MANAGEMENT OF INFECTIONS IN IMMUNOCOMPROMISED PATIENTSDr. Sujay IyerJR- 1, General MedicineMODERATOR: Dr. TARUN KUMAR DUTTA

TABLE OF CONTENT Introduction Cancer and Immunosuppression Febrile Neutropenia Catheter-related Infections Pneumonia Gastrointestinal Infections Conclusion References

INTRODUCTION An immunocompromised host is a patient

who does not have the ability to respond normally to an infection due to an impaired or weakened immune system. This inability to fight infection can be caused by a number of conditions including illness (cancer and its treatment) and disease (Diabetes, HIV), malnutrition, and drugs.

IMMUNOCOMPROMISING CONDITIONSCongenital conditions Syndromes B-cell defects Combined B-cell and T-cell defects T-cell defects Macrophage, cytokine, and miscellaneous defects Phagocyte deficiency or dysfunction Complement deficienciesAcquired conditions Malnutrition HIV infection Trauma Medical conditions

Cancer Immunosuppressive drugs

Anti-cancer medication

CANCER AND IMMUNOSUPPRESSIONType of Cancer Hematologic malignancies with neutropenia Lymphomas with B-cell or T-cell deficiencies Solid organ malignanciesTransplantation Hematopoietic stem cell transplantation Solid organ transplantationTreatment Chemotherapy Biologic agentsAnatomic Issues Mucositis Indwelling central venous catheters Epidemiologic exposure

FEBRILE NEUTROPENIAFEVER The Infectious Diseases Society of America

(IDSA) defines fever in neutropenic patients as a single oral temperature of >38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained for >1 hour.

NEUTROPENIA It is defined as absolute neutrophil count (ANC)

of less than 500 cells/microL, or ANC expected to fall below 500 cells/microL over 48 hour period.

Profound neutropenia is less than 100 cells/microL and functional neutropenia is qualitative defect in neutrophils.

NEUTROPENIC FEVER SYNDROMESThe International Immunocompromised Host

Society has classified initial neutropenic fever syndromes into the following three categories:

Microbiologically documented infection – Neutropenic fever with a clinical focus of infection and an associated pathogen

Clinically documented infection – Neutropenic fever with a clinical focus (eg, cellulitis, pneumonia) but without the isolation of an associated pathogen

Unexplained fever – Neutropenic fever with neither a clinical focus of infection nor an identified pathogen

ETIOLOGY OF FEBRILE NEUTROPENIABacterial Infections Most common, typically derived from patient’s flora.

(80%). Gram positive bacteria are the most common pathogens

(approx. 60%). Staphylococcus epidermis (most common),

Stapylococcus aureus, Streptococcus viridans, Enterococci are most common gram positive organisms.

Other gram positive organisms: Cornybacterium jeikeium, Bacillus spp, Leuconostoc spp, Lactobacillus spp, etc.

Gram negative pathogens are usually associated with more serious infections.

Common gram negative organisms are Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae.

ETIOLOGY OF FEBRILE NEUTROPENIAFungal Infections They are common in high-risk patients. Fungi are rarely the cause of first febrile epiode in

neutropenic patient, they are identified as the cause of persistent or recurrent fever, beyond the first week.

Risk of fungal infections with duration and severity of neutropenia.

Candida spp (GI tract) and Aspergillus spp (inhalation of airborne spores) account for most invasive fungal infections.

Candida albicans occurs most frequently. C. glabrata, C. tropicalis, and other Candida spp account for the remainder.

Mucorales and Fusarium are other less common fungal pathogens.

ETIOLOGY OF FEBRILE NEUTROPENIAViral Infections They occur in high-risk patients and are predominantly

due to Herpes virus. Common among them are: Herpes simplex- 1 virus,

Herpes simplex- 2 virus,Varicella zoster virus, Ebstein-Barr virus, Cytomegalovirus, etc. They primarily act through reactivation.

Infections caused by respiratory viruses have been documented with increasing frequency and occur commonly in neutropenic patients; these include Influenza virus, Respiratory syncytial virus, Parainfluenza virus, Adenovirus, and Metapneumovirus. 

