Multisystem Processes & Disorders

Pneumocystis pneumonia: diagnosis and treatment

Clinical Overview and When to Suspect Pneumocystis Pneumonia

— HIV/AIDS with CD4 < 200 cells/µL (or CD4 fraction <14%, oral thrush, prior AIDS-defining illness)

— Solid organ and hematopoietic stem cell transplant recipients

— Patients on chronic glucocorticoids ≥20 mg prednisone-equivalent for ≥4 weeks

— Hematologic malignancies (ALL, CLL, lymphoma), particularly on purine analogs, alemtuzumab, idelalisib

— Biologic therapy (rituximab, TNF-α inhibitors), methotrexate, cyclophosphamide

— Primary immunodeficiencies (SCID, hyper-IgM syndrome)

— HIV patients: indolent, 2–4 weeks of progressive dyspnea, lower mortality

— Non-HIV immunocompromised: abrupt, days-long fulminant course, higher mortality (~30–50%), often diagnosed when steroids are tapered

Board pearl: A patient newly diagnosed with HIV who has CD4 < 200, oral thrush, and a "normal-looking" chest x-ray but desaturates with walking — order high-resolution CT and start empiric therapy; PJP frequently has subtle early radiographs. The disproportion between symptoms/hypoxia and exam is the classic exam clue.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal pneumonia caused by an atypical, non-culturable fungus that does not respond to standard antifungals because it lacks ergosterol; it is treated like a protozoal infection with TMP-SMX.

Suspect PJP in any immunocompromised host with subacute hypoxemic dyspnea, dry cough, and bilateral interstitial infiltrates, especially when the degree of hypoxia is disproportionate to chest exam or imaging.

Highest-risk populations:

Clinical tempo separates hosts:

Step 3–relevant ambulatory triggers: a rheumatology or transplant patient calling clinic with new exertional dyspnea on chronic prednisone — do not dismiss as deconditioning; obtain pulse oximetry with ambulation.

Presentation Patterns and Key History

— Exertional dyspnea preceding rest dyspnea; patients often quantify by stairs climbed or block walked

— Dry cough; purulent sputum should raise suspicion for bacterial co-infection

— Fever 38–39 °C, fatigue, weight loss, night sweats

— Pleuritic chest pain or hemoptysis is atypical — consider TB, fungal, or malignancy

— Last CD4 count and viral load, ART adherence, prior opportunistic infections

— Prophylaxis history: was the patient on TMP-SMX, dapsone, atovaquone, or pentamidine? Breakthrough PJP on dapsone suggests G6PD-related discontinuation or resistance

— Steroid dose and duration, biologic agents, chemotherapy timing

— Transplant date, induction regimen, current immunosuppression, recent rejection treatment

— Travel, TB exposure, sick contacts, pets (Cryptococcus from birds, Histoplasma exposure)

— Sexual history and IV drug use in undiagnosed HIV

— Symptoms accelerating after a steroid taper in a non-HIV host is classic — falling steroid dose unmasks inflammation against organisms acquired earlier

— In HIV, the insidious 3–4 week prodrome lets patients normalize the dyspnea until they cannot speak in full sentences

Key distinction: Bacterial pneumonia presents over 1–3 days with productive cough, rigors, and focal consolidation; PJP presents over 1–4 weeks with dry cough and diffuse interstitial disease. TB overlaps but typically has hemoptysis, upper-lobe cavitation, and weight loss over months.

Step 3 management: When taking the history in a CCS case, document HIV status, CD4, and prophylaxis adherence first; these single-handedly shift pretest probability and dictate empiric therapy decisions before labs return.

Classic triad: progressive dyspnea, nonproductive cough, low-grade fever evolving over days (non-HIV) to weeks (HIV).

Symptom inventory:

History elements that Step 3 will plant in the stem:

Time course pearls:

Physical Exam Findings (and Hemodynamic Assessment)

— Tachypnea (RR > 24) is the most sensitive sign

— Hypoxemia at rest or with ambulation — always perform a 6-minute walk or simple desaturation test if resting SpO₂ is borderline

— Fever 38–39 °C; hypotension suggests severe disease or sepsis

— Tachycardia proportional to fever and hypoxia

— Often strikingly normal auscultation despite profound hypoxia — a hallmark

— Fine bibasilar crackles in some; absence of consolidation signs (no egophony, no dullness)

— No pleural rub typically — pleural effusions argue against PJP

— Oral thrush, hairy leukoplakia, Kaposi sarcoma lesions → undiagnosed/advanced HIV

— Generalized lymphadenopathy, hepatosplenomegaly

— Cushingoid habitus, skin atrophy → chronic steroid use

— Transplant scar, AV fistula, central line

— Cotton-wool spots on funduscopy → CMV retinitis (concurrent OI)

— Calculate A-a gradient: an elevated A-a gradient (>35 mmHg) defines moderate-to-severe disease and triggers adjunctive steroids in HIV

— PaO₂ on room air: ≤70 mmHg or A-a ≥35 → severe category

— Assess work of breathing: nasal flaring, paradoxical abdominal movement, inability to lie flat predict imminent intubation

Board pearl: A young man with HIV who walks across the exam room and desaturates from 96% to 84% has exercise-induced hypoxemia highly suggestive of PJP — this finding alone justifies empiric therapy while diagnostics are pending. Resting pulse oximetry can be falsely reassuring.

