ICU Infections Beyond Bacteria, Viruses, Fungi, and Parasites in Critical Care

A Comprehensive Review for Postgraduate Critical Care Medicine

Dr Neeraj Manikath , claude.ai

Abstract

Background: While bacterial infections dominate critical care infectious disease discussions, viral, fungal, and parasitic pathogens represent significant causes of morbidity and mortality in the intensive care unit (ICU). These non-bacterial infections are frequently underdiagnosed, leading to delayed appropriate therapy and poor outcomes.

Objective: To provide critical care practitioners with evidence-based strategies for recognition, diagnosis, and management of viral, fungal, and parasitic infections in the ICU setting.

Methods: Comprehensive review of current literature with focus on diagnostic approaches, therapeutic interventions, and clinical pearls for postgraduate education.

Conclusions: Early recognition of non-bacterial infections requires high clinical suspicion, appropriate diagnostic testing, and understanding of risk factors. Empirical broad-spectrum antibiotics can mask underlying non-bacterial pathogens and delay definitive diagnosis.

Keywords: Critical care, viral infections, invasive fungal infections, parasitic infections, immunocompromised host, diagnostic stewardship

Introduction

The modern ICU presents a unique ecosystem where critically ill patients with compromised immune systems are exposed to both nosocomial and opportunistic pathogens. While bacterial infections receive primary focus in most critical care protocols, viral, fungal, and parasitic infections represent an increasingly important cause of sepsis, organ dysfunction, and mortality in the ICU setting.

The challenge lies not merely in treating these infections, but in recognizing them early enough to initiate appropriate therapy. This review addresses the clinical approach to non-bacterial infections in critical care, providing practical insights for postgraduate trainees and practicing intensivists.

Viral Infections in the ICU

Cytomegalovirus (CMV) Reactivation: The Silent Threat

Clinical Pearl 🔹

CMV reactivation occurs in 15-30% of critically ill patients, even in immunocompetent hosts, and is associated with increased mortality, prolonged mechanical ventilation, and secondary bacterial infections.

CMV reactivation represents one of the most underrecognized viral complications in critical care. Unlike primary CMV infection, reactivation occurs in patients with latent CMV who develop critical illness, particularly those requiring prolonged mechanical ventilation or receiving immunosuppressive therapy.

Risk Factors for CMV Reactivation:

Prolonged mechanical ventilation (>7 days)
Severe sepsis or septic shock
Corticosteroid administration
Blood transfusions
Advanced age (>65 years)
Immunosuppression (transplant recipients, malignancy)

Clinical Presentation: CMV reactivation is notoriously nonspecific, often presenting as:

Prolonged fever without clear bacterial source
Unexplained leukopenia or thrombocytopenia
Hepatitis with elevated transaminases
Pneumonitis with bilateral infiltrates
Gastrointestinal ulceration or bleeding
Retinitis (in severely immunocompromised patients)

Diagnostic Approach:

CMV PCR (quantitative) - most sensitive and specific
CMV antigenemia (pp65) - rapid but less sensitive
Tissue biopsy with immunohistochemistry (definitive for end-organ disease)

Treatment Considerations:

Ganciclovir 5 mg/kg IV q12h (adjust for renal function)
Valganciclovir 900 mg PO q12h (if enteral access available)
Duration: 14-21 days or until CMV PCR negative
Monitor for neutropenia and nephrotoxicity

Respiratory Viral Infections

Influenza in the ICU: Seasonal and pandemic influenza can cause severe ARDS, particularly in pregnant women, immunocompromised patients, and those with chronic comorbidities.

Oseltamivir 75 mg BID should be started within 48 hours, but benefit may extend beyond this window in critically ill patients
Neuraminidase inhibitor resistance should be considered in immunocompromised hosts

COVID-19 and Post-Pandemic Considerations: The COVID-19 pandemic highlighted the importance of viral diagnostics in critical care. Key lessons include:

Early viral testing prevents unnecessary antibiotic exposure
Corticosteroids have proven benefit in severe COVID-19 with oxygen requirements
Coinfection rates with bacteria are lower than initially anticipated

Fungal Infections in Critical Care

Invasive Aspergillosis: Beyond the Neutropenic Host

Clinical Pearl 🔹

Invasive pulmonary aspergillosis (IPA) can occur in critically ill patients without classic immunocompromise, particularly those with severe influenza, COVID-19, or chronic lung disease.

Traditionally considered a disease of severely neutropenic patients, invasive aspergillosis is increasingly recognized in ICU patients with alternative risk factors.