The risk for infection by these organisms tends to coincide with respiratory virus outbreaks in the general population.

PATHOGENESIS OF FEBRILE NEUTROPENIADirect Effects of Chemotherapy on Immune

System Chemotherapy-induced mucositis occurs throughout

the alimentary system, and seeding of the bloodstream from endogenous flora in the gastrointestinal tract is believed to cause the majority of episodes of neutropenic fever.

Breeches in Host Defenses related to Underlying Malignancy

Immune defects related to underlying hematologic disorders also place patients at higher risk for infection. In addition, the administration of chemotherapy not only decreases the number of neutrophils but also results in chemotactic and phagocytic defects.

RISK STRATIFICATION OF FEBRILE NEUTROPENIC PATIENTS Management of patients is guided by

knowledge of whether they are at high-risk or low-risk for complications.

The Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) use different definitions of risk in their guidelines.

IDSA RISK ASSESSMENTHigh-Risk Any of the following characteristics: ANC ≤100 cells/microL expected to last >7 days or Evidence of ongoing comorbid conditions, such as (but not limited

to): Hemodynamic instability Oral or gastrointestinal tract mucositis limiting swallowing or

causing severe diarrhea Gastrointestinal symptoms, such as abdominal pain, nausea

and vomiting, or diarrhea Neurologic or mental status changes of new onset Intravascular catheter infection New pulmonary infiltrate or hypoxia Underlying chronic lung disease or

Evidence of hepatic insufficiency (defined as aminotransferase levels >5 times normal values) or renal insufficiency (defined as a creatinine clearance <30 mL/min).

IDSA RISK ASSESSMENTLow-Risk Low-risk febrile neutropenic patients are

expected to have a duration of neutropenia (ANC <500 cells/microL) of 7 days or fewer and have no comorbidities or evidence of significant hepatic or renal dysfunction.

Most patients receiving chemotherapy for solid tumors are considered to be low risk for complications requiring hospitalization or prolonging hospitalization.

NCCN RISK ASSESSMENTHigh-riskIf ANY of the following criteria are met Inpatient status at time of development of fever Significant medical comorbidity or presence of clinical instability Anticipated prolonged profound neutropenia (ANC

≤100 cells/microL expected to last >7 days) Hepatic insufficiency (defined as aminotransferase levels >5 times

normal values) or renal insufficiency (defined as a creatinine clearance <30 mL/min)

Uncontrolled progressive cancer defined as any leukemic patient not in complete remission or any nonleukemic patient with evidence of disease progression after more than two courses of chemotherapy

Pneumonia or other complex infection at clinical presentation  Alemtuzumab within the past two months Grade 3 or 4 mucositis MASCC risk index score <21.

NCCN RISK ASSESSMENTLow-RiskIf patients do not meet ANY of the high-risk criteria

described above and if they meet most of the following criteria:

Outpatient status at time of development of fever No associated acute comorbid illness requiring

inpatient hospitalization or close observation Anticipated short duration of severe neutropenia (ANC

≤100 cells/microL expected to last 7 days or fewer) Good performance status (Eastern Cooperative

Oncology Group [ECOG] 0 to 1. No hepatic insufficiency No renal insufficiency MASCC risk index score ≥21.

MASCC SCORING SYSTEM

A score of ≥ 21 is considered low risk and a score of < 21 as high risk

DIAGNOSIS OF FEBRILE NEUTROPENIA Febrile Neutropenia is a medical emergency and prompt initial

evaluation and diagnostic work-up is critical. Detailed history (underlying malignancy, chemotherapy

received, environmental exposures, past infections, drug allergies) and detailed examination.

CBC with WBC differential. Metabolic panel Lactate level. Two sets of blood cultures Respiratory samples, if patient has respiratory symptoms. Chest X-ray CT Scan if needed (sinus, chest, abdomen, pelvis) CT Brain before spinal tap Stool test of Clostridium difficile Other laboratory tests depending on suspicion of specific

organisms.

