severe teratogenic effects when used in pregnant women, thalidomide is being tested and/or used in a wide array of clinical applications due to its anti-inflammatory, immunomodulatory, and anti-angiogenic effects. It inhibits tumour necrosis factor alpha (TNF-α‎), decreases neutrophil phagocytic activity, increases IL-10 production, alters adhesion molecule function, and enhances cell-mediated immunity through interaction with T-cells. Current approved applications include treatment of multiple myeloma, erythema nodosum leprosum, and dermatological disease due to systemic lupus erythematosis (SLE). It is under study for use in various oncologic conditions, myelodysplastic syndrome, and GVHD. Besides its teratogenic effects, thalidomide can cause peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk for deep venous thrombosis. Currently thalidomide may only be prescribed under close supervision from the manufacturer. The severe side effect profile has prompted the development and study of alternative agents known as immunomodulatory derivatives of thalidomide or IMiDs.


The first IMiD approved for treating patients with myelodysplastic syndrome and multiple myeloma, lenalidomide has fewer side effects than thalidomide, although concomitant use of anticoagulant therapy, close monitoring of renal function, and monitoring for neutropenia and thrombocytopenia remain important [17].

Cytotoxic agents and antimetabolites


Azathioprine is a prototypic immunosuppressive antimetabolite. It is a prodrug of mercaptopurine that is well-absorbed from the GI tract. Azathioprine is cleaved by xanthine oxidase to 6-thiouric acid, and care must be taken to reduce the dose to one-quarter to one-third the usual amount to avoid toxicity. Its mechanism of action is through interference with purine nucleic acid metabolism resulting in destruction of stimulated lymphoid cells, causing cell-mediated and humoral immune suppression. Azathioprine and mercaptopurine are used in renal allograft maintenance, lupus nephritis, Crohn’s disease, rheumatoid arthritis, multiple sclerosis, and steroid-resistant idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemias. Azathioprine’s primary toxicity is bone marrow suppression, but can also include rash, nausea, vomiting, diarrhoea, and hepatic dysfunction, particularly at higher doses.


Cyclophosphamide is an alkylating agent that is highly toxic to proliferating lymphoid cells and has some effect against resting cells. High doses may induce tolerance to a new antigen if the drug is administered with or immediately after the antigen, which can help improve rates of successful engraftment after HSCT. It is also used to prevent or treat GVHD. In addition to its use in oncology, it is used in modest doses for systemic lupus erythematosis, antibody-mediated factor XIII deficiency, pure red cell aplasia, and Wegener’s granulomatosis. Side effects include haemorrhagic cystitis, pancytopenia, nausea, vomiting, cardiac toxicity, and electrolyte abnormalities.


Leflunomide is an orally-active prodrug of a pyrimidine synthesis inhibitor. It has a half-life of several weeks, and is currently used for treatment of rheumatoid arthritis. Owing to its relative lack of cytochrome interactions and antiviral activity against cytomegalovirus, leflunomide is being studied in a wide array of transplant-associated and rheumatologic conditions [19]. Associated toxicities include hepatic dysfunction or damage, nephrotoxicity, and teratogenicity. Patients have also experienced angina and tachycardia while taking leflunomide.


An antimalarial agent that also possesses immunosuppressive activity, hydroxychloroquine suppresses antigen processing and loading onto MHC class II molecules, leading to decreased T-cell activation. This is thought to occur through increasing the pH in lysosomes and endosomes. Hydroxychloroquine is used in rheumatoid arthritis and SLE as well as the management and prevention of GVHD. Longitudinal monitoring for retinopathy and permanent visual impairment is necessary in patients on long-term therapy.


An inhibitor of dihydrofolate reductase, methotrexate is used both in chemotherapy and in the treatment of various malignancies as well as in rheumatoid arthritis and psoriasis [20]. It is a substrate of P-glycoprotein and has multiple drug-drug interactions. Additionally, methotrexate has multiple potential toxicities, including stomatitis, myelosuppression, skin rash, and short-term or long-term central nervous system effects (headache, vomiting, encephalopathy, among others).

Alkylating agents and platinum coordination complexes

These agents, which include nitrogen mustards, ethyleneimines, alkyl sulfonates, nitrosureas, triazenes, and DNA-methylating drugs, are primarily used in the treatment of neoplastic diseases. Their mechanisms of action all involve the alkylation of reactive amines, oxygens, or phosphates on DNA, resulting in cytotoxic effects. They are most effective in rapidly-proliferating tissues, which accounts in part for their immunosuppressive effects. This can result in suppression of all bone marrow-derived cell lines. For some agents, their effects can also be seen on resting-phase immune cells such as mature lymphocytes.

Other immunosuppressive drugs

Additional selected agents with immunosuppressive properties are listed in Table 290.1.

