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Pulmonary infection & immunosuppression

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

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Pulmonary infection & immunosuppression

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  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 50-100%

  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 (X2 = 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 ↑ • In US ↑ from ⅓ of 32,000 mycobacterial isolates • from 1979 -1980 → 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. Non-tuberculous mycobacterial infection Different organisms in different parts of the world – M.avium complex (USA) M.Kansasii (USA and UK) M. Malmoense (Scotland)

  18. Causes of pulmonary granulomata • 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

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

  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 Dis2007; 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 HPSin 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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