General appearance: tachypneic, often using accessory muscles, speaking in short phrases, anxious; cachexia in chronic HIV.

Vital signs:

Pulmonary exam:

Extrapulmonary clues for the underlying immunocompromise:

Hemodynamic and respiratory assessment:

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— CBC with differential: lymphopenia common; absolute CD4 if HIV

— CMP: baseline renal/hepatic function (drives TMP-SMX dosing and toxicity monitoring)

— LDH: elevated in ~90% of HIV-PJP; sensitive but nonspecific; useful for trending response

— ABG on room air: defines severity and A-a gradient → guides steroid use

— HIV testing (4th-generation Ag/Ab) if not known; viral load and CD4 if positive

— G6PD level before starting dapsone or primaquine alternatives

— β-D-glucan: serum assay, elevated in PJP (and other invasive fungi); high negative predictive value — a normal β-D-glucan in a low-pretest-probability patient argues against PJP

— Procalcitonin: typically low; helps distinguish from bacterial pneumonia

— CXR: bilateral, perihilar/diffuse reticular or ground-glass interstitial infiltrates; may be normal in up to 25% early

— Pneumothorax (spontaneous) and upper-lobe disease in patients who used aerosolized pentamidine prophylaxis

— Pleural effusions and lymphadenopathy are uncommon — their presence redirects diagnosis

— HRCT chest: diffuse ground-glass opacities with mosaic attenuation, often sparing the periphery; cysts/pneumatoceles in 30%

Step 3 management: When CXR is unrevealing but suspicion is high, the next step is HRCT before invasive sampling — a completely normal HRCT has a strong negative predictive value and may redirect the workup toward other opportunistic infections (CMV, MAC, fungal).

Key distinction: LDH and β-D-glucan are supportive, not confirmatory; never anchor on them. They are most useful when combined with imaging and host risk to either escalate to bronchoscopy or de-escalate suspicion.

Initial laboratory studies:

Chest imaging:

ECG: nonspecific sinus tachycardia; useful to exclude PE or cardiac etiology of dyspnea.

Diagnostic Workup — Confirmatory Microbiologic Studies

— Induced sputum with hypertonic saline nebulization: sensitivity 50–90% in HIV (organism burden high); much lower in non-HIV PJP (<30%); first-line if available

— Bronchoalveolar lavage (BAL): sensitivity >90% across populations; the gold-standard sampling method when induced sputum is negative or unavailable

— Transbronchial or surgical lung biopsy: rarely needed; reserved for diagnostic uncertainty or to evaluate alternative diagnoses

— Methenamine silver (GMS), toluidine blue, Giemsa, calcofluor white — visualize cysts/trophozoites

— Direct fluorescent antibody (DFA) — higher sensitivity than conventional stains

— PCR: highest sensitivity; can detect colonization, so a positive PCR with low pretest probability may not equal disease — interpret with clinical context and β-D-glucan

— Quantitative PCR may help distinguish colonization (low copy) from infection (high copy)

CCS pearl: Do not delay empiric TMP-SMX waiting for bronchoscopy — organisms remain detectable on BAL for 1–3 weeks after starting therapy because they clear slowly. Order BAL, start treatment, and continue both tracks in parallel.

Board pearl: A non-HIV transplant patient with negative induced sputum but classic imaging and host risk needs BAL, not repeat sputum.

Definitive diagnosis requires visualization of the organism because P. jirovecii cannot be cultured.

Sampling hierarchy (least to most invasive):

Stains and assays on respiratory specimens:

In non-HIV hosts, organism burden is low and inflammation is high → induced sputum often negative; proceed directly to BAL when feasible.

Concurrent workup: blood cultures, sputum bacterial culture and Gram stain, MRSA nasal swab, respiratory viral PCR, legionella and pneumococcal urinary antigens, CMV PCR, mycobacterial smear/culture if epidemiologic risk.

