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Pulmonary infection & immunosuppression Causes of immunosuppression Cancer Chemotherapy, including steroids Autoimmune disease Massive trauma Severe viral.

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Presentation on theme: "Pulmonary infection & immunosuppression Causes of immunosuppression Cancer Chemotherapy, including steroids Autoimmune disease Massive trauma Severe viral."— Presentation transcript:

1 Pulmonary infection & immunosuppression Causes of immunosuppression Cancer Chemotherapy, including steroids Autoimmune disease Massive trauma Severe viral infections, incl. HIV Immunosuppressive drugs Diabetes Hepatic cirrhosis Extremes of age Rare causes e.g. agammaglobulinaemia, complement deficiency, ↓ ↓ leucocyte function

2 Alcohol & cirrhosis are bad for you Xs alcohol consumption defined as known diagnosis of chronic alcoholism, previous admission for alcohol detox., alcohol withdrawal or reported consumption of > two drinks/day or >14 drinks/week History of significant alcohol consumption associated with ↑ risk of ARDS (odds ratio = 2.9, 95% CI 1.3–6.2) Patients with chronic alcohol abuse have lungs more vulnerable to oxidative stress & injury ? lack of Glutathione-GSH to scavenge the oxygen free radicals ↓levels of the free radical scavengers ↑ inflammatory injury to lung ?explain detrimental effects of alcohol Thakur L Int. J. Environ. Res. Public Health 2009, 6, 2426

3 Cirrhosis and ALI/ARDS Early predictors of mortality in patients with ALI/ARDS after widespread adoption of lung Protective ventilation Demographic & lab. variables identified in prior studies, incl. age, APACHE II, cirrhosis and pH still predictive of death Seeley E Thorax 2008; 63: 994

4 Cirrhosis & cardiac surgery Studies on CABG and valve replacement Mortality without cardio-pulmonary bypass 0-30% Mortality with CP bypass %

5 Cirrhosis Can manage well until stress occurs Sepsis Major surgery Trauma Metabolic and macrophage functions defective Need: better pre-intervention tests for cirrhosis

6 Basic principles of diagnosis of infection (1) Pneumonia classified according to possible source of causative organism & host immune status Main groups; community-acquired pneumonia (CAP), nosocomial (hospital or health care-acquired) pneumonia (NP) & pneumonia in the immunocompromised

7 Basic principles of diagnosis of infection (2) Microorganisms typically enter lungs by one of three routes: most commonly the airways, but also the pulmonary vasculature, and by direct extension from neck, mediastinum, chest wall, or across diaphragm

8 Basic principles of diagnosis of infection (3) Less commonly, airway involvement is the result of seeding from infected source e.g. peribronchial lymph nodes, bronchoscope, or tracheostomy site Aspiration - introduction of solid or liquid material into lungs, causing parenchymal damage two ways; in large amounts (macroaspiration), aspirated material causes injury by direct chemical or physical means, - lung secondarily infected by bacteria in small amounts (microaspiration), aspirated oral & nasal secretions with microorganisms may cause pneumonia because of organisms themselves

9 Basic principles of diagnosis of infection (4) Clinical features correlate poorly with causative pathogens Yield from routine microbiology poor, with pathogens (principally bacteria) found in only 23 – 26% of cases of community-acquired pneumonia Treatment influenced by such results in only 6 - 8% of cases Ewig S et al. Respiration 1996; 63:164-9 Woodhead MA et al. Respir Med 1991;85:313-7

10 Infections in sepsis 25-30% gram-negative infections 30-50% gram-positive infections 25% polymicrobial infections 25% multi-drug resistant organisms (e.g. MRSA and fungi) 2-4% viral and parasitic infections (but underestimated) ~30% negative cultures (community-acquired sepsis treated with antibiotics before admission)

11 Organ dysfunction in ITU USA data 1996

12 ARDS - HSV No typical hepatic viral inclusions in H & E HSV immunopositivity in 27/54 (50%) - intra-alveolar macs - interstitial macs - lining ep cells Controls -ve

13 ARDS - HSV 81% (13/16) ARDS cases +ve cf. with 37% (14/38) non-ARDS (X 2 = 7.194, p=0.007) No relationship of HSV with or without pneumonia Cases with pneumonia & ARDS – 73% +ve

14 Pulmonary disease due to nontuberculous mycobacteria (NTM) Three clinical patterns; TB-like pattern often affecting older male smokers with COPD; nodular bronchiectasis, classically in middle-aged or older women, never smokers; & hypersensitivity pneumonitis, following environmental exposure, after hot tubs & medicinal baths M. avium complex described in all three forms, many other NTM can produce one or another of them Glassroth J Chest 2008; 133:243–251 Khour A et al. Am J Clin Pathol 2001;115:755–762

15 Pulmonary disease due to nontuberculous mycobacteria (1) Spectrum Pathogenic NTM usually less virulent than M.tb Potential pathogens isolated without obvious disease Species considered benign “contaminants” may produce disease, especially in immunocompromised hosts Mode of transmission of NTM ill-defined - environmental exposure prob. major factor (person to person rare in IC) Most exposed and infected individuals never acquire NTM disease, some ostensibly immunocompetent persons do Both host and mycobacterial factors are involved