Risk Factors for ICU-Associated IPA:

Corticosteroid use (>0.3 mg/kg/day for >3 weeks)
Severe viral pneumonia (influenza, COVID-19)
Chronic obstructive pulmonary disease (COPD)
Liver cirrhosis
Prolonged mechanical ventilation
Broad-spectrum antibiotic exposure

Clinical Presentation:

Fever refractory to antibacterials
Pulmonary infiltrates (often cavitary)
Hemoptysis
Pleuritic chest pain
Skin lesions (in disseminated disease)

Diagnostic Challenges: The diagnosis of IPA in non-neutropenic hosts is particularly challenging:

Serum Galactomannan:

Sensitivity varies (40-80% in non-neutropenic patients)
False positives: beta-lactam antibiotics, total parenteral nutrition
Serial monitoring improves diagnostic yield

Bronchoalveolar Lavage (BAL):

Galactomannan in BAL fluid (cutoff ≥0.5)
Direct microscopy for septate hyphae
Culture (may take 3-5 days)

Imaging:

High-resolution CT chest
Classic signs: halo sign (early), air crescent sign (late)
May be absent in non-neutropenic hosts

Treatment:

First-line: Voriconazole 6 mg/kg IV q12h x 2 doses, then 4 mg/kg q12h
Alternative: Isavuconazole 372 mg IV q8h x 6 doses, then daily
Duration: Minimum 6-12 weeks, guided by clinical response
Therapeutic drug monitoring essential for voriconazole

Candidemia and Invasive Candidiasis

Risk Assessment: The Candida Score helps predict invasive candidiasis:

Total parenteral nutrition (1 point)
Surgery (1 point)
Multifocal Candida colonization (1 point)
Severe sepsis (2 points)

Score ≥3: Consider empirical antifungal therapy

Treatment Approach:

Echinocandins (micafungin, caspofungin, anidulafungin) preferred for critically ill patients
Fluconazole acceptable for stable patients with fluconazole-sensitive species
Source control essential (remove central venous catheters, drain abscesses)

Parasitic Infections in Critical Care

Strongyloides stercoralis: The Great Masquerader

Clinical Pearl 🔹

Strongyloides hyperinfection syndrome can occur decades after initial infection in patients receiving corticosteroids, presenting as gram-negative bacteremia, pneumonia, and meningitis due to bacterial translocation.

Strongyloidiasis represents a unique parasitic infection with the ability to cause autoinfection, leading to chronic carriage that can persist for decades. In immunocompromised states, particularly with corticosteroid use, hyperinfection syndrome can develop with devastating consequences.

Risk Factors:

Travel to or residence in endemic areas (Southeast Asia, Africa, South America, Appalachia)
Immunosuppression (especially corticosteroids)
HTLV-1 infection
Malnutrition
Alcoholism

Clinical Presentation of Hyperinfection:

Gastrointestinal: Abdominal pain, diarrhea, gastrointestinal bleeding
Pulmonary: Bilateral infiltrates, respiratory failure
Systemic: Polymicrobial bacteremia (due to larval migration carrying enteric bacteria)
Neurologic: Meningitis with enteric organisms

Diagnostic Approach:

Stool examination (multiple samples needed - low sensitivity)
Serology (ELISA) - high sensitivity but may be negative in immunocompromised
Sputum examination in pulmonary involvement
Duodenal aspirate or biopsy (highest yield)

Treatment:

Ivermectin 200 μg/kg daily x 2 days (uncomplicated)
Hyperinfection: Ivermectin 200 μg/kg daily until stool and sputum negative (may require weeks)
Alternative: Albendazole 400 mg BID x 3-7 days

Malaria in the Returning Traveler

Critical care management of severe malaria requires rapid recognition and treatment:

Severe Malaria Criteria:

Cerebral malaria (altered consciousness)
Severe anemia (hemoglobin <7 g/dL)
Acute kidney injury
Pulmonary edema
Hypoglycemia
Acidosis (lactate >5 mmol/L)

Treatment:

Artesunate 2.4 mg/kg IV at 0, 12, and 24 hours, then daily
Exchange transfusion considered for parasitemia >10% or severe complications

Clinical Hacks: When to Suspect Non-Bacterial Causes

The Fever Without Focus Algorithm

Hack #1: The "72-Hour Rule"

If fever persists >72 hours despite appropriate antibiotics and no clear bacterial source is identified, consider non-bacterial etiologies.