Risk Stratification and First-Line Management Logic

— Mild–moderate: PaO₂ >70 mmHg on room air AND A-a gradient <35 mmHg

— Moderate–severe: PaO₂ ≤70 mmHg OR A-a gradient ≥35 mmHg → add adjunctive corticosteroids in HIV

— Outpatient management possible for stable HIV patients with mild disease, reliable follow-up, oral tolerance, and SpO₂ ≥92% without exertional desaturation

— Admit for hypoxemia, inability to tolerate oral, social barriers, or non-HIV immunocompromise (higher mortality, more rapid progression)

— ICU for PaO₂/FiO₂ <200, need for noninvasive or invasive ventilation, hemodynamic instability

— Hold or minimize immunosuppression in non-HIV hosts where feasible (in coordination with the primary specialist)

— In HIV-naive patients, initiate ART within 2 weeks of starting anti-PJP therapy (per ACTG 5164) — earlier ART improves survival despite IRIS risk

— Start PJP prophylaxis transition planning for after treatment completion

— Screen and treat co-infections: TB, syphilis, hepatitis B/C, CMV if HIV

— Supplemental O₂ titrated to SpO₂ ≥92%

— VTE prophylaxis, nutrition, ambulation

— Pulmonary toilet; avoid unnecessary sedation

Step 3 management: The A-a gradient and PaO₂ on room air, drawn before supplemental O₂ is started, are decision-critical — if the patient is already on O₂ when you arrive, you have lost the clean ABG and must extrapolate.

Board pearl: Severity criteria for steroids were derived in HIV patients; benefit in non-HIV PJP is less clear but commonly extrapolated.

Severity classification drives whether to add corticosteroids and whether to admit to ICU:

Disposition logic:

Empiric therapy threshold: in a high-pretest-probability host, start TMP-SMX before microbiologic confirmation — diagnostic yield persists for days after initiation.

Concurrent issues to address up front:

Supportive care:

Pharmacotherapy — First-Line Regimen

— Dose: TMP 15–20 mg/kg/day + SMX 75–100 mg/kg/day, divided every 6–8 hours

— Route: IV for severe disease or NPO; transition to PO when clinically improving and absorbing (high oral bioavailability)

— Duration: 21 days total (HIV); 14–21 days non-HIV depending on response

— Monitor: CBC, BMP, LFTs every 3–5 days; potassium and creatinine commonly rise

— Start within 72 hours of anti-PJP therapy — delayed steroids lose mortality benefit

— Prednisone 40 mg BID × 5 days → 40 mg daily × 5 days → 20 mg daily × 11 days (21-day taper)

— IV methylprednisolone at 75% of oral dose if NPO

— Reduces respiratory failure and mortality in hypoxemic HIV-PJP

— Rash (including SJS/TEN), fever, hyperkalemia (TMP blocks ENaC like amiloride), hyponatremia, AKI (creatinine rise via OCT2 inhibition — partly artifactual), bone marrow suppression (leucopenia, thrombocytopenia, megaloblastic anemia — supplement folinic acid if cytopenias)

— Drug interactions: warfarin (↑ INR), methotrexate (↑ toxicity), sulfonylureas (hypoglycemia), ACEi/ARB/spironolactone (additive hyperkalemia)

— Clinical worsening in first 3–5 days is common (especially without steroids) — do not switch therapy prematurely

— Expect improvement by days 5–7; if no improvement by day 7, reassess for resistance, co-infection, or alternative diagnosis

Board pearl: A rising creatinine on TMP-SMX without other AKI markers often reflects competitive inhibition of tubular creatinine secretion, not true GFR decline — check cystatin C or trend BUN before switching.

First-line: TMP-SMX (Bactrim)

Adjunctive corticosteroids (HIV patients with moderate–severe disease):

Common TMP-SMX adverse effects (Step 3 favorites):

Treatment response timeline:

Alternative Pharmacotherapy and Sulfa Intolerance

— True sulfa allergy (especially severe cutaneous reactions — SJS/TEN, DRESS)

— Severe cytopenias, refractory hyperkalemia, hepatotoxicity

— Treatment failure after 5–7 days of optimal therapy

— IV pentamidine 4 mg/kg daily — toxicities: nephrotoxicity, pancreatitis, hypo- or hyperglycemia (β-cell lysis then destruction), hypotension during infusion, QT prolongation, torsades, hypocalcemia, hypomagnesemia

— Primaquine 30 mg PO daily + clindamycin 600 mg IV/PO q6–8h — check G6PD before primaquine to avoid hemolysis; methemoglobinemia possible

— Dapsone 100 mg + TMP 15 mg/kg/day — check G6PD; risk of methemoglobinemia and hemolysis

— Atovaquone 750 mg PO BID with fatty meal — best tolerated, less effective than TMP-SMX, useful for outpatients with mild disease; expensive

— Primaquine + clindamycin (as above)

Key distinction: Aerosolized pentamidine is only used for prophylaxis (not treatment) and is associated with upper-lobe breakthrough disease and pneumothorax.

