Jennifer N. Blanchard, MD of UC San Diego Owen Clinic presents "An Unusual Case of Pneumonia"

1. AIDS CLINICAL ROUNDS
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3.  DC is a 37yo with a h/o AIDS, (CD4= 6, VL = 527,104 1/11)
who presented with 1 mo h/o fever and cough
 Cough p/o green and black sputum; occ hemoptysis
 Pleuritic CP
 Dyspnea
 F/C/NS
 All sx similar to admissions in 4/09 and 1/11
 Bronch – silver stain negative, AFB negative. MTD PCR negative
 Quantiferon, Crag, cocci, & histo negative
 Responded as if CAP

4.  Teeth have been falling out for the past 3 mo
 + weight loss – d/t poor dentition & anorexia
 ROS: Poor historian
 No HA or photophobia
 Vision is “fair”
 No odynophagia
 No N/V/D
 +Abd pain
 Poor memory – fell out of care b/c he couldn’t remember to
make appointments

5.  PMHx: AIDS
 PCP
 Hepatitis C
 Neurosyphilis
 Thrombocytopenia – ITP vs myelosuppression d/t etoh
 Pancytopenia
 BMbx 4/09 unremarkable
 Alcohol abuse
 Meth abuse
 Non-compliance
 NKDA

6.  Meds: ARVs – can’t remember names – hasn’t been taking
them
 SHx:
 Tob: 1PPD
 Drugs: smokes meth – last used ~ 2 weeks ago
 No etoh
 Not currently sexually active
 Lives in Rosarito with his mom and step-father

7. 103 116 99/60 28 93% RA
 Cachetic
 Horrible dentition; white plaques c/w candida
 Coarse rhonchi heard throughout with ? Of rales at the L
base
 No supraclavicular or axillary LAD
 Tachy but no M
 Soft, NT, ND, NABS; no HSM
 No rash

8. Labs
 WBC 7.1 S86 B11 L1
 H/H = 9.9/29.4 MCV = 84
 Plt = 217
 NA 129; K 3.4 BUN 7; Cr 0.59 AG = 5
 Alb = 2.6 SGOT/SGPT = 148/60
 LDH = 232
 7.52/29/122 on RA

9. CXR

10. Hosp Course
 Started on Vanc/Zosyn, TMP/SMP
 Fluconazole 100mg for thrush
 Admitted to resp isolation
 Crag, Cocci, urine histo sent
 Of note, all previously negative 4/09 and 1/11;
 CSF Crag negative 6/09

11. Chest CT
 Multifocal consolidation predominantly in the upper lobes &
LLL.
 There are multiple areas of cavitation within the consolidation.
The LUL consolidation may invade the anterior chest wall.
 There are multiple micronodules, some with tree-in-bud
configuration
 Background of moderate centrilobular emphysema
 L pleural effusion
 Multiple enlarged mediastinal and hilar lymph nodes

12. Chest CT

15. Ddx?

16. Cavitary Lung Disease in HIV+ pts
 3 studies – Spain, USA, Taiwan
 Cavity definition: a gas containing space within the lung
surrounded by a wall of at least 1mm & >1cm
 Pts with bacterial causes had higher CD4 counts
 Pts with nonbacterial causes had lower CD4 counts
 Mycobacteria accounted for 25-30% of the disease at all
sites
 No malignancies identified

17. Cavitary Lung disease in HIV+:
Spain 1998
 78 cases of cavitation in 73 pts with HIV admitted from
1/89-12/94
 31 pts with unilobar cavity; 47 with multilobar
 Multiple cavities in 40 cases and solitary in 38
 7 cases (9%) d/t endocarditis
 93% of pts were IDUs
 Median CD4 = 30 (10-560)

18. Cavitary Lung Dis in HIV+ pts
Spain ‘98
 Pathogens:
 Fungi – 15 cases (19%)
 PCP (11), Crypto (2), Aspergillus (2)
 Bacteria – 33 cases (42%)
 Staph (14), Pseudomonas (13), Rohodococcus (6), anaerobes (5)
 Salmonella (3), Strep pneumo (2), Strep milleri (1)
 Mycobacteria 23 cases (30%)
 TB (22), M. kansasii (1)

19. Cavitary Lung Disease in HIV+ pts
USA ’01
 Miami
 Reviewed chest CTs April ‘96 – March ‘98
 25 patients
 20 with definitive diagnoses
 Median CD4 = 106 (2-934)
 No comment on HIV risk factor

