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Dengue and influenza are pathogens of global concern and cause febrile illness similar to COVID-19. We analyzed data from an enhanced surveillance system operating from three emergency departments and an urgent care clinic in Puerto Rico to identify clinical features predictive of influenza or dengue compared with COVID-19. Participants with fever or respiratory symptoms and aged ≥18 years enrolled May 2012–January 2021 with dengue, influenza, or SARS-CoV-2 confirmed by reverse transcriptase polymerase chain reaction were included. We calculated adjusted odds ratios (aORs) and 95% CIs using logistic regression to assess clinical characteristics of participants with COVID-19 compared to those with dengue or influenza, adjusting for age, subregion, and days from illness onset to presentation for clinical care. Among 13,431 participants, we identified 2,643 with dengue (N = 303), influenza (N = 2,064), or COVID-19 (N = 276). We found differences in days from onset to presentation among influenza (2 days [interquartile range: 1–3]), dengue (3 days [2–4]), and COVID-19 cases (4 days [2–7]; P < 0.001). Cough (aOR: 0.12 [95% CI: 0.07–0.19]) and shortness of breath (0.18 [0.08–0.44]) were less common in dengue compared with COVID-19. Facial flushing (20.6 [9.8–43.5]) and thrombocytopenia (24.4 [13.3–45.0]) were more common in dengue. Runny nose was more common in influenza compared with COVID-19 (8.3 [5.8–12.1]). In summary, cough, shortness of breath, facial flushing, and thrombocytopenia helped distinguish between dengue and COVID-19. Although few features distinguished influenza from COVID-19, presentation > 4 days after symptom onset suggests COVID-19. These findings may assist clinicians making time-sensitive decisions regarding triage, isolation, and management while awaiting pathogen-specific testing.

Background We evaluated clinical and laboratory findings among patients with nonsevere or severe dengue in Puerto Rico to examine whether clinical manifestations vary by age. Methods During 2012–2014, we enrolled patients who arrived at the emergency department with fever or history of fever within 7 days of presentation. Serum samples were tested for dengue virus (DENV) by reverse transcriptase-polymerase chain reaction (RT-PCR) and IgM enzyme-linked immunosorbent assay (ELISA). Severe dengue was defined as severe plasma leakage or shock, severe bleeding, or organ involvement at presentation, during hospitalization, or follow-up. Results Of 1089 dengue patients identified, 281 (26%) were severe. Compared to those with nonsevere dengue, patients with severe dengue were more often aged 10–19 years (55% vs 40%, P < .001) and hospitalized (87% vs 30%, P < .001). Severe plasma leakage or shock was more common among children aged 0–9 (59%) or 10–19 years (86%) than adults (49%) (P < .01). Severe bleeding was less common among 10–19 year olds (24%) compared to 0–9 year olds (45%) and adults (52%; P < .01). Conclusions Severe plasma leakage was the most common presentation among children, highlighting important differences from adults. Vaccination against dengue could help prevent severe dengue among children in Puerto Rico.

We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015–2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens.

Background Death in patients with chikungunya is rare and has been associated with encephalitis, hemorrhage, and septic shock. We describe clinical, histologic, and immunohistochemical findings in individuals who died following chikungunya virus (CHIKV) infection. Methods We identified individuals who died in Puerto Rico during 2014 following an acute illness and had CHIKV RNA detected by reverse transcriptase–polymerase chain reaction in a pre- or postmortem blood or tissue specimen. We performed histopathology and immunohistochemistry (IHC) for CHIKV antigen on tissue specimens and collected medical data via record review and family interviews. Results Thirty CHIKV-infected fatal cases were identified (0.8/100 000 population). The median age was 61 years (range: 6 days–86 years), and 19 (63%) were male. Death occurred a median of 4 days (range: 1–29) after illness onset. Nearly all (93%) had at least 1 comorbidity, most frequently hypertension, diabetes, or obesity. Nine had severe comorbidities (eg, chronic heart or kidney disease, sickle cell anemia) or coinfection (eg, leptospirosis). Among 24 fatal cases with tissue specimens, 11 (46%) were positive by IHC. CHIKV antigen was most frequently detected in mesenchymal tissues and mononuclear cells including tissue macrophages, blood mononuclear cells, splenic follicular dendritic cells, and Kupffer cells. Common histopathologic findings were intra-alveolar hemorrhage and edema in the lung, chronic or acute tenosynovitis, and increased immunoblasts in the spleen. CHIKV infection likely caused fatal septic shock in 2 patients. Conclusions Evaluation of tissue specimens provided insights into the pathogenesis of CHIKV, which may rarely result in septic shock and other severe manifestations.

Hispanics are the majority ethnic population in Puerto Rico where we reviewed charts of 109 hospitalized COVID-19 patients to better understand demographic and clinical characteristics of COVID-19 and determine risk factors for poor outcomes. Eligible medical records of hospitalized patients with confirmed COVID-19 illnesses were reviewed at four participating hospitals in population centers across Puerto Rico and data were abstracted that described the clinical course, interventions, and outcomes. We found hospitalized patients had a median of 3 underlying conditions with obesity and diabetes as the most frequently reported conditions. Intensive care unit (ICU) admission occurred among 28% of patients and 18% of patients died during the hospitalization. Patients 65 or older or with immune deficiencies had a higher risk for death. Common symptoms included cough, dyspnea, and fatigue; less than half of patients in the study reported fever which was less frequent than reported elsewhere in the literature. It is important for interventions within Hispanic communities to protect high-risk groups.

