01Approach to the Critical Patient/attcp42

Immediate priorities

›Airway and oxygenation threats

›Respiratory failure triggers

›SpO2 <92% on room air or supplemental O2

›PaO2 <70 mmHg on ABG

›Tachypnea >30/min with accessory muscle use

›Inability to speak in full sentences

›If progressing to respiratory failure, early intubation planning

›HFNC as bridge before intubation in cooperative patients

›NIV with caution; prone positioning consideration for ARDS

›Moderate-to-severe disease triggers adjunctive corticosteroids

›PaO2 <70 mmHg or A-a gradient ≥35 mmHg

›Must be initiated within 72 hours of starting TMP-SMX

›Hemodynamic and sepsis threats

›Shock physiology assessment

›SBP <90 mmHg or MAP <65 mmHg

›Lactate ≥2 mmol/l

›If septic shock, resuscitation with IV crystalloid

›Vasopressors for fluid-refractory shock

›Norepinephrine first-line vasopressor

›Avoid delaying antimicrobial therapy for diagnostic workup

›Organisms persist in specimens for weeks after therapy initiation

Key decision points

›Severity stratification on presentation

›Mild disease: PaO2 ≥70 mmHg or A-a gradient <35 mmHg

›Outpatient oral TMP-SMX acceptable in reliable HIV-positive patients

›Moderate disease: A-a gradient 35–45 mmHg

›Hospitalization and adjunctive corticosteroids required

02History/hx47

Presentation pattern

›Core symptom complex

›Dyspnea

›Exertional onset progressing to resting dyspnea

›Subacute progression over 1–4 weeks in HIV patients

›More acute onset over days in non-HIV immunocompromised patients

›Cough character

›Typically dry and non-productive

›Purulent sputum suggests bacterial co-infection

›Hemoptysis atypical for PCP; raises alternative diagnoses

›Fever

›Present in most cases

›Night sweats and weight loss common in HIV-associated PCP

›Chest discomfort

›Pleuritic chest pain atypical; suggests pneumothorax or bacterial process

Risk factors

›HIV and immunodeficiency

›HIV/AIDS with CD4 <200 cells/mm3

›Approximately 90% of HIV-associated PCP occurs at this threshold

›CD4 <100 cells/mm3 associated with highest risk

›Absence of PCP prophylaxis

›Only 5.4% of patients in a large modern cohort were on prophylaxis at diagnosis

›Non-HIV immunosuppression

›Corticosteroid use ≥20 mg prednisone equivalent daily for ≥4 weeks

›Tapering below this dose or adding prophylaxis reduces risk

›Hematologic malignancy

›32% of modern non-HIV PCP cohorts

›Solid tumors on chemotherapy

03Physical Exam/exam41

Vitals and general

›Vital sign snapshot

›Temperature

›Fever present in most cases

›Immunosuppression may blunt febrile response

›Respiratory rate

›Tachypnea >30/min as severity marker

›Rising trend indicates respiratory fatigue

›Oxygen saturation

›SpO2 often <92% in moderate-to-severe disease

›Ambulatory desaturation may unmask early disease

›Heart rate

›Tachycardia reflects hypoxemia and systemic illness

›General appearance

›Work of breathing

›Accessory muscle use

›Nasal flaring

›Inability to speak in full sentences

Lung and systemic exam

›Chest exam

›Bilateral diffuse dry "cellophane" rales in advanced disease

›Lung exam may be normal in mild disease at rest

›Exertional assessment may reveal rales not present at rest

›Absent focal consolidation

›Diffuse bilateral process is characteristic

›Focal consolidation suggests bacterial co-infection or alternative diagnosis

›Oropharyngeal exam

›Oropharyngeal candidiasis (thrush)

