Case Presentations 2

Case Presentations

Gamal Rabie Agmy ,MD ,FCCP

Professor of Chest Diseases, Assiut University

Case No. 4

• A 48-year-old woman is referred to you with chest heaviness and shortness of breath on exertion.

• She was recently investigated by a cardiologist who concluded her symptoms were noncardiac in origin after a normal angiogram.

• She has also noticed increasing fatigue for the past 6 months. She mentions she works in a stressful environment as a critical care nurse. She denies any associated wheezing, cough, nocturnal symptoms, radiation of chest discomfort, palpitations, or syncope.

• Her symptoms were not relieved with nitroglycerin spray. Her history is otherwise negative, she is a lifelong nonsmoker, and she is on no medications.

• Physical examination results are normal.

Pulmonary Function Test Results

• A methacholine challenge test:

Demonstrates a PC20 (percent concentration associated with a 20% fall in the FEV1) of 6.00 mg/mL.

Her symptoms were not reproduced during the methacholine challenge test.

• The patient underwent cardiopulmonary exercise testing, revealing the following data:

Cardiopulmonary Exercise Test Results

• There were no arrhythmias, significant ST segment, or T-wave changes.

• The patient reported discontinuing exercise because of shortness of breath.

• Spirometry performed immediately following exercise was done.

Results of Spirometry After Exercise

The results from these investigations are most consistent with which of the following?

• A. Exercise-induced bronchoconstriction (EIB).

• B. Deconditioning.

• C. Vocal cord dysfunction.

• D. Primary hyperventilation syndrome

• This patient has shortness of breath and chest discomfort with exertion in the setting of normal pulmonary function and a negative result of a methacholine challenge test.

• Cardiopulmonary exercise testing reveals normal performance and values, except for a 15% decrease in the FEV1 immediately following exercise, consistent with a diagnosis of EIB (choice A is correct).

• Exercise testing shows normal aerobic and work capacity with no significantly abnormal cardiac or respiratory responses (choice B is incorrect).

• While the patient works in a stressful occupation, there are no findings consistent with primary hyperventilation syndrome such as an erratic breathing pattern and hyperventilation, which is excessive for the simultaneous metabolic load (choice D is incorrect).

• Examination of the exercise tidal flow-volume curves, both at rest and with exercise, does not reveal any changes consistent with central airway obstruction (choice C is incorrect).

• Exercise associated airway narrowing occurs in the majority of patients with asthma. Although patients often deny or do not recognize other symptoms of asthma, these symptoms can often be detected with a careful clinical history.

• It is important to understand the diagnosis of EIB is not excluded by a negative result of a methacholine challenge test, although it is most commonly positive in this clinical setting. In this instance, the patient underwent cardiopulmonary exercise testing to objectively understand the patient’s symptoms of activity limitation, which was normal, as the patient demonstrated normal work and aerobic capacity.

• However, spirometry following exercise did reveal a significant decrement in the FEV1, which responded to the administration of a bronchodilator. Not mentioned is that the patient’s symptoms were also reproduced immediately following exercise. These findings confirm the diagnosis of EIB, although if these results were not demonstrated and clinical suspicion for EIB remained, a more specific EIB exercise protocol would have been indicated

• This typically consists of high intensity exercise on a treadmill or bicycle ergometer of 6 to 8 min duration intended to rapidly achieve the highest possible level of ventilation for 4 to 6 min. There should not be a significant warm-up period, which may lead to tolerance or refractoriness to EIB. This can also occur if exercise duration exceeds 12 min.

• A fall in the FEV1 of 10% or more is interpreted as abnormal, while a 15% or more fall is considered to be diagnostic. An appropriate post exercise testing schedule is 1, 3, 5, 10, 15, 20, and 30 min after cessation of exercise, although if the FEV1 has returned from its nadir to the baseline level or greater, spirometry testing may be terminated at 20 min post exercise.