Step 3 management: For a CCS patient with documented anaphylaxis to sulfa and moderate-severe PJP, the correct order is IV pentamidine (or clindamycin + primaquine after G6PD), plus prednisone taper, plus telemetry for QT monitoring on pentamidine.

Indications to switch from TMP-SMX:

Moderate-to-severe disease alternatives (PaO₂ ≤70 or A-a ≥35):

Mild-to-moderate disease alternatives:

Desensitization: in HIV with mild reaction to TMP-SMX, outpatient sulfa desensitization is preferred over permanent switch because TMP-SMX is most effective for both treatment and prophylaxis.

Adjunctive steroid criteria are the same regardless of which anti-PJP agent is used.

Salvage for refractory disease: addition of caspofungin (targets cyst wall β-glucan) has anecdotal benefit; consult ID.

Special Populations — Elderly and Renal/Hepatic Impairment

— TMP-SMX dose adjustment: CrCl 15–30 mL/min → reduce to 50% of standard dose; CrCl <15 → generally avoid or further reduce with levels; hemodialysis → dose post-HD

— Monitor potassium daily in early treatment; hyperkalemia risk is dose- and renal-function-dependent

— Pentamidine is nephrotoxic — avoid if alternative exists; if used, monitor creatinine daily and hold for ≥50% rise

— Atovaquone: no renal adjustment, attractive in CKD with mild disease

— TMP-SMX can cause cholestatic hepatitis; avoid in severe hepatic dysfunction

— Clindamycin requires caution; atovaquone preferred

— Polypharmacy increases interaction burden: warfarin INR can rise dramatically — check INR within 3 days of starting TMP-SMX and reduce warfarin dose empirically

— Volume status: elderly patients tolerate hyperkalemia and AKI poorly; daily BMP for first week

— Drug-induced delirium from steroids; consider lower steroid threshold

— Functional status drives goals-of-care conversations early — frail patients with respiratory failure may not benefit from prolonged ICU course

— Coordinate with rheumatology/oncology/transplant to adjust immunosuppression, not stop abruptly (rebound disease, rejection)

— Calcineurin inhibitors interact with TMP-SMX (hyperkalemia, nephrotoxicity)

Step 3 management: A 78-year-old on warfarin started on TMP-SMX for PJP — reduce warfarin by 25–50% and recheck INR in 3 days; do not wait for the next monthly clinic INR. Counsel on bleeding precautions at discharge.

Board pearl: An apparent creatinine bump on TMP-SMX in an elderly CKD patient is often not true AKI — check trajectory and potassium before switching agents.

Renal impairment:

Hepatic impairment:

Elderly considerations:

Underlying disease optimization:

Special Populations — Pregnancy and Pediatrics

— Pregnancy is itself a state of mild immune modulation; PJP risk is driven by underlying HIV or immunosuppression, not pregnancy alone

— TMP-SMX remains first-line in treatment of confirmed PJP in pregnancy — benefit outweighs theoretical risks

— First trimester: small increase in neural tube defects (folate antagonism) — supplement folic acid 4 mg/day

— Third trimester near delivery: theoretical kernicterus risk — coordinate timing with obstetrics; many continue therapy given severity of untreated PJP

— Adjunctive steroids: standard prednisone taper is acceptable in pregnancy

— Alternative: clindamycin + primaquine; avoid dapsone near term (hemolysis, methemoglobinemia in newborn)

— Prophylaxis in pregnant HIV with CD4 <200: TMP-SMX with folate supplementation

— PJP in children classically occurs in infants 3–6 months with undiagnosed perinatal HIV or primary immunodeficiency (SCID) — frequently the AIDS-defining illness

— Presentation: rapidly progressive tachypnea, hypoxia, retractions; mortality high without treatment

— TMP-SMX dosing: TMP 15–20 mg/kg/day divided q6–8h, identical weight-based logic

— Adjunctive steroids if hypoxemic: prednisone 1 mg/kg BID × 5 days then taper

— All HIV-exposed infants receive PJP prophylaxis with TMP-SMX starting at 4–6 weeks until HIV is excluded; continue if HIV-infected per CD4 guidelines

Board pearl: An infant with PJP as the index presentation mandates evaluation for SCID (lymphocyte subsets, immunoglobulins) and maternal/infant HIV testing — PJP in a non-HIV infant is a red-flag for primary immunodeficiency.

Step 3 management: Coordinate OB, ID, and pediatrics; do not delay treatment over pregnancy category concerns.

Pregnancy:

Pediatrics:

Breastfeeding: TMP-SMX compatible; avoid in infants <2 months (kernicterus) and in G6PD-deficient infants.