04Differential Diagnosis/ddx41

Infectious mimics

›Bacterial pneumonia

›Community-acquired pneumonia

›ICD-10: J18.9

›More acute onset, productive purulent cough, lobar consolidation

›Elevated procalcitonin and leukocytosis more pronounced

›Pulmonary tuberculosis

›ICD-10: A15.0

›Must always be considered in HIV-positive patients

›Cavitary disease, upper lobe predominance, AFB smear positivity

›Viral pneumonias

›CMV pneumonitis

›ICD-10: B25.0

›Common co-pathogen in transplant recipients

›Similar ground-glass pattern; CMV PCR and antigenemia positive

›Influenza and SARS-CoV-2 pneumonia

›ICD-10: J09–J12

›Rapid antigen or PCR testing differentiates

›Fungal infections

›Invasive pulmonary aspergillosis

›ICD-10: B44.1

›Neutropenic patients, nodules with halo sign, galactomannan positive

›Cryptococcal pneumonia

›ICD-10: B45.1

›Cryptococcal antigen in serum or CSF

Non-infectious mimics

›Drug-induced pneumonitis

›Methotrexate, bleomycin, checkpoint inhibitors

05Laboratory Tests/lt38

Biomarkers

›Serum lactate dehydrogenase

›Elevated in PCP; often >500 U/L

›Sensitive but non-specific marker

›Correlates with disease severity and prognosis

›Useful for monitoring treatment response

›Serum (1→3)-beta-D-glucan

›Elevated >80 pg/mL (Fungitell assay)

›Sensitivity approximately 83% for PCP diagnosis

›High NPV at 80 pg/mL threshold to rule out PCP

›Can remain elevated with other fungal infections (false positive)

›Not elevated by Cryptococcus or Mucor

Blood gas and severity markers

›Arterial blood gas

›PaO2 and A-a gradient as severity stratification tool

›Mild: PaO2 ≥70 mmHg; A-a gradient <35 mmHg

›Moderate: A-a gradient 35–45 mmHg

›Severe: A-a gradient ≥45 mmHg

›A-a gradient ≥35 mmHg triggers adjunctive corticosteroids

›Hypoxemia may be more severe than apparent on pulse oximetry

›Complete blood count

›Lymphopenia as risk factor and disease marker

›Lymphopenia <0.7 x 10^9/L is independent risk factor in non-HIV

›Monitor for TMP-SMX-induced myelosuppression during treatment

Immunologic and infectious workup

›CD4 count and HIV viral load

›CD4 <200 cells/mm3 in HIV: high risk threshold

›CD4 <100 cells/mm3 associated with most severe disease

06Diagnostic Tests/dt67

Scoring Systems

›Severity stratification for treatment decisions

›Mild PCP: PaO2 ≥70 mmHg and A-a gradient <35 mmHg

›Outpatient oral TMP-SMX in reliable HIV-positive patients

›Close follow-up within 48–72 hours required

›Moderate PCP: PaO2 <70 mmHg or A-a gradient 35–45 mmHg

›Inpatient IV TMP-SMX with adjunctive corticosteroids

›Severe PCP: A-a gradient ≥45 mmHg

›ICU-level care required

›ICU mortality 52% at 30 days and 67% at 90 days

›HIV-related scoring context

›CD4 count risk stratification

›CD4 <200 cells/mm3 = high PCP risk; prophylaxis threshold

›CD4 <100 cells/mm3 = highest risk; most severe disease

›CURB-65 not validated specifically for PCP but may inform general severity

MRI

›MRI chest role in PCP

›Not a primary diagnostic modality for PCP

›CT chest preferred for speed, availability, and sensitivity

›MRI brain if CNS complications suspected

›Extrapulmonary PCP is rare but can involve CNS

›MRI useful when CT is contraindicated (contrast allergy with renal failure)

