1. The Lung and the Immunocompromised Host
Steve Renshaw
Reader in Respiratory Medicine Consultant Respiratory Physician
University of Sheffield

2. Aims and Objectives To discuss causes of immunocompromised host
To discuss common infections causing problems in such patients
To discuss diagnosis and management of these conditions

3. At the end of this lecture you should be able to;
Understand how the lung is protected against infection
Appreciate that the lung is vulnerable to infection particularly in those who are immunocompromised
To appreciate that the presentation of these conditions may not be obvious
To understand how prompt investigation and treatment can improve the outcome

4. Case History Nov 2000 76 y.o. Man presented via GP with SOB
Hx: 12/12 progressive increase SOB
Retired steelworker, wife and family all well
o/e: O2 sats 90% on air
Bibasal fine end insp. crackles

6. Case History- continued
Diagnosed Cryptogenic Fibrosing Alveolitis (CFA= Idiopathic Pulmonary Fibrosis) +/- infection
Treated with po antibiotics
Deteriorated gradually over 3-4 days
Referred to respiratory medicine

7. Seen by me…
History revisited: Although more SOB over 12/12 was running on a treadmill 6/52 prior to admission, noticed rapid deterioration since
Also dry cough
On direct questioning, admitted longstanding same sex relationship

8. Clinical course Induced sputum: “Pneumocystic Carinii”
HIV test: Positive
CD4 Count: 10
Continued deterioration
Died on ITU 10 days post admission

9. 31 y.o. Woman Presented to respiratory take December 2011
RA, treated with Azathioprine
23/11/11 prior, sudden increased SOB, seen in A&E, CTPA: no clot. Discharged, no FU.
8/12/11 Admitted with abdominal pain, had CT in A&E, no intrabdominal pathology, but infiltrates in lungs
Admitted to respiratory take
Lymphopenic

10. Progress ?PCP, on treatment
Declined, taken to ITU that night, intubated
Bronchoscopy
PCP, CMV
Rising CMV titre from blood
Treated Gancyclovir, Prednisolone, Septin

11. The lung is different The lung is exposed to the outside
Not like the skin - no physical barrier
Not like the stomach – no chemical barrier
Inflammation causes loss of function

12. Lung immunity needs to be different
More robust – tackle all invading pathogens
Yet gentler – cannot afford lung injury

13. Immune compromise Congenital Immunosuppressant treatment
X-linked agammaglobulinaemia (XLA)
Chronic granulomatous disease (CGD)
Immunosuppressant treatment
Transplant recipients
Inflammatory disease
Vasculitits
Cancer chemotherapy
Haematological malignancy
HIV infection (rare in HAART era)
Non-specific – malnutrition, co-existing illness, alcohol

14. Respiratory immunity Innate Immune defenses Adaptive immune defenses
Mucosal defenses
Complement
Innate cellular defenses
Macrophages
Neutrophils
Adaptive immune defenses
B-cell mediated
Antibodies
T-cell mediated
Cytotoxicity

15. Mucosal Defenses Surface secretions Mucosal barrier Respiratory cilia
Coughing and sneezing

16. Structure of cilia
animalphysiology/anatomy/animalcellstructure/CiliaFlagella/CiliaFlagella.htm

18. Mucosal Defense - deficiency
Surface secretions – specific defects
Mucosal barrier – cystic fibrosis
Respiratory cilia – Ciliary Dyskinesias
(Kartagner’s Syndrome)
Coughing and sneezing – Sedation/Ventilation

19. Innate Cellular Defenses
Neutrophils
“Foot Soldiers”
First cells recruited, fastest migrating
Heavily armoured
Short-lifespan
Phagocytotic
Macrophages
Tissue Resident – alveolar macrophages
Recruited from Blood monocytes
Phagocytic
Orchestrate immune response

21. Red = zymosan (yeast cell wall particles)
Our group is interested in neutrophil based inflammation
This is a one hour timelapse I made which I like to show because it really illustrates the role of neutrophils in the body.
Green labelled neutrophils rapidly migrate to sites of infection and phagocytose foreign particles, in this case red labelled yeast.
Their job is to protect us against infectious diseases.
Green = neutrophils
Red = zymosan (yeast cell wall particles)
© The University of Sheffield

23. Defects in Innate Cellular Defenses
Neutrophils
Neutropenia
Congenital
Iatrogenic
Diseases of neutrophil function
Chronic granulomatous disease
Macrophages

24. Adaptive immune responses
B-cell
Antibodies
T-cell
Cell mediated cytotoxicity

25. Defects in adaptive immune responses
B-cell
Antibodies
X-linked agammaglobulinaemia
Multiple Myeloma
Iatrogenic (anti-CD20, Rituximab)
T-cell
Cell mediated cytotoxicity
Iatrogenic
Haematological malignancy
HIV infection (rare in HAART era)

