How to cite this article: Cabrera-Gaytán DA, Galván-Hernández AN. [Clinical features of Zika virus]. Rev Med Inst Mex Seguro Soc. 2016;54(2):230-41.
Received: December 30th 2015
Accepted: February 15th 2016
David Alejandro Cabrera-Gaytán,a Stephanie Anaid Galván-Hernándeza
aCoordinación de Vigilancia Epidemiológica, Instituto Mexicano del Seguro Social, Ciudad de México, México
Communication with: David Alejandro Cabrera-Gaytán
Telephone: (55) 5536 8861
Background: Zika virus was introduced to the country and threatens to spread, so the health personnel must be able to identify the disease and face an operational definition given case; in this review the clinical manifestations of probable cases of Zika of the last five years were described.
Methods: A search was performed in Google Scholar and PubMed with “Zika”. He settled for a database and obtained simple frequencies and calculated the limits for proportions with an alpha of 0.05 through test Wilson.
Results: 109 probable cases of fever came together by Zika, the clinical manifestations was heterogeneous, with predominant involvement to musculoskeletal, dermatological and systemic level.
Conclusions: It is necessary to continue the documentation of the clinical manifestations of Zika virus, which will be achieved by strengthening epidemiological surveillance.
Keywords: Arboviruses; Arbovirus infections; Epidemiological surveillance; Exanthema
In the past two years the introduction of the Zika virus to the Americas has been detected, and the threat of its expansion to various territories and countries is latent. Given this, the Pan American Health Organization (PAHO) issued an epidemiological alert on October 16, 2015, which recommended its Member States to establish and maintain "the ability to detect and confirm cases of Zika virus infection and prepare health services for a possible additional burden at all levels of health care".1
In the alert, they recommended operational definitions of suspected and confirmed cases, which was "patient with rash or elevated axillary body temperature (> 37.2 °C) and one or more of the following symptoms (which are not explained by other medical conditions): arthralgia or myalgia, non-purulent conjunctivitis or conjunctival hyperemia, and headache or malaise," while the case was confirmed as present when a suspected case has "laboratory tests positive for detection of Zika virus".1
Months prior, the organization issued an epidemiological alert, highlighting the outbreak in French Polynesia with 10,000 cases, of which approximately 70 were serious, with neurological complications such as Guillain- Barré syndrome (GBS) and meningoencephalitis syndrome, or autoimmune such as thrombocytopenic purpura and leucopenia.2
Faced with this situation, the Comité Nacional de Vigilancia Epidemiológica (CONAVE) of Mexico issued an epidemiological alert on the status of the virus in the Americas, in which it publicized the epidemiological situation at the time, as well as operational case definitions based on fever and exanthema.3
Recently, the Secretaría de Salud Federal in Mexico announced the presence of the first imported case of Zika virus in the country in a patient with a history of travel to Colombia,4 because the first cases were identified in that country in October 2015.5
Given the territorial expansion and the clinical manifestations in critically ill patients, cases were gathered from what was published in the scientific literature from the past five years.
A review was conducted on Google Scholar using the keyword "Zika" in the last five years, not including "patents" and "dates", sorted by date, reviewed on October 28, 2015. Similarly, a PubMed search was conducted with same keyword and period, consulted on November 23 2015. The publications relevant to clinical cases were selected, such as: case reports, case series, outbreak studies, and letters to the editor about these. Diagnostic laboratory studies were excluded, as were virological surveillance and viro-entomological surveillance, and prevention and vector control. 23 publications were identified from Google Scholar, of which 10 met the search inclusion criteria,6-15 while there were seven documents from PubMed.16-22
A database was then built with the variables available in these online publications on the clinical manifestations and results of clinical laboratory findings. A descriptive analysis of cases was made. Limits for proportions were calculated with an alpha of 0.05 by Wilson test in OpenEpi: Open Source Epidemiologic Statistics for Public Health.
