February 18th 2010

Grand conference
Pulmonary Division
Hwasun Chonnam National University Hospital

R3 김민형
 황 O O (56/F) #70800227

C/C Dyspnea (D: 2 weeks ago)

P/H No known Hx. of DM, HTN, Pul. Tbc, Hepatitis

Op(+) – 2009.9.4 Craniectomy & tumor removal
(d/t Glioblastoma)
 CCRT (09.09.29~11.13)
-180cGyx33Fr
이후 maintenance chemoTx
(09.12.09~)
 F/H N-S

Alcohol
S/H : none
Smoking : none

주부
O/H

Temozolomide (temodal ®)
Drug Hx
: 2009.9.29~11.13 CCRT (130mg/day)
 09.10 월 초 전신에 skin eruption (+)

2009.12.9~12.13 1st 유지요법 (270mg/day)

Valproate sodium (depakin ®) :2009.9.7~
Acetyl-L-carnitine (nicetile ®) :2009.9.7~
 Present illness

환자는 내원 약 2 주일 전부터 운동시 호흡곤란 (MRC Gr

II-III)
있었으나 경과 관찰 하던 도중 , 점점 더 악화되는 양상 보여
이에 대한 추가 검사 및 치료 위하여 내원함 .
 ROS

Fever / Chills (-/-)

Dizziness/vertigo (-/-)

Cough/sputum/coryza (+/-/-)

Chest pain/palpitation (-/-)

Epigastric soreness (-)

Abdominal pain/nausea/vomiting (-/-/-)

Dyspepsia / dysphagia (-/-)

Hematuria / dysuria (-/-)

Diarrhea/constipation (-/-)

Wt. loss (-)

B/H As usual

U/H As usual

V/S BP 130/80 mmHg BT 36.5 0C

PR 88 회 /min RR 22 회 /min
P/E

G/A Acutely ill appearance

Alert mental state

H/S No scar & deformity

Eye Not anemic conjunctiva

Anicteric sclera

ENT Externally free

Neck No LAP, No JVE

Neck stiffness (-)
P/E

Chest Symmetrically developed

RHB without murmur
NBS without crackles

Abdomen Soft & flat

No palpable organomegaly
No T/RT
No CVA tenderness

Extremity No pitting edema

IMPRESSION

1. r/o Tracheobronchitis
r/o Pneumonia

2. r/o Interstitial lung disease

3. r/o Bronchial asthma

4. s/p Glioblastoma
Diagnostic plan

1. Routine lab, EKG, chest X-ray

2. Pulmonary function test

3. Chest CT
Electrocardiogram (HD1)
Chest PA & Lt Lat
3month ago HD 1
 Laboratoy Findings

CBC & D/C

WBC 4200 (4000 ~ 10800/mm3)

N/L/E/M/B (72.1/18.4/6.4/8.5/0.8)
RBC 3.81 (4.2 ~ 6.1X106/mm3)
Hgb 12.4 (12 ~ 18g/dl)
Hct 37.4 (37 ~ 52%)
MCV 98.2 (80 ~ 99fl)
MCHC33.2 (32 ~ 37g/dl)
PLT 163K (130 ~ 450K/mm3)
Liver Function Test
AST 45 (< 37 U/L)
ALT 17 (< 37 U/L)
ALP 72 (35 ~ 129 U/L)
T-Protein 5.2 (6.4 ~ 8.3 g/dL)
Albumin 3.0 (3.5 ~ 5.2 g/dL)
T-bilirubin 0.7 (0.2~1.2 mg/dL)

Coagulation Profiles
PT 14.0/86/1.10 sec/%/INR

aPTT 36.1 sec (26.5 ~ 41)

Renal Function Study & electrolytes
BUN 14.2 (8 ~ 20 mg/dL)

Cr 0.9 (0.5 ~ 1.3 mg/dL)

Na 136 (136 ~ 146 mEq/L)

K 3.8 (3.5 ~ 5.1 mEq/L)

