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\def\RunningAuthor{Shilpa Palaksha et al. }
\firstPage{4342}
\articleType{Case Report}
\receivedDate{10 Feb 2020}
\acceptedDate{14 Apr 2020}
\revisedDate{12 Mar 2020}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i3.2650}
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\title{Ketorolac induced non allergic angioedema: A case report}
\author{Chinju\textsuperscript{1},  
            Mahesh~P~A\textsuperscript{2,3}, 
            Shilpa~Palaksha\textsuperscript{*}\textsuperscript{1,3}~\\[5pt]{\textsuperscript{1}Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education \& Research, Mysuru {\textendash} 570015, India}~\\{\textsuperscript{2}Department of Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education \& Research, Mysuru {\textendash} 570015, India}~\\{\textsuperscript{3}Special Interest Group, Quality \& Safe use of Medicine, JSS Academy of Higher Education \& Research, Mysuru {\textendash} 570015, India}}

\begin{abstract}
Non- Steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed category of drugs.  NSAIDs are the main cause of allergic reactions both in adults and children. Hypersensitivity reactions due to NSAIDs involve 0.3\% to 0.5\% of the overall population. Among the different types of NSAIDs induced hypersensitivity reactions, urticaria and angioedema are the most common. Angioedema can be of two types, allergic(IgE) \& Nonallergic (Non IgE) mediated. Allergic angioedema is immune mediated but non allergic angioedema mimic immune mediated allergic reaction without underlying evidence of immunological mechanism which can cause diagnostic difficulties for the clinician. Distinguishing immune-mediated and non-immune-mediated reactions can be difficult, so careful evaluation is needed. Pathomechanism of NSAIDs induced non allergic angioedema is based on cysteniyl leukotrienes and bradykinin pathway in which NSAIDs block cyclo oxygenase pathway and directs the lipoxygenase pathway and generates leukotrienes which result in the development of angioedema. NSAIDs induced allergic angioedema is quite frequent and NSAIDs induced nonallergic angioedema  are quite rare. The detailed information of these reactions is necessary to decrease morbidity and mortality associated with the reactions. The early recognition and discontinuation of suspected drug should be done in order to avoid further complications. Here, we report a case of a patient with non allergic angioedema in association with use of Ketorolac.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Angioedema,\newline Allergic,\newline Nonallergic,\newline NSAIDs
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Shilpa~Palaksha~\\ Phone:\ ~\\  Email:\ shilpapalaksha@jssuni.edu.in
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Non- Steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed category of drugs . NSAIDs are the main cause of allergic reactions both in adults and children \unskip~\citep{761182:18099256}. Hypersensitivity reactions due to NSAIDs involve 0.3\% to 0.5\% of the overall population \unskip~\citep{761182:18099247}. Among the different types of NSAIDs induced hypersensitivity reactions, urticaria and angioedema are the most common  \unskip~\citep{761182:18099256} . Angioedema is a swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities and genitalia \unskip~\citep{761182:18099248}. Angioedema can be of two types, allergic (IgE) \& Nonallergic (Non IgE) mediated \unskip~\citep{761182:18099244}. Allergic angioedema is immune mediated but non allergic angioedema mimic immune mediated allergic reaction without underlying evidence of immunological mechanism which can cause diagnostic difficulties for the clinician \unskip~\citep{761182:18099243,761182:18099254}. Distinguishing immune-mediated and non-immune-mediated reactions can be difficult, so careful evaluation is needed \unskip~\citep{761182:18099255}.

\textbf{Case Presentation}

A 42 year-old female came with complaints of having back pain for 4 years without any comorbidities. The patient was on ayurvedic medications and was on massage therapy for relief of back pain. The patient stopped ayurvedic medications a month before opting allopathy. She was prescribed with diclofenac. She complained of only angioedema without urticaria, which was unusual. She developed angioedema without itching, which was unusual, therefore, she was prescribed with other NSAIDs like nimesulide, Ibuprofen for which she developed the same reaction. She developed 3 episodes of drug-induced reaction in one month, which was always at least 10 hours after the ingestion of the drug, which was unusual. The patient was suspected to have a drug  allergy to NSAIDs. To confirm whether she does indeed have a drug allergy, as a cause of angioedema, initially skin prick test was advised for Diclofenac and to check the cross-reactivity with other NSAIDs, it was also advised to do for paracetamol. The patient was given an informed consent form and explained orally about the skin prick test procedure, its use and side effects in the patient's local language. The procedure was carried out after obtaining a written, informed consent form. SPT was done for diclofenac and paracetamol, they are without preservatives, pure form and the concentration used were 0.5 mg/ml \& 0.2mg/ml for paracetamol \& diclofenac respectively. The patient was observed for 45 min and no weal reaction was found for paracetamol and diclofenac followed by intradermal test. SPT, when negative was followed by the Intradermal test, which was done for diclofenac using a test dose of 22.5 mg/ml, which was negative. A key option to confirm drug allergy is a controlled drug challenge. Oral drug challenge test was done using ketorolac 10 mg sublingually because the patient had never used it so far, she had a history of definite reaction to other drugs, previous clinical experience showed that some patients who did not tolerate diclofenac tolerated ketorolac and patient was monitored. The patient couldn't tolerate 50\% of 10 mg ketorolac. After 9 hours, the patient complained about throat irritation without skin rashes. Inj. Pheniramine and Inj. Betamethasone was prescribed as a stat dose to subside the reaction. The patient had shown minimal response to anti-allergic medications. This was an indication that angioedema developed due to NSAIDs is probably non-allergic reaction, as non{\textendash}allergic angioedema takes several hours to days to develop and it is mediated either bradykinin or cysteinyl leukotrienes without skin rash, minimal response to anti-allergic medications, abdominal manifestations are more common, respiratory tract involvement is uncommon, symptoms can last for five days and minimal response to anti-allergic medications. Whereas drug-induced allergic angioedema is mediated by histamine, with the rapid onset of swelling of mucosa and submucosa tissues with an urticarial rash. Symptoms respond rapidly to antihistamine, epinephrine and corticosteroid therapy. Based on these observations and clinical response the reaction was confirmed to be NSAIDs induced non-allergic angioedema. The only management of this reaction is complete avoidance of the drug \unskip~\citep{761182:18099252}. 