Complications and Adverse Outcomes

— Acute respiratory failure requiring mechanical ventilation — mortality 30–60% once intubated

— Pneumothorax: classic in PJP due to cyst rupture; suspect with sudden worsening hypoxia or chest pain; manage with chest tube; recurrence common

— Pneumomediastinum, subcutaneous emphysema

— Bacterial superinfection during recovery (S. aureus, gram-negatives)

— ARDS with prolonged ventilation, fibrotic lung sequelae

— Reactivation of latent TB unmasked by steroids

— TMP-SMX: rash (5–50% in HIV), SJS/TEN, hyperkalemia, AKI, cytopenias, hyponatremia, hepatitis

— Pentamidine: pancreatitis, glucose dysregulation, QT prolongation/torsades, hypotension, nephrotoxicity, sterile abscess at IM site

— Dapsone/primaquine: methemoglobinemia (cyanosis with normal PaO₂, saturation gap on co-oximetry), hemolytic anemia

— Steroids: hyperglycemia, mood, opportunistic infection (CMV, candidiasis), avascular necrosis

— Occurs in HIV patients after ART initiation; paradoxical worsening of PJP symptoms 1–4 weeks into ART

— Managed with continued ART, anti-PJP therapy, and short course of corticosteroids

CCS pearl: A PJP patient on day 5 of TMP-SMX with new sudden hypoxia and ipsilateral decreased breath sounds — stat upright CXR for pneumothorax, not just a CT for treatment failure. Place chest tube; do not switch antibiotics reflexively.

Board pearl: Cyanosis with normal PaO₂ on ABG and SpO₂ ~85% in a patient on dapsone = methemoglobinemia → methylene blue (avoid if G6PD-deficient).

Disease complications:

Drug-related complications:

Immune reconstitution inflammatory syndrome (IRIS):

Long-term: reduced DLCO, exertional dyspnea, post-infectious bronchiectasis in some.

When to Escalate Care — ICU, Consult, and Inpatient Triage

— PaO₂/FiO₂ <200 or requirement for FiO₂ >50% to maintain SpO₂ ≥90%

— Need for noninvasive ventilation (HFNC, BiPAP) or intubation

— Hemodynamic instability, lactic acidosis, multiorgan involvement

— Respiratory rate >30 with rising PaCO₂ — impending failure

— Trial of HFNC or NIV may avert intubation in selected patients without altered mentation or severe ARDS

— Once intubated, low tidal volume ventilation (6 mL/kg IBW), plateau pressure <30, permissive hypercapnia per ARDSNet

— Prone positioning for refractory hypoxemia (PaO₂/FiO₂ <150)

— ECMO is a salvage option in centers; do not delay referral for severe young patients

— Infectious Disease for all confirmed or strongly suspected PJP

— Pulmonology for bronchoscopy and ventilator management

— HIV/ID for ART initiation and OI screening

— Transplant team to coordinate immunosuppression adjustment

— Rheumatology/Oncology in non-HIV hosts to modify immunosuppression

— Palliative care early in patients with advanced underlying disease and poor prognosis

— Floor: stable on ≤4 L NC, no respiratory distress

— Step-down/telemetry: ≥6 L NC, escalating O₂ needs, on IV pentamidine (QT monitoring)

CCS pearl: Order ABG, lactate, repeat CXR at the bedside when a PJP patient on the floor becomes more dyspneic — and call ICU consult before the patient frankly fails. Late ICU transfers worsen mortality.

Step 3 management: Document goals of care and code status on admission for every PJP patient with advanced HIV or active malignancy — these conversations are easier before respiratory failure.

ICU admission criteria:

Ventilation strategy:

Consultations:

Inpatient floor vs. step-down:

Key Differentials — Same-Category (Opportunistic) Causes

— Transplant > AIDS (CD4 <50); diffuse ground-glass mimicking PJP

— Diagnose by BAL CMV PCR and biopsy showing owl-eye inclusions

— Treat with ganciclovir/valganciclovir; foscarnet if resistant

— Often co-infects with PJP — a positive PJP does not exclude CMV

— Upper-lobe cavitation, hemoptysis, weight loss over months; miliary pattern in advanced HIV

— AFB smear, NAAT, culture; isolate in negative-pressure room

— CD4 <50; fever, night sweats, weight loss, hepatosplenomegaly, anemia, elevated alk phos

— Mycobacterial blood cultures; treat clarithromycin + ethambutol ± rifabutin

— Histoplasmosis (Ohio/Mississippi valley): pancytopenia, hepatosplenomegaly, urine antigen

— Coccidioidomycosis (Southwest): erythema nodosum, eosinophilia, serology

— Cryptococcus: pulmonary nodules with concurrent meningitis; serum CrAg

— Neutropenic or post-transplant; halo sign, air-crescent sign on CT; galactomannan and β-D-glucan positive

— Treat with voriconazole or isavuconazole

Key distinction: β-D-glucan is positive in PJP, candida, aspergillus, fusarium; it is negative in cryptococcus and mucormycosis — pattern recognition narrows the fungal differential quickly.

