Pneumocystis Pneumonia (PCP)

1. Overview

Pneumocystis Pneumonia (PCP), caused by the fungus Pneumocystis jirovecii, is a life-threatening opportunistic infection that predominantly affects immunocompromised individuals. Despite advances in antiretroviral therapy, PCP remains the most common AIDS-defining illness globally and a leading cause of morbidity and mortality in patients with HIV/AIDS, haematological malignancies, solid organ transplantation, and those receiving immunosuppressive therapy. [1,2]

The organism, previously known as Pneumocystis carinii, was reclassified in the 1980s when molecular studies revealed that the human pathogen was a distinct species. P. jirovecii is an atypical fungus that shares characteristics with both fungi and protozoa, which explains its unique response to specific antimicrobial agents and its resistance to conventional antifungal therapy. [3]

PCP presents a diagnostic and therapeutic challenge due to its insidious onset in HIV-positive patients (evolving over weeks) versus acute presentation in non-HIV immunocompromised hosts (developing over days). The classic "silent chest" phenomenon—severe hypoxia with minimal auscultatory findings—is a hallmark clinical feature that should prompt immediate investigation. Early diagnosis and treatment, particularly with adjunctive corticosteroids in severe cases, significantly reduces mortality. [4,5]

Clinical Pearls

The "Silent Chest": A classic exam finding. The patient is hypoxic and breathless, but when you listen to the chest, it sounds completely normal (no crackles/wheeze). This is because the pathology is interstitial, not alveolar filling.

Exercise Desaturation: If you suspect PCP in a patient with normal resting sats, walk them up and down the corridor. If sats drop from 98% to 92%, this is highly suggestive of PCP and reflects impaired gas exchange during increased oxygen demand.

Steroids Save Lives: In severe PCP (hypoxia pO2 less than 9.3 kPa or 70 mmHg), the dying fungus releases inflammatory antigens causing a "cytokine storm" that worsens respiratory failure. Giving corticosteroids before or with antimicrobial therapy suppresses this reaction and reduces mortality by approximately 50%. [6]

LDH as a Biomarker: Lactate dehydrogenase (LDH) levels > 500 IU/L are found in > 90% of HIV-associated PCP cases and correlate with disease severity. However, LDH is nonspecific and can be elevated in other conditions including lymphoma, haemolysis, and other pneumonias. [7]

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2. Epidemiology

Incidence and Prevalence

PCP epidemiology has transformed dramatically since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s and routine prophylaxis in at-risk populations. However, it remains a significant global health burden. [8]

Risk Factors

HIV/AIDS-Related Risk Factors:

1. CD4 count less than 200 cells/µL: The most significant predictor, with risk increasing exponentially below this threshold [14]
2. CD4 count less than 100 cells/µL: Risk rises to > 30% per year without prophylaxis
3. Previous PCP episode: 60% recurrence rate within 12 months without secondary prophylaxis [15]
4. Oral candidiasis: Marker of advanced immunosuppression
5. HIV viral load > 100,000 copies/mL: Independent risk factor
6. Lack of HAART: Non-adherence or treatment-naïve status

Non-HIV Risk Factors:

1. Prolonged corticosteroid therapy: > 20mg prednisolone (or equivalent) for > 4 weeks, or > 16mg for > 8 weeks [16]
2. Haematological malignancy: Particularly during chemotherapy-induced neutropenia
3. Solid organ transplantation: Highest risk with lung and heart transplants
4. Stem cell transplantation: Both autologous and allogeneic recipients
5. Inflammatory conditions: Systemic lupus erythematosus, granulomatosis with polyangiitis, inflammatory bowel disease
6. Immunosuppressive medications:
   • Methotrexate
   • Cyclophosphamide
   • Anti-TNF agents (infliximab, adalimumab, etanercept)
   • Anti-CD20 antibodies (rituximab)
   • Calcineurin inhibitors (tacrolimus, ciclosporin)
7. Combination immunosuppression: Synergistic risk when multiple agents used
8. Primary immunodeficiencies: Severe combined immunodeficiency (SCID), hyper-IgM syndrome

Demographics

• Age: Bimodal distribution—infants with primary immunodeficiency and adults with HIV/AIDS or iatrogenic immunosuppression
• Sex: Males predominate in HIV-associated PCP (reflecting HIV epidemiology); equal sex distribution in non-HIV PCP
• Geography: Worldwide distribution; higher incidence in regions with high HIV prevalence (sub-Saharan Africa, Southeast Asia)
• Seasonality: No clear seasonal pattern, unlike bacterial pneumonias

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3. Aetiology & Pathophysiology

The Organism: Pneumocystis jirovecii

Pneumocystis jirovecii is an atypical fungus with unique biological characteristics:

Taxonomic Classification:

• Originally classified as a protozoan based on morphology and response to antiprotozoal drugs
• Molecular phylogenetic analysis in the 1980s revealed fungal ribosomal RNA sequences [3]
• Now classified within the Ascomycota phylum of fungi
• Human-specific pathogen (cannot infect animals; animal Pneumocystis species are host-specific)

Microbiological Features:

• Cannot be cultured using standard mycological or bacteriological media
• Lacks ergosterol in cell membrane (explaining resistance to azole antifungals)
• Contains cholesterol instead, making it susceptible to specific anti-Pneumocystis agents
• Cell wall contains β-1,3-D-glucan (target for diagnostic testing)

Life Cycle:

1. Trophic form (trophozoite): 1-5 µm, pleomorphic, actively replicating haploid form
2. Precyst: Early cyst formation stage
3. Cyst: 5-8 µm, thick-walled, contains 8 intracystic bodies (sporozoites)
4. Sporozoites: Released when cyst ruptures, differentiate into trophozoites

Transmission and Acquisition

Mode of Transmission:

• Primarily airborne transmission via aerosol droplets [17]
• Colonization of healthy individuals occurs in early childhood (> 80% of children have antibodies by age 2-4 years)
• PCP results from either:
  • Reactivation of latent infection during immunosuppression (historical view)
  • New acquisition/reinfection from environmental or person-to-person transmission (increasingly supported by genotyping studies) [18]

Evidence for Person-to-Person Transmission:

• Nosocomial outbreaks documented in renal transplant units and oncology wards
• Molecular typing shows clustering of identical genotypes
• Case reports of healthcare worker-to-patient transmission

