A 42 - year - old male is admitted to your intensive care day 4 post induction chemotherapy for acute promyelocytic leukemia (AML - M3). The patient was initially treated with idarubicin and all - trans retinoic acid (ATRA). He has progressively become more dyspnoeic in the ward. A Chest X - Ray demonstrates a bilateral, diffuse pulmonary infiltrate.
Initial examination reveals:
- RR 40 breaths/min,
- SpO 2 88% on 10 L/min O 2 by face mask.
- GCS 14 (E4 M6 V4)
- Temp 38.9ºC
- HR 144 beats/min,
- BP 95/50 mmHg
Full blood count is as follows on admission:
||Normal Adult Range
|White Cell Count
||26 × 109/L
||(4.0-11.0) No differential
||22 × 109/L
Comment: Blasts visible.
Suggest a differential diagnosis.
Some candidates gave a limited differential for respiratory failure in this patient, focussing on infective causes only, and some mentioned graft versus host disease although the patient had not had a bone marrow transplant.
The stem of this viva is virtually identical to Question 4 from the second paper of 2015, which also asked for differential diagnosis of this respiratory failure, and then went on to ask for "major issues", which - judging by the college answer - were hypoxia, sepsis, prognosis from AML and "other".
Suggest a differential diagnosis.
- Pulmonary haemorrhage
- Cardiogenic pulonary oedema
- Infiltrative neoplasm
- Idiopathic pneumonia syndrome
- Eosinophilic pneumonitis
- Alveolar haemorrhage
- Goodpastures (haemorrhagic)
- Rheumatoid pneumonitis
- Graft vs host disease in BMT
- Engraftment syndrome
- ATRA syndrome
- Bilateral atelectasis
- Pulmonary contusions
- Chemical pneumonitis
ATRA syndrome is listed above (see the 2008 paper by Patatanian and Thompson). A good article from CHEST (Shorr et al, 2004) is a fine resource when it comes to researching further differentials.
What are the major issues in this scenario?
- Airway: The need to avoid intubation
- Respiratory: Hypoxic respiratory failure
- Circulatory: Haemodynamic instability: likely, septic shock (HR 144, BP 95/50)
- Neuro: A decreased level of consciousness (GCS 14)
- Haematological: anaemia, thrombocytopenia, likely neutropenia, and coagulopathy.
- Infectious: High fever (38.9°C) and raised WCC (26)
- Definitive diagnosis: cause of respiratory failure is uncertain
- Social: prognosis and family understanding of the situation, medical consensus
All of these suggested answers were derived directly from Question 4 from the second paper of 2014, partly because this author is lazy, but also partly because this likely represents the true trend in CICM viva writing. They are also legitimate questions. The management answer alone might take up several minutes of discussion.
For lack of any better thoughts, the rest of this viva is concerned wth the management of ventilation in the neutropenic host.
How will you manage this respiratory failure?
Specific respiratory management:
- Commence CPAP NIV
- Aim for SpO2 >90%, PaO2 > 60mmHg
- Breaks every 2 hours for chest physiotherapy (on high flow nasal prongs)
- Ensure humidified circuit
- Ensure frequent cough; encourage expectoration of sputum
Specific circulatory management:
- Assess for fluid responsiveness using dynamic parameters
- If fluid responsive, resuscitate with 20% albumin
- Also transfuse platelets to prepare for CVC insertion
- Reverse coagulopathy with Vitamin K
- If fluid resuscitation is ineffective, maintain MAP >65 with noradrenaline
- Consider stress dose steroids (unless steroids are already being given)
Empiric antimicrobial therapy:
- Fungal cover with voriconazole or caspofungin
- PJP cover with Bactrim
- Viral cover with aciclovir
- Atypical cover with azithromycin
- Gram negative and anaerobe cover with meropenem
- Gram-positive cover with vancomycin
- Keep patient fasted (nil by mouth) in the event intubation is required
- Assess prognosis with team
- Assess family understanding of the situation
- Ensure analgesia is available (mucositis is likely)
- Blood and sputum cultures
- Atypical pneumonia serology
- Urinary legionella and pneumococcal antigens
- Sputum culture
- TTE to exclude the contribution of cardiac failure to shock and hypoxia
- Discussion with haematology team regarding the use of high dose steroids for ATRA syndrome (10mg bd of dexamethasone for 3 days, or addition of cytarabine to the chemotherapy cocktail to suppress the bone marrow).
