Pneumocystis Jirovecii (PJP)

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)
Good Syndrome
- Physiology
  - B-Cell Immunodeficiency Syndrome
- Diagnosis
  - Hypogammaglobulinemia
  - Thymoma (Usually Spindle Cell Histology) (see Thymoma)

Hematologic Malignancy

Acute Lymphocytic Leukemia (ALL) (see Acute Lymphocytic Leukemia)
- Epidemiology
  - Pneumocystis Jirovecii Predominantly Occurs in Childhood Acute Lymphocytic Leukemia Cases
Chronic Lymphocytic Leukemia (CLL) (see Chronic Lymphocytic Leukemia)
- Epidemiology
  - While there are a Few Reported Cases of Pneumocystis Jirovecii with Chronic Lymphocytic Leukemia Alone, the Risk Appears to Be the Greatest in Patients Who Have Received Corticosteroids and/or Fludarabine

Other Immunosuppression

Anti-CD20 Therapy (see Anti-CD20 Therapy)
- Epidemiology
  - Anti-CD20 Therapy is a Clear Risk Factor for Pneumocystis Jirovecii
  - Majority of Reported 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 is High in These Cases
Anti-Tumor Necrosis Factor-α (Anti-TNFα) Therapy (see Anti-Tumor Necrosis Factor-α Therapy)
- Epidemiology
  - Pneumocystis Jirovecii Cases 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 Reports of at Least 14 Cases of Bendamustine-Associated Pneumocystis Jirovecii (Health Sci Rep, 2022) [MEDLINE]
    - Rituximab was Also Used in the Majority of These Cases (see Rituximab)
- Pharmacology
  - Bendamustine is Associated with the Development of Lymphopenia
Chlorambucil (see Chlorambucil)
- Epidemiology
  - Case Reports of Chlorambucil-Associated Pneumocystis Jirovecii (Postgrad Med J, 2004) [MEDLINE]
Corticosteroids (see Corticosteroids)
- Epidemiology
  - Corticosteroid Use is One of the Strongest Risk Factors for Pneumocystis Jirovecii Infection
  - Pneumocystis Jirovecii is Associated with Corticosteroid Equivalent to >16 mg Prednisone/Day for at Least 8 wks (Arch Intern Med, 1995) [MEDLINE]
Cyclophosphamide (Cytoxan) (see Cyclophosphamide)
- Epidemiology
  - Risk of Cyclophosphamide-Associated Pneumocystis Jirovecii Appears to Be Low (J Clin Rheumatol, 2008) [MEDLINE]
Cyclosporine A (see Cyclosporine A)
Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) (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 Count >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 of Ruxolitinib-Associated Pneumocystis Jirovecii (BMJ Case Rep, 2014) [MEDLINE]
- Tofacitinib (Xeljanz) (see Tofacitinib)
Methotrexate (see Methotrexate)
- Epidemiology
  - Cases of Methotrexate-Associated Pneumocystis Jirovecii Have Been Reported (Some with Low-Dose Methotrexate Therapy for Rheumatoid Arthritis) (J Rheumatol, 1991) [MEDLINE] (Respir Med Case Rep, 2020) [MEDLINE]
  - Cases of Methotrexate-Associated Pneumocystis Jirovecii Have Been Reported in Patients Also Receiving Corticosteroids (Although at Corticosteroid Doses Lower than that Generally Associated with Pneumocystis Jirovecii) (Rev Rhum Engl Ed, 1996) [MEDLINE]

Physiology

Microbiology

Pneumocystis Jirovecii (Formerly Pneumocystis Carinii)

Using a Guinea Pig, Model, Pneumocystis Jirovecii was First Identified by Carlos Chagas in Early 1900’s
Although Formerly Thought to be a Protozoan, rRNA Subunit Analysis Links Pneumocystis Jirovecii 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 the Most Likely Source of 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 Therapy with the Anti-B-Cell Agent, Rituximab
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 Chronic Obstructive Pulmonary Disease (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

There is a Greater Degree of Lung Inflammation in Pneumocystis Jirovecii Patients Who are Not HIV-Positive (Am Rev Respir Dis, 1989) [MEDLINE]

While This Observation Provides a Rationale for Use of Corticosteroids in the Treatment of Pneumocystis Jirovecii in Non-Human Immunodeficiency Virus Patients, Retrospective Studies Suggest that Addition of Early Corticosteroids to Anti-Pneumocystis Therapy in Non-Human Immunodeficiency Virus Patients is Not Associated with Improved Respiratory Outcomes (Chest, 2018) [MEDLINE]