›Radiation avoidance in pregnancy or repeated imaging scenarios

CT

›CT chest without contrast

›Gold standard imaging modality for PCP

›Diffuse or patchy bilateral ground-glass opacities (GGO) is hallmark

›Abnormal even when chest X-ray is normal in early disease

›Normal CT has high negative predictive value for PCP

›Classic CT pattern

›Bilateral perihilar GGO in a geographic or mosaic distribution

›Sparing of lung periphery may occur

›No pleural effusion in typical PCP

›Atypical CT findings

›Cysts or pneumatoceles: risk factor for spontaneous pneumothorax

›Upper lobe predominance associated with aerosolized pentamidine prophylaxis

›Pneumomediastinum as complication

›Findings suggesting alternative diagnosis

›Cavitation suggests TB, aspergillosis, or bacterial abscess

›Pleural effusion suggests bacterial pneumonia or malignancy

›Focal lobar consolidation suggests bacterial etiology

›Intrathoracic lymphadenopathy suggests lymphoma or TB

Ultrasound

›Lung ultrasound role in PCP

›Bedside lung ultrasound for rapid assessment of respiratory failure

›B-lines (comet-tail artifacts) indicate interstitial edema or GGO

›Bilateral diffuse B-lines consistent with bilateral interstitial process

›Point-of-care ultrasound differentiates from pleural effusion

›Absence of effusion supports PCP over bacterial pneumonia

›Cardiac ultrasound for hemodynamic assessment

›Right heart strain in severe hypoxemia

›Rules out cardiac pulmonary edema as mimic

›Microbiologic diagnostic testing

›Induced sputum with immunofluorescence staining

›Sensitivity variable: <50% to >90% depending on lab technique

›Less invasive than bronchoscopy; reasonable first step

›Bronchoscopy with BAL

›Diagnostic procedure of choice

›Sensitivity 90–99% with DFA or PCR

›Appropriate when sputum inconclusive or patient deteriorating

›Quantitative PCR on respiratory specimens

›Increasingly replacing staining methods

›High sensitivity but cannot reliably distinguish colonization from infection

›Higher organism loads favor true infection over colonization

›Oral wash PCR combined with serum BDG

›Emerging non-invasive strategy with accuracy 97.9% in non-HIV patients

›Useful when bronchoscopy not feasible

›Methenamine silver stain

›Identifies cyst walls; classic cup-shaped organisms in foamy alveolar exudate

›Direct immunofluorescence assay

›Higher sensitivity than colorimetric stains (~95% on BAL specimens)

07Disposition/dispo28

Admission criteria

›Inpatient admission indications

›PaO2 <70 mmHg or A-a gradient ≥35 mmHg (moderate-to-severe disease)

›IV TMP-SMX and adjunctive corticosteroids required

›Inability to tolerate oral medications

›Nausea, vomiting, or GI intolerance

›Non-HIV immunocompromised patients

›Higher mortality and more fulminant course than HIV patients

›Mortality 30–60% in non-HIV versus 10–20% in HIV

›Significant comorbidities or hemodynamic instability

›Social factors: inability to follow up or adhere to outpatient regimen

ICU criteria

›ICU admission indications

›Respiratory failure requiring HFNC, NIV, or mechanical ventilation

›A-a gradient ≥45 mmHg

›Hemodynamic instability or septic shock

›Expected clinical course

›ICU mortality 52% at 30 days; 67% at 90 days

Discharge criteria

›Outpatient management eligibility

›Mild disease: PaO2 ≥70 mmHg and A-a gradient <35 mmHg

›HIV-positive patients with reliable follow-up only

›Oral TMP-SMX highly effective for mild disease

›Tolerating oral medications and hydration

›Stable oxygenation on room air or minimal supplemental O2

›Reliable follow-up within 48–72 hours arranged

›Follow-up requirements

›Repeat clinical assessment within 1 week of discharge

08Treatment/t78

Empiric and definitive antimicrobial therapy

›TMP-SMX (first-line therapy, 21-day course)

›IV dosing for moderate-to-severe disease

›TMP 15–20 mg/kg/day IV divided every 6–8 hours

›Transition to PO when clinically improving

›Total treatment duration 21 days

›Oral dosing for mild disease

›TMP-SMX DS (160/800 mg) 2 tablets PO three times daily

›Low-dose TMP-SMX consideration in non-HIV patients

›TMP <12.5 mg/kg/day may have similar efficacy with fewer adverse events

›Evidence limited to retrospective observational data

›Monitoring parameters during TMP-SMX therapy

›Serum potassium every 2–3 days (hyperkalemia risk)