MANAGEMENT OF FEBRILE NEUTROPENIA: HIGH-RISK General Principles Broad-spectrum antibacterials should be given as soon as possible

(within 60 minutes of triage) and at full doses, adjusted for renal and/or hepatic function.

Antibiotics are usually administered empirically but should always include appropriate coverage for suspected or known infections. Even when the pathogen is known, the antibiotic regimen should provide broad-spectrum empiric coverage for the possibility of other pathogens.

In high-risk patients, antibiotics should generally be administered intravenously (IV) in a hospital setting.

Ideally, antibiotics should be bactericidal. Clinical response and culture and susceptibility results should be

monitored closely, and therapy should be adjusted in a timely fashion in response to this information.

Febrile neutropenic patients should be monitored frequently. Temporarily holding administration of systemic chemotherapy should

be considered during the management of the sepsis syndrome until the patient stabilizes.

MANAGEMENT OF FEBRILE NEUTROPENIA: HIGH-RISK IDSA Recommendations Initiation of monotherapy with beta lactam antibiotics. Cefepime – 2 g IV every eight hours Meropenem – 1 g IV every eight hours Imipenem-cilastatin – 500 mg IV every six hours Piperacillin-tazobactam – 4.5 g IV every six to eight hours Ceftazidime – 2 g IV every eight hours Other antibiotics (eg, aminoglycosides, fluoroquinolones, and/or V

ancomycin) may be added to the initial regimen in patients with complicated presentations (eg, hypotension and/or mental status changes), focal findings (eg, pneumonia or cellulitis), or if antimicrobial resistance is suspected or proven.

Vancomycin (or other agents that target gram-positive cocci) is not recommended as a standard part of the initial regimen but should be added in certain patients.

Modifications to the initial regimen should be considered for patients at risk for infection with antibiotic-resistant organisms.

MANAGEMENT OF FEBRILE NEUTROPENIA: HIGH-RISK Anaerobic coverage may be included if there is evidence of

necrotizing mucositis, sinusitis, periodontal cellulitis, perirectal cellulitis, intraabdominal infection (including neutropenic enterocolitis [typhlitis]), pelvic infection, or anaerobic bacteremia.

Persistent fever —  Modification of the initial antibacterial regimen is not needed for persistent fever alone.

An empiric Antifungal Agent should be added after four to seven days in high-risk neutropenic patients who are expected to have a total duration of neutropenia >7 days who have persistent or recurrent fever and in whom reassessment does not yield a cause.

The 2010 IDSA guidelines recommend Amphotericin B deoxycholate, Caspofungin, Voriconazole, or Itraconazole as suitable options.

Duration – Antibiotics should be continued for at least the standard duration indicated for the specific infection (eg, 14 days for Escherichia coli bacteremia); antibiotics should also continue at least until the absolute neutrophil count (ANC) is ≥500 cells/microL or longer.

MANAGEMENT OF FEBRILE NEUTROPENIA: LOW-RISK Same general principles. In contrast, patients who clearly meet all criteria

for being low risk can be given oral antibiotics as outpatients, following either a brief period of observation or a short hospital admission.

The recommended initial empiric oral antibacterial regimen for low-risk patients involves a combination of a fluoroquinolone (Ciprofloxacin 750 mg orally twice daily or Levofloxacin 750 mg orally once daily) and a beta-lactam agent, such as Amoxicillin-Clavulanic acid (500 mg/125 mg orally three times daily).

MANAGEMENT OF FEBRILE NEUTROPENIA: LOW-RISK Patients receiving fluoroquinolone-based

antibacterial prophylaxis should not receive a fluoroquinolone-based initial empiric antibacterial therapy. Such patients should receive one of the IV regimens in order to provide adequate activity against P. aeruginosa.

For patients who have a history of penicillin hypersensitivity, Clindamycin (300 mg four times daily) may be given, if a cephalosporin is deemed to be safe, Cefixime (400 mg once daily) may be given.

Duration- In general, antibacterial therapy is continued until myeloid reconstitution, defined by recovery of the ANC to ≥500 cells/microL.