To estimate the frequency and duration of detectable Zika virus (ZIKV) RNA in human body fluids, we prospectively assessed a cohort of newly infected participants in Puerto Rico.We evaluated samples obtained from 150 participants (including 55 men) in whom ZIKV RNA was detected on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay in urine or blood in an enhanced arboviral clinical surveillance site. We collected serum, urine, saliva, semen, and vaginal secretions weekly for the first month and then at 2, 4, and 6 months. All specimens were tested by means of RT-PCR, and serum was tested with the use of anti-ZIKV IgM enzyme-linked immunosorbent assay. Among the participants with ZIKV RNA in any specimen at week 4, biweekly collection continued until all specimens tested negative. We used parametric Weibull regression models to estimate the time until the loss of ZIKV RNA detection in each body fluid and reported the findings in medians and 95th percentiles.The medians and 95th percentiles for the time until the loss of ZIKV RNA detection were 14 days (95% confidence interval [CI], 11 to 17) and 54 days (95% CI, 43 to 64), respectively, in serum; 8 days (95% CI, 6 to 10) and 39 days (95% CI, 31 to 47) in urine; and 34 days (95% CI, 28 to 41) and 81 days (95% CI, 64 to 98) in semen. Few participants had detectable ZIKV RNA in saliva or vaginal secretions.The prolonged time until ZIKV RNA clearance in serum in this study may have implications for the diagnosis and prevention of ZIKV infection. Current sexual-prevention guidelines recommend that men use condoms or abstain from sex for 6 months after ZIKV exposure; in 95% of the men in this study, ZIKV RNA was cleared from semen after about 3 months. (Funded by the Centers for Disease Control and Prevention.).

Introduction Zika virus infection during pregnancy causes serious birth defects and might be associated with neurodevelopmental abnormalities in children. Early identification of and intervention for neurodevelopmental problems can improve cognitive, social, and behavioral functioning. Methods Pregnancies with laboratory evidence of confirmed or possible Zika virus infection and infants resulting from these pregnancies are included in the U.S. Zika Pregnancy and Infant Registry (USZPIR) and followed through active surveillance methods. This report includes data on children aged ≥1 year born in U.S. territories and freely associated states. Receipt of reported follow-up care was assessed, and data were reviewed to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection. Results Among 1,450 children of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and with reported follow-up care, 76% had developmental screening or evaluation, 60% had postnatal neuroimaging, 48% had automated auditory brainstem response-based hearing screen or evaluation, and 36% had an ophthalmologic evaluation. Among evaluated children, 6% had at least one Zika-associated birth defect identified, 9% had at least one neurodevelopmental abnormality possibly associated with congenital Zika virus infection identified, and 1% had both. Conclusion One in seven evaluated children had a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both reported to the USZPIR. Given that most children did not have evidence of all recommended evaluations, additional anomalies might not have been identified. Careful monitoring and evaluation of children born to mothers with evidence of Zika virus infection during pregnancy is essential for ensuring early detection of possible disabilities and early referral to intervention services.

BACKGROUND: Since the Zika virus epidemic in the Americas began in 2015, Zika virus transmission has occurred throughout the Americas. However, limited information exists regarding possible risks of transmission of Zika virus and other flaviviruses through breast feeding and human milk. We conducted a systematic review of the evidence regarding flaviviruses detection in and transmission through milk, specifically regarding Zika virus, Japanese encephalitis virus, tick-borne encephalitis virus, Powassan virus, West Nile virus, dengue virus, and yellow fever virus. METHODS: Medline, Embase, Global Health, CINAHL, Cochrane Library, Scopus, Popline, Virtual Health Library, and WorldCat were searched through June 12, 2017. Two authors independently screened potential studies for inclusion and extracted data. Human and nonhuman (animal) studies describing: 1) confirmed or suspected cases of mother-to-child transmission through milk; or 2) the presence of flavivirus genomic material in milk. RESULTS: Seventeen studies were included, four animal models and thirteen observational studies. Dengue virus, West Nile virus, and Zika virus viral ribonucleic acid was detected in human milk, including infectious Zika virus and dengue virus viral particles. Human breast-feeding transmission was confirmed for only yellow fever virus. There was evidence of milk-related transmission of dengue virus, Powassan virus, and West Nile virus in animal studies CONCLUSIONS: Because the health advantages of breast feeding are considered greater than the potential risk of transmission, the World Health Organization recommends that mothers with possible or confirmed Zika virus infection or exposure continue to breast feed. This review did not identify any data that might alter this recommendation.

CDC has updated the interim guidance for U.S. health care providers caring for pregnant women with possible Zika virus exposure in response to 1) declining prevalence of Zika virus disease in the World Health Organization's Region of the Americas (Americas) and 2) emerging evidence indicating prolonged detection of Zika virus immunoglobulin M (IgM) antibodies. Zika virus cases were first reported in the Americas during 2015-2016; however, the incidence of Zika virus disease has since declined. As the prevalence of Zika virus disease declines, the likelihood of false-positive test results increases. In addition, emerging epidemiologic and laboratory data indicate that, as is the case with other flaviviruses, Zika virus IgM antibodies can persist beyond 12 weeks after infection. Therefore, IgM test results cannot always reliably distinguish between an infection that occurred during the current pregnancy and one that occurred before the current pregnancy, particularly for women with possible Zika virus exposure before the current pregnancy. These limitations should be considered when counseling pregnant women about the risks and benefits of testing for Zika virus infection during pregnancy. This updated guidance emphasizes a shared decision-making model for testing and screening pregnant women, one in which patients and providers work together to make decisions about testing and care plans based on patient preferences and values, clinical judgment, and a balanced assessment of risks and expected outcomes.

We modeled the potential cost-effectiveness of increasing access to contraception in Puerto Rico during a Zika virus outbreak. The intervention is projected to cost an additional $33.5 million in family planning services and is likely to be cost-saving for the healthcare system overall. It could reduce Zika virus-related costs by $65.2 million ($2.8 million from less Zika virus testing and monitoring and $62.3 million from avoided costs of Zika virus-associated microcephaly [ZAM]). The estimates are influenced by the contraception methods used, the frequency of ZAM, and the lifetime incremental cost of ZAM. Accounting for unwanted pregnancies that are prevented, irrespective of Zika virus infection, an additional $40.4 million in medical costs would be avoided through the intervention. Increasing contraceptive access for women who want to delay or avoid pregnancy in Puerto Rico during a Zika virus outbreak can substantially reduce the number of cases of ZAM and healthcare costs.

