Here, we present four patients with confirmed Chikungunya virus infection showing atypical neurologic manifestations and death. This case series includes patients ranging in age from five to 92 years, with or without comorbidities. This report is important, as very few cases in the literature reporting death due to atypical Chikungunya virus infection are available.

INTRODUCTION Chikungunya fever is transmitted to humans by mosquitoes of the genus Aedes and is caused by the chikungunya virus (CHIKV). CHIKV was first isolated in 1952 in Tanzania and was responsible for major epidemics in Asia in the 1950s and 1960s. CHIKV reemerged in 2005 and is currently found in at least one country of each continent1. In Brazil, the first CHIKV case was reported in 20102. Autochthonous transmission was detected in September of 20143. In 2016, through the 13th epidemiological week, 39,017 suspected cases were notified, and 6,159 were confirmed. The Northeastern Region showed the highest incidence rate (56 cases/100,000 inhabitants) with 12 deaths4. Infection by CHIKV is characterized by an abrupt onset of fever and moderate to severe arthralgia, myalgia, headache, rash, fatigue, and nausea5. Atypical manifestations have been described, such as cardiovascular; ocular; gastrointestinal; renal; and neurological impairments, including altered level of consciousness, alterations in cranial nerves, seizures, psychosis, hemi/paraparesis, paraplegia, involuntary movements, and Guillain-Barré syndrome (GBS)(6, 7). Here, four cases of severe CHIKV infection are described, with ages varying between 5- and 92-years-old, both sexes, with and without comorbidities. All of the cases experienced fast and fatal evolution.

CASE REPORTS The four patients were admitted to the Hospital Regional de Emergência e Trauma Dom Luiz Gonzaga Fernandes at Campina Grande, Paraíba, Brazil. Patient 1 and Patient 3 were from Campina Grande (7°13'20.4"S 35°52'48.1"W) located in the Agreste region of Paraíba State, 112km from the capital city of João Pessoa. Patient 2 and Patient 4 were from Monteiro (7°53'30.1"S 37°07'34.6"W), a city with 33,039 inhabitants located in the Borborema region of Paraíba State, 300km from João Pessoa and 170km from Campina Grande. Patients 2 and 4 were admitted to a local Health Service in the municipality of Monteiro and then moved to the hospital at Campina Grande. Patient 1 . A <5-year-old child, previously healthy, was admitted on January 12, 2016. He presented with a 1-day history of fever, intense myalgia, arthralgia, headache, and vomiting; he experienced two tonic-clonic seizures 7 hours prior to admission and cardiorespiratory arrest (CRA) 4 hours prior to admission. He was brought to our service on mechanical ventilation, with a Glasgow Coma Scale (GCS) score of 3. During examination, the patient was afebrile, dehydrated (++/4+), showed unaltered cardiac and respiratory auscultations, and had a flaccid abdomen; he showed no signs of visceromegaly or bleeding, but presented with deep areflexia (negative corneal-palpebral, oculomotor, and cough reflexes). Cranial computed tomography (CT) scan showed diffuse cerebral edema. Lumbar puncture was contraindicated. Intravenous antibiotic therapy was started. The patient developed leukopenia by the third day of hospitalization. On the sixth day, he showed a diffuse rash on his trunk, abdomen, and limbs. At this time, serological tests for CHIKV [positive Mac-enzyme-linked immunosorbent assay (ELISA) immunoglobulin M (IgM)] and dengue [negative non-structural protein 1 (NS1)] were performed. Blood, urine, and tracheal secretion cultures were negative. Death was declared on February 4, 2016. Patient 2. A 51-year-old female farmer with noninsulin-dependent diabetes was admitted on February 9, 2016. She complained of sudden lumbosacral pain in the previous 2 days, followed by loss of bowel control; 15-day history of fever, arthralgia, and skin rash also reported. At admission, she was conscious, oriented, and breathing spontaneously, but also sleepy and febrile. She presented with tetraparesis and stiff neck, without signs of joint inflammation. Cardiac and respiratory auscultation was unaltered and her blood pressure and blood glucose test (HGT) were normal. A complete blood count (CBC) and cerebrospinal fluid (CSF) analysis were obtained by lumbar puncture (Table 1). An anti-human immunodeficiency virus (HIV) ELISA was negative, as were blood and CSF