Page 549 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 37 Infections in the Immunocompromised Host 527

immunomodulators in autoimmune and inflammatory disorders,
SECONDARY NON–MEDICATION-ASSOCIATED and graft-versus-host disease (GvHD). These drugs inhibit
IMMUNODEFICIENCY B-cell and T-cell proliferation and hinder cellular and humoral
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immune responses in a dose-dependent fashion. One of the
Cytokine Autoantibodies main side effects of these agents is hematopoietic toxicity; they
In recent years, there has been greater recognition of susceptibility induce neutropenia to varying degrees. Fever occurs during
to infection associated with anticytokine autoantibodies. 27-30 chemotherapeutic-induced neutropenia in 10–50% of patients
Autoimmune polyendocrinopathy with candidiasis and ecto- with solid tumors and in >80% of those with hematologic
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dermal dysplasia (APOCED) is a disorder caused by mutations malignancies. Common sites of infection include the intes-
in the autoimmune regulator gene (AIRE). Many autoimmune tinal tract, lungs, and skin; bacteremia occurs in up to 25% of
manifestations are seen in APOCED, including hypoparathyroid- patients. Probably because of the high incidence of indwelling
ism, diabetes, and adrenal failure as a result of persistent autoreac- catheters and widespread use of prophylactic antibiotics, currently
tive T cells caused by failure of thymic deletion. The main coagulase-negative staphylococci are the most common blood
infectious complication is severe CMC. Neutralizing autoantibod- isolates, followed by drug-resistant Enterobacteriaceae and non-
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ies to IL-17 and IL-22 have been detected and may contribute fermenting GNB (e.g., P. aeruginosa). Invasive mold infections
to the occurrence of CMC, similar to other defects along the (e.g., aspergillosis) typically occur after prolonged neutropenia
Th17/IL-17/IL-22 pathway, such as AD-HIES. 29,30 Neutralizing (>2 weeks). Invasive yeast (usually Candida spp.) infections are
autoantibodies to IFN-γ leading most frequently to disseminated more commonly seen in patients with severe mucositis and
27
NTM infections have been described. This disorder typically neutropenia. Detailed guidelines for the use of antimicrobial
presents in adulthood and has an increased prevalence in Asians. agents in the setting of chemotherapy-induced neutropenic fever
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Although the primary manifestation of autoantibodies against have been published. Although bacterial infections are the most
granulocyte macrophage–colony-stimulating factor (GM-CSF) common infections, when used as immunomodulators, a higher
antibodies is PAP, an increased frequency of OIs, such as with frequency of OIs, such as PJP, and infections with Listeria spp.,
Nocardia and Cryptococcus, has been described. 30 NTM, Cryptococcus, and VZV, has been described.
Glucocorticoids
tHEraPEutIC PrINCIPLES
Prevention of Infection in Patients With a Defect Depending on the dose and duration, glucocorticoids can induce
a vast range of immune defects through decreasing cytokine
in Host Defenses production (IL-1, IL-6, and tumor necrosis factor-α [TNF-α),
and impairing neutrophil and lymphocyte trafficking and func-
• Use of prophylactic antibiotics in patients at high risk for a specific
type of infection tion. Infections are a frequent complication of corticosteroid
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• Immunization to prevent specific bacterial and viral infections: use. Bacterial infections are the most common infectious
• Active immunization, especially in patients who should be capable complication, but opportunistic fungal, viral, and mycobacterial
of mounting an effective response (e.g., before elective splenectomy infections are also seen, particularly with high doses and long
or before elective initiation of immunosuppressive therapy) duration of systemic therapy. Some associated infections include
• Passive immunization through administration of high-titer pooled GPB and GNB, superficial and invasive candidiasis, invasive
immunoglobulin to patients exposed to or at high risk of specific
viral infections. aspergillosis and nocardiosis, cryptococcosis, PJP, listeriosis,
endemic mycoses, tuberculosis (TB), and infections with NTM,
and VZV, among others. Outside of the setting of SOT and HSCT,
INFECTIONS IN PATIENTS RECEIVING routine use of antimicrobials for patients receiving corticosteroids
IMMUNOSUPPRESSIVE MEDICATIONS is not recommended, except for anti-TB treatment (e.g., isoniazid)
for those with a positive tuberculin skin test (purified protein
31
Immunosuppressive drugs have been used for over 60 years and derivative [PPD]) or a positive IFN-γ release assay, and TMP-SMX
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are essential for the management of autoimmune/inflammatory in those receiving high-dose steroid for extended periods.
diseases and hematological and oncological malignancies and Alternate-day use of corticosteroids has been associated with a
in transplant recipients. Early immunosuppressive agents lacked lower risk of severe infection; therefore whenever possible, this
specificity and therefore led to serious and numerous adverse dosing schedule should be used. 31
effects. Newer immunosuppressive agents have revolutionized
the treatment of multiple diseases, but many of these have led Calcineurin Inhibitors and Mammalian Target of
to an increase in specific infectious complications. Knowledge of Rapamycin Inhibitors
the particular infection or treatment associations is imperative. 32 The calcineurin inhibitors, cyclosporine and tacrolimus, have
Described below are the most common classes of drugs that been cornerstones in improving the outcome of transplant
have been linked to infectious complications. Notably, immu- recipients by reducing T-cell function and thus preventing allograft
nosuppressive agents are frequently used in combination, and rejection in SOT and GvHD in HSCT. Infectious complications,
therefore establishing clear causality is challenging. typically viral, seem to be dose dependent and seen more often
when these drugs are used in combination with other immunosup-
Cytotoxic Agents (e.g., Cyclophosphamide, pressants. 32,33 The mammalian target of rapamycin (mTOR)
Methotrexate, Azathioprine) inhibitors sirolimus and everolimus have been associated with
Initially developed to control neoplastic growth in oncologi- a lower incidence of CMV infection, compared with other
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cal and hematological malignancies, cytotoxic drugs have also immunosuppressive agents used in transplantation. Although
found their niche as an essential component of the conditioning impaired wound healing has been seen, this has not correlated
regimen for HSCT and solid organ transplantation (SOT), as with an increased incidence of infections.