1. 1. UPDATES IN DIAGNOSIS & MANAGEMENT OF PNEUMOCYSTIS PNEUMONIA Dr. SIBA P. DALAI
2. 2. INTRODUCTION Pneumocystis carinii pneumonia (PCP), as the condition is commonly termed (renamed Pneumocystis jiroveci [pronounced yee-row-vet- zee] is the most common opportunistic infection in persons infected with HIV. Discovered in the early 1900s the first cases of Pneumocystis pneumonia in humans were initially recognized after the Second World War in premature and malnourished infants. In the 1980s, with the onset of the HIV epidemic, Pneumocystis prevalence increased dramatically and became widely recognized as an opportunistic infection that caused potentially life-threatening pneumonia in patients with impaired immunity..
3. 3. HISTORICAL CONSIDERATION Antonio Carini -1912 - Pasteur Institute in Paris - in rat - christened this organism Pneumocystis carinii Van der Meer and Brug - 1942 - the first human case Vanek and Jrovec -1952 -cause of interstitial pneumonia in neonates ( p. jirovecii in humans ) ( p. carini in rats )
4. 4. Trends for PJP in United States
5. 5. PREVALENCE SCENARIO IN INDIA INCIDENCE IN HIV POSITIVE ADMISSIONS IN INDIA ON AN AVEARAGE IS AROUND 8- 14 %
6. 6. LIFE CYCLE : trophozoite , sporozoite and cyst
7. 7. PATHOPHYSIOLOGY Pneumocystis organisms are commonly found in the lungs of healthy individuals. Most children are believed to have been exposed to the organism by age 3 or 4 years,. Airborne transmission has been reported. Human evidence of this is provided by molecular analysis of Pneumocystis isolates obtained from groups of patients involved in hospital outbreaks. Further evidence of human transmission has been found in cases of recurrent pneumonia in which the genotype of Pneumocystis organisms in the same person differed from prior episodes. Despite this, barrier precautions are not required for patients hospitalized with P carinii pneumonia (PCP) except to protect other patients with depressed immunity.
8. 8. PATHOPHYSIOLOGY Development of PCP Disease occurs when both cellular immunity and humoral immunity are defective. Once inhaled, the trophic form of Pneumocystis organisms attach to the alveoli. Multiple host immune defects allow for uncontrolled replication of Pneumocystis organisms and development of illness. Activated alveolar macrophages without CD4+ cells are unable to eradicate Pneumocystis organisms. Increased alveolar-capillary permeability is visible on electron microscopy.
9. 9. PATHOPHYSIOLOGY Physiologic changes include the following: Hypoxemia with an increased alveolar- arterial oxygen gradient Respiratory alkalosis Impaired diffusing capacity Changes in total lung capacity and vital capacity There have been reports of PCP occurring as part of the immune reconstitution syndrome.
10. 10. PATHOPHYSIOLOGY Risk Factors for PCP in HIV-negative Patients Patients taking steroids or other immunosuppressants. Eg.Patients with Haematological malignancy. Organ transplant recipients. Connective tissue diseases such as rheumatoid arthritis. Congenital immune deficiency - eg, thymic aplasia, SCID, hypogammaglobulinaemia. Severe malnutrition (poor nutrition in HIV-positive individuals increases risk). Pre-existing lung disease
11. 11. PATHOPHYSIOLOGY CD4+ T-lymphocyte cell count < 200 per mm3 (200 106 per L) Unexplained fever of > 37.7C (100F) for > two weeks History of oropharyngeal candidiasis Previous episode of PCP Other AIDS-defining illness Risk Factors for PCP in HIV-Positive Patients
12. 12. EPIDEMIOLOGY Prior to the widespread use of highly active antiretroviral therapy (HAART), PCP occurred in 70-80% of patients with HIV infection. The frequency of PCP is decreasing with the use of PCP prophylaxis and HAART. PCP is still the most common opportunistic infection in patients with HIV infection Currently, the frequency of documented Pneumocystis infection is increasing in Africa, with Pneumocystis organisms found in up to 80% of infants with pneumonia who have HIV infection. In sub-Saharan Africa and India, tuberculosis is a common co-infection in persons with PCP.