Table 290.1 Other immunosuppresive drugs

Primary mechanism of action

Major toxicities


Fluorouracil (5-FU)

Blocks DNA methylation during DNA synthesis

Myelosuppression, CNS, heart failure


Pyrimidine synthesis inhibitor

Myelosuppression, bleeding

Cytotoxic agents


Inhibits neutrophil migration, adherence

Haemolysis, agranulocytosis


Inhibits mast cell degranulation

Marrow suppression


Causes DNA strand breaks

Myelosuppression, fevers, skin changes


Adenosine deaminase inhibitor

Leukopenia, thrombocytopenia


Decreases lymphocyte recirculation

Lymphopenia, Flu-like syndrome

Immunosuppressive antibodies and other biological agents

First utilized as antisera derived from animals for treatment of infections in the pre-antibiotic era, antibody-mediated therapies for rheumatologic and oncologic disorders have experienced a rapid expansion in development and utilization in the past two decades [18]. Current therapies use hybrid antibodies composed of murine- or human-derived constant regions paired with specific active regions that target cell receptors and cytokines. Humanized murine monoclonal antibodies and now even fully human monoclonal antibodies are in clinical use. Table 290.2 lists the common biological agents currently in use for a variety of indications with immunosuppressive or immunomodulatory effects and major infection risks. Some of the agents are markedly immunosuppressive (e.g. rituximab, TNF inhibitors, alemtuzumab) and place the patient at major risk for opportunistic infections, while others are well tolerated or increase infection risk for a specific set of pathogens [6,7,8,9,10,11,12,13,14,15].

Table 290.2 Common biological agents and their principal immunological effects and infection risks

Biological agent or antibody

Molecular target


Infection risk

Polyclonal anti-thymocyte or anti-lymphocyte antibodies

T lymphocytes

Organ transplant rejection

Impaired cell-mediated immunity increases risk of numerous OI

Infliximab (Remicade)

Chimeric murine-human mAb blocks TNF and tmTNF

RA, psoriasis, AS, ulcerative colitis, Crohn’s disease

TB, Herpes virus, histo, cocci, other opportunistic bacterial, viral infections

Entanercept (Enbrel)

Type 2 TNFr:Fc IgG blocks sTNF and lymphotoxin

RA, psoriasis, AS, JRA

Lower risk than Infliximab-TB, histo, cocci, other fungi, bacterial, viral infection, OIs

Adalimumab (Humira)

Humanized anti-TNF mAb targets sTNF, tmTNF

RA, psoriasis, AS Crohn’s disease

TB, other fungal, viral and bacterial OIs

Golmumab (Simpori)

Human anti-TNF mAb targets sTNF and tmTNF

RA, psoriasis, AS

TB, other bacterial, viral OIs

Certolizumab pegol

Pegylated humanized anti-TNF Fab fragment

Crohn’s disease, RA

Limited data, likely similar to other TNF inhibitors

Anakinra (Kineret)

IL-1 receptor antagonist targets IL-1 beta


OI risk less than with TNF inhibitors; URI, pneumonia

Daclizumab (zenapax)

Humanized mAb blocks IL-2R (CD25) on T-cells

Transplant rejection

Low risk of CMV, other OIs

Basiliximab (Simulect)

mAb blocks IL-2R (CD25) on T-cells

Transplant rejection

Low risk of OI, CMV reactivation

Rituximab (Rituxan)

Blocks CD20 on B cells

RA, SLE, B cell neoplastic disease

Some Bacterial infections, CMV, VZV, HBV, PML

Alemtuzumab (Campath)

mAb blocks CD52 on T and B cells, NK cells, myeloid cells

Transplant rejection, CLL, neoplastic disease

Neutropenia; multiple OI with bacterial, viral, fungal pathogens, PJP, PTLD

Tocilizumab (Actemra)

mAb blocks IL-6R on T and B cells

Autoimmune disease, neoplastic disease

URI, might increase risk of other infections

Natalizumab (Tysabri)

Humanized mAb, blocks alpha-4 integrin and lymphocyte trafficking

MS, Crohn’s disease

PML, especially if anti-JC virus + and prolonged immune suppression


mAb blocks co-receptor CD28 on T-cells

Kidney transplantation

EBV-associated PTLD, ?PML, UTI, CMV infection

Brodalumab (AMG 827)

mAb blocks IL-17AR


Limited experience, increased pharyngitis, URI

OI, opportunistic infections; mAb, monoclonal; TNF, tumour necrosis factor; RA, rheumatoid arthritis; histo, histoplasmosis; cocci, coccidioidomycosis; AS, ankylosing spondylitis; JRA, juvenile rheumatoid arthritis; MS, multiple sclerosis; R, receptor; Fc, crystallizable component of immunoglobulin; IL, interleukin; CMV, cytomegalovirus; VZV, varicella zoster virus; HBV, hepatitis B virus; SLE, systemic lupus erythematosis; PML, progressive multifocal leukocencephalopathy; PJP, Pneumocystis jirovecii pneumonia; CLL, chronic lymphocytic leukaemia; EBV, Epstein–Barr virus; PTLD, post-transplant lymphoproliferative disorder; UTI, urinary tract infection, URI, upper respiratory infection.

Worth noting is the remarkable association with the opportunistic JC virus-induced PML associated with natalizumab. This integrin inhibitor is highly effective for some forms of multiple sclerosis and is widely used despite the risk of PML. Patients should be screened for antibodies against JC virus and treated for as short a period as possible to avoid this complication. PML has also occurred during rituximab therapy and is a potential risk with the use of other broadly immunosuppressive agents in this class. As a testament to the degree of immune suppression induced by these biological agents, IRIS (immune reconstitution inflammatory syndrome) has occurred with withdrawal from natalizumab therapy and often necessitates the use of corticosteroids to control this reaction.


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