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Purpura with fever is a worrisome finding in children, raising the possibility of meningococcemia, disseminated intravascular coagulation, or drug eruption. A common cause of purpura among pediatric patients is Henoch-Schönlein Purpura (HSP), with the classic presentation of dependent purpura, renal disease, abdominal pain, and arthritis or arthralgias. Acute hemorrhagic edema of infancy (AHEI), however, is a less common etiology of pediatric purpura with approximately 500 reports in the literature. AHEI presents with purpuric lesions of the face, ears, and extremities, and nonpitting edema of the extremities. Although the lesions have a dramatic onset over a 24- to 48-hour period, the child with AHEI is nontoxic appearing without visceral involvement. Patients with AHEI usually make a complete recovery within 1–3 weeks of presentation with supportive care only. Recurrence of symptoms is rare, described in only three other published reports to our knowledge.
We describe a case of an 8-month-old female who presented with progressive purpura in a nondependent distribution, low-grade fevers, and extremity swelling and who was ultimately diagnosed with AHEI. To our knowledge, this is the first case of AHEI associated with coronavirus NL63 and one of the first to demonstrate recurrence.
An 8-month-old previously healthy female was admitted for evaluation of progressive purpura and extremity swelling. The rash initially began on her inner thighs and rapidly progressed over the course of the day to the soles of her feet, face, and bilateral ears. She also developed swelling of her hands, feet, and right eyelid. Despite the dramatic progression of her rash, she remained happy and playful with normal oral intake.
Her acute symptoms were preceded by a mild cough for one week and two days of bilateral conjunctivitis with clear, mucoid discharge. Review of systems was otherwise negative for diarrhea, bloody stools, abdominal pain, vomiting, gross hematuria, change in urination, or joint swelling or pain.
Vital signs were notable for a fever of 38.5°C and a normal blood pressure of 100/59. Physical exam showed a smiling infant with multiple erythematous and violaceous nonblanching plaques over her face, trunk, feet, and bilateral ears. Nonpitting edema of her hands and feet was also appreciated (Figure 1).
Laboratory testing showed white blood cell count 11,6000 per microliter, platelets 437,000 per microliter, blood urea nitrogen 6 mg/dL, creatinine 0.23 mg/dL, prothrombin time 10.6 sec, and activated partial thromboplastin time 33.7 seconds. Urinalysis was also normal. C-reactive protein was mildly elevated at 3.3 mg/dL (reference range 0.0–1.0 mg/dL).
She was initially started on intravenous ceftriaxone with concern for possible bacteremia. Overnight, her extremity swelling worsened and she developed new purpuric lesions, though remained well appearing. The diagnosis of AHEI was made the following morning based on clinical characteristics and in consultation with a dermatologist and a rheumatologist. No skin biopsy was performed given the classic appearance of the rash. Antibiotics were discontinued. A respiratory viral panel sent on admission returned positive for coronavirus NL63 by nucleic acid amplification testing.
48 hours after the onset of purpura, her rash began to dissipate and fade along with the edema. Corticosteroids were not administered due to this clinical improvement. She had complete resolution of her symptoms three days later.
Three weeks after initial presentation, the patient had a recurrence of periorbital and extremity swelling and purpuric rash without end organ involvement. She had resolution of these symptoms within four days with supportive care only.
Enteric viruses are the etiological agents for a series of health disturbances for commercial chickens around the world. They cause severe economic losses for the poultry industry because they negatively affect productive parameters, causing growth retardation, low feed consumption, high mortality, poor egg and meat production, and Runting-Stunting Syndrome (RSS). These kinds of infections affect mostly young birds, but it is common to find viral infections in birds of all ages, including broilers, layers, and breeders. The main enteric viruses reported to cause enteric diseases are found in single and multiple infections and include the Fowl Adenovirus of group I (FAdV-I); Chicken Parvovirus (ChPV); two viruses from the Astroviridae family: Chicken Astrovirus (CAstV) and Avian Nephritis Virus (ANV); two viruses from the Reoviridae family: Avian Reovirus (AReo) and Avian Rotavirus (ARtV); and a member of the Coronaviridae family, Infectious Bronchitis Virus (IBV). Several laboratory analytical methods have been used to detect enteric viruses in organic tissues from sick and healthy birds. Conventional polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR) are two of the most commonly used methods for diagnosis and characterization of viruses in the poultry industry. The objective of this study was to determine the prevalence of enteric viruses affecting commercial chicken flocks in Brazil, encompassing an analysis of the relationships between single and multiple infections, the age of birds, clinical signs, and geographical distribution in the Brazilian states of Mato Grosso, Goias, Piaui, Ceara, Paraiba, Pernambuco, Bahia, Minas Gerais, Espirito Santo, São Paulo, and Santa Catarina.
Chikungunya virus (CHIKV) (family Togaviridae, genus Alphavirus), is the causative agent of chikungunya fever. After first isolation of CHIKV in 1952 in present-day Tanzania, outbreaks and epidemics were limited to regions of Asia, Africa, and the Pacific Islands. In 2013, CHIKV emerged for the first time in the Americas, with sustained autochthonous transmission and rapid spread through the region [1–3]. The acute symptoms of CHIKV infection are similar to those of infection with other arbovirus species, including Dengue virus (DENV), Zika virus (ZIKV), and Mayaro virus (MAYV), each presenting with a constellation of symptoms including fever, headache, and myalgias/arthralgias. Long-term, CHIKV infections have been linked with persistent arthralgias in a subset of cases; it has also been reported that upwards of 90% of CHIKV-infected individuals are symptomatic, in contrast to findings with ZIKV, where it is estimated that only 20% of infected persons are symptomatic.
The similarity of the clinical presentation of acute-phase arbovirus infections is further complicated by the potential for simultaneous infection with multiple arboviruses. In a recent literature review, co-infections with CHIKV and DENV ranged from 1% to 34% of patients. However, virtually no data are available on frequency of co-infection with CHIKV and arboviruses other than DENV. Even where good laboratory diagnostic facilities are available, identification of co-infections often does not occur, as there is a tendency to cease investigation once an initial pathogen has been identified, and/or identification of a second pathogen may require facilities for virus isolation, which may not be available.
