Immunocompromised Hosts

Question 1

Physical Defense Barriers

Answer 1

• Skin and mucosa ⇒ 1° defense against endogenous and exogenous infection
• Causes for disruption:
  
  • Trauma
  • Tumor invasion
  • Effects of chemo- or radiotherapy
  • Use of invasive procedures (IV catheters)

Question 2

Neutropenia

Overview

Answer 2

• Quantitative Phagocyte Defect
• Absolute neutrophil count < 1,000 mm3 ⇒ ↑ risk of infection
• Absolute neutropenia < 500 cells/mm3 ⇒ sign. neutropenia
• Risk of infection is higher if count is falling
• ↑ Duration of neutropenia ⇒ ↑ risk

Question 3

Neutropenia

Etiologies

Answer 3

• Congenital cyclic neutropenia
• Malignancy and Rx w/ cytotoxic effect
• Hematologic malignancies
• Primary bone marrow failure, e.g. aplastic anemia

Question 4

Neutropenic Fever

Etiologies

Answer 4

• Bacterial infections
  
  • Gram ⊖s
    
    • Enterics (E.coli, Klebsiella, Enterobacter) and Pseudomonas aeruginosa
    • Presumed sources are lines, GI tract, GU tract, respiratory tract, or exogenous sites
  • Gram ⊕s
    
    • S. aureus, Coagulase ⊖ staph, Enterococci, Bacillus species, Corynebacterium
    • Common source is indwelling vascular catheters
• Fungal Infections
  
  • Candida species
    
    • Usually occurs after at least 3-5 days of neutropenia
    • ↑ in pts on abx
    • Albicans is most common
    • Types of infection include candidemia, catheter infection, disseminated candidiasis often w/ hepatosplenic involvement, mucosal candidiasis (oral, esophageal, lower GI), or skin infection
  • Aspergillus
    
    • Primary sites upper airways (oral or nasal cavity, sinuses) or lungs
  • Other fungi
    
    • Mucor, Fusarium, Trichosporon beigelli

Question 5

Phagocyte Qualitative Defects

Answer 5

Major functions of neutrophils for microbicidal activity include:

• Chemotaxis
• Cell activation
• Phagocytosis
• Intracellular and extracellular killing
• Defects in any of these may ↑ risk for infection

Question 6

Chronic Granulomatous Disease

Answer 6

• PMNs do not make peroxide
• Defective oxidative metabolism ⇒ impaired oxidative burst
• ↑ infections occur 1° due to catalase ⊕ organisms
• Catalase ⊖ organisms produce peroxidase which is sufficient for polys to use for killing
• In catalase producing organisms, catalase degrades the peroxide produced by the bacteria
• Infections usually begin in 1^st year of life
• Common pathogens: S. aureus, Enteric gram-⊖ rods, Pseudomonas, Nocardia, Aspergillus
• Common sites of infections: lung common (pneumonia and abscesses), skin and soft tissue infections, visceral abscesses, osteomyelitis

Question 7

Myeloperoxidase Deficiency

Answer 7

• Most common granulocyte disorder
• Myeloperoxidase ⇒ lysosomal enzyme that catalyzes H2O2 → hypochlorous acid
• Despite defect, infectious complications rare; most individuals are healthy

Question 8

Chediak Higashi

Answer 8

• AR, rare disease
• Characterized by impaired degranulation and defective chemotaxis of neutrophils
• Pts may have recurrent infections, oculocutaneous albinism, central and peripheral neuropathy, and ↑ bleeding time
• Some have neutropenia
• Typically see infections of skin, mucous membranes, and respiratory tract
• Common organisms: S. aureus, Gram ⊖ bacilli

Question 9

Lazy Leukocyte Syndrome

Answer 9

Gingivitis, recurrent otitis media, stomatitis

Question 10

Hyperimmunoglobulin E Syndrome (Job’s syndrome)

