Pneumocystis Jirovecii (Carinii) (PCP)

Epidemiology

Risk Factors

Immunodeficiency States

Agammaglobulinemia (see Agammaglobulinemia)
- Clinical Syndromes
  - Autosomal Recessive Agammaglobulinemia: severe hypogammaglobulinemia, antibody deficiency, and increased susceptibility to infection
  - X-Linked Agammaglobulinemia (Bruton Agammaglobulinemia): severe hypogammaglobulinemia, antibody deficiency, and increased susceptibility to infection
Common Variable Immunodeficiency (CVID) (see Common Variable Immunodeficiency)
- Epidemiology:
Good Syndrome
- Physiology: B-cell immunodeficiency syndrome
- Diagnosis
  - Hypogammaglobulinemia (see xxxx)
  - Thymoma (see Thymoma): usually spindle cell histology

Hematologic Malignancy

Acute Lymphocytic Leukemia (ALL) (see Acute Lymphocytic Leukemia)
- Epidemiology: predominantly in cases in children
Chronic Lymphocytic Leukemia (CLL) (see Chronic Lymphocytic Leukemia)
- Epidemiology: few reported cases of Pneumocystis Jirovecii with CLL alone, however, risk appears to be the greatest in CLL patients that have received steroids and/or fludarabine

Other Immunosuppression

Anti-CD20 Therapy (see Anti-CD20 Therapy)
- Epidemiology: clear risk factor
  - Majority of Cases Had Also Received Cytotoxic Chemotherapy and Significant Doses of Glucocorticoids (Chest, 2013) [MEDLINE]
- Agents
  - Rituximab (Rituxan) (see Rituximab): monoclonal antibody that binds to the CD20 antigen on B lymphocytes
- Prognosis: mortality rate in these cases is high
Anti-Tumor Necrosis Factor-α (Anti-TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy)
- Epidemiology
  - Dosing: patients had received an average of 2 drug infusions
  - Mean Latency Between Drug Infusion and Onset of Symptoms: 21 days
- Relative Risk: infliximab > etanercept/adalimumab
  - Adalimumab (Humira) (see Adalimumab)
  - Etanercept (Enbrel) (see Etanercept)
  - Infliximab (Remicade) (see Infliximab)
- Physiology: little is known about the role of TNFα in the host defense against Pneumocystis Jirovecii, but infliximab decreases peripheral and gut mucosal CD4 counts in patients with Crohn’s Disease (Dig Dis Sci, 2004) [MEDLINE] (Gastroenterology, 1999) [MEDLINE]
- Prognosis
  - Mortality Rate: 27% (Dig Dis Sci, 2007) [MEDLINE]
Bendamustine (Treakisym, Ribomustin, Levact, Treanda, SDX-105, Bendeka) (see Bendamustine)
- Epidemiology: case report
Chlorambucil (see Chlorambucil)
- Epidemiology:
Corticosteroids (see Corticosteroids)
- Epidemiology
  - Associated with corticosteroids equivalent to >16 mg prednisone/day for at least 8 wks (Arch Intern Med, 1995) [MEDLINE]
Cyclophosphamide (Cytoxan) (see Cyclophosphamide)
Cyclosporine A (see Cyclosporine A)
Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
- Epidemiology
  - Pneumocystis Jirovecii Occurs Most Frequently with (T-Helper) CD4 Count <250 Cells/mm3
    - Only 5% of cases occur in HIV patients with CD4 >400
  - Incidence of Pneumocystis Jirovecii Has Decreased in the Era of Antiretroviral Therapy for HIV
Janus Kinase (JAK) Inhibitors (see Janus Kinase Inhibitors)
- Ruxolitinib (Jakafi) (see Ruxolitinib)
  - Epidemiology: case report (BMJ Case Rep, 2014) [MEDLINE]
- Tofacitinib (Xeljanz) (see Tofacitinib)
Methotrexate (see Methotrexate)
- Epidemiology