\textbf{Case Discussion}

Pathomechanism of nonallergic angioedema is based on two pathways,

\textbf{cysteinyl leukotrienes synthesis}

This pathway is followed by NSAIDs that inhibit the function of cyclooxygenase, which directs the metabolism of arachidonic acid towards the 5-Lipoxygenase pathway which produce intermediate 5-HPETE which generates LTA4 through LTA synthase. LTA4 gives rise to  (LTB4 (by LTA4 hydrolase) and LTC4 (by LTC4 synthase) (Figure~\ref{f-9007499ea744} ). LTC4 is extracellularly converted into LTD4 and then to cysLTs, a stable metabolite, which acts on G-protein coupled LTE4 receptors to induce bronchoconstriction, vascular leakage \& eosinophilia \unskip~\citep{761182:18099253,761182:18099257}. 


\bgroup
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\centering \makeatletter\IfFileExists{images/9d674d0c-1cce-44df-b311-281fb3d8ee01-upicture1.png}{\includegraphics{images/9d674d0c-1cce-44df-b311-281fb3d8ee01-upicture1.png}}{}
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\caption{\boldmath {The role of Cysteinyl leukotriene in the development of non-allergic angioedema.}}
\label{f-9007499ea744}
\end{figure*}
\egroup

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\caption{\boldmath {The Kallikrein and the bradykinin pathways and the mechanisms for nonallergic angioedema due to NSAIDs and ACE inhibitors}}
\label{f-8d3836e9c442}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Differences between allergic \& Nonallergic angioedema } }
\label{tw-b5f3778b23e8}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.33\linewidth-2\tabcolsep}p{\dimexpr.3676\linewidth-2\tabcolsep}p{\dimexpr.3024\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Characteristics & Allergic angioedema & Nonallergic angioedema\\
\tblmidrule 
Itching &
  Frequent &
  No\\
Urticaria &
  Frequent &
  No\\
Time of onset &
  Less than an hour &
  Several hours to days\\
Response to treatment &
  Effective &
  Not effective\\
Duration to subside &
  Within 24 hour &
  Last up 3 to 5 days\\
Abdominal pain &
  Possible &
  Frequent\\
Bronchospasm &
  Frequent &
  Rare\\
IgE antibodies &
  with Elevated specific serum IgE antibodies. &
  without Elevated specific serum IgE antibodies.\\
Tryptase  &
   With Elevated tryptase level  &
  Without elevation of tryptase level\\
Chymase &
  With Elevated chymase level &
  Without elevated chymase level\\
C1 INH &
  Present &
  Absent\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Bradykinin Mechanism}

The Kallikrein Kinin System (KKS) is a proteolytic enzymes in which plasma kallikrein breaks human high molecular weight kininogen and generates bradykinin which activates beta 2-adrenergic receptors and results in the release of nitric oxides and eicosanoids (prostaglandins, thromboxanes, leukotrienes) which result in local vasodilatation and increased vascular permeability which leads to the development of angioedema.NSAIDs inhibit the synthesis prostaglandins, thromboxanes and release leukotrienes which result in angioedema (Figure~\ref{f-8d3836e9c442}). Other medications such as ACE inhibitors also are known to cause non-allergic angioedema via the same pathway(pathway (Figure~\ref{f-8d3836e9c442}).

The KKS antagonizes the renin-angiotensin-aldosterone system (RAAS) in its vascular effect. The KKS \& RAAS are paired by the ACE. The function of ACE is to metabolize Bradykinin in the KKS and generate angiotensin II from angiotensin I~in the RAAS. This antagonism results in the accumulation of Bradykinin which leads to angioedema. 

Another function of proteolytic enzymes is through the activation of complement system which result in the release of anaphylatoxins (C3a, C4a, and C5a). Anaphylatoxins leads to the development of angioedema.

The KKS is paired with complement system by the C1 inhibitor. The C1 INH is a serine protease that inhibits both KKS and complement system which induces angioedema. Dipeptidyl peptidase IV inactivates substance P, a vasoactive peptide that causes swelling whereas dipeptidyl peptidase IV inhibitor like sitagliptin may cause angioedema. Both bradykinin and substance P are metabolized by ACE. During ACEI accumulation of bradykinin and substance, P results in Angioedema \unskip~\citep{761182:18099251,761182:18099252}.

Differences between allergic \& Nonallergic angioedema based on clinical manifestations and laboratory parameters is presented in Table~\ref{tw-b5f3778b23e8},\unskip~\citep{761182:18099246,761182:18099249,761182:18099252,761182:18099250}.
    
\section{Conclusion}
A high degree of suspicion is needed to identify nonallergic angioedema. It is extremely important to note that, desensitization cannot be performed in these patients. The main cause of concern in non-allergic angioedema is that these, patients do not respond to any anti-allergic medication, treatment is only supportive and sometimes angioedema can be fatal, especially when there is laryngeal edema. Stopping the culprit drug is the most important and only treatment.

\textbf{Funding Support}

None.

\textbf{Conflict of Interest}

None.
    

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