Aidsa Rivera

Update: Ongoing Zika Virus Transmission — Puerto Rico, November 1, 2015–July 7, 2016

Zika virus is a flavivirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, and infection can be asymptomatic or result in an acute febrile illness with rash (1). Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects (2). Infection has also been associated with Guillain-Barré syndrome (GBS) (3) and severe thrombocytopenia (4,5). In December 2015, the Puerto Rico Department of Health (PRDH) reported the first locally acquired case of Zika virus infection. This report provides an update to the epidemiology of and public health response to ongoing Zika virus transmission in Puerto Rico (6,7). A confirmed case of Zika virus infection is defined as a positive result for Zika virus testing by reverse transcription-polymerase chain reaction (RT-PCR) for Zika virus in a blood or urine specimen. A presumptive case is defined as a positive result by Zika virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay (MAC-ELISA)* and a negative result by dengue virus IgM ELISA, or a positive test result by Zika IgM MAC-ELISA in a pregnant woman. An unspecified flavivirus case is defined as positive or equivocal results for both Zika and dengue virus by IgM ELISA. During November 1, 2015-July 7, 2016, a total of 23,487 persons were evaluated by PRDH and CDC Dengue Branch for Zika virus infection, including asymptomatic pregnant women and persons with signs or symptoms consistent with Zika virus disease or suspected GBS; 5,582 (24%) confirmed and presumptive Zika virus cases were identified. Persons with Zika virus infection were residents of 77 (99%) of Puerto Ricos 78 municipalities. During 2016, the percentage of positive Zika virus infection cases among symptomatic males and nonpregnant females who were tested increased from 14% in February to 64% in June. Among 9,343 pregnant women tested, 672 had confirmed or presumptive Zika virus infection, including 441 (66%) symptomatic women and 231 (34%) asymptomatic women. One patient died after developing severe thrombocytopenia (4). Evidence of Zika virus infection or recent unspecified flavivirus infection was detected in 21 patients with confirmed GBS. The widespread outbreak and accelerating increase in the number of cases in Puerto Rico warrants intensified vector control and personal protective behaviors to prevent new infections, particularly among pregnant women.

Virus-Specific Differences in Rates of Disease during the 2010 Dengue Epidemic in Puerto Rico

Background Dengue is a potentially fatal acute febrile illness (AFI) caused by four mosquito-transmitted dengue viruses (DENV-1–4) that are endemic in Puerto Rico. In January 2010, the number of suspected dengue cases reported to the passive dengue surveillance system exceeded the epidemic threshold and an epidemic was declared soon after. Methodology/Principal Findings To characterize the epidemic, surveillance and laboratory diagnostic data were compiled. A suspected case was a dengue-like AFI in a person reported by a health care provider with or without a specimen submitted for diagnostic testing. Laboratory-positive cases had: (i) DENV nucleic acid detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in an acute serum specimen; (ii) anti-DENV IgM antibody detected by ELISA in any serum specimen; or (iii) DENV antigen or nucleic acid detected in an autopsy-tissue specimen. In 2010, a total of 26,766 suspected dengue cases (7.2 per 1,000 residents) were identified, of which 46.6% were laboratory-positive. Of 7,426 RT-PCR-positive specimens, DENV-1 (69.0%) and DENV-4 (23.6%) were detected more frequently than DENV-2 (7.3%) and DENV-3 (<0.1%). Nearly half (47.1%) of all laboratory-positive cases were adults, 49.7% had dengue with warning signs, 11.1% had severe dengue, and 40 died. Approximately 21% of cases were primary DENV infections, and 1–4 year olds were the only age group for which primary infection was more common than secondary. Individuals infected with DENV-1 were 4.2 (95% confidence interval [CI]: 1.7–9.8) and 4.0 (95% CI: 2.4–6.5) times more likely to have primary infection than those infected with DENV-2 or -4, respectively. Conclusions/Significance This epidemic was long in duration and yielded the highest incidence of reported dengue cases and deaths since surveillance began in Puerto Rico in the late 1960s. This epidemic re-emphasizes the need for more effective primary prevention interventions to reduce the morbidity and mortality of dengue.

Travel-associated dengue infections in the United States, 1996 to 2005.