Board pearl: A transplant patient with diffuse ground-glass and BAL positive for both PJP and CMV needs both TMP-SMX and ganciclovir — treating only one explains apparent "treatment failure."

CMV pneumonitis:

Mycobacterium tuberculosis:

Disseminated MAC:

Endemic fungi:

Invasive aspergillosis:

Toxoplasma pneumonia: rare; CD4 <100; concurrent CNS lesions common.

Kaposi sarcoma pulmonary involvement: HHV-8; flame-shaped perihilar opacities, bloody BAL, characteristic bronchoscopic lesions.

Key Differentials — Non-Opportunistic Causes

— Acute presentation, productive cough, focal consolidation, leukocytosis with left shift, elevated procalcitonin; treat per CAP guidelines

— Patchy interstitial pattern; Legionella urinary antigen, hyponatremia, GI symptoms; treat with macrolide or fluoroquinolone

— Influenza, RSV, SARS-CoV-2, adenovirus — respiratory viral PCR; bilateral ground-glass on imaging mimics PJP

— Sudden dyspnea, pleuritic chest pain, hypoxemia with clear lungs — classic mimic for the "hypoxia out of proportion" clue; obtain CT-PA when imaging is clear

— Orthopnea, PND, JVD, S3, elevated BNP; bilateral infiltrates with Kerley B lines, effusions

— Methotrexate, bleomycin, amiodarone, immune checkpoint inhibitors — temporal association; treat by drug withdrawal ± steroids

— Hemoptysis (may be absent), dropping hemoglobin, BAL with progressively bloodier returns

Key distinction: PJP causes diffuse interstitial disease without pleural effusion or lobar consolidation; the presence of effusion or lobar consolidation strongly favors bacterial pneumonia or malignancy instead.

Step 3 management: When the differential is broad and pretest probability for PJP is intermediate, send respiratory viral PCR, urinary antigens (Legionella, pneumococcus), procalcitonin, and β-D-glucan simultaneously to avoid sequential delays.

Bacterial community-acquired pneumonia:

Atypical pneumonia (Mycoplasma, Chlamydia, Legionella):

Viral pneumonia:

Pulmonary embolism:

Heart failure / cardiogenic pulmonary edema:

Drug-induced pneumonitis:

Diffuse alveolar hemorrhage:

Acute interstitial pneumonia / ARDS from other causes

Lymphangitic carcinomatosis or organizing pneumonia (COP): subacute, ground-glass with consolidation; biopsy diagnostic

Hypersensitivity pneumonitis: exposure history (birds, molds); BAL lymphocytosis with low CD4/CD8

Secondary Prevention and Discharge Medications

— First-line: TMP-SMX 1 single-strength (SS) daily or 1 DS three times weekly

— Alternatives: dapsone 100 mg daily (check G6PD), atovaquone 1500 mg daily with food, aerosolized pentamidine 300 mg monthly

— Stop secondary prophylaxis when CD4 >200 for ≥3 months on ART with suppressed viral load

— Restart if CD4 falls <200

— HIV with CD4 <200 or CD4% <14%, oral thrush, or prior AIDS-defining illness

— Solid organ transplant — typically 6–12 months post-transplant; lifelong in lung transplant

— Allogeneic HSCT — at least 6 months post-engraftment and longer if GVHD/immunosuppression continues

— Chronic prednisone ≥20 mg/day for ≥4 weeks plus another immunosuppressant

— Specific regimens: alemtuzumab, idelalisib, temozolomide+radiation, fludarabine, high-dose methotrexate

— Complete 21-day TMP-SMX course

— Steroid taper schedule written explicitly

— Folic acid if cytopenic

— Anti-retroviral therapy initiated/optimized (HIV)

— Vaccinations: pneumococcal (PCV20 or PCV15+PPSV23), influenza, COVID-19, hepatitis B if non-immune

— Smoking cessation counseling

— Address co-infections: TB screening with IGRA, hepatitis B/C, syphilis, STI panel in HIV

Step 3 management: A patient discharged on TMP-SMX prophylaxis needs CBC and BMP in 2 weeks to catch delayed cytopenias and hyperkalemia, then every 3 months while on therapy.

Board pearl: Lung transplant recipients receive lifelong PJP prophylaxis — unique among solid organ transplants.