As part of ongoing studies of acute undifferentiated febrile illness in a cohort of school children in rural Haiti, we identified 82 children with RT-PCR-confirmed CHIKV infections during May-August 2014, corresponding with the time period when the Caribbean CHIKV epidemic was moving through Haiti. Specimens were also simultaneously screened by RT-PCR for DENV1-4, then additionally for ZIKV. Aliquots of the plasma specimens were then inoculated onto cell cultures for the isolation of additional pathogens of potential interest. We report here results of these studies, focusing on rates of arbovirus co-infection in our patient cohort and potential sources of origin of the co-infecting strains.
Canine infectious diarrhea has been considered a challenge for veterinarians because of its pathogenic variability and the concurrent presence of viral, bacterial, and protozoan co-infections. Whereas some pathogens remain on the mucosal surface and produce potent enterotoxins that can disrupt the fluid flux, others penetrate and replicate within intact epithelial cells, producing inflammatory damage and/or destroying the host cells, which are overlapping pathological processes. However, many dogs harbor potential pathogens without any clinical signs, so the cause–effect relationships are far from clear.
Molecular tools have been used for the identification and diagnosis of infectious diseases, in addition to conventional culture techniques and antibody-based tools. Among these molecular approaches, the use of real-time polymerase chain reaction (PCR) has greatly improved the sensitivity and sensibility of standard PCR assays of pathogens in canine fecal samples.
Therefore, although a number of pathogens have been individually detected with real-time PCR, including Salmonella spp. and pathogenic Escherichia coli strains, a comprehensive panel of potentially diarrhea-causing pathogens in owned dogs is yet to be established. Therefore, the aim of this study was to investigate pathogenic co-infections in populations of diarrheic and control owned dogs using a real-time PCR analysis of a panel of diarrhea-causing agents.
During the whole study, 3,282 medical consultations were carried out, 29% (955/3282) of
which were coded as common cold or acute upper respiratory infections of multiple and
unspecified sites. Of these 955 common cold cases, a sample of 134 patients who met the
inclusion criteria was obtained, median age 2.9 years (0.1-11.2 y), 49% male. The most
frequent symptoms were coryza (91.8%, 123/134), cough (90.3%, 121/134), fever (56%,
75/134) and wheezing (46.3%, 62/134). Respiratory viruses were detected in 73.9%
(99/134) of nasopharyngeal wash samples (1 sample per patient) with a coinfection rate
of 30.3% (30/99). The laboratory tests findings are described in Table I.
Overall, the antibiotic prescription rate was 39.6% (53/134), among which 60.4% (32/53)
was amoxicillin, 22.6% (12/53) macrolides, 9.4% (5/53) cephalosporins and 7.6% (4/53)
amoxicillin plus sulbactam (Table II). Of 53
patients who received antibiotics during the follow-up, only 30.2% (16/53) received them
judiciously and the other 69.8% (37/53) received them inappropriately. Among these 37
cases with inappropriate use, the clinical justifications for prescription of
antibiotics were: in 37.7% (20/53) to treat nasal or postnasal discharge during the
first week of common cold symptoms in patients without fever, in 18.9% (10/53) to treat
persistence of cough during the first week of symptoms, in 11.3% (6/53) to treat common
cold and in 1.9% (1/53) to treat wheezing symptom.
Among 75 children who had fever at the onset of symptoms, 45.3% (34/75) were prescribed
antibiotics whereas 32.2% (19/59) of those who did not have fever at the onset of
symptoms received antibiotics. Thus, there was no difference in the proportion of
antibiotic prescriptions between children who had fever at the onset of symptoms and
those who did not (p = 0.123).
Of a total of 53 children who received antibiotics, 34 presented fever at onset of
symptoms and of these, 29.4% (10/34) received judicious prescription of antibiotics. Of
the remaining 19 children who did not have fever at the onset of common cold symptoms
and received antibiotics, 31.6% (6/19) were prescribed antibiotics judiciously. Thus,
there was also no difference for judicious prescription of antibiotics between children
with fever and those without fever at the onset of common cold symptoms (p = 0.869).
The average time to the resolution of symptoms of children with signs of secondary
bacterial infection was of 16.7 days and, within this group, all children received
antibiotics. Among children with no signs of bacterial infection, the average time to
the resolution of symptoms was 8.9 days for the group that received antibiotics and 7.0
days for the group that did not.
Among patients with respiratory virus monoinfection, all patients with influenza
received antibiotics inappropriately (10/10), whereas those with respiratory syncytial
virus were prescribed antibiotics inappropriately in 60% (3/5) and those with rhinovirus
were prescribed antibiotics inappropriately in 44.4% of cases (5/9) (p = 0.016). Also,
of seven patients coinfected with influenza, 71.4% (5/7) received antibiotics
inappropriately, as showed in Table II. None of
the patients were vaccinated against influenza by the time of the study.
level and the use of antibiotics
Historical information as well as microbial sequencing and phylogenetic constructions make it clear that infectious diseases have been emerging and reemerging over millennia, and that such emergences are driven by numerous factors (Table 1). Notably, 60 to 80 percent of new human infections likely originated in animals, disproportionately rodents and bats, as shown by the examples of hantavirus pulmonary syndrome, Lassa fever, and Nipah virus encephalitis–. Most other emerging/reemerging diseases result from human-adapted infectious agents that genetically acquire heightened transmission and/or pathogenic characteristics. Examples of such diseases include multidrug-resistant and extensively drug-resistant (MDR and XDR) tuberculosis, toxin-producing Staphylococcus aureus causing toxic shock syndrome, and pandemic influenza–.
Although precise figures are lacking, emerging infectious diseases comprise a substantial fraction of all consequential human infections. They have caused the deadliest pandemics in recorded human history, including the Black Death pandemic (bubonic/pneumonic plague; 25–40 million deaths) in the fourteenth century, the 1918 influenza pandemic (50 million deaths), and the HIV/AIDS pandemic (35 million deaths so far),.