BACKGROUND As the incidence of dengue increases globally, US travelers to endemic areas may be at an increased risk of travel-associated dengue. METHODS Data from the US Centers for Disease Control and Preventions laboratory-based Passive Dengue Surveillance System (PDSS) were used to describe trends in travel-associated dengue reported from January 1, 1996 to December 31, 2005. The PDSS relies on provider-initiated requests for diagnostic testing of serum samples via state health departments. A case of travel-associated dengue was defined as a laboratory-positive dengue infection in a resident of the 50 US states and the District of Columbia who had been in a dengue-endemic area within 14 days before symptom onset. Dengue infection was confirmed by serologic and virologic techniques. RESULTS One thousand one hundred and ninety-six suspected travel-associated dengue cases were reported-334 (28%) were laboratory-positive, 597 (50%) were laboratory-negative, and 265 (22%) were laboratory-indeterminate. The incidence of laboratory-positive cases varied from 1996 to 2005, but had an overall increase with no significant trend (53.5 to 121.3 per 10(8) US travelers, p = 0.36). The most commonly visited regions were the Caribbean, Mexico and Central America, and Asia. The median age of laboratory-positive cases was 37 years (range: <1 to 75 y) and 166 (50%) were male. Of the 334 laboratory-positive cases, 41 (12%) were hospitalized, and 2 (1%) died. CONCLUSIONS Residents of the US traveling to dengue-endemic regions are at risk of dengue infection and need to be instructed on appropriate prevention measures prior to travel. Especially in light of the potential transmissibility of dengue virus via blood transfusion, consistent reporting of travel-associated dengue infections is essential.

Incidence of Zika Virus Disease by Age and Sex — Puerto Rico, November 1, 2015–October 20, 2016

Zika virus is a flavivirus transmitted primarily by Aedes species mosquitoes; symptoms of infection include rash, arthralgia, fever, and conjunctivitis.*,† Zika virus infection during pregnancy can cause microcephaly and other serious brain anomalies (1), and in rare cases, Zika virus infection has been associated with Guillain-Barré syndrome (2) and severe thrombocytopenia (3). This report describes the incidence of reported symptomatic Zika virus disease in the U.S. territory of Puerto Rico by age and sex. During November 1, 2015-October 20, 2016, 62,500 suspected Zika virus disease cases were reported to the Puerto Rico Department of Health (PRDH); 29,345 (47%) were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) testing, or were presumptively diagnosed based on serological testing. The highest incidence among confirmed or presumptive cases occurred among persons aged 20-29 years (1,150 cases per 100,000 residents). Among 28,219 (96.2%) nonpregnant patients with confirmed or presumptive Zika virus disease, incidence was higher among women (936 per 100,000 population) than men (576 per 100,000) for all age groups ≥20 years, and the majority (61%) of reported Zika virus disease cases occurred in females. Among suspected Zika virus disease cases in nonpregnant adults aged ≥40 years, the percentage that tested positive among females (52%) was higher than that among males (47%) (p<0.01). Reasons for the higher incidence of Zika virus disease among women aged ≥20 years are not known; serosurveys of persons living near confirmed Zika virus disease cases might help to elucidate these findings. Residents of and travelers to Puerto Rico should remove or cover standing water, practice mosquito abatement, employ mosquito bite avoidance behaviors, take precautions to reduce the risk for sexual transmission, and seek medical care for any acute illness with rash or fever.

Case Series of Fatal Leptospira spp./Dengue Virus Co-Infections—Puerto Rico, 2010–2012

Co-infection with pathogens that cause acute febrile illness creates a diagnostic challenge as a result of overlapping clinical manifestations. Here, we describe four fatal cases of Leptospira species/dengue virus co-infection in Puerto Rico. Although all patients sought care early, antibiotic administration was delayed for most. Steroids were administered to all patients, in most cases before antibiotics. These cases show the need for clinicians evaluating patients in or recently returned from the tropics with acute febrile illness to consider both dengue and leptospirosis. Furthermore, they illustrate the need for nucleic acid- or antigen-based rapid diagnostic tests to enable timely patient diagnosis and management. In particular, antibiotic therapy should be initiated early for patients with suspected leptospirosis, and steroids should not be administered to patients with suspected dengue.

