1. UPDATES IN DIAGNOSIS & MANAGEMENT OF PNEUMOCYSTIS
PNEUMONIA Dr. SIBA P. DALAI
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. 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. Trends for PJP in United States
5. PREVALENCE SCENARIO IN INDIA INCIDENCE IN HIV POSITIVE
ADMISSIONS IN INDIA ON AN AVEARAGE IS AROUND 8- 14 %
6. LIFE CYCLE : trophozoite , sporozoite and cyst
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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Acute (A) and healed (B) Pneumocystis carinii choroiditis
in a patient with AIDS
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. 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. 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. 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. 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. 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. 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. GIEMSA STAINING
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. 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. Workup : Laboratory Studies Less invasive procedures :
sputum induction and bronchoalveolar lavage are now the methods of
choice
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. 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. RADIOLOGICAL FINDINGS Chest radiograph demonstrating
diffuse bilateral infiltrates in a patient with Pneumocystis
jiroveci pneumonia.
36. X-ray of a patient with Pneumocystis jirovecii Pneumonia in
a setting of AIDS
37. Pneumothorax in PCP (right sided), a relatively common
complication.
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. RADIOLOGICAL FINDINGS CT scan of chest, with classic patchy
areas of ground-glass attenuation
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. 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. 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.
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. TMP-SMX DS - 2 tablets TID
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. 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. 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 .
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.
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
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.