Cryptococcosis is the leading cause of meningitis in adults living with HIV in sub-Saharan Africa1,2. In 2008, the number of cryptococcal meningitis (CM) cases in this region was estimated to be 720,000 (range 144,000–1.3 million)3. Recent estimates from 2014 indicate that over 160,000 (95%CI 113,600–193,900) cases of CM, including more than 130,000 deaths occurred in sub-Saharan Africa4. This significant decrease in the absolute number of cases from 2008 to 2014 seems to be related to the scale-up of effective antiretroviral therapy (ART)5. However, the proportion of AIDS-related deaths due to Cryptococcus remains similar (around 15%), representing the second most common cause of AIDS-related mortality in adults, after tuberculosis4. Cryptococcal infection is believed to be acquired by inhalation of fungal cells from the environment. In immunocompetent hosts, the pathogen can be cleared or establish a latent infection6. In immunocompromised patients, Cryptococcus may induce pneumonia and its dissemination to the central nervous system (CNS) causes meningitis, the most severe form of the infection, which is fatal without appropriate treatment. In low income countries, the one-year mortality of CM, even in HIV-infected patients in care, has been estimated to be as high as 70%4.
Human cryptococcal infections were traditionally attributed to Cryptococcus neoformans until Cryptococcus gattii was classified as a distinct species by molecular methods in 20027. Cryptococcus gattii is further divided into four molecular types (variety gattii; VGI-VGIV) and little is known about C.gatti infections in Africa, where this pathogen has been isolated from both clinical and environmental samples8. Most VGIV strains have been described in the southern part of Africa, whereas VGI and VGII strains have been reported in central Africa8. C. gattii infections were thought to occur mainly in the tropics9 until 2004, when an outbreak of C. gattii in North America was recognized10. This outbreak was caused by VGII strains and included the emergence of hypervirulent variants11. Current knowledge on the epidemiology and clinical presentation of C. neoformans infection is clearly greater than that related to C. gattii. C. neoformans infections occur predominantly in people infected with HIV or with other immunocompromising conditions, whereas C. gattii infections have been mainly described in apparently immunocompetent patients9. Autopsy findings reveal that the CNS and the lungs are the organs most frequently affected in disseminated infections12,13, which may also affect multiple organs, especially in HIV-infected patients14. However, reported autopsy series do not usually include cryptococcal species identification, and therefore, knowledge regarding the histopathology of C. gattii remains limited.
In the present study, we determined the Cryptococcus-associated mortality of a series of 284 autopsies performed in two hospitals located in high prevalence HIV areas, Mozambique in sub-Saharan Africa and the Brazilian Amazonia. We also analysed the clinical presentation, management, and histopathological and microbiological findings of 17 cases of fatal cryptococcal infection.
Bovine respiratory disease complex (BRDC) is a major problem for cattle breeders worldwide, causing serious economic losses. BRDC is associated with infection by certain viruses, bacteria, and parasites (33). In addition to these infectious agents, stress factors such as transport, gestation, and poor management conditions play an important role in the onset of the disease (30). Bovine herpes virus 1 (BHV-1), bovine respiratory syncytial virus (BRSV), and bovine parainfluenza virus-3 (BPIV3) are the most common viral agents of the respiratory system. Some opportunistic agents (Mannheimia haemolytica, Pasteurella multocida, Haemophilus somnus, and Mycoplasma spp.) contribute to the appearance of clinical signs and thus increase mortality and cause losses in the herds (18). Suppressed immunity also has an important role in the prognosis. Diseases such as bovine leucosis and bovine viral diarrhoea suppress immunity and lead to more animal loss by worsening clinical symptoms.
BPIV3 (the new name of which is bovine respirovirus 3) is an RNA virus assigned to the Paramyxoviridae family under the Respirovirus genus. BRSV (the new name of which is bovine orthopneumovirus) is in the Pneumoviridae family under the Orthopneumovirus genus. To date, three genotypes of BPIV3 have been described. These genotypes, termed A, B, and C, were differentiated based on phylogenetic analysis. Genotype A strains have been isolated in North America, China, and Japan. Genotype B was originally found in Australia. Isolations of genotype C were in China, South Korea, and Japan. In addition, all three genotypes have been reported in Argentina (23).
Initially BRSV subgroups were identified (A, B, and AB or intermediary) based on monoclonal antibody and polyclonal sera analyses against F and G proteins (31). Additionally, Valarcher et al. (36) proposed that six genetic subgroups may be found in BRSV strains, when F, G, and nucleoprotein sequences are phylogenetically analysed by maximum-likelihood algorithms. Therefore, six subgroups were detected in BRSV. These subgroups termed I (the subgroup B prior to the recommendation of Valarcher et al. (36)), III (subgroup A), and II, IV, V, and VI (subgroup AB) were differentiated based on phylogenetic analysis. Subgroup I consists of European strains (UK and Switzerland). Subgroup III includes viruses exclusively from the USA. Subgroup II aggregates strains from the Netherlands, Belgium, France, Denmark, Sweden, and Japan. Subgroup IV is of European and USA strains while subgroups V and VI are found only in French and Belgian isolates (29, 36). Subgroup VII was detected in later years (9) and some strains are known which are still not classified (these are regarded as untyped) (10).
BPIV3 and BRSV can cause mild symptoms or subclinical disease when present alone. However, when there is a co-infection, they may cause bronchopneumonia, severe cough, high fever, and nasal discharge and contribute to a more serious clinical course of infection (33). Regardless of the infecting agent in BRDC, clinical symptoms may be similar and the process of detecting the underlying primal agent may be hindered due to mixed bacterial infections. This situation makes viral diagnosis difficult and decreases the specificity and sensitivity of the molecular methods (when compared to immunofluorescence antibody tests) (15).
Data on virological detection of these agents in Turkey is limited (2, 6), but there are more studies on seroprevalence of these viruses among cattle herds. The studies reported lowest and highest seropositivity of 11% (1) and 92.8% (13) for BPIV3 and 28% (1) and 94% (13) for BRSV. Serological studies on BRSV and BPIV3 were previously conducted in different geographic regions of our country. In these studies the following percentage values for BRSV and BPIV3 prevalence were determined respectively: Alpay et al. (5) 26.6% and 44.6%, Alkan et al. (3) 62.0% and 44.6%, Avci et al. (7) 78.2% and 85.6%, Çabalar and Can Sahna (11) 67.3% and 18%, Yavru et al. (40) 46% and 53.9%, and Yesilbag and Gungor (41) 73.0% and 43%. These studies were conducted either countrywide (3) or in selected regions (40, 41).