Fatal Human Co-infection with Leptospira spp. and Dengue Virus, Puerto Rico, 2010

To the Editor: Leptospirosis, caused by Leptospira spp. bacteria, and dengue, caused by dengue viruses (DENVs), are potentially fatal acute febrile illnesses (AFI) endemic to the tropics (1,2). Because their clinical manifestations are similar (3), leptospirosis may be misidentified as dengue (4). We report a fatal case of co-infection with Leptospira spp. and DENV-1 in a man in Puerto Rico. On May 23, 2010, a 42-year-old unemployed male carpenter came to an outpatient clinic in Puerto Rico reporting a 4-day history of fever, headache, generalized myalgia, anorexia, nausea, and vomiting. He was being treated for chronic hypertension and had been released from jail 2 weeks before illness onset. On evaluation, he was febrile, hypertensive, and tachycardic; laboratory results showed thrombocytopenia and leukocytosis with a predominance of neutrophils. Viral syndrome was diagnosed, and the patient was given acetaminophen, solumedrol, and ketoprofen. The patient returned to the clinic on May 25 with continued fever, myalgia, worsening headache, and bilateral calf pain; he was afebrile and tachycardic and appeared acutely ill. He had no rash, jaundice, icteric sclera, cardiac murmurs, or organomegaly, and his lungs were clear on auscultation. He was given intravenous (IV) saline, and results of laboratory tests performed afterward showed leukocytosis with a predominance of neutrophils, thrombocytopenia, increased blood urea nitrogen (BUN)–to-creatinine ratio, hyponatremia, hyperglycemia, and elevated aspartate aminotransferase. He was given IV ampicillin, meperidine, and promethazine and was transferred to a local hospital for admission, with a presumptive diagnosis of pre–renal azotemia and leptospirosis. On arrival at the emergency department on the same day, the patient was febrile, tachycardic, and hypotensive, with cold, clammy skin. Results of an electrocardiogram showed sinus tachycardia; cardiac enzymes were not elevated. He was given repeat IV saline and piperacillin/tazobactam. New laboratory findings included anemia, prolonged prothrombin time, elevated creatinine kinase, hematuria, and a further increase in BUN-to-creatine ratio. Chest radiograph showed cardiomegaly with increased pulmonary vascularity and perihilar alveolar densities. Arterial blood gas (ABG) results showed compensated metabolic acidosis, with low oxygen partial pressure (pO2). He was given IV saline again, and vancomycin and ceftriaxone were added to his medication regimen. On admission to the intensive care unit, the patient continued to be hypotensive and was again given IV saline. Although ABG results on the morning of May 26 were somewhat improved, the patient was started on respiratory treatments for new-onset cough and increasing respiratory rate. Laboratory test results showed a large drop in hematocrit, worsening thrombocytopenia and leukocytosis, hypocalcemia, and hypoalbuminemia; he was given an infusion of 25% albumin. The patient’s condition continued to worsen, with ABG results showing further decline in pO2. Severe respiratory distress developed, and he was placed on mechanical ventilation and given IV saline. Repeat ABG results showed severe respiratory acidosis and metabolic acidosis. Soon after, generalized edema developed, and the patient became cyanotic, with no measurable pulse; despite aggressive resuscitation efforts, he died on March 26. All results of bacterial cultures were negative, as was detection of anti-Leptospira IgM. Postmortem examination showed rash and pleural effusion, and blood and tissue specimens were taken for diagnostic testing. Liver sections showed bile stasis, dilated sinusoidal space, and pericentral hepatocellular necrosis (Figure, panel A); lung sections showed intraalveolar hemorrhage, edema, and focal inflammatory infiltrates (Figure, panel B). Heart sections showed perivascular edema, and kidney sections showed evidence of interstitial inflammatory infiltrates and acute tubular necrosis (Figure, panel C). Immunohistochemical analysis of kidney (Figure, panel D), liver, lung, and heart sections showed Leptospira antigen. Dengue virus nonstructural (NS) protein 1 was detected in whole blood, and flavivirus NS5 gene was amplified from RNA extracted from the liver; sequencing showed 98% homology with DENV-1. Figure Histopathologic evaluation of tissue samples collected postmortem from a person co-infected with Leptospira spp. and dengue virus 1. Tissue specimens were taken from the liver (A), lung (B) and kidney (C and D) and stained with hemotoxylin-eosin (A, B, ... This case report demonstrates the need for antigen-based rapid diagnostic tests (RDT) for AFI patients. All available leptospirosis RDTs detect anti-Leptospira IgM (5), which was not detectable in this patient’s blood on the seventh day of illness, although Leptospira antigen was detected in postmortem analysis. Therefore, it is unlikely that any available leptospirosis RDT would have been clinically useful when leptospirosis signs first were recorded on the fourth day of illness. Because the incidence of both dengue and leptospirosis is increasing worldwide (6,7), physicians should have access to antigen-based RDT to make timely and thorough diagnoses. Nonetheless, even if leptospirosis had been diagnosed in this patient, dengue virus infection would likely still have been overlooked. Therefore, clinicians in areas where both Leptospira spp. and DENVs are endemic should include both pathogens in the differential diagnosis when evaluating AFI patients and should consider the possibility of co-infection. Early administration of doxycycline and penicillin G to treat mild and severe leptospirosis, respectively, may reduce the duration and severity of illness (8). For cases of severe dengue, packed red blood cells should be given in response to severe anemia. For patients with either dengue or leptospirosis, intravenous fluid administration should be closely monitored to prevent fluid overload.

