Building the vaccine allergy flow chart

A brief blog describing how we built the flow chart for the UK Chemotherapy Board Guidance for patients with a history of allergic response who are having the coronavirus vaccine.

Calum Polwart
03-14-2021

Background

I’ve recently been doing some work with some colleagues for the UK Chemotherapy Board to create guidance for the administration of the COVID-19 vaccine to patients undergoing Systemic Anti-cancer Therapy. For version 3 of the guidance we needed to add a flow diagram to explain the choices of vaccine to be used for patients with a history of allergy and highlight the most common agents including potential cross reacting agents.

Drawing flowhcarts is easy. If everyone who is going to edit it has the same software, and sometimes the same version. Otherwise shared edits can get very messy. As I spend a lot of time in text based files like mark-down it seemed only sensible to build the diagram in a text based system. Plant UML is just such a system. This post describes how that diagram was built.

You can edit a UML file at . It turns out github will also render a UML file written in plantUML with the file extension .puml with reasonable reliability (see the note later on).

The Basic Diagram

The very first step is to define a diagram. (If like in this blog post you happen to want to render uml in R Markdown - you need to install the plantuml package in R.)

UML Diagrams in Markdown

If you are working within Markdown - you need to follow these steps, otherwise simply move to the next section and copy the code blocks to planttext.com or save them as .puml files in github.

# If you are working in R you would run these commands to
# install and load plantuml. (Once the first 2 are run you only need to run the last each time)

install.packages("devtools")
devtools::install_github("rkrug/plantuml")
require(plantuml)
plantuml_knit_engine_register()

# You can now insert a code chunk in r which uses `\`\`{plantuml} as the starting line

A basic diagram, with two choices and an action:

Diagrams start and end with @start and @endmul.

To begin a diagram with a black circle use start.

To place a decision in the diagram us if … then … else … endif

@startuml
  start
  if (a decision) then (yes)
    : Do something]
  else (no)
    : Do something else]
  endif
@endmul

We start by replacing the basic if then else model with our opening questions and actions:

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    : We will need to decide what to do]
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
  endif
@enduml

We don’t actually want to end back at a single end-point, so we should detach from the diagram when we have finished the action (e.g. given a vaccine)

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    : We will need to decide what to do]
    detach
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif
@enduml

This diagram isn’t quite right though, as we need to remember someone could have reacted to other medicines than SACT.

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    : We will need to decide what to do]
    detach
  else (No)
    if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
      :Need to decide what to do]
    else (No)
      : Offer either AstraZeneca or Pfizer Vaccine]
      detach
    endif  
  endif
@enduml

We can now add the next layer of decision. If the reaction was not serious enough to require discontinuation of the treatment, they can still have either vaccine provided they havent had other reactions.

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    if (Did reaction result in permanent discontinuation of this treatment?) then (Yes)
        : still need to decide what to do]
        detach
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
      :Need to decide what to do]
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    if (Did reaction result in permanent discontinuation of this treatment?) then (Yes)
      if (Did this treatment contain polyethylene glycol or a related molecule?) then (Yes)
        :Decide what to do]
        detach
      else (No)
        : May be OK with either. Check the other rules ! ]
      endif
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
    :Need to decide what to do]
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

Things are starting to take shape! We can add a few extra decisions around prior vaccine safety…

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    if (Did reaction result in permanent discontinuation of this treatment?) then (Yes)
      if (Did this treatment contain polyethylene glycol or a related molecule?) then (Yes)
        :Decide what to do]
        detach
      else (No)
      endif
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
          if (Has the patient had a recent Influenza Vaccine) then (Yes)
            if (Was there any systemic reaction?) then (No)
              :Offer AstraZeneca Vaccine]
              detach
            else (Yes)
              :Refer to allergy specialist]
              detach
            endif
          else (No)
            :Discuss with allergy specialist]
            detach
        endif
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

And now we can go back and answer the remaining question of what to do if you had a prior reaction to something containing PEG

