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Pulmonary Infiltrates in
Secondary Immunodefficiency
Maggie Louis Naguib, M.D., FCCP Professor of Pediatrics and
Pediatric Pulmonology Cairo University Faculty of Medicine
Overview• Causes of pulmonary infiltrates in
the immunocompromised child
• General approach to diagnosis
• Case presentations: CCHE 57357
Introduction• Increase in immunocompromised patient
population : a product of modern medicine • Prolonged survival & treatment of childhood
malignancy • Organ transplantation • Immunosuppressive therapy • HIV-AIDS
• Extensive variety of etiologic agents • Urgent need to establish a diagnosis:- rapid
progress & serious consequences
Causes of Pulmonary Infiltrates in Immunocompromised Patients• Infection: usual infections + opportunistic
infections – Bacteria (Pseudomonas aeruginosa, Staphylococcus
aureus) – Fungi (Aspergillus, Mucormycosis, Candida) – PCP (Pneumocystis jirovecii) – Viruses (CMV, VZV, HSV, RSV, parainfluenza,
influenza, adenovirus) –Mycobacteria (MTB & NTM) – Parasites
Causes of Pulmonary Infiltrates in Immunocompromised Patients• Non Infectious – Pulmonary edema – Progression of underlying disease – Radiation toxicity – Drug toxicity – DAH – Engraftment syndromep – Idiopathic pneumonia syndrome – Bronchiolitis obliterans organizing pneumonia
(BOOP) – Secondary alveolar proteinosis – PTLD (in SOT & HSCT) – TRALI
Drugs associated with pulmonary toxicity• Alkylating agents – Busulfan, Chlorambucil, Cyclophosphamide
• Antimetabolites – Azathioprine, Cytosine arabinoside, Fludarabine,
Gemcitibine, Methotrexate • Cytotoxic antibiotics – Bleomycin, Dactinomycin, Mitomycin
• Nitrosoureas – BCNU (carmustine), CCNU (lomustine)
• Assorted agents – Antithymocyte globulin, Doxorubicin, Interleukin-2,
Procarbazine, Sirolimus, Taxanes, Vinca alkaloids
General Considerations• Nature of the immune defect
• Multiple immune defects may be present • Neutropenia:
• usual cut-off is 500-1000 /cu mm, the lower the cell count, the higher the risk for infection 1
• more infections are encountered when neutropenia > 30 days 2
• The duration of immunosuppression: • acute immunosuppression e.g. chemotherapy predisposes
to infection more than chronic e.g. congenital neutropenia. • A longer “acute” neutropenia predisposes to fungal
infections
1-Jagarlamudi et al., 2000, 2-Afessa and Peters, 2006
Risks From Treatment of Hematologic Malignancies• Neutropenia from chemotherapy • Mucositis, radiation & indwelling catheters • Hodgkin’s disease/splenectomy – Streptococcus pneumoniae, H. influenzae, N.
meningitidis • HSCT & GVHD – Fungal, mycobacterial and viral
14
Immuncompromised host
T°+ pulmonary infiltrate
Neutropenia PMN < 1000 cells/mcl T-cell immunodeficiency B-cell immunodeficiency
Short duration (<48 days) Conventional bacteria : . Oral bacterial flora . Enterobacteriacae . Ps. aeruginosa
Long duration (> 48 days) Aspergillus sp. Mucorales Candida sp.
Fungi: . Coccidioides sp. . M. capsulatum . PCP . C. neoformans Bacteria : . M. tuberculosis . Legionella sp. . Nocardia sp. . R. equi Parasites : . S. stercoralis . T. gondii Viruses : . CMV . HSV and VZV . Adenovirus . RSV . Measles
Encapsulated bacteria : . S. pneumoniae . H. influenzae . (PCP)
15G.P. Bodey, Ann Int Med, 1966
The risk of infection increases with the severity and duration of neutropenia
General Considerations• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • Degree of RESIDUAL host immunity
Intervention• A source of infection: e.g. indwelling catheter
>> hematogenous seeding of lung & pneumonia – Staphylococcus, candida
• Inhaled pentamidine >> PCP confined in apices (resemble TB)
• Radiation therapy >> sparing PCP in certain areas.
