Fever in an immunocompromised patient

Fever in an immunocompromised patient is a temperature of 38.0 degrees Celsius or over (a single reading of 38.3 degrees Celsius or over, or 38.0 degrees Celsius or over sustained for 1 hour) in a patient with impaired host defences. Signs of inflammation may be muted or absent, deterioration is fast, and mortality is high when treatment is delayed.

Classification by immune defect

• Neutropenia (absolute neutrophil count under 0.5 x 10^9/L, or expected to fall under 0.5 x 10^9/L): chemotherapy, haematological malignancy, bone marrow failure, drug induced agranulocytosis. Risk is high with duration over 7 days and counts under 0.1 x 10^9/L.
• Cell mediated immune defects: HIV (CD4 count under 200 cells/microlitre), solid organ and stem cell transplant, corticosteroids (prednisolone 20 mg daily or more for over 3 weeks), calcineurin inhibitors, anti-tumour necrosis factor drugs, rituximab, lymphoma, and congenital T cell defects.
• Humoral defects: hypogammaglobulinaemia, chronic lymphocytic leukaemia, myeloma, rituximab, nephrotic syndrome.
• Asplenia or hyposplenism: surgical splenectomy, sickle cell disease, coeliac disease.
• Complement deficiency, phagocyte defects, diabetes, cirrhosis, chronic kidney disease, malnutrition, burns, and extremes of age.
• Barrier loss: central lines, mucositis, indwelling devices, surgery, catheters, and skin disease.

Classification by infection

• Bacterial: Gram negative (Escherichia coli, Klebsiella, Pseudomonas), Gram positive (viridans streptococci, coagulase negative staphylococci, Staphylococcus aureus, enterococci), encapsulated organisms in asplenia, Listeria, Nocardia, Salmonella, and mycobacteria.
• Fungal: Candida, Aspergillus, mucormycosis, Cryptococcus, Pneumocystis, endemic fungi (histoplasmosis).
• Viral: herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, adenovirus, respiratory viruses, BK virus, hepatitis B reactivation.
• Parasitic: toxoplasmosis, strongyloides hyperinfection, cryptosporidiosis, malaria, leishmaniasis.
• Noninfectious: drug fever, transfusion reaction, graft versus host disease, tumour fever, pulmonary embolism, engraftment syndrome, haemophagocytic lymphohistiocytosis, immune reconstitution inflammatory syndrome, and adrenal insufficiency.

Epidemiology. Fever occurs in 10% to 50% of patients with solid tumours and over 80% of patients with haematological malignancy during neutropenia. A source is identified in about a third, and bacteraemia in 10% to 25%. Mortality from febrile neutropenia is about 5% to 10% overall and over 20% with bacteraemia and shock. Opportunistic infections occur at predictable time points after transplant. Mechanisms.

Loss of neutrophils and barrier integrity permits bacterial invasion from the gut and skin. T cell defects permit reactivation of latent infections. Humoral defects predispose to encapsulated organisms. Broad spectrum antibiotics and prolonged neutropenia promote fungal infection.

Key distinctions. Fever with neutropenia within 7 to 14 days of chemotherapy suggests bacterial infection and needs immediate antibiotics. Fever persisting beyond 4 to 7 days of broad antibiotics suggests fungal infection or an unrecognised focus. Dry cough with hypoxia and low lactate dehydrogenase in HIV or on steroids suggests Pneumocystis. Fever and headache with CD4 count under 100 cells/microlitre suggests cryptococcal meningitis.

Fever after transplant at 1 to 6 months suggests cytomegalovirus and opportunistic infection. Fever with rash and diarrhoea after stem cell transplant suggests graft versus host disease.

History

• Underlying disease and treatment: chemotherapy regimen and date of last cycle, expected count recovery, corticosteroid dose and duration, biologic agents, transplant type and time since transplant, immunosuppressants, HIV status and CD4 count, antiretroviral therapy adherence.
• Prophylaxis taken: antibacterial, antifungal, antiviral, and Pneumocystis prophylaxis.
• Symptoms: cough, dyspnoea, headache, neck stiffness, visual change, mouth pain, dysphagia, abdominal pain, diarrhoea, perianal pain, dysuria, skin lesions, line site pain, and rigors during line flush.
• Exposures: sick contacts, travel, pets, soil, construction (aspergillus), contaminated food, and tuberculosis contacts.
• Previous infections and cultures (resistant organisms), antibiotic allergy, previous transfusions.
• Risk assessment: Multinational Association for Supportive Care in Cancer (MASCC) score (maximum 26; 21 or more low risk) or Clinical Index of Stable Febrile Neutropenia.