@startuml
start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    if (Did reaction result in permanent discontinuation of this treatment?) then (Yes)
      if (Did this treatment contain polyethylene glycol or a related molecule?) then (Yes)
        if (Has the patient had polysorbate-80 (e.g. Docetaxel or Influenza Vaccine without systemic reaction?) then (Yes)
            :Offer AstraZeneca Vaccine]
            detach
        else (No / Unknown)
            :Refer to allergy specialist]
            detach
        endif
      else (No)
      endif
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
          if (Has the patient had a recent Influenza Vaccine) then (Yes)
            if (Was there any systemic reaction?) then (No)
              :Offer AstraZeneca Vaccine]
              detach
            else (Yes)
              :Refer to allergy specialist]
              detach
            endif
          else (No)
            :Discuss with allergy specialist]
            detach
        endif
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

The basic structure of the diagram is now complete. Lets add some cosmetic bits. skinparam will allow us to set a few settings - wrapWidth sets the maximum width of the text boxes, padding says how close boxes can get to each other and ConditionEndStyle hline will remove the diamonds when lines rejoin (saving sapce).

@startuml
skinparam wrapWidth 150
skinparam Padding 8
skinparam ConditionEndStyle hline

start
  if (Systemic hypersensitivity reaction to SACT?) then (Yes)
    if (Did reaction result in permanent discontinuation of this treatment?) then (Yes)
      if (Did this treatment contain polyethylene glycol or a related molecule?) then (Yes)
        if (Has the patient had polysorbate-80 (e.g. Docetaxel or Influenza Vaccine without systemic reaction?) then (Yes)
            :Offer AstraZeneca Vaccine]
            detach
        else (No / Unknown)
            :Refer to allergy specialist]
            detach
        endif
      else (No)
      endif
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis  to more than one class of medicine (or unexplained anaphylaxis) in the past?) then (Yes)
          if (Has the patient had a recent Influenza Vaccine) then (Yes)
            if (Was there any systemic reaction?) then (No)
              :Offer AstraZeneca Vaccine]
              detach
            else (Yes)
              :Refer to allergy specialist]
              detach
            endif
          else (No)
            :Discuss with allergy specialist]
            detach
        endif
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

The wrap command doesn’t work for decisions (? bug) so we will need to manually wrap those using \n as a new line character.

@startuml
skinparam wrapWidth 150
skinparam Padding 8
skinparam ConditionEndStyle hline

start
  if (Systemic hypersensitivity\nreaction to SACT?) then (Yes)
    if (Did reaction result in permanent\ndiscontinuation of this treatment?) then (Yes)
      if (Did this treatment contain\npolyethylene glycol\nor a related molecule?) then (Yes)
        if (Has the patient had polysorbate-80\n(e.g. Docetaxel or Influenza Vaccine\nwithout systemic reaction?) then (Yes)
            :Offer AstraZeneca Vaccine]
            detach
        else (No / Unknown)
            :Refer to allergy specialist]
            detach
        endif
      else (No)
      endif
    else (No)
    endif
  endif
  if (Has the patient has an immediate onset-anaphylaxis\n to more than one class of medicine\n(or unexplained anaphylaxis) in the past?) then (Yes)
          if (Has the patient had\na recent Influenza Vaccine) then (Yes)
            if (Was there any systemic reaction?) then (No)
              :Offer AstraZeneca Vaccine]
              detach
            else (Yes)
              :Refer to allergy specialist]
              detach
            endif
          else (No)
            :Discuss with allergy specialist]
            detach
        endif
  else (No)
    : Offer either AstraZeneca or Pfizer Vaccine]
    detach
  endif  
@enduml

We now have the basic structure of the flow chart. A note to explain which things have “peg” in them would be helpful.

@startuml

note left 
              Notes on Polyethylene glycol
              Polyethylene glycol (PEG) may appear in the medicine name (e.g. pegfilgrastim) or the excipients (see section 6.1 of SmPC).
            
              Polysorbate is related to PEG.
            
