14. Infections in the immunocompromised host

INFECTIONS IN THE IMMUNOCOMPROMISED HOST Bernardino Roca Villanueva Servicio de Medicina Interna, Hospital General de Castellón Departamento de Medicina, Universidad Jaume I [email protected] Infectious Diseases Lesson 14 Objectives, learning goal and contents Objective To understand the principal mechanisms of infection in the immunocompromised host To know the clinical presentation of infection in the most common immunodeficiency states Learning goal To develop enough skills to recognize and properly manage the principal infections related to immunodeficiency states, in the most prevalent clinical scenarios Contents •The immunocompromised host: general concepts •Pathogenesis and microbiology of infection in patients with… •…neutropenia and mucositis •…cell-mediated immunodeficiency •…with mixed deficits found in bone marrow transplantation •Management of infection in patients with… •…neutropenia and mucositis •…cell-mediated immunodeficiency •Infections related to splenectomy •Infections related to immunosuppressive agents and immune modulators used in inflammatory diseases •Key messages •Further reading The immunocompromised host: general concepts General causes of immunodeficiency •Treatment of leukemia, lymphoma, or solid tumors with: •Chemotherapy •Bone marrow transplant (including stem cell transplant), or solid organ transplant •Splenectomy •Treatment with immunosuppressive agents and immune modulators of inflammatory disorders •HIV infection •Genetic, mainly of pediatric interest General causes of immunodeficiency •Treatment of leukemia, lymphoma, or solid tumors with: •Chemotherapy •Bone marrow transplant (including stem cell transplant), or solid organ transplant •Splenectomy •Treatment with immunosuppressive agents and immune modulators of inflammatory disorders •HIV infection •Genetic, mainly of pediatric interest Wiskott-Aldrich syndrome: •Eczema •Thrombocytopenia •Recurrent infections Pathogenesis and microbiology of infection in patients with neutropenia and mucositis Infecting organisms •In most cases those found in: •Skin (coagulase-negative staphylococci and S. aureus) •Oral cavity (Streptococcus viridans and anaerobes) •Gastrointestinal tract (gram negative rods and anaerobes) •Sometimes those introduced by contamination from environment, for example in ingested food •Generally bacteria and fungi Bacteria: gram-positive pathogens •The most frequent cause of infection in neutropenic patients •They usually originate in vascular catheter or other devices •Incidence has ↑ in recent years, probably as a consequence of •Use of long-lasting indwelling venous catheters •Overuse of fluoroquinolones •Mainly: •Coagulase-negative staphylococci •Staphylococcus aureus •Streptococcus viridans •Enterococci •Corynebacterium spp. Bacteria: gram-negative pathogens •Second in frequency •They usually originate from the gastrointestinal tract •Polymicrobial sometimes •Mainly •Escherichia coli •Klebsiella species •Pseudomonas aeruginosa •Less commonly, Enterobacter spp., Proteus spp., Acinetobacter spp., Stenotrophomonas spp., and Citrobacter spp. Bacteria: anaerobes •Despite their presence in large numbers in the gastrointestinal tract, anaerobic gram-negative rods such as Bacteroides spp. are not frequent causes of bacteremia in neutropenic patients •Occasionally seen in association with severe mucositis Fungi •Generally after 7 days of febrile neutropenia, when antibiotics have ↓ bacterial flora, so “superinfections” •If patient has received antibiotics recently and fungal colonization in the gut is high, they may produce infection earlier •Some fungi are acquired by inhalation, and become symptomatic later, after they have multiplied and invaded lung parenchyma and blood vessels, thus appearing a superinfection •Candida spp. (albicans, tropicalis, krusei, glabrata, and others), occasionally Aspergillus spp. and rarely Mucor spp or other Pathogenesis and microbiology of infection in patients with cell-mediated immunodeficiency Causes of cell-mediated immunodeficiency •Prevalence of infections related to suppression of T lymphocyte function is progressively increasing •Those infections affect: •Patients with autoimmune disease, receiving cytokine antagonists: corticosteroids →new cytokine antagonists •Organ transplant recipients, receiving agents directed against T lymphocytes Post-transplant infections occurring