PREVENTION OF INFECTION Antibacterial prophylaxis should be cnsidered

in high-risk patients. Fluoroquinolones are most commonly used

(Levaquin recommended). Antifungal prophylaxis is recommended in

high-risk patients, targeting Candida infections undergoing intensive chemotherapy for acute leukemia and HCT recipients.

Prophylaxis with Posaconazole should be considered.

CATHETER-RELATED INFECTIONSCentral venous catheters facilitate

administration of chemotherapy, drugs, frequent blood draws, infusion of blood products and hyperalimentation.

CATHETER-RELATED INFECTIONSClassification Exit site infection Tunnel infection Port-a-cath pocket infection Catheter associated bacteremia or fungemia Septic thrombophlebitis

CATHETER-RELATED INFECTIONS

CATHETER-RELATED INFECTIONSEtiology Infections are caused by the skin flora,

contamination of the lumen during manipulation, or secondary seeding during bacteremia or fungemia.

Most common organism associated with CVC infections are Staphylococcus epidermis, followed by Staphylococcus aureus.

Gram-negative bacilli, fungi (Candida) and Mycobacteria are less common.

CATHETER-RELATED INFECTIONSClinical Presentation Exit site infection present with pain,

erythema, tenderness, or purulent discharge at exit site. Although, purulence is usually absent in neutropenic patient.

Tunnel infections are associated with pain or swelling along the subcutaneous tract, and may have erythema, induration or fluctuance.

Bloodstream infections are manifested by fever, chills, sepsis and there may be complete lack of signs pertaining to the CVC’s.

CATHETER-RELATED INFECTIONLaboratory Evaluation Blood cultures from all the lumens of the

CVC. Peripheral site blood culture. Differential time to positivity and quantitative

colony count methodology may be helpful. Culture of drainage, if any from exit site.

CATHETER-RELATED INFECTIONSManagement Removal of CVC. Empiric antimicrobial therapy should target

the most commonly implicated organisms and subsequently streamlined specifically for the organism isolated.

The duration of therapy is 14 days for uncomplicated infection, and 4-6 weeks in patients with complicated infection.

PNEUMONIAIntroduction It is a common complication in cancer

patients.

Risk Factors Multiple risk factors predispose to

pneumonia. These include neutropenia, cellular and

humoral immunodeficiencies, impaired tracheobronchial clearance, and the epidemiologic setting or exposures.

PATTERN OF INFECTION IN PNEUMONIA Patient exposures and the nature of the host

immune defects influence the pattern of pulmonary infection. These infections can be divided into the following general categories:

Community acquired Nosocomial Reactivation Environmental exposure

ETIOLOGY OF PNEUMONIABacterial Infection Community-acquired pathogens include S.

pneumoniae, H.influenzae, Mycoplasma, Legionella, Chlamydia, and others.

Fungal Infection The three most important causes of fungal pulmonary infection

are Pneumocystis jirovecii, Aspergillus spp (especially A. fumigatus), and Cryptococcus neoformans.

Viral Infection Cytomegalovirus is the most common virus of concern in

immunocompromised patients, especially transplant recipients. However, other viruses such as Influenza, Parainfluenza, and Respiratory Syncytial virus are diagnosed with greater frequency.

Parasites Parasitic pathogens are not common. However, infection

with Strongyloides stercoralis and Toxoplasma gondii are important diagnostic considerations since they can lead to life-threatening infections.

CLINICAL PRESENTATION OF PNEUMONIA Patients may be asymptomatic, however

fever is often present. Symptoms include non-productive cough,

pleuritic chest pain and dyspnea. Hemoptysis when present is concerning

necrotizing infection.

DIAGNOSTIC WORK-UP IN PNEUMONIA Rapid assessment of vital signs, including oxygen

saturation Complete blood count with differential Electrolytes, blood urea nitrogen, and creatinine Blood cultures (minimum of two sets, with at least one

peripheral set and one set from any indwelling catheter) Urine sediment examination and culture Sputum for Gram stain, fungal smears, and cultures Imaging of the lungs (chest radiography or, whenever

possible, chest computed tomographic scanning) and imaging of any symptomatic site (eg, abdomen)

Brochoscopic alveolar lavage (smears, cultures and cytology, PCR)

If etiologic diagnosis is still lacking, transthoracic needle biopsy under CT-guidance may be done.

