A. Introduction

1. Potential infectious organisms in immunosuppressed patients
   1. Depends primarily on part of the immune system which is deficient
   2. Also depends on duration of immunosuppression
2. Etiology of Immunosuppression
   1. Congenital
   2. Acquired
   3. Iatrogenic
3. Factors in Acquired Immunosuppression
   1. Duration of immunosuppression is a major contributor
   2. Degree of immunosuppression is also important
   3. The specifics of immune system malfunction determine types of organisms
   4. Integrity of mucocutaneous borders - skin, gut, oral cavity, lungs
   5. Devitalized tissues
   6. Contributing metabolic conditions: uremia, malnutrition, diabetes, alcoholic cirrhosis
   7. Presence of viruses which affect immune system: EBV, CMV, HIV, Hepatitis B and C

B. Suppressed Cell Mediated Immunity

1. Diabetes Mellitus (DM) [6]
   1. General immunosuppression is not present
   2. Susceptibility to very specific organisms is increased
   3. Neutrophil function is depressed
   4. Leukocyte adhesion and chemotaxis may be inhibited
   5. T cell function is usually depressed
2. Glucocorticoid therapy - long term
3. Uremia (Renal Failure)
4. Immunosuppressive agents
   1. Cyclosporine or Tacrolimus (FK506)
   2. Azathioprine (Imuran®)
   3. Methotrexate (Rheumatrex®, others)
   4. Cyclophosphamide (Cytoxan®), Chlorambucil
   5. Mycophenolic Acid (CellCept®)
   6. Glucocorticoids (mainly long term)
   7. Sirolimus (rapamycin, Rapamune®)
5. HIV Infection / AIDS
6. Hematologic Malignancy - especially leukemias
7. Typical Organisms
   1. Pneumocystis carinii [10]
   2. Typical and Atypical Mycobacteria
   3. Nocardia [2]
   4. Legionella
   5. Viruses - herpesviruses including HSV, EBV, CMV, HHV-6
   6. Cryptococcus
   7. Pathogenic fungi - especially candida, aspirgillus
   8. Toxoplasma gondii
   9. Progressive multifocal leukoencephalopathy (PML) due to JC virus uncommon [9]
   10. Human herpesvirus 8 (HHV-8) - etiologic agent for Kaposi Sarcoma

C. Suppressed Antibody Mediated Immunity

1. Splenectomy
   1. Functional asplenia - sickle cell disease, others
   2. Anatomic - usually post-traumatic
   3. Encapsulated organisms (see below) and Capnocytophaga canimorsus (DF2)
2. Cytotoxic Agents
   1. Chemotherapy: neoplasia, autoimmune diseases
   2. Bone Marrow / Stem Cell Transplantation
3. Congenital Hypoglobulinemic Diseases
4. Complement Deficiency (see below)
5. Hematologic Malignancy - especially multiple myeloma, chronic lymphocytic leukemia
6. Children who under heart transplants at age <4 respond poorly to pneumococcal vaccine [3]
7. Typical Organisms
   1. Streptococcus pneumoniae
   2. Haemophilus influenza
   3. Neisseria ssp.
   4. Salmonella ssp.
   5. Gram negative bacilli
8. Recurrent pneumococcal bacteremia is often a sign of underlying immundeficiency