26. Iatrogenic immunosuppression
Corticosteroid therapy (predominantly T-cell function)
Cytotoxic chemotherapy (Neutrophils>Lymph>others)
Immune suppression – eg solid organ transplantation, inflammatory disease etc (T-cells predominantly)

27. Non-specific immunosuppression
Malnutrition
Co-existing illness
Sepsis
Alcohol
Trauma
Endurance sports

28. Presentation of pulmonary infection in the immunocompromised
Pyrexia
Respiratory symptoms (Cough, SOB)
Pulmonary infiltrates on CXR or CT
Hypoxia
at rest
Exertional

29. Clinical syndromes:
Can divide types of immunosuppression into 2 categories:-
Granulocyte/humoral defect
T-cell defect

30. Humoral/granulocyte defect
Particularly associated with:
Myeloma
Leukaemias
Chemotherapy
XLA, CGD
At risk of:
Gram positive bacteria
Gram negative bacteria
Fungal infection (esp. Aspergillus and Candida)

31. T-cell defect Particularly associated with: Increased risk of:
Lymphoma
Solid organ transplantation
Corticosteroids
HIV
Increased risk of:
Viral infection (CMV, EBV, adenovirus)
Fungal (esp. criptococcus and nocardia)
Mycobacterial (esp. MTB)
PneumoCystis jirovecii Pneumonia (PCP)

32. Likely organism Early (<1 month) Late (1-6 months) bacterial CMV
Aspergillus
Mycobacterial
Pneumocystis

33. Likely organism Onset over few days Onset over 1-2 weeks
Bacterial
CMV
Aspergillus
Pneumocystis
Onset over 1-2 weeks
CMV
Aspergillus
Cryptococcus
Pneumocystis
Insidious onset
Mycobacterial

34. Likely organism Focal infiltrates Diffuse Nodular/cavitation Bacterial
Aspergillus
Cryptococcus
Mycobacterial
Diffuse
CMV
Pneumocystis
Nodular/cavitation
G-ve bacteria (abscesses)
Aspergillus
Nocardia
Mycobacterial

35. Prevention strategies
Handwashing, no flowers at bedside
Isolation of at risk/infected patients
Neutropenic diet
Septrin (co-trimoxazole) or Pentamidine prophylaxis for patients with reduced lymphocyte numbers or function
Antibacterial prophylaxis post BM Tx (Ciprofloxacin)
GCSF (or GMCSF) for prolonged neutropenia
Education for at risk groups
Identification and treatment of immunocompromise before opportunistic infection

36. Treatment strategies Aggressive management of neutropenic sepsis
Early broad spectrum antibiotics
Piperacillin/tazobactam and gentamicin
Early escalation
Addition of broader antibiotic cover (Teicoplanin)
Addition of anti-fungal therapy (Amphotericin)
Screening and pre-emptive treatment for CMV
Early bronchoscopy and lavage

37. Specific Diseases
PCP (“PneumoCystis Pneumonia”, caused by Pneumocystis Jirovecii)
Typically ~6/52, progressive breathlessness and dry cough
Lymphopenia nearly always present (CD4)
Exertional hypoxia is typical
Induced sputum or BAL for pneumocysts/PCR
Treat with very high dose co-trimoxazole (trimethoprim/sulphamethoxazole)
Supplemental Steroids for hypoxia - Prednisolone

38. Specific Diseases TB Cough, haemoptysis, weight loss, insidious onset
General debility/malnutrition/alcohol as well as specific T-cell defects
HIV even with normal counts
Focal signs on CXR, cavitating upper lobe lesions
2/12 Rifampicin, isoniazid, pyrazinamide +/- ethambutol
4/12 Rifampicin and isoniazid

39. Specific Diseases Invasive Aspergillosis
Fever in neutropenic patient, usually on broad spectrum antibiotics
Multiple pulmonary nodules or infiltrates
Characteristic appearance on CT Rx
Amphotericin (Renal toxicity)
Caspofungin
Liposomal Amphotericin

40. Management Culture – blood, urine, sputum Serology – CMV, legionella
Imaging
CXR, diffuse vs focal infiltrates
High resolution CT scan
Identification of pathogen
Induced sputum – nebulised hypertonic saline
Bronchoscopy and lavage

41. Fibreoptic Bronchoscopy

42. Specific Treatments
PCP – high dose iv Septrin (Co-trimoxazole), +/- Prednisolone
Bacterial – broad spectrum, guided by laboratory sensitivity
Fungal infection
Amphotericin, caspofungin, Voriconazole
Viral infection
CMV - ganciclovir or foscarnet
RSV – ribovirin
HSV – acyclovir, valcyclovir
VZV – acyclovir, valcyclovir

43. Summary
Pulmonary infection is a life threatening complication of immunocompromise of any cause
Early identification of the pathogen is important in reducing unnecessary treatment, identifying resistant organisms, and is associated with improved outcomes