Chest radiograph demonstrating diffuse bilateral infiltrates in a patient with Pneumocystis carinii pneumonia

High-resolution computed tomography scan obtained through the upper lobes in the prone position in a patient with a history of Pneumocystis carinii pneumonia. This image shows parenchymal and subpleural cysts and patchy fibrosis that resulted from the Pneumocystis carinii infection.

MANAGEMENT OF PNEUMONIA IN IMMUNOCOMPROMISED PATIENTS Empiric therapy based on neutropenic fever

regimens is acceptable. Empiric therapy should be broad-spectrum

and if indicated, cover for MRSA and Pseudomonas aeroginosa should be provided.

Patients with later onset of Pneumonia, prolonged and profound neutropenia should receive empiric antifungal therapy.

GASTROINTESTINAL INFECTIONS Cancer chemotherapy may lead to mucosal

injury of the gastrointestinal tract and risk for infection.

The commonly encountered syndromes are: Neutropenic enterocolitis (Typhilitis) Clostridium difficile enterocolitis.

Other organisms can also be encountered: Bacterial (Salmonella, Listeria, Aeromonas) Viral (Adenovirus, CMV, Norovirus) Parasites (Strongyloides)

NEUTROPENIC ENTEROCOLITIS Neutropenic enterocolitis is a life-threatening,

necrotizing enterocolitis occurring primarily in neutropenic patients. Other terms that have been used to describe this syndrome include "necrotizing enterocolitis" and "ileocecal syndrome." Neutropenic enterocolitis occurs most commonly in individuals with hematologic malignancies who are neutropenic and have breakdown of gut mucosal integrity as a result of cytotoxic chemotherapy.

"Typhlitis" describes neutropenic enterocolitis of the ileocecal region.

PATHOGENESIS OF NEUTROPENIC ENTEROCOLITIS The pathogenesis is incompletely understood. It involves

mucosal injury by cytotoxic drugs or other means, profound neutropenia, and impaired host defense to invasion by microorganisms.

The microbial infection leads to necrosis of various layers of the bowel wall. The cecum is usually affected, and the process often extends into the ascending colon and terminal ileum. The predilection for the cecum is possibly related to its distensibility and its diminished vascularization relative to the rest of the colon.

Gross and histologic examinations may reveal bowel wall thickening, discrete or confluent ulcers, mucosal loss, intramural edema, hemorrhage, and necrosis. Various bacterial and/or fungal organisms are often seen infiltrating the bowel wall. Polymicrobial infection is frequent.

MICROBIOLOGY OF NEUTROPENIC ENTEROCOLITIS Various bacterial and/or fungal organisms,

including gram-negative bacilli, gram-positive cocci, anaerobes (eg, Clostridium septicum), and Candida spp, are often seen infiltrating the bowel wall, and polymicrobial infection is frequent.

Bacteremia or fungemia is also common; pathogens include Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp, viridans group streptococci, enterococci, Bacteroides spp, Clostridium spp, and Candida spp.

CLINICAL MANIFESTATIONS OF NEUTROPENIC ENTEROCOLITIS Fever and abdominal pain. The location of abdominal pain is often in the

right lower quadrant. Additional symptoms may include abdominal

distension, cramping, tenderness, nausea, vomiting, watery or bloody diarrhea, and frank hematochezia. Paralytic ileus may occur but is uncommon.

Peritoneal signs and shock suggest the possibility of bowel wall perforation. Stomatitis and pharyngitis, suggesting the presence of widespread mucositis, may be present.

DIAGNOSIS OF NEUTROPENIC ENTEROCOLITIS Computed tomography (CT) is the preferred

imaging modality. CT findings included bowel wall thickening,

mesenteric stranding, bowel dilatation, mucosal enhancement, and pneumatosis.

