crypto ,meningitis cyrpotcoccous

1. CRYPTOCOCCAL INFECTIONS
and
PNEUMOCYSTIC JIROVECII
PNEUMONIA.
Aziz, Nana K.
PGY₁
Supervisor ; Prof. Seni J.
1/21/2023 Aziz, Nana K.

2. Learning outcomes
At the end of this session the participants should be able to understand
and describe;
• Epidemiological distribution
• Life cycle and pathogenesis
• Host response
• Clinical presentation
• Diagnostic modalities
• Management
1/21/2023 Aziz, Nana K.

3. Cryptococcosis
• Cryptococcosis is an infectious disease with worldwide distribution
and wide array of clinical presentations caused by pathogenic
encapsulated heterobasidiomycetes in the genus Cryptococcus.
• Currently, there are 2 species of Cryptococcus that commonly cause
disease in humans: Cryptococcus neoformans and Cryptococcus gattii.
1/21/2023 Aziz, Nana K.

4. • This fungus causes life-threatening infections in approximately 7–15%
of patients with HIV/AIDS around the world, and up to 40% in Africa.
Patients with AIDS-associated cryptococcal infections account for
80%-90% of all patients with cryptococcosis, Do Santos et al 2008.
• Sub-Saharan Africa accounted for 73% of the estimated cryptococcal
meningitis cases in 2014.
• In 2014 cryptococcal meningitis was responsible for 15% of AIDS-
related deaths globally, by Derbie et al, & accounted for 26% of all
in-hospital AIDS deaths at BMC, Wajanga et al 2011
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5. Fungal disease burden
in Tanzania
Faini D, Maokola W, Furrer H, Hatz C,
Battegay M, Tanner M, Denning DW,
Letang E. Burden of serious fungal
infections in Tanzania. Mycoses. 2015
Oct;58:70-9.
1/21/2023 Aziz, Nana K.

6. Park BJ et al. Estimation of the current global burden of cryptococcal meningitis among persons living with
HIV/AIDS. Aids. 2009 Feb 20;23(4):525-30. data collected from 1997-2007.
1/21/2023 Aziz, Nana K.

7. Distribution based on immune status
• HIV
• Non HIV immunosuppressive states
- malignancy,
- steroid therapy, solid organ transplant & SLE.
- primary immunodeficiencies i.e. adaptive immunity or of innate
immunity disorders
• Immunocompetent (phenotypically normal) individuals
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8. 1/21/2023 Aziz, Nana K.
Evolution of the incidence of cryptococcosis, by year of diagnosis in France (1985–2001), as reported to the
National Reference Centre for Mycosis.

9. • Lomes et al 2016 reported a case series of of 29 non-HIV/nontransplant patients
with cryptococcal disease during the period 2007–2014 at Em´ılio Ribas Hospital,
a tertiary public hospital and reference center for infectious diseases in Brazil
with different manifestations depending on the primary site of infection or
dissemination.
• Wilson et al in 2018 reported a case of disseminated cryptococcosis in a 42-year
old immunocompetent female with diagnosis of disseminated Cryptococcus at
BMC, she was successfully treated with fluconazole but remained with visual loss.
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Lomes NR, Melhem MS, Szeszs MW, Martins MD, Buccheri R. Cryptococcosis in non-HIV/non-transplant patients: a Brazilian case series. Medical mycology. 2016 Oct
1;54(7):669-76.
Wilson RM, Moremi N, Mushi MF, Bader O, Ngoya PS, Desderius BM, Rambau P, Kabangila R, Groß U, Mshana SE. Disseminated cryptococcosis in a HIV-negative
patient: Case report of a newly diagnosed hypertensive adult presenting with hemiparesis. Medical mycology case reports. 2018 Dec 1;22:4-7

10. Carroll KC, Butel J, Morse S. Jawetz Melnick & Adelbergs Medical Microbiology 27 E. McGraw Hill
Professional; 2015 Aug 12. pg 688.
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11. Virulence factors
• Capsule
• Melanin production
• Growth in body physiologic-Temperatures
• Degradative enzymes - Phospholipase, protease and urease activities.
• Phenotypic switching- Strains can also rapidly change their virulence potential by
passage through animals.
1/21/2023 Aziz, Nana K.