during the first postoperative month - I •The same hospital-acquired pathogens as other hosts •Gram-negative bacilli such as P. aeruginosa, etc. •Gram-positive cocci, such as vancomycin-resistant enterococci and methicillin-resistant S. aureus •Fungi, such as Aspergillus spp. and azole-resistant Candida spp. •Clostridium difficile Post-transplant infections occurring during the first postoperative month - II •Before organs are harvested, adequate therapy is provided, but bacteria can survive in a vascular aneurysm or other protected sites •Infections transmitted by the donor organ: S. aureus or pneumococci or gram-negative rods •Asymptomatic low-grade infection in the donor that becomes apparent only when the organ is transplanted; examples: West Nile virus, lymphocytic choriomeningitis virus, rabies, leishmaniasis, and Chagas disease Cryptococcus neoformans pneumonia Invasive pulmonary aspergillosis: halo sign (A) and air-crescent sign (B) after recovery of neutropenia Post-transplant infections occurring one to six months after transplantation: viruses - I •Viruses that are latent in the body of the recipient •Infections with new viruses, through: •Transfusion •Transplanted organ Post-transplant infections occurring one to six months after transplantation: viruses -II •Cytomegalovirus (CMV) the most common, reactivated or acquired; risk of infection depends on antibody status: •Recipient -, donor + →high risk •Recipient +, donor - →intermediate risk •Recipient -, donor - →lowest risk •General symptoms, gasteroenteritis, and retinitis •Tests to diagnosis and monitor response to therapy in CMV infection: •Antigen test, correlates with active replication •PCR test, can detect latent and active infection (high copy number indicate active invasive infection) Cytomegalovirus retinitis Post-transplant infections occurring one to six months after transplantation: viruses -III •Epstein-Barr actively replicates in 20-30 % of transplant recipients and can cause a lymphoproliferative syndrome •Other viral infections: •Herpes simplex •Herpes zoster •Human herpesvirus-6 •Hepatitis B and C viruses Post-transplant infections occurring one to six months after transplantation: other pathogens •Pneumocystis jiroveci, pneumonia, that should be prevented with trimethoprim-sulfamethoxazole during the period of peak immunosuppression •Toxoplasmosis, brain abscesses and encephalitis •Disseminated strongyloidiasis, often fatal, patients with unexplained eosinophilia should undergo stool sampling to exclude Strongyloides stercoralis before transplant Pathogenesis and microbiology of infection in patients with mixed deficits found in bone marrow transplantation Phases of immunosuppression - I •I (days 0–30 post-transplant), neutropenic •II (days 30-100 post-transplant), primarily compromised cell-mediated immunity, infection with CMV particularly common; acute graft-versus-host disease also frequent Phases of immunosuppression - II •III (beyond day 100 post-transplant), defects in cell-mediated immunity, plus depressed humoral immunity from: •Functional hyposplenism after total body irradiation •Chronic GVHD * → dysfunctional B lymphocytes → •→↓ production of IgG2 •→ ↓ production of specific pneumococcal antibodies * GVHD = graftversus-host disease ** Infections with encapsulated bacteria: -Haemophilus influenzae -Streptococcus pneumoniae ** Choosing antibiotics - I •Monotherapy and dual therapy comparable results •Vancomycin: •Should not be routinely administered as empiric therapy •Should be added if: •Intravascular device infection is suspected •Colonization with methicillin-resistant S. aureus •Blood cultures grow gram-positive cocci before final identification and sensitivity testing •If the patient is hypotensive or has other evidence of cardiovascular compromise Choosing antibiotics - II •Linezolid equivalent to vancomycin in the neutropenic patient, however, with selective serotonin-reuptake inhibitors →severe myelosuppression in bone marrow transplant patients •Blood cultures may guide adjustments in treatment •Broad-spectrum coverage should be generally maintained at least 7 days or until the neutrophil > 500/mm3, to prevent breakthrough bacteremia Choosing antibiotics - III •If fever persists after 3-5 days, reevaluation is needed: •Complete physical examination repeated •Additional imaging, such as computed tomography of the chest •Bronchoscopy if lung infiltrates •Cultures