From the review of online publications, 109 probable cases of fever from Zika were gathered, the range of clinical manifestations was heterogeneous, predominantly with affectation at the musculoskeletal, dermatologic, and systemic level (Table I). Also, a publication was identified on the clinical manifestations in pregnancy characterized by fever, maculopapular rash, generalized pruritus and myalgia, as well as hypoglycemia, maculopapular rash, and hypotrophy in the neonate.
|Table I Absolute and relative frequency of clinical manifestations of Zika cases by author and year of publication (n = 109)|
|Clinical manifestations||Total||%||95% CI||p|
|Maculopapular rash (6, 7, 8, 9, 10, 13, 14, 15, 18, 19, 20, 21, 22)||69||63.3||53.95, 71.75||0.0054750|
|Fever (6, 7, 8, 10, 12, 13, 14, 15, 16, 18, 19, 21, 22)||48||44.0||35.08, 53.4||0.2131000|
|Headache (7, 8, 9, 10, 12, 14, 16, 18, 19, 20)||44||40.4||31,64, 49.75||0.0442800|
|Myalgia (6, 7, 8, 9, 12, 14, 16, 18, 20, 21, 22)||44||40.4||31,64, 49.75||0.0442800|
|Arthralgia (7, 8, 9, 10, 12, 13, 14, 19, 22)||36||33.0||24.91, 42.3||0.0003942|
|Conjunctivitis (7, 8, 9, 10, 15, 16, 19, 21, 22)||25||22.9||16.05, 31.67||0.0000001|
|Retroocular pain (7, 8, 10, 19)||15||13.8||8.521, 21.47||0.0000001|
|Edema in lower limbs (7, 9, 12, 13, 14)||11||10.1||5.729, 17.17||0.0000001|
|Edema in upper limbs (12, 14, 15)||8||7.3||3.766, 13.82||0.0000001|
|Asthenia (8, 9, 12, 15)||5||4.6||1975, 10.29||0.0000001|
|Vomiting (7, 16)||4||3.7||1.436, 9.057||0.0000001|
|Lymphadenopathy in subdmandibular or cervical neck (14, 22)||4||3.7||1.436, 9.057||0.0000001|
|Oral ulcers (9, 19)||3||2.8||0.9404, 7.781||0.0000001|
|Nausea (8, 16)||2||1.8||0.5047, 6.444||0.0000001|
|Hematospermia (9, 12)||2||1.8||0.5047, 6.444||0.0000001|
|General discomfort (13, 20)||2||1.8||0.5047, 6.444||0.0000001|
|Odynophagia (16)||1||0.9||0.1621, 5.014||0.0000001|
|Low back pain (19)||1||0.9||0.1621, 5.014||0.0000001|
|Epigastric pain (16)||1||0.9||0.1621, 5.014||0.0000001|
|Diarrhea (8)||1||0.9||0.1621, 5.014||0.0000001|
|Anorexia (16)||1||0.9||0.1621, 5.014||0.0000001|
|Dry cough (20)||1||0.9||0.1621, 5.014||0.0000001|
|Facial paralysis (21)||1||0.9||0.1621, 5.014||0.0000001|
|Paresthesia in the extremities (21)||1||0.9||0.1621, 5.014||0.0000001|
|Ascending muscle weakness (21)||1||0.9||0.1621, 5.014||0.0000001|
|Areflexia of pelvic members (21)||1||0.9||0.1621, 5.014||0.0000001|
|Orthostatic hypotension (21)||1||0.9||0.1621, 5.014||0.0000001|
|Photophobia (9)||1||0.9||0.1621, 5.014||0.0000001|
|Dysuria (9)||1||0.9||0.1621, 5.014||0.0000001|
|Perineal pain (9)||1||0.9||0.1621, 5.014||0.0000001|
|Prostatitis (9)||1||0.9||0.1621, 5.014||0.0000001|
|* Report of cases series, two pregnant women and two babies; one newborn did not develop clinical signs.|
The results were not documented by clinical laboratory in all cases; of the 10 publications, 14 cases were assembled with this information, with thrombocytopenia predominant (Table II).
|Table II Main laboratory findings in Zika cases by author and year of publication (n = 14)|
(n = 2)
(n = 1)
(n = 3)
(n = 1)
(n = 2)
(n = 1)
(n = 1)
(n = 1)
(n = 1)
(n = 1)
|High LDH||1||1 (7.1)||1,272,
|Elevated Fibrinogen||1||1 (7.1)||1,272,
In determining the duration of the disease, this data was recorded in 10 publications, with five cases with one week,6,9,15 one to two weeks in four patients,10,13,20 and more than three weeks in four cases.9,12,19,21 The range of duration was described by Duffy et al. as two to 14 days,7 with an average of six, and 40 days is reported in one case with neurological manifestations.21
Regarding the transmission path, the most reported was through a vector; however some reported other ways.
