Agranulocytosis following injection of inactivated Japanese encephalitis vaccine (Vero cell): A case report

Abstract

BACKGROUND

Japanese encephalitis virus (JEV), a mosquito borne flavivirus, is the leading cause of viral encephalitis in Asia, in terms of frequency and severity. JEV infection is thought to confer lifelong immunity. With the near eradication of poliomyelitis, JEV is now the continent’s leading cause of childhood viral neurologic infection and disability. The most common clinical manifestation of JEV infection is acute encephalitis, and currently there is no specific antiviral therapy. Japanese Encephalitis Vaccine (JE-VC) is an effective prevention measure, including JE-VC, Live (JE-MB), and Inactivated JE-VC.

CASE SUMMARY

A 9-mo-old girl received injection of Inactivated JE-VC (Vero cell) (Liaoning Chengda, batch number 201611B17) on August 31, 2017. On that night, she developed a fever with the body temperature up to 38.5 °C, for which Ibuprofen Suspension Drops 1.25 mL was given as antipyretic treatment. On September 1, the patient developed apocleisis, and her parents noticed herpes in her oral cavity. The patient was sent to our hospital on September 3. Physical examination led to a diagnosis of herpetic stomatitis, for which Stomatitis Spray 1 puff, tid, Kangfuxin Liquid 2 mL, tid, and vitamin B₂ 0.5 tablet, tid, were prescribed. Routine blood tests for low fever on September 6, 2017 revealed an absolute neutrophil count (ANC) of 0.62 × 10⁹/L, hemoglobin (Hb) of 109 g/L, and platelet count (PLT) of 308 × 10¹²/L, and the tests were monitored regularly thereafter. The patient was followed until July 26, 2020, when routine blood tests revealed ANC 1.72 × 10⁹/L, Hb 138 g/L, and PLT 309 × 10¹²/L, indicating that the neutropenia count had normalized.

CONCLUSION

This report attempts to bring to clinical attention that Inactivated JE-VC (Vero cell) might cause prolonged granulocytopenia or even agranulocytosis.

Key Words: Inactivated Japanese Encephalitis Vaccine (Vero cell); Neutropenia; Agranulocytosis; Japanese Encephalitis virus; Case report

Core Tip: So far, there has been no report of vaccine-induced neutropenia that persisted for 2 years until recovery. Japanese Encephalitis virus, a mosquito borne flavivirus, is the leading cause of viral encephalitis in Asia, in terms of frequency and severity. This report attempts to bring to clinical attention that Inactivated Japanese Encephalitis Vaccine (Vero cell) might cause prolonged neutropenia or even agranulocytosis.

INTRODUCTION

Japanese Encephalitis virus (JEV), a mosquito borne flavivirus, is the leading cause of viral encephalitis in Asia, in terms of frequency and severity[1].

JEV infection is thought to confer lifelong immunity. With the near eradication of poliomyelitis, JEV is now the continent’s leading cause of childhood viral neurologic infection and disability[2]. The most common clinical manifestation of JEV infection is acute encephalitis, and currently there is no specific antiviral therapy. Japanese Encephalitis Vaccine (JE-VC) is an effective prevention measure, including JE-VC, Live (JE-MB), and Inactivated JE-VC[2]. Inactivated Vero cell culture-derived JE-VC is the only JE vaccine licensed and available in the United States. In 2009, the U.S. Food and Drug Administration licensed JE-VC for use in persons aged > 17 years. In 2013, licensure was extended to include children aged > 2 mo. The studies on adverse events with JE-VC have reported fever (≥ 38 °C) within 7 d after the first dose or second dose[3].

CASE PRESENTATION

Chief complaints

A 9-mo-old girl received injection of Inactivated JE-VC (Vero cell) on August 31, 2017. On that night, she developed a fever with the body temperature up to 38.5 °C.

History of past illness

No special history of past illness.

Physical examination

Physical examination led to a diagnosis of herpetic stomatitis.

Laboratory examinations

Routine blood tests for low fever on September 6, 2017 revealed an absolute neutrophil count (ANC) of 0.62 × 10⁹/L, hemoglobin (Hb) of 109 g/L, and platelet count (PLT) of 308 × 10¹²/L, and the tests were monitored regularly thereafter (Table 1). The patient was followed until July 26, 2020, when routine blood tests revealed ANC 1.72 × 10⁹/L, Hb 138 g/L, and PLT 309 × 10¹²/L, indicating that the neutrophil count had normalized. Routine blood tests revealed ANC 2.18 × 10⁹/L before injection of Inactivated JE-VC (Vero cell) on May 24, 2017 and ANC 2.12 × 10⁹/L on July 3, 2017, indicating a normal neutrophil count.

Table 1 Results of blood tests.

Date	ANC (× 109/L)	Hb (g/L)	PLT (× 1012/L)
September 9, 2017	0.52	113	459
September 16, 2017	0.13	118	460
October 7, 2017	0.06	120	335
October 27, 2017	0.34	110	311
November 28, 2017	0.15	113	353
January 2, 2018	0.35	116	375
February 12, 2018	0.21	115	365
April 22, 2018	0.11	118	313
May 25, 2018	0.37	124	252
November 15, 2019	3.98	129	287
June 2, 2020	1.49	131	297
July 26, 2020	1.72	138	309

ANC: Absolute neutrophil count; Hb: Hemoglobin; PLT: Platelet count.

FINAL DIAGNOSIS

Neutropenia.

TREATMENT

No treatment was given for neutropenia, but treatment for complications such as fever was administered.

OUTCOME AND FOLLOW-UP

The patient developed neutropenia. After September 2017, regular tests were performed to monitor the neutrophil values, as shown in Table 1. The blood test showed that the lowest of ANC was 0.06 × 10⁹/L, indicating neutropenia developed agranulocytosis. The patient was followed until July 26, 2020, when routine blood tests revealed ANC 1.72 × 10⁹/L, Hb 138 g/L, and PLT 309 × 10¹²/L, indicating that the neutrophil count had normalized.

DISCUSSION

It is important to evaluate the safety profile of new vaccines. Abnormal hematological values, such as neutropenia, are often reported. We should not only identify potentially important safety signals but also understand their implications and clinical relevance.

In many cases, neutropenia occurs in people of African descent because they have a lower ANC compared to other ethnic groups. Neutropenia is not listed as a potential adverse reaction in the package insert of Inactivated JE-VC (Vero cell), nor have there been literature reports on neutropenia induced by inoculating such vaccine. There have been few literature reports on vaccine-induced neutropenia. Only one article on randomized, controlled clinical trials and systematic review[4] suggests that several cases of neutropenia were reported as post-inoculation adverse events within the first 2 wk after inoculation. However, such cases of neutropenia were generally transient, and expected to have favorable clinical outcome after receiving various novel or widely recognized licensed vaccines. Furthermore, vaccine recipients with neutropenia typically have a lower baseline ANC than those without neutropenia. Neutropenia is usually caused by a variety of diseases, including infections, drug treatments, autoimmune diseases, nutritional deficiencies, or hematological malignancies, but there is also genetic conditions such as benign ethnic neutropenia (BEN). Those of African descent are particularly affected by BEN which is believed to be caused by the regulatory variation of the chemokine gene Duffy Antigen Receptor and has no connection with the increase in the incidence of infection.

CONCLUSION

So far, there has been no report of vaccine-induced neutropenia that has persisted for 2 years until recovery. This report attempts to bring to clinical attention that Inactivated JE-VC (Vero cell) might cause prolonged neutropenia or even agranulocytosis.

ACKNOWLEDGEMENTS

Heartfelt thanks to Miss DeAnn.