›CBC for myelosuppression

›Serum creatinine and hepatic enzymes

›Do NOT add leucovorin — associated with higher treatment failure rates

Adjunctive corticosteroids

›Corticosteroids for moderate-to-severe disease

›Indication threshold

›PaO2 <70 mmHg or A-a gradient ≥35 mmHg

›Must be initiated within 72 hours of starting TMP-SMX

›Prednisone taper regimen

›40 mg PO twice daily on days 1–5

›40 mg PO once daily on days 6–10

›20 mg PO once daily on days 11–21

›IV methylprednisolone for patients unable to take PO

›80% of the prednisone dose equivalence

›32 mg IV twice daily for days 1–5, then taper accordingly

›Class I recommendation based on multiple randomized controlled trials

›Reduces risk of respiratory failure and death in moderate-to-severe PCP

Alternative regimens

›Mild-to-moderate disease alternatives (TMP-SMX intolerance)

›Dapsone plus trimethoprim

›Dapsone 100 mg PO daily plus TMP 5 mg/kg PO three times daily

›Check G6PD before initiating dapsone

›Atovaquone monotherapy

›750 mg PO twice daily with food

›Bioavailability increases approximately 3-fold when taken with fatty meal

›Less effective than TMP-SMX for mild disease

›Clindamycin plus primaquine

›Clindamycin 600 mg IV or 300–450 mg PO every 6–8 hours

›Primaquine 30 mg base PO daily

›Check G6PD before initiating primaquine

›Moderate-to-severe disease alternative

›IV pentamidine

›4 mg/kg/day IV infused over 60–120 minutes

›Toxicity monitoring required

›Hypoglycemia (during and after infusion)

›Nephrotoxicity

›Pancreatitis

›QT prolongation and torsades de pointes

›ECG monitoring required throughout pentamidine course

Prophylaxis management

›Primary prophylaxis indications

›HIV patients with CD4 <200 cells/mm3

›TMP-SMX DS 1 tablet daily (preferred)

›Alternative: TMP-SMX SS 1 tablet daily or DS 3 times per week

›Non-HIV immunosuppressed patients

›Corticosteroids ≥20 mg prednisone equivalent for ≥4 weeks

›Hematologic malignancy on intensive chemotherapy

›Post-transplant: continue for minimum 6–12 months

›Prophylaxis alternatives

›Atovaquone 1500 mg PO daily with food

›Dapsone 100 mg PO daily (check G6PD first)

›Aerosolized pentamidine 300 mg monthly via Respirgard II nebulizer

›Less effective; associated with upper lobe predominance pattern on CT

›Secondary prophylaxis

›All patients post-PCP require prophylaxis until immune reconstitution

›HIV patients: continue until CD4 >200 cells/mm3 for >3 months on ART

›Non-HIV patients: continue as long as immunosuppression present

ART and immunosuppression management

›ART initiation in newly diagnosed HIV

›Start ART within 2 weeks of PCP therapy initiation

›Earlier initiation reduces secondary infections and mortality

›Balance against IRIS risk (immune reconstitution inflammatory syndrome)

›IRIS recognition

›Clinical worsening after ART initiation in known HIV

›Paradoxical inflammatory response as CD4 count recovers

›Treat with corticosteroids if IRIS is severe

›Immunosuppression reduction in transplant recipients

›Consider dose reduction with caution

›Rejection risk must be balanced against PCP mortality risk

›ID and transplant team co-management required

09Special Populations/sp56

Pregnancy

›Pregnancy considerations

›PCP in pregnancy is rare but carries high maternal and fetal risk

›Associated with preterm delivery and fetal loss

›Trimester-specific treatment considerations

›TMP-SMX generally preferred first-line despite theoretical risks

›Folate supplementation recommended during TMP-SMX use in pregnancy

›Avoid dapsone in first trimester (teratogenicity concern) and near term

›Avoid dapsone in third trimester (neonatal hemolysis and methemoglobinemia)

›Adjunctive corticosteroids: use for moderate-to-severe disease as in non-pregnant adults