Examination

• Vital signs including oxygen saturation and mental state, and sepsis assessment. Hypothermia may occur.
• Full head to toe search, because inflammatory signs are muted: mouth (mucositis, thrush, gingivitis), sinuses, ears, throat, eyes (fundoscopy: candida chorioretinitis, cytomegalovirus retinitis), skin (including perineum, axillae, nail beds, line sites, previous biopsy sites, vesicles, ecthyma gangrenosum, nodules), lymph nodes, lungs, heart (murmurs), abdomen (tenderness, typhlitis in the right iliac fossa), liver and spleen, perianal region (inspection only, with no digital examination in neutropenia), joints, and neurological examination (meningism, focal signs).
• Central venous catheter exit site and tunnel.
• Signs of graft versus host disease: rash, jaundice, diarrhoea.

Red flags

• Hypotension, tachycardia over 120 beats/min, respiratory rate over 24 breaths/min, confusion, oliguria, or lactate over 2 mmol/L.
• Neutrophil count under 0.5 x 10^9/L (or expected to fall) with any fever.
• Hypoxia, new infiltrates, or dyspnoea (Pneumocystis, aspergillosis, resistant bacteria, viral pneumonitis).
• Severe headache, neck stiffness, altered consciousness, seizures (cryptococcal, listerial or viral meningoencephalitis).
• Necrotic skin lesions, ecthyma gangrenosum, or purpura fulminans.
• Perianal or abdominal pain (typhlitis, perianal abscess).
• Vesicular rash in a dermatomal or disseminated pattern.
• Persistent fever over 96 hours of broad antibiotic therapy.
• Central line tunnel or pocket infection.
• Asplenia with fever (overwhelming sepsis within hours).
• New visual loss.
• Fever shortly after rituximab or checkpoint inhibitor with hepatic or pulmonary signs.

Special groups

• Neutropenic cancer patients: urgent assessment as an emergency (door to antibiotic within 60 minutes).
• Transplant recipients: infections follow a timetable (first month: hospital acquired and donor derived; months 1 to 6: opportunistic and viral; later: community acquired and malignancy).
• HIV: guide diagnosis by CD4 count (under 200: Pneumocystis; under 100: toxoplasmosis, cryptococcosis, mycobacterium avium complex, cytomegalovirus).
• Asplenia: a medical emergency, with risk from encapsulated organisms.
• Children: cancer and neutropenic children need paediatric oncology regimens. Use weight based doses.
• Pregnancy: treat promptly, with obstetric input.
• Region specific: tuberculosis, histoplasmosis, strongyloides, malaria, leishmaniasis and cryptococcosis are common.

Bacterial

• Gram negative bacteraemia: Escherichia coli, Klebsiella, Pseudomonas aeruginosa, Enterobacter, and resistant organisms.
• Gram positive bacteraemia: viridans streptococci, Staphylococcus aureus, coagulase negative staphylococci, enterococci.
• Central line infection and tunnel infection.
• Pneumonia, urinary tract infection, skin and soft tissue infection, perianal infection, and typhlitis.
• Encapsulated organisms in asplenia (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Capnocytophaga).
• Listeria meningitis, Nocardia, Salmonella, Legionella.
• Tuberculosis and nontuberculous mycobacteria.

Fungal

• Candidaemia and invasive candidiasis.
• Invasive aspergillosis, mucormycosis, Fusarium.
• Cryptococcal meningitis, histoplasmosis, and Pneumocystis pneumonia.

Viral and parasitic

• Herpes simplex and varicella zoster.
• Cytomegalovirus disease, Epstein-Barr virus lymphoproliferative disease, adenovirus, BK virus.
• Respiratory viruses (influenza, respiratory syncytial virus, COVID-19, parainfluenza), hepatitis B reactivation.
• Toxoplasmosis, strongyloides hyperinfection, cryptosporidiosis, malaria, leishmaniasis.

