Question 18

Last updated 27/11/2021 - 17:00
 Topic: Haematology and Oncology
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The following blood tests are obtained for a newly admitted patient in the ICU, who is intubated and mechanically ventilated.

Parameter Patient Value Adult Normal Range
FiO2 0.5  
pH 7.17* 7.35 – 7.45
pO2 93 mmHg (12.2 kPa)  
pCO2 40.0 mmHg (5.2 kPa)     35.0 – 45.0 (4.6 – 6.0)
SpO2 95%  
Bicarbonate 14.0 mmol/L* 22.0 – 26.0
Base Excess -13.8 mmol/L* -2.0 – +2.0
Lactate 1.4 mmol/L 0.5 – 1.6
Glucose 7.3 mmol/L* 3.5 – 6.0
     
Parameter Patient Value Adult Normal Range
Sodium 129 mmol/L* 135 – 145
Potassium 5.5 mmol/L* 3.5 – 5.0
Chloride 96 mmol/L 95 – 105
Bicarbonate 14.0 mmol/L* 22.0 – 26.0
Urea 16.3 mmol/L* 3.0 – 8.0
Creatinine 659 μmol/L* 45 – 90
Albumin 27 g/L* 35 – 50
Protein 45 g/L* 60 – 80
Total bilirubin 148 μmol/L* < 26
Aspartate transferase 1,945 U/L* < 35
Alanine transferase 1,218 U/L* < 35
Alkaline phosphatase 43 U/L 30 – 110
g-Glutamyl transferase     68 U/L* < 40
Ionised calcium 0.97 mmol/L* 1.10 – 1.35
Phosphate 1.11 mmol/L 0.80 – 1.50
Ferritin 181,900 mg/L* 30 – 400
Parameter Patient Value Adult Normal Range
Haemoglobin 132 g/L 120 – 160
White Cell Count 5.2 x 109/L 4.0 – 11.0
Platelet count 24 x 109/L* 150 – 350
     
Parameter Patient Value      Adult Normal Range
Prothrombin time      20.0 sec* 12.0 – 16.5
INR 1.8* 0.9 – 1.3
APTT 77.0 sec* 27.0 – 38.5
Fibrinogen 0.7 g/L* 2.0 – 4.0
D-Dimer 66.7 mg/L* < 0.5

a)    List the abnormalities.    (60% marks)

b)    List the most likely diagnosis.    (10% marks)

c)    List appropriate further investigations, and the initial specific pharmacological treatments of this condition.    (30% marks)
 

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College answer

Not available.

Discussion

Let's go through his systematically:

  1. The A-a gradient is markedly raised:
    PAO2 = (0.5 × 713) - (43× 1.25) = 306.5
    Thus, A-a = (306.5 - 93) = 213.5 mmHg.
  2. There is acidaemia.
  3. The PaCO2 is completely normal, which is unexpected considering the pH.
  4. The SBE is -13.8, suggesting a metabolic acidosis. The bicarbonate is 14.
  5. There is no attempt to compensate; the expected CO2 is (40 - 13.8) = 26.2, or (1.5 × 14) + 8 = 29 mmHg. Thus, there is a respiratory acidosis as well.
  6. The anion gap is modestly raised:
    129-(96+14) = 19. 
  7. The delta ratio is:
    (19-12)/(24-14) = 0.7 i.e. this is a mixed HAGMA and NAGMA.

So, there's a triple disorder: a respiratory acidosis, as well as a mixed high and normal anion gap metabolic acidosis. Also:

  • Hyponatremia, which is mild
  • Hyperkalemia, which is pretty trivial
  • Urea and creatinine are raised, creatinine more so - the ratio suggests that the failure is not due to pre-renal causes
  • Albumin is slightly low
  • Total protein is also slightly low
  • The bilirubin is markedly elevated
  • The LFTs are deranged, with a "transaminitis" - this suggests some sort of hepatotoxicity
  • The ionised calcium is low
  • Phosphate is not elevated, which is unexpected given the severity of renal dysfunction
  • Of the haematology, only the platelet lineage is markedly depressed (24)
  • There's a coagulopathy which suggests consumption of factors, with a very raised D-dimer and increased INR and APTT. Something seems to be eating up all the fibrinogen.
  • The ferritin is vastly, ridiculously elevated. In fact, the number is so large ... and so distinct... that an attentive reader may find it looks a little familiar. That's right, it's the same ferritin value as was used in Question 24.1 from the first paper of 2020.

That's right, this question is a basically unchanged version of Question 24.1, except the stem in 2020 had read, "A previously well 24-year-old male presents with fevers, malaise and jaundice. Microbiological cultures are negative, and despite treatment with broad spectrum antibiotics he continues to deteriorate." This time, the examiners have removed this history from the stem, perhaps because one could make the potent argument that with a ferritin of almost 200,000, there's really nothing else this could be.

b) This is haemophagocytic syndrome, or haemophagocytic lymphohstiocytosis (HLH).

c)  

Appropriate further investigations would have to include some additional tests, as what results we have been given do not yet fit the diagnostic criteria for HLH. From Henter et al (2004),

The diagnosis of HLH can be established if Criterion 1 or 2 is fulfilled.
1. A molecular diagnosis consistent with HLH 
2. Diagnostic criteria for HLH fulfilled (5 of the 8 criteria below) 
 Fever 
 Splenomegaly 
 Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood) 
  Hemoglobin <90 g/L (hemoglobin <100 g/L in infants <4 wk) 
  Platelets <100 × 109/L 
  Neutrophils <1.0 × 109/L 
 Hypertriglyceridemia and/or hypofibrinogenemia 
  Fasting triglycerides ≥3.0 mmol/L (ie, ≥265 mg/dL) 
  Fibrinogen ≤1.5 g/L 
 Hemophagocytosis in bone marrow or spleen or lymph nodes. No evidence of malignancy. 
 Low or no NK cell activity (according to local laboratory reference) 
 Ferritin ≥500 μg/L 
 sCD25 (ie, soluble IL-2 receptor) ≥2400 U/mL 

So, we don't have a molecular diagnosis, and zero history (so we can't confirm fever or splenomegaly). We do have low platelets, low fibrinogen, and raised ferritin. We need a few more criteria to be satisfied. Thus, the tests we need to send are as follows:

  • Serum triglycerides
  • NK cell count
  • Serum sCD25 level
  • Bone marrow or lymph node biopsy

Initial specific pharmacological treatments, from La Rosée et al (2019):

  • High dose dexamethasone: start with 10mg/m2 BSA, so about 17-20mg/d
  • Etoposide 150mg/m2 BSA (so, 250-300mg)- this is a podophylootoxin derivative which tends to target T cells and macrophages; the aim is to abort the cytokine storm
  • Two weeks later, start cyclosporin A and methotrexate; mainly to prevent relapse
  • Etoposide and pulsed dexamethasone will need to continue until the precipitating cause of the HLH has subsided, or until the patient gets a bone marrow transplant.

References

Henter, Jan‐Inge, et al. "HLH‐2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis." Pediatric blood & cancer 48.2 (2007): 124-131.

La Rosée, Paul, et al. "Recommendations for the management of hemophagocytic lymphohistiocytosis in adults." Blood, The Journal of the American Society of Hematology 133.23 (2019): 2465-2477.

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