›Prednisone preferred over methylprednisolone for systemic use

›Prophylaxis in pregnancy

›TMP-SMX preferred with folate supplementation

›Dapsone acceptable mid-pregnancy if TMP-SMX not tolerated

›Aerosolized pentamidine as alternative if systemic options contraindicated

›Fetal monitoring with maternal hypoxemia

›SpO2 target >95% to prevent fetal hypoxia

Geriatric

›Geriatric considerations

›Atypical presentation more common

›Absent or blunted fever response

›Cognitive changes may predominate over respiratory symptoms

›Higher rates of non-HIV risk factors

›Corticosteroid use, malignancy, autoimmune disease

›Baseline pulmonary reserve may be reduced

›TMP-SMX toxicity concerns in older adults

›Renal impairment: dose adjust TMP-SMX based on creatinine clearance

›Higher risk of hyperkalemia and myelosuppression

10Background/b60

Epidemiology

›Global burden and incidence

›PCP is among the most common AIDS-defining illnesses worldwide

›Mortality 10–20% in HIV-positive patients with optimal care

›Mortality 30–60% in non-HIV immunocompromised patients

›ICU mortality 52% at 30 days; 67% at 90 days

›Modern epidemiologic shift

›Non-HIV cases now account for a growing proportion of PCP in high-income countries

›Hematologic malignancy (32%), solid tumors (22%), autoimmune disease (18%) in non-HIV cohorts

›Only 5.4% of patients in a large recent cohort were on prophylaxis at diagnosis

›HIV-related epidemiology

›~90% of HIV-associated PCP occurs at CD4 <200 cells/mm3

›PCP incidence markedly reduced in regions with high ART coverage

›ICD-10 code: B59 (Pneumocystis pneumonia)

›SNOMED CT: 42386007 (Pneumocystis jirovecii pneumonia)

Pathophysiology

›Organism characteristics

›Pneumocystis jirovecii is a fungus (formerly classified as protozoan)

›Obligate extracellular pathogen; cannot be cultured in vitro

›Human-specific pathogen; airborne transmission

›Ubiquitous environmental exposure in childhood; latent colonization in most adults

›Organism lifecycle

›Trophic forms: adhere to type I pneumocytes via fibronectin and vitronectin

›Asci (cysts): contain 8 intracystic bodies (ascospores); identified by GMS stain

›High organism burden in HIV patients despite lower inflammatory response

›Low organism burden in non-HIV patients with intense inflammatory response

›Disease mechanism

›Proliferation in alveolar space during immunosuppression

›Destruction of type I pneumocytes and surfactant disruption

›Foamy alveolar exudate with decreased diffusing capacity

›Progressive hypoxemia and A-a gradient widening

›Non-HIV inflammatory pathology

›Intense CD4+ T-cell and neutrophil response despite low organism burden

›Explains more fulminant presentation and higher mortality in non-HIV patients

›Complications

›Pneumatocele formation from direct lung tissue damage

›Spontaneous pneumothorax from cyst rupture

›IRIS with ART initiation: paradoxical worsening from immune recovery

Therapeutic Considerations

›TMP-SMX mechanism and resistance

›TMP inhibits dihydrofolate reductase; SMX inhibits dihydropteroate synthase

›Synergistic inhibition of folate synthesis pathway in Pneumocystis

›Leucovorin bypasses the drug target and reduces efficacy; do not co-administer

›Emerging DHPS mutations (sulfa resistance mutations)

›Mutations in dihydropteroate synthase gene identified in some isolates

›Clinical significance of resistance mutations remains under investigation

›TMP-SMX still first-line; no validated clinical resistance threshold

›Rationale for adjunctive corticosteroids

›Class I recommendation based on multiple RCTs and meta-analyses

›Reduces mortality and need for mechanical ventilation in moderate-to-severe PCP

›Must be started within 72 hours of antimicrobial therapy initiation

›Benefit in non-HIV patients less clearly established but extrapolated

›Beta-D-glucan as therapeutic monitoring tool

›Declining beta-D-glucan levels correlate with treatment response

›Persistent elevation may indicate treatment failure

›Serial monitoring every 5–7 days in severe cases

›Treatment failure considerations

›If no improvement after 5–7 days of TMP-SMX

›Switch to IV pentamidine as salvage therapy

›Pursue definitive BAL diagnosis if not yet obtained

›Consider clindamycin-primaquine as alternative salvage regimen

›Co-pathogens common in non-HIV patients

›CMV, bacterial superinfection; metagenomic NGS may identify co-pathogens

11Patient Discharge Instructions/pdi27

copy discharge instructions

›Discharge instructions for Pneumocystis jirovecii Pneumonia (PCP)