Background: Infection with Zika virus (ZIKV) during pregnancy is known to cause birth defects and could also be linked to pregnancy loss. Case: A pregnant woman in Puerto Rico contracted ZIKV at 16 weeks gestation. ZIKV RNA persisted in serum from her initial test at 16 weeks through 24 weeks gestation, when fetal demise occurred, and was detected in placental tissue. Conclusion: Prolonged detection of ZIKV RNA in maternal serum was associated with ZIKV RNA detection in the placenta of a patient who experienced fetal demise. While detection of placenta ZIKV RNA does not establish that ZIKV conclusively caused the demise, these findings support emerging evidence that the placenta may serve as a reservoir for ZIKV, which may be associated with prolonged detection of ZIKV RNA in serum.

Background Burkholderia pseudomallei is a soil-dwelling bacterium and the causative agent of melioidosis. The global burden and distribution of melioidosis is poorly understood, including in the Caribbean. B. pseudomallei was previously isolated from humans and soil in eastern Puerto Rico but the abundance and distribution of B. pseudomallei in Puerto Rico as a whole has not been thoroughly investigated. Methodology/Principal findings We collected 600 environmental samples (500 soil and 100 water) from 60 sites around Puerto Rico. We identified B. pseudomallei by isolating it via culturing and/or using PCR to detect its DNA within complex DNA extracts. Only three adjacent soil samples from one site were positive for B. pseudomallei with PCR; we obtained 55 isolates from two of these samples. The 55 B. pseudomallei isolates exhibited fine-scale variation in the core genome and contained four novel genomic islands. Phylogenetic analyses grouped Puerto Rico B. pseudomallei isolates into a monophyletic clade containing other Caribbean isolates, which was nested inside a larger clade containing all isolates from Central/South America. Other Burkholderia species were commonly observed in Puerto Rico; we cultured 129 isolates from multiple soil and water samples collected at numerous sites around Puerto Rico, including representatives of B. anthina, B. cenocepacia, B. cepacia, B. contaminans, B. glumae, B. seminalis, B. stagnalis, B. ubonensis, and several unidentified novel Burkholderia spp. Conclusions/Significance B. pseudomallei was only detected in three soil samples collected at one site in north central Puerto Rico with only two of those samples yielding isolates. All previous human and environmental B. pseudomallei isolates were obtained from eastern Puerto Rico. These findings suggest B. pseudomallei is ecologically established and widely dispersed in the environment in Puerto Rico but rare. Phylogeographic patterns suggest the source of B. pseudomallei populations in Puerto Rico and elsewhere in the Caribbean may have been Central or South America., Author summary The objective of this study was to examine the distribution and abundance of Burkholderia pseudomallei in the environment in Puerto Rico. B. pseudomallei is a microbe that lives in soil and causes the disease melioidosis. We conducted sampling around Puerto Rico to survey for the presence of B. pseudomallei in the environment. Of the 600 environmental samples collected, we isolated live B. pseudomallei from just two soil samples collected from the same site, which was in a region of the island where B. pseudomallei had never been previously reported. These results suggest B. pseudomallei is widely dispersed but rare in the environment in Puerto Rico. B. pseudomallei isolates from Puerto Rico are most closely related to other strains from the Caribbean. Caribbean strains are inside a larger group that contained all analyzed isolates from Central/South America, suggesting that B. pseudomallei populations in the Caribbean may have been introduced from Central or South America.

Chikungunya, a mosquito-borne viral, acute febrile illness (AFI) is associated with polyarthralgia and polyarthritis. Differentiation from other AFI is difficult due to the non-specific presentation and limited availability of diagnostics. This 3-year study identified independent clinical predictors by day post-illness onset (DPO) at presentation and age-group that distinguish chikungunya cases from two groups: other AFI and dengue. Specimens collected from participants with fever ≤7 days were tested for chikungunya, dengue viruses 1–4, and 20 other pathogens. Of 8,996 participants, 18.2% had chikungunya, and 10.8% had dengue. Chikungunya cases were more likely than other groups to be older, report a chronic condition, and present, Author summary Chikungunya is an acute febrile illness (AFI), caused by the chikungunya virus (CHIKV), that is transmitted by mosquitoes. Patients with chikungunya exhibit joint, muscle, or bone pain, and may also have skin rash, red eyes (conjunctiva), and red swollen joints (arthritis). Up to 20% of cases develop long lasting arthritis, fatigue or psychiatric conditions. We used data from our prospective study to identify signs and symptoms that predict chikungunya. We enrolled 8,996 AFI patients and tested for CHIKV, dengue viruses 1–4 (DENV 1–4), and other pathogens. A pathogen was detected in 55% of participants; 18.2% had CHIKV and 10.8% had DENV 1–4 infections. This study compared the clinical presentation of chikungunya with that of all other AFI and dengue alone. Regardless of timing of presentation, significant predictors of chikungunya were joint pain, muscle, bone or back pain, and red conjunctiva when compared to other AFI, and arthritis, joint pain, skin rash, any bleeding, and irritability, when dengue was the comparator group. Chikungunya patients were less likely than AFI and dengue patients to have low platelets, signs of poor circulation, diarrhea, headache, and cough. By enrolling febrile patients at presentation, we identified unbiased predictors of chikungunya. These findings can assist physicians to clinically diagnose chikungunya and initiate proper patient management.