The aim of this study was the detection and molecular characterisation of BPIV3 and BRSV strains retrieved from nasal swabs and lung samples of cows in the eastern region of Turkey. The determination of BRSV and BPIV3 types and associated co-infections for respiratory system infections was conducted.
Zika virus (ZIKV) is a recently emerged mosquito-borne virus, which in 2016 was declared as an international public health emergency by the World Health Organization (WHO, http://www.who.int/csr/en/). ZIKV is a member of the Flavivirus genus that belongs to the Flaviviridae family and is closely related to other mosquitoes-transmitted flaviviruses of public health relevance such as Dengue virus (DENV), Yellow fever virus (YFV), Japanese encephalitis virus (JEV) and West Nile virus (WNV). ZIKV was first isolated in 1947 of a sentinel rhesus monkey in the Zika forest of Uganda and has been associated with sporadic human cases detected across Africa and Asia, resembling a mild version of DENV or Chikungunya virus (CHIKV). These similarities with DENV and CHIKV has interfered with ZIKV diagnosis and most probably underestimated the number of cases for ZIKV infections. Symptomatic disease generally is present with a mild febrile illness characterized by fever, rash, muscle pain, headache and conjunctivitis, although as up to 80% of the ZIKV cases are asymptomatic. However, the outbreak in the island of Yap in 2007, French Polynesia in 2013–2014 and the massive epidemic that emerge in Brazil in 2015 have caused major concerns due to the association of ZIKV infection with severe congenital abnormalities, including microcephaly in infants and an increased risk of Guillain-Barré syndrome in adults. ZIKV is mainly transmitted to people through the bite of an infected Aedes spp. mosquito (Ae. Aegypti and Ae. Albopictus), which carries a high risk for pregnant woman due to the ability to cross the placenta and infected fetal nervous tissues. In addition to maternal-fetal transmission, ZIKV can also be transmitted from mother to child during pregnancy or spread through sexual contact, breastfeeding, blood transfusion and non-human primate bites.
Zika virus (ZIKV) is an emergent arthropod-borne virus that belongs to the genus Flavivirus of the Flaviviridae family [International Comittee on Taxonomy of Viruses (ICTV), 2017]. This virus is primarily transmitted through the bite of the Aedes mosquito (Zanluca and Duarte dos Santos, 2016). Unlike most other flaviviruses, however, person-to-person ZIKV transmission is possible, although the contribution of this transmission mode to maintaining an epidemic is unclear. Transmission by sexual and perinatal interactions and from blood and platelet transfusions has been described (Mlakar et al., 2016; Noronha et al., 2016; Miner and Diamond, 2017).
In general, ZIKV infection in humans is characterized as a self-limiting disease, and the most frequent signs and symptoms are low fever, myalgia, rash, arthralgia, headache and conjunctival hyperemia (Duffy et al., 2009; Zanluca et al., 2015). Nevertheless, cases of neurological manifestations, such as Guillain-Barré syndrome (Beckham et al., 2016; Noronha et al., 2016; Schuler-Faccini et al., 2016), have been reported in patients diagnosed with ZIKV. In addition, ZIKV infection during pregnancy has been associated with fetal malformations. Brain microcalcification and other central nervous system disorders, ocular abnormalities, and arthrogryposis are all a part of congenital Zika syndrome (Brasil et al., 2016; Melo et al., 2016; Schuler-Faccini et al., 2016). By March 17, 2017, thirty-one countries or territories in the Americas had reported central nervous system malformations that were potentially associated with ZIKV infection, and Brazil is the most affected country to date [World Health Organization (WHO), 2017].
Since June 2015, we have been receiving samples of serum, urine and other body fluids for ZIKV diagnosis. Additionally, during the peak of the ZIKV outbreak in Brazil, in agreement with the local health authorities, most pregnant women in Paraná State suspected of having ZIKV infection were monitored. Samples of tissues, such as the placenta and umbilical cord, as well as fetal tissues (in the case of stillbirths), all of which were collected at the time of delivery, were sent to our laboratory for analysis.
Here, we present a case series in which we analyzed placental tissues from women infected with ZIKV at different pregnancy stages, focusing on the anatomopathological and morphometric findings, target cells and viral persistence.
For this study, we used 270 positive samples of single and multiple enteric viral infections from broilers, layers and breeders of different ages, collected from eleven Brazilian states: Mato Grosso, Goias, Piaui, Ceara, Paraiba, Pernambuco, Bahía, Minas Gerais, Espirito Santo, São Paulo, and Santa Catarina. The samples were collected between 2010 and 2017. Each sample was composed of a pool of maximum five organs of the same type, and each sample came from different farms across the mentioned states. The main reported symptoms of the birds were enteritis, diarrhea, decreased feed absorption, a decrease in production, mortality, signs of respiratory disease, and stunting syndrome. Samples were processed and analyzed by conventional PCR and RT-PCR for detection of seven main enteric viruses reported in Brazil: FAdV-I, ChPV, CAstV, ANV, IBV, AReo, and ARtV. The organs used for viral detection were the intestines, liver, pancreas, and caecal tonsils, and also cloacal swabs were used for fecal samples. The results were categorized according to the viral infection in each sample, the type of birds (broilers, layers, or breeders), the age of birds (days for broilers and weeks for layers and breeders), clinical signs, and origin of the samples based on their geographical distribution in Brazil. Known positive samples for FAdV-1, ChPV, CAstV, ANV, and ARtV, validated through Sanger sequencing, and commercial vaccines for IBV and AReo were used as positive controls.