Noninfectious

• Drug fever (beta-lactams, allopurinol, phenytoin, amphotericin, cytarabine, bleomycin).
• Tumour fever (lymphoma, leukaemia, renal cell carcinoma).
• Blood product reaction and engraftment syndrome.
• Graft versus host disease.
• Haemophagocytic lymphohistiocytosis.
• Pulmonary embolism and deep vein thrombosis.
• Pancreatitis, adrenal insufficiency, and thyroiditis.
• Immune reconstitution inflammatory syndrome after starting antiretroviral therapy.
• Immune checkpoint inhibitor toxicity (colitis, pneumonitis, hepatitis).

Step 1. Triage and resuscitate. This is an emergency. Record vital signs, lactate, and oxygen saturation. Establish access. Start antibiotics within 1 hour of presentation without waiting for results.

Step 2. First line tests (before antibiotics, without delaying them)

• Two sets of blood cultures (one from each lumen of a central line and one peripheral).
• Full blood count with differential, urea, creatinine, electrolytes, liver tests, C-reactive protein, glucose, lactate, and coagulation.
• Urine analysis and culture, and midstream urine even if no symptoms.
• Chest radiograph in all patients with respiratory symptoms, and in most neutropenic patients.
• Swabs from skin lesions, wounds, line sites, and throat. Respiratory virus polymerase chain reaction.
• Stool culture and Clostridioides difficile test when diarrhoea is present.
• Malaria test when exposure is possible.

Step 3. Targeted tests

• CT chest (high resolution) for fever lasting over 96 hours, suspected pulmonary infection, or hypoxia; CT sinuses, abdomen and pelvis as directed.
• Serum galactomannan and beta-D-glucan for invasive fungal infection (not for patients on mould active prophylaxis for galactomannan), and cryptococcal antigen in HIV and other high risk patients.
• Bronchoscopy with bronchoalveolar lavage for pulmonary infiltrates: Gram stain, cultures, Pneumocystis polymerase chain reaction, fungal and mycobacterial tests, cytology, and viral polymerase chain reaction.
• Cytomegalovirus, Epstein-Barr virus, BK virus and adenovirus quantitative polymerase chain reaction in transplant.
• Lumbar puncture (after imaging if focal signs or reduced consciousness, and after correcting platelets to over 50 x 10^9/L) for headache, neck stiffness, confusion, or seizures, with cryptococcal antigen, India ink, Gram stain, bacterial and fungal culture, viral polymerase chain reaction, and Listeria cultures.
• MRI brain for focal signs (toxoplasmosis, aspergillus, progressive multifocal leukoencephalopathy).
• Biopsy of skin lesions (histology and culture), lymph nodes, or organs.
• Ophthalmological examination for candidaemia and viral retinitis.
• Echocardiogram when bacteraemia with Staphylococcus aureus, Candida, or enterococci persists.
• Quantitative immunoglobulins, CD4 count, HIV viral load, ferritin, triglycerides, soluble interleukin-2 receptor (haemophagocytic lymphohistiocytosis), and drug levels (tacrolimus, ciclosporin).

Step 4. Interpretation. A neutrophil count under 0.5 x 10^9/L with fever is febrile neutropenia until proven otherwise, regardless of source. Positive blood cultures with coagulase negative staphylococci in only one bottle may be contaminants, but may be real in line infection. Differential time to positivity between central and peripheral cultures (central positive 2 hours earlier) supports line infection.

Fever persisting over 4 to 7 days on broad antibiotics should prompt a search for fungal infection or an undrained focus. Do not attribute fever to drugs or tumour until infection has been excluded.

Limits. Cultures are negative in about 70% of febrile neutropenia. Radiographs are insensitive in neutropenia, and infiltrates may appear only as counts recover. Serological tests are unreliable in immunosuppression. Biomarkers have lower sensitivity with prophylaxis.

Immediate. Resuscitate with intravenous crystalloid 500 mL boluses (30 mL/kg in septic shock), oxygen to saturation 94% to 98%, and urgent cultures. Give the first antibiotic dose within 1 hour. Isolate the patient (protective environment for profound neutropenia) and review all drugs.

