Clinical syndromes: experience from the bedside. Professor Rob Miller University College Hospital, London

Transcription

1 Clinical syndromes: experience from the bedside Professor Rob Miller University College Hospital, London Presented at ECCMID Berlin April 30 th 2013

2 Pneumocystis jirovecii pneumonia

3 Clinical syndromes: experience from the bedside Outline of presentation Who is at risk of getting PCP in 2013? Can we predict outcome from PCP? New syndromes

4 Who is at risk of getting PCP in 2013?

5 Who is at risk of PCP in 2013? Increasing numbers of patients with HIV infection Cancer Transplantation Rheumatologic disease General medical problems requiring disease modifiers/biologics or corticosteroids But who is at risk of PCP?

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7 Patients at risk of developing PCP HIV infected patients: Not receiving prophylaxis or ART CD4 <200 cells/µl Hodgkin or non-hodgkin lymphoma, irrespective of CD4 count, receiving chemotherapy Unknown CD4 count, but stigmata of immune suppression eg OHL, oral candida, seb dermatitis, cutaneous Kaposi sarcoma Ther Adv Respir Dis 2011; 5: 41-59

8 Patients at risk of developing PCP HIV infected patients: CD4 >300 cells/µl (5% in one series of >550 episodes) As an IRIS phenomenon a) Apparent deterioration in PCP following starting ART b) de novo presentation of PCP = 2-6/52 after starting ART

9 Baseline CD4 =20, VL = ; asymptomatic at the time. Onset of fever, dyspnoea and hypoxemia =3 weeks after starting ART (bpi monotherapy). BAL =Pneumocystis jirovecii.

10 Patients at risk of developing PCP Cancer patients receiving: Corticosteroids Alemtuzumab during & for at least 2 months after treatment until CD4 >200 cells/µl Temozolomide & RT and until CD4 >200 cells/µl Fludarabine & T cell depleting agents (eg cladribine) until CD4 >200 cells/µl ALL patients receiving anti-leukaemia therapy Ther Adv Respir Dis 2011; 5: 41-59

11 Patients at risk of developing PCP Rheumatology patients receiving: TNF α inhibitors Cyclophosphamide & corticosteroids for granulomatosis with polyangiitis (GPA) Patients with primary immunodeficiency: Severe combined immunodeficiency Idiopathic CD4 lymphopenia Hyper-IgM syndrome Chronic granulomatous disease Ther Adv Respir Dis 2011; 5: 41-59

12 Patients at risk of developing PCP Transplant recipients: Allogenic stem cell <180 days Autologous peripheral blood stem cell <3-6 months Solid organ <6-12 months Renal <6 months (??24 months) Ther Adv Respir Dis 2011; 5:

13 Patients at risk of developing PCP General medical patients receiving: Prednisolone 20mg od >4 weeks if patient has underlying immunosuppressive disorder or COPD TNF-α inhibitors, especially if on corticosteroids or other immunosuppression Corticosteroids & a steroid-sparing agent eg methotrexate or azathioprine & cyclophosphamide Ther Adv Respir Dis 2011; 5: 41-59

14 Can we predict outcome from PCP?

15 Outcome from PCP In HIV-associated PCP <10% mortality in era of ART Higher mortality among those with respiratory failure Mortality not related to use of ART (lack of) awareness of HIV serostatus is not a factor Higher mortality for non-hiv associated PCP Unrecognised/late diagnosis? Significance of the underlying disease condition?

16 kpa Admission PaO Died Survivors

17 g/dl Admission haemoglobin Died Survivors

18 Prognosis of HIV-associated PCP Prognostic factors LDH, A-aO 2, % neutrophils in BAL fluid APACHE II score, LDH Resp rate, degree of fever, cough, dyspnoea, CXR abnormality BMI, A-aO 2 CRP Clinical factors present at, or soon after hospitalization Age IVDU Bilirubin Albumin A-aO 2 Age Repeat episode of PCP Low Hb PaO 2 Medical co-morbidity eg pregnancy Pulmonary KS

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23 Factors present at/soon after admission associated with mortality Variable Adjusted Odds Ratio [95%CI] Co-morbidity 3.93 [1.77, 8.72] Pulmonary Kaposi sarcoma 6.95 [2.26, 21.37] Age 1.54 [1.11, 2.23] PaO [0.60, 0.81] 2nd or 3rd episode of PCP 2.27 [1.14, 4.52] Haemoglobin 0.70 [0.60, 0.83]

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25 Prognosis of PCP Risk of death score (RODS) age/ (if repeat PCP) + 3 (if co-morbidity) + 4 (if pulmonary KS) - PaO 2 (kpa, breathing room air) - Hb (g/dl) Gives scores = 0-19

26 Prognosis of PCP Group RODS Mortality, (95% CI) (0-9) (1-7) (5-14) (21-38) (31-73)

27 Mortality (%) 80 Mortality rate (95% CI) Group 1 Group 2 Group 3 Group 4 Group 5 (n=41) (n =202) (n =190) (n =121) (n =23)

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29 Prognostic scores Utility Enable identification of HIV-infected patients with PCP at greatest need of ICU who can safely be managed in an OPD setting Problems Neither prognostic score has been validated prospectively in the cohorts from which they are derived in other cohorts of HIV-infected patients in HIV-uninfected patients with PCP

30 New syndromes

31 Pneumocystis and the airways Primary exposure to Pneumocystis murina Two strains of mice (BALB/c & C57BL/6) marked up-regulation of mucus-secreting genes (ClCa3-dependant; goblet airway epithelial cell) airway hyper-responsiveness responses were genetically-determined (STAT-6 ) ie Pneumocystis not exclusively alveolar in host interactions as also interacts with airways Am J Respir Cell Mol Biol 2012; 46:

32 Pneumocystis & sudden unexplained infant death (SUID)

33 SIDS Poisoning & overdose Accidental suffocation Cardiac channelopathies SUID Unknown IBEM Infection Redrawn from

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35 Pneumocystis and SUID Pneumocystis previously identified in lungs of infants Patchy 2-4 months of age Correlates with peak age for SUID Bronchiolitis

36 Pneumocystis and SUID Lung samples from 128 infants (mean age =101d) dying with SUID in Santiago, Chile Presence of P. jirovecii by PCR and IF Among infants >28d old +/- P. jirovecii mucus expression (MUC5AC) by Western blotting burden of P. jirovecii by qpcr

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41 Pneumocystis and SUID MUC5AC was consistently increased in P. jirovecii (+) infants unaffected by P. jirovecii burden =in keeping with the concept that pathogenesis of Pneumocystis infection is (genetically-determined) host-dependant NB MUC5AC levels are also associated with respiratory viral infection respiratory/non-respiratory bacterial infection

42 Pneumocystis and SUID Hypothesis: 1 exposure to P. jirovecii needs Priming by viral co-infection genetic (host) predisposition then release of mucin into narrow airways airway mucin is rapidly hydrated/expands mucin causes occlusion of narrow airways

43 Summary Clinical suspicion of PCP among new at risk patient groups Prognostication at time of hospitalisation who will survive? Role of Pneumocystis in SUID?