Plain films of the abdomen are nonspecific, but, occasionally, a fluid-filled, distended cecum with dilated adjacent small bowel loops, thumbprinting, or localized pneumatosis intestinalis is seen (Plain films are useful for detecting free air).

A CT scan through lower abdomen shows severe edema and thickening of the cecal wall (single arrow). There are surrounding ascites (arrowhead) and bubbles of free air (double arrow). The descending colon is uninvolved (dashed arrow). The patient has colon carcinoma and is receiving chemotherapy.

MANAGEMENT OF NEUTROPENIC ENTEROCOLITIS In patients without complications (ie,

peritonitis, perforation, or severe bleeding), nonsurgical management with bowel rest, nasogastric suction, intravenous (IV) fluids, nutritional support, blood product support and broad-spectrum antibiotics is a reasonable initial approach.

Although surgery is typically avoided in neutropenic and thrombocytopenic patients, surgical intervention is recommended in patients with free perforation or other process that cannot be controlled medically.

MANAGEMENT OF NEUTROPENIC ENTEROCOLITIS Piperacillin-tazobactam (4.5 g IV every six

hours Cefepime (2 g IV every eight hours) or

Ceftazidime (2 g IV every eight hours) PLUS Metronidazole (500 mg IV every eight hours).

Imipenem-cilastatin (500 mg IV every six hours;) or Meropenem (1 g IV every eight hours).

Duration — Antimicrobial therapy should be continued until well after recovery from neutropenia and until the patient has experienced resolution of the signs and symptoms.

CLOSTRIDIUM DIFFICILE COLITIS Clostrdium difficile is a gram-positive,

anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis.

The prevalence of C difficile infection has been increasing.

The increase inn incidence and severity is attributed to emergence of hyper virulent strain (NAP1/B1/027 strain)

PATHOPHYSIOLOGY OF CDC C difficile colitis results from a disturbance of the

normal bacterial flora of the colon, colonization with C difficile, and the release of toxins that cause mucosal inflammation and damage.

Feco-oral route. Hospitalized patients are the primary targets of

C difficile. The use of antibiotics suppress the gut flora

which normally resist the colonization of C difficile.

Two distinct toxins are produced by C difficile. Toxin A is an enterotixin and Toxin B is a cytotoxin.

ETIOLOGY OF CDC Antibiotic exposure

Cephalosporins Fluoroquinolones Clindamycin Ampicillin/ Amoxicillin

Proton pump inhibitors Chemotherapeutic agents

Cisplatin Cyclophosphamide 5-Fluorouracil Methotrexate

Surgery, Enteral feeding, Uremia, Age, Hospitalization.

CLINICAL PRESENTATION OF CDC Wide spectrum. From asymptomatic carrier

state; mild, self-limited diarrhea; pseudomenbranous colitis; and fulminant colitis.

Mild to moderate watery diarrhea Cramping abdominal pain Anorexia Malaise Fever Dehydration, marked tenderness, rigidity and

decreased bowel sounds indicates the presence of complications such as pseudomembranous colitis, toxic megacolon and bowel perforation.

DIAGNOSIS OF CDC Stool test for C difficile:

Enzyme immunoassay (EIA) PCR Cytotoxin assay (gold standard)

Stool culture Endoscopy

Presence of pseudomenbranous colitis is highly suggestive.

CT Abdomen

MANAGEMENT OF CDC De-escalation or discontinuing the offending

antimicrobial. However, this approach is rarely possible in the neutropenic febrile patient.

Patients should be treated with oral Vancomycin (125 mg QID).

Intravenous Metronidazole may be considered as an addition.

Other available agents are Fidoxamicin (200 mg BD for 10 days) or Rifaximin (400 mg TDS for 20 days)

CONCLUSION Infections in cancer patients are of diverse

etiology. The type of infection and its severity reflects

underlying immune-deficient state and knowledge of these factors can aid in management of these patients.

REFERENCES Harrison’s Principles of Internal Medicine Progress in Medicine 2016 www.uptodate.com www.medscape.com

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