Diagnosis

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

Diagnostically Useful, as the Cyst Wall Contains β-D-Glucan

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 Manifestations

General Comments

Pneumocystis Jirovecii Cases Associated with Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus)
- Immune Reconstitution Inflammatory Syndrome (IRIS) (see Immune Reconstitution Inflammatory Syndrome)
  - May Occur (See Below)
Pneumocystis Jirovecii Cases Not Associated with HIV
- 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]
- Disease is Often Associated with the Tapering of an Immunosuppressive Agent (Such as Prednisone or Cyclophosphamide)

Normal Chest X-Ray (CXR) Presentation

Epidemiology
- Occurs in Approximately 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)
  - Serum LDH Elevation is Highly Sensitive, But Not Very Specific (as Serum LDH 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 Computed Tomography (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)

Clinical
- May Present with Pneumonia-Like Presentation

Interstitial Pneumonia (see Interstitial Lung Disease)

Diagnosis
- Serum Lactate Dehydrogenase (LDH) (see Serum Lactate Dehydrogenase)
  - Serum LDH Elevation is Highly Sensitive, But Not Very Specific (as Serum LDH 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 Computed Tomography (Chest CT) (see Chest Computed Tomography)
  - Mosaic Pattern or Ground-Glass Infiltrates
  - Lymphadenopathy is 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)
- Patient Presented with Dry Cough 2 Days Prior to Admission, at Which Time CXR was Read as Normal
- On the Day of Admission, CXR was Remarkable for Faint Interstitial Infiltrates
- On the Day After Admission, CXR was Remarkable for Alveolar and Interstital Infiltrates
- Pneumocystis Jirovecii was Subsequently Diagnosed by Bronchoscopy with Bronchoalveolar Lavage

Lung Nodules (see Lung Nodule or Mass)

Diagnostic
- Chest Computed Tomography (Chest CT) (see Chest Computed Tomography)
  - Nodules May Cavitate

Pleural Effusion (see Pleural Effusion-Exudate)

Epidemiology
- Pneumocystis Jirovecii 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

Treatment of Pneumocystis Jirovecii in the Setting of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) (see Human Immunodeficiency Virus)

General Comments

Indications for Hospitalization
- Anticipated Significant Disease Worsening During Initial Therapy
  - Since Some Patients with Pneumocystis Jirovecii May Initially Worsen After the First 2-3 Days of Therapy
- Moderate-Severe Disease Requiring Corticosteroid Therapy
- Initial Treatment with Pentamidine Therapy (Due to the Potential Side Effects of Hypotension and/or Hypoglycemia)
- Poor Outpatient Compliance with Medication or Laboratory Monitoring

Mild Disease (A-a Oxygen Gradient <35 mm Hg and/or pO2 ≥70 mm Hg)

Oral Therapy (in Patient with Adequate Oral Drug Absorption) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Dapsone + Trimethoprim (see Dapsone and Trimethoprim)
  - Second-Line Regimen
  - For Dapsone-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Dapsone Dose: 100 mg PO qday
  - Trimethoprim Dose: 5 mg/kg PO TID
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Third-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Atovaquone (Mepron, Malarone) (see Atovaquone)
  - Fourth-Line Regimen (Indicated in the Setting of Sulfa Allergy and Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Dose: 750 mg PO BID (Taken with Food)
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids are Not Required

Moderate Disease (A-a Oxygen Gradient ≥35 and <45 mm Hg and/or pO2 ≥60 and <70 mm Hg)

Oral Therapy (in Patient with Adequate Oral Drug Absorption) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Dapsone + Trimethoprim (see Dapsone and Trimethoprim)
  - Second-Line Regimen
  - For Dapsone-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Settin of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Dapsone Dose: 100 mg PO qday
  - Trimethoprim Dose: 5 mg/kg PO TID
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Third-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Settin of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids (see Corticosteroids)
- Prednisone: 40 mg PO BID x 5 Days, then 40 mg PO qday x 5 Days, then 20 mg PO qday x 11 Days (see Prednisone)
  - For Patients Unable to Take Oral Prednisone, Methylprednisolone IV Can Be Used Instead at 75% of the Prednisone Dose (see Methylprednisolone)
  - In HIV Patients with Pneumocystis Jirovecii Infection, Adjunctive Corticosteroids Decrease the Mortality Rate and Risk of Respiratory Failure (Cochrane Database Syst Rev, 2015) [MEDLINE]