Zika virus is a flavivirus transmitted primarily by Aedes species mosquitoes, and symptoms of infection can include rash, fever, arthralgia, and conjunctivitis (1).* Zika virus infection during pregnancy is a cause of microcephaly and other severe brain defects (2). Infection has also been associated with Guillain-Barré syndrome (3). In December 2015, Puerto Rico became the first U.S. jurisdiction to report local transmission of Zika virus, with the index patient reporting symptom onset on November 23, 2015 (4). This report provides an update to the epidemiology of and public health response to ongoing Zika virus transmission in Puerto Rico. During November 1, 2015-April 14, 2016, a total of 6,157 specimens from suspected Zika virus-infected patients were evaluated by the Puerto Rico Department of Health (PRDH) and CDC Dengue Branch (which is located in San Juan, Puerto Rico), and 683 (11%) had laboratory evidence of current or recent Zika virus infection by one or more tests: reverse transcription-polymerase chain reaction (RT-PCR) or immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA). Zika virus-infected patients resided in 50 (64%) of 78 municipalities in Puerto Rico. Median age was 34 years (range = 35 days-89 years). The most frequently reported signs and symptoms were rash (74%), myalgia (68%), headache (63%), fever (63%), and arthralgia (63%). There were 65 (10%) symptomatic pregnant women who tested positive by RT-PCR or IgM ELISA. A total of 17 (2%) patients required hospitalization, including 5 (1%) patients with suspected Guillain-Barré syndrome. One (1%) patient died after developing severe thrombocytopenia. The public health response to the outbreak has included increased laboratory capacity to test for Zika virus infection (including blood donor screening), implementation of enhanced surveillance systems, and prevention activities focused on pregnant women. Vector control activities include indoor and outdoor residual spraying and reduction of mosquito breeding environments focused around pregnant women's homes. Residents of and travelers to Puerto Rico should continue to employ mosquito bite avoidance behaviors, take precautions to reduce the risk for sexual transmission (5), and seek medical care for any acute illness with rash or fever.

Dengue, a mosquito-borne viral illness caused by dengue virus types (DENV)-1 to DENV-4, is endemic in Puerto Rico. Severe dengue usually occurs in individuals previously infected with DENV or among infants born to previously infected mothers. To describe clinical features of dengue in infants, we retrospectively characterized dengue patients aged < 18 months reported to the Passive Dengue Surveillance System (PDSS) during 1999-2011. To determine frequency of signs, symptoms, and disease severity, case report forms and medical records were evaluated for patients who tested positive for dengue by reverse transcriptase polymerase chain reaction or anti-DENV immunoglobulin Menzyme-linked immunosorbent assay. Of 4,178 reported patients aged < 18 months, 813 (19%) were laboratory positive. Of these, most had fever (92%), rash (53%), bleeding manifestations (52%), and thrombocytopenia (52%). Medical records were available for 145 (31%) of 472 hospitalized patients, of which 40% had dengue, 23% had dengue with warning signs, and 33% had severe dengue. Mean age of patients with severe dengue was 8 months. Anti-DENV immunoglobulin G (IgG) titers were not statistically different in patients with (50%) and without (59%) severe dengue. In this study, one-third of DENV-infected infants met the severe dengue case definition. The role of maternal anti-DENV IgG in development of severe disease warrants further study in prospective cohorts of mother-infant pairs.

BACKGROUND In the absence of active blood donation screening, dengue viruses (DENV) have been implicated in only a limited number of transfusion transmissions worldwide. This study attempted to identify if blood from donors testing negative by an NS1-antigen (Ag) enzyme-linked immunosorbent assay (ELISA) but confirmed positive for DENV RNA caused DENV-related disease in recipients during the epidemic years of 2010 to 2012 in Puerto Rico. STUDY DESIGN AND METHODS Donation aliquots testing negative by an investigational NS1-Ag ELISA were stored frozen and retested retrospectively using a research transcription-mediated amplification assay (TMA) detecting DENV RNA. All RNA-reactive donations were subject to confirmatory RNA and antibody testing. Recipient tracing was conducted for all components manufactured from TMA-reactive components. Medical chart review, recipient interview, and follow-up sampling occurred for 42 recipients transfused with TMA-reactive components. RESULTS Six of 42 recipients developed new-onset fever in the 2 weeks posttransfusion; three (50%) received RNA confirmed-positive, NS1-Ag–negative red blood cell (RBC) units. One recipient of a high-titer unit (7 × 107 DENV-4 RNA copies/mL) developed severe dengue, and a second recipient had only fever recorded but had a negative sepsis work-up. New fever attributable to DENV infection in a third recipient was confounded by fever potentially attributable to posttransfusion sepsis. CONCLUSIONS In our retrospective study, NS1-Ag detected 20% of all RNA confirmed-positive donations demonstrating limitations of NS1-Ag ELISA for blood donation screening. We identified one recipient with a clinical syndrome compatible with severe dengue who had received an NS1-Ag–negative but RNA confirmed-positive RBC unit. This investigation illustrates the difficulty in confirming transfusion transmission in dengue-endemic areas among severely ill transfusion recipients.

Pregnant women living in or traveling to areas with local mosquito-borne Zika virus transmission are at risk for Zika virus infection, which can lead to severe fetal and infant brain abnormalities and microcephaly (1). In February 2016, CDC recommended 1) routine testing for Zika virus infection of asymptomatic pregnant women living in areas with ongoing local Zika virus transmission at the first prenatal care visit, 2) retesting during the second trimester for women who initially test negative, and 3) testing of pregnant women with signs or symptoms consistent with Zika virus disease (e.g., fever, rash, arthralgia, or conjunctivitis) at any time during pregnancy (2). To collect information about pregnant women with laboratory evidence of recent possible Zika virus infection* and outcomes in their fetuses and infants, CDC established pregnancy and infant registries (3). During January 1, 2016-April 25, 2017, U.S. territories† with local transmission of Zika virus reported 2,549 completed pregnancies§ (live births and pregnancy losses at any gestational age) with laboratory evidence of recent possible Zika virus infection; 5% of fetuses or infants resulting from these pregnancies had birth defects potentially associated with Zika virus infection¶ (4,5). Among completed pregnancies with positive nucleic acid tests confirming Zika infection identified in the first, second, and third trimesters, the percentage of fetuses or infants with possible Zika-associated birth defects was 8%, 5%, and 4%, respectively. Among liveborn infants, 59% had Zika laboratory testing results reported to the pregnancy and infant registries. Identification and follow-up of infants born to women with laboratory evidence of recent possible Zika virus infection during pregnancy permits timely and appropriate clinical intervention services (6).