12. Ma H, May RC. Virulence in Cryptococcus species. Advances in applied microbiology. 2009 Jan 1;67:131-90.
Aziz, Nana K.

13. Ma H, May RC. Virulence in Cryptococcus species. Advances in applied microbiology. 2009 Jan 1;67:131-90.
Aziz, Nana K.

14. Sabiiti W, May RC. Mechanisms of infection by the human fungal pathogen Cryptococcus neoformans. Future microbiology. 2012 Nov;7(11):1297-
313.pg 1303

15. Clinical manifestations
The two common sites for
infection with this
encapsulated yeast, the lung
and the CNS
Three other sites of infection
(skin, prostate, and eye) have
clinical significant too.
However, it should be noted
that C. spp has been found to
infect any organ of the human
body.
Tabassum S, Rahman A, Herekar F, Masood S. Cryptococcal meningitis with
secondary cutaneous involvement in an immunocompetent host. The Journal of
Infection in Developing Countries. 2013 Sep 16;7(09):680-5.
Aziz, Nana K.

16. Pappas PG. Cryptococcal infections in non-HIV-infected patients. Transactions of the American Clinical
and Climatological Association. 2013;124:61.
1/21/2023 Aziz, Nana K.

17. Diagnostic modalities and Treatment
• Microscopy – CSF, Indian ink, a rapid modality (positive in 70-80% HIV
+ve, 30-50% HIV -ve)
Mandell, Douglas, and Bennett's principles and practice of infectious diseases. The Lancet. Infectious Diseases. 2010 May;10(5):303.
Aziz, Nana K.

18. • CrAg. Waiting period 20-45mins
-LFA; immunochromatography ( sens and spec > 95%),
newer test
-lattex agglutination (sens > 90% spec 93-98%)
FP attributes ; rheumatoid factors, K. pneumoniae infections
FN attributes ; acapsular yeast, Prozone effect, low CrAg
Conc.
- EIA (sens and spec > 95%)
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19. • Fungal Cultures , waiting time 48-72 and longer , Gold Standard.
• Histopathology studies – tissue biopsies like skin, brain tissues, Lung
tissues
• Radiology; Chest X-ray granuloma, cavitation, mediastinal
lymphadenopathy.
Brain CT/MRI – cryptococcoma.
• Molecular diagnostic for serotype identifications.
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20. Management of cryptococcal meningitis
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG. Clinical practice
guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clinical infectious diseases. 2010 Feb
1;50(3):291-322.
Aziz, Nana K.

21. Kaplan-Meier time to death following diagnosis of cryptococcal meningitis and subsequent admission into
hospital.
Lightowler JVJ, Cooke GS, Mutevedzi P, Lessells RJ, Newell ML, et al. (2010) Treatment of Cryptococcal Meningitis in KwaZulu-Natal, South Africa.
PLOS ONE 5(1): e8630. https://doi.org/10.1371/journal.pone.0008630
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008630

22. • Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200
mg/d) fluconazole is ‘‘very cost effective’’ per World Health Organization criteria
and may be a worthy investment.
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23. Rolfes MA, et al , 2014 reported therapeutic LPs were associated with
a 69% relative improvement in survival, regardless of initial intracranial
pressure, same reported by Meda et al, 2014.
Corticosteroid in HIV associated meningoencephalitis during induction
is not recommended. Justin Beardsley, M.B et al 2016 & IDSA
Recommended in crypt pneumonitis with signs of ARDS and in NHNT
pts with evidence of CNS cryptococcoma. IDSA.
• For non severe localized non-meningeal cryptococcal infection
No clinical trials, WHO recommends Rx with fluconazole 800 mg/day
for 2 weeks followed by 400 mg/day for 8 weeks followed by
fluconazole 200 mg/day maintenance therapy .
1/21/2023 Aziz, Nana K.