Clinical and epidemiologic characteristics of dengue and other etiologic agents among patients with acute febrile illness, Puerto Rico, 2012-2015.

Identifying etiologies of acute febrile illnesses (AFI) is challenging due to non-specific presentation and limited availability of diagnostics. Prospective AFI studies provide a methodology to describe the syndrome by age and etiology, findings that can be used to develop case definitions and multiplexed diagnostics to optimize management. We conducted a 3-year prospective AFI study in Puerto Rico. Patients with fever ≤7 days were offered enrollment, and clinical data and specimens were collected at enrollment and upon discharge or follow-up. Blood and oro-nasopharyngeal specimens were tested by RT-PCR and immunodiagnostic methods for infection with dengue viruses (DENV) 1–4, chikungunya virus (CHIKV), influenza A and B viruses (FLU A/B), 12 other respiratory viruses (ORV), enterovirus, Leptospira spp., and Burkholderia pseudomallei. Clinical presentation and laboratory findings of participants infected with DENV were compared to those infected with CHIKV, FLU A/B, and ORV. Clinical predictors of laboratory-positive dengue compared to all other AFI etiologies were determined by age and day post-illness onset (DPO) at presentation. Of 8,996 participants enrolled from May 7, 2012 through May 6, 2015, more than half (54.8%, 4,930) had a pathogen detected. Pathogens most frequently detected were CHIKV (1,635, 18.2%), FLU A/B (1,074, 11.9%), DENV 1–4 (970, 10.8%), and ORV (904, 10.3%). Participants with DENV infection presented later and a higher proportion were hospitalized than those with other diagnoses (46.7% versus 27.3% with ORV, 18.8% with FLU A/B, and 11.2% with CHIKV). Predictors of dengue in participants presenting <3 DPO included leukopenia, thrombocytopenia, headache, eye pain, nausea, and dizziness, while negative predictors were irritability and rhinorrhea. Predictors of dengue in participants presenting 3–5 DPO were leukopenia, thrombocytopenia, facial/neck erythema, nausea, eye pain, signs of poor circulation, and diarrhea; presence of rhinorrhea, cough, and red conjunctiva predicted non-dengue AFI. By enrolling febrile patients at clinical presentation, we identified unbiased predictors of laboratory-positive dengue as compared to other common causes of AFI. These findings can be used to assist in early identification of dengue patients, as well as direct anticipatory guidance and timely initiation of correct clinical management.