Zika virus (ZIKV) is a single-stranded, positive sense RNA flavivirus,1 spread primarily through the bite of infected Aedes mosquitos.2–4 However, during the recent outbreak in South and Central America, novel mechanisms of ZIKV transmission have been described including sexual and transplacental transmission.5–7 The virus is endemic in parts of Africa and Asia and has spread unabated through South America, Mexico and the Caribbean over the last 2 years.8,9 Factors including increased global travel and an expansion of the range of Aedes mosquitos owing to climate change portend further spread of this virus, expanding its range in the southern United States over the next few years.5,9
ZIKV infection presents with a prodrome of myalgias, arthralgias, malaise and low-grade fever with a rash appearing approximately 7 days post infection that may occur with conjunctivitis and retro-orbital pain. The clinical presentation is similar to, albeit less severe than, chikungunya and dengue viral infections, which are also transmitted through the same mosquito vectors. During the French Polynesian outbreak in 2013, an increased risk of Guillain Barre’ syndrome was identified in infected individuals.4,6,10 Alarmingly, during the recent outbreak in South and Central America, microcephaly and other congenital abnormalities in infants have been observed in mothers who were infected by ZIKV during pregnancy.11–13 In April 2016, the United States Centers for Disease Control and Prevention confirmed the link between ZIKV infection and microcephaly establishing ZIKV as a teratogen. There are currently no licensed therapies or vaccines against ZIKV infection. Therefore, the development and evaluation of potential vaccines to control and halt the spread of this rapidly emerging infectious agent is of high priority.14 Here we describe the development and evaluation of a synthetic ZIKV prME DNA vaccine delivered by electroporation for its immunogenicity and its impact on ZIKV infection in a pathogenic animal challenge model.
The emergence of the novel influenza A/H1N1 pandemic virus (H1N1pdm) significantly affected the utilization of healthcare resources and increased morbidity and mortality in children and young adults,. From April through September 2009, during the fall/winter in the southern hemisphere, Brazil experienced the first wave of the H1N1pdm virus, and by the end of December 2009, over 1600 H1N1pdm-related deaths had been reported in Brazil.
Emerging data on the clinical course of severe H1N1pdm infection have allowed the identification of high-risk groups, which include pregnant women and patients with morbid obesity,. However, an analysis of the impact of this novel virus in a highly susceptible population, such as cancer patients, through clinical and virological perspectives, needs to be highlighted,,,,,. The atypical clinical presentation of influenza infections in cancer patients, which delays clinical suspicion, antiviral treatment and adequate prevention of viral transmission, is a major challenge for clinical management in this population. Cancer patients are more likely to suffer from severe seasonal influenza infections,, and prolonged viral shedding, as has been reported for an H3N2 seasonal virus. Prolonged shedding and the development of oseltamivir resistance in cancer patients infected with the H1N1pdm virus have not been thoroughly evaluated. Data on these aspects could have major implications for the clinical management and infection control practices for H1N1pdm-infected cancer patients.
Because the analysis of this novel viral infection in cancer patients is an important component of the 2009 pandemics, we conducted a prospective cohort study aimed at evaluating the clinical course of influenza infection, the duration of viral shedding, H1N1pdm evolution and the emergence of antiviral resistance in hospitalized cancer patients with a severe H1N1pdm infection in a reference cancer center during the winter of 2009 in Brazil.
Real-time PCRs were validated analytically and clinically. For the analytical validation, each assay was required to meet six validation criteria: amplification efficiency, linearity, intra-run reproducibility, inter-run reproducibility, r2 value, and signal-to-noise ratio of the fluorescent signal using a specific synthetic positive control. Each assay had an analytical sensitivity of 10 molecules and an amplification efficiency between 95% and 100%. Clinical samples were selected based on a reference method for each test and a correlation study was performed. The analytical specificity of all real-time PCR tests was confirmed by resequencing the clinical sample material using additional primer pairs positioned outside the synthetic positive control. Diagnostic sensitivity and specificity based on comparisons with reference testing methods were in the high 90% for each real-time PCR test. Gold standard tests included the immunofluorescence antibody assay for CDV, enzyme-linked immunosorbent assay for CPV-2 and Giardia, and real-time PCR performed at the University of California Davis for CCoV, Cryptosporidium, and Salmonella.
To validate each PCR panel test result, seven quality controls were used for each sample tested: 1) PCR positive controls (quantitative); 2) PCR negative controls; 3) negative extraction controls (five per 96-well plate); 4) DNA internal sample control targeting the host 18S rRNA to quantify the DNA in the submitted diagnostic sample; 5) RNA internal sample control targeting the host 18S rRNA to quantify the cDNA in the submitted diagnostic sample after reverse transcription; 6) control to monitor environmental contamination; and 7) spike in the internal positive control to monitor PCR inhibition. These controls were used to assess the functionality of the PCR test protocol (1), the absence of contamination in the reagents (2) and laboratory (5), the absence of cross-contamination during the extraction process (3), the quality and integrity of the DNA and RNA as a measure of sample quality (4 and 5), the RT protocol (5), the absence of random positive PCR signals within the PCR laboratory (6), and the absence of PCR inhibitory substances carried over from the sample matrix (7).
Diarrhea in piglets represents one of the major health problems affecting swine production farms. In fact, enteric infections have become one of the main causes of morbidity and mortality in neonatal farm pigs, resulting in economic losses especially when suckling and weaned piglets are affected. The disease has a multifactorial etiology influenced by environmental, management and physiological factors that include interaction of pathogens, farm procedures, and host immunity.
Diarrhea in piglets can be caused by several pathogenic agents, including Campylobacter spp., Clostridium perfringens, Escherichia coli, Salmonella spp., group A rotavirus (RV-A), coronaviruses (transmissible gastroenteritis virus—TGEV; porcine epidemic diarrhea virus—PEDV), as well as by nematode and protozoan parasites. However, most studies have focused on a few or only one agent and consequently our understanding of the relative importance of pathogens and other factors may have strong biases.
The present case–control study was carried out with piglets under field conditions in the state of São Paulo, Brazil, in order to evaluate the relative significance of pathogens in the development of intestinal disorders. It integrates microbiologic and epidemiologic data through the investigation of pathogenic agents and virulence factors in case and control animals.
The demographic features, HIV status, clinical presentation and management of the 17 patients with fatal cryptococcal infection are summarized in Table 1. The median age was 34 years (range 6–44 years); 11 cases (65%) were men. In 13 out of the 16 (81%) HIV-infected patients, a positive HIV test result was reported in the clinical records and was apparently unknown by the clinician in the other 3 cases. Four out of the 16 (25%) HIV-infected patients were on ART, but the duration of ART was only reported in one case.