24. • Among adult in-patients with CM, 32 of 35
patients (91%) had elevated ICP on
admission.
• CSF pressure measured using the improvised
IV tubing set demonstrated excellent
agreement (r2 = 0.96) with manometer
measurements.
• The new ICP management protocol was
associated with a significant reduction in 30-
day mortality (16/35 [46%] vs. 48/64 [75%]
in historical controls; hazard ratio =2.1 [95%
CI: 1.1 to 3.8]; P = 0.018]

25. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG. Clinical practice guidelines for
the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clinical infectious diseases. 2010 Feb 1;50(3):291-322.

26. Pneumocystic Jirovecii Pneumonia
• Pneumocystis is an unusual, opportunistic fungal pathogen and a member of the
Ascomycota division of fungi.
• Given the opportunity, Pneumocystis causes pneumonia (PCP) in susceptible
hosts. It is important to note that Pneumocystis is host specific.
• It has been postulated that humans serve as the reservoir for Pneumocystis
jirovecii and this is supported by a high prevalence in childhood autopsy studies
where high.
1/21/2023 Aziz, Nana K.

27. Epidemiology
• Incidence of HIV associated PCP fell from 4.9 cases per 100 person-years before
March 1995 to 0.3 cases per 100 person-years after March 1998 in industrialized
regions, Weverling et al 1999 (pre and post HAART)
• Meta analysis review by Wassermann et al 2016. reported a prevalence of 15·4 %
among HIV at clinical settings in sub Saharan region.
1/21/2023 Aziz, Nana K.

28. Incidence of PCP in the
different PCP patient
groups
Other*
lung diseases , patients with malignancy
other than hematology , dermatology
patients , auto-immune diseases, rheumatoid
arthritis , hyperthyroidism, mental health
patient.
Overgaard UM, Helweg-Larsen J. Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002–2004. Scandinavian journal
of infectious diseases. 2007 Jan 1;39(6-7):589-95.
Aziz, Nana K.

29. • Tanzania had 1,500,000 people reported to be HIV-infected. Estimated burden of
fungal infections was: 4412 CM, 9600 PCP, 81,051 and 88,509 oral and
esophageal candidiasis cases respectively by 2014. Faini et al 2015
• PCP was diagnosed in 10.4% (13/125) among HIV Patients with cough. Low CD4+
cell counts were associated with increased risk to PCP reported by Mwita et al
2012, at MNH.
1/21/2023 Aziz, Nana K.

30. Pneumocystic Life cycle
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Skalski JH, Kottom TJ, Limper AH. Pathobiology of Pneumocystis pneumonia: life cycle, cell wall
and cell signal transduction. FEMS yeast research. 2015 Sep 1;15(6).

31. pathogenesis
2 Theories
• reactivation of latent infection, evident from serological studies that showed
about 80% healthy children have been exposed to Pneumocystis by 2 to 3
years of age.
• that exposure to Pneumocystis is transient, but that individuals are frequently
exposed to different environmental sources of the organism throughout their
lives.
1/21/2023 Aziz, Nana K.

32. Host response
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Hoving JC, Kolls JK. New advances in understanding the host immune response to Pneumocystis.
Current opinion in microbiology. 2017 Dec 1;40:65-71.

33. Symptoms
The clinical manifestations of PCP are most commonly gradual in onset, and are
characterized by ;
• fever (80 to 100%),
• cough (95%), generally nonproductive.
• dyspnea (95%) progressing over days to weeks.
• fatigue with usual activities.
Approximately 5 to 10 percent of patients are asymptomatic
1/21/2023 Aziz, Nana K.

34. 1/21/2023 Aziz, Nana K.
Blood markers
• ABG: Hypoxemia characteristic, may be mild or severe: PO2
<70 mmHg
• LDH >500 mg/dL is common but nonspecific
• 1,3β-D-glucan may be elevated; uncertain sensitivity and
specificity)

35. 1/21/2023 Aziz, Nana K.
Pathological
• P. jeroveci cannot be cultured in-vitro
• Pathological staining of respiratory secretions or tissue
(Gold standard)
CDC, MMWR; April 2009 (Vol 58)
Lung biopsy using Gomori Methenamine silver
stain to demonstrate P jiroveci organisms in
tissue
Credit: A. Ammann, MD; UCSF Center for HIV
Information Image Library
-Induced sputum: sensitivity <50-
90%
-Bronchoscopy with
bronchoalveolar lavage (BAL):
sensitivity 90-99%
-Lung biopsy: sensitivity 95-100%
• Note that PCR has high sensitivity for BAL sample; but may not
distinguish disease from colonization