Cl 106 (98 ~ 106 mEq/L)

I- Ca 2.2 (2.0 ~ 2.4 mEq/L)

I–P 3.4 (2.5 ~ 5.5 mg/dL)

Acute Phase Reactant
CRP 1.28 (0.2 ~ 0.5 mg/dL)
ABGA at O2 2L

pH 7.474 (7.35 ~ 7.45)

PCO2 26.2 (35 ~ 48 mmHg)

PO2 62.9 (75 ~ 100 mmHg)

HCO3- 19.4 (21 ~ 28 mmHg)

O2 Sat 94.8 (92 ~ 98.5 %)

U/A
S.G 1.025
pH 7.0 (5.0~8.0)
Protein negative (0~50mg/dL)

Ketone negative (0~0.4mg/dL)

Bilirubin negative (0~0.4mg/dL)
Urobilinogen 0.2 (0~0.2mg/dL)
Nitrite negative
WBC +1
RBC negative
Chest CT (HD1)
 Tentative Diagnosis

1. r/o ILD

2. r/o interstitial pneumonia

(viral, H1N1, other atypical pneumonia)

3. s/p Glioblastoma
 Plan

1. Bronchoscopy / BAL

2. Empirical antibiotics

3. Viral culture
Bronchoscopy (HD2)
 HD 2
• Dyspnea aggravation
• BP 80/50mmHg, RR 35, HR 108
• P/E) Crackle in both lung

ABGA at O2 mask 15L

pH 7.474 (7.35 ~ 7.45)

PCO2 31.5 (35 ~ 48 mmHg)
PO2 39.6 (75 ~ 100 mmHg)
HCO3- 17.6 (21 ~ 28 mmHg)
O2 Sat 73.5 (92 ~ 98.5 %)

Reservoir O2 mask 15L -> 85~90%

Solumedrol 1mg/kg qD
 HD 3
BAL : Lymphodominant (45%)
Neutrophil (22%)

ABGA at Reservoir O2 mask 15L

pH 7.418 (7.35 ~ 7.45)
PCO2 33.0 (35 ~ 48 mmHg)
PO2 74.5 (75 ~ 100 mmHg)
HCO3- 20.8 (21 ~ 28 mmHg)
O2 Sat 95.3 (92 ~ 98.5 %)

Solumedrol 1mg/kg qD

Tamiflu 75mg Bid for 5 days

 HD 5

ABGA at Reservoir O2 mask 15L

pH 7.421 (7.35 ~ 7.45)
PCO2 37.2 (35 ~ 48 mmHg)
PO2 48.4 (75 ~ 100 mmHg)
HCO3- 23.6 (21 ~ 28 mmHg)
O2 Sat 85.2 (92 ~ 98.5 %)

TBLB : suggestive for bronchiolitis

obliterans organizing pneumonia

Solumedrol 125mg q 6hrs

Transbronchial lung biopsy
 Viral culture

Novel influenza rRT-PCR Negative

Influenza A,B culture Negative
Parainfluenza 1,2,3 culture Negative
Adenovirus Negative
RSV culture Negative

Sputum exam

Sputum AFB Negative

Sputum & BAL, Bronchial washing culture No growth

 Final Diagnosis

1. r/o Drug-induced ILD

BOOP
(bronchiolitis obliterans organizing pneumonia)

2. s/p Glioblastoma
 Treatment plan

1. High dose corticosteroid

 Chest CT (HD7)
HD 1 HD 7
 Hospital course
HD
HD
HD 10
6
1
OPD f/u
HDHD 18 21
Ceftriaxone 2g q24hr Cefditoren 100mg (T)
Clarythro
mycin
500mg
(B)

Oseltamivir 75mg
(B)

mPRD mPRD mPRD mPRD PRD

70mg 125mg 62.5mg 62.5mg
q24hr 60mg/day
q6hr q6hr q12hr

HD1 HD3 HD5 HD7 HD10 HD13 HD19 HD23

Chest CT Chest CT f/u Discharge

Bronchoscopy
 Drug-associated
Bronchiolitis Obliterans
Organizing Pneumonia

Arch Intern Med. 2001;161:158-164

Semin Respir Crit Care Med. 2002;21(2):135-146
Clin Chest Med. Mar 2004;25(1):89-84
Mayo Clin Proc. June 2007;82(6):771-773
Chest 2008;133:528-538
 Pulmonary complicatons of
antineoplastic agents for solid
tumors Chest 2008;133:528-538
 Anti-neoplastic agent-induced pulmonary toxicity Dx  Exclusion !!