Physiology

Microbiology

Pneumocystis Jirovecii

Pneumocystis Jirovecii was First Identified by Carlos Chagas in Early 1900’s: using a guinea pig model
Although Formerly Thought to be a Protozoan, rRNA Subunit Analysis Links it Phylogenetically to the Ascomycetous Fungi: Pneumocystis Jirovecii was reclassified as a fungus in 1988
Pneumocystis Species Have Been Identified in Almost All Mammals
- Humans Demonstrate Near Universal Seropositivity to Pneumocystis Jirovecii by Age 2
- Pneumocystis Jirovecii is the Only Pneumocystis Species Which Infects Humans
Transmission: airborne person-to-person transmission is most likely the source on infection (although acquisition from environmental sources may also occur)
- Despite the Probable Role of Airborne Transmission, Respiratory Isolation is Not Currently Recommended
- Asymptomatic Carriage of Pneumocystis Jirovecii May Occur
Immune Defense Against Pneumocystis Jirovecii: although defense against Pneumocystis Jirovecii has classically been attributed to CD4 cells, animal data also indicates roles for B-cells and antibodies
- This Likely Explains the Occurrence of Pneumocystis Jirovecii Following the Anti-B-Cell Agent Rituximab Therapy
Culture: Pneumocystis Jirovecii cannot be propagated in culture

Pneumocystis Jirovecii Colonization

Pneumocystis Jirovecii Colonization (PCR-Detected in the Absence of Infection) Has Been Associated with Upper Respiratory Tract Illness in Children
Pneumocystis Jirovecii Colonization (PCR-Detected in the Absence of Infection) Has Been Associated with Smoking and COPD in Adults (AIDS 2004) [MEDLINE] (Am J Respir Crit Care Med, 2004) [MEDLINE]
- Animal Models Suggest an Association of Pneumocystis Jirovecii Colonization with the Development of COPD

Diagnosis

Serum (1–3)-β-D-Glucan (see Serum (1-3)-β-D-Glucan)

May Be Useful Diagnostically

Induced Sputum

General Comments

Widely-Used Diagnostic Method

Sensitivity/Specificity

Sensitivity (with Staining) in HIV-Related Cases: approximately 50-90%
- Sensitivity is Lower in Non-HIV-Related Cases (Due to Decreased Organism Burden)

Staining for Pneumocystis Jirovecii

Gomori Methenamine Stain: useful to stain cyst forms
Wright–Giemsa Stain: can be used for identification of trophic forms within foamy exudates (sputum, bronchoalveolar lavage)
- However, Requires a High Organism Burden and Expertise in Interpretation
Calcofluor White Stain: fungal cyst-wall stain that can be used for identification of cyst forms
Immunofluorescence Staining: can sensitively and specifically identify both pneumocystis trophic forms and cysts

Polymerase Chain Reaction (PCR) for Pneumocystis Jirovecii

Improves the Sensitivity for the Detection of Pneumocystis Jirovecii, Particularly in Non-HIV-Related Cases: however, due to high sensitivity, it may be difficult to differentiate organism carriage from infection
Sensitivity/Specificity (J Med Microbiol, 2002) [MEDLINE]
- Induced Sputum: Sensitivity = 100%, Specificity = 90%
- Bronchoalveolar Lavage: Sensitivity = 84%, Specificity = 93%
- Negative Predictive Value: near 100%
  - Negative PCR Has Been Suggested to Allow Safe Discontinuation of Treatment (Chest, 2009) [MEDLINE]
Real-Time PCR: may allow differentiation of carriage vs infection (using threshold values of organism load)

Bronchoscopy (see Bronchoscopy)

Techniques
- Bronchoalveolar Lavage (BAL): widely-used diagnostic method
  - Typically Higher BAL Neutrophil Counts and Lower Organism Counts are Found in Non-HIV-Related Cases
  - Sensitivity (with Staining) in HIV-Related Cases: >90%
  - Similar to Induced Sputum, Sensitivity is Lower (Approximately 38-53%) in Non-HIV-Related Cases (Due to Decreased Organism Burden)
- Transbronchial Biopsy (TBB): may add to the diagnostic yield of induced sputum and bronchoalveolar lavage