Pathophysiology

Initial Attachment and Colonization:

1. Trophozoites are inhaled and reach alveolar spaces
2. Organisms attach to type I pneumocytes via surface glycoproteins (major surface glycoprotein - MSG)
3. Proliferation occurs when host immunity is impaired

Alveolar Damage:

• Extensive proliferation fills alveolar spaces with trophozoites and cysts
• Direct cytotoxic damage to type I pneumocytes
• Type II pneumocyte hypertrophy and hyperplasia (compensatory response)
• Formation of characteristic foamy intra-alveolar exudate (visible on histology)

Inflammatory Response:

• Host immune response (particularly CD4+ T-cells and alveolar macrophages) is crucial for organism clearance
• In immunocompromised hosts, organism burden increases exponentially
• Paradoxically, immune reconstitution or treatment-induced organism death triggers intense inflammation
• Release of β-glucan and other pathogen-associated molecular patterns (PAMPs)
• Cytokine storm (TNF-α, IL-1, IL-6, IL-8) mediates much of the lung injury [19]

Gas Exchange Impairment:

1. Diffusion defect: Thickened alveolar-capillary membrane from inflammation and cellular infiltration
2. V/Q mismatch: Perfusion of poorly ventilated alveoli
3. Shunt: Severe cases develop right-to-left shunting
4. Result: Progressive hypoxia with characteristically widened A-a gradient

Differential Response: HIV vs Non-HIV:

• HIV patients: Gradual onset, lower organism burden, less intense inflammation, better tolerance initially
• Non-HIV patients: Rapid onset, higher organism burden, exuberant inflammatory response, rapid deterioration [20]

Exam Detail: Molecular Pathophysiology:

The interaction between P. jirovecii and host immunity involves complex molecular mechanisms:

1. CD4+ T-cell mediated immunity: CD4+ lymphocytes recognize Pneumocystis antigens and orchestrate clearance through:

   • Th1 response (IFN-γ production)
   • Macrophage activation
   • CD8+ T-cell recruitment

2. Alveolar macrophage dysfunction: Reduced phagocytosis and impaired oxidative burst in immunocompromised hosts allow organism persistence

3. Surfactant abnormalities: P. jirovecii binds to surfactant proteins A and D, impairing surfactant function and contributing to V/Q mismatch

4. Nitric oxide: Both host-derived NO (antimicrobial) and Pneumocystis-induced NO (contributing to lung injury) play roles

5. Apoptosis: Organism-induced apoptosis of type I pneumocytes via Fas/FasL pathway contributes to alveolar damage

Immune Reconstitution Inflammatory Syndrome (IRIS):

• Occurs in 7-27% of HIV patients starting HAART with concurrent or recent PCP
• Paradoxical worsening despite appropriate treatment
• Results from restoration of pathogen-specific immune responses
• May require extended corticosteroid therapy [21]

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4. Clinical Presentation

Symptom Timeline and Onset

The tempo of symptom onset is a key distinguishing feature:

Cardinal Symptoms

1. Dyspnoea (95% of patients)

• Progressive exertional breathlessness is the hallmark symptom
• Initially noticed with significant exertion (climbing stairs)
• Progresses to dyspnoea with minimal activity (walking, dressing)
• Late stages: dyspnoea at rest
• Exercise desaturation is a key clinical sign (SpO2 drop ≥4% with ambulation)

2. Cough (95% of patients)

• Characteristically dry and non-productive
• Minimal or absent sputum production
• May be confused with "cardiac cough" in HIV patients with concurrent cardiomyopathy
• Productive cough suggests alternative or concurrent diagnosis (bacterial superinfection, TB)

3. Fever (80-90% of patients)

• Usually low-grade (37.5-38.5°C)
• May be higher in non-HIV patients
• Absence of fever does not exclude PCP

4. Chest Discomfort (30-40%)

• Vague retrosternal tightness or discomfort
• Not true pleuritic pain (suggests pneumothorax if present)

5. Constitutional Symptoms

• Weight loss (chronic cases in HIV)
• Night sweats
• Fatigue and malaise
• Anorexia

Clinical Signs

General Inspection:

• Signs of underlying immunosuppression:
  • Oral thrush (candidiasis) - marker of advanced HIV
  • Kaposi's sarcoma lesions
  • Wasting/cachexia
  • Lymphadenopathy
  • Cushingoid features (if on corticosteroids)

Vital Signs:

• Tachypnoea: Respiratory rate > 20/min, often 24-30/min
• Tachycardia: Compensatory response to hypoxia
• Fever: As above
• Hypoxia: SpO2 less than 95% on room air (severity-dependent)
  • "Mild PCP: SpO2 92-96%"
  • "Moderate PCP: SpO2 85-91%"
  • "Severe PCP: SpO2 less than 85%"

Respiratory Examination:

• Inspection:
  • Use of accessory muscles
  • Cyanosis (late sign in severe cases)
  • No chest wall abnormalities
• Palpation: Usually normal
• Percussion: Resonant (unless complications like effusion)
• Auscultation: THE HALLMARK—"Silent Chest"
  • Clear lungs in 50-70% of cases despite severe hypoxia [22]
  • Fine end-inspiratory crackles in 30-40%
  • Rhonchi or wheeze rare (suggests alternative diagnosis)
  • This discordance between hypoxia and normal examination is pathognomonic

Important Physical Exam Manoeuvre:

• Exercise desaturation test: Walk patient 20-30 meters or have them perform 6-minute walk test
• Positive if SpO2 drops ≥4% from baseline
• Highly suggestive of PCP in appropriate clinical context

Atypical Presentations

Extrapulmonary PCP (Rare, less than 3% of cases):

• Usually occurs with aerosolized pentamidine prophylaxis (protects lungs but not systemic)
• Sites: lymph nodes, spleen, liver, bone marrow, retina, thyroid
• Presents as disseminated disease with organ-specific symptoms
• Higher mortality than pulmonary PCP alone

Concurrent Infections:

• PCP frequently coexists with other opportunistic infections in advanced HIV:
  • Cytomegalovirus (CMV) pneumonitis
  • Mycobacterium tuberculosis
  • Mycobacterium avium complex (MAC)
  • Cryptococcal pneumonia
• Coinfection should be suspected if atypical features present

