Basics
Description
Opportunistic lung infection caused by Pneumocystis jiroveci (PJ). This organism is currently considered a primitive fungus based on DNA sequence analysis. It has two developmental forms (the cysts contain sporozoites that become trophozoites when excised).
- Although previously known as Pneumocystis carinii pneumonia (PCP), the acronym PCP is still in use and refers to Pneumocystis pneumonia.
- PCP occurs almost exclusively in the immunocompromised host.
- PCP is an AIDS-defining illness. It is the most common opportunistic life-threatening lung infection in infants with perinatally acquired human immunodeficiency virus (HIV) disease.
- PJ causes a diffuse pneumonitis characterized by fever, dyspnea at rest, tachypnea, hypoxemia, nonproductive cough, and bilateral diffuse infiltrates in the roentgenogram. It is a severe condition frequently leading to respiratory failure, necessitating intubation and mechanical ventilation.
- Chemoprophylaxis against this microorganism has proven successful. Therefore, early identification of the HIV-infected mother becomes essential.
- Despite advances in therapy, the infection continues to be associated with significant morbidity and mortality.
Epidemiology
- Ubiquitous in mammals worldwide, particularly rodents
- Growth on respiratory tract surfaces
- Mode of transmission is unknown:
- Airborne person-to-person transmission is possible, but case contacts are rarely identified.
- Environmentally acquired
- Asymptomatic infection appears early in life; >70% of healthy individuals have antibodies by age 4 years.
- Primary infection is likely to be the mechanism in infants. Reactivation of latent disease with immunosuppression was proposed as an explanation for disease later in childhood; however, animal models of PCP do not support this proposition.
- PCP in the HIV patient can occur at any time but usually presents during the 1st year of life. The highest incidence is between 3 and 6 months of age.
Risk Factors
- Immunocompromised host
- Children with congenital or acquired immunodeficiency syndrome (AIDS) and recipients of suppressive therapy in the treatment of malignancies or after organ transplantation are at high risk.
- In leukemic patients, the incidence of PCP has been directly related to the degree of immunodeficiency resulting from chemotherapy.
- Epidemics of PCP were reported in premature and malnourished infants and children in resource-limited countries and during times of famine.
Pathophysiology
- In the immunodeficient child, the pathologic changes occur predominantly in the alveoli. Cysts and trophozoites are seen adhering to the alveolar lining cells or in the cytoplasm of macrophages.
- As infection progresses, the alveolar spaces are filled with a pink, foamy exudate containing fibrin, abundant desquamative cells, and a large number of organisms. Alveolar septal thickening with mononuclear cell infiltration is also seen.
Diagnosis
History
- In malnourished host
- Subacute onset with nonspecific manifestations
- Poor feeding, weight loss, and restlessness
- Chronic diarrhea
- Usually without fever
- After 1 " 2 weeks, the patient develops progressive tachypnea, respiratory distress, and cough.
- In sporadic or immunocompromised host
- This form has a more abrupt onset, sometimes even fulminant:
- Fever (>38.5 °C)
- Nonproductive cough
- Dyspnea at rest
- These subtypes are characterized by general clinical guidelines. Symptoms may be superimposed and can be seen in infants, children, and adolescents.
Physical Exam
- Fever and significant tachypnea are characteristic.
- Hypoxemia: early in the course of disease and disproportionate to the auscultatory findings
- Rapidly progressive respiratory distress with cyanosis: respiratory failure early in course
- Absence of crackles is a common initial finding.
- Chest auscultation can reveal decreased breath sounds, crackles, and rhonchi.
- Coryza and wheezing have infrequently been reported.
Diagnostic Tests & Interpretation
Diagnostic Procedures/Other
- Arterial blood gas
- pH is usually increased.
- Reduced Pao2 in room air (<70 mm Hg)
- Alveolar " arterial oxygen gradient (>35 mm Hg)
- Chest radiograph
- Most common radiologic presentation is diffuse bilateral alveolar infiltrates:
- Initially a perihilar distribution that spreads to the periphery
- Apices are the least affected.
