• Medical advances given rise of new populations of patients --> immunocompromised.
      • Leukemia, lymphoma, solid tumors with cytotoxic chemotherapy or who received bone marrow transplant (including stem cell transplant), solid organ transplant, etc...
      • Special attention to splenectomy patients (absence of opsonic antibody, cannot clear encapsulated organisms such as pneumococcus and H.influenzae)
    • Generally divided into:
      • Medically Immunocompromised
      • Iatrogenically Immunocompromised
      • Genetically Immunocompromised
    • Two main types of defects:
      • Neutropenia = count < 500/mm^3
        • From cytotoxic chemo or irradiation causes neutropenia and mucosal barrier damage.
        • Risk of infection increases as cell number drops below this point.
        • Risk especially high if ANC (Absolute neutrophil count) < 200.
      • Cell-mediated immune deficiencies:
        • Often corticosteroids and drugs given following organ transplant.
    • Mixed defects: bone marrow transplant who are either neutropenic in early stages or have depressed cell-mediated immunity after bone marrow repopulates.


    Primary Immunodeficiencies

    • Uncommon.
    • Consider in pts with frequent, multiple or prolonged infections with pathogens like S. pneumo, Neisseria, H. influenzae.
    • Very rare, usually manifest in children.


    Selective IgA Deficiency

    • Most common primary immunodeficiency. (most common, usually in children)
    • 1:300 to 1:700 persons.
    • Etiology:
      • Lack of serum and secretory IgA inherited as an incompletely penetrant autosomal dominant or autosomal recessive trait.
    • Major immunoglobulin in saliva, tear, nasal secretions, etc.. blocks antigens, toxins.
    • Manifestations:
      • Chronic recurrent respiratory tract infections (sino-pulmonary)
      • Atopic disorders
      • Autoimmune disorders
      • GI infections
      • Celiac Disease
    • Other Igs are normal, but IgG2 subclass deficiency also reported with IgA --> worse symptoms.
      • Serum auto-antibodies anti-IgA found in 40% of pts with recurrent infections. (some have anaphylaxis with IgA infusion).


    Common Variable Immunodeficiency (CVID)

    • Both adults + children (most present <30yo)
    • 1:6000 persons, Northern European Descent.
    • Impaired B-Cell differentiation and defective Ig production.
    • Serum IgG levels are markedly reduced, IgA and IgM are also frequently low.
    • Main Manifestation: Hypogammaglobulinemia (Involves B and T cell abnormalities)
    • More susceptible to:
      • Mucosal Diseases  (Poor response to PneumococciMycoplasmaHaemophilus influenzae)
        • Chronic Sinopulmonary Diseases
        • Ear Infections
        • Conjunctivitis
        • Lung infections
      • Autoimmune Disorders
      • GI Disorders (20%)
        • Malabsorption
        • IBD
        • Sprue-like disorders
        • Pernicious Anemia
      • Lymphoma
      • Poor Response to Vaccinations
      • Granulomatous Diseases (20%)
        • (non-caseating in lymphoid and solid organs)
    • Other Susceptibilities: Enteroviruses, Candida, Giardia lamblia.
    • Investigations:
      • Quantitative Serum IgG, IgA, IgM levels
      • If levels are low, antibody response to vaccination should be tested.
        • If Ig level is "variable" <200mg/dL or "undetectable", no point testing, will most likely not respond to vaccines.
    • Management
      • Immunoglobulin replacement therapy (reduces number of infections in CVID)
      • Prophylactic antibiotics are NOT indicated
        • ---> Only for chronic lung disease, or those on oral steroids for >1mo.


    Complement Deficiency

    • Predispose to bacterial infections and autoimmune disorders
    • 0.03% incidence of complement deficiencies
      • Autosomal recessive traits.
      • C1 inhibitor deficiency is a dominant trait 
      • Properdin deficiency --> X-linked disorder.
    • Deficiencies:
      • SLE is the most common autoimmune disorder (esp with inherited complement disorders): C1,C4,C2,C3.
      • C3, Factor H, Factor I, Properdin Severe recurrent infections by encapsulated organisms
        (I.e. Strep pneumoniae)

        Terminal Complement Components:

        (C5, C6, C7, C8)

        Disseminated neisserial infections (meningococci and gonococci)

        Alternate Complement Pathway:

        Factor D, Properdin

        VERY RARE.  Higher risk of neisserial infections, recurrent

        pneumonia, otitis media. 