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5. Differential Diagnosis

PCP must be distinguished from other causes of hypoxia and bilateral infiltrates in immunocompromised patients:

Primary Differential Diagnoses

"Must Not Miss" Diagnoses

1. Pulmonary embolism: Can coexist; consider if sudden deterioration or pleuritic pain
2. Pneumothorax: Complication of PCP itself; sudden-onset pleuritic chest pain and desaturation
3. Acute coronary syndrome: Chest pain in context of tachycardia and hypoxia
4. Pulmonary Kaposi's sarcoma: May be indistinguishable from PCP radiologically; requires bronchoscopy

Clinical Clues Favouring PCP

• HIV with CD4 less than 200 cells/µL
• Insidious onset (in HIV) or acute onset (in non-HIV)
• Exercise desaturation despite normal resting oxygen saturation
• Silent chest on auscultation
• LDH > 500 IU/L (sensitivity 90%, specificity low)
• Bilateral perihilar interstitial infiltrates or ground-glass opacities on imaging
• Absence of pleural effusion (effusion suggests alternative diagnosis)

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6. Investigations

Diagnosis of PCP requires a combination of clinical suspicion, imaging findings, and microbiological confirmation. However, empirical treatment should not be delayed pending diagnostic confirmation in critically ill patients.

First-Line Investigations

1. Arterial Blood Gas (ABG)

• Essential for severity assessment
• Findings:
  • "Hypoxia: PaO2 less than 11 kPa (80 mmHg) is common; less than 8 kPa indicates severe disease"
  • "Respiratory alkalosis: Hyperventilation in response to hypoxia"
  • "Widened A-a gradient: Hallmark finding"
    • Normal A-a gradient = (Age/4) + 4 mmHg
    • PCP typically shows A-a gradient > 35 mmHg
  • "Hypocapnia: PaCO2 often low due to tachypnoea"
• Severity stratification (crucial for corticosteroid decision):
  • "Mild: PaO2 > 11 kPa (80 mmHg) on room air"
  • "Moderate: PaO2 9.3-11 kPa (70-80 mmHg)"
  • "Severe: PaO2 less than 9.3 kPa (70 mmHg) or A-a gradient > 35 mmHg"

2. Chest X-Ray (CXR)

• Initial imaging modality
• Classic findings (60-80% of cases):
  • Bilateral perihilar interstitial infiltrates ("bat's wing" pattern)
  • Reticulonodular opacities
  • Diffuse haziness
  • Symmetrical distribution
• Atypical patterns (20-30%):
  • Upper lobe predominance (especially with aerosolized pentamidine prophylaxis)
  • Asymmetric infiltrates
  • Focal consolidation
  • Cystic changes/pneumatoceles
  • Pneumothorax (8-35% of cases, particularly in mechanically ventilated patients)
• Normal CXR (10-20% of early PCP): Does NOT exclude diagnosis [23]

3. High-Resolution CT Chest (HRCT)

• Gold standard imaging modality
• Sensitivity: ~100% (if HRCT is completely normal, PCP is highly unlikely)
• Classic findings:
  • "Ground-glass opacification (GGO): Hallmark finding (> 90% of cases)"
    • Diffuse, bilateral, predominantly perihilar
    • Geographic or patchy distribution
    • Spares subpleural spaces ("sparing sign")
  • "Crazy-paving pattern: GGO with superimposed septal thickening"
  • "Cysts and pneumatoceles: Thin-walled, upper lobe predominant (20-30% of cases)"
    • Risk factor for pneumothorax
  • "Mosaic attenuation: Areas of GGO interspersed with normal lung"

4. Lactate Dehydrogenase (LDH)

• Elevated in > 90% of HIV-associated PCP [7]
• Level correlates with disease severity and organism burden
• LDH > 500 IU/L highly suggestive (but nonspecific)
• Limitations:
  • "Also elevated in: haemolysis, lymphoma, liver disease, myocardial infarction, muscle injury"
  • Less reliable in non-HIV PCP
• Utility: Useful for monitoring response to treatment (should decline with successful therapy)

5. Serum Beta-D-Glucan (BDG)

• Component of P. jirovecii cell wall
• High negative predictive value (> 95%): If negative, PCP is very unlikely [24]
• Positive predictive value is lower (60-70%): False positives with other fungal infections (invasive aspergillosis, candidemia), bacterial infections, and haemodialysis
• Cut-off: > 80 pg/mL (assay-dependent)
• Clinical utility: Rule-out test; helps avoid invasive testing in low-probability cases

Microbiological Diagnosis

Gold Standard: Bronchoalveolar Lavage (BAL)

• Procedure: Fibreoptic bronchoscopy with lavage of affected lobe (usually lingula or right middle lobe)
• Sensitivity: 90-99% (highest yield)
• Diagnostic methods on BAL fluid:

1. Microscopy with Staining:

   • Grocott-Gomori methenamine silver (GMS) stain: Stains cyst walls black; most commonly used
   • Toluidine blue O stain: Stains cysts blue-purple
   • Giemsa stain or Diff-Quik: Stains trophozoites and intracystic sporozoites; does not stain cyst wall
   • Immunofluorescence antibody (IFA) staining: High sensitivity and specificity

2. Polymerase Chain Reaction (PCR):

   • Highly sensitive (> 95%)
   • Major limitation: Cannot distinguish colonization from active infection
   • Positive PCR + compatible clinical/radiological picture = PCP
   • Negative PCR effectively rules out PCP
   • Quantitative PCR may help (high organism load suggests infection vs. colonization)

3. Histopathology (if transbronchial biopsy performed):

   • Foamy eosinophilic intra-alveolar exudate
   • Cysts visible with GMS staining

Non-Invasive Sampling:

Induced Sputum (IS)

• Obtained by nebulized hypertonic saline (3-5%) inhalation
• Patient coughs deep sputum sample
• Sensitivity: 50-90% (lower than BAL, highly operator/lab-dependent)
• Specificity: > 95%
• Advantages: Non-invasive, cheaper, faster
• Disadvantages:
  • Lower sensitivity than BAL
  • Many patients cannot produce adequate sample
  • Quality depends on lab expertise
• Best used: In HIV patients with high clinical probability of PCP

