Infectious Disease

THE HIGH RISK ONCOLOGY PATIENT

Lalitha Parameswaran

Monika K. Shah

Background: Identification of the High Risk Host

Pts undergoing CA tx are at ↑ risk for infxn due to disease itself or its therapies. NCCN divides pts into risk categories based on w/c tx & prophylactic strategies are advised (J Natl Compr Canc Netw 2012;10:1412).

Infection Risk	Factors Contributing to High Infectious Risk
Low	Standard chemotherapy for most solid tumors Anticipated neutropenia <7 d
Intermediate	Autologous HSCT Lymphoma MM CLL Purine analog Rx (fludarabine, clofarabine, nelarabine, cladribine, or pentostatin) Anticipated neutropenia 7-10 d
High	Acute myeloid leukemia Acute lymphoid leukemia MDS Allogeneic HSCT Alemtuzumab or Bortezomib Rx GVHD treated w/high-dose steroids Anticipated neutropenia >10 d

Predisposing Diseases and Conditions

Disease: Leukemias, MDS, or lymphoma: Leukopenia 2° to marrow dysfunction or leukemic infiltration; MM: Functional hypogammaglobulinemia- predisposes to infxn w/encapsulated organisms. CLL: Hypogammaglobulinemia; heavily pretreated w/lymphotoxic purine analogs such as Fludarabine or Pentostatin causes defects in cell-mediated immunity against pathogens like Listeria, Pneumocystis jiroveci, mycobacteria, opportunistic viral & bacterial pathogens (Cancer 2002;94:2033; Clin Exp Immunol 1992;89:374; Oncology (Huntingt) 2000;14:41). Refractory CA: ↑ risk due to marrow infiltration or poor marrow function due to previous toxic therapies.
Chemotherapy: Monoclonal Ab: Anti CD52- Alemtuzumab causes sev. & prolonged T cell depletion; Anti CD20- rituximab & Ofatumumab cause reactivation of viral diseases such as Hepatitis B and PML (Ann Hematol 2011;90:1219; Blood 2009;113:4834). Bortezomib, Temozolomide: Lymphocyte-depleting agents; can cause disseminated VZV, Pneumocystis jiroveci infxn. Corticosteroids: Dose & duration dependent- Pneumocystis jiroveci & Nocardiosis can occur.
Tumor size: Bulky tumors overgrow their blood supply & necrose, serving as nidus for infxn. Anatomical disruption: Hepatobiliary, urinary or GI tract tumors cause stasis due to obstruction w/infxn; culprit organisms are usually commensal bacteria.
Transplantation: Allogeneic transplant: ↑ predisposition for infxn compared to autologous. Splenic radiation; sev. GVHD: Functional asplenia- can cause overwhelming infxn w/ encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae, & Neisseria meningitidis (J Natl Compr Canc Netw 2012;10:1412).

Strategies for Antimicrobial Therapy

A. Therapeutic: Use of antimicrobials to treat an established infxn

B. Preemptive: Tx of a subgroup of pts who are predisposed to high rates of clinically relevant disease

C. Prophylactic: Administering antimicrobials to high risk population of pts in order to prevent infxn w/c have high morbidity or mortality (N Engl J Med 1998;338:1741).

Host Risk	Prophylaxis
Low	Bacterial & Fungal – None; Viral – none unless prior HSV episode
Intermediate	Bacterial – FQ; Fungal – fluconazole during neutropenia; Viral – HSV: During neutropenia & at least 30 d after HSCT; VZV: 1 y after HSCT
High	Bacterial – FQ; Fungal – fluconazole/echinocandin during neutropenia; posaconazole for MDS/AML/sev. GVHD. For allogeneic HSCT-atleast 75 d after HSCT. *Pneumocystis jiroveci:* TMP/SMX (preferred); alternatives: Dapsone/pentamidine/atovaquone. Viral – HSV: During neutropenia & at least 30 d after HSCT; VZV: 1 y after HSCT; CMV: Preemptive Rx for alemtuzumab/allogeneic HSCT/GVHD; HBV: Give antiviral Rx to prevent reactivation (J Natl Compr Canc Netw 2012;10:1412).