Headache was the most common symptom (13 patients, 76%), followed by fever and vomiting (eight cases each, 47%). Upon admission to hospital, eight patients (47%) were confused and/or agitated, two patients (12%) were lethargic, and another two (12%) were fully comatose. Meningeal signs were detected in seven patients (41%). The mean time from admission to death was 9.3 days (95%CI: 2.4–16.2). Cryptococcal infection was considered the first clinical diagnostic option in only 4/17 (23%) of the confirmed cases, whereas it was included in the differential diagnosis in eight patients (47%). Antifungal treatment (fluconazole or Amphotericin B) had been prescribed to seven patients but to only five of the clinically suspected cases. Seven of the patients (41%) died within 72 hours of admission, and 12 out of the 16 HIV-positive patients (75%) died within one week of admission.
The clinical records of the remaining 267 cases included in this study were reviewed for clinical diagnosis of cryptococcal infection. Among these, three HIV-infected patients were clinically diagnosed with cryptococcal meningitis, but no evidence of cryptococcal infection was found in the autopsy (the cause of death was identified as toxoplasmosis in two cases and tuberculosis in one case).
Viruses belonging to the Astroviridae (AstV) family are spherical, non-enveloped, 28–30 nm in size, with a surface that forms a characteristic star-like structure.1 The RNA genome of AstV ranges from 6.8 to 7.9-kb in size, polyadenylated at the 3′ end, and contains three ORFs designated as ORF1a, ORF1b and ORF2. ORF1a encodes a protease, ORF1b encodes an RNA-dependent RNA-polymerase,2, 3 while ORF2 encodes the viral capsid structural polyprotein that is required for virion assembly.4
The viral classification was previously based on the host and consisted of two genera, Avastrovirus and Mamastrovirus. However, recent characterization of novel astroviruses has taken in consideration that isolates from different animal species can be genetically similar, while genetically diverse viruses can be isolated from the same animal species.2 Based on this analysis, the International Committee on Taxonomy of Viruses renamed canine astrovirus as Mamastrovirus 5 (MAstV5).5
Astroviruses have been detected in fecal samples from a wide variety of mammals and birds that are associated with gastroenteritis.2 In children, AstVs are the second most common cause of gastroenteritis after rotaviruses.2, 6 Human AstVs can also cause significant disease in the elderly7 and immune-compromised patients.8, 9 In addition to enteric manifestations, AstVs have been associated with fatal hepatitis in ducks,10 interstitial nephritis in young chickens,11 stunting and pre hatching mortality in duck and goose embryos,12 as well as shaking mink syndrome13. Recently, an AstV was also hypothesized to be the causative agent of nonsuppurative encephalitis in cattle.14
Since the 1980s, astrovirus-like particles have been reported in dogs with and without diarrhea.15, 16, 17 To date, canine astroviruses or astrovirus-like particles infecting dogs have been reported in several countries.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Despite the detection of MAstV5 in association with gastroenteritis in dogs, which suggests a possible role for MAstV5 as a canine enteric pathogen, the association of MAstV5 with clinical disease remains obscure in such reports. Here, we investigated the presence of MAstV5 using RT-PCR in fecal samples from dogs of different ages with and without diarrhea. The partial genomes of selected MAstV5 RNA-positive samples were also sequenced to perform a phylogenetic analysis comparing them with the MAstV5 sequences described in the literature as the cause of enteric disease.18, 20, 23, 26 Additionally, MAstV5 was proposed to be classified in four putative genotypes.
Rhinovirus infections are among the most frequent causes of the common colds (18). It is the most common etiology of viral respiratory infections among diverse populations, including adults, children and more recent studies have linked HRVs to more severe lower respiratory illnesses in otherwise healthy young children (11–12), immunocompromised (4, 6), and elderly patients. (5, 13, 23). In Brazil, there are few HRV studies, Arruda et.al. (1991), realized the first Brazilian study detecting a 45.5% rate on symptomatic children in Fortaleza – CE. Another study realized in Salvador – BA also showed a high prevalence (48.5%) (Souza ,2003). The only study describing adults was realized by Bellei and colleagues (2007) detecting 37.7%.
The dynamic of rhinovirus transmission is relevant to address for the epidemiology characteristics of infection within families, schools and nosocomial outbreaks. Rhinovirus can be easily transmitted from person to person mainly through hand contact with infected respiratory secretions (15). Studies of asymptomatic infected individuals pointed to 15 – 30% rates (9, 19, 14, 20, 7, 19) of HRV infection but the role of infected subjects as reservoirs for secondary cases infections is unknown.
Many studies have investigated the occurrence of rhinovirus among community cases but there is a lack of information about the frequency of rhinovirus asymptomatic cases. We investigated HRV infections rates on selected populations of a pair of one child and one family member, health care workers (HCW), and immunocompromised patients with and without respiratory symptoms from June to September.
In this study, a total of 191 nasal swab (NS) specimens were collected from three groups. One hundred and eleven health care workers (HCW) from São Paulo Hospital, 36 pairs of one child and one family member and 8 blood marrow transplanted hospitalized patients (BMT). They were considered eligible symptomatic patients if possible viral etiology within 7 days of symptoms onset. The clinical criterion was presentation of at least one respiratory symptom (cough, sore throat, or nasal congestion) and one constitutional symptom (headache, malaise, myalgia, chills). For asymptomatic patients the criteria was the absence of respiratory symptoms up to one week before sampling. All subjects were interviewed by a research team after evaluation by a physician. Written informed consent was obtained from all adult participants; parents provided consent on behalf of children participants and a questionnaire was applied including demographic data, place of work, their clinical presentation and household children contact.
The symptomatic group included subjects with acute respiratory infections (ARI): children, BMT patients and health care workers. The asymptomatic group included one parent of each symptomatic children, health care workers caring for BMT symptomatic patients or others referring a close contact with symptomatic patient in the hospital.
The nasal swab was obtained from the single nostril from a depth of 2 – 3 cm by using a sterile swab that was then inserted into a vial containing 2.0 ml of viral transport medium (Cultilab, Brazil). The samples were immediately transported to the Clinical Virology Laboratory for routine respiratory viruses testing. All samples were stored at -70ºC until analyzed.