Nasopharyngeal Aspirate

• Rarely used; very low sensitivity
• May be attempted in intubated patients when bronchoscopy unavailable

Other Supportive Investigations

Routine Blood Tests:

• Full Blood Count (FBC):
  • Lymphopenia (in HIV/AIDS)
  • Leukocytosis or leukopenia possible
  • Anaemia (chronic HIV, concurrent bone marrow pathology)
• Renal Function (U&Es): Baseline before starting treatment (pentamidine/co-trimoxazole nephrotoxicity)
• Liver Function Tests (LFTs): May be deranged in HIV, drug toxicity
• C-Reactive Protein (CRP): Often surprisingly normal or mildly elevated (unlike bacterial pneumonia)

HIV Testing:

• All patients with suspected PCP should have HIV testing (if status unknown)
• CD4 count and HIV viral load (if HIV-positive)

Sputum Microscopy and Culture:

• To exclude concurrent bacterial or mycobacterial infection
• Mycobacterium tuberculosis (AFB smear, GeneXpert, culture)

Blood Cultures:

• If febrile to exclude bacteraemia

Diagnostic Algorithm

SUSPECTED PCP
(Immunosuppressed + Progressive Dyspnoea + Hypoxia)
           ↓
    INITIAL ASSESSMENT
    - ABG (severity)
    - CXR
    - LDH, Beta-D-Glucan
    - HIV test (if unknown)
           ↓
  HIGH CLINICAL SUSPICION?
  (CD4 less than 200, Hypoxia, Ground-glass on imaging, LDH > 500)
     ┌──────┴──────┐
    YES            NO
     ↓              ↓
START EMPIRICAL   Further Ix
TREATMENT         Beta-D-Glucan
Don't delay!      Consider BAL
     ↓
BRONCHOSCOPY + BAL
(Confirms diagnosis, excludes alternatives)
     ↓
Continue treatment based on results

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7. Classification and Severity Assessment

Severity Classification

Severity assessment guides management decisions, particularly regarding adjunctive corticosteroid therapy and level of care.

Key Threshold: PaO2 less than 9.3 kPa (70 mmHg) → GIVE CORTICOSTEROIDS

Prognostic Factors

Poor Prognostic Indicators:

1. Non-HIV immunosuppression (higher mortality than HIV-PCP)
2. Delayed diagnosis and treatment (> 7 days from symptom onset)
3. Severe hypoxia (PaO2 less than 8 kPa)
4. Elevated LDH (> 500 IU/L)
5. Mechanical ventilation requirement (mortality 50-80%)
6. Pneumothorax (mortality doubles)
7. Age > 65 years
8. Concurrent infection (CMV, bacterial, fungal)
9. Albumin less than 30 g/L

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8. Management

Early initiation of treatment is critical. Empirical therapy should be started based on clinical suspicion and should NOT be delayed pending bronchoscopy or microbiological confirmation, particularly in severely hypoxic patients.

General Principles

1. Start treatment immediately in high-probability cases
2. Severity stratification (using ABG) determines adjunctive corticosteroid use
3. Treatment duration: 21 days (longer than bacterial pneumonia)
4. Bronchoscopy can be performed after treatment initiation (organisms remain detectable for 7-14 days)
5. Avoid oxygen toxicity: Target SpO2 88-92% in severe cases (balance with preventing hypoxic organ damage)

Management Algorithm

CONFIRMED OR SUSPECTED PCP
         ↓
  ASSESS SEVERITY (ABG)
  - "Mild: pO2 > 11 kPa"
  - "Moderate: pO2 9.3-11 kPa"
  - "Severe: pO2 less than 9.3 kPa"
         ↓
START ANTIMICROBIAL THERAPY
(Co-trimoxazole first-line)
         ↓
  SEVERE HYPOXIA?
  (pO2 less than 9.3 kPa or A-a gradient > 35 mmHg)
    ┌─────┴─────┐
   YES         NO
    ↓           ↓
ADD STEROIDS   ANTIBIOTICS
(Prednisolone   ALONE
 40mg BD)       Monitor
  Day 1-5       closely
    ↓
Monitor response:
- Clinical improvement expected by day 4-7
- Repeat ABG
- LDH trend
- CXR (may worsen initially)

Antimicrobial Therapy

First-Line Treatment: Co-trimoxazole (Trimethoprim-Sulfamethoxazole, TMP-SMX)

Mechanism:

• Trimethoprim: Inhibits dihydrofolate reductase
• Sulfamethoxazole: Inhibits dihydropteroate synthase
• Sequential blockade of folate synthesis pathway

Dosing:

• High-dose regimen: 15-20 mg/kg/day (based on trimethoprim component) divided into 3-4 doses

  • "Example: For 70kg patient = 1050-1400mg trimethoprim/day"
  • "Standard formulation: Co-trimoxazole 960mg tablet contains 160mg trimethoprim"
  • "Typical dose: 2 tablets (1920mg) three times daily (6 tablets/day total)"

• Route:

  • "Oral: Mild-to-moderate PCP"
  • "Intravenous: Severe PCP, unable to tolerate oral, malabsorption concerns"

• Duration: 21 days (not 14 days as in bacterial pneumonia)

Efficacy:

• Response rate: 70-90% in HIV-PCP
• Lower response in non-HIV PCP (60-70%)
• Clinical improvement expected by day 4-7
• Radiological improvement lags clinical improvement (may worsen initially)

Adverse Effects (Common):

• Rash: 30-55% (maculopapular, typically appears day 7-14)
• Fever: Drug-related fever common
• Nausea and vomiting: 20-30%
• Cytopenias: Neutropenia, thrombocytopenia (dose-related)
  • Monitor FBC weekly
  • Consider folinic acid (leucovorin) 15mg daily to mitigate marrow toxicity (does NOT impair efficacy)
• Hyperkalaemia: Trimethoprim inhibits renal potassium excretion
• Renal impairment: 5-10%
• Hepatitis: Transaminitis 10-15%
• Stevens-Johnson syndrome/TEN: Rare but serious (less than 1%)

Monitoring:

• Weekly: FBC, U&Es, LFTs
• Hydration: Maintain adequate hydration to prevent crystalluria

Second-Line Treatments (Intolerance or Treatment Failure)