›You have been treated for PCP, a serious lung infection that occurs when the immune system is weakened

›It is critical that you take all of your antibiotic medication as prescribed for the full 21 days

›Medication instructions

›Take TMP-SMX (trimethoprim-sulfamethoxazole) at the prescribed dose with a full glass of water

›Take atovaquone with food if prescribed — absorption is much better with a fatty meal

›Do not stop any medications without talking to your doctor first

›Prevention medication after discharge

›You will need to take a daily antibiotic to prevent PCP from coming back

›This preventive medication must be continued until your immune system has recovered

›Activity and recovery

›Rest and gradually increase activity as tolerated

›Avoid contact with people who are sick while your immune system is recovering

›Maintain good nutrition and hydration to support recovery

›Follow-up appointments

›Return to clinic within 1 week of discharge

›Repeat blood tests will be needed to monitor your immune system and medication levels

›If HIV was newly diagnosed, an HIV specialist appointment has been arranged

›Return to the emergency department immediately for

›Worsening shortness of breath or difficulty breathing at rest

›New or worsening chest pain, especially sharp pain that worsens with breathing

›Fever that is not improving after 5–7 days of treatment

›Skin rash, especially blisters or mouth sores (possible drug reaction)

›Yellowing of skin or eyes, dark urine, or easy bruising (liver or blood problems)

›Swelling in legs or face, or decreased urine output (kidney problems)

›Confusion, severe headache, or new neurological symptoms

›Sudden onset severe chest pain or sharp pleurisy (pneumothorax risk)

12References/r28

Guidelines and key sources

›DHHS Adult OI Guidelines 2025

›Benson C, Brooks J, Dhanireddy S, et al. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. IDSA/OARAC. 2025

›Available at: clinicalinfo.hiv.gov

›Primary source for TMP-SMX dosing, prophylaxis thresholds, and corticosteroid indications

›DHHS Pediatric OI Guidelines 2025

›Kapogiannis BG, Yates F, Li W, et al. Guidelines for Prevention and Treatment of Opportunistic Infections in Children with and Exposed to HIV. OARAC. 2025

›Prophylaxis thresholds and pediatric dosing protocols

›American Society of Transplantation Infectious Diseases Practice Guidelines

›Fishman JA, Gans H, AST IDCP. Pneumocystis jiroveci in solid organ transplantation. Clin Transplant. 2019

›Post-transplant prophylaxis duration and risk stratification

Landmark studies and systematic reviews

›Thomas CF, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350:2487-2498

›Foundational review: pathophysiology, epidemiology, diagnosis, and treatment

›Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014

›Evidence base for prophylaxis in non-HIV populations

›Fishman JA. Pneumocystis jiroveci. Semin Respir Crit Care Med. 2020

›Non-HIV PCP: distinct pathophysiology and higher mortality

›Giacobbe DR, Dettori S, Di Pilato V, et al. Pneumocystis jirovecii pneumonia in intensive care units. Crit Care. 2023

›ICU mortality data: 52% at 30 days, 67% at 90 days

›Prosty C, Luo OD, Khalaf R, et al. Diagnostic test accuracy of the Fungitell beta-D-glucan assay for PCP. Clin Microbiol Infect. 2025

›Meta-analysis of BDG sensitivity (~83%) and NPV for PCP diagnosis

›Nagai T, Matsui H, Fujioka H, et al. Low-dose vs conventional-dose TMP-SMX for PCP in non-HIV patients. Chest. 2023

›Retrospective data on lower-dose TMP-SMX in non-HIV PCP

›Falco-Roget A, Albasanz-Puig A, Perez-Gonzalez A, et al. Combined serum BDG and oral wash PCR for PCP diagnosis. Open Forum Infect Dis. 2026

›Non-invasive diagnostic strategy: accuracy 97.9% in non-HIV patients

›Pulsipher AM, Vikram HR, Gotway MB, et al. Observational analysis of a large PCP cohort. Open Forum Infect Dis. 2025

›Modern epidemiology: non-HIV cohort distribution and prophylaxis rates

Evidence & Review

Evidence & Review