For each sample the viral RNA was extracted using QIAamp Viral RNA extraction Kit (QIAGEN, Germany), according manufacturer´s instructions. Amplification of 5’NCR and VP4/VP2 genes of HRV was done by RT-PCR assay described elsewhere (17–18), with minor modifications. The eluted RNA was transcribed into cDNA with Moloney Murine Reverse Transcriptase (MMLV-RT; Invitrogen, USA) and virus specific oligonucleotide primer, for 1 h at 37°C. After, MMLV-RT denaturation at 70°C, virus-specific oligonucleotide primer (0.6µM), 2.5U Platinum Taq DNA Polymerase (Invitrogen, USA), 1x PCR Buffer, 0.2mM each dNTP, 3.5mM MgCl2 and nuclease-free water were added. The amplification condition was performed in a thermo cycler under the following settings: initial denaturation at 95° for 10 min, followed by 40 cycles consisting of denaturation (45 sec at 95°), annealing (45 sec at 61°C), and DNA extension (1 min at 72°C). The presence of PCR products were visualized on an 1,5% agarose gel electrophoresis according to their 549bp molecular weight. Positive (HRV-39) and negative controls (water) were tested in all reactions.
Descriptive statistics consisted of the characterization of the studied individuals and the assessment of symptomatology and rhinovirus infection through calculation of the respective percentages, median value and range. Bivariate analysis consisted of Fisher’s Exact Test for the comparison of categorical values, with a significance level of p < 0.05. In multivariate analysis, non-conditional logistic regression was used to identify associations between presence of symptomatology, groups of individuals and rhinovirus infection status. All reported values are two-tailed. The dependent variable was presence of rhinovirus infection and the independent variables were presence of symptomatology and groups of individuals. The results were presented as odds ratio (OR) with the respective 95% confidence interval (CI) and p value. All data were entered into and analyzed by using SPSS version 11.0 (SPSS Inc., Chicago, IL, USA).
Epidemiological and clinical characterization of patients is shown in Table 1.
A total of 191 samples from both symptomatic (81) and asymptomatic cases (110) were tested for the presence of rhinovirus and 23 samples (12%) were positive. HRV was detected in 23.5% (19/81) of symptomatic subjects, compared with 3.6% (4/110) of asymptomatic subjects. The HRV infection was associated with the presence of symptoms [p <0.0001, OR 8.1 (95% CI 2.6 – 25.0)].
Table 2 shows the HRV infection rates among symptomatic and asymptomatic individuals, divided by groups. Six isolated cases of symptomatic parents negative for HRV were excluded from this analysis. There were no significant associations.
The symptoms reported by symptomatic group were fever (38.5%), coryza (86.7%), cough (74.7%), headache (21.7%), sore throat (35%), myalgia (12%). Wheezing was observed in 39% of children, but none of them were HRV positive. The symptoms among positive children cases were coryza (100%), cough (77.8%) and fever and sore throat (22%).
The rate of rhinovirus infection among a pair of asymptomatic parent of a rhinovirus symptomatic child was 2.8% (1/36). This was the only case with a close contact with a laboreatory confirmed patient. The others three asymptomatic infection had no close contact with positive symptomatic studied patients. Two symptomatic patients reported close contact a BMT patient and his nurse.
Rhinovirus infections occurred all over the year in Brazil (2). There is a lack of studies about asymptomatic rhinovirus infections. The majority of reported data regarding asymptomatic rhinovirus infections have been conducted in hospitalized children elsewhere and high rates were reported -12% to 45% (16, 14, 7, 3). Jartti et al. (2008) reviewed many studies describing asymptomatic subjects with high respiratory virus detection rates using PCR techniques. Van Kraajj and colleagues (2005) identified etiology in 63% and 9% of symptomatic and asymptomatic adult stem cell transplants recipients respectively, and rhinovirus was the predominant pathogen detected.
In our study, HRV was detected more frequently in symptomatic than asymptomatic individuals as previous reported (21, 22, 10) and a low rate as identified by Johnson et al. (1993) in their study among in immunocompetent adults (4%). Discrepancies among different studies may be explained by the fact that most of them included hospitalized children instead of community population. Indeed nosocomial transmission may occur without clinical expression.
Health care workers group had a 25.8 % rate. Bellei and colleagues (2007) reported the detection of HRV in 37.7% of symptomatic health care workers samples. Professional profile is an important transmission pathway in hospitals. Long-term clinical studies can clarify the impact of this reservoir in the transmission of the virus for patients (10).
We found a high frequency of rhinovirus infection in parents than health care works. The study from Bellei and colleagues (2008) also reported that 39% of those HCW had exposure to children up to 5 years old and rhinoviruses were detected in half of the personnel from pediatric wards.
Despite of the small number of subjects included, our study showed lower detection in selected asymptomatic individuals in contrast to previous studies that found higher frequencies on epidemiological surveys. Further studies would contribute to better understand the dynamic of rhinoviruses infections.
Two major categories of emerging infections—newly emerging and reemerging infectious diseases—can be defined, respectively, as diseases that are recognized in the human host for the first time; and diseases that historically have infected humans, but continue to appear in new locations or in drug-resistant forms, or that reappear after apparent control or elimination. Emerging/reemerging infections may exhibit successive stages of emergence. These stages include adaptation to a new host, an epidemic/pathogenic stage, an endemic stage, and a fully adapted stage in which the organism may become nonpathogenic and potentially even beneficial to the new host (e.g., the human gut microbiome) or stably integrated into the host genome (e.g., as endogenous retroviruses). Although these successive stages characterize the evolution of certain microbial agents more than others, they nevertheless can provide a useful framework for understanding many of the dynamic relationships between microorganisms, human hosts, and the environment.
It is also worth noting that the dynamic and complicated nature of many emerging infections often leaves distinctions between emerging and reemerging infections open to question, leading various experts to classify them differently. For example, we describe as “reemerging” new or more severe diseases associated with acquisition of new genes by an existing microbe, e.g., antibiotic resistance genes, even when mutations cause entirely new diseases with unique clinical epidemiologic features, e.g., Brazilian purpuric fever. Similarly, we refer to SARS as an emerging disease a decade after it disappeared, and apply the same term to the related MERS (Middle East Respiratory Syndrome) β coronavirus which appeared in Saudi Arabia in late 2012.