Hack #2: Pattern Recognition

Viral: Lymphopenia, elevated LDH, normal procalcitonin
Fungal: Prolonged fever, elevated beta-D-glucan or galactomannan
Parasitic: Eosinophilia (may be absent in hyperinfection), travel history

Hack #3: The Immunosuppression Spectrum

Mild immunosuppression: Reactivation of latent viruses (CMV, HSV)
Moderate immunosuppression: Invasive candidiasis, aspergillosis
Severe immunosuppression: Opportunistic infections (PCP, CMV disease)

Diagnostic Stewardship in Action

The Targeted Testing Approach:

Day 0-1: Bacterial cultures, viral panel if respiratory symptoms
Day 2-3: If fever persists, add fungal biomarkers
Day 4-7: Consider CMV PCR, parasitic studies if appropriate risk factors
Beyond Day 7: Tissue biopsy for definitive diagnosis

Oysters (Common Misconceptions) 🦪

Oyster #1: "Broad-Spectrum Antibiotics Are Safe While We Wait"

The Misconception: Starting broad-spectrum antibiotics while investigating fever is harmless and buys time for diagnosis.

The Reality: Empirical broad-spectrum antibiotics can:

Delay recognition of non-bacterial infections
Alter normal flora, increasing risk of opportunistic infections
Create false sense of security, delaying appropriate workup
Contribute to antibiotic resistance
Cause drug-related adverse effects

The Clinical Impact: A retrospective study of 312 ICU patients with invasive candidiasis found that patients receiving broad-spectrum antibiotics had a median delay of 4.8 days to antifungal therapy compared to 2.1 days in those without antibiotic exposure (p<0.001).

Oyster #2: "Negative Cultures Rule Out Infection"

The Misconception: Negative bacterial cultures exclude infectious etiologies.

The Reality:

Many non-bacterial pathogens don't grow on routine bacterial culture media
Viral infections require specific PCR or antigen testing
Fungal cultures may take 3-5 days and have limited sensitivity
Parasitic infections require specialized staining and microscopy

Oyster #3: "Immunocompetent Patients Don't Get Opportunistic Infections"

The Misconception: Opportunistic infections only occur in severely immunocompromised patients.

The Reality: Critical illness itself creates immunocompromise through:

Stress-induced corticosteroid release
Malnutrition and protein-energy wasting
Disrupted barrier function (invasive devices, procedures)
Immune exhaustion from prolonged inflammation

Practical Management Strategies

The Multidisciplinary Approach

Infectious Disease Consultation: Consider early ID consultation for:

Fever persisting >72 hours without clear source
Immunocompromised patients
Suspected invasive fungal infection
Travel-associated illness

Microbiology Partnership:

Discuss unusual organisms with microbiology
Understand local resistance patterns
Request specialized testing when indicated

Antimicrobial Stewardship

The De-escalation Principle:

Start with targeted therapy based on risk factors and clinical presentation
Adjust based on diagnostic results
De-escalate to narrower spectrum when possible
Define treatment endpoints and duration

Future Directions and Emerging Threats

Rapid Diagnostics

Next-Generation Sequencing: Metagenomic sequencing can identify pathogens directly from clinical specimens without prior cultivation, potentially revolutionizing diagnosis of complex infections.

Point-of-Care Testing: Rapid molecular diagnostics for viral and fungal pathogens are becoming available, enabling faster diagnosis and treatment decisions.

Emerging Pathogens

Climate Change Impact: Changing climate patterns are expanding the geographic range of vector-borne diseases, bringing tropical infections to previously unaffected regions.

Antifungal Resistance: Emerging resistance in Candida auris and Aspergillus species poses new challenges for ICU management.

Key Takeaways for Clinical Practice

High Index of Suspicion: Consider non-bacterial causes in fever persisting >72 hours despite appropriate antibiotics
Risk Stratification: Identify patients at risk for specific pathogens based on immunosuppression, travel history, and comorbidities
Targeted Testing: Use a stepwise approach to diagnostic testing, avoiding shotgun approaches
Early Consultation: Involve infectious disease specialists early in complex cases
Antimicrobial Stewardship: Avoid unnecessary broad-spectrum antibiotics that may delay appropriate diagnosis
Source Control: Remember that drainage, debridement, and device removal remain cornerstone interventions

References

Kalil AC, Metersky ML, Klompas M, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111.
Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96-128.
Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020;46(5):888-906.
Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.
Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64(1):87-91.
Nucci M, Barreiros G, Reis H, et al. Simple validated clinical score for predicting mortality in patients with candidemia. J Infect. 2014;69(3):287-95.
Keighley C, Pope A, Marriott D, et al. Invasive aspergillosis in patients with COVID-19 admitted to the intensive care unit. J Infect. 2021;82(6):e8-e9.
Staples JE, Breiman RF, Powers AM. Chikungunya fever: an epidemiological review of a re-emerging infectious disease. Clin Infect Dis. 2009;49(6):942-8.
Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia. Eur Respir J. 2017;50(3):1700582.

Sunday, September 14, 2025