• TMP/SMX prophylaxis ↓↓ PCP incidence
• BSA >> predisposes to fungal infection
General Considerations• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • Degree of RESIDUAL host immunity
INITIAL radiographic patternConsolidative Nodular /Cavitary Diffuse
Bacteria Cryptococcus Aspergillus Nocardia Legionella Mycobacteria Hemorrhage Pulmonary Embolus Radiation
Cryptococcus Aspergillus Legionela Nocardia Bacterial abscess Septic emboli Neoplasm
Pneumocystis Virus Pulmonary edema Hemorrhage Radiation Drug Lymphangitic tumor
Conces D The Immunocompromised Patient in Freundlisch & Bragg eds A Radiologic Approach to Diseases of the Chest 1992Williams & Wilkins pp115-126
General Considerations• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • Degree of RESIDUAL host immunity
Rate of ProgressAcute Subacute Chronic
S. Pneumoniae Staphylococcus Gram-Negative Legionella
Pneumocysitis Aspergillus Zygomycetes Cryptococcus Nocardia Legionella Mycobacteria Viruses
Mycobacteria Cryptococcus Nocardia
General Considerations• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • Degree of RESIDUAL host immunity
Pulmonary Complications after BMT
Time Association Infection Noninfectious
Early (<30d)Neutropenia, mucositis, antibiotics, radiation
Bacteria, HSV, RSV, candida
Pulmonary edema, ARDS, DAH, TRALI
Delayed (30-120d)
Acute GVHD, failed engrafment
CMV, adenovirus, Aspergillus Mucor, HHV6, EBV
Intersititial pneumonia, Lymphoproliferative syndrome, Drug toxicities
Late (>120d)
CGVHD Delayed CMV, VZV, PCP, encapsulated bacteria, mycobacteria
Bronchiolitis Obliterans , BOOP
General Considerations 6• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • Degree of RESIDUAL host immunity
Extrapulmonary symptoms
• CNS abnormality: e.g. Cryptococcus, Toxoplasma, Mycobacteria & Nocardia
• GIT esp diarrhea: e.g. Legionella
• Dermatologic affection: e.g. Cryptococcus, Nocardia & Pseudomonas
General Considerations• INTERVENTIONS: e.g. Indwelling catheter
/ medication • INITIAL radiologic pattern • RATE of progress of symptoms • TEMPORAL association: e.g. Organ
transplantation • ASSOCIATED symptoms • RESIDUAL host immunity
Residual Host Immunity
• Fungal pulmonary infections : – chemotherapy-induced neutropenia >> mild clinical &
radiological changes – neutrophil count rises & often >> significant
inflammation, lung destruction & cavitation and may >> clinical deterioration.
• PCP improves with corticosteroid therapy in AIDS patients suggesting an inflammatory immune response
Immunocompromised child with pulmonary infiltrate
Pizzo & Poplack 2005 Principles & Practice of Pediatric Oncology
Children's Cancer Hospital in Egypt 57357
Case Presentation- Samira• 8 y/o girl with bilateral metastatic Wilms’
tumor :- right basal pulmonary nodule (1 cm) [Fig.1] + a positive focus in the lumbar spine (99mTC-HDP bone scan).
• Treatment : pre and postoperative multiple agent chemotherapy (actinomycin D, vincristine & doxorubicin) > regression in size of renal masses & resolution of pulmonary and bone lesions.
Fig. 1 Image at diagnosis. Post contrast CT examination of the chest >> a well-defined right posterior basal pulmonary nodule likely representing metastatic
deposit.
Case Presentation cont.
• Surgery : right radical & left partial nephrectomy; operative tissue samples confirmed the diagnosis as bilateral Wilms’ tumor with favorable histology [Fig.2]
• Radiotherapy included bilateral flank irradiation, together with lung bath.