Hepatitis C Virus (HCV) infection treatment has dramatically improved thanks to the introduction of direct-acting antiviral agents (DAAs). These antivirals have significantly increased response rates (up to 98%) and greatly reduced treatment duration. Currently available DAAs are classified into four categories given their molecular targets in the HCV replication cycle: (1) NS3/4A protease inhibitors (PIs) bind to the active site of the NS3/4A protease; (2) NS5A inhibitors interact with domain 1 of the NS5A dimer, although the exact mechanism of NS5A inhibition remains to be fully elucidated; (3) nucleos(t)ide analog NS5B polymerase inhibitors are incorporated into the nascent RNA chain resulting in chain termination by compromising the binding of the incoming nucleotide; (4) nonnucleoside NS5B polymerase inhibitors interact with either the thumb 1, thumb 2, palm 1, or palm 2 domain of NS5B and inhibit polymerase activity by allosteric mechanisms [2–4]. However, the extreme mutation and high replication rates of HCV, together with the immune system pressure, lead to a remarkable genetic variability that can compromise the high response rates to DAAs due to the preexistence of resistance-associated substitutions (RASs) [5, 6].
Each drug or class of DAA is characterized by specific resistance profiles. The likelihood that a DAA will select for and allow outgrowth of viral populations carrying RASs depends on the DAA's genetic barrier to resistance (the number and type of mutations needed to generate an amino acid substitution that confers resistance), the viral fitness (replicative capacity) of the resistant variant, and viral genotypes and subtypes [7, 8].
The prevalence of RASs in treatment-naïve patients has been broadly reported worldwide [9–16]. However, apart from Brazil and Argentina, this issue has not been fully addressed in other South American countries yet [9, 17–19]. The lack of information in relation to preexisting baseline RASs, added to the high cost of these new drugs, are the major limiting factors for the broad implementation of these new therapies in Uruguay as well as in other Latin American countries (low- or lower-middle income).
In this study, we explored the presence of resistance variants to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients chronically infected with hepatitis C. Here, we aimed to contribute to the knowledge of the circulation of HCV resistant variants in the South American region.
Overall, 13 patients (five adults and eight children) were admitted to the ICU. Six patients were directly admitted from the emergency department, and the other seven patients were transferred from other hospital wards (Table S2). Ventilatory support was given to 12 patients (Table 1 and S9). Invasive mechanical ventilation was performed in 10 patients (76.9%), and non invasive ventilation (NIV) was performed in 3 patients (23.1%; Table 1). Among the NIV patients, one required subsequent endotracheal intubation and mechanical ventilation, and all three patients were discharged from the hospital. Extra-pulmonary organ failure occurred in eight patients (33.3%; Table 1 and S9).
Of the 13 critically ill patients, 12 were treated with oseltamivir, and treatment was initiated 48 h after the first signs/symptoms of viral infection in 5 of them. Adjunct or non-conventional supportive therapies for ARDS were performed for 12 of the 13 patients that entered the ICU (92.3%). A total of 10 patients (76.9%) received systemic corticosteroids (eight due to previous use and two for shock and persistent ARDS); five (38.5%) were ventilated in a prone position, and four (30.8%) required recruitment maneuvers. No patient received extra-corporeal membrane oxygenation.
Tuberculosis (TB) has variable presentations ranging from classic presentation of respiratory symptoms to less common presentations such as involvement of lymph nodes and gastrointestinal system and to some rare hematological manifestations. Hematological manifestations of TB vary from common presentations such as anemia and pancytopenia to rare presentations such as immune thrombocytopenia. Thrombocytopenia can be either due to bone marrow infiltration with granuloma or immune-mediated thrombocytopenia presenting as immune thrombocytopenic purpura (ITP). ITP in association with TB has rarely been reported. In this paper, the authors describe a case of ITP that was later found to be secondary to TB; unfortunately, the diagnosis of TB was delayed because the patient had refused the procedure required to reach a definitive diagnosis during his initial presentation. The purpose of this report is to highlight the association between the two conditions because early diagnosis and treatment are important to avoid an extreme outcome.
HRSV infections are frequent worldwide, and the most severe cases mainly affect children during the first year of life, elderly and immunocompromised individuals. HRSV is the most common causal agent of respiratory infections in infants, which occur at predictable annual seasons [1, 2].
HRSV is an enveloped virus (genus Orthopneumovirus, family Pneumoviridae). Its genome consists of a nonsegmented single-stranded RNA that encodes 11 proteins. The surface proteins F and G are important antigenic targets of neutralizing antibodies. Variations in the G protein and in the gene regions that encode this protein allowed for the classification of HRSV into two subgroups (A and B) and into many genotypes. Different HRSV genotypes of the two subgroups generally cocirculate during a season in the same region, and the predominant genotypes are replaced by others in subsequent years [4, 5].
Such antigenic and genetic variability allows the virus to escape immunity acquired by the population of patients that have been subjected to previous infections. Several genotypes have been described in subgroups A (GA1 to GA7, SAA1 and NA1, NA2) and B (URU1, URU2, and GB1 to GB4, SAB1 to SAB3, and BA1 to BA13). The recently described genotype HRSV A ON1 is characterized by the duplication of 72 nucleotides in gene G. After being reported in Canada, HRSVA ON1 has also been identified in Europe, India, Africa, South America, and Asia [6–11].
Knowledge on the molecular epidemiology of HRSV infections is important to assess the clinical implications of infections by different genotypes. The clinical presentation, severity, response to treatment, and prophylaxis are among these implications. The occurrence of genotypes that have not been previously identified leads to concerns about the severity of new cases or an increased number of infected individuals when considering the possible absence of immunological memory in the affected population.
In this study, the authors describe the main genotypes of HRSV A and B, which caused infections in infants hospitalized in the University Hospital of Universidade de São Paulo in São Paulo city, from 2013 to 2015. The genotype characteristics and clinical and epidemiological features of HRSV are analyzed, and the infections caused by the new genotype HRSV AON1 are compared to other genotypes that were circulating during the study period. To our knowledge, this is the first report to perform an analysis of the association between clinical features and genotypes in infections caused by HRSV A ON1 in the southeast region of Brazil.