20. Cavitary Lung Disease in HIV+ Pts
USA ‘01
 Pathogens:
 Fungi - 4 cases (16%)
 Candida (2), Aspergillus (1), PCP (1)
 Bacteria – 17 cases (68%)
 Staph Aureus (5), Pseudomonas (5), Klebsiella (4), Nocardia (3),
 Enterobacter (2), E. Coli (2), Rhodococcus (1)
 Mycobacteria – 8 cases (32%)
 TB (4), MAI (3), M. kansasii (1), M. fortuitum (1)
 Viruses – 3 cases (12%)
 CMV
 Polymicrobial in 17 pts (85%)

21. Cavitary Lung Dis in HIV+ pts
Taiwan ‘09
 Time Period June ‘94 – March ‘08
 Open Cohort study
 66 pts with 73 episodes of cavitary lung disease out of 1790
pts (3.7%)
 Median CD4 = 25 (1-575)
 95% had AIDS
 10% IDUs
 70% naïve to ARVs
 1 case possibly d/t IRIS

22. Cavitary Lung Dis in HIV+ pts
Taiwan ‘09
 81(!) pathogens found
 Fungi - 34 cases (42%)
 Penicillium marneffei (19), Cryptococcus neoformans (11)
 PCP (2), Aspergillus (2)
 Bacteria - 24 cases (30%)
 SA (7), Rhodococcus (6), Pseudomonas (4)
 Strep Pneumo (3), Klebsiella (2), Nocardia (1)
 Mycobacteria - 21 cases (26%)
 TB (11), MAC (9), kansasii (1)
 CMV 2%

23. Cavitary Lung Dis in HIV+ pts
Taiwan ‘09
 15% were polymicrobial
 Penicillium + PCP
 Pseudomonas + MAC
 Pseudomonas + PCP
 Propensity to cavitate by bug
 11/205 (5.4%) of TB
 19/36 (53%) of P. marneffi
 11/64 (17%) of crypto

24. Updated Labs/Course
 AFB smear negative x 3
 Modified AFB negative
 Crag, Cocci, histo negative
 Quantiferon negative
 Sputum growing MRSA
 Blood cultures negative
 TTE: normal valves; no e/o vegetation

25.  Maintained on vanc (pip/tazo d/c’d after 3 days)
 Cough and SOB improve significantly
 Defervesces w/in 24 hours

26. MRSA Pneumonia
 Risk Factors

27. Bronch
 Procedure unremarkable
 BAL cultures:
 Heavy MRSA
 AFB smears/culture negative
 Cytology negative for PCP
 CMV Shell Vial culture negative
 Aspergillus Galactomannan +
 Start vori?

28. Dx of invasive fungal infections
 Proven: fungal elements detected by histological analysis
or culture of tissue from diseased tissue
 Probable - host factor & clinical criterion & mycological
criterion
 Possible - host factor & clinical criterion but no
mycological criteria

29. Dx of invasive fungal infections
 Probable and possible depend on 3 criteria:
 Host factors
 Immunosuppression
 Clinical manifestations
 Findings on imaging +/- exam findings
 Mycological evidence
 Direct test (cytology, direct microscopy or culture)
 Indirect test (detection of antigen or cell wall constituents)
 Aspergillus Galactomannan (GM) in blood, BAL or CSF
 β-D-glucan in serum for diseases other than crypto or zygomycosis

30. Galactomannan
 Galactomannan (GM) is a fungal antigen produced by
Aspergillus during its growth
 GM is a validated criterion for the diagnosis of probable
invasive aspergillosis in immunocompromised pts
 Several studies have demonstrated false + serum GM in
pts on pip/tazo in ‘03-’04
 Pip/tazo itself has GM in it
 1 study demonstrated false + GM in both serum and BAL

31. False + GM in serum & BAL
 Intubated pts who did not meet diagnostic criteria for IA
(proven, probable or possible)
 73 pts on at least 1 abx for at least 3 days
 14 pts not on abx
 False + GM in serum:
 Pip/Tazo, AMP/CLA
 Cefipime, cefoperazone/sulbactam
 False + GM in BAL:
 Pip/tazo, AMP/CLA
 Ceftriaxone & cefipime

32. Really a false +?
 Pip/tazo seems to be no longer responsible for false-positive
results in Journal of Antimicrobial Chemotherapy, 4/12
 10/09-10/10
 Pip/tazo manufactured by Pfizer
 Tested serum from HSCT pts both off & on pip/tazo
 25/1606 (1.6%) drawn in the absence of pip/tazo tested +
 10/394 (2.5%) while on pip/tazo tested +
 90 vials from 30 randomly selected batches tested negative
 UCSD uses pip/tazo manufactured by Baxter for Wyeth
 Studies suggest repeating test at least 5 days after last dose