Transthoracic Fine Needle Aspiration (TTNA) (see Transthoracic Fine Needle Aspiration)

May Be Required in Some Cases

Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see Video-Assisted Thoracoscopic Surgery)

May Be Required in Some Cases

Clinical Presentations

General Comments

Non-HIV-Related Cases
- Clinical Presentation is Generally Less Typical Than HIV-Associated Cases (Am Rev Respir Dis. 1989) [MEDLINE]
- Clinical Course is More Fulminant Than HIV-Associated Cases (Am Rev Respir Dis. 1989) [MEDLINE]
- Mortality Rate is Higher than in HIV-Associated Cases (Am Rev Respir Dis. 1989) [MEDLINE]
- Often Associated with the Tapering of an Immunosuppressive Agent (Such as Prednisone or Cyclophosphamide)
HIV-Related Cases
- Immune Reconstitution Inflammatory Syndrome (IRIS) (see Immune Reconstitution Inflammatory Syndrome): may occur (see below)

Normal Chest X-Ray (CXR) Presentation

Epidemiology: occurs in 10% of cases
- However, in Such Cases, Chest CT is Abnormal

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome)

Epidemiology: respiratory failure (with ARDS) may occur (Chest, 2005) [MEDLINE]

Alveolar Pneumonia

Diagnosis
- Serum Lactate Dehydrogenase (LDH) (see Serum Lactate Dehydrogenase): elevation is highly sensitive, but not very specific (as can also be elevated in other pulmonary processes, such as bacterial pneumonia or tuberculosis)
- Chest X-Ray (CXR) (see Chest X-Ray)
  - Alveolar infiltrates
- Chest CT (see Chest Computed Tomography)
  - Mosaic Pattern or Ground-Glass Infiltrates: most common pattern is that with central densities
  - Lymphadenopathy: uncommon
  - Pneumatoceles/Pneumocysts: may occur (see Cystic-Cavitary Lung Lesions)
Clinical: pneumonia-like presentation

Cryptogenic Organizing Pneumonia (COP) (see Cryptogenic Organizing Pneumonia)

Epidemiology: xxx
Clinical: may have pneumonia-like presentation

Interstitial Pneumonia (see Interstitial Lung Disease)

Diagnosis
- Serum Lactate Dehydrogenase (LDH) (see Serum Lactate Dehydrogenase): elevation is highly sensitive, but not very specific (as can also be elevated in other pulmonary processes, such as bacterial pneumonia or tuberculosis)
- Chest X-Ray (CXR) (see Chest X-Ray): interstitial infiltrates
- Chest CT (see Chest Computed Tomography): mosaic pattern or ground-glass infiltrates
  - Lymphadenopathy: uncommon
Clinical
- Dyspnea (see Dyspnea)
- Dry Cough (see Cough)
Example: 40 y/o white female on prednisone 40 mg PO qday, tapered to 30 mg qday 1 wk prior to admission (not on Pneumocystis Jirovecii prophylaxis), who presented with faint interstitial infiltrates on CXR 5 days prior to admission, then, worsening interstitial infiltrates on day of admission -> Pneumocystis Jirovecii was diagnosed by bronchoalveolar lavage

Lung Nodules (see Lung Nodule or Mass)

Diagnostic
- Chest CT (see Chest Computed Tomography): nodules may cavitate

Pleural Effusion (see Pleural Effusion-Exudate)

Epidemiology: rarely causes pleural effusion
Diagnosis: usually exudative

Pneumothorax (see Pneumothorax)

Epidemiology: predisposed by presence of pneumocysts

Upper Lobe Cavitary Disease (see Cystic-Cavitary Lung Lesions)