• These bronchoconstriction responses may also occasionally be demonstrated with eucapnic voluntary hyperventilation or cold air challenge. While a positive response (ie, a fall in the FEV1) may also be seen in patients with upper airway obstruction or vocal cord dysfunction, the cases can be readily distinguished from EIB by examination of the exercise tidal flow-volume curves

So the finial diagnosis is

• A. Exercise-induced bronchoconstriction (EIB).

• B. Deconditioning.

• C. Vocal cord dysfunction.

• D. Primary hyperventilation syndrome

• Exercise testing shows normal aerobic and work capacity with no significantly abnormal cardiac or respiratory responses (choice B is incorrect).

• While the patient works in a stressful occupation, there are no findings consistent with primary hyperventilation syndrome such as an erratic breathing pattern and hyperventilation, which is excessive for the simultaneous metabolic load (choice D is incorrect).

• Examination of the exercise tidal flow-volume curves, both at rest and with exercise, does not reveal any changes consistent with central airway obstruction (choice C is incorrect).

Case No. 5

• A 74-year-old man with a history of mild COPD has a 3-month history of worsening dyspnea on exertion.

• He was seen by his primary care provider 3 weeks ago, diagnosed with a COPD exacerbation, and received a 5-day course of azithromycin that did not provide much relief.

• He now notes a nonproductive cough and intermittent low-grade fevers.

• He has no other medical problems and takes no regular medications. He smoked 1 pack of cigarettes a day for 30 years but quit 25 years ago.

• He denies taking any over-the-counter medications or supplements.

• He has no pets or other unusual exposures, and he has not travelled out of the United States

• Vital signs on admission are only remarkable for a temperature of 37.9C and an oxygen saturation of 89% on 4 L/min nasal cannula.

• Physical examination is notable for diffuse inspiratory crackles.

• There is no clubbing, cyanosis, or edema.

His chest radiograph:

• A CBC reveals a WBC count of 12,300/L (12.3 × 109/L) with 55% neutrophils, 3% bands, 30% lymphocytes, 4% monos, and 8% eosinophils; hemoglobin level of 14.2 g/dL (142 g/L); and a platelet count of 223 × 103/L (223 × 109/L). His electrolyte levels are normal.

• His erythrocyte sedimentation rate (ESR) is 52 mm/h.

• C-reactive protein level is 8.2 mg/L (78.1 nmol/L)

• Serum IgE level is not markedly elevated.

• Total eosinophil count is 400/L (0.400 × 109/L).

• Cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) findings are negative.

• Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) findings are positive at 1:80.

• He is admitted to the hospital and started on a regimen of broad-spectrum antibiotics.

• Over the next 3 days, his symptoms and radiograph worsen, and IV methylprednisolone, 60 mg tid is added.

A CT scan of the chest is obtained

• A bronchoscopy is performed and is nondiagnostic; no organisms are seen and there are no eosinophils on cell count.

• His oxygen requirement remains high and a thoracoscopic lung biopsy is performed

What is your diagnosis?

• A. Acute interstitial pneumonia (AIP).

• B. Cryptogenic organizing pneumonia (COP).

• C. Nonspecific interstitial pneumonia (NSIP).

• D. Chronic eosinophilic pneumonia (CEP).

• This patient’s clinical history and imaging could be consistent with any of the diagnoses listed above.

• The lung biopsy specimen, however, reveals a uniform temporal appearance with preservation of the lung architecture. • There is fibroblastic tissue within the alveolar airspace

and the lumina of the respiratory bronchioles without evidence of vasculitis or granuloma formation. These changes are classic for COP (choice B is correct).

• This organizing pneumonia pattern can be secondary to collagen vascular disease, infection, or drug reactions.

• When the cause is not known, the term cryptogenic organizing pneumonia is used. Although this patient may have had an infection early in his course, nothing could be identified after thorough evaluation in the hospital

• Patients with COP often present with a subacute illness, typically complaining of cough and dyspnea.