- Interstitial infiltrates and air bronchograms can be seen.
- Rapid progression to whole lung consolidation
- Presence of hilar or mediastinal adenopathy may indicate another process such as Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, fungal infections, cytomegalovirus, or lymphoma.
- Other tests:
- Lactate dehydrogenase (LDH) can be elevated in patients with AIDS and PCP, but this finding is nonspecific.
- WBC count is usually normal.
Pathologic Findings
- Definitive diagnosis can be obtained by demonstration of PJ in pulmonary specimens:
- Induced sputum
- Bronchoalveolar lavage (BAL) usually through flexible bronchoscopy (90% sensitivity)
- Open lung or transbronchial biopsy
- Staining
- Cysts stain with methenamine-silver, toluidine blue-O stains, calcofluor white, and fluorescein monoclonal antibody
- Sporozoites and trophozoites are identified with Giemsa stain, modified Wright-Giemsa stain, and fluorescein-conjugated monoclonal antibody stain.
- Polymerase chain reaction assays of BAL fluid or induced sputum is available and more sensitive for detecting PJ than microscopic methods but is not USFDA approved for diagnosis.
Differential Diagnosis
- Viral infections
- Common viral respiratory pathogens
- Cytomegalovirus
- Epstein-Barr virus
- Bacterial infections
- M. tuberculosis
- M. avium-intracellulare
- Other:
- Lymphocytic interstitial pneumonitis
Treatment
Medication
First Line
- Minimum duration of therapy is 2 weeks; 3 weeks of therapy recommended in patients with AIDS.
- Antibiotics
- Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice:
- TMP (15 " 20 mg/kg/24 h) and SMX (75 " 100 mg/kg/24 h) IV/PO divided q6h
- Oral therapy is reserved for patients with mild illness who do not have malabsorption or diarrhea.
Second Line
- Minimum duration of therapy is 2 weeks; 3 weeks of therapy recommended in patients with AIDS.
- Pentamidine isethionate
- 3 " 4 mg/kg/dose IV (or IM) given in a single daily dose
- Used in patients who cannot tolerate TMP-SMX or are unresponsive after 5 " 7 days of therapy
- If clinical improvement is seen after 7 " 10 days of IV pentamidine, consider oral regimen to complete the 21-day course.
- Atovaquone
- 1 " 3 months and >24 months of age: 30 mg/kg/24 h PO divided into 2 doses
- 4 " 24 months of age: 45 mg/kg/24 h PO divided into 2 doses
- Maximum dose: 750 mg b.i.d.
- Dapsone plus trimethoprim
- Dapsone: 2 mg/kg PO daily to a maximum of 100 mg daily
- Trimethoprim: 15 mg/kg/24 h PO divided into 3 doses
- Primaquine plus clindamycin
- Primaquine: 0.3 mg/kg PO daily to a maximum of 30 mg PO daily
- Clindamycin: 40 mg/kg/24 h PO divided into 4 doses to a maximum of 600 mg q6h
Additional Treatment
General Measures
- Supply oxygen as necessary to keep PaO2 >70 mm Hg.
- Mechanical ventilation must be considered if PaO2 is <60 mm Hg on FiO2 of 0.5.
- Corticosteroids
- May be beneficial in HIV patients with moderate to severe PCP
- Not systematically evaluated in children
- Consider when PaO2 is <70 mm Hg or the alveolar " arterial oxygen gradient is >35 mm Hg.
- In patients >13 years of age, suggested dose is prednisone 40 mg PO b.i.d. for days 1 " 5, 40 mg PO once daily for days 6 " 10, and 20 mg PO once daily for days 11 " 21 with tapering. Doses of methylprednisolone or prednisone at 1 mg/kg given b.i.d. " q.i.d. for 5 " 7 days with a taper over the next 5 days have been suggested.