Epidemiology: may be seen in patients who have been receiving inhaled pentamidine prophylaxis
Diagnosis
- Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy): typically higher BAL neutrophil counts and lower organism counts are seen in non-AIDS cases
Clinical: mimics tuberculosis

Prophylaxis (Med Mal Infect, 2014) [MEDLINE]

Indications

Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)

Indications for Primary Prophylaxis: primary prophylaxis is indicated even in pregnant patients or patients on antiretroviral therapy
- CD4 <200 Cells/μL or with History of Oropharyngeal Candidiasis
Indications for Secondary Prophylaxis
- History of Pneumocystis Jirovecii: lifelong secondary prophylaxis is recommended (unless antiretroviral therapy results in immune reconstitution, as defined below))
  - Following Initiation of Antiretroviral Therapy, Once CD4 Increases to >200 Cells/μL x 3 mo, Prophylaxis Can Be Discontinued
  - If CD4 Decreases to <200 Cells/μL x 3 mo, Prophylaxis Should Be Restarted

Transplant

Hematopoietic Stem Cell Transplant (HSCT) (Bone Marrow Transplant, BMT) (see Hematopoietic Stem Cell Transplant)
- Allogeneic Stem Cell Transplant
  - Prophylaxis is Typically Administered for 6 mo After Engraftment (As Long as Immunosuppressives are Aministered)
  - Prophylaxis May Be Required for Longer in Patients Receiving Immunosuppression for Graft vs Host Disease
- Autologous Stem Cell Transplant
  - Prophylaxis is Typically Administered for 3-6 mo
  - Prophylaxis Should Be Administered in Patients with an Underlying Hematologic Mlignancy (Lymphoma, Multiple Myeloma, Leukemia), Especially when Intensive Treatment Regimens have Included a Purine Analog (Cladribine, Fludarabine) or High-Dose Corticosteroids
Solid Organ Transplant
- Prophylaxis is Indicated for 6 mo-1 yr After Transplant and For At Least 6 wks During Periods of High-Dose Immunosuppression (Such as During the Treatment of Acute Rejection)

Immunosuppressive Administration

Alemtuzumab (Campath, MabCampath, Campath-1H, Lemtrada) Administration (see Alemtuzumab)
- Prophylaxis is Indicated for a Minimum of 2 mo After Completing Therapy or Until the CD4 Count is >200 Cells/μl
Anti-Tumor Necrosis Factor-α (Anti-TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy)
- Prophylaxis Should Be Considered, Although This Has Not Been Adopted as a Standard of Care: especially if patient is also receiving corticosteroids (see Corticosteroids)
Concomitant Purine Analog (Cladribine, Fludarabine) + Cyclophosphamide Administration (see Fludarabine and Cyclophosphamide)
- Prophylaxis is Indicated Until Recovery of Lymphopenia to CD4 >200 Cells/μL
Concomitant Temozolomide (Temodar, Temodal) + Radiation Therapy (see Temozolomide)
- Prophylaxis is Indicated Until Recovery of Lymphopenia to CD4 >200 Cells/μL
Concomitant Temsirolimus + Corticosteroids or Other Immunosuppressives (see Temsirolimus)
- Prophylaxis Should Be Considered in these Patients
Corticosteroid Administration (see Corticosteroids)
- Prophylaxis is Indicated for Those Receiving the Equivalent of Prednisone >20 mg qday for at Least 1 mo
Cyclophosphamide (Cytoxan) (see Cyclophosphamide)
- Prophylaxis Should Be Considered, Especially if Corticosteroids are Also Administered: as in (see Wegeners Granulomatosis)
Rituximab (Rituxan) (see Rituximab)
- Prophylaxis Should Be Considered in Patients at Risk

Primary Immunodeficiency States

Severe Combined Immunodeficiency (SCID) (see Severe Combined Immunodeficiency)
Idiopathic CD4 T-Lymphocytopenia
Hyper-IgM Syndrome (see Hyper-IgM Syndrome)

Other

Acute Lymphocytic Leukemia (ALL) (see Acute Lymphocytic Leukemia)
- Prophylaxis is Indicated While Receiving Anti-Leukemic Therapy