16 Pulmonary disease due to nontuberculous mycobacteria (2) Isolation of NTM and diagnosis of clinical disease ↑ appear to be ↑ ↑ from In US ↑ from ⅓ of 32,000 mycobacterial isolates → from → ¾ of isolates from 33 state laboratories by 1992 → Isolates of MAC most frequent → rapidly growing mycobacteria (RGM) (M fortuitum, M abscessus, and M chelonae) & M kansasii Many isolates probably related to disease ?HIV Good RC J Infect Disk 1980; 146:829–833 Ostroff S et al.93rd American Society for Microbiology General Meeting,1993, abstr U-9:170

17 Different organisms in different parts of the world – M.avium complex (USA) M.Kansasii (USA and UK) M. Malmoense (Scotland) Non-tuberculous mycobacterial infection

18  Infection - Bacterial (TB, Syphilis, B. pseudomallei etc) - Fungi (incl. BCG) - Parasites (e.g. Dirofilaria)  Sarcoid and sarcoid-like infection  Occupational (e.g. berylliosis, talc, silicosis)  Vascular - Wegner’s, Churg-Strauss disease, necrotising sarcoid granulomatosis Causes of pulmonary granulomata

19  Bronchocentric granulomatosis  Rheumatoid disease  Amyloid  Aspiration  Hyalinising granulomatosis of lung, pleura and mediastinum Causes of pulmonary granulomata

20 Vasculitis common in all granulomatous inflammation Chronic inflammation in blood vessel walls with marked intimal fibrosis – adjacent to parenchymal inflammation NON-NECROTISING AND NO NEUTROPHILS

21 H1N1 In first two wks April 09, infection with an untypable influenza A virus identified in Mexico and S. California Exact sequence of events uncertain, but by third week of April established illness resulted from a triple recombination of human, avian, and swine Influenza viruses - H1N1 (S –OIV) Baden et al. NEJM 2009; 360: 266-7

22 H1N1 H1N1 Influenza Centre at NEJM.org - available to all Non-specific clinical features - fever, hepatosplenomegaly, lymphadenopathy, jaundice & hyperferritinaemia Cytopenia, coagulopathy, hypertriglyceridaemia & deranged liver function tests Most of above features could be directly attributed to HIV infection Haemophagocytosis in bone marrow, spleen or lymph nodes Doyle T Curr Opin Infect Dis 2009; 22 :1–6 Rouphael NG Lancet Infect Dis 2007; 7:814–22

23 The issues Diagnosis of H1N1 Tissue samples? Swabs? Automated PCR technology Influenza A H1 Pathology H1N1-related and/or Co-morbidities Air travel from Mexico init. Obesity Pregnancy Childhood Respiratory disease

24 Case Male 40yr, Caucasian Learning disabilities D1: Unwell, cough D1: GP prescribes Abx D3: not better D3: GP prescribes Tamiflu [not taken] D4: respiratory collapse, ambulance to hospital, dead on arrival Professor S Lucas

25 Case Autopsy Normal apart from lungs & spleen Lungs 1000gm, heavy red Spleen 360gm, soft

26 Haematophagocytic activation syndrome (HPS) (1) Primary form (familial HPS) typically occurs in infancy, & assoc. with underlying genetic abnormalities (immune deficiency syndromes) Viral infection, e.g. primary exposure to EBV, often precedes presentation Reactive (secondary) HPS can occur in both children & adults, in assocn. with variety of underlying disorders, e.g. infection, neoplasia and autoimmune conditions, & has a better prognosis Doyle T Curr Opin Infect Dis 2009; 22 :1–6

27 Haematophagocytic activation syndrome (HPS) (2) In autopsy study of 56 AIDS patients, histopath evidence of haemophagocytosis in 20% Mutations in perforin gene, which encodes a membranolytic protein, found in the cytotoxic granules of CD8+ T lymphocytes [cytotoxic T lymphocytes] & natural killer (NK) cells Perforin appears to create pore-like structures in membranes of target cells, facilitating entrance of cytotoxic molecules into the target cell cytoplasm Stepp SE Science 1999; 286:1957–1959 Doyle T Curr Opin Infect Dis 2009; 22 :1–6

28 Haematophagocytic activation syndrome (HPS) (1) Primary form (familial HPS) typically occurs in infancy, & assoc. with underlying genetic abnormalities Viral infection, e.g. primary exposure to EBV, often precedes presentation Reactive (secondary) HPS can occur in both children & adults, in assocn. with variety of underlying disorders, e.g. infection, neoplasia and autoimmune conditions, & has had a better prognosis Doyle T Curr Opin Infect Dis 2009; 22 :1–6

29 Haematophagocytic activation syndrome (HPS) (2) Effect of these mutations is defective triggering of apoptosis and ↓ T- and NK-cell cytotoxicity ↓ NK-cell cytotoxicity also shown in reactive HPS, such as EBV-associated HPS End-point of these processes in human disease is excessive activation of T cells leading to ↑ cytokine secretion and hyperactivation of macrophages Kogawa K Blood 2002 ; 99 : 61–66 Villanueva J Arthritis Res Ther 2005 ; 7: R30–R37

30 Important associations of HPS in patients with HIV infection Viruses HIV, EBV, CMV, HHV-6, HHV-8, adenovirus, influenza viruses, parvovirus B19 Bacteria Streptococcus pneumoniae M. tb complex, M.avium complex, M. kansasii Fungi Histoplasmosis, Pneumocystis jirovecii, Candida albicans, Penicillium marnefii, Aspergillus spp, cryptococcii Protozoa Toxoplasma gondii, Leishmania donavanni Neoplasia Hodgkin’s lymphoma, NHL,KS Doyle T Curr Opin Infect Dis 2009; 22 :1–6


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