Severe Disease (A-a Oxygen Gradient ≥45 mm Hg, pO2 <60 mm Hg, and/or Potential for Hypoxemic-Hypercapnic Respiratory Failure)

Intravenous Therapy (Until Clinically Stable with pO2 ≥60 mmHg and Respiratory Rate <25 Breaths/min, Then, May Switch to Oral Therapy) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Second-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Settin of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Pentamidine (see Pentamidine)
  - Third-Line Regimen
  - Dose: 4 mg/kg IV qday
  - Adverse Effects (Common and May Be Severe): hypotension, hypoglycemia, nephrotoxicity, and pancreatitis
  - Contraindications: pregnancy
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids (see Corticosteroids)
- Prednisone: 40 mg PO BID x 5 Days, then 40 mg PO qday x 5 Days, then 20 mg PO qday x 11 Days (see Prednisone)
  - For Patients Unable to Take Oral Prednisone, Methylprednisolone IV Can Be Used Instead at 75% of the Prednisone Dose (see Methylprednisolone)
  - In HIV Patients with Pneumocystis Jirovecii Infection, Adjunctive Corticosteroids Decrease the Mortality Rate and Risk of Respiratory Failure (Cochrane Database Syst Rev, 2015) [MEDLINE]

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

Background
- Immune Reconstitution Inflammatory Syndrome is a Common Complication of Antiretroviral Therapy for Human Immunodeficiency Virus in the Setting of Various AIDS-Defining Illnesses
  - Immune Reconstitution Inflammatory Syndrome Represents a Paradoxical Worsening of a Treated Opportunistic Infection or Unmasking of Previously Subclinical, Untreated Infection
- Initiating Antiretroviral Therapy Within 2 wks After Starting Treatment for Pneumocystis Jirovecii (with Clinical Stability) Provides the Best Benefit (PLoS One, 2009) [MEDLINE]
Clinical Data
- Systematic Review and Meta-Analysis of Immune Reconstitution Inflammatory Syndrome (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

Treatment Failure

Treatment Failure is Defined as Failure to Demonstrate Clinical Improvement After 4-8 Days of Therapy

Treatment of Pneumocystis Jirovecii in Other Settings

Mild Disease (A-a Oxygen Gradient <35 mm Hg and/or pO2 ≥70 mm Hg)

Oral Therapy (in Patient with Adequate Oral Drug Absorption) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Atovaquone (Mepron, Malarone) (see Atovaquone)
  - Second-Line Regimen
  - Dose: 750 mg PO BID (Taken with Food)
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Third-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Dapsone + Trimethoprim (see Dapsone and Trimethoprim)
  - Third-Line Regimen
  - For Dapsone-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Dapsone Dose: 100 mg PO qday
  - Trimethoprim Dose: 5 mg/kg PO TID
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids are Not Required

Moderate Disease (A-a Oxygen Gradient ≥35 and <45 mm Hg and/or pO2 ≥60 and <70 mm Hg)

Oral Therapy (in Patient with Adequate Oral Drug Absorption) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Second-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Dapsone + Trimethoprim (see Dapsone and Trimethoprim)
  - Third-Line Regimen
  - For Dapsone-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Dapsone Dose: 100 mg PO qday
  - Trimethoprim Dose: 5 mg/kg PO TID
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids (see Corticosteroids)
- Studies Indicate that There is a Greater Degree of Inflammation in Non-HIV Patients with Pneumocystis Jirovecii, Suggesting that Corticosteroid Treatment May Be Required (as it is in HIV Patients with Pneumocystis Jirovecii) (Am Rev Respir Dis, 1989) [MEDLINE]
  - Early Small Studies Indicated that High-Dose Adjunctive Corticosteroids May Accelerate Recovery in Severe Adult Non-HIV Pneumocystis Jirovecii (Chest, 1998) [MEDLINE]
  - Other Small Retrospective Studies Indicated that Corticosteroids Do Not Improve the Survival of Non-HIV-Infected Patients with Severe Pneumocystis Jirovecii, as Had Been Described for HIV-Infected Patients with Severe Pneumocystis Jirovecii Patients (Clin Infect Dis, 1999) [MEDLINE]
  - However, Larger Retrospective Studies Suggest that Addition of Early Corticosteroids to Anti-Pneumocystis Therapy in Non-HIV Patients is Not Associated with Improved Respiratory Outcomes (Chest, 2018) [MEDLINE]