Background. Melioidosis results from infection with Burkholderia pseudomallei and is associated with casefatality rates up to 40%. Early diagnosis and treatment with appropriate antimicrobials can improve survival rates. Fatal and nonfatal melioidosis cases were identified in Puerto Rico in 2010 and 2012, respectively, which prompted contact investigations to identify risk factors for infection and evaluate endemicity. Methods. Questionnaires were administered and serum specimens were collected from coworkers, neighborhood contacts within 250 m of both patients’ residences, and injection drug user (IDU) contacts of the 2012 patient. Serum specimens were tested for evidence of prior exposure to B. pseudomallei by indirect hemagglutination assay. Neighborhood seropositivity results guided soil sampling to isolate B. pseudomallei. Results. Serum specimens were collected from contacts of the 2010 (n = 51) and 2012 (n = 60) patients, respectively. No coworkers had detectable anti–B. pseudomallei antibody, whereas seropositive results among neighborhood contacts was 5% (n = 2) for the 2010 patient and 23% (n = 12) for the 2012 patient, as well as 2 of 3 IDU contacts for the 2012 case. Factors significantly associated with seropositivity were having skin wounds, sores, or ulcers (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.2–17.8) and IDU (OR, 18.0; 95% CI, 1.6–194.0). Burkholderia pseudomallei was isolated from soil collected in the neighborhood of the 2012 patient. Conclusions. Taken together, isolation of B. pseudomallei from a soil sample and high seropositivity among patient contacts suggest at least regional endemicityof melioidosis in Puerto Rico. Increased awareness of melioidosis is needed to enable early case identification and early initiation of appropriate antimicrobial therapy.

Background Hospitalization of patients during outbreaks of chikungunya virus has been reported to be uncommon (0.5–8.7%), but more frequent among infants and the elderly. CHIKV was first detected in Puerto Rico in May 2014. We enrolled patients with acute febrile illness (AFI) presenting to two hospital emergency departments in Puerto Rico and tested them for CHIKV infection to describe the frequency of detection of CHIKV-infected patients, identify risk factors for hospitalization, and describe patients with severe manifestations. Methodology/Principal findings Serum specimens were collected from patients with AFI and tested by rRT-PCR. During May–December 2014, a total of 3,035 patients were enrolled, and 1,469 (48.4%) had CHIKV infection. A total of 157 (10.7%) CHIKV-infected patients were hospitalized, six (0.4%) were admitted to the intensive care unit, and two died (0.1%). Common symptoms among all CHIKV-infected patients were arthralgia (82.6%), lethargy (80.6%), and myalgia (80.5%). Compared to patients aged 1–69 years (7.3%), infant (67.2%) and elderly (17.3%) patients were nine and two times more likely to be hospitalized, respectively (relative risk [RR] and 95% confidence interval [CI] = 9.16 [7.05–11.90] and 2.36 [1.54–3.62]). Multiple symptoms of AFI were associated with decreased risk of hospitalization, including arthralgia (RR = 0.31 [0.23–0.41]) and myalgia (RR = 0.29 [0.22–0.39]). Respiratory symptoms were associated with increased risk of hospitalization, including rhinorrhea (RR = 1.68 [1.24–2.27) and cough (RR = 1.77 [1.31–2.39]). Manifestations present among, Author summary Chikungunya is an emerging infectious disease caused by a virus (chikungunya virus, CHIKV) transmitted through the bite of infected mosquitos; typical symptoms are fever and joint pain. After CHIKV was first detected in Puerto Rico in 2014, an epidemic quickly spread across the island. Because previous reports identified varying frequencies of hospitalization of CHIKV-infected patients, we used an existing hospital-based disease detection system to better understand the frequency and reasons for hospitalization of CHIKV-infected patients in Puerto Rico. Among 1,469 patients with laboratory-confirmed CHIKV infection, 11% were hospitalized, most of whom were infants or elderly. Six CHIKV-infected patients were admitted to the intensive care unit, and two died. Although several illness characteristics were associated with hospitalization, most of these were not typical of chikungunya and instead suggested underlying or concomitant respiratory disease. By enrolling patients when they presented to the emergency department and testing them for evidence of CHIKV infection, we determined that hospitalization in this population occurred in roughly one-in-ten CHIKV-infected patients, one-in-two hundred were admitted to the intensive care unit, and one-in-one thousand died. These findings provide information on the spectrum of disease caused by CHIKV, and identified underlying or concomitant respiratory illness as a risk factor associated with hospitalization.

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., Author Summary Dengue is a major public health problem in the tropics. Despite its global importance, population-based mortality rates attributable to dengue are largely unknown. Dengue vaccines are now in late stage clinical trials and one vaccine has been licensed in several countries. Evidence-based decisions regarding the future use of dengue vaccines will depend on robust estimates of disease burden which should include mortality. To estimate mortality due to dengue in Puerto Rico, where dengue is endemic, we developed an enhanced surveillance system to detect fatalities due to a preceeding dengue-like acute febrile illness using more sensitive case identification and laboratory methods than the previous passive method. This surveillance system found the dengue mortality rate was 1.05 per 100,000 Puerto Rico residents in 2010, the highest rate ever detected. Among adults aged 19–64 years, mortality from dengue (1.17 deaths per 100,000) was higher than from other infectious diseases, including influenza. The utility of this enhanced surveillance system was further proven through the identification of an outbreak of leptospirosis as well as detection of other diseases of public health importance, including melioidosis and meningitis.

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-Barre 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 Rico's 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.

We report two patients that developed severe thrombocytopenia after Zika virus (ZIKV) infection. The first patient had 1000 platelets/μL and died after multiple hemorrhages. The second patient had 2000 platelets/μL, had melena and ecchymoses, and recovered after receiving intravenous immunoglobulin. ZIKV may be associated with immune-mediated severe thrombocytopenia.