Additional Therapies
- Chemoprophylaxis indications: During high-risk periods, PCP can be effectively prevented in the immunodeficient host by chemoprophylaxis in the following groups:
- HIV exposed: 4 " 6 weeks to 4 months
- HIV infected or indeterminate: 4 " 12 months
- HIV infected: 1 " 5 years if CD4+ T-lymphocyte count is <500 cells/ ¼L or <15%
- HIV infected: ≥6 years if CD4+ T-lymphocyte count is <200 cells/ ¼L or <15%
- Severely symptomatic HIV patients or those with rapidly declining CD4 counts
- HIV patients who have had previous PCP illness
- Children who have received hematopoietic stem cell transplants (HSCTs)
- All HSCT recipients with hematologic malignancies (e.g., leukemia, lymphoma)
- All HSCT recipients receiving intense conditioning regimens or graft manipulation
- Prophylaxis is initiated at engraftment and administered for 6 months; longer than 6 months in children receiving immunosuppressive therapy or with chronic graft-versus-host disease
- Drug regimen for prophylaxis
- TMP-SMX is the drug of choice.
- 150 mg/m2 body surface area per day of TMP or 750 mg/m2 body surface area per day of SMX PO divided into 2 doses on 3 consecutive days per week
- TMP-SMX can also be given 7 days a week when prevention against other bacterial infections is sought.
- For patients who cannot tolerate TMP-SMX
- Dapsone (>1 month of age): 2 mg/kg (maximum 100 mg) PO daily or 4 mg/kg (maximum 200 mg) PO weekly
- Aerosolized pentamidine (>5 years of age): 300 mg via Respirgard II nebulizer inhaled monthly
- Atovaquone at age 1 " 3 months and >24 months: 30 mg/kg (max 1,500 mg/dose) PO daily; at age 4 " 24 months: 45 mg/kg (max 1,500 mg/dose) PO daily
Ongoing Care
Follow-up Recommendations
- After 5 " 7 days of treatment
- If no improvement, TMP-SMX should be replaced with pentamidine.
- Standard precautions are required. Isolation from other immunodeficient patients is recommended.
Prognosis
- 5 " 40% mortality in treated patients
- Near 100% mortality if patient is untreated
- ¢ ¼35% of patients will have recurrence unless lifetime prophylaxis is instituted.
Complications
- High rate of respiratory failure necessitating intubation and mechanical ventilation ( ¢ ¼60%)
- HIV-infected patients have a higher rate (40%) of adverse reactions to TMP-SMX than the general population. Rash is most common, with fever, neutropenia, anemia, renal dysfunction, nausea, vomiting, and diarrhea occurring as well.
- Prophylactic medication protects the patient as long as the drug is administered. However, this does not eradicate PJ.
Additional Reading
- King SM. Evaluation and treatment of the human immunodeficiency virus-1 " exposed infant. Pediatrics. 2004;114(2):497 " 505. [View Abstract]
- Miller RF, Huang L, Walzer PD. Pneumocystis pneumonia associated with human immunodeficiency virus. Clin Chest Med. 2013;34(2):229 " 241. [View Abstract]
- Mofenson LM, Brady MT, Danner SP, Centers for Disease Control and Prevention. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children. MMWR Recomm Rep. 2009;58(RR-11):1 " 166. [View Abstract]
- Morris A, Wei K, Afshar K, et al. Epidemiology and clinical significance of pneumocystis colonization. J Infect Dis. 2008;197(1):10 " 17. [View Abstract]
Codes
ICD09
ICD10
SNOMED
- 75549005 Infection by Pneumocystis jiroveci
- 420403001 Pneumocystosis associated with AIDS
- 415125002 Pneumocystosis jiroveci pneumonia (disorder)
FAQ
- Q: Which are the most common side effects of pentamidine?
- A: They include hypoglycemia, impaired renal or liver function, anemia, thrombocytopenia, neutropenia, hypotension, and skin rashes. These side effects can be expected in 50% of patients.
- Q: How frequently is prophylaxis failure seen?
- A: Adequate TMP-SMX treatment has only a 3% failure rate.
- Q: How are adverse reactions to TMP-SMX during PCP therapy managed?
- A: Continuation of treatment, if the reactions are not severe, is recommended.