Febrile neutropenia (high risk and inpatients)

• First line monotherapy: piperacillin with tazobactam 4.5 g intravenously every 6 hours (creatinine clearance 20 to 40 mL/min, 4.5 g every 8 hours; under 20 mL/min, 4.5 g every 12 hours), or meropenem 1 g intravenously every 8 hours (creatinine clearance 26 to 50 mL/min, 1 g every 12 hours; 10 to 25 mL/min, 500 mg every 12 hours; under 10 mL/min, 500 mg every 24 hours), or cefepime 2 g intravenously every 8 hours (creatinine clearance 30 to 60 mL/min, 2 g every 12 hours; 11 to 29 mL/min, 2 g every 24 hours; neurotoxicity in renal impairment).
• Add gentamicin 5 to 7 mg/kg once daily or amikacin 15 mg/kg once daily when septic shock, suspected resistant Gram negative bacteria, or local resistance (monitor levels and creatinine).
• Add vancomycin 15 to 20 mg/kg intravenously every 8 to 12 hours (target trough 15 to 20 mg/L, or area under the curve of 400 to 600 mg x h/L), or linezolid 600 mg every 12 hours, when there is catheter related infection, skin or soft tissue infection, pneumonia, known MRSA, haemodynamic instability, or Gram positive bacteraemia. Stop at 48 hours if cultures are negative.
• Penicillin allergy (nonsevere): the same agents with caution; severe allergy: ciprofloxacin 400 mg intravenously every 8 to 12 hours plus vancomycin or teicoplanin, or aztreonam 2 g every 8 hours plus vancomycin (specialist advice).
• Persistent fever beyond 4 to 7 days of broad antibiotics: CT chest, galactomannan and beta-D-glucan, and start empirical or pre-emptive antifungal therapy: liposomal amphotericin B 3 mg/kg intravenously daily, or caspofungin 70 mg on day 1 then 50 mg daily (35 mg daily in hepatic impairment), or voriconazole 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours (check levels; avoid in renal impairment with intravenous form).
• Low risk (MASCC 21 or more, expected neutropenia under 7 days, no comorbidity, outpatient capable): oral amoxicillin with clavulanic acid 625 mg three times daily plus ciprofloxacin 500 mg twice daily (when not on fluoroquinolone prophylaxis), after initial intravenous dose and observation, with reliable follow up.
• Duration: continue until afebrile for 48 hours and neutrophil count over 0.5 x 10^9/L (rising); stop earlier in selected patients after at least 72 hours of treatment if afebrile 48 hours and clinically well, with documented infection treated for the organism and site (10 to 14 days for bacteraemia from Gram negative bacilli, at least 14 days for Staphylococcus aureus bacteraemia, and longer for deep infection).
• Granulocyte colony-stimulating factor: filgrastim 5 micrograms/kg subcutaneously daily may be used in selected high risk patients (sepsis, pneumonia, invasive fungal infection) until neutrophil recovery.