1. Clindamycin + Primaquine

• Dosing:

  • "Clindamycin: 600mg IV/PO every 6-8 hours OR 900mg IV every 8 hours"
  • "Primaquine: 15-30mg (base) PO once daily"

• Efficacy: Comparable to co-trimoxazole (75-85% response rate)

• Advantages: Better tolerated; oral option available

• Adverse Effects:

  • "G6PD deficiency screening mandatory: Primaquine causes haemolysis in G6PD-deficient patients"
  • Diarrhoea (clindamycin-associated, including C. difficile)
  • Rash
  • Methaemoglobinaemia (primaquine)

2. Intravenous Pentamidine Isethionate

• Dosing: 4mg/kg IV once daily (infused over 60-120 minutes)

• Route: Must be given intravenously (or by nebulization for prophylaxis, not treatment)

• Efficacy: 60-70% response rate (inferior to co-trimoxazole)

• Indication: Reserved for patients who cannot tolerate or have failed co-trimoxazole AND clindamycin-primaquine

• Major Adverse Effects (occur in > 50% of patients):

  • "Severe hypotension: Give patient lying down during infusion"
  • "Hypoglycaemia: Can occur during or after treatment (pancreatic beta-cell toxicity)"
  • "Hyperglycaemia/Diabetes mellitus: Paradoxically follows hypoglycaemia"
  • "Nephrotoxicity: Acute kidney injury (dose-dependent)"
  • "Pancreatitis: 5-10%"
  • "QTc prolongation: Arrhythmia risk"
  • "Electrolyte abnormalities: Hypocalcaemia, hypomagnesaemia, hyperkalaemia"
  • Leucopenia

• Monitoring: Daily glucose, renal function, electrolytes, BP during infusion, ECG

3. Atovaquone (Oral Suspension)

• Dosing: 750mg PO twice daily with food (high-fat meal enhances absorption)

• Efficacy: 60-70% (inferior to first-line agents)

• Indication: Mild-to-moderate PCP only; NOT for severe PCP

• Advantages: Well tolerated, oral administration

• Adverse Effects: Generally mild

  • Rash
  • GI upset (nausea, diarrhoea)
  • Headache

• Limitations:

  • Requires functioning GI tract and adequate absorption
  • Expensive
  • Limited data in severe PCP

4. Other Agents (Rarely Used)

• Trimetrexate + folinic acid: No longer available in many countries
• Dapsone + trimethoprim: Alternative; requires G6PD screening (dapsone causes haemolysis)

Adjunctive Corticosteroid Therapy

Landmark Evidence: Adjunctive corticosteroids reduce mortality by ~50% in moderate-to-severe PCP (multiple RCTs and meta-analyses from the late 1980s-early 1990s). [6]

Indications (Either of the following):

1. PaO2 less than 9.3 kPa (70 mmHg) on room air
2. A-a gradient > 35 mmHg

Mechanism of Benefit:

• Suppresses inflammatory response triggered by dying organisms
• Prevents progression to acute lung injury/ARDS
• Reduces alveolar-capillary membrane permeability

Timing:

• Give BEFORE or WITH first dose of antimicrobial therapy
• Maximum benefit if started within 72 hours of antimicrobial initiation
• Minimal benefit if started > 72 hours after antimicrobials

Dosing Regimen (Standard Protocol):

• Total duration: 21 days (concurrent with antimicrobial therapy)
• IV route if patient unable to take oral medications
• Do NOT taper too rapidly: Rebound inflammation may occur

Adverse Effects of Corticosteroids:

• Hyperglycaemia (monitor glucose in diabetics)
• Increased risk of other opportunistic infections (CMV reactivation, invasive aspergillosis)
• GI upset
• Psychiatric effects
• Osteonecrosis (rare with short course)

Evidence Base:

• Bozzette SA, et al. (1990): NEJM consensus statement; 50% mortality reduction with corticosteroids in severe PCP [6]
• Cochrane meta-analysis (2006): Confirmed benefit (RR 0.56 for death, 95% CI 0.32-0.98)

Supportive Care

1. Oxygen Therapy

• Target SpO2: 88-92% (avoid hyperoxia to prevent oxygen toxicity)
• Delivery methods:
  • Nasal cannulae (mild hypoxia)
  • Venturi mask/high-flow nasal oxygen (moderate-severe)
  • "Non-invasive ventilation (NIV): CPAP or BiPAP if hypoxic despite high-flow oxygen"
  • Invasive mechanical ventilation (if respiratory failure despite maximal non-invasive support)

2. Intensive Care Management

• Indications for ICU admission:
  • PaO2 less than 8 kPa despite oxygen
  • Respiratory rate > 30/min
  • Exhaustion/impending respiratory arrest
  • Haemodynamic instability
• Mechanical ventilation: Associated with high mortality (50-80%)
• Lung-protective ventilation: Low tidal volumes (6 mL/kg ideal body weight) if ARDS develops

3. Fluid Management

• Maintain euvolaemia
• Avoid fluid overload (worsens pulmonary oedema)

4. Nutrition

• Nutritional support in critically ill patients
• Manage HIV-associated wasting

Management in Special Populations

Pregnant Women:

• PCP in pregnancy is rare but associated with high maternal and fetal mortality
• Co-trimoxazole: Avoid in first trimester (theoretical teratogenicity); may use in second/third trimester if benefits outweigh risks
• Alternatives: Clindamycin + primaquine (after G6PD screening) or pentamidine
• Corticosteroids: Use if indicated

Renal Impairment:

• Adjust co-trimoxazole dose based on eGFR
• Pentamidine: Increased toxicity; avoid if possible

Paediatric Patients:

• Dosing weight-based
• Co-trimoxazole: 15-20 mg/kg/day (trimethoprim component) divided every 6-8 hours

Treatment Failure

Definition: No clinical improvement or deterioration by day 7-10 of therapy

Causes:

1. Incorrect diagnosis: Alternative or concurrent infection (TB, CMV, fungal)
2. Drug resistance: Rare but described
3. Severe disease: Overwhelming organism burden
4. Inadequate drug levels: Malabsorption, suboptimal dosing
5. Immune reconstitution inflammatory syndrome (IRIS)

Management:

• Review diagnosis: Consider bronchoscopy if not done; send additional samples for TB, CMV, fungi
• Switch to alternative antimicrobial if drug intolerance suspected
• Ensure adequate corticosteroid coverage
• Exclude pneumothorax (repeat CXR)
• Consider therapeutic drug monitoring (if available)

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9. Complications

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10. Prognosis and Outcomes

Mortality Rates

Prognosis depends heavily on patient population, disease severity, and timeliness of treatment:

Factors Contributing to Higher Mortality in Non-HIV PCP

1. More rapid progression (shorter time to diagnosis)
2. Lower clinical suspicion leading to delayed diagnosis
3. Higher organism burden
4. More intense inflammatory response
5. Underlying comorbidities and immunosuppression
6. Often older age

Long-Term Outcomes

Survivors:

• Majority achieve full clinical recovery within 3-6 months
• Residual radiological changes may persist (cysts, scarring)
• Pulmonary function: Mild restrictive defect or reduced DLCO may persist in some patients
• Quality of life: Generally returns to baseline

Risk of Recurrence:

• Without secondary prophylaxis: 60% recurrence within 12 months [15]
• With secondary prophylaxis: less than 5% recurrence
• Prophylaxis should be continued lifelong or until immune reconstitution (CD4 > 200 cells/µL for > 3 months on HAART)

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11. Prevention and Prophylaxis

Primary and secondary prophylaxis are highly effective at preventing PCP in at-risk populations.

Primary Prophylaxis (HIV/AIDS)

Indications:

1. CD4 count less than 200 cells/µL (or CD4 less than 14% of total lymphocytes)
2. Oral candidiasis (marker of advanced immunosuppression, even if CD4 > 200)
3. Previous AIDS-defining illness (regardless of CD4 count)
4. CD4 count 200-250 cells/µL if monitoring is unreliable

First-Line: Co-trimoxazole (Trimethoprim-Sulfamethoxazole)

• Dosing:
  • 960mg (one double-strength tablet) once daily, OR
  • 480mg (one single-strength tablet) once daily, OR
  • 960mg three times weekly (Monday-Wednesday-Friday)
• Efficacy: 85-95% reduction in PCP incidence
• Additional benefits:
  • Protects against toxoplasmosis (90% reduction)
  • Reduces bacterial infections (pneumonia, UTI)
  • Possible reduction in malaria (in endemic areas)
• Adverse effects: Rash, nausea, hyperkalaemia, bone marrow suppression (generally well-tolerated at prophylactic doses)

Second-Line Options (if intolerant to co-trimoxazole):

1. Dapsone

   • Dose: 100mg PO once daily
   • Must check G6PD status before starting (haemolysis risk)
   • May be combined with pyrimethamine (50mg weekly) + folinic acid (15mg weekly) for toxoplasmosis prophylaxis
   • Adverse effects: Haemolysis, methaemoglobinaemia, rash

2. Atovaquone

   • Dose: 1500mg PO once daily with food
   • Well-tolerated
   • Expensive
   • Does NOT protect against toxoplasmosis

3. Aerosolized Pentamidine

   • Dose: 300mg via Respigard II nebulizer monthly
   • Advantage: Minimal systemic toxicity
   • Disadvantages:
     • Does NOT protect against toxoplasmosis or bacterial infections
     • Risk of extrapulmonary PCP (disseminated disease)
     • Requires specialized equipment and administration
     • Bronchospasm (pre-treat with bronchodilator)

Discontinuation of Primary Prophylaxis:

• CD4 count > 200 cells/µL for > 3 months on effective HAART
• Sustained viral suppression
• Can be safely stopped; restart if CD4 falls below 200 again

Secondary Prophylaxis (After PCP Episode)

Indication: All patients who have had PCP

Regimen: Same as primary prophylaxis (co-trimoxazole preferred)

Duration:

• HIV patients: Until CD4 > 200 cells/µL for > 3 months on HAART
• Non-HIV immunocompromised: Continue as long as immunosuppression persists

Prophylaxis in Non-HIV Immunocompromised Patients

Indications (vary by guideline and risk stratification):

1. Haematological malignancy:

   • Acute lymphoblastic leukaemia (ALL): Routine prophylaxis during chemotherapy
   • Other leukaemias/lymphomas: If receiving intensive chemotherapy with prolonged lymphopenia

2. Solid organ transplant recipients:

   • All lung transplant recipients (highest risk): 6-12 months post-transplant
   • Heart, liver, kidney transplant: 6 months post-transplant (protocols vary)

3. Haematopoietic stem cell transplant:

   • Allogeneic HSCT: Minimum 6 months post-transplant; longer if ongoing immunosuppression (e.g., graft-versus-host disease)
   • Autologous HSCT: During neutropenic period and until lymphocyte recovery

4. Prolonged high-dose corticosteroids:

   • 20mg prednisolone (or equivalent) for > 4 weeks, particularly if combined with other immunosuppressants

   • Consider if > 16mg for > 8 weeks

5. Specific immunosuppressive regimens:

   • Rituximab (anti-CD20): Consider for duration of B-cell depletion
   • Alemtuzumab (anti-CD52): High risk; prophylaxis recommended
   • Combined immunosuppression (e.g., methotrexate + anti-TNF)

Regimen: Co-trimoxazole 480-960mg once daily or three times weekly

Duration: Continue for duration of immunosuppression or risk period

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12. Key Guidelines and Evidence

Major Society Guidelines

Landmark Evidence

1. Adjunctive Corticosteroids (NEJM 1990)

• Bozzette SA, et al. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med. 1990;323(21):1500-1504. [6]
• Finding: Corticosteroids reduce mortality by ~50% in moderate-to-severe PCP (pO2 less than 70 mmHg)
• Impact: Standard of care worldwide

2. Co-trimoxazole Prophylaxis (Lancet 1992)

• Multiple trials (ACTG 081, others) demonstrated 85-95% reduction in PCP incidence with co-trimoxazole prophylaxis
• Additional benefit: Protection against toxoplasmosis and bacterial infections

3. HAART Era Epidemiology (CID 2001)

• Kaplan JE, et al. Epidemiology of HIV-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. CID. 2000;30(Suppl 1):S5-14.
• Finding: Dramatic decline in PCP incidence post-HAART introduction (from 80% lifetime risk to less than 5%)

4. Non-HIV PCP Mortality (Chest 2014)

• Roux A, et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Médecine et Maladies Infectieuses. 2014;44(5):185-198. [20]
• Finding: Non-HIV PCP has 2-3 times higher mortality than HIV-PCP despite treatment

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13. Patient and Layperson Explanation

What is PCP?