Severe Disease (A-a Oxygen Gradient ≥45 mm Hg, pO2 <60 mm Hg, and/or Potential for Hypoxemic-Hypercapnic Respiratory Failure)

Intravenous Therapy (Until Clinically Stable with pO2 ≥60 mmHg and Respiratory Rate <25 Breaths/min, Then, May Switch to Oral Therapy) x 21 Days
- Sulfamethoxazole-Trimethoprim (Bactrim) (see Sulfamethoxazole-Trimethoprim)
  - First-Line Regimen
  - Dose: 15-20 mg/kg/day of the trimethoprim component PO or IV given in 3-4 divided doses
  - In Cases with Prior Sulfa Allergy, Some Patients Can Be Desensitized to Sulfamethoxazole-Trimethoprim
  - Cases of Sulfamethoxazole-Trimethoprim Resistance Have Been Reported
- Clindamycin + Primaquine (see Clindamycin and Primaquine)
  - Second-Line Regimen
  - For Primaquine-Containing Regimen, Patient Should Be Tested for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency, Due to Risk of Hemolytic Anemia in the Setting of Glucose-6-Phosphate Dehydrogenase Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
  - Clindamycin Dose: 900 mg IV q8hrs or 600 mg IV q6hrs or 600 mg PO TID
  - Primaquine Dose: 30 mg (Base) PO qday
- Pentamidine (see Pentamidine)
  - Third-Line Regimen
  - Dose: 4 mg/kg IV qday
  - Adverse Effects (Common and May Be Severe): hypotension, hypoglycemia, nephrotoxicity, and pancreatitis
  - Contraindications: pregnancy
- Echinocandins (see Echinocandins)
  - Cyst Wall of Pneumocystis Jirovecii Contains β-D-Glucan
  - While Studies Have Suggested that Echinocandins May Be Used in the Setting of Sulfamethoxazole-Trimethoprim Intolerance or Failure, Their Role Requires Further Study
Corticosteroids (see Corticosteroids)
- Studies Indicate that There is a Greater Degree of Inflammation in Non-HIV Patients with Pneumocystis Jirovecii, Suggesting that Corticosteroid Treatment May Be Required (as it is in HIV Patients with Pneumocystis Jirovecii) (Am Rev Respir Dis, 1989) [MEDLINE]
  - Early Small Studies Indicated that High-Dose Adjunctive Corticosteroids May Accelerate Recovery in Severe Adult Non-HIV Pneumocystis Jirovecii (Chest, 1998) [MEDLINE]
  - Other Small Retrospective Studies Indicated that Corticosteroids Do Not Improve the Survival of Non-HIV-Infected Patients with Severe Pneumocystis Jirovecii, as Had Been Described for HIV-Infected Patients with Severe Pneumocystis Jirovecii Patients (Clin Infect Dis, 1999) [MEDLINE]
  - However, Larger Retrospective Studies Suggest that Addition of Early Corticosteroids to Anti-Pneumocystis Therapy in Non-HIV Patients is Not Associated with Improved Respiratory Outcomes (Chest, 2018) [MEDLINE]

Prognosis

Clinical Data

Comparative Small Taiwanese Study of Pneumocystis Jirovecii in Patients with/without Human Immunodeficiency Virus 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 Lung Transplant was 2.4 ± 3.0 years
- 65% of Patients were Not on Prophylaxis at the Time of PJP Diagnosis While All Patients were Receiving Steroids at the Time of PJP Diagnosis
- 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

General

Pneumocystis pneumonia. Semin Respir Crit Care Med. 2011 Dec;32(6):775-82. doi: 10.1055/s-0031-1295725 [MEDLINE]