13. 13. PROGNOSIS In patients with HIV infection PCP once carried a mortality rate of 20-40%, depending on disease severity at presentation. Currently, mortality rates of 10-20% are reported. In patients without HIV infection PCP carries a worse prognosis in persons without HIV infection ; this has not changed significantly in the past 20 years. Mortality rates of 30-50% have been documented in several large studies. The higher mortality rate is likely a result of delayed diagnoses and initiation of appropriate treatment .
14. 14. CLINICAL MANIFESTATIONS Symptoms of PCP include the following: Progressive exertional dyspnea (95%) Fever (>80%) Nonproductive cough (95%) Chest discomfort Weight loss Chills Hemoptysis (rare)
15. 15. CLINICAL MANIFESTATIONS The physical examination findings ( SIGNS ) of PCP are nonspecific and include the following : Tachypnea Fever Tachycardia Pulmonary symptoms: Pulmonary examination may reveal mild crackles and rhonchi but may yield normal findings in up to half of patients. Additional findings in children with severe disease include cyanosis, nasal flaring, and intercostal retractions.
16. 16. CLINICAL MANIFESTATIONS Almost all patients with PCP have at least two of the following: fever, cough, dyspnea, lactate dehydrogenase (LDH) level of more than 460 U per L an arterial partial pressure of oxygen (PaO2) of less than 75 mm Hg
17. 17. CLINICAL MANIFESTATIONS Elevated serum LDH is not specific enough to distinguish PCP from other types of pneumonia, but the degree of elevation may provide evidence of the severity of the illness. A decrease in oxygen saturation as measured by pulse oximetry during exercise suggests PCP, especially in the patient who has minimal symptoms, does not appear acutely ill and has an unimpressive chest radiograph. When blood gas analysis reveals hypoxemia or a widened alveolar-to-arterial oxygen difference ([A-a]Do2), the prognostic and therapeutic implications are unfavorable .
18. 18. CLINICAL MANIFESTATIONS A. Calculation of alveolar-arterial oxygen difference Specimens for arterial blood gas analysis are drawn while patient is breathing room air (Flo2 = 21%). The following formula is used to determine alveolar- to-arterial oxygen difference: [A-a]DO2 = 150 - 1.2(Paco2) - Pao2 Use of [A-a]Do2 to Determine PCP Severity
19. 19. CLINICAL MANIFESTATIONS B. Grading severity of PCP by oxygenation Severity [A-a]Do2 (mm Hg) Pao2 (mm Hg) Mild < 35 > 70 Moderate 35 to 45 > 70 Severe > 45 70 - 50 [A-a]Do2 = alveolar-to-arterial oxygen difference; Flo2 = fraction of inspired oxygen; Paco2 = arterial partial pressure of carbon dioxide; Pao2 = arterial partial pressure of oxygen
20. 20. CLINICAL MANIFESTATIONS Extrapulmonary manifestations present in patients receiving aerosolized pentamidine for prophylaxis or in patients with advanced HIV infection who are not taking any prophylaxis. Central nervous system & Gastrointestinal tract Bone marrow (may have necrosis with resultant pancytopenia) Lymphadenopathy Eyes (may have retinal cotton-wool spots) Thyroid (may present as a rapidly enlarging thyroid mass) Complications A pathophysiologic process similar to acute respiratory distress syndrome (ARDS) may occur in patients with severe PCP. These patients may require intubation. This greatly diminishes the prognosis.
21. 21. Acute (A) and healed (B) Pneumocystis carinii choroiditis in a patient with AIDS
22. 22. Pneumocystis carinii choroiditis in a patient with acquired immunodeficiency syndrome. Multifocal, whitish lesions are seen at the level of the choroid. Macular involvement often reduces vision, although the lesions are asymptomatic and clear promptly with appropriate antibiotic therapy
23. 23. DIFFERENTIAL DIAGNOSES Cytomegalovirus Lymphocytic Interstitial Pneumonia Acute Respiratory Distress Syndrome Mycoplasma Infections Pneumonia, Viral Pulmonary Embolism Other Problems to Be Considered Legionellosis Tuberculosis Mycobacterium avium complex (MAC) inection
24. 24. Workup :Lab Studies Lactic dehydrogenase study as part of the initial workup Lactic dehydrogenase (LDH) levels are usually elevated (>220 U/L) in patients with P carinii pneumonia (PCP). This study has a high sensitivity (78-100%). The LDH level is elevated in 90% of patients with PCP who are infected with HIV. LDH levels appear to reflect the degree of lung injury. Consistently elevated LDH levels during treatment may indicate therapy failure and a worse prognosis. LDH levels should decline with successful treatment
25. 25. Workup : Laboratory Studies -D-Glucan (BDG) has been shown to be a sensitive test to detect PCP in a meta-analysis of 12 studies assessing the sensitivity, specificity and overall accuracy of the test.