Fever and Neutropenia

Definitions: ANC < 500 cells/mm³ or if expected to ↓ in next 48 h; profound neutropenia: ANC < 100 cells/mm³; functional neutropenia: Counts are nl or ↑, but do not function appropriately
Epidemiology: Occurs in 10-50% of pts w/ solid tumors & >80% of pts w/

hematologic tumors (Clin Infect Dis 2004;39:32). Infxn occur in 20-30% of febrile episodes; common sites are intestinal tract, lung, & skin. Bacteremia occurs in 10-25% of all pts, particularly in profound & prolonged neutropenia (Ann Intern Med 1966;64:328; Blood 2006;107:4628; Clin Infect Dis 2004;39:25).

Neutropenic Host at High Risk of Complications

Profound neutropenia expected to last >7 d after chemotherapy

Hemodynamic instability

Sev. oral or GI mucositis

Abdominal pain, nausea, vomiting, or diarrhea

Altered mental status or neurologic complaints of new onset

Intravascular catheter infxn, esp tunnel infxn

New pulm infiltration or hypoxemia

Hepatic or renal insufficiency

Antibiotic Therapy of Fever and Neutropenia

Figure 12-1

First-line Rx: Should be w/antipseudomonal abx. Vancomycin & aztreonam can be used in case of allergy (hives/bronchospasm) to first-line abx.
Adjunct abx: Should not be started first line, unless there are specific indications, like suspected catheter-related infxn, skin or soft tissue infxn, PNA, hemodynamic instability, or multidrug-resistant organisms (such as MRSA, resistant gram-negative organisms) (Clin Infect Dis 2011;52:56). Must use local antibiogram & institution-specific guidelines to make choices.
Empiric fungal coverage: Choices are echinocandins, liposomal Amphotericin B, or Voriconazole

INFECTIONS IN THE TRANSPLANT HOST

Lalitha Parameswaran

Monika K. Shah

Background

Infxn occurring after HSCT cause ↑ morbidity & mortality. RF for infxn include skin breakdown & mucositis from conditioning, use of central venous catheters, neutropenia, & immunodeficiency (N Engl J Med 2006;17:1813).

Stages of Transplant and Related Infections

Pre & tx of infxn in HSCT pts is based on understanding the type of pretransplant conditioning regimen, type of graft used, the different stages of immune recovery after transplant, & the infxn a/w each of those stages (MMWR Recomm Rep 2000;49(RR-10):1)

Transplant Period	Immune Defects and Other Predisposing Conditions	Commonly Seen Infections
Phase I, preengraftment (D 0-D 30)	Predominant immune defects: Neutropenia Mucocutaneous barriers breakdown Hypogammaglobulinemia 2° immune defects: Lymphopenia Other predisposing conditions: Central venous catheters	Bacterial infxn (Oral, GI, Skin flora): Viridans group Streptococci Gram-negative bacteria Coagulase-negative Staphylococci *Candida* Early *Aspergillus* HSV
Phase II, early postengraftment (D 30-D 100)	Predominant immune defects: Impaired cell-mediated immunity Lymphopenia Hypogammaglobulinemia Other predisposing conditions: Central venous catheters GVHD & its tx	CMV (Pneumonitis, Hepatitis, Colitis) EBV VZV Adenovirus HHV-6 Community-acquired respiratory viruses (episodic-endemic) *Pneumocystis jiroveci* Late *Aspergillus* *Mucormycosis* *Toxoplasma* *Strongyloides*
Phase III, late postengraftment (D 100-D 365)	Predominant immune defects: Impaired cell-mediated immunity (Quicker resolution in autologous than in allogeneic recipients) Hypogammaglobulinemia Other predisposing conditions: Central venous catheters GVHD & its tx	CMV VZV EBV-related post-transplant lymphoproliferative disorder Community-acquired respiratory viruses Encapsulated bacteria