D. Organ Transplantation [1]

1. Transplantation should not be carried out in presence of active infection
2. With current immunosuppression for transplantation, likely organisms are time-dependent
   1. Infections within first month
   2. Infections from 1-6 months
   3. Infections after six months
   4. Bone marrow transplant patients have slightly different infections
3. In first month after transplant, most infections are nosocomial
   1. Active infection transmitted by allograft is rare
   2. Nosocomial bacterial and fungal infections account for >90% of infections
   3. Pneumocystis and nocardia are rare in first month, and the presence of these suggest underlying medical condition or specific nosocomial hazards
   4. Herpes simplex virus and hepatitis B/C viruses may appear in 2-4 weeks post transplant
   5. Candidal infections occur within 2-6 weeks
   6. CMV disease can occur acutely in seronegative recipients of seropositive donor organ
   7. Cardiac transplant patients seronegative for toxoplasma who receive a heart from a seropositive donor are at high risk for dissemination toxoplasmosis
4. Infections 1-6 Months
   1. Immunomodulating viruses (CMV, HIV, herpesviruses, hepatitis B and C) appear
   2. Varicella zoster virus (VZV, shingles)
   3. Pulmonary virus infections: influenza, RSV, adenovirus
   4. Atypical Bacterial Infections: Nocardia, Listeria, Mycobacteria
   5. Pneumocystis appears at 1-6 months
   6. Aspirgillus appears at 1-3 months
   7. Geographically restricted endemic fungi usually appear after 4-5 months
   8. Cryptococcus appears late, usually after 4 months
   9. Various parasitic infections occur in the >1-2 month time frame
5. Infections >6 Months
   1. CMV retinitis or colitis
   2. Papillomavirus infections (invasive HPV infections in cervix and other areas)
   3. About 10% of patients have chronic or progressive infections with HBV, HCV, CMV, EBV
   4. Post-transplant lymphoproliferative disorder (PTLD) also occurs in this time period and most PTLD are associated with reactivated EBV infection [13]
   5. Geographically restricted endemic fungal infections continue to appear
   6. Typical bacterial infections are relatively uncommon
6. EBV in Immunosuppressed Hosts
   1. Congenital or acquired lymphoproliferative immunodeficiency
   2. Includes severe combined immunodeficiency, ataxia-telangiectasia
   3. Stem cell transplantation (PTLD)
   4. EBV transforms B cells in various development stages in PTLD [8]
   5. Immunosuppressive drugs (as in solid organ transplantation)
   6. HIV Infection and AIDS
   7. EBV associated PTLD occurs in ~5% of pediatric heart transplant cases
7. Kaposi Sarcoma (KS) in Renal Transplant [11]
   1. KS associated with cyclosporine immunosuppression
   2. Human herpesvirus 8 (HHV-8) etiologic for KS
   3. Sirolimus (rapamycin) has antitumor effects against KS
   4. Sirolimus can replace CsA in patients with Kaposi's sarcoma (KS) and renal transplant leading to regression of KS and maintenance of graft function
8. Prevention of Infection in Organ Transplant Patients
   1. Prophylactic therapy is most effective
   2. Essentially all patients receive trimethoprim (80mg)-sulfamethoxazole (400mg)
   3. This is one table daily of single-strength TMP/SMX (Bactrim®, Septra®, others)
   4. This reduces pneumocystis, urinary tract infections, listeria, nocardia and toxoplasma
   5. All patients at risk for CMV disease should receive low-dose ganciclovir prophylaxis
   6. Universal prophylaxis against CMV reduced bacterial infections 50% and death 38% in solid organ transplant recipients [12]
   7. Patients at risk for disseminated toxoplasmosis receive pyramethamine and a sulfonamide
   8. Repeated pneumococcal vaccination is likely required in children transplanted age <4 [3]

E. Complement Deficiency

1. Mainly encapsulated bacterial organisms
2. Most common is Neiseria

F. Fever in Immunocompromised Patients [4]

1. Conditions Requiring Urgent Evaluation
   1. Fevere and Severe neutropenia with neutrophil count <500/µL (see below)
   2. Splenectomy and fever
2. Immunocompromised Conditions
   1. Cancer
   2. Bone Marrow Transplantation
   3. Solid Organ Transplantation
   4. Splenectomy
   5. HIV Infection or AIDS
3. Evaluation of Fever in Immunocompromised Patients
   1. History and physical examination
   2. High level of suspicion based on category of immunosuppression
   3. Complete blood count and leukocyte differential count
   4. Blood cultures in ALL cases
   5. Coagulation studies (PT/aPTT) for suspected sepsis (DIC) or other coagulopathy
   6. Urinalysis for white blood cells and culture
   7. Stool analysis only for symptomatic patients (usually HIV+)
   8. Nose and throat swabs only for symptoms
   9. CMV angiten for all transplant and symptomatic HIV+ patients
   10. Epstein-Barr virus PCR for all transplant and symptomatic HIV+ patients
   11. Cerebrospinal fluid only in patients with symptoms
   12. Radiologic studies: chest CT preferred over radiography
   13. Sinus films only for symptomatic patients and if prolonged fever with no explanation
   14. Special studies - low threshold in patients with specific symptoms
4. Summary of treatments for immunocompromised patients with new fever
   1. Microbiologic cultures and specimens should be obtained prior to therapy if possible
   2. Empiric therapy is necessary due to the rapidity of progression of these conditions
   3. Once organisms are isolated and specified, treatment may be targeted
   4. Cancer (low risk) - consider oral broad spectrum (ciprofloxacin + Augmentin®)
   5. Cancer (high risk) - single parenteral agent (ceftazidime, cefepime, imipenam, others)
   6. Marrow Transplant - depends on timing after transplant (consider fungal coverage)
   7. Liver Transplant - bactermia, ascending cholangitis, CMV, parasites, fungi
   8. Kidney - septicemia (gram negative bacteremia), pyelonephritis, pneumonia
   9. Heart Transplants - Gram positive and negative bactermias, pneumonia, mediastinitis
   10. Lung Transplants - consider gram negative pulmonary infections
   11. Splenectomy - encapsulated G+ and G- bacteremias, sepsis
   12. HIV - direct therapy to sympatomic site (most likely organisms)