36. Laboratory
diagnosis of
PCP
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Esteves F, Calé SS, Badura R, De Boer MG, Maltez F, Calderon EJ, Van der Reijden TJ, Márquez-Martín E, Antunes F,
Matos O. Diagnosis of Pneumocystis pneumonia: evaluation of four serologic biomarkers. Clinical Microbiology and
Infection. 2015 Apr 1;21(4):379-e1.

37. • Chest radiographs — Chest x-rays are initially normal in up to one-fourth of
patients with PCP. The most common radiographic abnormalities are diffuse,
bilateral, interstitial, or alveolar infiltrates.
• High resolution computed tomography — High resolution computed tomography
(HRCT) has a high sensitivity for PCP among HIV-positive patients .
1/21/2023 Aziz, Nana K.

38. 1/21/2023
Mandell, Douglas, and Bennett's principles and practice of infectious diseases. The Lancet. Infectious Diseases. 2010 May;10(5):303.

39. Mofenson LM, Brady MT, Danner SP, Dominguez KL, Hazra R, Handelsman E, Havens P, Nesheim S, Read JS, Serchuck L, Van Dyke R. Guidelines for the prevention
and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine
Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR. Recommendations
and reports: Morbidity and mortality weekly report. Recommendations and reports/Centers for Disease Control. 2009 Sep 4;58(RR-11):1.

40. • Wang et al 2016, whose study indicated that the use of adjunctive corticosteroids
for the treatment of PCP in patients with HIV reduces mortality in the early
stages of the disease.
• Dunban et al 2020, reported four out of five patients, who were at risk, with PCP
did not received prophylaxis,.
• Also Jiang X et al 2015 and Park et al 2018 reported the prophylaxis was
dramatically effective in preventing PCP in rituximab-received lymphoma patient
and rheumatic diseases who were treated with prolonged high-dose steroids
respectively .
1/21/2023 Aziz, Nana K.

41. Preventive therapy
• Compared TMP-SMX,
Dapsone and aerosolizes
Pentamidine and found that
Despite its adverse reaction
profile, trimethoprim-
sulfamethoxazole is the
most effective agent to
prevent the occurrence and
recurrence of PCP , Martin
et al, 1992.
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Mandell, Douglas, and Bennett's principles and practice of infectious diseases. The
Lancet. Infectious Diseases. 2010 May;10(5):303. pg 3021

42. IRIS
• Occurrence or worsening of clinical and/or laboratory parameters
despite a favorable the outcome in HIV surrogate markers (CD4
counts) and plasma viral load.
• Lower CD4 cell counts or high HIV RNA at the time of treatment and
undetected presence of antigens poses a greater the risk.
• Occurs in 2 forms: “unmasking” IRIS, or “paradoxical” IRIS.
• The leading pathogens include: Mycobacterium tuberculosis,
Mycobacterium avium complex, Cytomegalovirus, Cryptococcus
neoformans and Pneumocystis jirovecii
1/21/2023 Aziz, Nana K.

43. REFFERENCES
• Mandell, Douglas, and Bennett's principles and practice of infectious diseases. The Lancet. Infectious
Diseases. 2010 May;10(5):303.
• Derbie A, Mekonnen D, Woldeamanuel Y, Abebe T. Cryptococcal antigenemia and its predictors among HIV
infected patients in resource limited settings: a systematic review. BMC infectious diseases. 2020
Dec;20(1):1-0
• McCarthy KM, Morgan J, Wannemuehler KA, Mirza SA, Gould SM, Mhlongo N, Moeng P, Maloba BR, Crewe-
Brown HH, Brandt ME, Hajjeh RA. Population-based surveillance for cryptococcosis in an antiretroviral-naive
South African province with a high HIV seroprevalence. Aids. 2006 Nov 14;20(17):2199-206.
• Faini D, Maokola W, Furrer H, Hatz C, Battegay M, Tanner M, Denning DW, Letang E. Burden of serious fungal
infections in Tanzania. Mycoses. 2015 Oct;58:70-9.
• Park BJ et al. Estimation of the current global burden of cryptococcal meningitis among persons living with
HIV/AIDS. Aids. 2009 Feb 20;23(4):525-30. data collected from 1997-2007.
• Evolution of the incidence of cryptococcosis, by year of diagnosis in France (1985–2001), as reported to the
National Reference Centre for Mycosis.
1/21/2023 Aziz, Nana K.