Enhanced Surveillance for Fatal Dengue-Like Acute Febrile Illness in Puerto Rico, 2010-2012

Background Dengue is a leading cause of morbidity throughout the tropics; however, accurate population-based estimates of mortality rates are not available. Methods/Principal Findings We established the Enhanced Fatal Acute Febrile Illness Surveillance System (EFASS) to estimate dengue mortality rates in Puerto Rico. Healthcare professionals submitted serum and tissue specimens from patients who died from a dengue-like acute febrile illness, and death certificates were reviewed to identify additional cases. Specimens were tested for markers of dengue virus (DENV) infection by molecular, immunologic, and immunohistochemical methods, and were also tested for West Nile virus, Leptospira spp., and other pathogens based on histopathologic findings. Medical records were reviewed and clinical data abstracted. A total of 311 deaths were identified, of which 58 (19%) were DENV laboratory-positive. Dengue mortality rates were 1.05 per 100,000 population in 2010, 0.16 in 2011 and 0.36 in 2012. Dengue mortality was highest among adults 19–64 years and seniors ≥65 years (1.17 and 1.66 deaths per 100,000, respectively). Other pathogens identified included 34 Leptospira spp. cases and one case of Burkholderia pseudomallei and Neisseria meningitidis. Conclusions/Significance EFASS showed that dengue mortality rates among adults were higher than reported for influenza, and identified a leptospirosis outbreak and index cases of melioidosis and meningitis.

Use of Household Cluster Investigations to Identify Factors Associated with Chikungunya Virus Infection and Frequency of Case Reporting in Puerto Rico

Background Chikungunya virus (CHIKV) is transmitted by Aedes species mosquitoes and is the cause of an acute febrile illness characterized by potentially debilitating arthralgia. After emerging in the Caribbean in late 2013, the first locally-acquired case reported to public health authorities in Puerto Rico occurred in May 2014. During June–August 2014, household-based cluster investigations were conducted to identify factors associated with infection, development of disease, and case reporting. Methodology/Principal Findings Residents of households within a 50-meter radius of the residence of laboratory-positive chikungunya cases that had been reported to Puerto Rico Department of Health (PRDH) were offered participation in the investigation. Participants provided a serum specimen and answered a questionnaire that collected information on demographic factors, household characteristics, recent illnesses, healthcare seeking behaviors, and clinical diagnoses. Current CHIKV infection was identified by rRT-PCR, and recent CHIKV infection was defined by detection of either anti-CHIKV IgM or IgG antibody. Among 250 participants, 74 (30%) had evidence of CHIKV infection, including 12 (5%) with current and 62 (25%) with recent CHIKV infection. All specimens from patients with CHIKV infection that were collected within four days, two weeks, and three weeks of illness onset were positive by RT-PCR, IgM ELISA, and IgG ELISA, respectively. Reporting an acute illness in the prior three months was strongly associated with CHIKV infection (adjusted odds ratio [aOR] = 21.6, 95% confidence interval [CI]: 9.24–50.3). Use of air conditioning (aOR = 0.50, 95% CI = 0.3–0.9) and citronella candles (aOR = 0.4, 95% CI = 0.1–0.9) were associated with protection from CHIKV infection. Multivariable analysis indicated that arthralgia (aOR = 51.8, 95% CI = 3.8–700.8) and skin rash (aOR = 14.2, 95% CI = 2.4–84.7) were strongly associated with CHIKV infection. Hierarchical cluster analysis of signs and symptoms reported by CHIKV-infected participants demonstrated that fever, arthralgia, myalgia, headache, and chills tended to occur simultaneously. Rate of symptomatic CHIKV infection (defined by arthralgia with fever or skin rash) was 62.5%. Excluding index case-patients, 22 (63%) participants with symptomatic CHIKV infection sought medical care, of which 5 (23%) were diagnosed with chikungunya and 2 (9%) were reported to PRDH. Conclusions/Significance This investigation revealed high rates of CHIKV infection among household members and neighbors of chikungunya patients, and that behavioral interventions such as use of air conditioning were associated with prevention of CHIKV infection. Nearly two-thirds of patients with symptomatic CHIKV infection sought medical care, of which less than one-quarter were reportedly diagnosed with chikungunya and one-in-ten were reported to public health authorities. These findings emphasize the need for point-of-care rapid diagnostic tests to optimize identification and reporting of chikungunya patients.

Postmortem Findings in Patient with Guillain-Barré Syndrome and Zika Virus Infection

Postmortem examination results of a patient with Guillain-Barré syndrome and confirmed Zika virus infection revealed demyelination of the sciatic and cranial IV nerves, providing evidence of the acute demyelinating inflammatory polyneuropathy Guillain-Barré syndrome variant. Lack of evidence of Zika virus in nervous tissue suggests that pathophysiology was antibody mediated without neurotropism.