• Systemic symptoms such as fever, night sweats, and weight loss are common.

• Examination of the lungs will typically reveal crackles. Laboratory findings include an elevated ESR and C-reactive protein.

• Chest radiographs will reveal diffuse, patchy opacities, typically in the subpleural or lower lung fields.

• CT scan features include ground-glass attenuation and consolidation, which is either peribronchial or subpleural, as in this patient. Although relapses and chronic fibrosis can occur, most patients will recover after receiving a course of oral corticosteroids

• As mentioned above, the radiographic features of this case are not specific, and the pattern seen could also be consistent with AIP, NSIP, and given the subpleural predominance, CEP.

• The pathologic features, however, are distinctive. The hallmark pathologic finding in AIP is diffuse alveolar damage, with alveolar wall thickening, airspacem filling with proteinaceous exudates, and hyaline membranes along the airways. None of these features is present in this patient (choice A is incorrect).

• Classic features of CEP (interstitial and alveolar eosinophils, interstitial fibrosis, and eosinophilic microabscesses) are also absent (choice D is incorrect).

• NSIP is histologically characterized by interstitial inflammation and fibrosis that is temporally uniform without specific features that allow the identification of other idiopathic pneumonias, such as the temporal heterogeneity and prominent honeycombing of usual interstitial pneumonia or the numerous alveolar macrophages of desquamative interstitial pneumonitis and respiratory bronchiolitis-associated interstitial lung disease. Although small foci of organizing pneumonia can be seen, this is not the dominant feature (choice C is incorrect).

Idiopathic Interstitial Pneumonias

Gamal Rabie Agmy ,MD ,FCCP

Professor of Chest Diseases, Assiut University

Idiopathic Interstitial

Pneumonias

7 histological categories

• Usual interstitial pneumonia (UIP)

• Nonspecific interstitial pneumonia (NSIP)

• Organising pneumonia (OP)*

• Diffuse alveolar damage (DAD)

• Desquamative interstitial pneumonia (DIP)**

• Respiratory bronchiolitis (RB)

• Lymphocytic interstitial pneumonia (LIP)

* previously BOOP

** previously AMP

Correlation with HRCT patterns

7 clinical-radiological-pathological categories

ATS/ERS International Multidisciplinary Consensus Classification of the

Idiopathic Interstitial Pneumonias, AJRCCM Vol 165. pp 277-304, 2002

UIP

+ NSIP

+ OP

+ DAD

+

DIP

+ RB

+

LIP

+

=

IPF

=

NSIP =

COP

=

AIP =

DIP

=

RB-ILD =

LIP

Histology:

• Heterogeneous appearance

ü(hardly any inflammation)

• Temporal heterogeneity

Old + new fibrosis (fibroblastic foci)

IPF/UIP „disease status‟

Non-specific interstitial pneumonia ‟IIP-NSIP cellular / fibrotic variant‟

• temporal uniformity on biopsy

• no / few fibroblastic foci

• fine reticulation

• ground glass

Cryptogenic organising

pneumonia

(BOOP)

• patchy consolidations (95%)

• perilobular opacity (50%)

Ujita, Radiology 2004; 232: 757-61

Congestion & oedema

Exudative phase

Acute interstitial

pneumonia

acute onset, with systemic features: idiopathic ARDS

granulocytes + occasional lymphocytes; debris

survival from diagnosis often days despite mechanical support

Desquamative interstitial pneumonia (AMP)

smoker

BAL: AM+++N+E+L

Respiratory bronchiolitis

associated interstitial lung disease

cigarette smoker

obstructive or restrictive lung function

AM with smoker’s inclusions on BAL

LIP Lymphocytic interstitial

pneumonia

AIDS

lymphoproliferative

rheumatological

idiopathic (rare)

lymphocytes on BAL

Scenario 1: HRCT appearances are

pathognomonic

To be useful in the routine diagnosis of IIP, a test MUST be

good at diagnosing IPF

IPF/usual interstitial pneumonia

Key conclusion

• Typical HRCT features of IPF in association with a compatible clinical profile obviate surgical biopsy

