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Comprehensive Guide to Pulmonary Infections and Immunocompromised State

Understand causes of immunosuppression and pulmonary infections, including alcohol effects, cirrhosis, diagnostic principles, and diverse infection sources. Learn about nontuberculous mycobacteria diseases and predicting mortality in patients with acute lung injury and cirrhosis.

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Comprehensive Guide to Pulmonary Infections and Immunocompromised State

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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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