              Polyoxyl 35 castor oil is a pegylated oil.
              ....
              Common cancer treatments that contains PEG or PEG relatives:

              * Cabazitaxel (1)
              * Caelyx (Liposomal Doxorubicin) (2)
              * Docetaxel (1)
              * Lipegfilgrastim (2)
              * Most monoclonal antibodies (drugs ending -mab) (3)
              * Paclitaxel (but not Abraxane) (4)
              * Pegaspargase (2)
              * Pegfilgrastim (2)

            end note
@enduml

We obviously need to add a key to explain the numerical footnotes. (Actually during development of the diagram we tested a number of footnote methods - but settled on numerical notes as the easiest approach).

@startuml
legend   right
    Key:
    1 contains polsorbate-80 
    2 molecule has a polyethylene glycol chain attached 
    3 contains polysorbate-20
    4 contains Polyoxyl 35 castor oil
EndLegend
@enduml

We can then add some style, using a mix of CSS style and markup.

@startuml

note left #white
              **__Notes on Polyethylene glycol__**
              Polyethylene glycol (PEG) may appear in the medicine name (e.g. //peg//filgrastim) __or__ the excipients (see section 6.1 of SmPC).
            
              Polysorbate is //related// to PEG.
            
              Polyoxyl 35 castor oil is a pegylated oil.
              ....
              //Common// cancer treatments that contains PEG or PEG relatives:

              ** Cabazitaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Caelyx (Liposomal Doxorubicin) <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Docetaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Lipegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Most monoclonal antibodies (drugs ending -mab) <back:#696969>** 3 **</back></color>
              ** Paclitaxel (but not Abraxane) <color:#ffffff><back:#696969>** 4 **</back></color>
              ** Pegaspargase <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Pegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>

            end note
              
              legend   right
    **Key:**
    <color:#ffffff><back:#696969>** 1 **</back></color> contains polsorbate-80 
    <color:#ffffff><back:#696969>** 2 **</back></color> molecule has a polyethylene glycol chain attached 
    <color:#ffffff><back:#696969>** 3 **</back></color> contains polysorbate-20
    <color:#ffffff><back:#696969>** 4 **</back></color> contains Polyoxyl 35 castor oil
EndLegend
@enduml

We can then add the note and legend to the original diagram and add some markdown to the diagram.

@startuml
skinparam wrapWidth 150
skinparam Padding 8
skinparam ConditionEndStyle hline
start
If (Systemic hypersensitivity\n reaction to SACT?) then
    -> Yes;

    If (Did reaction result in permanent\ndiscontinuation of this treatment?) then
        -> Yes;

        If (Did this treatment contain\n **polyethylene glycol** \nor a //related// molecule?) then
            -> Yes;
            note left
              **__Notes on Polyethylene glycol__**
              Polyethylene glycol (PEG) may appear in the medicine name (e.g. //peg//filgrastim) __or__ the excipients (see section 6.1 of SmPC).

              Polysorbate is //related// to PEG.

              Polyoxyl 35 castor oil is a pegylated oil.
              ....
              //Common// cancer treatments that contains PEG or PEG relatives:

              ** Cabazitaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Caelyx (Liposomal Doxorubicin) <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Docetaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Lipegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Most monoclonal antibodies (drugs ending -mab) <color:#ffffff><back:#696969>** 3 **</back></color>
              ** Paclitaxel (but not Abraxane) <color:#ffffff><back:#696969>** 4 **</back></color>
              ** Pegaspargase <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Pegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>

            end note

        If (Has the patient had \npolysorbate-80 (e.g. Docetaxel<color:#ffffff><back:#696969>** 1 **</back></color>\nor Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>)\nwithout **systemic** reaction?) then
            -> Yes;   
            #LawnGreen:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
            detach

        Else (No / Unknown)
            #Red:Refer to allergy specialist]
            detach
        EndIf

    Else (No)

    EndIf

    Else(No)

    EndIf

Else(No)

EndIf
    If (Has the patient has an immediate onset-anaphylaxis\n to more than one class of medicine\n (or unexplained anaphylaxis) in the past?) then
        -> Yes;

        If (Has the patient had\n a recent Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>?) then
            -> Yes;  

            If (Was there any **systemic** reaction?) then
                -> No;  

                #LawnGreen:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
                detach

            Else (Yes)
                #Red:Refer to allergy specialist]
                detach

