Fever in the Immune Compromised Host & Recurrent Fever

Introduction for MCCQE1 Preparation

Fever in an immunocompromised host is a medical emergency and a high-yield topic for the MCCQE1. As a future Canadian physician, you must demonstrate the CanMEDS Medical Expert role by rapidly identifying the underlying immune defect, stratifying risk, and initiating empiric therapy to prevent mortality.

The immune system can be compromised due to malignancy, chemotherapy, transplantation, HIV/AIDS, or congenital defects. The presentation of infection in these patients is often atypical, with fever sometimes being the only sign of severe sepsis.

Classification of Immune Defects

Understanding the specific type of immune defect helps predict the likely pathogen. This is crucial for selecting the correct empiric therapy in a Canadian clinical setting.

Febrile Neutropenia: A Canadian Emergency

Febrile neutropenia is the most common and dangerous presentation in this category.

Definitions

• Neutropenia: Absolute Neutrophil Count (ANC) < 1.5 x 10⁹/L.
• Severe Neutropenia: ANC < 0.5 x 10⁹/L (or expected to fall below this within 48 hours).

Calculation of ANC

Risk Stratification (MASCC Score)

The Multinational Association for Supportive Care in Cancer (MASCC) index is widely used in Canada to identify low-risk patients who may be eligible for outpatient management.

• Score ≥ 21: Low Risk (Predictive of uncomplicated course).
• Score < 21: High Risk (Requires inpatient admission and IV antibiotics).

Clinical Approach and Management

Recurrent Fever in the Immunocompromised

Recurrent fever implies episodes of fever separated by afebrile periods. In the immunocompromised host, this suggests:

1. Inadequate Source Control: undrained abscess, infected hardware.
2. Resistant Organisms: MRSA, VRE, ESBL-producing Gram-negatives.
3. Secondary Infections: Clostridioides difficile colitis (common in Canadian hospitals), fungal superinfection.
4. Non-Infectious Causes:
   • Drug Fever: Beta-lactams, anticonvulsants.
   • Tumor Fever: Lymphoma (Pel-Ebstein fever), Renal Cell Carcinoma.
   • Thromboembolism: PE/DVT.
   • Reconstitution Syndrome: IRIS in HIV patients starting ART.

Specific Syndromes

• Post-Transplant Lymphoproliferative Disorder (PTLD): EBV-driven malignancy presenting as recurrent fever and lymphadenopathy in transplant recipients.
• CMV Syndrome: Fever, leukopenia, and thrombocytopenia in transplant recipients.

Canadian Guidelines & Epidemiology

When preparing for the MCCQE1, be aware of specific Canadian contexts:

• AMMI Canada Guidelines: Emphasize antimicrobial stewardship. Do not use Vancomycin indiscriminately.
• Vaccination (The Health Advocate Role):
  • Splenectomy: Patients must receive Pneumococcal (Prevnar-20 or V15+P23), Meningococcal (ACWY and B), and Hib vaccines.
  • Flu/COVID: Annual vaccination is critical for all immunocompromised patients.
  • Live Vaccines: Generally contraindicated (e.g., MMR, Varicella, Yellow Fever) in severe immunocompromise.
• Endemic Mycoses:
  • Blastomycosis: Northwestern Ontario, Manitoba.
  • Histoplasmosis: St. Lawrence River Valley.

Key Points to Remember for MCCQE1

• Neutropenic Fever: Treat as Pseudomonas until proven otherwise.
• Rectal Exam: Contraindicated in neutropenic patients due to risk of bacterial translocation.
• Corticosteroids: Mask signs of inflammation (including fever); maintain a high index of suspicion.
• Splenectomy: Medical emergency if febrile; requires immediate coverage for encapsulated organisms (Ceftriaxone or Cefotaxime + Vancomycin).
• Listeria: Add Ampicillin to the regimen if suspected (e.g., meningitis in an immunocompromised patient).

Sample Question

Clinical Vignette

A 45-year-old female is currently undergoing induction chemotherapy for acute myeloid leukemia (AML). She presents to the emergency department with a 4-hour history of feeling unwell and chills. Her last chemotherapy session was 10 days ago. On examination, she appears flushed. Her vitals are: Temperature 38.9°C, HR 115 bpm, BP 105/65 mmHg, RR 22/min, O2 Sat 96% on room air. Physical examination reveals a Hickman catheter in the right chest with no erythema, and mild mucositis. Chest auscultation is clear.

Complete blood count reveals:

• Hemoglobin: 85 g/L
• Platelets: 40 x 10⁹/L
• WBC: 0.8 x 10⁹/L
• Neutrophils: 10%
• Bands: 0%

Which of the following is the most appropriate immediate management step?

Options

• A. Administer G-CSF (Granulocyte-colony stimulating factor) and await culture results.
• B. Draw blood cultures and discharge home with oral Ciprofloxacin and Amoxicillin-Clavulanate.
• C. Draw blood cultures and initiate intravenous Piperacillin-Tazobactam immediately.
• D. Draw blood cultures and initiate intravenous Vancomycin immediately.
• E. Order a CT chest/abdomen/pelvis prior to initiating antibiotics.

Explanation

The correct answer is:

• C. Draw blood cultures and initiate intravenous Piperacillin-Tazobactam immediately.

Detailed Analysis

• Diagnosis: This patient has Febrile Neutropenia. Her ANC is $0.8 \times 0.10 = 0.08 \times 10^9/L$ (or 80 cells/$\mu$L), which is severe neutropenia (<0.5).
• Risk Stratification: She is a high-risk patient (inpatient induction chemotherapy for AML, tachycardia). She requires admission and IV antibiotics.
• Why C is correct: The cornerstone of management is immediate empiric coverage for Gram-negative organisms, particularly Pseudomonas aeruginosa. Piperacillin-Tazobactam is a standard anti-pseudomonal beta-lactam used in Canada for this indication.
• Why A is incorrect: G-CSF is not an immediate treatment for sepsis and should not delay antibiotic administration. It is used prophylactically or in specific refractory cases.
• Why B is incorrect: This patient is high-risk (AML induction, tachycardia). Outpatient management (oral antibiotics) is reserved for low-risk patients (MASCC score ≥ 21) who are hemodynamically stable and have solid tumors.
• Why D is incorrect: Vancomycin is not routinely indicated as initial monotherapy. It is added only if there are specific indications (hemodynamic instability, line infection, MRSA history). While she has a line, Pseudomonas coverage is the priority. If instability worsens, Vancomycin could be added to the beta-lactam, but monotherapy with Vancomycin is inadequate.
• Why E is incorrect: Imaging is important but must never delay antibiotic administration in febrile neutropenia. Time to antibiotics is a key quality metric.

References

1. Taplitz, R. A., et al. (2018). Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. Journal of Clinical Oncology.
2. Bow, E. J., et al. (2019). Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America. (Endorsed by AMMI Canada).
3. Toronto Notes 2024. Infectious Diseases Chapter: Febrile Neutropenia.
4. Public Health Agency of Canada. Canadian Immunization Guide: Immunization of Immunocompromised Persons. Available online