BUT

• Atypical features on HRCT for IPF do NOT exclude the diagnosis

Scenario 2: HRCT and clinical features

are, together, diagnostic

RBILD

• Exaggerated form of smoking-related respiratory bronchiolitis

• Generally benign/self limited vs survival

• Significant symptoms/functional impairment

• Is a thoracoscopic biopsy necessary to make the diagnosis?

RBILD vs HP

Ask the patient!

BAL: lymphocytosis vs

pigmented macrophages

Key conclusion

The combination of HRCT, smoking and exposure history and BAL allows most RBILD patients to be diagnosed

non-invasively

Scenario 3: Diagnoses in which a

biopsy is required

Is an HRCT diagnosis of NSIP

inherently invalid?

The key concept of NSIP sub-groups

“If my pathologist tells me the biopsy shows NSIP, then my job has only just begun”

Scenario 4: Clinico-radiologic sub-groups

• Clinical features of IPF, HRCT overlap….

• Organizing pneumonia variant

• HP variant

• Connective tissue disease

• Post diffuse alveolar damage

• Smoking related?

The OP variant of NSIP

Nagai S. Eur Respir J 1998; 12:1010-1019

Kim TS. AJR 1998; 171:1645-1650.

Consolidation a prominent feature on CT (admixed with ground-glass/reticular elements)

A component of organizing pneumonia (<10%) often present at biopsy

The concept of “fibrosing organizing

pneumonia”

Does this equate with the “OP variant” of NSIP?

NSIP presenting with the clinical

features of IPF

• A rather different HRCT profile (compared to the organizing pneumonia variant)

• Organizing pneumonia, nodules not present on HRCT

• Predominant findings are ground-glass attenuation, fine reticulation, traction bronchiectasis

NSIP presenting with the clinical

features of IPF

• A rather different HRCT profile (compared to the organizing pneumonia variant)

• Organizing pneumonia, nodules not present on HRCT

• Predominant findings are ground-glass attenuation, fine reticulation, traction bronchiectasis

Key conclusion

NSIP should be separated into clinico-radiologic sub-groups.

Typical COP

• HRCT is often less discriminatory (vis a vis diagnosis) than serial chest radiography

• Evanescent (“immunological disorders”) versus fixed consolidation (alveolar cell cancer, non-bacterial infection)

• HRCT valuable in disclosing fibrosing variants

Lee JS. JCAT 2003; 27:260-265.

• 26 patients with histopathologic diagnosis of organizing pneumonia (“BOOP”)

• Persistent or progressive disease on HRCT despite treatment in 35%

• Predominant consolidation/nodules = good outcome

• Reticular abnormalities on HRCT = bad outcome

11-99

08-00

02-2001

Key conclusion

The greatest utility of HRCT in COP is to identify patients progressing or more

likely to progress to fibrosis

Scenario 5: Prognosis based on

reconciling HRCT and biopsy

Fibrotic NSIP

NSIP…. or is it really UIP?

UIP

Scenario 6: Prognosis based on

reconciling baseline data and disease

behaviour

Essentially, biopsy and HRCT are “silver standards” against the true clinical “gold standard” of disease

behaviour/ outcome

The real utility of the ATS/ERS

classification……….

What clinicians need from a

classification….

• Captures clusters of disease behaviour

• Articulates logical therapeutic goals

• Makes approach to monitoring obvious

This can be achieved

A classification based on pragmatic

management ...