Secondary prophylaxis (after treatment of PJP episode) — required until immune reconstitution:

HIV-specific discontinuation criteria:

Primary prophylaxis indications:

Discharge medication checklist:

Follow-Up, Monitoring, and Counseling

— Daily SpO₂, work of breathing, temperature trend

— CBC, BMP every 3–5 days while on TMP-SMX (K, Cr, WBC, platelets)

— LDH trending downward correlates with response

— Repeat CXR not routinely needed; obtain for clinical deterioration or new symptoms

— Afebrile ≥24 hours, stable or improving oxygenation, tolerating oral medications, reliable follow-up

— Many patients can complete oral TMP-SMX at home given high bioavailability

— Phone or clinic visit within 3–5 days of discharge to confirm tolerance and adherence

— Clinic visit at 2 weeks with CBC, BMP, LFTs

— At 4–6 weeks: repeat chest imaging if symptoms persist; baseline pulmonary function testing if dyspnea on exertion lingers

— HIV: CD4 and viral load at 4 and 12 weeks after ART initiation

— Transplant/rheum: coordinate immunosuppression resumption and dose modification

— Medication adherence: emphasize completing the 21-day course even when feeling well

— Recognize rash, mouth ulcers, jaundice, easy bruising, decreased urination — call clinic

— Hydration to mitigate crystalluria from sulfonamides

— Pulmonary rehabilitation referral if persistent exertional limitation

— Smoking cessation, alcohol moderation

— Sun protection on sulfa drugs (photosensitivity)

Step 3 management: A patient finishing PJP therapy who still has DLCO reduction at 6 weeks deserves pulmonary rehab referral and outpatient pulmonology follow-up — not repeat empiric antibiotics.

Board pearl: LDH that fails to decline by day 7–10 of therapy warrants reassessment for co-infection or alternative diagnosis.

Inpatient response monitoring:

Discharge timing:

Outpatient follow-up cadence:

Counseling:

Vaccinations and prevention reinforcement at every visit; influenza annually, COVID-19 boosters, pneumococcal series.

Ethical, Legal, and Patient Safety Considerations

— A new HIV diagnosis made during PJP workup triggers required reporting to state public health and partner notification, often through anonymous public health services

— Counsel before testing when feasible; document opt-out testing per CDC recommendations

— Maintain confidentiality — HIV status appears in records only with patient awareness; do not disclose to family without consent

— Risks (bleeding, pneumothorax, hypoxia, infection), benefits, alternatives; obtain before sedation

— In an altered or intubated patient, identify legal surrogate decision-maker

— Medication reconciliation: TMP-SMX–warfarin interaction is a top discharge safety issue → reduce warfarin dose, schedule INR, communicate explicitly to outpatient prescriber

— Steroid taper: ensure patient receives a written schedule; failure to taper risks adrenal insufficiency; failure to complete risks relapse

— Prophylaxis prescription must be filled before discharge — confirm with pharmacy

— Schedule outpatient labs and follow-up before the patient leaves

— Advanced HIV with multiple OIs or refractory malignancy on immunosuppression — discuss code status, intubation preferences, palliative options

— Document surrogate decision-maker and advance directive

— PJP is not transmitted person-to-person in any clinically relevant way; standard precautions only

— TB must be ruled out before doffing isolation in patients with relevant imaging

— Mandatory for HIV, TB, and certain reportable conditions discovered during workup; varies by state

— Late HIV diagnosis presenting as PJP signals a missed screening opportunity — counsel and engage in care; address insurance, housing, and transportation barriers

Step 3 management: Before discharge, call the outpatient anticoagulation clinic about the TMP-SMX-warfarin interaction; phone handoffs reduce adverse drug events.

HIV diagnosis disclosure and partner notification:

Informed consent for bronchoscopy:

Transition-of-care risks (high-yield Step 3):

Goals-of-care conversations:

Occupational and infection control:

Reporting:

Health equity:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: When the question stem mentions a patient on chronic high-dose steroids developing dyspnea during a steroid taper, the answer is almost always PJP.

PJP defines AIDS in HIV-infected patients

Risk threshold: CD4 <200 for HIV; chronic prednisone ≥20 mg ≥4 weeks for non-HIV

Hypoxia disproportionate to chest exam and CXR is the cardinal clue

Normal CXR in ~25% of early PJP — get HRCT

Elevated LDH sensitive (~90% HIV); β-D-glucan sensitive but nonspecific; negative β-D-glucan has strong NPV

TMP-SMX is first-line treatment and prophylaxis

Add prednisone if PaO₂ ≤70 mmHg or A-a ≥35 mmHg (HIV); start within 72 hours

Pneumothorax is a classic complication — especially with aerosolized pentamidine prophylaxis

ART within 2 weeks of starting PJP therapy in HIV (ACTG 5164)

Initial 3–5 days of clinical worsening on therapy is expected; do not switch reflexively

Pentamidine causes pancreatitis, glucose dysregulation, QT prolongation, nephrotoxicity

Dapsone and primaquine require G6PD testing; risk methemoglobinemia (saturation gap)

Atovaquone — best tolerated, requires fatty meal for absorption, mild disease only

