PCP in adults: Presentation , Treatment and Prophylaxis Prof. David W. Denning Professor of Infectious Diseases in Global Health The University of Manchester, UK

Presentation in adults

Clinical presentation of PCP in adults When do you suspect PCP in an adult? Atypical presentation of pneumonia with the following risk factors:- HIV-infection ART-naïve, CD4<200 Non-compliant with ART Previous PCP episode Not on PCP prophylaxis Unknown HIV status Bone marrow transplant Solid-organ transplant Lymphoma and haematological malignancy Chronic corticosteroid use / immunosuppressive therapy Katz et al. Arch Intern Med 1991;151:105-110.

Clinical presentation of PCP in adults HIV-infected adults INSIDIOUS progression of symptoms over SEVERAL Weeks Non-productive cough Exertional dyspnoea Fatigue Fevers Chills Sweats Other associated events Weight loss Recurrent bacterial pneumonias Oral candidiasis Extra-pulmonary pneumocystosis In ART-naïve patients with advanced AIDS CNS, GIT or disseminated infections

Clinical presentation of PCP in adults HIV-negative adults More RAPID progression and SEVERE disease Non-productive cough Exertional dyspnoea Fatigue Fevers Chills Sweats Onset of symptoms often during the time of discontinuation or dose reduction of immunosuppressive therapy

Clinical presentation of PCP in adults Physical examination Non-specific signs Fevers Tachypnoea Tachycardia Cyanosis; uncommon in adults Physical examination Pulmonary exam Often normal Mild crackles Diminished breath sounds Sign of pneumothorax

Differential diagnoses The commonest differential diagnoses are: Bacterial pneumonia (especially non-HIV) CMV or other viral pneumonitis Invasive aspergillosis (especially non-HIV) Pulmonary embolism

Differential diagnoses Pulmonary FUNGAL infections Histoplasmosis Cryptococcosis Invasive aspergillosis Cocidioidomycosis Blastomycosis (rare) Pulmonary mucormycosis Pulmonary and systemic symptoms of pulmonary fungal infections are quite similar Except for mucormycosis, cutaneous skin manifestations are common in many of these fungal infections Unlike PCP, pulmonary mucormycosis is common in diabetics

Differential diagnoses Pulmonary (MYCO)BACTERIAL infections Pulmonary TB Bacterial pneumonia Mycoplasma pneumonia Legionella pneumonia Non-tuberculous mycobacterial infections Similar pulmonary manifestations Bacterial pneumonias tend to be more rapid and acute Focal lung findings, chest pain and productive sputum are frequent in bacterial pneumonia PTB presents with systemic symptoms similar to PCP Atypical bacterial infections present with dry cough similar to that of PCP

Differential diagnoses Pulmonary VIRAL infections Cytomegalovirus pneumonitis Influenza Other viral pneumonias CMV pneumonitis is usually associated with a non-productive cough and minimal findings on lung examination and is more common in HIV-negative patients Influenza has signs and symptoms similar to PCP and does not respond to empirical antibiotic therapy

Differential diagnoses Pulmonary OTHER conditions Pulmonary Kaposi's sarcoma Acute respiratory distress syndrome Pulmonary embolus Sarcoidosis Non-infectious interstitial lung diseases Lymphoid interstitial pneumonitis Pulmonary symptoms similar to those of PCP are common in this conditions Unlike PCP, these conditions are often associated with pleural effusion

PCP versus other conditions In PCP: Hypoxia or exercise-induced hypoxia (reduced O2 saturation) is worse than the chest X-ray would suggest.

Treatment

Treatment considerations Severity of the disease Based on blood gas analysis or Room air partial pressure of oxygen (pO2) Toxicities of the agents Adjunctive therapy Moderate-severe PCP

Grading of severity of PCP In adults and children, the severity of PCP may be graded as: Mild-to-moderate PCP: Arterial blood gas room air pO2 ≥70 mmHg or Alveolar-arterial (A-a) gradient ≤35 mmHg. Moderate-to-severe PCP: Arterial blood gas room air pO2 <70 mmHg or Alveolar-arterial (A-a) gradient >35 mmHg

Mild to moderate Pneumocystis pneumonia Drug of choice Co-trimoxazole in high dosage Alternative agents (in patients intolerant of cotrimoxazole) Clindamycin + primaquine Atovaquone (mild only) Dapsone + trimethoprim (mild only) 1. Atovaquone is licensed for the treatment of mild to moderate pneumocystis infection in patients who cannot tolerate co-trimoxazole. 2. A combination of dapsone with trimethoprim is given by mouth for the treatment of mild to moderate disease [unlicensed indication]. 3. A combination of clindamycin and primaquine by mouth is used in the treatment of mild to moderate disease [unlicensed indication]; this combination is associated with considerable toxicity