Zika virus is a flavivirus transmitted primarily by Aedes species mosquitoes. Increasing evidence links Zika virus infection during pregnancy to adverse pregnancy and birth outcomes, including pregnancy loss, intrauterine growth restriction, eye defects, congenital brain abnormalities, and other fetal abnormalities. The virus has also been determined to be sexually transmitted. Because of the potential risks associated with Zika virus infection during pregnancy, CDC has recommended that health care providers discuss prevention of unintended pregnancy with women and couples who reside in areas of active Zika virus transmission and do not want to become pregnant. However, limitations in access to contraception in some of these areas might affect the ability to prevent an unintended pregnancy. As of March 16, 2016, the highest number of Zika virus disease cases in the United States and U.S. territories were reported from Puerto Rico. The number of cases will likely rise with increasing mosquito activity in affected areas, resulting in increased risk for transmission to pregnant women. High rates of unintended and adolescent pregnancies in Puerto Rico suggest that, in the context of this outbreak, access to contraception might need to be improved. CDC estimates that 138,000 women of reproductive age (aged 15-44 years) in Puerto Rico do not desire pregnancy and are not using one of the most effective or moderately effective contraceptive methods, and therefore might experience an unintended pregnancy. CDC and other federal and local partners are seeking to expand access to contraception for these persons. Such efforts have the potential to increase contraceptive access and use, reduce unintended pregnancies, and lead to fewer adverse pregnancy and birth outcomes associated with Zika virus infection during pregnancy. The assessment of challenges and resources related to contraceptive access in Puerto Rico might be a useful model for other areas with active transmission of Zika virus.

We report a laboratory confirmed case of vertical transmission of dengue in a mother-child pair in the eastern part of Puerto Rico. The clinical course of the pregnant female suggested a GBS infection, but laboratory tests confirmed it was dengue infection, one week after delivery. The male infant was healthy at birth, but one week after birth developed clinical complications related to vertical transmission of dengue. This report targets physicians in dengue endemic countries like Puerto Rico to be aware of the possibility of vertical transmission of dengue in symptomatic pregnant patients, especially around the time of delivery.

In the absence of active blood donation screening, dengue viruses (DENV) have been implicated in only a limited number of transfusion transmissions worldwide. This study attempted to identify if blood from donors testing negative by an NS1-antigen (Ag) enzyme-linked immunosorbent assay (ELISA) but confirmed positive for DENV RNA caused DENV-related disease in recipients during the epidemic years of 2010 to 2012 in Puerto Rico.Donation aliquots testing negative by an investigational NS1-Ag ELISA were stored frozen and retested retrospectively using a research transcription-mediated amplification assay (TMA) detecting DENV RNA. All RNA-reactive donations were subject to confirmatory RNA and antibody testing. Recipient tracing was conducted for all components manufactured from TMA-reactive components. Medical chart review, recipient interview, and follow-up sampling occurred for 42 recipients transfused with TMA-reactive components.Six of 42 recipients developed new-onset fever in the 2 weeks posttransfusion; three (50%) received RNA confirmed-positive, NS1-Ag-negative red blood cell (RBC) units. One recipient of a high-titer unit (7 × 10(7) DENV-4 RNA copies/mL) developed severe dengue, and a second recipient had only fever recorded but had a negative sepsis work-up. New fever attributable to DENV infection in a third recipient was confounded by fever potentially attributable to posttransfusion sepsis.In our retrospective study, NS1-Ag detected 20% of all RNA confirmed-positive donations demonstrating limitations of NS1-Ag ELISA for blood donation screening. We identified one recipient with a clinical syndrome compatible with severe dengue who had received an NS1-Ag-negative but RNA confirmed-positive RBC unit. This investigation illustrates the difficulty in confirming transfusion transmission in dengue-endemic areas among severely ill transfusion recipients.

Aedes species mosquitoes transmit chikungunya virus, as well as dengue and Zika viruses, and bite most often during the day.* Infectious mosquito bites frequently occur in and around homes (1,2). Caribbean countries first reported local transmission of chikungunya virus in December 2013, and soon after, chikungunya virus spread throughout the Americas (3). Puerto Rico reported its first laboratory-positive chikungunya case in May 2014 (4), and subsequently identified approximately 29,000 suspected cases throughout the island by the end of 2015.(†) Because conventional vector control approaches often fail to result in effective and sustainable prevention of infection with viruses transmitted by Aedes mosquitoes (5), and to improve surveillance of mosquito population densities, CDC developed an Autocidal Gravid Ovitrap (AGO) (6) to attract and capture the female Aedes aegypti mosquitoes responsible for transmission of infectious agents to humans (Figure). The AGO trap is a simple, low-cost device that requires no use of pesticides and no servicing for an extended period of time (6).

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, Author summary We conducted a prospective study of acute febrile illness (AFI) in Puerto Rico to better understand the etiology of AFI among all age groups in the tropics. Such findings could assist clinicians to identify disease-specific characteristics, which can then be used to initiate proper patient management. We enrolled 8,996 AFI patients and tested them for dengue viruses 1–4 (DENV 1–4) and 21 other pathogens. A pathogen was detected in 55% of patients, most frequently chikungunya virus (CHIKV, 18%), influenza A or B virus (FLU A/B, 12%), DENV 1–4 (11%), or another respiratory virus (ORV, 10%). Participants with dengue presented later after symptom onset and were hospitalized more often (47%) than patients with another etiology of AFI (27% with ORV, 19% with FLU A/B, and 11% with CHIKV). Predictors of patients with dengue differed by timing of presentation but included eye pain, nausea, and low white blood cell or platelet counts; negative predictors included symptoms of respiratory illness. By enrolling febrile patients at clinical presentation, we identified unbiased predictors of patients with dengue as compared to other common AFI. Findings can be used to diagnose dengue patients to provide early and appropriate clinical management.