44. • Pappas PG. Cryptococcal infections in non-HIV-infected patients. Transactions of the American Clinical and
Climatological Association. 2013;124:61. adult presenting with hemiparesis. Medical mycology case reports.
2018 Dec 1;22:4-7
• Rolfes MA, Hullsiek KH, Rhein J, Nabeta HW, Taseera K, Schutz C, Musubire A, Rajasingham R, Williams DA,
Thienemann F, Muzoora C. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal
meningitis. Clinical infectious diseases. 2014 Dec 1;59(11):1607-14.
• Meda, J., Kalluvya, S., Downs, J.A., Chofle, A.A., Seni, J., Kidenya, B., Fitzgerald, D.W. and Peck, R.N., 2014.
Cryptococcal meningitis management in Tanzania with strict schedule of serial lumber punctures using
intravenous tubing sets: an operational research study. JAIDS Journal of Acquired Immune Deficiency
Syndromes, 66(2), pp.e31-e36.
• Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L,
Phuong L. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. New England Journal of
Medicine. 2016 Feb 11;374(6):542-54.
• Weverling GJ, Mocroft A, Ledergerber B, Kirk O, Gonzales-Lahoz J, d’Arminio Monforte A, et al.
Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral
therapy in HIV-1 infection. EuroSIDA Study Group. Lancet. 1999;353:1293–8.
• Wasserman S, Engel ME, Griesel R, Mendelson M. Burden of pneumocystis pneumonia in HIV-infected adults
in sub-Saharan Africa: a systematic review and meta-analysis. BMC infectious diseases. 2016 Dec;16(1):1-9.
• Mwita J, Mugusi F, Pallangyo K. Pneumocyctis pneumonia and pulmonary tuberculosis among HIV-infected
patients at Muhimbili National Hospital, Tanzania. East African journal of public health. 2012;9(1):10-2.
1/21/2023 Aziz, Nana K.

45. • Park, J.W., Curtis, J.R., Moon, J., Song, Y.W., Kim, S. and Lee, E.B., 2018. Prophylactic effect of trimethoprim-
sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged
high-dose glucocorticoids. Annals of the rheumatic diseases, 77(5), pp.644-649.
• Jiang X, Mei X, Feng D, Wang X. Prophylaxis and treatment of Pneumocystis jiroveci pneumonia in lymphoma
patients subjected to rituximab-contained therapy: a systemic review and meta-analysis. PloS one. 2015 Apr
24;10(4):e0122171.
• Martin MA, Cox PH, Beck K, Styer CM, Beall GN. A comparison of the effectiveness of three regimens in the
prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients. Archives
of Internal Medicine. 1992 Mar 1;152(3):523-8.
• Mofenson LM, Brady MT, Danner SP, Dominguez KL, Hazra R, Handelsman E, Havens P, Nesheim S, Read JS,
Serchuck L, Van Dyke R. Guidelines for the prevention and treatment of opportunistic infections among HIV-
exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV
Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society,
and the American Academy of Pediatrics. MMWR. Recommendations and reports: Morbidity and mortality
weekly report. Recommendations and reports/Centers for Disease Control. 2009 Sep 4;58(RR-11):1.
• Dos Santos WR, Meyer W, Wanke B, Costa SP, Trilles L, Nascimento JL, Medeiros R, Morales BP, Bezerra CD,
Macêdo RC, Ferreira SO. Primary endemic Cryptococcosis gattii by molecular type VGII in the state of Pará,
Brazil. Memórias do Instituto Oswaldo Cruz. 2008 Dec;103(8):813-8
1/21/2023 Aziz, Nana K.