At the time of the search and with the predefined criteria, the number of publications was more limited to the clinical picture. While most publications included are case reports or cases series, these reveal a limitation in the detailed description of the clinical picture. Furthermore, identification of the suspected or probable case is based on operational definitions in each country or region without knowing the criteria of these (this was not studied). Mostly the diagnostic key was the history of travel to areas with vector and virus movement, since they were imported cases. The predominant clinical data was maculopapular rash, which is described as affecting anterior and posterior thorax, upper limbs, and face, accompanied by mild fever or fever and damage to the musculoskeletal system. When comparing the percentage distribution of the clinical manifestations of the experience of the first 297 cases in French Polynesia, the predominant feature was rash (≈ 90%), followed by asthenia (≈ 75%), fever (≈ 72%) and arthralgia (≈ 65%).23 While the percentage magnitude was different from this publication (probably due to the number of cases studied and the operational definition based on maculopapular rash and / or fever <38.5 °C), the order of frequency was very similar. In that sense, in Mexico during the first half of December 2015, the CONAVE published the Standardized Guidelines for Epidemiological Diagnosis and Laboratory Surveillance of Zika Virus Infection, where the operational definition of a probable case is based on three clinical data: fever, non-purulent conjunctivitis, and maculopapular rash; and accompanied by one or more of the following: myalgia, arthralgia, headache or retroocular pain, and any epidemiological association identified.24 This includes two of the most frequent clinical data found in this review, but not non-purulent conjunctivitis.
A few days before the issuance of these Guidelines, the Secretaría de Salud announced the first imported case of Zika in the country with a history of travel to Colombia,4 and nine days later the first two indigenous cases in the city of Monterrey, Nuevo Leon and the municipality of Huixtla, Chiapas.25 Retroocular pain is characteristic of dengue fever, in this review it represented 13.8%, similar to the figure detected among cases in French Polynesia;23 and since the cardinal sign was the maculopapular rash and those affected presented with fever, these data would be valuable for differential diagnosis by a clinic.
In this review rare clinical manifestations were identified that will increase with the threatened expansion. An example almost not studied because it is a recent finding subject to clinical and epidemiological research as well as public health implications, has been the increase in cases of microcephaly reported by the Ministerio de Salud of Brazil in states with Zika virus circulation; but so far it has not been possible to ensure the cause of the unusual increase. However, the presence of the Zika virus genome in samples from two pregnant women from Paraiba is revealing, with fetuses confirmed to have microcephaly by ultrasound examinations. Viral RNA was detected in amniotic fluid samples by RT-PCR. Therefore, current data do not allow causal correlation of Zika infection with microcephaly.26
In a more reserved way, this situation was unveiled by PAHO on November 17, 2015, with the recommendation to analyze the database of live births, specifically in relation to malformations / neurological disorders, in order to detect any unusual increase.27 In Brazil from January to December 19 2015 2782 cases of microcephaly have been identified in 618 municipalities; so it has become a national priority to study this disease where the Zika virus is circulating.28
While it was not considered in this review, it stands out that the Zika virus is phylogenetically and antigenically related to the virus Spondweni,29,30 so there may be neurological tropism, which is clinically reflected in the appearance of GBS or neurological manifestations, where it was reported in one case in the present study,21 or more cases in the experience of French Polynesia.23 Although to date the underlying pathophysiological mechanisms of Zika related to GBS are unknown, and could be of immunological origin as described with other infectious agents,31 or the hypothesis of immune stimulation of arboviruses;32 so the consideration of Musso et al. about diagnosis in saliva by ZIKV RT-PCR is an option to consider and evaluate.33
With regard to route of transmission, there is suggestion of infection sexually,9,12 by blood transfusion,11 perinatally,6 and through breastfeeding.6 However, greater consistency and specificity of the association is needed to then determine more causal criteria with internal validity.34
It is necessary to continue documenting the wide range of clinical manifestations generally and in particular conditions (pregnancy, newborns, co-infections with other arboviruses, etc.), which will be achieved by strengthening epidemiological surveillance in regions where the virus is in circulation and to learn from this heterogeneity for adjustments in the operational definitions as more evidence of the natural history of disease is generated.
Declaración de conflicto de interés: los autores han completado y enviado la forma traducida al español de la declaración de conflictos potenciales de interés del Comité Internacional de Editores de Revistas Médicas, y no fue reportado alguno que tuviera relación con este artículo.