Dengue is a potentially fatal acute febrile illness caused by four mosquito-transmitted dengue viruses (DENV-1–4). Although dengue outbreaks regularly occur in many regions of the Pacific, little is known about dengue in the Republic of the Marshall Islands (RMI). To better understand dengue in RMI, we investigated an explosive outbreak that began in October 2011. Suspected cases were reported to the Ministry of Health, serum specimens were tested with a dengue rapid diagnostic test (RDT), and confirmatory testing was performed using RT-PCR and IgM ELISA. Laboratory-positive cases were defined by detection of DENV nonstructural protein 1 by RDT, DENV nucleic acid by RT-PCR, or anti-DENV IgM antibody by RDT or ELISA. Secondary infection was defined by detection of anti-DENV IgG antibody by ELISA in a laboratory-positive acute specimen. During the four months of the outbreak, 1,603 suspected dengue cases (3% of the RMI population) were reported. Of 867 (54%) laboratory-positive cases, 209 (24%) had dengue with warning signs, six (0.7%) had severe dengue, and none died. Dengue incidence was highest in residents of Majuro and individuals aged 10–29 years, and ,95% of dengue cases were experiencing secondary infection. Only DENV-4 was detected by RT-PCR, which phylogenetic analysis demonstrated was most closely related to a virus previously identified in Southeast Asia. Cases of vertical DENV transmission, and DENV/Salmonella Typhi and DENV/Mycobacterium leprae co-infection were identified. Entomological surveys implicated water storage containers and discarded tires as the most important development sites for Aedes aegypti and Ae. albopictus, respectively. Although this is the first documented dengue outbreak in RMI, the age groups of cases and high prevalence of secondary infection demonstrate prior DENV circulation. Dengue surveillance should continue to be strengthened in RMI and throughout the Pacific to identify and rapidly respond to future outbreaks.

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., Author Summary Chikungunya is a mosquito-borne virus that causes an acute febrile illness that often occurs with severe joint pain. The virus first arrived in the Western Hemisphere in late 2013 and has since caused epidemics in much of the Caribbean and the Americas. During the first months of the 2014 epidemic in Puerto Rico, we conducted household-based cluster investigations to identify factors associated with chikungunya virus infection and progression to disease. We found that using air conditioning and citronella candles in and around the home were associated with decreased rates of infection. Symptoms significantly associated with chikungunya virus infection included fever, joint pain, skin rash, and arthritis. Less than one-quarter of participants infected with chikungunya virus that sought medical care were diagnosed with chikungunya and one-in-ten were reported to public health authorities. This investigation demonstrates the importance of household-level behavioral interventions to avoid chikungunya virus infection, as well as the need for rapid diagnostic tests to improve identification of chikungunya patients.

Importance Zika virus (ZIKV) infection during pregnancy is a cause of congenital microcephaly and severe fetal brain defects, and it has been associated with other adverse pregnancy and birth outcomes. Objective To estimate the number of pregnant women infected with ZIKV in Puerto Rico and the number of associated congenital microcephaly cases. Design, Setting, and Participants We conducted a modeling study from April to July 2016. Using parameters derived from published reports, outcomes were modeled probabilistically using Monte Carlo simulation. We used uncertainty distributions to reflect the limited information available for parameter values. Given the high level of uncertainty in model parameters, interquartile ranges (IQRs) are presented as primary results. Outcomes were modeled for pregnant women in Puerto Rico, which currently has more confirmed ZIKV cases than any other US location. Exposure Zika virus infection in pregnant women. Main Outcomes and Measures Number of pregnant women infected with ZIKV and number of congenital microcephaly cases. Results We estimated an IQR of 5900 to 10 300 pregnant women (median, 7800) might be infected during the initial ZIKV outbreak in Puerto Rico. Of these, an IQR of 100 to 270 infants (median, 180) may be born with microcephaly due to congenital ZIKV infection from mid-2016 to mid-2017. In the absence of a ZIKV outbreak, an IQR of 9 to 16 cases (median, 12) of congenital microcephaly are expected in Puerto Rico per year. Conclusions and Relevance The estimate of 5900 to 10 300 pregnant women that might be infected with ZIKV provides an estimate for the number of infants that could potentially have ZIKV-associated adverse outcomes. Including baseline cases of microcephaly, we estimated that an IQR of 110 to 290 total cases of congenital microcephaly, mostly attributable to ZIKV infection, could occur from mid-2016 to mid-2017 in the absence of effective interventions. The primary limitation in this analysis is uncertainty in model parameters. Multivariate sensitivity analyses indicated that the cumulative incidence of ZIKV infection and risk of microcephaly given maternal infection in the first trimester were the primary drivers of both magnitude and uncertainty in the estimated number of microcephaly cases. Increased information on these parameters would lead to more precise estimates. Nonetheless, the results underscore the need for urgent actions being undertaken in Puerto Rico to prevent congenital ZIKV infection and prepare for affected infants.

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly reported as a complication of dengue, a common tropical acute febrile illness. Methodology/Principal Findings After a cluster of pediatric dengue-associated HLH patients was identified during the 2012–2013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008–2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012–2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p ≤ 0.02). Conclusions/Significance During this cluster of dengue-associated HLH cases that was temporally associated with the 2012–2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury., Author Summary Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal medical condition that can occur after a patient has an infection. While HLH is most commonly associated with Epstein-Barr virus infections, it has been reported as a complication of dengue, a common mosquito-borne, acute febrile illness. After a cluster of pediatric dengue-associated HLH patients was identified in Puerto Rico, active surveillance and a case-control investigation was conducted to determine the rate of HLH in children and identify risk factors for HLH following dengue. During 2008–2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Most (91%) dengue-associated HLH patients had illness onset during the 2012–2013 epidemic, however, HLH was not found to be associated with a particular type of dengue virus. Dengue-associated HLH cases were younger than dengue inpatient controls, were hospitalized longer, and were admitted more frequently to the pediatric intensive care unit. Cases had longer duration of fever, and were more likely to have anemia, hepatomegaly and elevated liver transaminases than controls. Physicians in the tropics should be aware that HLH may complicate dengue, and they should evaluate dengue patients who develop anemia and severe liver injury.