- D/Dx) pneumonia, cardiogenic pulmonary edema, diffuse alveolar hemorrhage

 Bronchoscopy with BAL is very useful. TBLB can helpful

- cessation of the implicated causative agent and treatment with

systemic corticosteroids may result in rapid improvement
** The diagnosis of chemotherapy-induced pneumonitis
- pneumonitis develops shortly after the initiation of treatment
- lack of an alternative explanation for respiratory failure
- resolution after corticosteroid Tx & withdrawal of the presumed agent

 Pathogenesis : poorly understood

 Risk factors : preexisting pulmonary disease
- IPF, COPD, radiation therapy, extensive pulmonary metastatic disease,
poor functional status
Drug-Induced Respiratory Disease
In Clinical Practice

Department of Pulmonary and Intensive Care

University Medical Center at Dijon
www.pneumotox.com

– Total references 12893

– .pdf files 3028
 Temozolomide-associated
organizing pneumonitis
Mayo Clin Proc. June 2007;82(6):771-3
Chest 2008;133:528-538
 Temozolomide

 Alkylating agent - anaplastic astrocytoma, glioblastoma multiforme

metastatic melanoma

 Numerous alkylating agents (cyclophosphamide, busulfan, chlorambucil)

 clearly associated with pulmonary adverse reactions

 Dacarbazine (closely related to temozolomide)  pulmonary toxicity

 Adverse effect : thrombocytopenia, neutropenia, peripheral edema, nausea, constipation,

weakness

 Respiratory adverse reactions: pharyngitis, sinusitis, cough, upper respiratory tract

infection, dyspnea
 pneumonitis developed in 4.8% of patients
 Temozolomide-associated
organizing pneumonitis
Mayo Clin Proc. June 2007;82(6):771-3
 88-year-old man

 fever, weakness, shortness of breath, nonproductive cough (4-week)

 P/H CAD, hyperlipidemia, HTN, hypothyroidism
Rt occipital GBM (6month ago)  surgical resection
 RT + low-dose (75mg/m2/d) temozolomide for 6 week
 adjuvant CTx with 200mg/m2 of temozolomide
(daily for 5 days every 4weeks, completing 2 cycles before presentation)
 Drug) atenolol, nifedipine, simvastatin, levothyroxine, hydrocholorothiazide

 BT 38.5℃, BP 115/65mmHg, HR 65beats/min, RR 18 beats/min

 P/E) inspiratory crackles in both lung bases
 Lab & blood culture) N-S // sputum stain & culture (-)
Fungal serology (-) // BAL culture (-)
 Chest CT: diffuse GGO in both lungs
 TBLB: typical for organizing pneumonitis, no evidence of granuloma /vasculitis

 Discontunue temozolomide, prednisone (1mg/kg/d) with TMP-SMX

 tapering the doses of prednisone for 6months
 TYPES of BOOP
 Postinfection BOOP (Chlamydia, Legionella, Mycoplasma, HIV)

 Drug-related BOOP

 BOOP in connective tissue disorders

(inflammatory myopathy, RA, SLE, scleroderma, Sjogren syndrome)

 BOOP in transplant patients (BMT, Liver / Lung transplantation)

 BOOP after radiotherapy (RT for breast cancer)

 Environment-related BOOP
(textile printing dye-related / penicillium mold dust-related)

 Miscellaneous BOOP (Hematologic malignancy, UC, CD)