        Classical Pathway:

        C1, C4, C2

        Rheum Disorders: SLE, Vasculitis, Dermatomyositis, Scleroderma

        (Infection frequency low, possibly worse encapsulated organisms)

    • Workup:
      • Test for Total Hemolytic Complement (CH50).
      • If CH50 concenration is low or undetectable --> measure specific compement components.
    • Management
      • Vaccinations is the most effective way to prevent infections.
        • Meningococcal
        • Pneumococcal
        • Haemophilus influenzae

    FUO in HIV

    • Most common:
      • Mycobacterial infections:   (Mycobacterial blood culture)
        • Mycobacterium tuberculosis
        • M. avium intracellulare
        • Other atypical mycobacteria
      • Other bacterial infections
      • CMV   (CMV quantitative PCR)
        • if CD4 counts < 100/uL
        • MRI: shows periventricular involvement.
      • Pneumocystis
      • Toxoplasmosis
        • CD4 < 100/uL
        • Can cause encephalitis
        • MRI: multiple ring-enhancing lesions of toxoplasmic abscesses.
        • ...
      • Cryptococcus (Cryptococcal serum antigen)
        • Yeast - can cause meningitis (headache, mental status change, cranial nerve involvement).
        • Fungal culture (CSF and Blood): very slow.
        • Cryptococcal antigen of CSF and Blood is faster (>95% sensitivity).
        • Treat with: Amphotericin B (IV) + long term fluconazole
          • Manage increased ICP.
      • Histoplasmosis (hard,  if disseminated - Bone marrow culture)
        • Histoplasma capsulatum - thermal dimorphic fungus endemic to midwestern states (Ohio, Mississipi)
        • Acute or chronic pulmonary disease.
        • Immunocompromised pts can have disseminated disease.  (often pulmonary symptoms + systemic).



    Febrile Neutropenia

    • Protocols site-specific.  Ensure Gram+ coverage PLUS Pseudomonas
      • Options:
        • High Dose pip-tazo +/- Vancomycin (if risk factors for MRSA)
        • cefazolin + tobramycin (+vancomycin if concern for MRSA)
        • pip-tazo + tobramycin (+/- vancomycin)
      • Consider empiric antifungal coverage if prolonged (fluconazole or broader spectrum veroconazole)
    • Risk factors for MRSA:
      • Mucositis
      • History of MRSA (prev. swabs?)
      • Lines In Situ
    • When to stop board-spectrum antibiotics:
      • If afebrile by day 3, stop antibiotics if:

           1.  ANC ≥ 0.5 x2 days, afebrile for ≥48hrs, cultures negative, no signs of infection

           2. ANC < 0.5 by day 7, afebrile for 5-7d, low risk, no subsequent complications


        Otherwise continue antibiotics if criteria not met.


        If persistent fever on day 3

           Stop antibiotics if ANC ≥ 0.5 for 4-5 consequetive days.

           Continue antibiotics if ANC < 0.5, reassess and continue x2 weeks.  Consider

              stopping if no source is found.


        (From David Hui book, based on ACSO guidelines 2006)

    • Antifungal therapy:
      • If remains febrile without a source for 4-7 days of broad-spectrum antimicrobial therapy.



    Human Immunodeficiency Virus (HIV)

    • Treatments note:
      • Once starting antiretrovirual therapy, patients can develop acute immune reconstitution inflammatory response (IRIS), where viral counts drop, and CD4 counts come up, and immune system reacts to any opportunistic reactions (mainly cryptococcus and mycoplasma).
    • CD4 counts:
      • <200
        • Oral Thrush (oral disease: nystatin/clotrimazole.  Esophageal disease (dysphagia) needs oral fluticasone)
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