cultures. A CT scan of both the thoracic and lumbosacral spine was performed on February 10, 2016, which showed a slight thickening of the thoracic segment of the spinal cord. Broad spectrum antibiotic therapy was started. In serum samples, IgM (Mac-Elisa) was negative for dengue and positive for CHIKV. She developed lethargy and respiratory difficulties, and oxygen therapy with a reservoir bag was started. The patient did not respond well to supportive care measures and, 38 hours after hospital admission, she went into CRA and died. TABLE 1 Cases Sex Age (years) Comorbidity Leukocytes Lymphocytes Ionogram (mEq/L) Urea Creatinine (mg/dL) CSF CT Scan Serology Patient 1 M 5 No 5,700 456 Na 157 K 3.7 20 1 Not analyzed Diffuse cerebral edema IgM + Chikungunya; NS1 negative dengue. Patient 2 F 51 DM 20,100 (16% band cells) 1,800 Na 151 K 3.5 92 0.9 Leukocytes: 113 (90% lymphocytes) Glucose: 269mg/dL Proteins: 291 mg/dL Slight thickening of thoracic segment of the spinal cord and small collections/abscesses in the right iliopsoas muscles, measuring 3.0 x 2.0 cm in its major axis. IgM + Chikungunya; IgM negative dengue. Patient 3 M 65 DM and alcoholism 12,100 (20% band cells) 726 Na 154 K 3.1 134 2.9 Leukocytes: 4 Glucose: 327mg/dL Proteins: 57.5mg/dL Bilateral frontal hypoattenuation IgM + Chikungunya; IgM negative dengue. Patient 4 Fe 92 No 15,900 (5% band cells) 954 Na 123 K 4.1 27 1.1 Not analyzed No acute alterations IgM + Chikungunya; IgM negative dengue. CHIKV: Chikungunya virus; CSF: cerebrospinal fluid; CT: computed tomography; M: male; F: female; DM: diabetes mellitus; IgM: immunoglobulin M; NS1: non-structural protein 1. Patient 3. A 65-year-old male farmer with history of alcohol abuse and diabetes was admitted to the hospital on January 22, 2016. He presented with a decreased level of consciousness and reported seizures 1.5 hours before arriving at the hospital. Family members informed hospital staff that the patient had fever, joint pain, and exanthema 10 days prior. Examination on admission revealed an absence of fever, normal blood pressure levels, elevated capillary blood glucose (CBG), normal urine output, GCS score of 9, and respiratory difficulties. The patient had normal cardiac and respiratory auscultations, a flaccid abdomen, and no visceromegaly. Petechiae were identified on the lower legs as well as periorbital ecchymosis. Pedal pulses were bilaterally absent. He was placed on mechanical ventilation, then intravenous antibiotic therapy with acyclovir was started. The blood and urine cultures collected were negative for bacteria, dengue virus, and HIV; and positive for CHIKV (IgM+). Cranial CT scan showed bilateral frontal hypoattenuation. Complete CSF analysis was performed (Table 1). The patient died 27 hours after hospital admission. Patient 4. A 92-year-old woman was admitted to the hospital on March 13, 2016 with 9-day history of fever, arthralgia, and exanthema; she also described episodes of vomiting and diarrhea in the previous 3 days. She developed a decreased level of consciousness and was brought to our service already on mechanical ventilation. She demonstrated involuntary movements in lower limbs, but had no significant alterations in cardiac and respiratory auscultations, or signs of bleeding. A computed tomography scan showed no acute alterations. The patient evolved with no neurological improvement, dying 10 days after her admission to the hospital. Laboratory analyses such as hematological, biochemical, and microbiological (bacteria and fungi) as well as imaging exams were performed at the Hospital Regional de Emergência e Trauma Dom Luiz Gonzaga Fernandes at Campina Grande. Specific serology for chikungunya, dengue, HIV, and hepatitis viruses were performed at Paraíba State Central Laboratory [Laboratório Central de Saúde Pública da Paraíba (LACEN-PB)], the public reference laboratory for diagnosis of infectious diseases and member of a National Network for certified diagnostic laboratories under the auspices of the Brazilian Ministry of Health. All four patients yielded negative results for dengue, HIV, and hepatitis serologies. Microbiological cultures of the CSF, urine, and blood were also negative. Ethical considerations This work was part of a larger project on Arbovirosis approved by UFPB Ethical Committee on Human Research (protocol #032/2009/CEP/HULW/UFPB). Written informed consent was obtained from the patient for publication of this case report.