 Idiopathic BOOP – cryptogenic organizing pneumonia (m/c)

 BOOP
 no gender predominence, mean age – about 55 to 65 years
majority of patients are nonsmokers

 Clinical manifestations : N-S

 viral-like infection with fever, nonproductive cough, malaise, anorexia,
weight loss
dyspnea is usually mild
Bronchorrhea, chest pain, hemoptysis are rare

 P/E : crackles may be heard over consolidated areas, but wheezes are absent

 Lab: increased ESR, CRP, moderate leukocytosis with increased neutrophils

 Imaging finding
- Multiple alveolar patchy opacities (usually bilateral) : often migratory
- Solitary focal COP
: predominates in the upper lobes & usually presents as mass
- Infiltrative diffuse opacities
- Multiple nodular lesions
 BOOP
 Pulmonary function test
- no airflow obstruction, except in smokers or underlying obstructive lung disease
- ventilatory restrictive defect is the most common finding
- decreased DLCO, increased Rt to Lt shunt
- mild hypoxemia is usually present

 Bronchoscopy
- exclusion of bronchial obstruction
- typical differential WBC in COP consists of a ‘mixed pattern’ with increased
lymphocytes (20~40%), neutrophils (about 10%), eosinophils (about 5%)
- the ratio of CD4 to CD8 lymphocytes is decreased

 Pathological diagnosis
- TBLB may provide the Dx of organizing pneumonia by showing the typical intra-
alveolar characterisitic buds of granulation tissue
- In patients with nonrepresentative or noninformative TBLB  surgical Bx
: Video-assisted thoracoscopic procedure
: Open lung surgical biopsy
 TREAMENT OF BOOP
 Spontaneous improvement has been reported in some patients
 Erythromycin & tetracycline  occasionally reported to induce response

 Corticosteroid treatment
 Prednisone : potent anti-inflammatory property
 The doses & treatment duration have not been established
- Epler (Semin Respir Infect 1995;10:65-77)
: predisone 1mg/kg for 1 to 3 months
 decreasing dosage to 40mg for 3 months
 10 to 20mg daily for a total 1 year
- King (Interstitial lung disease 1998:645-684)
: prednisone in a dose of 1 to 1.5mg/kg/day for 4 to 8 week
 gradually tapers to 0.5~1mg/kg/day for the ensuring 4 to 6 weeks
 gradually tapered to zero after 3 to 6 months
: therapy being reinstituted aggressively with any sign of recurrence
* Rapidly progressive severe disease
: high-dose parenteral glucocorticoid Tx
(methylprednisolone 125 to 250mg every six hours IV for 3~5 days)
(Wells AU, Semin Respir Crit Care Med. 2001 Aug;22(4):449-460)
: cyclophosphamide or azathioprine, cyclosporin A (Diazo, Int Med 2002 42:26-9)
 PROGNOSIS OF BOOP
 Prognosis

 Overall prognosis of BOOP is good

 Mortality rate is about 5 to 15%

 Predictors of poor outcomes

: predominantly interstitial pattern on imaging, lack of lymphocytosis at BAL
differential cell count, pathological lesions of scarring & remodeling of the
background lung parenchyma in addition to organizing pneumonia

 Rapidly progressive BOOP : dyspnea, cough, fever, crackles, hypoxemia

 underlying connective tissue disease, exposure to birds, chronic
nitrofurantoin therapy

 Patients with life-threatening disease, early diagnosis & subsequent early initiation of
corticosteroid therapy was considered a major determinant of outcome
 Drug-induced BOOP
 More than 20 medications are associated with the BOOP

 BOOP reaction represents an inflammatory response of the lung

 generally reversible by drug cessation or corticosteroid therapy

 Symptoms : nonproductive cough, shortness of breath

 Occasionally, fever & rash / rarely eosinophilia

 CXR : bilateral patchy infiltration

 Cessation of the medication or treatment with corticosteroid therapy

 results is resolution of symptoms and radiographic abnormalities
for most patients

 In rare situations, the outcome is fatal