Answer 10

Multiple cutaneous abscesses due to staphylococci

Question 11

Malignancy or Myelodysplasia

Answer 11

• Neutrophils are functionally defective d/t impaired phagocytosis, chemotaxis, and/or bactericidal activity
• Infectious complications ↑ but still rare
• However, borderline ↓in neutrophil number can lead to significant infectious complications

Question 12

Phagocyte Qualitative Defects

Non-Malignant Hematologic Disease

Answer 12

• Aplastic anemia
  
  • In addition to neutropenia, neutrophils also have impaired bactericidal activity
• Paroxysmal Nocturnal Hemoglobinuria (PNH)
  
  • Impaired chemotaxis
• Sickle cell anemia
  
  • Impaired bactericidal activity

Question 13

Phagocyte Qualitative Defects

Iatrogenic Causes

Answer 13

• Pharmacologic agents
• Glucocorticoids
• ↑ risk of infection
• Several effects on neutrophils:
• impaired chemotaxis
• impaired phagocytosis
• impaired microbicidal activity
• Steroids also contribute to infection by multiple other mechanisms:
• impair wound healing
• ↑ skin fragility
• ↓ lymphocyte function
• ↓ cytokine production
• ↓ humoral immune responses
• In addition, signs and symptoms of infection may be dangerously masked in pts on steroids

Question 14

Disorders of Cell-mediated Immunity

Overview

Answer 14

Causes infections predominantly due to intracellular pathogens

Organisms include bacteria, fungi, viruses and protozoa Mycobacteria, Legionella, Nocardia, Salmonella, Cryptococcus, Histoplasma, Coccidiodes, VZV, HSV, CMV, EBV, Pneumocystis, Toxoplasma, Cryptosporidium, Strongyloides

Question 15

Disorders of Cell-mediated Immunity

Etiologies

Answer 15

• Malignancy
• Hodgkin’s lymphoma, Leukemias
• HIV
• Pharmacologic agents:
• Corticosteroids
• Degree of immunosuppression depends on dose and duration of steroids
• Give prophylaxis w/ INH if previously untreated ⊕ PPD pt to start steroids
• Cytotoxic therapy ⇒ Methotrexate, Cyclophosphamide, 6-MP, Azathioprine
• Anti-rejection drugs ⇒ Cyclosporine, antilymphocyte Ab
• Radiotherapy, especially when combined w/ other immunosuppressive agents

Question 16

Severe Combined Immunodeficiency Syndrome (SCID)

Answer 16

• 1° Disorder of Cell-Mediated Immunity
• Infants develop failure to thrive and recurrent infections in 1st few months of life
• Infections due to S. aureus, S. pneumoniae, H. influenzae, Pneumocystis, Candida and herpes group
• Children usually die by age 2

Question 17

Wiscott-Aldrich Syndrome

Question 18

Ataxia-Telangectasia

Answer 18

• 1° Disorder of Cell-Mediated Immunity
• Absent serum and secretory IgA
• Pts have recurrent sinopulmonary infections w/ encapsulated bacteria
• W/ progressive loss of T cell function they develop additional associated infections

Question 19

Digeorge Syndrome

Answer 19

• 1° Disorder of Cell-Mediated Immunity
• Absence of thymus and parathyroid glands
• Susceptible to overwhelming infections w/ HSV, VZV, albicans, pneumocystis

Question 20

Disorders of Humoral Immunity

Overview

Answer 20

• Major components:
  
  • Immunoglobulins
  • Complement
• Infection risk:
  
  • Infection w/ encapsulated bacteria
  • Infections w/ other streptococci, S. aureus, gram ⊖ rods
  • To a lesser extent see infections w/ enteroviruses and Giardia

Question 21

Multiple Myeloma

Answer 21

• Malignant plasma cells induce a protein that selectively suppresses B cell function
• Recurrent infections are predominantly due to encapsulated bacteria
• Infections due to enteric GNR and S. aureus are also seen
• Infections usually occur in the upper respiratory tract, urinary tract or skin.