What are the advantages and disadvantages of NIV as compared to intubaiton in this scenario?
Disadvantages of intubation/ventilation:
- Invasive ventilation is associated with poorer outcomes.
- This is perhaps because of the increased risk of nosocomial pneumonia and poorer secretion clearance
- Data in support of NIV actually compares it to standard oxygen instead of mechanical ventilation
- There is no mortality benefit with NIV at 28 days (Lemiale et al, 2015)
- Using NIV to delay intubation may actually increase mortality (by delaying an essential therapy)
- If the patient requries intubation for increasing work of breathing or poor gas exchange, intubation should be offered (i.e. no different to any other case)
Blood and sputum gram stains come back positive for hyphae. How does this narrow your range of differential diagnoses?
Adding hyphae is supposed to make the candidate think of fungus. Specifically, Aspergillus.
The list of possible culprits produced by any given candidate will not be long. Possible options consist of
- Aspergillus fumigatus
- Acremonium strictum
- Coccidioides immites
What other features are normally associated with aspergillosis?
Confirmatory testing for aspergillus has been asked about in Question 9 from the second paper of 2014. Specific features:
- Radiological features
- Pulmonary nodule on CXR
- A "halo" of ground-glass opacity surrounds the nodules on CT
- Wedge-like haemorrhagic pulmonary infarcts
- Air crescents following resolution (necrotic lung separating from the rest of the parenchyma)
- Pulmonary clinical features:
- Extrapulmonary involvement:
- Laboratory testing:
- Elevated serum IgE
- Aspergillus PCR on BAL
- Aspergillus galactomannan (blood, BAL)
- Aspergillus hyphae identified on microscopy (gold standard)
The hyphae are identified as Aspergillus fumigatus and the serum galactomannan is positive. Does this confirm that the patient's respiratory failure is due to aspergillosis?
The major issues to discuss there need to be the limitations of sputum microscopy and the serum galactomannan test.
- Sputum samples cannot discriminate among those who have invasive aspergillosis and those who are merely colonised.
- The meaning of expectorated sputum samples is questionable
- Galactomannan test can return false positives - it is a ubiquitous organic molecule, and can be found everywhere, including in ice cream(as a texture stabiliser). Sensitivity is 71% and specificity is 89% according to a 2006 meta-analysis.Causes of confused results include:
The haematology team wish to commence antifungal therapy. What are the treatment options for invasive pulmonary aspergillosis?
The Sanford Guide recommends the following:
- Voriconazole (loading dose of 6mg/kg, followed by 4mg/kg)
- Amphotericin B
After 10 days of treatment, no further hyphae are seen on sputum microscopy.
The patient remains pancytopenic. Chest xray appearance has not improved and gas exchange remains poor. How would you investigate the cause of this failure to progress?
This is now turning into a viva about the investigation of a non-resolving pneumonia in a neutropenic patient. The list of differentials remains broad.
Possible investigations for non-resolving pneumonia in an immunocompetent host were asked about in Question 7 from the second paper of 2012. Such investigations could be listed as follows:
- High-resolution CT
- Bronchoalveolar lavage, with culture, gram stain, PCR for atypical bacterial fungal and viral pathogens
- Serology for atypical bacterial fungal and viral pathogens
- Investigations to explain ongoing immune compromise, i.e. bone marrow biopsy
- Bronchoscopy for sampling
- Lung biopsy if other diagnostic modalities fail to yield an answer
What are the pros and cons of lung biopsy in this scenario?
- Diagnosis cannot be established by less invasive means
- The lung disease is not responding to the current management
- Management for the differentials is substantially different (eg. COP - steroids, bacterial pneumonia- more antibiotics)
- Prognosis will be influenced by tissue diagnosis, and may be grounds for a palliative course of management
- Increased risk of bleeding (pancytopenic patient)
- High likelihood of negative result this late in the disease process: this now follows a ten-day course of illness, so likely the sample will contain only fibrosed or necrotic tissue). A retrospective series by Lim et al (2007) reported that in 64% changes to management occurred, and that those who were biopsied earlier (within 1 week of intubation) did better in terms of mortality (63% survival vs 11%).
- High risk of procedure (already the patient has severe respiratory failure - a pneumothorax or bronchopleural fistula will be disastrous)
- The result may not change management (i.e. the antibiotics spectrum is already massively broadened, and the only possible addition is a course of steroids)