33. (1-3) β-D-glucan
 A major component of the cell wall of most fungal species
except cryptococcus and zygomycetes
 Levels are elevated in blood with systemic infections
 Consistently negative levels in pts with mucosal
candidiasis but no systemic disease
 Sensitive marker of PCP
 More sensitive than GM in pts with invasive aspergillosis

34. β-D-glucan: False Positives
 Hemodialysis – cellulose membranes contain BG
 IVIG, albumin or other commercial blood components
 BG is released from cellulose filters used during the
manufacturing process
 Gauze used intraoperatively (see false + in the first 3 days
after surgery)
 Antibiotics:
 Pip/tazo
 Cefazolin, SMP/TMZ, cefotaxime, cefepime, amp/sul – all + at
reconstituted vial concentrations but not when diluted to usual
plasma concentrations

35. Transbronchial biopsy
 Path
 No Atypical or Malignant cells
 Respiratory mucosa and alveolar tissue with acute and
chronic inflammation, edema, and fibrosis, see comment

36. Comment

37. Comment

38. Cryptococcus & GM
 Glucuronoxylomannan in crypto
 90% of capsular mass
 Governs serotype
 Prominent virulence factor
 Galactoxylomannan – the OTHER polysaccharide
 7% of the capsular mass
 Galactoxylomannan cross reacts with GM assays

39. GM in pts with Crypto &
Penicillium marneffei
 Tested serum samples from 48 HIV+ pts for GM
 15 with penicilliosis – 73% had OD >0.5
 22 with crypto – 14% had OD >0.5
 11 w/o fungal infection – 9% had OD >0.5
 No pts with aspergillus or on PIP/tazo or amox/clav
 GM strongly + for penicilliosis pts
 OD range 0.16 - >20, median = 4.4
 + for crypto
 OD range 0.11-3.8; median 0.25

40. Hosp course cont’d
 Serum Crag negative on 6/3 and 6/12
 CSF Crag negative
 Serum GM negative 6 days after last dose of pip/tazo
 Treated with fluconazole 400mg bid
 Treated with vanc for 6-8 weeks
 Lung biopsy by IR non-diagnostic; cx negative
 TEE negative

41. Post CXR

42. Serum Crag
 Latex particles covered with anti-cryptococcal globulin
 Latex reacts with the antigen, causing visible
agglutination
 Pronase, a proteolytic enzyme, reduces the number of
false + tests by eliminating nonspecific interference w/
globulins (such as RF and other immune complexes which
could cause false +)
 False negative rarely reported (none since ‘96)
 False + with trichosporonosis

43. Serum Crag
 Sensitivity ranges from 83-97% in pts with cx+ disease
 Sensitivity = 82% in pulmonary disease
 Specificity ranges from 93-100%
 Animal studies:
 Low titers or negative titers in pulmonary infection that has
not disseminated
 High titers seen in mice with pulmonary infection that has
disseminated
 Intratracheal administration of crypto did not result in
measurable levels

44. Pulmonary Cryptococcosis
 25-55% of cryptococcal meningitis has pulm involvement
 Clinical manifestations:
 Asymptomatic colonization to severe pneumonia/resp failure
 Typically:
 Cough, dyspnea, hemoptysis, chest pain
 Fever, weight loss, night sweats
 Onset:
 Weeks to months in immunocompetent
 Subacute to rapidly progressive in immunocompromised

45. Crypto Radiography: Non-AIDS
 Solitary or multiple pulmonary nodules – 60-80%
 Size varies
 Appearance varies: smooth to spiculated
 Peripheral predominance
 Focal or multifocal consolidation - 10-30%

46. Crypto: Radiography - AIDS
 Diffuse interstitial infiltrates
 Ground glass opacities
 Lobar, often mass-like infiltrates
 Pulmonary nodules; diffuse reticulonodular opacities
 Mediastinal and hilar lymphadenopathy
 Cavitation in only 10-15% of cases
 Infiltrates or effusion often ass’d with disseminated
disease

47. After the fact
 β-D glucan + at 88pg/ml (drawn 8 days after last dose of
Pip/tazo)
 6/09 Crag 1:4 at San Ysidro
 CSF negative with nl chemistries & cell counts
 7/09 treated with flucon 800mg qday
 8/09 Crag 1:8; flucon decreased to 400mg qday
 Notes after that say Crag negative

48. The End