• Cause

• Predominant morphologic abnormality

• Severity

• Longitudinal behaviour

Integrate these

Self-limited inflammation

• Examples: hypersensitivity pneumonitis, sarcoidosis, drug-induced lung disease

• Outcome good

• Avoidance of antigen, where applicable, crucial

• Repeated attempts to limit treatment justified

• Monitor to confirm disease regression

Stable/indolent fibrotic disease

• Diagnosis often incidental: CTD, hypersensitivity pneumonitis, sarcoidosis

• Key is not to over-react

• Management: MICO therapy…..

• Monitor to confirm disease stability

“Indolent disease”

MICO:

Masterful Inactivity

with Cat-like Observation

The role of the doctor is to amuse the patient while nature takes its course

(Voltaire)

Major inflammation with variable

fibrosis

• Severe sarcoidosis, hypersensitivity pneumonitis, drug-induced lung disease

• Key is distinguishing these cases from extensive irreversible fibrotic disease

• Essential to treat vigorously

• Monitor early to establish best treated PFT and later to exclude relapse

Inexorably progressive fibrosis

• Sarcoidosis, hypersensitivity pneumonitis

• Key to management is to find the right balance between slowing progression and poisoning the patient

• Monitor to evaluate rate of progression

Explosive ILD

• Sudden onset of disease. Idiopathic, “cryptogenic fibrosing alveolitis”

• Often life-threatening

• Exact diagnosis usually uncertain

• Key issue: biopsy on ventilator?

• Policy of “treat the treatable”

• Very stressful for doctors, patients and relatives

We investigate to distinguish between…….

• Self-limited inflammation

• Stable fibrotic disease

• Major inflammation with variable fibrosis

• Inexorably progressive fibrosis

• Explosive ILD

What clinicians need from a

classification….

• Captures clusters of disease behaviour

• Articulates logical therapeutic goals

• Makes approach to monitoring obvious

Self-limited inflammation

RBILD

Stable/indolent fibrotic disease

Fibrotic NSIP

Major inflammation with

variable fibrosis

DIP COP

Inexorably progressive fibrosis

UIP

Explosive ILD

AIP, accelerated UIP

Conclusions: useful points for

clinicians (1)

• Biopsy is no longer the diagnostic gold standard

• Diagnosis of IIP is now multidisciplinary

• IPF can be diagnosed on HRCT in the majority of cases but a crucial sub-group have very atypical HRCT appearances

• RBILD can be diagnosed using a combination of clinical and HRCT data

• DIP and NSIP require a biopsy for diagnosis

Conclusions : useful points for

clinicians (2)

• NSIP should be classified according to the disease it most closely represents

• In a small OP subset, there is progression to inexorable fibrosis

• Prognosis is based upon the reconciliation of HRCT, biopsy and clinical data

• A simple pragmatic clinical classification underlies best management

• Biopsy when these key clinical distinctions are blurred

Case No. 6

• You are called to suggest additional therapeutic options after a patient just underwent a diagnostic and therapeutic thoracentesis.

• The patient is a 65-year-old man with a long-standing left pleural effusion.

• The patient has had thoracentesis for the effusion on several occasions over the last year.

• The most recent pleural fluid values from 6 weeks ago include:

A protein level of 2.9 g/dL (29.0 g/L),

Lactate dehydrogenase (LDH) level of 124 U/L (2.1 kat/L) (serum: 220 U/L, 3.7 kat/L), and

pH of 7.34.

All culture results and cytologic evaluations have been negative

• The patient notes that he is able to perform his daily activities without difficulty.

• He notes only a mild increase in dyspnea on exertion over the last year while climbing stairs; he notes no other respiratory symptoms.

• His past medical history includes hypertension and dyslipidemia, both well controlled with medications.

• He had three-vessel coronary artery bypass grafting 2½ years ago and currently has no anginal symptoms.

• His most recent echocardiogram 4 months ago shows good left ventricular function, with an ejection fraction of 50%.

• After today’s thoracentesis, he notes no new symptoms specifically, also noting that he has no shortness of breath or chest discomfort.

