PNEUMOCYSTIS INFECTIONS (PCP)

Focus the Pathophysiology, Evaluation & Management based on Course Outline.

I. Definition
- Pneumocystis is an opportunistic pathogen that is an important cause of pneumonia in
immunocompromised hosts esp HIV patients.
- Discovered in rodents and was initially believed to be a protozoan.
- Fungus: Pneumocystis carinii - old name
Pneumocystis jiroveci- new name
II. Epidemiology
- First reported in men who had sex with men and in IV drug users.
- PCP has continued to be a leading cause of AIDS-associated morbidity in the United States and
Western Europe.
- PCP also develops in HIV-uninfected patients who are immunocompromised secondary to
hematologic or malignant neoplasms, stem cell or solid organ transplantation, and treatment with
immunosuppressive medications.
III. Pathogenesis and Pathology
A. Life Cycle
- Sexual and Asexual reproduction
- Trophic form to a Cyst and a Precyst back to Trophic.
B. Transmission
1. P. carinii - reservoirs: rodents
Transmission: Animals to Animals Only
Infect other animals such as:
a. P. carminii (rats)
b. P. murina (mice)
c. P. oryctolagi (rabbits)
2. P. jirovecii
- Developed from reactivation of latent infection.
- De novo infections from environmental sources.
- Person-to-Person transmission.
- Humans cannot be infected with species of Pneumocystis that infect other animals.
C. Role of Immunity
- Defects in cellular and/or humoral immunity.
- Defects may be congenital.
- Defects may be acquired as a result of HIV infection.
- Defects may be acquired by treatment with immunosuppressive drugs. Eg. glucocorticoids,
fludarabine, temozolomide (all tem-), cyclophosphamide, rituximab (all-imab).
- Inversely related to the CD4+ T cell count, development starts at <100/μL.
D. Lung Pathology
1. Inhaled into the alveolar space.
2. Pneumocystis proliferates in the lung.
3. Alveoli become filled with proteinaceous material.
4. Increased alveolar-capillary injury and surfactant abnormalities.
5. Alveolar damage.
IV. Clinical Features
A. Clinical Presentation
1. Presents as acute or subacute pneumonia with dyspnea.
2. Fever
3. Nonproductive cough
4. Progressive shortness of breath
5. Respiratory Failure - Cause of Death
6. Organs Involved: lymph nodes, spleen, and liver.
B. Physical Exam
1. Decreased oxygen saturation—at rest or with exertion.
2. Severe Hypoxemia - if untreated
3. Early: Normal chest examination and no adventitious sounds.
4. Late: Diffuse rales and signs of consolidation.
C. Laboratory Findings
1. Lactate dehydrogenase (LDH) - elevated, sign for pulmonary damage.
2. WBC count- elevated
3. Hepatic & Renal Function- Normal
D. Radiographic Findings
1. Classic Radiograph: (Non- specific)
- Diffuse bilateral interstitial infiltrates, Symmetric and Perihilar.
- Cysts and pneumothoraces for HIV (+).
- Asymmetric patterns
- Upper-lobe infiltrates
- Mediastinal adenopathy
- Nodules, cavities, and effusions.
2. High-resolution chest CT: (Most specific)
- Diffuse ground-glass opacities.
E. Direct Microscopy
1. Transbronchial lung biopsy stained with Hematoxylin and Eosin:
- Eosinophilic alveolar filling
- Foamy, vacuolated alveolar exudates
- Mononuclear Infiltrates
- Largely of viable and nonviable organisms
2. Methenamine silver–stained bronchoalveolar lavage (BAL) fluid:
- Interstitial edema .
- Fibrosis.
- Organisms can be seen in the alveolar space
3. Giemsa-stained BAL fluid:
- Organisms can be seen in the alveolar space
4. Immunofluorescent stain of BAL fluid:
- Organisms can be seen in the alveolar space
V. Diagnosis
A. Pathognomonic Feature:
- Foamy alveolar infiltrate and a mononuclear interstitial infiltrate.
B. Diagnostic Tests
 Specimen: Bronchoalveolar lavage (BAL) fluid is almost 100% sensitive and specific for PCP in
patients with HIV. Expectorated sputum or throat swabs have very low sensitivity.
 Available Tests:
1. PCR Test: Most sensitive
2. Hematoxylin and eosin staining : Most specific
3. Transbronchial lung biopsy
4. Open lung biopsy
5. Methenamine silver
6. Toluidine blue O Staining
7. Giemsa Staining
8. Specific immunofluorescent antibody Staining
9. Serologic Test: (1→3)-β-d-glucan - elevated