Prophylaxis Regimens

Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim): first-line agent for prophylaxis
- Administration
  - 1 single-strength (SS) tablet PO qday: first choice
  - 1 double-strength (DS) tablet PO qday: first choice
  - 1 double-strength (DS) tablet 3x/wk (M/W/F): alternate choice
Dapsone (see Dapsone)
- Pre-Administration: test for glucose 6-phosphate deydrogenase (G6PD) deficiency (see Glucose 6-Phosphate Dehydrogenase Deficiency)
- Administration: 50 mg PO BID or 100 mg PO qday
Dapsone + Pyrimethamine + Leucovorin (see Dapsone, Pyrimethamine, and Leucovorin)
- Pre-Administration: test for glucose 6-phosphate deydrogenase (G6PD) deficiency (see Glucose 6-Phosphate Dehydrogenase Deficiency)
- Administration
  - Dapsone 50 mg PO BID + pyrimethamine 50 mg PO qweek + leucovorin 25 PO qweek
  - Dapsone 200 mg PO qweek + pyrimethamine 75 mg PO qweek + leucovorin 25 PO qweek
Pentamidine (Aerosolized) (see Pentamidine)
- Administration: 300 mg nebulized qmonth
Atovaquone (Mepron) (see Atovaquone):
- Administration: 1500 mg PO qday (with high fat meal to maximize absorption)

Treatment

Antimicrobials

Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
- First-Line Therapy: most effective treatment
- Regimen: 3 week course
- Resistance: cases of sulfamethoxazole-trimethoprim resistant Pneumocystis Jirovecii have been reported
Alternative Agents
- Atovaquone (Mepron) (see Atovaquone)
  - Administration: 750 mg PO BID
  - Only Indicated for Mild-Moderate Cases
- Primaquine + Clindamycin (see Primaquine, and Clindamycin)
  - Administration: primaquine 30 mg pO day + clindamycin 600 mg PO TID
- Pentamidine (Intravenous or Aerosolized) (see Pentamidine)
  - Administration: 4 mg/kg IV qday
  - Aerosolized: 600 mg nebulized qday
Salvage Therapy
- Caspofungin (see Caspofungin): case reports of use as salvage therapy
  - Administration: 70 mg IV load on day 1, then 50 mg qday IV

Antimicrobial Response Rates

Antimicrobial Response Rates are Believed to Be Better in HIV-Related Cases than in Non-HIV-Related Cases

Antimicrobial Resistance

Resistance of Pneumocystis Jirovecii Sulfamethoxazole-Trimethoprim Has Been Reported

Corticosteroids (see Corticosteroids)

Indications
- Pneumocystis Jirovecii with Hypoxemia Associated with Room Air pO2 <70 mm Hg (or A-a Gradient >35) (see Hypoxemia)
Regimens
- Prednisone (see Prednisone)
  - HIV-Associated Pneumocystis Jirovecii: prednisone 40 mg PO BID x 5 days, then 40 mg PO qday on days 6-11, then 20 mg PO qday on days 12-21
  - Non-HIV-Associated Pneumocystis Jirovecii: prednisone 60 mg PO qday (better outcome has been demonstrated with higher prednisone dose in this population) (Chest, 1998) [MEDLINE]

Specific Treatment of Pneumocystis Jirovecii in the Setting of Human Immunodeficiency Virus (HIV) Infection

Immune Reconstitution Inflammatory Syndrome (IRIS) (see Immune Reconstitution Inflammatory Syndrome)