Question 22

B Cell CLL

Answer 22

• Unbalanced immunoglobulin chain synthesis results in hypogammaglobulinemia
• Infection risk is associated w/ duration and stage of disease and IgG levels
• Recurrent infections are predominantly due to encapsulated bacteria
• Infections due to enteric GNR and S. aureus are also seen
• Infections usually occur in the upper and lower respiratory tract, urinary tract or skin

Question 23

Disorders of Humoral Immunity

Non-malignant Etiologies

Answer 23

• Non-malignant Etiologies
• Etiologies include ↑ immunoglobulin loss or ↑ immunoglobulin catabolism
• Examples
• Nephrotic syndrome, burns, protein-losing enteropathy
• ↓ Ab levels result in ↑ infection risk

Question 24

B-Cell Immunodeficiency States

1° Disorders of Humoral Immunity

Answer 24

• Sex-linked hypogammaglobulinemia
  
  • Recurrent pyogenic infections and septicemia due to S. pneumonia, H. influenzae, S. aureus, N. meningitidis, P. aeruginosa
• Hyperimmunoglobulin M
  
  • Recurrent respiratory, soft tissue and GI infections
• Selective IgM Deficiency
  
  • Recurrent pyogenic infections
• Selective IgA Deficiency
  
  • Some pts have ↑ upper respiratory tract infections or chronic diarrhea due to Giardia
• Common Variable Immunodeficiency
  
  • Respiratory infections w/ S. pneumonia, H. influenza and S. aureus, diarrhea due to Giardia lamblia

Question 25

Complement Deficiencies 1° Disorders of Humoral Immunity

Answer 25

* **Early components (C1, C2, C4) deficiencies** * Infection is rare * **C3 or C5 deficiencies** * Pts develop severe infections w/ encapsulated bacteria, S. aureus and enteric GNR * **Deficiencies of later components (C5b, C6, C7, C8, C9)** * Pts present w/ recurrent Neisseria infections (both N. menigitidis and N. gonorrhoeae) * Infectious episodes typically begin in the teen years

Question 26

Splenectomy or Splenic Dysfunction

Answer 26

* Major infectious complication can be fulminant infection due to encapsulated organisms * Classic organisms include S. pneumoniae, H. influenzae, Neisseria species and Capnocytophaga * Sickle cell asplenia ⇒ ↑ risk for Salmonella infection

Question 27

Prevention of Infection

Answer 27

* Prevent acquisition or suppress flora * Hand Washing * Isolation * Prophylactic antibiotics, antivirals, antifungals, and antiparasitics as indicated * Useful in high risk neutropenic and transplant pts * Improve or Modify Host Defenses * Immunization * Active * Pneumococcus, VZV * Passive * VZIG * Accelerate granulocyte recovery * G-CSF, GM-CSF * Cell component replacement * Leukocyte transfusions

Question 28

Clinical Pearls

Answer 28

Time Clinical Pearls Neutropenia: 1st few days ⇒ bacterial 4-5 days ⇒ fungal Transplant: 1st month ⇒ bacterial, HSV \> 1 month ⇒ HSV, VZV, CMV, Aspergillus, Nocardia, Pneumocystis pneumonia (PCP) \> 3 months ⇒ Cryptococcus Pace Clinical Pearls Fast ⇒ bacterial Indolent ⇒ Nocardia, Cryptococcus, Mycobacterial Symptoms Clinical Pearls Pleuritic chest pain, think fungus, especially aspergillus Chest XR or CT Nodules ⇒ Aspergillus, Nocardia Interstitial ⇒ CMV, Pneumocystis pneumonia (PCP) Focal ⇒ bacterial, mycobacterial, fungal Sinus involvement Think fungus, especially Mucor or Aspergillus

Question 29

Common Management Approach

Answer 29

Fever and Neutropenia History P.E. Cultures Chest x-ray Begin broad spectrum abx active vs gram ⊖ enteric pathogens + S. aureus (esp. if central venous catheter in place) If fever persists for \> 3 days on broad antibiotics, add antifungal Rx G-CSF may shorten duration of neutropenia and resultant infectious complications