Chandipura virus (CHPV) belongs to the Rhabdoviridae family, a group of enveloped viruses with nonsegmented, single-stranded RNA genomes. Within the Rhabdoviridae family, CHPV is classified under the Vesiculovirus genus, which includes other notable members such as vesicular stomatitis virus.¹ The shape of CHPV resembles a typical bullet, which is 150–165 nm long and 50–65 nm wide. The CHPV genome is approximately 11 119 nucleotides in length and contains a 49 nt leader gene (l), five transcriptional units coding for Nucleoprotein (N), Phosphoprotein (P), Matrix protein (M), Glycoprotein (G), and RNA-dependent RNA polymerase (L) separated by spacer regions and followed by a short nontranscribed 46 nt trailer sequence (t).² Currently, there are no standardized treatments for CHPV infection. Several studies have shown that Ribavirin, Vesiculopolins, a synthetic peptide targeting the P protein, and Favipiravir can inhibit CHPV growth in laboratory settings.^3-5 However, more research is needed to determine the effectiveness of these treatments in humans. Furthermore, in vivo testing of anti-CHPV drugs has been limited to CHPV P gene small interfering RNA, minocycline, and nitrosporeusine.^6-8

The CHPV is primarily transmitted through the bites of infected sandflies. It was first identified during an outbreak in the Nagpur district of Maharashtra, India. After its discovery and subsequent isolation during the years 1967–69,¹ there were no reported human cases or significant public health outbreaks for a period of around three decades. However, starting in the year 2003, sporadic outbreaks of CHPV infection have been documented in the Indian states of Andhra Pradesh, Gujarat, and Maharashtra.^9-14 While most cases typically manifest with symptoms like fever and central nervous system involvement, it's worth noting that hemorrhagic manifestations are quite rare but can substantially worsen the disease's clinical progression.^9-14 In this context, we present a case of Chandipura infection with hemorrhagic manifestations.

On July 4, 2023, a 5-year-old boy from Khedbrahma in the Sabarkantha district of Gujarat, India, was admitted to a tertiary care hospital in Himmatnagar, Gujarat, with a 1-day history of fever, vomiting, and diarrhoea. Upon admission, the child was in a semiconscious state, had cold extremities, and a feeble pulse. His blood pressure was intractable, with severe hypoglycaemia of 22 mg/dL. Considering this, the patient was provided a 10% dextrose (D10%) bolus, along with intravenous fluid support for hypoglycaemic shock and dehydration. Antibiotics were also started along with supportive management. All the tropical diseases including malaria, dengue, chikungunya and leptospirosis were ruled out. The patient continued to have recurring episodes of hypoglycaemia and was again given D10% bolus with the a dextrose infusion at a rate of 6 mg/kg/min.

On July 5, 2023, the infusion rate was increased to 12 mg/kg/min based on monitoring of the random blood sugar level, which showed persistent hypoglycemia. The patient further deteriorated and became unconscious. The cerebrospinal fluid (CSF) examination was performed, and on analysis, viral encephalitis was suspected, and the patient was started on acyclovir. Later on the same day, the patient experienced bleeding from the mouth and passed blood-streaked stool. The laboratory investigations revealed leukopenia (3.7 × 10⁴/L), thrombocytopenia (65 000/µL), along with abnormal prothrombin time (PT: 8 s), activated partial thromboplastin time (aPTT: 45 s), and an international normalized ratio (INR: 0.63) (Table 1). The platelet, and fresh frozen plasma transfusions along with Vitamin K injections were initiated in response to internal bleeding, and thrombocytopenia.

Due to hemorrhagic manifestation and the reported livestock contact by family members as well as the state of Gujarat being endemic for Crimean-Congo haemorrhagic fever (CCHF), the patient was isolated and started on Ribavirin, and antifibrinolytic agent (Tranexamic acid injection). The patient continued to deteriorate and had severe bleeding from the mouth and nose and became unresponsive with impalpable pulse. Despite packed red cell transfusions, mechanical ventilation, inotropic and triple vasopressin support (adrenaline, dobutamine and noradrenaline), the bleeding persisted and the patient's condition further worsened. In the early morning hours of July 6, 2023, the patient suffered cardiac arrest and succumbed to infection.