Fig.3 CT chest showing well defined pleural based nodule (1.5 cm) in anterior segment of left upper lobe with no evidence of calcification or
cavitation.
End of treatment evaluation chest CT
Case Presentation cont.
• ? metastatic lung deposit: favored by patient’s history & absence of other symptoms (eg. Fever/cough) and a negative TST*.
• Combined clinic decision was surgical removal (pulmonary metastatectomy).
*TST: Tuberculin Skin Test
Case Presentation cont.• Histo-pathologicy of excised lung tissue :
negative for malignant growth but revealed a “caseating granuloma”. [Fig. 4,5]
• Ziehl–Neelsen stain demonstrated acid-fast bacilli (AFB) [Fig.6] : pulmonary tuberculosis (TB)*.
• Negative history of contact with a known case of TB and screening of household contacts failed to identify a source of infection.*Direct detection of the DNA of Mycobacterium Tuberculosis using polymerase chain reaction (PCR) was not available.
Case Presentation cont.• Treatment : daily 4-drug antituberculous
regimen (RHZE) for 2 months followed by a daily 2-drug regimen (RH) for another 7 months + vitamin B.
• Clinical & laboratory monthly follow up. • The patient is currently clinically and
radiologically free 20 months after treatment for WT and 10 months after concluding anti-tuberculous treatment.R: Rifampicin 15 mg/kg, H: Isoniazid 10 mg/kg, Z: Pyrazinamide 25 mg/kg , E: Ethambutol 15mg/kg
Youssef
• 2 y/o male known ALL patient under Chemotherapy
• c/o fever, cough & increasing respiratory distress
• Chest imaging : CT – bilateral patchy infiltrates + cavitation – Increased in size + consoldation & cavitation of
lt lower lob – Pleural effusion
Youssef• BL C&S: Burkholderia cepacia / central line
removed • Galactomannan serum: 1.06 (>0.5) • No improvement on BS ABX / antifungal • BAL: – +ve culture for Aspergillus flavus
• Rapidly accumulating lt Pl effusion • Pl Aspirate >>> – Apspergillus – Acid Fast Bacillli (NTM) +
Youssef
• Treatment started for NTM (Ciprofloxacin – Azithromycin – rifampicin d/c) • Antifungal ttt: amphotericin B
Youssef
Ola• A16 y/o patient known case of NK-ALL &
allogenic BMT recipient • D230 : CGVHD • CMV+ • non productive cough, wheezing, and
increasing shortness of breath • progressive decline in PFTs with evidence
of small airway obstruction
Ola• O2 dependant • Repeated hospital & ICU admissions • PFT often very difficullt due to RD • CGVHD: immunosuppression • CMV: ganciclovir • BOOP / IP: steroids
Nada• A12 y/o patient presenting 4w non-productive
cough & chest tightness & fever 2wk • Treated from asthma since age 5 y • Antibiotics, bronchodilators & cetrizine with partial
improvement (fever) • Examination – Normal measurements – Afebrile, non distressed SPO2 100% RA – Cervical LNs 1 cm
• CBC: Normal • TST: 11 mm induration
Nada• Surgical pathology: – LNs with multiple granulomas formed of
epithelioid histiocytes, multinucleated Langhan’s giant cells with extensive caseation. Inflammatory infiltrate of plasma cells, neutrophils & eosinophils.
• ZN stain : negative for AFB • Antitiberculous ttt • Clinical & radiological improvement
Conclusion • Pulmonary infiltrates in the imunocompromised
child present a clinical challenge & carry a significant risk of morbidity & mortality
• No one pattern of symptoms or radiographic findings is conclusive for diagnosis >>
• Approach to each patient must be individualized
• Early and aggressive specific diagnosis increases the likelihood of survival
Acknowledgement Children’s Cancer Hospital in Egypt 57357
TEAMS & DEPARTMENTS • Clinical Research • Infectious Disease • Microbiology • Oncology • Pathology: Dr. Hala Taha • Radiodiagnosis