Pneumocystis pneumonia (PCP) is a serious lung infection caused by a fungus called Pneumocystis jirovecii. This fungus is found commonly in the environment, and most healthy people breathe it in without getting sick. However, if your immune system is very weak—such as with HIV/AIDS, cancer treatment, or medications that suppress immunity—the fungus can multiply in your lungs and cause pneumonia.

What are the symptoms?

The main symptom is shortness of breath that gradually gets worse over several weeks. You might notice:

• Feeling breathless when climbing stairs or walking
• A dry cough (without mucus)
• Fever
• Feeling tired and weak

A key sign is that you might feel fine sitting still but become very breathless when you move around. Your doctor might notice that your oxygen levels drop when you walk.

How is it diagnosed?

Your doctor will:

1. Listen to your chest (often it sounds normal despite low oxygen)
2. Measure your oxygen levels
3. Order a chest X-ray or CT scan (shows cloudy patches in the lungs)
4. Perform a test called bronchoscopy—a thin camera is passed into your lungs to collect samples

How is it treated?

PCP is treated with a strong antibiotic called co-trimoxazole (Septrin) for 3 weeks. If your oxygen levels are very low, you'll also receive steroid medication (prednisolone) to calm inflammation in your lungs. This combination is very effective when started early.

Some people need oxygen support while the treatment works. Most people start feeling better within 4-7 days, but it's crucial to complete the full 3-week course.

Is it contagious?

Technically, yes—the fungus can spread from person to person through the air. However, you can only catch PCP if your immune system is very weak. Healthy people will not get sick even if exposed. If you have PCP, you don't need to isolate from healthy family members, but you should avoid close contact with other immunocompromised people.

Can it be prevented?

Yes! If you have HIV with a low CD4 count (below 200) or are on strong immunosuppression, you can take a preventive antibiotic (usually co-trimoxazole, one tablet daily). This reduces your risk of getting PCP by over 90%. Your doctor will discuss whether you need this prevention medication.

What is the outlook?

With early treatment, most people with PCP recover fully. The infection is more serious if:

• Treatment is delayed
• You have severe oxygen problems
• You're not HIV-positive (this form of PCP tends to be more aggressive)

After recovering, you may need to continue taking preventive antibiotics to stop PCP from coming back.

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14. Examination Focus

Common MRCP/Postgraduate Exam Questions

1. Investigation Question: "A 35-year-old man with HIV (CD4 count 80 cells/µL) presents with 3 weeks of progressive dyspnoea and dry cough. CXR shows bilateral perihilar infiltrates. What is the most appropriate initial investigation?"

• Answer: Arterial blood gas (to assess severity) + induced sputum for Pneumocystis staining, OR bronchoscopy with BAL if induced sputum negative/unavailable

2. Management Question: "A patient with PCP has a PaO2 of 8.5 kPa on room air. In addition to high-dose co-trimoxazole, what else should be given?"

• Answer: Adjunctive corticosteroids (prednisolone 40mg BD for 5 days, then taper over 21 days total)

3. Diagnostic Question: "A 45-year-old with known HIV presents with exertional dyspnoea. Resting oxygen saturations are 96%. What bedside test would support a diagnosis of PCP?"

• Answer: Exercise desaturation test (walk patient; SpO2 drop ≥4% suggests PCP)

4. Imaging Question: "HRCT chest shows bilateral ground-glass opacification with subpleural sparing. What is the most likely diagnosis in an immunocompromised patient?"

• Answer: Pneumocystis pneumonia (PCP)

5. Prophylaxis Question: "At what CD4 count should primary prophylaxis for PCP be started in an HIV-positive patient?"

• Answer: CD4 less than 200 cells/µL (or less than 14% of total lymphocytes)

6. Microscopy Question: "Which stain is used to identify Pneumocystis cysts in bronchoalveolar lavage fluid?"

• Answer: Grocott-Gomori methenamine silver (GMS) stain OR toluidine blue

7. Complication Question: "A patient with PCP on mechanical ventilation develops sudden-onset pleuritic chest pain and further desaturation. What complication has likely occurred?"

• Answer: Pneumothorax (occurs in 8-35% of PCP cases, especially with mechanical ventilation)

Viva Points

Viva Point: Opening Statement: "Pneumocystis pneumonia is a life-threatening opportunistic fungal infection caused by Pneumocystis jirovecii, predominantly affecting immunocompromised hosts, particularly those with HIV/AIDS (CD4 less than 200 cells/µL), haematological malignancies, solid organ transplantation, or prolonged high-dose immunosuppression. It remains the most common AIDS-defining illness globally."

Key Facts to Mention:

1. Epidemiology:

   • Pre-HAART era: 70-80% lifetime risk in HIV/AIDS
   • Post-HAART: Incidence reduced to 3-5 per 100 person-years
   • Non-HIV PCP now represents 30-40% of cases in developed countries

2. Pathophysiology:

   • Atypical fungus lacking ergosterol (resistant to azoles)
   • Proliferates in alveolar spaces, causing interstitial pneumonitis
   • Impaired gas exchange via diffusion defect and V/Q mismatch

3. Clinical Presentation:

   • HIV patients: Insidious onset over 2-4 weeks
   • Non-HIV: Acute onset over days
   • Classic "silent chest" (hypoxia with minimal auscultatory findings)
   • Exercise desaturation

4. Investigations:

   • HRCT: Ground-glass opacification (100% sensitivity)
   • BAL with GMS stain: Gold standard (90-99% sensitivity)
   • LDH > 500 IU/L in > 90% of HIV-PCP
   • Beta-D-glucan: High negative predictive value

5. Severity Stratification:

   • Based on ABG: Mild (pO2 > 11 kPa), Moderate (9.3-11 kPa), Severe (less than 9.3 kPa)

