Lecture: Infxn In The Immunocomp

INFECTIONS IN THE IMMUNOCOMPROMISED HOST Mario M. Panaligan, MD, FPCP Microorganism

Host Defenses

Infection

Management of Infectious Complications → Causes → Predisposing factors → Anti-infective strategy Predisposing Factors → Single, isolated deficiencies not commonly encountered → Malfunction of one part of the immune system influences the other components OVERVIEW → Components of host defenses → Approach in the management of infections in the immunocompromised host

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Diagnosis, Treatment, Prevention

Granulocytes → Primary defense mechanism → Defects:  Qualitative ♣ Use of corticosteroids (granulocytosis)

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↓ phagocytosis and intracellular microbial killing Quantitative (granulocytopenia) ♣ usually due to cytotoxic agents against malignancies and therapeutic irradiation

Defect in Neutrophil Function → Pathogens:     

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S. aureus and CoNS Viridans strep Enterococcus E. coli P. aeruginosa K. pneumoniae Enterobacter and Citrobacter Aspergillus Fusarium

Cellular Immunity → Responsible for eliminating intracellular pathogens and virus-infected cells → Defects - either congenital or acquired (from disease or treatment) → Pathogens: Herpes viruses, HPV, Adenovirus, RSV, Influenza, L. monocytogenes, Nocardia,

Fungal

infections

Humoral Immunity → Responsible for clearing extracellular bacteria → Defects - either congenital or acquired (from disease or treatment)  Spleen - produces opsonizing antibodies for efficient phagocytosis → Pathogens: S. pneumoniae, H. influenzae PHYSICAL BARRIERS → Skin  Healthy intact skin  Acid mantle with lower surface temperature  Sweat  Normal microbial flora → Compete for binding sites and nutrients → Release fatty acids  hydrophobic milieu → Maintain low pH → Elaborate bacteriocins SKIN → Clinical infection results from:  Breaks in the skin  Loss of local immunity  Disturbances within the resident flora → Non-intact skin  Chemotherapy and irradiation  Skin abrasion  Needle punctures and catheters

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↓ adherent and chemotactic activities

Impact of Granulocytopenia → Most important risk factor for infection → Fever develops in nearly all patients with granulocyte count < 100/cu.mm. → Risk of infection and infection-related mortality increases proportionally with time

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Mycobacterium, Pneumocystis, (Aspergillus, Cryptococcus)

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Exit-site infections  soft tissue infections

Intraluminal colonization  Bacteremia Loss of local immunity / Alteration of the normal flora  Antibiotic use  Disinfectants  Chemotherapy and irradiation

PHYSICAL BARRIERS → Alimentary tract  Non-damaged mucosal surface ♣ Contain inhibitory substances  Normal microbial flora  Gastric Acidity  Intestinal motility  Clinical infection ♣ Mucositis due to various chemotherapeutic agents

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↑colonization due to  Loss of gastric barrier  Hypomotility Ecologic collapse 2’ to antibiotic intake

Underlying or Concurrent Illnesses → Solid tumors - local obstruction or invasion → Herpesvirus co-infection

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↓ lymphocyte function  Damaged mucosal surfaces Thrombocytopenia

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↓ capacity to repair tissues ↑ risk for bacteremia Poor nutritional status  Hypoalbuminemia  Fe deficiency

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Diabetes mellitus  Impaired opsonization

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↓ chemotaxis of granulocytes and monocytes Smoking Psychological stress

ETIOLOGIC CAUSES: PROBLEMS → Microbiologic confirmation in < 50% → Muted inflammatory response → Difficult to treat organisms or unusual pathogens Diagnostic Evaluation → Careful history-taking → Extensive PE  Blunted inflammatory response  Unusual manifestations → Diagnostic tests  Microbiologic examinations  Antigen detection tests  Serologic tests

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Approach to Fever or Infection in Special Hosts

1997 IDSA Guidelines for the Use of Antimicrobial Agents for Febrile Neutropenia (CID, 1997) Guidelines for Empirical Treatment → Who should receive therapy and when should it be started?  Candidates:

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ANC < 500/mm3 OR < 1000/mm3 if with evidence of rapid decline PLUS

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Fever (single T > 38.5 C or 3 elevations > 38oC / 24 hrs) Who should receive therapy and when should it be started?  Pre-antibiotic evaluation - attenuated signs and symptoms ♣ Careful PE ♣ Microbiologic examinations of blood, urine ♣ Baseline CXR / Urinalysis What constitutes appropriate initial empirical therapy?  Categories: ♣ Low Risk - neutropenic less than 7 - 10 days ♣ High Risk - neutropenic beyond 10 days What constitutes appropriate initial empirical therapy?  High Risk

Combination Tx (Extended spectrum PCN + Aminoglycoside) Combination Tx vs Monotherapy  no significant difference in success rates

What constitutes appropriate initial empirical therapy?  High Risk ♣ Add Vancomycin for MRSA

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Sites of Infection → Oral cavity → Lungs → Skin with its underlying tissue

Febrile Neutropenia → Granulocytopenia  single most important risk factor for infection in patients with hematologic malignancy  80% of pathogens from the patient’s endogenous microbial flora

Monotherapy (Cefta, Cefipime, Carbapenems)

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DIAGNOSTIC EVALUATION

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Add Aminoglycoside or Aztreonam for Pseudomonas aeruginosa infections What constitutes appropriate initial empirical therapy?  Low Risk ♣ Oral antibiotic therapy (Co-amoxyclav + Ciprofloxacin) ♣ No significant difference in clinical failure rates compared to IV  Inconclusive with regard to mortality and OPD effectiveness How should the initial therapy be modified?  Daily examination while febrile and neutropenic  Modifications based on new findings ♣ Identified focus of infection ♣ Positive initial cultures - specific antibiotic ♣ Superinfections or breakthrough infections  Empiric antifungal therapy ♣ If still neutropenic PLUS ♣ Persistent fever after 1 week of abx therapy ♣ Recurrence of fever  Drug of choice: Amphothericin B  Alternative: Fluconazole How long should empirical antibiotic therapy be continued?