should be repeated •If fever persists for more than 5 days, and… •…the patient is improving his condition and neutrophil count is expected to recover quickly →continue the same antibiotics •…sepsis persists or worsens →antibiotic changed and antifungal added Duration of antibiotic treatment - I •Afebrile patient after 3–5 days of therapy, and neutrophil count has been > 500/mm3 for 2 days →discontinued after the patient has been afebrile for 48 hours •Afebrile for 5 to 7 days, neutrophil count < 500/mm3, initially low risk and not currently septic → can be discontinued •Afebrile, initially at high risk, neutrophil count < 100/mm3, or the patient has mucositis or is clinically unstable → continued Duration of antibiotic treatment - I •Persistently febrile and neutrophil count is > 500/mm3 for 4-5 days → can be discontinued but patient should be reassessed •Persistently febrile and neutrophil count < 500/mm3, → continued for 2 weeks, with reassessment at that time; then, if no infection is evident and the patient is clinically stable → discontinued Prevention •Antiviral therapy is not indicated in neutropenic patients unless a specific viral infection is documented •Fluoroquinolone prophylaxis indicated in high-risk patients who are expected to have a prolonged duration of profound neutropenia, < 100 cells/mm3 for > 7 days, despite the concern of development of widespread antibiotic resistance Management of infections in patients with cellmediated immunodeficiency Patient evaluation - I •List of organisms that can cause infection is so large that empiric therapy is not recommended unless… •…a specific site of infection is identified •…a specific pathogen is the most likely cause •Cellulitis may have a nonbacterial origin •Empiric therapy may be given for central catheter or urinary tract infections, because the usual organisms continue to cause these infections •Complete clinical and social history required to assess community-acquired infections Patient evaluation - II •Living in certain geographic areas predisposes to specific infections (reactivation or new infection), such as •Histoplasmosis and coccidioidomycosis in the US •Visceral leishmaniasis in Spain •Certain sites of infection do require urgent action: •Headache or other central nervous system complaint →lumbar puncture if not contraindicated, as cryptococcal or listerial meningitis are possible and require immediate treatment •Blood, urine, and any suspicious sites should be cultured Patient evaluation - III •Certain sites of infection do require urgent action (contd.): •Inflamed central line → treatment for gram-positive cocci •Chest radiograph abnormal or patient producing sputum → gram, acid-fast, silver staining and culture of sputum; if no sputum produced, bronchoscopy etc. may be needed Infections related to immunosuppressive agents and immune modulators used in inflammatory diseases Corticosteroids •Decreasing function and/or numbers of: •Neutrophils •Lymphocytes, both B cells and T cells •Monocytes and macrophages •Anatomical barrier function of the skin •Risk of infection related to dose and the duration of therapy •Most common pathogens: •Pyogenic bacteria •Intracellular pathogens such as Listeria spp., fungi, and herpes viruses Biologic therapy •Increasingly used to treat many systemic inflammatory conditions •Antibodies or other peptides that: •Inhibit inflammatory cytokine signaling •Inhibit T-cell activation •Deplete B-cells •Increased risk of: •Respiratory, intestinal and other common infections •Atypical and opportunistic infections by Mycobacterium tuberculosis, herpes zoster virus, Legionella spp., and Listeria spp. Key messages To remember… In the immunodeficient patient, high-grade life-threatening infection is common, therefore rapid evaluation and empiric antibiotics are frequently required in this population Clinical presentations of these infections is protean, so a high index of suspicion must be kept when attending the immunodeficient patient Further reading Used references Southwick F. Infectious disease. A clinical short course. 3rd Edition. New York: McGraw-Hill, 2014. Chapter 15. Tolan RT Jr, MD et al. Infections in the Immunocompromised Host. Available at: http://emedicine.medscape.com/article/973120overview#aw2aab6b3. Preparing the exam •Southwick F. Infectious disease. A clinical short course. 3rd Edition. New York: McGraw-Hill, 2014. Chapter 15. •These slides !!!.