Based on suspicion of CCHF and to rule out causes for acute encephalitic syndrome (AES), clinical samples (whole blood, serum, urine) of the case were sent to ICMR-National Institute of Virology (NIV), Pune for diagnosis on July 5, 2023. Unfortunately the volume of CSF sample which was collected previously for analysis was low and hence could not be referred for viral aetiology testing. Also, considering the deteriorating condition of the patient, no further CSF was collected.

At ICMR-NIV, Pune, the samples were tested negative for CCHF using real-time RT-PCR (rRT-PCR).¹⁵ Subsequently, the samples were tested for AES aetiologies i.e., Japanese encephalitis, West Nile virus and CHPV based on neurological manifestations and geographical location. The serum sample was found to be negative for Japanese encephalitis, and West Nile virus by rRT-PCR and immunoglobulin M enzyme-linked immunosorbent assay (IgM ELISA). The presence of CHPV RNA in the serum and whole blood was confirmed using CHPV N gene specific RT-PCR with an amplicon size of 400 base pair.^{16, 17}

Though hemorrhagic complications in CHPV infection are rare, it can significantly impact the disease course and patient outcome. Earlier, the cases with bleeding manifestations have been reported during the CHPV outbreaks from Andhra Pradesh and Maharashtra states in India during the year 2003 and 2007, respectively.^{5, 9} The exact reason for the hemorrhagic manifestation in this fatal case was unknown, but it is hypothesized that the virus directly affects the endothelial cells, leading to increased vascular permeability and disseminated intravascular coagulation. Management of severe CHPV infection with hemorrhagic complications remains challenging due to the lack of specific antiviral therapies. Even though this case was managed rigorously using supportive care, including platelet and packed cell transfusions, for managing coagulopathy, the child succumbed to infection. Early recognition and aggressive multidisciplinary care becomes very crucial for improving patient outcomes.

This study emphasizes the need for considering CHPV as one of the differential diagnosis in cases presenting with hemorrhagic manifestations from areas endemic for Chandipura infection. This would help the physicians in timely diagnosis, intensive management, with supportive care for addressing the challenges posed by this rare manifestation.

Further research is needed to better understand the pathogenesis of reasons for the hemorrhage in Chanidpura infection and to develop targeted therapeutic interventions. The case underscores the importance of maintaining vigilance for atypical presentations of emerging infectious diseases, especially in endemic regions, to ensure prompt intervention which will improve patient outcomes.

AUTHOR CONTRIBUTIONS

Pranav Punasanvala, Pragya D. Yadav, Rima R. Sahay, Deepak Y. Patil: contributed to study design, data analysis, interpretation and writing and critical review. Pranav Punasanvala, Rima R. Sahay, Hiren Chandegara, Deepak Y. Patil, Anita M. Shete, Chandhu Balachandran, Vipul Patel, Rizwana Rustam, Karma Patel, Triparna Majumdar, Savita Patil, Kavya Shah, Jayesh Solanki, Pranita Gawande, Vaishnavi Kumari: contributed to data collection, interpretation, writing and critical review. Pragya D. Yadav, Rima R. Sahay, Deepak Y. Patil: contributed to the critical review and finalization of the paper.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The study was approved by the Institutional Human Ethics Committee of ICMR-NIV, Pune, India under the project titled “Sustainable laboratory network for monitoring of Viral Haemorrhagic Fever viruses in India and enhancing bio-risk mitigation for high risk group pathogens” [NIV/IEC/March/2021/D-9 dated April 9, 2021]. The patient's father provided with the written informed consent for the use of the clinical details in the study.