26. 26. Quantitative PCR for pneumocystis may become useful in distinguishing between colonization and active infection, but these assays are not yet available for routine clinical use.
27. 27. MycAssay Pneumocystis assay While more sensitive than any of these three assays analyzed individually, the MycAssay Pneumocystis assay demonstrated 100% sensitivity, 100% specificity, a 100% negative predictive value, and a 100% positive predictive value for detecting the presence of P. jirovecii in BAL specimens compared to the laboratory standard.
28. 28. Microscopy Since Pneumocystis cannot be cultured, the gold standard for diagnosis is microscopic visualization of the organism. Traditionally different stains have been used to identify either the trophic form (GramWeigert, WrightGiemsa or modified Papanicolaou stains) or the cyst forms (calcofluor white, cresyl violet, Gomori methenamine silver or toluidine blue) Methenamine silver stain of a bronchoalveolar lavage specimen showing a cluster of P. carinii cysts
29. 29. GIEMSA STAINING
30. 30. Workup : Laboratory Studies However, the most common technique used currently in the majority of the laboratories is fluorescein-conjugated monoclonal antibodies Indirect immunofluorescence using monoclonal antibodies against Pneumocystis jirovecii
31. 31. Direct immunofluorescence antibody stain using monoclonal antibodies that target Pneumocystis jirovecii. This image is from a bronchoalveolar lavage (BAL) specimen from a patient with a malignancy
32. 32. Workup : Laboratory Studies Less invasive procedures : sputum induction and bronchoalveolar lavage are now the methods of choice
33. 33. Workup : Laboratory Studies Induced sputum Bronchoalveolar lavage Nebulized saline inhaled by patient to promote deep cough Saline instilled through bronchoscope wedged in airway and fluid withdrawn Inexpensive; noninvasive More expensive, more invasive, risk of Periprocedural sedation, requires skilled personnel Specimen processing more complex, Larger samples can be sent for staining and can be used to diagnose other infections (bacterial, fungal, viral and mycobacterial cultures) Less sensitive > 95 percent sensitive Comparison of Induced Sputum and Bronchoalveolar Lavage
34. 34. RADIOLOGICAL FINDINGS The chest radiographic findings may be normal in patients with early mild disease. Diffuse bilateral infiltrates extending from the perihilar region are visible in most patients with P jiroveci pneumonia (PJP). Less-common findings include patchy asymmetric infiltrates and pneumatoceles. Pleural effusions and intrathoracic adenopathy are rare. Pneumothorax may develop in patients using aerosolized pentamidine. Apical disease may also be found in patients using aerosolized pentamidine for prophylaxis.
35. 35. RADIOLOGICAL FINDINGS Chest radiograph demonstrating diffuse bilateral infiltrates in a patient with Pneumocystis jiroveci pneumonia.
36. 36. X-ray of a patient with Pneumocystis jirovecii Pneumonia in a setting of AIDS
37. 37. Pneumothorax in PCP (right sided), a relatively common complication.
38. 38. OTHER RADIOLOGICAL TECHNIQUES The most typical findings on chest CT are bilateral ground glass opacities with a background of interlobular septal thickening. Negative (normal or unchanged) CT scan findings alone do not rule out PJP. Less-common features can include reticular, granular, and cystic lesions . Other radiological techniques such as 18- fluorodeoxyglucose positron emission tomography (FDG-PET) and Ga-67 scintigraphy have been reported as potential tools to assist in the early diagnosis of Pneumocystis pneumonia [Zhuang and Alavi, 2002]
39. 39. RADIOLOGICAL FINDINGS CT scan of chest, with classic patchy areas of ground-glass attenuation
40. 40. Other Noninvasive Tests 1.Pulmonary function tests should be obtained as part of the initial noninvasive workup in patients with suspected P jiroveci pneumonia (PJP). decreased diffusion capacity of carbon monoxide (DLCO) of less than 75% predicted.. Decreased DLCO has a high sensitivity (89%-100%) but poor specificity (53%). PJP is unlikely if DLCO is normal. 2. Pulse oximetry Pulse oximetry on room air should be measured in all patients both at rest and with exertion. If any hypoxemia is found (O2 saturation < 90%), then an arterial blood gas (ABG) level should be obtained to evaluate the need for possible adjunctive
41. 41. INVASIVE PROCEDURES Bronchoalveolar lavage most common invasive procedure used to diagnose P jiroveci pneumonia (PJP). Diagnostic yield that exceeds 90% BAL yields a lower sensitivity in patients receiving aerosolized pentamidine, in which case a transbronchial biopsy may be performed in conjunction with BAL. Obtain BAL if PJP is strongly suspected and the induced sputum sample findings are negative. used in patients who are unable to cooperate with an induced sputum sample (eg, because of altered mental status). Lung biopsy most invasive procedure yields 100% sensitivity and specificity because it provides the greatest amount of tissue for diagnosis. reserved for rare cases when bronchoscopy findings are non- diagnostic.