            EndIf

        Else (No)

            #Orange:Discuss with allergy specialist]
            detach

        EndIf

    Else (No)

            #LawnGreen:Offer either AstraZeneca or Pfizer Vaccine]
            detach
    EndIf

legend   right
    **Key:**
    <color:#ffffff><back:#696969>** 1 **</back></color> contains polsorbate-80 
    <color:#ffffff><back:#696969>** 2 **</back></color> molecule has a polyethylene glycol chain attached 
    <color:#ffffff><back:#696969>** 3 **</back></color> contains polysorbate-20
    <color:#ffffff><back:#696969>** 4 **</back></color> contains Polyoxyl 35 castor oil
EndLegend
@enduml

Finally, we have an almost complete diagram. It needs a title, and a copyright footer so that people can legitimately reproduce it in a local SOP etc. And we will add a few extra style features

@startuml
skinparam wrapWidth 150
skinparam NoteFontSize 10
skinparam LegendFontSize 10
skinparam Padding 8
skinparam ConditionEndStyle hline

Title Decision aid for selection of coronavirus vaccine in patients with\na  history of allergic reaction to Systemic Anti-Cancer Therapies (SACT)\n

start
If (Systemic hypersensitivity\n reaction to SACT?) then
    -> Yes;

    If (Did reaction result in permanent\ndiscontinuation of this treatment?) then
        -> Yes;

        If (Did this treatment contain\n **polyethylene glycol** \nor a //related// molecule?) then
            -> Yes;
            note left
              **__Notes on Polyethylene glycol__**
              Polyethylene glycol (PEG) may appear in the medicine name (e.g. //peg//filgrastim) __or__ the excipients (see section 6.1 of SmPC).

              Polysorbate is //related// to PEG.

              Polyoxyl 35 castor oil is a pegylated oil.
              ....
              //Common// cancer treatments that contains PEG or PEG relatives:

              ** Cabazitaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Caelyx (Liposomal Doxorubicin) <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Docetaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Lipegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Most monoclonal antibodies (drugs ending -mab) <color:#ffffff><back:#696969>** 3 **</back></color>
              ** Paclitaxel (but not Abraxane) <color:#ffffff><back:#696969>** 4 **</back></color>
              ** Pegaspargase <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Pegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>

            end note

        If (Has the patient had \npolysorbate-80 (e.g. Docetaxel<color:#ffffff><back:#696969>** 1 **</back></color>\nor Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>)\nwithout **systemic** reaction?) then
            -> Yes;   
            #LawnGreen:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
            detach

        Else (No / Unknown)
            #Red:Refer to allergy specialist]
            detach
        EndIf

    Else (No)

    EndIf

    Else(No)

    EndIf

Else(No)

EndIf
    If (Has the patient has an immediate onset-anaphylaxis\n to more than one class of medicine\n (or unexplained anaphylaxis) in the past?) then
        -> Yes;

        If (Has the patient had\n a recent Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>?) then
            -> Yes;  

            If (Was there any **systemic** reaction?) then
                -> No;  

                #LawnGreen:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
                detach

            Else (Yes)
                #Red:Refer to allergy specialist]
                detach

            EndIf

        Else (No)

            #Orange:Discuss with allergy specialist]
            detach

        EndIf

    Else (No)

            #LawnGreen:Offer either AstraZeneca or Pfizer Vaccine]
            detach
    EndIf

legend   right
    **Key:**
    <color:#ffffff><back:#696969>** 1 **</back></color> contains polsorbate-80 
    <color:#ffffff><back:#696969>** 2 **</back></color> molecule has a polyethylene glycol chain attached 
    <color:#ffffff><back:#696969>** 3 **</back></color> contains polysorbate-20
    <color:#ffffff><back:#696969>** 4 **</back></color> contains Polyoxyl 35 castor oil
EndLegend
@enduml

This is the figure we published in version 3 of the guidelines. Since then we have had some useful feedback and so there is a slighlty updated version. Firstly Bruce Burnett reminded us to be more colourblind friendly. On Bruce’s advice, we have removed the coloured boxes and replaced them with coloured boundaries on the boxes. And based on user feedback, we have clarified that mono-clonal antibodies could contain polysorbate 20 or 80.