Mild-to-moderate PCP: Drug dosing Co-trimoxazole 15-20 mg/ kg/day, PO or IV given in divided doses every 6-8 hours Dapsone 100mg, PO, once daily Trimethoprim 15 mg/kg/day, PO, given in divided doses every 8 hours Clindamycin 300-450mg, PO, every 6-8 hours Primaquin 15-30mg, PO, once daily Atovaquone 750 mg , PO, twice daily 1. Atovaquone is licensed for the treatment of mild to moderate pneumocystis infection in patients who cannot tolerate co-trimoxazole. 2. A combination of dapsone with trimethoprim is given by mouth for the treatment of mild to moderate disease [unlicensed indication]. 3. A combination of clindamycin and primaquine by mouth is used in the treatment of mild to moderate disease [unlicensed indication]; this combination is associated with considerable toxicity

Severe Pneumocystis pneumonia Drug of choice Co-trimoxazole, high dosage, by mouth or intravenously i.e. 15-20 mg/kg daily in 2–4 divided doses for 14–21 days. Alternative agents Indications: Intolerance or lack of response to co-trimoxazole Clindamycin IV + primaquine PO Pentamidine, by intravenous infusion Potentially toxic drug causing hypotension during or immediately after infusion Co-trimoxazole dose for treatment is 120 mg/kg daily in 2–4 divided doses for 14–21 days.

Severe PCP: Drug dosing Co-trimoxazole: 15-20 mg/kg/day , IV, in divided doses every 6-8 hours Clindamycin: 600-900 mg, IV , every 6-8 hours; OR 300-450 mg , PO, every 6-8 hours -and- Primaquine: 15-30 mg, PO, once daily Pentamidine: 4 mg/kg , IV, once daily Prednisolone: 40 mg, PO, BD, for 5 days, then 40 mg, PO, OD, for 5 days, then 20 mg , PO, OD, for 11 days OR Methylprednisolone 30mg, IV, BD for 5 days, then 30mg, IV, OD for 5 days, then 15mg once daily until patient can be given oral prednisone Co-trimoxazole dose for treatment is 120 mg/kg daily in 2–4 divided doses for 14–21 days.

Adjunctive therapy Prednisolone (or IV hydrocortisone) for 21 days Life-saving addition in moderate-severe PCP Standard dose for 5 days , then reduced to complete the 21 days Should be commenced at the same time as anti-PCP therapy Most effective if initiated within 24-72 hours Corticosteroids should be withdrawn before anti-PCP therapy is completed

PCP prophylaxis

Primary prophylaxis Indicated for patients with severe immunodeficiency Prophylaxis continues until immune recovery This should be in addition to ART PCP prophylaxis should NOT be discontinued in the following scenarios:- On going immunosuppressive therapy Oral candidiasis or any other opportunistic infections Continued weight loss

Secondary prophylaxis All patients with previous PCP infection Prophylaxis continues until immune reconstitution CD4>200 cells/µL for 3 consecutive months Secondary prophylaxis should be started concurrently with the end of PCP treatment and continued for life, unless immune reconstitution occurs with antiretroviral therapy

*Inhaled pentamidine is better tolerated compared to IV Anti-PCP prophylaxis Drug of choice Co-trimoxazole By mouth Daily or alternative days Reduce dose to improve tolerance Alternative agent Petamidine Inhaled (preferred) or IV route* Patients on inhaled pentamidine have a small risk of extrapulmonary pneumocystosis Dapsone or atovaquone can also be used 1. Both dapsone and atovaquone have been used for PCP prophylaxis but none of the two has been licensed for this indication 2. Cotrimoxazole dosing regimens for PCP prophylaxis are as follows: Daily dosing: 960 mg once daily, reduced if not tolerated to 480 mg once daily. Alternatively day dosing: 960 mg once daily on alternate days (3 times weekly) or alternatively 960 mg twice a day on alternate days (3 times weekly). *Inhaled pentamidine is better tolerated compared to IV

Summary Pneumocystis jirovecii pneumonia (PCP) is the most common AIDS- defining opportunistic infection associated with significant morbidity and mortality The clinical manifestation tend to be insidious in HIV-infected patients but rapidly progressive and severe in HIV-negative patients Cotrimoxazole is the drug of choice for primary and secondary prophylaxis, and treatment of PCP Alternative agents are used in case of lack of response to co- trimoxazole or intolerance to it

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