42. 42. Histologic Findings Because clinical and radiologic findings are not specific for PJP and because P jiroveci cannot be grown in vitro, histopathologic demonstration is necessary before a definitive diagnosis is established.
43. 43. Silver Gram stain showing Pneumocystis jiroveci Papanicolaou smear of Pneumocystis jiroveci
44. 44. MANAGEMENT OF PJP
45. 45. Suggested Hierarchy of Treatment Choices for PCP Mild to moderate PCP (oral regimens) First choice Trimethoprim-sulfamethoxazole (Bactrim) Second choice Trimethoprim and dapsone or Clindamycin and primaquine Third choice Atovaquone Moderate to severe PCP (IV regimens) First choice Trimethoprim-sulfamethoxazole Second choice Trimetrexate/leucovorin and oral dapsone or Clindamycin and oral primaquine Third choice Pentamidine
46. 46. TMP-SMX DS - 2 tablets TID
47. 47. For Moderate to Severe PCP Total Duration = 21 Days Preferred Therapy: TMP-SMX : (TMP 1520 mg and SMX 75100 mg)/kg/day IV given q6h or q8h , may switch to PO after clinical improvement . Alternative Therapy: Pentamidine 4 mg/kg IV once daily infused over at least 60 minutes ; may reduce the dose to 3 mg/kg IV once daily because of toxicities or Primaquine 30 mg (base) PO once daily + (Clindamycin [IV 600 q6h or 900 mg q8h] or [PO 300 mg q6h or 450 mg q8h]). Adjunctive corticosteroid may be indicated in some moderate to severe cases
48. 48. For Mild to Moderate PCP Total Duration = 21 days Preferred Therapy: TMP-SMX: (TMP 1520 mg/kg/day and SMX 75100 mg/kg/day), given PO in 3 divided doses or TMP-SMX DS - 2 tablets TID . Alternative Therapy: Dapsone 100 mg PO daily + TMP 15 mg/kg/day PO (3 divided doses) or Primaquine 30 mg (base) PO daily + Clindamycin PO (300 mg q6h or 450 mg q8h) or Atovaquone 750 mg PO BID with food
49. 49. Adjunctive Corticosteroids: For Moderate to Severe PCP Based on the Following Criteria : PaO2 200 cells/mm3, prophylaxis should probably be continued for life regardless of CD4 cell count rise as a consequence of ART . Indications for Restarting Secondary Prophylaxis: CD4 count falls to 200 cells/mm3, lifelong prophylaxis should be administered .
50. 55. NEWER TARGETS PjRtt109 is a functional Rtt109 HAT that supports the development of anti-Pneumocystis agents directed at Rtt109- catalyzed histone acetylation as a novel therapeutic target for human Pneumocystis Pneumonia.
51. 56. TAKE MESSAGE Determination of [A-a]DO2 is critical because the degree of impairment is the most important prognostic indicator. Administration of corticosteroids within the first 72 hours of anti- Pneumocystis treatment helps to prevent respiratory failure and death in AIDS patients. PULSE OXIMETRY & PFT are minimum requirements for a confident diagnosis apart from a good lab support for guiding the clinical acumen of the
52. 57. TAKE MESSAGE Despite effective antimicrobial therapy, mild to moderate episodes of PCP still carry a mortality risk upto 9 %. The mortality rate approaches 100% without therapy. SO SALVAGE RATE = 90 % towards which all the attention needs to be diverted.