• The consulting physician has obtained a postthoracentesis chest radiograph

CT scan of the chest

• Upon review of prior chest radiographs postthoracentesis, findings are similar to the current radiograph; similarly, a prior CT scan postthoracentesis 4 months ago has findings similar to the current CT scan.

• Pleural fluid values now available include a WBC count of 986/mm3 (0.986 × 109/L), protein level of 2.8 g/dL (28.0 g/L), and LDH level of 80 U/L (1.3 kat/L) (serum: 140 U/L [2.3 kat/L]).

Which is the most appropriate therapeutic approach for this patient?

• Place two 32F chest tubes, apply 20 cm of water suction to each.

• B. Consult surgery to perform a decortication.

• C. Start indomethacin.

• D. No specific treatment, monitor.

• This patient has a chronic stable and nearly asymptomatic pleural effusion with a thickened visceral pleural surface seen both on the chest radiograph (best seen at the apex) and the CT scan, compatible with a diagnosis of a trapped lung.

• The space between the thickened visceral pleural surface and the parietal pleura (chest wall) could represent a pneumothorax ex vacuo, but does not reflect lung injury during thoracentesis with consequent air entry into the pleural space (iatrogenic pneumothorax).

• Given the patient’s nearly asymptomatic state, no specific treatment is warranted (choice D is correct). The incidence of trapped lung is unknown but likely higher than recognized.

• Events producing initial pleural inflammation such as pneumonia, including with empyema; hemothorax; or prior thoracic surgery, including coronary artery bypass grafting (CABG), as in this patient, precede the development of a trapped lung and usually have an accompanying exudative effusion.

•

• The lung may first become “entrapped,” demonstrating limited reexpansion and an active pleural inflammatory process.

• At this stage, therapy is directed at the active process. As the inflammatory process becomes temporally remote, if the visceral pleural fibrosis (fibrous pleural peel) does not resolve, the lung becomes trapped and will not fully re-expand.

• Pleural fluid fills the space between the lung and parietal pleura.

• In one series, the most common cause out of 11 cases of trapped lung was coronary artery bypass graft (CABG), with the other causes found to be uremia, thoracic radiation, pericardiectomy, and complicated parapneumonic effusion

• Pleural fluid analysis from patients with a trapped lung often reveals borderline exudative values, with one series noting a mean pleural fluid pH of 7.30, LDH level of 124 U/L (2.1 kat/L), and protein level of 2.9 g/dL (29 g/L).

• The fluid is paucicellular with a mononuclear cell predominance, including an elevated lymphocyte percentage ( 50%) in most patients.

• Pleural manometry usually shows an initial negative pleural pressure with a rapid and steep decline in pleural pressure as fluid is removed, reflecting the inability of the lung to re-expand.

• However, most clinicians do not perform manometry, and the diagnosis can be made by a chest radiograph or CT chest after thoracentesis, demonstrating a thickened pleural surface and an unexpanded lung, as in this patient.

• The time between the inciting pleural event (eg, CABG), chronic nature of the effusion, pleural fluid findings, and all the radiographic findings are compatible with a trapped lung, and not an entrapped lung, in this patient.

• Placement of chest tubes with application of negative pressure will not cause reexpansion of a trapped lung (choice A is incorrect).

• Indomethacin may be useful in the management of postcardiac injury syndrome (PCIS), but the clinical picture in this patient, which includes the chronic nature of this patient’s effusion and limited clinical symptoms, including no fever, make PCIS very unlikely (choice C is incorrect).

• The definitive therapy for a trapped lung is decortication to allow lung reexpansion. However, this is major surgery and should only be employed in patients with significant symptoms arising from the trapped lung (choice B is incorrect).

So the best management of this patient is

• Place two 32F chest tubes, apply 20 cm of water suction to each.

• B. Consult surgery to perform a decortication.

• C. Start indomethacin.

• D. No specific treatment, monitor.