G. Neutrophil Dysfunction / Neutropenia

1. Definitions
   1. Mild Neutropenia: <1000 Neutrophils / µL
   2. Moderate: <500/µL (Grade IV neutropenia)
   3. Severe: <200/µL
   4. Moderate to severe neutropenia for >10 days is extremely concerning
2. Chemotherapy
   1. Cancer Chemotherapy most common
   2. Treatment of autoimmune diseases
3. Medications
   1. Ticlopidine
   2. Clozapine
   3. Carbamazepine (Tegretol®)
   4. Felbamate
   5. Chloramphenicol
   6. Methimazole
4. Felty's Syndrome
5. Diabetes Mellitus (see above) [6]
   1. Neutrophil counts are normal
   2. Neutrophil function is depressed
   3. Impaired neutrophil killing and phagocytosis
6. Typical Organisms [4]
   1. Staphylococcus ssp.
   2. Gram negative baccili
   3. Fungi - especially Candida, Aspirgillus, Mucormyces

H. Treatment of Fever and Neutropenia

1. Studies apply to chemotherapy induced neutropenia
2. Major risk for infection (bacterial and fungal) with neutrophil count <500/µL
3. Intravenous antibiotics should be given empirically after cultures have been obtained
   1. Blood Cultures - 2 sets
   2. Urine Cultures
   3. Other: sputum, oropharyngeal, wound, etc.
   4. Central (and peripheral) venous lines should be examined very carefully
   5. Negative results on cultures from central and peripheral venous lines are useful [5]
   6. Positive predictive value of centrally drawn cultures was only 63% (false positives) [5]
   7. Therefore, positive cultures from central venous lines should be interpreted cautiously
4. Choice of empiric antibiotics includes [7]:
   1. Antipseudomonal penicillin PLUS aminoglycoside
   2. Antipseudomonal penicillin with ß-lactamase inhibitors are increasingly used
   3. These include Timentin® (ticarcillin/clavulanate) or Zosyn® (piperacillin/sulbactam)
   4. Ceftazidime +/- aminoglycoside
   5. Imipenem or Meropenem
5. Key is to cover pseudomonas because these infections are rapidly fatal
6. Broaden coverage to include Staphylococci with vancomycin if patient fails to defervesce
7. If still febrile after one week of neutropenia, add amphotericin
8. Diligently search for source of infection (often occult)
9. Continue antibiotics until neutropenia (not fever) resolves
10. Most experts advocate use of G-CSF or GM-CSF for infection with neutrophils <500/µL

References

1. Fishman JA. 2007. NEJM. 357(25):2601
2. Safdar N, Kaul DR, Saint S. 2007. NEJM. 356(9):943 (Case Discussion)
3. Gennery AR, Cant AJ, Spickett GP, et al. 1998. Lancet. 351(9118):1778
4. Pizzo PA. 1999. NEJM. 341(12):893
5. DesJardin JA, Falagas ME, Ruthazer R, et al. 1999. Ann Intern Med. 131(9):641
6. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. 1999. NEJM. 341(25):1906
7. Choice of Antibacterial Drugs. 2001. Med Let. 43(1111):69
8. Timms JM, Bell A, Flavell JR, et al. 2003. Lancet. 361(9353):217
9. Koralnik IJ, Schellingerhout D, Frosch MP. 2004. NEJM. 350(18):1882 (Case Record)
10. Thomas CF Jr and Limper AH. 2004. NEJM. 350(24):2487
11. Stallone G, Schena A, Infante B, et al. 2005. NEJM. 352(13):1317
12. Kalil AC, Levitsky J, Lyden E, et al. 2005. Ann Intern Med. 143(12):870
13. Webber SA, Naftel DC, Fricker FJ, et al. 2006. Lancet. 367(9506):232