Vl. Course of PCP

A. Initial Manifestation:
- Mild exercise intolerance
- Chest tightness without fever or cough
- Normal or nearly normal posterior–anterior chest radiograph
B. Advanced Manifestation: (days, weeks, or even a few months)
- Fever
- Cough
- Diffuse alveolar infiltrates
- Profound hypoxemia
- Respiratory Failure
C. Extrapulmonary manifestations
- skin or soft tissue, retina, brain, liver, kidney, or spleen.

VII. Prognosis
A. Mortality Risk
- Patient’s age
- Degree of immunosuppression as well as comorbidities
- The presence of preexisting lung disease
- A low serum albumin level
- The need for mechanical ventilation, and the
- Development of a pneumothorax
VIII. Management
A. Flow of PCP Management
- 4-8 Days: Patient Usually do not respond to therapy.
- 10 Days Minimum is needed for Supportive care.
- Observe After 3-4 Days: If Patient deteriorates, reevaluate after 7-10 days if patient doesn't
improved. Not PCP.
- For TMP-SMX Tx Failure:
- Option A: Switch to either IV pentamidine or IV clindamycin plus oral primaquine.
- Option B: Add the second drug or drug combination to TMP-SMX.
- Immune reconstitution inflammatory syndrome (IRIS): May occur on patients with HIV infection who
present with PCP before the initiation of ART.

B. Trimethoprim-Sulfamethoxazole (TMP-SMX)
- Treatment of choice for PCP.
- Given either IV or PO for 14 days to non-HIV-infected patients with mild disease and for 21 days to all
other patients.
- MOA: Interferes with the organism’s folate metabolism.
- AE: leukopenia, hepatitis, rash, and fever as well as anaphylactic and anaphylactoid reactions.

C. Sulfadiazine plus pyrimethamine / Dapsone plus pyrimethamine /Dapsone plus trimethoprim

- Highly effective for use if mutations in the target gene for sulfamethoxazole that confer in vitro sulfa
resistance to other organisms have been found in Pneumocystis.

D. Intravenous Pentamidine
- An option for patients who cannot tolerate TMP-SMX
- For TMP-SMX treatment failure.
- AE: Lethal hypotension, renal dysfunction, dysglycemia, neutropenia, and torsades des pointes.

E. Clindamycin plus Primaquine

- An option for patients who cannot tolerate TMP-SMX
- For TMP-SMX treatment failure.
- Primaquine can be given only by the oral route, a disadvantage for patients who cannot ingest or
absorb oral drugs.

F. Oral atovaquone
- For patients with mild disease who have no impediments to absorbing an oral drug that requires a
high-fat meal for optimal absorption.

G. Glucocorticoids
- Improve survival rates among HIV-infected patients with moderate to severe disease (room air PO2,
<70 mmHg; or alveolar–arterial oxygen gradient, ≥35 mmHg).
- Reduce the pulmonary inflammation.
- Tx should be started for moderate or severe disease when therapy for PCP is initiated, even if the
diagnosis has not yet been confirmed.
- Advantages of increasing the steroid dose: reduce the inflammatory response to the dying
organisms.
- Advantages of decreasing the steroid dose: improve immune function.
XI. Prevention

1. The most effective method for preventing PCP is to eliminate the cause of immunosuppression by
withdrawing immunosuppressive therapy or treating the underlying cause.
2. For patients with HIV infection, CD4+ T cell counts are a reliable marker of susceptibility, and counts
below 200/μL are an indication to start prophylaxis.
3. Chemoprophylaxis is useful for patients receiving certain immunosuppressive agents (e.g., tumor
necrosis factor inhibitors, antithymocyte globulin, rituximab, and alemtuzumab).
4. TMP-SMX is the most effective prophylactic drug.
5. Hypersensitivity or bone marrow suppressionis the most common cause of TMP-SMX intolerance.
6. Alternative drugs:
a. Dapsone - Rarely useful in patients with a history of life-threatening reactions to TMP-SMX.
b. Aerosolized pentamidine - May not provide protection in areas of the lung that are not well
ventilated.
c. Atovaquone - Available only as an oral preparation, and gastrointestinal absorption is
unpredictable in patients with abnormal gastrointestinal motility or function.