@startuml
<style>
note {
  LineColor black
  FontSize 10
  }
activity {
  LineColor black
  .red {
    LineColor red
    LineThickness 5
  }
    .orange {
    LineColor orange
    LineThickness 5
  }
    .green {
    LineColor lawngreen
    LineThickness 5
    }
}
legend {
  FontSize 10
}
</style>
skinparam wrapWidth 150
skinparam Padding 8
skinparam ConditionEndStyle hline
' skinparam monochrome true
skinparam ArrowColor black


Title Decision aid for selection of coronavirus vaccine in patients with\na  history of allergic reaction to Systemic Anti-Cancer Therapies (SACT)\n
start
If (Systemic hypersensitivity\n reaction to SACT?) then
    -> Yes;

    If (Did reaction result in permanent\ndiscontinuation of this treatment?) then
        -> Yes;

        If (Did this treatment contain\n **polyethylene glycol** \nor a //related// molecule?) then
            -> Yes;
            note left #white
              **__Notes on Polyethylene glycol__**
              Polyethylene glycol (PEG) may appear in the medicine name (e.g. //peg//filgrastim) __or__ the excipients (see section 6.1 of SmPC).
            
              Polysorbate is //related// to PEG.
            
              Polyoxyl 35 castor oil is a pegylated oil.
              ....
              //Common// cancer treatments that contains PEG or PEG relatives:

              ** Cabazitaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Caelyx (Liposomal Doxorubicin) <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Docetaxel <color:#ffffff><back:#696969>** 1 **</back></color>
              ** Lipegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Most monoclonal antibodies (drugs ending -mab) <color:#ffffff><back:#696969>** 1 **</back></color><color:#ffffff>, <back:#696969>** 3 **</back></color>
              ** Paclitaxel (but not Abraxane) <color:#ffffff><back:#696969>** 4 **</back></color>
              ** Pegaspargase <color:#ffffff><back:#696969>** 2 **</back></color>
              ** Pegfilgrastim <color:#ffffff><back:#696969>** 2 **</back></color>

            end note

        If (Has the patient had \npolysorbate-80 (e.g. Docetaxel<color:#ffffff><back:#696969>** 1 **</back></color>\nor Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>)\nwithout **systemic** reaction?) then
            -> Yes;   
            <<green>>:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
            detach

        Else (No / Unknown)
            <<Red>>:Refer to allergy specialist]
            detach
        EndIf

    Else (No)

    EndIf

    Else(No)

    EndIf
    
Else(No)

EndIf
    If (Has the patient has an immediate onset-anaphylaxis\n to more than one class of medicine\n (or unexplained anaphylaxis) in the past?) then
        -> Yes;
    
        If (Has the patient had\n a recent Influenza Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>?) then
            -> Yes;  

            If (Was there any **systemic** reaction?) then
                -> No;  
                
                <<green>>:Offer AstraZeneca Vaccine<color:#ffffff><back:#696969>** 1 **</back></color>]
                detach
                
            Else (Yes)
                <<Red>>:Refer to allergy specialist]
                detach
                
            EndIf
        
        Else (No)
    
            <<Orange>>:Discuss with allergy specialist]
            detach
            
        EndIf

    Else (No)

            <<green>>:Offer either AstraZeneca or Pfizer Vaccine]
            detach
    EndIf

legend   right
    **Key:**
    <color:#ffffff><back:#696969>** 1 **</back></color> contains polsorbate-80 
    <color:#ffffff><back:#696969>** 2 **</back></color> molecule has a polyethylene glycol chain attached 
    <color:#ffffff><back:#696969>** 3 **</back></color> contains polysorbate-20
    <color:#ffffff><back:#696969>** 4 **</back></color> contains Polyoxyl 35 castor oil
EndLegend
footer 
    This work is licensed under CC BY-SA 4.0. To view a copy of this license, visit http://creativecommons.org/licenses/by-sa/4.0/.
    Please ensure you are using the most up to date version by accessing ukchemotherapyboard.org
EndFooter
@enduml

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