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Low risk: < 1 week (resolution of granulocytopenia and fever) High risk ♣ No focus identified: D/C once granulocytopenia resolves or maximum of 14 days ♣ Focus / etiologic agent identified: 14 days of appropriate therapy

Prevention of Infection in the Prevent acquisition and/or suppress or eliminate microbial flora  isolation  prophylactic antibiotics

Neutropenic Host Improve or modify host defenses immunization ? acceleration granulocyte recovery

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 prophylactic antivirals  prophylactic antifungals / pneumocystis prophylaxis Infections in Transplant Recipients → Important problem due to its contribution to the failure and rejection of the transplanted organ → Clinical manifestations vary depending on:  infecting pathogen  prior immune status of the host  time after transplantation  level of pharmacologic immunosuppression → Often occur during the first 4-6 months Factors that Contribute to Infection after Transplantation

Pretransplant host factors  Underlying medical condition  Lack of specific immunity  Prior colonization  Prior latent infection  Prior medications → Transplantation factors - type of transplantation, surgical stress → Immunosuppression - therapy, infections → Allograft reactions Effects of Immunosuppresants → Steroids  Inhibit migration of monocytes to areas of inflammation ♣ Prevent induction of IL-1 and IL-6 in macrophages

Neutropenic infection TB Pneumococcus

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↓ Chemotactic activity and adhesion of neutrophils at the site of infection Cyclosporine

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↓ Generation of CD4 (T-helper cells) ↓ Proliferation of CD4 cells

Approach to Fever or Infection in the Transplant Patient → Careful history and PE  Focus of infection → Diagnostic Work-up  CXR  Microbiologic studies  CBC, LFTs, Renal Function tests  Viral studies (CMV) →

↓ Proliferation of B and T lymphocytes

Timetable of Occurrence of Infection in Organ Transplant Recipients ** see diagram

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Prophylactic Measures Pathogen Protozoa Toxoplasmosis Viral HSV CMV Fungal Candida Aspergillus Pneumocystis Bacterial UTI

Microbiology: S. pneumoniae, H. influenzae, N. meningitidis ♣ Appropriate antibiotics against these organisms

Prevention of Infection in Asplenic Patients → Patient education → Vaccination - at least 2 weeks before elective surgery → →

Prophylactic antibiotics ? Spleen-sparing treatments Potential immunologic measures

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GM-CSF - ↑ macrophage bactericidal activity Corynebacterium parvum – stimulates RES

HIV → Antiretroviral therapy (HAART)  Triple combination therapy → Treatment of concurrent infections → Prevention of opportunistic infections  General isolation procedures  Prophylactic antimicrobials

renal

Prophylactic Agents Pyrimethamine, TMP-SMX Acyclovir Acyclovir, Ig, Ganciclovir Fluco, Nystatin, Clotrimazole Ampho B TMP-SMX TMP-SMX

Diagnosis: Microbiologic exams of blood]

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Diagnosis and Control of Infection → Routine Lab Tests  Before Transplantation ♣ CMV / EBV / HSV / VZV IgG ♣ Toxoplasma IgG ♣ Hep B screening ♣ Hep C ELISA ♣ HIV Ab ♣ PPD ♣ Stool for ova and parasites  After Transplantation ♣ Viral surveillance ♣ Antibody studies (as indicated) Prophylactic measures → Immunization  Passive ♣ CMV-specific Ig for seronegative transplants  Active – inactivated vaccines

Important to remember:  Infections may occur without fever  Not all fevers are due to infections

ASPLENIA → Postsplenectomy sepsis  Rapid deterioration accompanied by CV collapse, seizures, coma and DIC ♣ High mortality rate

↓ Production of cytotoxic T-cells from the precursors Mycophenolate mofetil  Inhibits inosine monophosphate dehydrogenase

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Quinolones Isoniazid Penicillin

Prophylactic Regimens → Any CD4 level  M. tb: INH 300mg qd or 900 mg 2x/wk → CD4 < 200/mm2  PCP: TMP-SMX DS qd or 3x/wk → CD4 < 100/mm2  Toxoplasma gondii: TMP-SX DS qd → CD4 < 50/mm2  MAI: Clarithro 500 mg qd or Azithro 1.2 g qweek

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Cryptococcus (for 2ndry prevention): Fluco 200 mg qd CMV (for 2ndry prevention): Ganciclovir 1g TID

SUMMARY → High index of suspicion  Careful history and thorough PE  Rigorous diagnostic tests  Immediate institution of appropriate therapeutic interventions → Adequate preventive measures

Timetable of Occurrence of Infection in Organ Transplant Recipients VIRAL

CMV Onset

HSV

CMV chorioretinitis

EBV VZV PAPOVA ADENOVIRUS FUNGAL TB PNEUMOCYSTIS

CNS BACTERIAL

Listeria Cryptococcus

Aspergillus, Nocardia, Toxoplasma

Wound Pneumonia Line-related

HEPATITIS Hep B

Non-A, Non-B Hep

UTI: BACTEREMIA, PYELITIS, RELAPSE

Transplant 1

2

3

4

UTI: BENIGN

5

6

MONTHS