6. Treatment:

   • First-line: High-dose co-trimoxazole (15-20 mg/kg/day) for 21 days
   • Adjunctive corticosteroids if pO2 less than 9.3 kPa or A-a gradient > 35 mmHg (reduces mortality by ~50%)
   • Start steroids BEFORE or WITH antimicrobials
   • Standard steroid regimen: Prednisolone 40mg BD (days 1-5) → 40mg OD (days 6-10) → 20mg OD (days 11-21)

7. Second-Line Options:

   • Clindamycin + primaquine (check G6PD first)
   • IV pentamidine (severe toxicity: hypotension, hypoglycaemia, nephrotoxicity)
   • Atovaquone (mild PCP only)

8. Prophylaxis:

   • Primary prophylaxis if CD4 less than 200 cells/µL
   • Co-trimoxazole 960mg OD (or TIW): 85-95% efficacy; also protects against toxoplasmosis
   • Discontinue if CD4 > 200 for > 3 months on HAART

9. Prognosis:

   • HIV-PCP mortality: 5-15% (mild-moderate), 30-50% (severe with mechanical ventilation)
   • Non-HIV PCP mortality: 30-60% (2-3 times higher than HIV-PCP)

10. Complications:

    • Pneumothorax (8-35%, higher with mechanical ventilation)
    • ARDS
    • Drug toxicity (rash in 30-55%)

Common Mistakes (That Fail Candidates)

❌ Failing to give adjunctive corticosteroids in severe PCP (pO2 less than 9.3 kPa)

• This is evidence-based and reduces mortality by 50%

❌ Treating for only 14 days (bacterial pneumonia duration)

• PCP requires 21 days of treatment

❌ Starting corticosteroids AFTER antimicrobials (e.g., day 3-4)

• Steroids must be given BEFORE or WITH first antimicrobial dose for maximal benefit

❌ Assuming normal CXR excludes PCP

• 10-20% of PCP cases have normal CXR; HRCT is gold standard imaging

❌ Not checking G6PD status before giving primaquine or dapsone

• Both cause severe haemolysis in G6PD-deficient patients

❌ Forgetting to initiate primary prophylaxis in HIV patients with CD4 less than 200

• Co-trimoxazole prophylaxis reduces PCP risk by > 90%

❌ Discontinuing prophylaxis too early

• Must wait until CD4 > 200 for > 3 months on effective HAART

❌ Missing the diagnosis in non-HIV immunocompromised patients

• PCP is increasingly common in transplant recipients, chemotherapy patients, and those on high-dose steroids

Model Viva Answers

Q: "How would you manage a patient with suspected PCP?"

A: "I would approach this systematically:

Initial Assessment:

• Confirm immunosuppression status (HIV status and CD4 count if positive, or other causes like transplant, chemotherapy, steroids)
• Assess severity with arterial blood gas (stratify as mild, moderate, or severe based on PaO2)
• Obtain chest imaging (CXR initially; HRCT if available—shows ground-glass opacification)

Immediate Management:

• Start empirical high-dose co-trimoxazole (15-20 mg/kg/day based on trimethoprim component, divided doses) for 21 days—do NOT delay for diagnostic confirmation in severe cases
• If PaO2 less than 9.3 kPa or A-a gradient > 35 mmHg, add adjunctive corticosteroids (prednisolone 40mg BD for days 1-5, then taper over 21 days total)—give BEFORE or WITH first antimicrobial dose
• Provide supplemental oxygen to maintain SpO2 88-92%

Diagnostic Confirmation:

• Arrange bronchoscopy with bronchoalveolar lavage (BAL) for GMS staining and PCR
• Can perform after starting treatment (organisms detectable for 7-14 days)
• Send additional samples to exclude TB, CMV, and bacterial pathogens

Monitoring:

• Weekly FBC, U&Es, LFTs (drug toxicity monitoring)
• Repeat ABG and LDH to assess treatment response
• Expect clinical improvement by day 4-7

Prophylaxis:

• After treatment, initiate secondary prophylaxis with co-trimoxazole until immune reconstitution (CD4 > 200 for > 3 months if HIV-positive)

This approach is in line with BHIVA and CDC/NIH guidelines."

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Q: "What are the indications for adjunctive corticosteroids in PCP, and what is the evidence?"

A: "Adjunctive corticosteroids are indicated in moderate-to-severe PCP, defined by either:

1. PaO2 less than 9.3 kPa (70 mmHg) on room air, OR
2. A-a gradient > 35 mmHg

Evidence Base: This recommendation is based on multiple randomized controlled trials and a consensus statement published in the New England Journal of Medicine in 1990 (Bozzette et al.), which demonstrated that corticosteroids reduce mortality by approximately 50% in severe PCP.

Mechanism of Benefit: Corticosteroids suppress the intense inflammatory response triggered by dying Pneumocystis organisms during antimicrobial treatment, preventing progression to acute lung injury and ARDS.

Timing: Steroids must be administered BEFORE or WITH the first dose of antimicrobials for maximum benefit. Starting steroids > 72 hours after antimicrobials confers minimal benefit.

Regimen: The standard regimen is prednisolone 40mg twice daily for days 1-5, then 40mg once daily for days 6-10, then 20mg once daily for days 11-21 (total 21 days, concurrent with antimicrobial therapy).

Cautions: While steroids are highly beneficial in severe PCP, they do increase the risk of other opportunistic infections (e.g., CMV reactivation, invasive aspergillosis), so vigilance for concurrent infections is essential."

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15. References

Primary Sources

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15. Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med. 1992;327(26):1836-1841. doi:10.1056/NEJM199212243272603

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20. Roux A, Gonzalez F, Roux M, et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Médecine et Maladies Infectieuses. 2014;44(5):185-198. doi:10.1016/j.medmal.2014.01.007

21. Wislez M, Bergot E, Antoine M, Parrot A, Carette MF, Mayaud C, Cadranel J. Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 2001;164(5):847-851. doi:10.1164/ajrccm.164.5.2101030

22. Miller RF, Ambrose HE, Wakefield AE. Pneumocystis carinii f. sp. hominis DNA in immunocompetent health care workers in contact with patients with P. carinii pneumonia. J Clin Microbiol. 2001;39(11):3877-3882. doi:10.1128/JCM.39.11.3877-3882.2001

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24. Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-β-D-glucan for Pneumocystis jirovecii pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol. 2012;50(1):7-15. doi:10.1128/JCM.05267-11

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