Lung transplant recipients receive lifelong PJP prophylaxis

PJP in a non-HIV infant → evaluate for SCID

Aerosolized pentamidine → upper-lobe disease and spontaneous pneumothorax

Cysts on GMS stain, trophozoites on Giemsa

PCR is most sensitive; may detect colonization without disease

Pneumocystis cannot be cultured — lab cannot grow it

TMP-SMX raises K (ENaC block) and creatinine (OCT2 block — partly artifactual)

Folinic acid (not folic acid) rescues cytopenia without antagonizing TMP-SMX

Discontinue secondary prophylaxis when CD4 >200 ≥3 months

Combine with vaccine update at every visit

IRIS within 1–4 weeks of ART → continue ART, add steroids

Board Question Stem Patterns

— 32-year-old man, dry cough for 3 weeks, oral thrush, SpO₂ 96% rest → 84% with ambulation, bilateral perihilar infiltrates, LDH 480 → start TMP-SMX + prednisone; check CD4, viral load; initiate ART within 2 weeks

— 60-year-old with GPA on prednisone 30 mg + cyclophosphamide, now tapering, presents with dyspnea, A-a 45 → empiric TMP-SMX, prednisone adjunct, BAL; reassess immunosuppression

— Anaphylaxis to sulfa, PaO₂ 58 mmHg → IV pentamidine + prednisone; monitor QT, lipase, glucose, K

— Day 5 of TMP-SMX, new sudden hypoxia, decreased breath sounds left → pneumothorax, chest tube

— Patient switched to dapsone, now blue, SpO₂ 86%, PaO₂ 95 → methemoglobinemia, methylene blue (after confirming no G6PD deficiency)

— INR rises to 6 a week after starting TMP-SMX → hold warfarin, vitamin K if bleeding, resume at lower dose

— Worsening day 2–3 of therapy → expected; do not switch; add steroids if not already on them and severity criteria met

— 4-month-old with tachypnea, hypoxia, lymphopenia → evaluate for SCID and HIV; start TMP-SMX

— HIV with CD4 180 → start TMP-SMX prophylaxis

— HIV on ART, CD4 250 sustained 4 months, VL undetectable → stop secondary prophylaxis

— Lung transplant 5 years out, dyspnea, ground-glass on CT → still on PJP prophylaxis? If non-adherent, suspect breakthrough; BAL and TMP-SMX

Step 3 management: When the stem gives you ABG values, calculate the A-a gradient before choosing answer options — steroids vs. no steroids depends on it.

Stem 1 — New HIV with subacute dyspnea:

Stem 2 — Rheumatology patient on tapering steroids:

Stem 3 — Sulfa allergy with severe PJP:

Stem 4 — Sudden deterioration on therapy:

Stem 5 — Cyanosis with normal PaO₂:

Stem 6 — TMP-SMX drug interaction:

Stem 7 — Apparent treatment failure:

Stem 8 — Infant with PJP:

Stem 9 — Prophylaxis indication:

Stem 10 — Stopping prophylaxis:

Stem 11 — Transplant context:

One-Line Recap

Pneumocystis jirovecii pneumonia is an opportunistic fungal infection of CD4 <200 HIV patients and other immunocompromised hosts (especially those on chronic steroids) presenting with subacute dyspnea, dry cough, and bilateral ground-glass infiltrates with hypoxia out of proportion to exam, diagnosed by BAL with GMS/PCR and treated for 21 days with high-dose TMP-SMX plus adjunctive prednisone when PaO₂ ≤70 mmHg or A-a gradient ≥35 mmHg.

Board pearl: The Step 3 image of PJP is hypoxia disproportionate to the chest exam in an immunocompromised host — start TMP-SMX before bronchoscopy confirms the diagnosis.

Suspect: immunocompromised + subacute dyspnea + dry cough + bilateral interstitial infiltrates + exertional desaturation; LDH ↑, β-D-glucan ↑

Confirm: induced sputum first in HIV; BAL when sputum negative or non-HIV host; cannot culture — visualize via GMS, DFA, or PCR

Treat: TMP-SMX 15–20 mg/kg/day TMP component × 21 days; add prednisone 40 BID → 40 daily → 20 daily when PaO₂ ≤70 or A-a ≥35 in HIV; do not switch in first 3–5 days of clinical worsening

Alternatives: IV pentamidine or clindamycin + primaquine (severe); atovaquone or dapsone + TMP (mild); check G6PD before dapsone/primaquine

Prevent: TMP-SMX prophylaxis when CD4 <200, chronic steroids ≥20 mg ≥4 weeks plus another immunosuppressant, post-transplant per protocol; discontinue in HIV when CD4 >200 sustained ≥3 months on ART; start ART within 2 weeks

Watch: pneumothorax, IRIS, hyperkalemia, AKI, cytopenias, warfarin interaction, QT on pentamidine, methemoglobinemia on dapsone — all are board-favorite complications that shape the next best step