Pneumocystis jirovecii

• Opportunistic fungal infection of the lower respiratory infection

Background

Microbiology

• Yeast-like fungus in the Ascomycota phylum
• Has not been able to be grown in culture, and species within the genus have tropism for their specific host
• It's cell wall lacks ergosterol, so has inherent resistance to many antifungals
• β-1,3 glucan, however, is an important cell wall component
• The major immunogenic protein is major surface glycoprotein (Msg), or gpA

History

• P. jirovecii was previously thought to be P. carinii, but it was later realized that they were two species within the same genus
  • P. carinii and P. wakefieldiae infect rats, P. murina infects mice and P. jiroveci infects humans
• Also previously thought to be a protozoan, but reclassified as fungus based on phylogenetic analysis, most closely related to Schizosaccharomyces pombe

Epidemiology

• Worldwide distribution
  • May be environmental, associated with outdoor activities and spaces (but not clear)
  • Human-to-human transmission is possible
• Only circulates within humans, with reservoirs including children and immunocompromised patients
  • Primary infection occurs in infants, who are likely the natural host; most have been exposed by 2-3 years of age
  • Includes asymptomatic carriage by patients with HIV, malignancy, and long-term steroid use, and in pregnant women
• Colonization is common, associated with the following:
  • Immunosuppressive conditions (HIV, low CD4 cell count, cancer, autoimmune diseases, organ transplantation)
  • Immunosuppressive drugs (corticosteroids, TNF-α inhibitors)
  • COPD and other chronic lung disorders
  • Other conditions (pregnancy, cigarette smoking)
  • Lack of surfactant
  • But also 20% of healthy people
• Infection is mostly associated with HIV
  • Much higher risk with HIV/AIDS with low CD4 count <200
  • More common in Asian and South/Central America
• Infection is still possible in immunocompetent hosts
  • TNF-alpha inhibitors, B-cell inhibitors, and corticosteroid use

Pathophysiology

• After inhalation of cyst, trophic forms are released and adhere to type I pneumocytes in the alveolar epithelium
• The immune response involves a combination of humoral and cell-mediated immunity
  • Alveolar macrophages are the first response, but require CD4 cells to respond fully
  • IgM antibodies recognize common fungal carbohydrate antigens
  • CD4 cells are important for the memory response
• The alveolus fills with Pneumocystis
• The inflammatory response may damage the lung

Clinical Manifestations

Infants

• Interstitial plasma cell pneumonia between 6 weeks and 4 months
• Typically in orphanages under crowded conditions
• Insidious onset with poor feeding, progressing to cyanosis

Adults

• Worsening exertional dyspnea, fever, and non-productive cough
  • Symptoms usually more insidious in severe HIV
  • Symptoms may develop after tapering immunosupressive drugs like steroids
• Tachypnea and tachycardia with exertional hypoxemia
• CXR may initially be normal, then progresses to whiteout
  • Can also show unilateral consolidation, nodules, cysts, pneumatoceles, mediastinal lymphadenopathy, and pleural effusions
• High LDH from lung damage
• In advanced HIV, can disseminate to lymph nodes, spleen, liver, bone marrow, GI tract, eyes, thyroid, adrenal glands, and kidneys

Investigations

• CXR
  • Typical: bilateral diffuse patchy disease
  • Atypical:
    • Normal (15%)
    • Localized
    • Pneumothorax
    • Upper lobe, if on pentamidine
• 6min walk test: will desaturate, even if well-oxygenated at rest
• LDH increased
• CBC often normal

Diagnosis

• Cannot be cultured
• Specimens include sputum (best), BAL, or biopsy
• Microscopy
  • The gold standard
  • Direct fluorescent antibody (DFA) staining from induced sputum or BAL
  • Can also use Gomori Methenamine-Silver or Diff-Quik staining
• Molecular
  • PCR from induced sputum or BAL
  • Can detect lower burden of PJP, especially in immunocompetent hosts where it is likely not causing disease but is instead helping to circulate it among the population
• Serology
  • Not sensitive or specific
  • 1,3-β-D glucan levels may be elevated (Sn 95%, Sp 86%)
    • diagnostic accuracy was not different between HIV positive and HIV negative patients
    • Can be used as a screening tool
    • False positives with other IFIs, Candida species, IV amoxicillin-clavulanic acid, treatment of patients with immunological preparations (albumins or globulins), use of cellulose membranes and filters made from cellulose in hemodialysis, and use of cotton gauze swabs/packs/pads and sponges during surgery

Management

• First-line: TMP-SMX 15-20 mg/kg IV or PO divided q6-8h
  • If mild-moderate, can give TMP-SMX DS 2 tabs PO tid
• Alternatives:
  • Clindamycin 600-900 mg IV q6-8h with primaquine 15 to 30 mg PO daily
  • Pentamidine 4 mg/kg IV daily
  • Trimethoprim 15 mg/kg PO divided q8h with dapsone 100 mg PO daily
  • Atovaquone 750 mg PO bid (for mild-moderate only)
  • Possibly anidulafungin1
• Adjunctive: Prednisone 40 mg PO bid for 5 days, followed by 40 mg PO daily for 5 days, followed by 20 mg po daily for 11 days
  • Can use methylprednisolone at 75% of predisone dose
  • Typically indicated if PaO₂ ≤70 mmHg or A-a O₂ gradient >35 mmHg
• Duration is 21 days (3 weeks)

Prevention

Prophylaxis

• Indicated in population with risk of PJP >3.5% per year
  • HIV: prior Pneumocystis pneumonia; CD4 <200; oropharyngeal Candida regardless of CD4
  • Medications: prednisolone ≥20 mg daily for >4 weeks; TNF-α inhibitors; steroids plus a steroid-sparing agent
  • Cancer treatment: steroids and cyclophosphamide; alemtuzumab for at least 2 months after treatment and until CD4 >200; temozolomide and radiation therapy, until CD4 >200; fludarabine and T-cell depletion, until CD4 >200; any antileukemic therapy
  • Rheumatology treatment: GPA receiving cyclophosphamide, especially with steroids
  • Transplantation: allogeneic stem cell transplantation for at least 180 days; autologous stem cell transplantation for at least 3 to 6 months
  • Primary immunodeficiency: SCID; idiopathic CD4 lymphocytopenia; hyper-IgM syndrome
• First-line: TMP-SMX DS or SS 1 tab PO daily
• Alternatives:
  • TMP-SMX DS 1 tab po tiw
  • Dapsone 100 mg po daily, or 50 mg po bid
  • Dapsone 50 mg po daily with pyrimethamine 50 mg po weekly and leucovorin 25 mg po weekly
  • Pentamidine 300 mg inhaled monthly
  • Atovaquone 1500 mg po daily (or 750 mg po bid)
  • Atovaquone as above with pyrimethamine 25 mg po daily and leucovorin 10 mg po daily
• Although there are no clear data guiding when to stop prophylaxis, it is probably reasonable to stop once the dose prednisone drops below 15-20 mg daily or equivalent
  • However, at least one guideline recommends continuing for 6 weeks after the steroid-tapering period2

Further Reading

• Pneumocystis Colonization Is Highly Prevalent in the Autopsied Lungs of the General Population. Clin Infect Dis. 2010;50:347. doi: 10.1086/649868
• Near-Universal Prevalence of Pneumocystis and Associated Increase in Mucus in the Lungs of Infants With Sudden Unexpected Death. Clin Infect Dis. 2013;56:171. doi: 10.1093/cid/cis870