Specific infections

• Central line infection: remove the catheter for Staphylococcus aureus, Pseudomonas, Candida, mycobacteria, tunnel infection, septic shock, or persistent bacteraemia over 72 hours. Otherwise, treat for 7 to 14 days with antibiotic lock therapy as an option.
• Invasive candidiasis: caspofungin 70 mg then 50 mg daily (or anidulafungin 200 mg then 100 mg daily), switching to fluconazole 800 mg loading then 400 mg daily for susceptible isolates; at least 14 days after the first negative culture; remove lines; ophthalmological review.
• Invasive aspergillosis: voriconazole 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours (or isavuconazole 372 mg isavuconazonium sulphate every 8 hours for 6 doses, then 372 mg daily) for at least 6 to 12 weeks, with levels monitoring. Mucormycosis: liposomal amphotericin B 5 to 10 mg/kg daily with surgical debridement.
• Pneumocystis pneumonia: co-trimoxazole 120 mg/kg daily in 3 to 4 divided doses for 21 days (intravenous or oral) with prednisolone 40 mg twice daily for 5 days, 40 mg daily for 5 days, then 20 mg daily for 11 days when arterial oxygen pressure is under 9.3 kPa; monitor potassium, creatinine and blood count. Alternatives: pentamidine 4 mg/kg intravenously daily, or clindamycin 600 mg every 8 hours with primaquine 30 mg daily (check glucose-6-phosphate dehydrogenase).
• Cryptococcal meningitis: liposomal amphotericin B 3 to 4 mg/kg daily with flucytosine 25 mg/kg every 6 hours for 2 weeks, then fluconazole 400 to 800 mg daily for 8 weeks, then 200 mg daily maintenance. Therapeutic lumbar punctures if opening pressure is over 25 cmH2O. Start antiretroviral therapy 4 to 6 weeks later.
• Cytomegalovirus: ganciclovir 5 mg/kg intravenously every 12 hours for 14 to 21 days (adjust for creatinine clearance: 50 to 69 mL/min, 2.5 mg/kg every 12 hours; 25 to 49 mL/min, 2.5 mg/kg every 24 hours; 10 to 24 mL/min, 1.25 mg/kg every 24 hours), or valganciclovir 900 mg orally twice daily for treatment in mild disease. Monitor neutrophil count.
• Herpes simplex or varicella zoster in the immunocompromised: aciclovir 10 mg/kg intravenously every 8 hours (adjust for renal function) for 7 to 14 days (14 to 21 days for encephalitis).
• Influenza: oseltamivir 75 mg twice daily for 5 to 10 days (renal dose adjustment as needed).
• Toxoplasmosis: pyrimethamine 200 mg then 50 to 75 mg daily with sulphadiazine 1 to 1.5 g every 6 hours and folinic acid 10 to 25 mg daily for 6 weeks.
• Tuberculosis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg and ethambutol 15 mg/kg daily for 2 months, then isoniazid and rifampicin for 4 months, with drug interaction review (rifampicin).
• Asplenic fever: ceftriaxone 2 g intravenously immediately, then at the same dose daily, and urgent hospital care.
• Typhlitis: piperacillin with tazobactam or meropenem plus metronidazole 500 mg every 8 hours when not covered, bowel rest, and surgical review.
• Drug fever and noninfectious causes: diagnosis of exclusion; stop the suspected drug.

Prophylaxis and prevention

• Antibacterial prophylaxis with levofloxacin 500 mg daily for expected neutropenia over 7 days (specialist decision). Pneumocystis prophylaxis with co-trimoxazole 960 mg three times weekly or 480 mg daily. Antiviral prophylaxis with aciclovir 400 mg twice daily or valganciclovir by risk. Antifungal prophylaxis with posaconazole 300 mg daily after a loading dose of 300 mg twice daily on day 1, or fluconazole 400 mg daily. Vaccination before immunosuppression, and for contacts.
• Hand hygiene, protective isolation, line care, and food safety.

Special populations

• Pregnancy: avoid voriconazole, ciprofloxacin, and ganciclovir where alternatives exist; seek specialist advice.
• Children: weight based doses (piperacillin with tazobactam 100 mg/kg of the piperacillin component every 8 hours up to a maximum of 4 g every 6 hours; meropenem 20 mg/kg every 8 hours up to 1 g; gentamicin 7 mg/kg once daily).
• Older adults: adjust for renal function; avoid cefepime overdose.
• Renal and hepatic impairment: adjust doses and measure levels.
• Transplant patients: consider drug interactions with calcineurin inhibitors (azoles, macrolides, rifampicin).

Monitoring. Vital signs every 1 to 4 hours, urine output, temperature chart, daily full blood count and creatinine, C-reactive protein, culture results at 24, 48 and 72 hours, drug levels (vancomycin, gentamicin, voriconazole, tacrolimus), and imaging for persisting fever.

Referral and escalation. Oncology or haematology, transplant medicine and infectious diseases for all febrile neutropenic or immunocompromised patients. Intensive care for septic shock or respiratory failure. Surgery for typhlitis, perianal abscess, and necrotising infection. Ophthalmology for visual symptoms.

Admission criteria. All neutropenic patients unless low risk (MASCC 21 or more) with reliable follow up, all patients with sepsis, new organ dysfunction, hypoxia, central nervous system symptoms, asplenia, or recent transplant.

Discharge and follow up. Discharge only when afebrile for 48 hours, clinically stable, neutrophil count rising, and an oral plan is established. Counsel on temperature monitoring, line care, and emergency access. Safety net advice: any temperature of 38.0 degrees Celsius or over, rigors, new cough, breathlessness, headache, confusion, rash, diarrhoea, or abdominal pain needs same day review.