Etiology

Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis. 1989;140(5):1204-1209 [MEDLINE]
The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. N Engl J Med 1990;322:161-5 [MEDLINE]
Low dose methotrexate therapy for rheumatoid arthritis complicated by pancytopenia and Pneumocystis carinii pneumonia. J Rheumatol. 1991 Aug;18(8):1257-9 [MEDLINE]
Pneumocystis carinii pneumonia in patients with connective tissue disease. Chest 1992; 101:375-378 [MEDLINE]
Pneumocystis carinii pneumonia in patients without AIDS. Clin Infect Dis 1993; 17:S416-S422 [MEDLINE]
Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis. Arch Intern Med. 1995 Apr 24;155(8):872-4 [MEDLINE]
Pneumocystis carinii pneumonia in rheumatoid arthritis patients treated with methotrexate. A report of two cases. Rev Rhum Engl Ed. 1996 Jun;63(6):453-6 [MEDLINE]
Tumor necrosis factor alpha antibody (infliximab) therapy profoundly downregulates the inflammation in Crohn’s ileocolitis. Gastroenterology 1999; 116:22-28 [MEDLINE]
Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome. Clin Infect Dis. 2002 Apr 15;34(8):1098-107. Epub 2002 Mar 21 [MEDLINE]
Pneumocystis carinii carriage in immunocompromised patients with and without human immunodeficiency virus infection. J Med Microbiol 2002;51(7):611–4 [MEDLINE]
Pneumocystis pneumonia. N Engl J Med. 2004 Jun 10;350(24):2487-98 [MEDLINE]
Pneumocystis carinii pneumonia in chronic lymphocytic leukaemia. Postgrad Med J. 2004 Apr;80(942):236-8. doi: 10.1136/pgmj.2003.012252 [MEDLINE]
Pneumocystis carinii pneumonia with oral candidiasis after infliximab therapy for Crohn’s disease. Dig Dis Sci 2004; 1458- 1460 [MEDLINE]
Prevalence and clinical predictors of Pneumocystis colonization among HIV-infected men. AIDS 2004;18:793–798 [MEDLINE]
Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am J Respir Crit Care Med 2004;170:408–413 [MEDLINE]
Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodeficiency virus infection: outcome and associated features. Chest. 2005 Aug;128(2):573-9 [MEDLINE]
Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases. Dig Dis Sci 2007; 52:1481-1484 [MEDLINE]
Pneumocystis carinii pneumonia in a patient on etanercept for psoriatic arthritis. Ir J Med Sci 2007; 176:309-311 [MEDLINE]
Pneumocystis carinii pneumonia in a rheumatoid arthritis patient treated with adalimumab. Scand J Infect Dis 2007; 39:475-478 [MEDLINE]
Pneumocystis jirovecii pneumonia in patients with and without human immunodeficiency virus infection. J Microbiol Immunol Infect. 2008 Dec;41(6):478-82 [MEDLINE]
Prophylactic antibiotic usage for Pneumocystis jirovecii pneumonia in patients with systemic lupus erythematosus on cyclophosphamide: a survey of US rheumatologists and the review of literature. J Clin Rheumatol. 2008 Oct;14(5):267-72. doi: 10.1097/RHU.0b013e31817a7e30 [MEDLINE]
An official ATS workshop report: Emerging issues and current controversies in HIV-associated pulmonary diseases. Proc Am Thorac Soc. 2011 Mar;8(1):17-26. doi: 10.1513/pats.2009-047WS [MEDLINE]
Pneumocystis pneumonia in patients treated with rituximab. Chest. 2013 Jul;144(1):258-65. doi: 10.1378/chest.12-0477 [MEDLINE]
Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Med Mal Infect. 2014 May;44(5):185-98. doi: 10.1016/j.medmal.2014.01.007. Epub 2014 Mar 11 [MEDLINE]
Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. BMJ Case Rep. 2014 Jun 2;2014. pii: bcr2014204950. doi: 10.1136/bcr-2014-204950 [MEDLINE]
Fungal Infections and New Biologic Therapies. Curr Rheumatol Rep. 2016 May;18(5):29. doi: 10.1007/s11926-016-0572-1 [MEDLINE]
Non-lymphopenic pneumocystis pneumonia in low-dose methotrexate therapy: An exception to every rule. Respir Med Case Rep. 2020 Nov 11;31:101289. doi: 10.1016/j.rmcr.2020.101289. eCollection 2020 [MEDLINE]
Bendamustine and pneumocystis pneumonia: A systematic review. Health Sci Rep. 2022 Apr 26;5(3):e610. doi: 10.1002/hsr2.610. eCollection 2022 May [MEDLINE]

Physiology

Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis. 1989;140(5):1204 [MEDLINE]

Diagnosis

Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates. Chest 2009;135(3):655–61 [MEDLINE]

Treatment

Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest 1998;113:1215-24 [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(5):1215 [MEDLINE]
Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients. Clin Infect Dis. 1999;29(3):670 [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]
Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575 [MEDLINE]
Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010 Apr;10(4):251-61. doi: 10.1016/S1473-3099(10)70026-8 [MEDLINE]
Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane Database Syst Rev. 2015 Apr 2;2015(4):CD006150. doi: 10.1002/14651858.CD006150.pub2 [MEDLINE]
Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome. Chest. 2018;154(3):636 [MEDLINE]

Prognosis

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