Padua, Paula Francezca C. VENOLYMPHATIC MALFORMATION in a 4 year old male treated with PICIBANIL (OK-432) with SYSTEMIC INFLAMMATORY RESPONSE SYNDROME as a complication A CASE REPORT Good morning doctors! In this presentation, I will be reporting a case of a child with a congenital disease, treated with a popularly used drug for such condition, only to develop an unexpected complication. Padua, Paula Francezca C.

OBJECTIVES To present a case of venolymphatic malformation & OK-432 as its management To discuss the mechanism of action of OK-432 To discuss the known complications of OK-432

The patient is a 4 year old male, born full term in a tertiary hospital, with note of right facial and cervicothoracic mass. At 3 years of age, of all the customers of a fastfood chain he was in, patient was approached by a anonymous philantropist who offered financial help for his case.

CT SCAN Patient was then worked up in a private hospital and CT scan demonstrated a lymphatic malformation with venous, vascular component. The patient was diagnosed with venolymphatic malformation and injection of OK-432 or Picibanil was planned. Picibanil is a drug which in some literatures is the mainstay sclerosing agent for such conditions.

Injection of OK-432 He was admitted and cleared for injection of OK-432. Skin testing was done and under ultrasound guidance, cystic areas of the mass were identified and injected with OK-432.

3 Mos Post-Therapy 2 Mos Post-Therapy 1 Day Post-Therapy Before Therapy No serious post-op complications were noted. Here are pictures of the patient pre-and post treatment showing promising change in the size of the mass

2nd Injection of OK-432 Five months after the first injection, the patient was again admitted and cleared for a 2nd dose of  OK-432 on the upper and lower eyelid and hemifacial region.

Respiratory distress Hypotensive episodes Decreased sensorium This time, things did not go as expected. 24 hrs post-op patient later on developed respiratory distress, with hypotensive episodes, and decreased sensorium, and was subsequently admitted to a Pediatric ICU.

Sepsis? = Not Sepsis Serum Pro-Calcitonin Negative Cultures: ETA Urine Equivocal Serum Pro-Calcitonin = Not Sepsis Negative Cultures: ETA Urine Blood CSF The possibility of sepsis was entertained. Sepsis work-up was done. The results, however, were inconsistent with sepsis.

Anaphylaxis? = Not Anaphylaxis IgE Hours after event: >24 Hours Elevated IgE = Not Anaphylaxis Hours after event: >24 Hours Allergic or anaphylactic reaction was also considered, hence serum IgE was requested, showing elevated results. However, complications aroused more than 24 hours post-treatment, making this event unlikely.

So what is it then? Let us first discuss Venolymphatic malformation, OK-432, and its possible connection to SIRS

Venolymphatic Malformation Venolymphatic malformation is one of the most common types of vascular malformations with an overall prevalence of up to 1% in the general population. The most accepted treatment for this condition is surgical excision. However, when it infiltrates vital neurovascular neck structures, complete excision is difficult, and if only partial, the recurrence rate is very high as well as high risk of surgical complications. Due to the limitations of surgery in treating this condition, alternative treatments were introduced, the most frequently used of which is OK-432 (Picibanil).

OK-432 (PICIBANIL) OK-432 (Picibanil) is a lyophilized incubation mixture of group A Streptococcus Pyogenes of human origin. It is injected to into the macrocystic spaces and produces sclerosis by inducing circumscribed inflammation, resulting in fluid drainage, shrinkage, and fibrotic adhesion of the cyst.5

COMPLICATIONS Local inflammatory reaction Fever Majority of reported complications with the use of these treatment are minor.

SERIOUS SIDE EFFECTS Dexamethasone Intubation Hypopharyngeal edema The first serious side effect encountered with OK-432, which is soft tissue swelling after the first treatment, resulting in hypopharyngeal edema with swallowing problems. Dexamethasone Laranne, et al One of the reported serious side effect of this drug is hypopharyngeal edema. Hence, in our patient, he was given dexamethasone and intubated prophylactically to address this expected event. Intubation …15% of all children reviewed required a tracheostomy tube. Boardman, et al

SERIOUS SIDE EFFECTS Ultrasound Guidance Check for backflow Hypopharyngeal edema Systemic Immunomodulatory Response Ultrasound Guidance Injections into blood vessels must be avoided, as this would induce systemic immunomodulatory responses with sepsis-like, life threatening conditions. Check for backflow Bittmann, et al Systemic immunomodulatory response has also been reported. This justifies the need for ultrasound guidance and checking for backflow of blood when injecting the drug, as was done to our patient.

SERIOUS SIDE EFFECTS Skin Test Hypopharyngeal edema Systemic Immunomodulatory Response Anaphylaxis Other potential risks include anaphylaxis to either the bacteria-derived protein or the penicillin contained within the preparation (used for bacterial breakdown). That is why hypersensitivity to penicillin  must be ruled out before treatment… These kinds of complications would all develop within a few hours after Picibanil injections. Skin Test Other potential risk includes anaphylaxis. Hence, skin test was done prior to giving the treatment. Bittmann, et al

Procalcitonin = Equivocal Lymphocytopenia… Another possible cause? Patients with large bilateral lymphatic malformations often have low numbers of circulating lymphocytes, placing them at risk for bacterial dissemination secondary to reduced immunomodulatory response. Negative cultures Although our patient did not have a bilateral malformation, he had a decreased lymphocyte count prior to the procedure and immunodeficiency panel showed lymphocytopenia after the procedure. However, cultures were negative for streptococcus, and procalcitonin levels were equivocal.   Procalcitonin = Equivocal Bittmann, et al

Systemic Inflammatory Response Syndrome?    Systemic Inflammatory Response Syndrome was eventually considered since the patient was able to fulfil the criteria. 

? OK-432 SIRS This is what makes our case interesting. Our patient’s condition was managed with something that some studies even consider to be first line of treatment, especially in cases where surgical treatment is associated with the possibility of serious functional or cosmetic side effects. He however, presented with a systemic inflammatory response syndrome, which was unexpected, and with no documented case reports of such. Is there a relationship?

Conclusion OK-432 showed promising results of regression of malformations in published literature. We are presented with a case of SIRS after OK- 432 use. Further studies are recommended to establish if there is an association between SIRS and OK-432 use. OK-432, which is the most widely used alternative treatment for venolymphatic malformations, showed promising results of regression of malformations in published literature. Published studies only mention minor local inflammatory complications in most cases. Other serious complications were a remote possibility for our patient as discussed. We are presented with a case of SIRS after OK-432 use. Due to lack of published studies showing this event as a complication, a relationship between SIRS and OK-432 cannot be established. Further studies are recommended therefore to establish if there is an association between SIRS and OK-432 use.

Thank You!