Background Leptospirosis is a potentially fatal bacterial zoonosis that is endemic throughout the tropics and may be misdiagnosed as dengue. Delayed hospital admission of leptospirosis patients is associated with increased mortality. Methodology/Principal Findings During a concurrent dengue/leptospirosis epidemic in Puerto Rico in 2010, suspected dengue patients that tested dengue-negative were tested for leptospirosis. Fatal and non-fatal hospitalized leptospirosis patients were matched 1:1–3 by age. Records from all medical visits were evaluated for factors associated with fatal outcome. Among 175 leptospirosis patients identified (4.7 per 100,000 residents), 26 (15%) were fatal. Most patients were older males and had illness onset during the rainy season. Fatal case patients first sought medical care earlier than non-fatal control patients (2.5 vs. 5 days post-illness onset [DPO], p < 0.01), but less frequently first sought care at a hospital (52.4% vs. 92.2%, p < 0.01). Although fatal cases were more often diagnosed with leptospirosis at first medical visit (43.9% vs. 9.6%, p = 0.01), they were admitted to the hospital no earlier than non-fatal controls (4.5 vs. 6 DPO, p = 0.31). Cases less often developed fever (p = 0.03), but more often developed jaundice, edema, leg pain, hemoptysis, and had a seizure (p ≤ 0.03). Multivariable analysis of laboratory values from first medical visit associated with fatal outcome included increased white blood cell (WBC) count with increased creatinine (p = 0.001), and decreased bicarbonate with either increased WBC count, increased creatinine, or decreased platelet count (p < 0.001). Conclusions/Significance Patients with fatal leptospirosis sought care earlier, but were not admitted for care any earlier than non-fatal patients. Combinations of routine laboratory values predictive of fatal outcome should be considered in admission decision-making for patients with suspected leptospirosis., Author Summary Leptospirosis is a common tropical illness that results from exposure to the urine of animals infected with Leptospira bacteria. Because leptospirosis shares signs and symptoms with other common tropical illnesses such as dengue, identification of patients with leptospirosis can be challenging. Early identification of patients with leptospirosis is necessary to initiate antibiotic therapy and in some cases provide in-hospital management. During an epidemic of leptospirosis in Puerto Rico that occurred during a concomitant dengue epidemic, we identified leptospirosis patients by screening specimens from suspected dengue patients. Of 175 leptospirosis patients identified, 26 (15%) died. After comparing leptospirosis patients that died to patients of a similar age that were hospitalized but survived, we observed that fatal cases were more often sent home after their first medical visit. We next identified several routinely available laboratory values from patients’ first medical visit that were associated with patients that died. Clinicians can use such laboratory values to diagnose and hospitalize leptospirosis patients at increased risk for fatal outcome.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal hematologic syndrome characterized by hyperinflammation due to uncontrolled proliferation of activated lymphocytes, resulting in prolonged fever, pancytopenia, jaundice, and hepatosplenomegaly. While infection with Epstein Barr virus (EBV) is the most common recognized cause of infection-triggered HLH, there have been cases associated with other viral infections including dengue. Dengue is an acute febrile illness that is caused by any of four related but serologically distinct, mosquito-borne dengue viruses (DENV-1–4) that are endemic throughout the tropics and subtropics including Puerto Rico, a territory of the United States. Dengue can lead to a wide range of clinical outcomes, ranging from no symptoms or mild fever to potentially fatal severe dengue. In Puerto Rico, dengue most commonly affects adolescents 10–19 years old. Dengue-associated HLH (dengue-HLH) has been described in 26 case reports since 1966, but has not been previously recognized in Puerto Rico. During the start of a dengue epidemic in December 2012, the Centers for Disease Control and Prevention Dengue Branch were notified of several dengue-HLH cases at four hospitals in Puerto Rico. An investigation was conducted to: 1) determine the incidence of HLH in children since 2008; and 2) determine the infecting agent(s) associated with HLH cases. Medical records were queried to identify patients with findings compatible with HLH. To date, 681 records have been reviewed and 38 patients identified that met accepted criteria for HLH. The majority (25 patients) of the HLH cases had diagnostic evidence of DENV infection by anti-dengue IgM Enzyme Linked Immunosorbent Assay (36%) and/or DENV Polymerase Chain Reaction (68%): DENV types -1 and -4 were detected. Other causes of HLH identified were EBV and Cytomegalovirus co-infections (2), Herpes Simplex Virus (2), EBV (1), and systemic onset juvenile arthritis (2). There was one fatal dengue-HLH case (case-fatality rate [CFR]: 4.0%). Dengue-HLH cases ranged in age from 0.1–16 years, 48% were infants, and all resided in northern Puerto Rico. Among children aged 0–16 years, the average annual incidence of dengue-HLH cases in Puerto Rico from 2008 through 2011 was 0.1 cases per 100, 000 versus 2.2 cases per 100,000 in the last 12 months from June 1, 2012 to May 31, 2013, which demonstrates the dramatic increase in recent cases. The number of HLH cases may have been higher since in 14 additional cases with suspected HLH who only fullfilled 4 of the required 5/8 diagnostic criteria, laboratory investigations were incomplete. This is an unusual cluster of dengue-HLH cases in time and space afflicting mostly infants and cannot be explained by heredity. Currently there is no explanation for this outbreak of dengue-HLH. Some cases of dengue-HLH may have been overlooked in the past if severe dengue cases were not investigated for the presence of HLH criteria. We are presently conducting a case-control study to identify risk factors for developing dengue-HLH and determine why in contrast to previous experience infants were predominantly affected. Physicians in dengue endemic areas should be made aware that infection with dengue virus may lead to the hyperinflammatory syndrome HLH. Disclosures: No relevant conflicts of interest to declare.