Background
- IRIS is a Common Complication of Anti-Retroviral Therapy for HIV in the Setting of Various AIDS-Defining Illnesses: it represents a paradoxical worsening of treated opportunistic infections or unmasking of previously subclinical, untreated infections
Clinical Data
- Systematic Review and Meta-Analysis of IRIS (Lancet Infect Dis, 2010) [MEDLINE]
  - Incidence of IRIS is Variable Across Different AIDS-Defining Illnesses
    - Illnesses Associated with the Highest Incidence of IRIS: CMV retinitis, cryptococcal meningitis, tuberculosis
    - Illnesses Associated with the Lowest Incidence of IRIS: Kaposi sarcoma, herpes zoster
  - Incidence of IRIS is Inversely Correlated with the CD4 Count at Baseline
    - Higher Incidence of IRIS is Observed in Patients with CD4 <50 cells/μL: particularly in patients with tuberculosis, CMV-associated immune recovery uveitis, and cryptococcal meningitis
    - Higher Incidence of IRIS at Lower CD4 Counts is Not Surprising, Since CMV Retinitis is Typically an Infection Which Occurs at CD4 <50 cells/μL, Cryptococcal Meningitis Typically Occurs at Low CD4 Counts (While Tuberculosis and Kaposi Sarcoma Tend to Occur at Higher CD4 Counts)
  - Mortality Rate Associated with IRIS: 4%
    - Mortality Rate from IRIS is Much Higher with Cryptococcal Meningitis

Prognosis

Clinical Data

Comparative Small Taiwanese Study of Pneumocystis Jirovecii in Patients with/without HIV Infection (J Microbiol Immunol Infect, 2008) [MEDLINE]: n = 49
- Most Common Immunocompromising Conditions in Study: HIV, malignancies
  - Mean CD4 Count: 110 cells/μL (higher in malignancy than in HIV, but difference was not statistically significant)
- Mortality Rate of *Pneumocystis Jiroveciii HIV-Positive Patients: 6.7%*
- Mortality Rate of *Pneumocystis Jirovecii in HIV-Negative Patients: 50%*
Retrospective Study of Pneumocystis Jirovecii Pneumonia in Lung Transplant Patients (Respir Med, 2020) [MEDLINE]: n = 47
- Annual Incidence Rate: 2.7 Cases/1000 Lung Transplant Patients Per Year
- Median time from LT was 2.4 ± 3.0 years
- Sixty-five percent of patients were not on prophylaxis at the time of PCP while all patients were receiving steroids at the time of PCP
- PCP was Associated with a High Mortality in Lung Transplant Patients
  - 28-Day Mortality Rate: 15%
  - 90-Day Mortality: 23%
  - Factors Associated with Increased Mortality in PJP in Lung Translant Patients
    - Decreased FEV1
  - Everolimus treatment
  - Pseudomonas aeruginosa coinfection
  - Fungal coinfection (especially Aspergillus sp.)
  - Mechanical Ventilation
  - Vasopressors
  - Factors Not Associated with Increased Mortality in PJP in Lung Translant Patients
    - PCP Primary Prophylaxis
    - Steroid Modification During PJP
    - Number of Immunosuppressive Molecules
- Data Suggest the Need for Lifetime PJP Prophylaxis in Lung Transplant Patients
- Benefit of Adjuvant Steroids Remains Unclear

References

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The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. N Engl J Med 1990;322:161-5
Pneumocystis carinii pneumonia in patients with connective tissue disease. Chest 1992; 101:375-378
Pneumocystis carinii pneumonia in patients without AIDS. Clin Infect Dis 1993; 17:S416-S422
Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis. Arch Intern Med. 1995 Apr 24;155(8):872-4 [MEDLINE]
Treatment and prophylaxis of Pneumocystis carinii pneumonia. Semin Respir Infect 1998; 13:296-303
Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest 1998;113:1215-24 [MEDLINE]
Tumor necrosis factor alpha antibody (infliximab) therapy profoundly downregulates the inflammation in Crohn’s ileocolitis. Gastroenterology 1999; 116:22-28 [MEDLINE]
Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 2001 Sep 1;164(5):847-51 [MEDLINE]
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Prognosis

Pneumocystis pneumonia after lung transplantation: a retrospective multicenter study. Respir Med. 2020 Aug;169:106019. doi: 10.1016/j.rmed.2020.106019 [MEDLINE]