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