UPDATES IN DIAGNOSIS & MANAGEMENT OF PNEUMOCYSTIS PNEUMONIA

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 Jírovec -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 > 37.7°C (100°F) 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
 β-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 (Gram–Weigert, Wright–Giemsa 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.

43. Silver Gram stain showing Pneumocystis jiroveci
Papanicolaou smear of Pneumocystis jiroveci

44. MANAGEMENT OF PJP

46. 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

47. TMP-SMX DS - 2 tablets TID

48. For Moderate to Severe PCP
Total Duration = 21 Days
Preferred Therapy:
TMP-SMX : (TMP 15–20 mg and SMX 75–100 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

49. For Mild to Moderate PCP
Total Duration = 21 days
Preferred Therapy:
 TMP-SMX: (TMP 15–20 mg/kg/day and
SMX 75–100 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

50. Adjunctive
Corticosteroids:
For Moderate to Severe PCP Based on the Following
Criteria :
 PaO2 <70 mmHg at room air or
 Alveolar-arterial O2 gradient ≥35 mmHg
Prednisone doses (beginning as early as possible and within 72
hours of PCP therapy)
Schedule Dosage
Days 1 to 5 40 mg of prednisone twice daily
Days 6 to 10 40 mg of prednisone once daily
Days 11 to 21 20 mg of prednisone once daily*
* No further tapering is necessary.
 IV methylprednisolone can be given as 75% of prednisone
dose
 The risk of reactivating tuberculosis or acquiring another
infection appears to be minimal.

51. CHEMOPROPHYLAXIS
Chemoprophylaxis in patients with HIV Infection
 Adults, adolescents, and pregnant patients with a CD4 count of
less than 200/µL
 oropharyngeal candidiasis
 CD4% <14%
 History of AIDS-defining illness
 CD4 count >200 but <250 cells/mm3 and if CD4 cell count
monitoring (e.g., every 3 months) is not possible
Prophylaxis may be discontinued in patients with HIV infection
whose CD4 count exceeds 200/µL for 3 consecutive months
while on HAART.
Prophylaxis should be restarted if the CD4 count drops below
200/µL.Prophylaxis should be continued for life in patients who
developed PJP while their CD4 level exceeded 200/µL.

52. CHEMOPROPHYLAXIS …
Chemoprophylaxis in patients without HIV infection
 Patients with an underlying primary immune deficiency
(eg, severe combined immunodeficiency,
hypogammaglobulinemia)
 Patients with a persistent CD4 count less than 200/µL
 Solid organ transplant recipients
 Hematopoietic stem cell transplant (HSCT) recipients,
 Patients receiving daily systemic corticosteroid therapy
(at least 20 mg daily for at least 1 month)
 Patients with cancer, vasculitides, or collagen vascular
disorders
 Patients receiving cytotoxic or immunosuppressive
treatments such as cyclosporine or the purine analogs
fludarabine or cladribine

53. PRIMARY PROPHYLAXIS
Drug Dosage
TMP-SMZ (Bactrim) 1 double-strength tablet (160 mg
TMP/800 mg SMZ) orally once daily
Dapsone 100 mg orally once daily for PCP.
Aerosolized pentamidine
(NebuPent)
300 mg aerosolized by Respirgard II
jet nebulizer every month; pretreat with
inhaled bronchodilator in patients who
experience cough or bronchospasm
Atovaquone (Mepron) 750 mg orally twice daily (1,500 mg
per day)

54. Preventing Subsequent Episode of PCP
(Secondary Prophylaxis)
Indications for Initiating Secondary
Prophylaxis: Prior PCP
Preferred Therapy: TMP-SMX, 1 DS PO
daily or
Alternative Therapy:
 TMP-SMX 1 DS PO Thrice weekly or
 Dapsone 100 mg PO daily or
 Dapsone 200 mg + pyrimethamine 75 mg +
leucovorin 25 mg) PO weekly or
 Aerosolized pentamidine 300 mg via
Respigard IITM nebulizer every month
 Atovaquone 1500 mg PO daily with food or
 (Atovaquone 1500 mg + pyrimethamine 25
mg + leucovorin 10 mg) PO daily with food

55. Secondary prophylaxis
Indications for Discontinuing Secondary
Prophylaxis:
 CD4 count increased from <200 cells/mm3 to
>200 cells/mm3 for >3 months as a result of ART
or
 If PCP diagnosed when CD4 count >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 or
 If PCP recurred at a CD4 count >200 cells/mm3,
lifelong prophylaxis should be administered .

56. 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.

57. 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

58. 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.