Pneomucystis Jirovecii Pneumonia

Pneumocystis is a fungal organism that cannot be cultured, and which causes opportunistic infections in immunocompromised hosts. Despite advances in care, PJP has continued to be a leading cause of AIDS-associated morbidity in the United States and Western Europe, particularly in individuals who do not know they are infected with HIV until they are profoundly immunosuppressed and in HIV-infected patients with CD4+ T lymphocyte counts of <200/μL who are not receiving ART or PJP prophylaxis.

Epidemiology

Most people are exposed early in life and may be colonized by this fungus. Clinical infections can represent reactivation of latent infection or represent de novo infections which can also be nosocomial.

Pathophysiology

Defects in cellular immunity predispose to PJP. CD4+ T cells are critical in the host defence against PJP. Any disruption in these leads to increased risk. At least 80% of cases occur in HIV+ patients when CD4+ counts are <200/uL, and most cases develop at <100/uL.

Clinical Features of PJP

• clinical presentation
  • acute or subacute pneumonia
  • respiratory failure
  • extrapulmonary: spleen, liver, lymph nodes
• physical examination is nonspecific and can be initially normal
• radiographic findings: the classic picture is diffuse bilateral interstitial infiltrates that are perihilar and symmetric that can progress to frank airspace disease. HRCT will show diffuse GGOs, and a normal chest CT rules out the diagnosis.
  • cysts and pneumothoraces are common as well

Diagnosis of PJP

• H&E staining shows foamy alveolar infiltrate and a mononuclear interstitial infiltrate (pathognomonic)
• BAL stains or IFA in HIV+ positive patients is near 100% specific and sensitive for PJP and almost as sensitive in other immunocompromised patients
• Induced sputum statins or IFA can be reasonably sensitive and specific
• PJP PCR is highly sensitive but can represent colonization
• Beta-D-glucan can be elevated and aid in the diagnosis

Course and Prognosis of PJP

• PJP is lethal if not treated.
• HIV+ patients can have a more indolent course without severe inflammatory symptoms or CXR findings
• HIV- patients and other immunocompromised patients tend to present more acutely and with a more fulminant picture of respiratory and organ failure
• patients generally do not respond to therapy for about 1 week, so supportive care for at least 10 days is reasonable

Prevention of PJP

Indications

The risk for PCP is determined by the degree of cell-mediated immune deficiency and can occur due to immunocompromising conditions or receipt of immunosuppressive agents:

• certain primary immunodeficiencies (eg, severe combined immunodeficiency, idiopathic CD4 T-lymphocytopenia, hyper-immunoglobulin IgM syndrome)
• acute lymphocytic leukemia
• Solid organ transplant recipients, often for at least six months to one year following transplantation and during periods of high doses of immunosuppressive medications
• Allogeneic hematopoietic cell transplant (HCT) recipients beginning after engraftment and continuing for as long as immunosuppressive therapy is given; the typical duration of PCP prophylaxis is six months in allogeneic HCT recipients but is longer in those requiring treatment for graft-versus-host disease
• Selected autologous HCT recipients, including those who have an underlying hematologic malignancy, such as lymphoma, myeloma, or leukemia, especially when intensive treatment or conditioning regimens have included a purine analog (eg, fludarabine, cladribine) or high-dose glucocorticoids
• glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer who also have another cause of immunocompromise
• phosphatidylinositol 3-kinase inhibitors
• alkylating agents alone
• triazenes with steroids or radiotherapy
• anti-CD20 monoclonal antibody (RTX) with or without concurrent glucocorticoid
• checkpoint inhibitor with or without concurrent glucocorticoid
• anti-CD52 monoclonal antibody

Regimens

• TMP-SMX is the recommended first-line agent for PJP prophylaxis. Associated with an 85 percent reduction in the occurrence of PCPJPP compared with no prophylaxis or fluoroquinolone prophylaxis
  • Dosages: 1 DS OD (preferred), 1 DS M/W/F, 1 SS OD
  • Renal dosing required
  • Desensitization preferred if intolerant
  • Adverse effects: leukopenia and agranulocytosis. Sulfonamide-containing antibiotics, including TMP-SMX, can cause exacerbations of SLE as well,
• Alternatives
  • Dapsone (with pyrimethamine if Toxoplasma prophylaxis is indicated)
    • cause agranulocytosis and hemolytic anemia
    • less expensive than atovaquone
    • contraindicated in G6PD deficiency
  • Atovaquone
  • Aerosolized pentamidine
• PCP prophylaxis should be continued until the risk factor for the disease is no longer present

Treatment of PJP

Adjunctive Corticosteroids

Indicated for patients with PaO2 < 70 mmHg or A-A gradient >= 35 mmHg, hypoxic on room air (SpO2 < 92%).

The rationale is that there is pulmonary inflammation that occurs once specific therapy is started and the organisms begin to die.

Regimen (21 days): Prednisone 40 mg orally twice daily for five days, followed by 40 mg orally once daily for five days, followed by 20 mg orally once daily for 11 days. IV methylprednisolone can be administered as 75 percent of prednisone dose.

Antibiotics

Drug	Priority	Dosing/Notes
TMP-SMX	1st	15-20 mg/kg IV or PO daily in 3 or 4 divided doses. IV therapy until they are clinically stable and have a functioning GI tract.
Clindamycin + primaquine	2nd	For any severity of disease
Trimethoprim + dapsone	2nd	For mild or moderate disease
Atovaquone	2nd	For mild disease only
IV pentamidine	2nd	For severe disease

Patients should be tested for glucose-6-phosphate dehydrogenase deficiency before taking dapsone or primaquine.

These medications have largely been studied only in PJP with HIV+ and not in patients without HIV.

IV pentamidine can cause lethal hypotension, renal failure, neutropenia, dysglycemia, TdP

Duration of treatment is at least 21 days (not studied well). Patients without HIV who have PCP should start to show clinical improvement by the seventh day of therapy.

Secondary Prophylaxis

After completing the course of treatment, patients should be considered for antimicrobial therapy at a reduced dose to prevent recurrent infection (ie, secondary prophylaxis). The antimicrobial regimens used for secondary prophylaxis are the same as those used to prevent initial infection

References

1. UpToDate
2. Harrison's Ch 215 Pneumocystis Infections