Abstract
Since the first cases of Zika were identified and reported in Brazil, the magnitude and consequences of the outbreak in the Americas have increased tremendously, leading the World Health Organization to consider Zika and its link with clusters of microcephaly a Public Health Emergency of International Concern. Only a previous large outbreak in French Polynesia was known and no neurological anomalies have been reported. Differences in African and Asian lineage and differences in genetic evolution of the Zika virus may possibly provide an explanation for the development of the recent outbreaks and their variable presentation. However, the similar clinical presentation between Zika and other diseases like Dengue and Chikungunya can support that Zika has been circulating and spreading inadvertently. This hypothesis gains strength when rates of laboratory confirmation diagnosis for Dengue are observed in Brazil and Colombia, two of the most affected countries by Zika virus (ZIKV) infection.
The lack of attention and resources on neglected diseases supposes a huge risk that new lethal pathogens camouflage themselves to spread into large areas and populations.
Introduction
On 1 February 2016, the World Health Organization (WHO) declared the Zika virus (ZIKV) outbreak in the Americas and its probable link with adverse neurological outcomes a Public Health Emergency of International Concern 1 (PHEIC). Since then, many efforts have been made to clarify the causality between ZIKV infection during pregnancy and microcephaly in new-borns, as well as a link between ZIKV and Guillain-Barré syndrome in the general population.
Initially, there were doubts about these links and further confirmation was insisted upon. 2 Unlike the onset of the Ebola outbreak in West Africa in 2014 or the current Yellow Fever outbreak in Angola, the ZIKV outbreak in the Americas and its potential links has been thoroughly covered by the mass media since the beginning, even when evidence was not well established, contributing in some way to feed confusion and conspiracy theories.
Clearly, the WHO feared repeating previous delays in announcing a potential catastrophe, in view of the tardy exposure of the Ebola outbreak. Thus, the WHO was keen to initiate preventive measures, even when data and evidence were non-existent or imprecise.
Subsequent research has clarified the facts: a clear timeline has been described concerning the temporal progression of Zika from its first isolation in Africa in 1947 to the present. 3 Furthermore, retrospective studies carried out on previous outbreaks have established associations not formerly recognised. 4
Questions remain, however, concerning the lack of attention and general knowledge attributed to neglected diseases and also the continued poor resources of most low- and middle-income countries (LMICs) regarding their diagnostic capabilities and epidemiological surveillance strength.
This article highlights the risk and potential dangers of neglected diseases and shows how ZIKV infection and its complications may be exactly a new example of such neglect.
Evidence and explanations
Important studies have proved the causal link between Zika and microcephaly and other neurological anomalies5,6 and have examined the pathological changes induced in fetal brain tissue.7,8 Nonetheless, two controversial questions remain regarding behavioural changes of ZIKV: why did it not cause large outbreaks till 2007? Why were no adverse neurological sequelae observed in the previous 60 years?
These questions have been, at least in part, answered.
The first known outbreak of ZIKV infection occurred in Yap, an island in Micronesia, in 2007; in 2009 details were published in an article 9 detailing observations consistent with what has been subsequently observed in French Polynesia and currently in the Americas, in regard to clinical presentation, attack rates and ratios of symptomatic to asymptomatic infection. At that time, no link between ZIKV and neurological anomalies was detected; but in view of the small population in Yap, this in retrospect is not surprising. Despite the paucity of data and the low incidence of adverse outcome, the authors explicitly expressed their worries concerning a possible spread of the infection into Oceania and to the Americas. 9
Differences in African and Asian lineage and differences in genetic evolution of the ZIKV virus may possibly provide an explanation for the development of the recent outbreaks and their variable presentation. 10
Investigations on co-factors and co-associations are ongoing, but the consistent results justify the alarm raised by the WHO and national authorities, raising awareness and mounting precaution concerning ZIKV and especially its teratogenic effects.
What this article considers is the possibility that an emerging pathogen may spread widely, inadvertently masking itself in the endemicity of a neglected disease with clinical similarities. Further, resource-poverty in health systems in endemic areas may contribute to this masking effect; the ZIKV outbreak in the Americas seems to be a prime example of this process.
Case definitions
Zika and Dengue: Brazilian and Colombian examples
ZIKV disease case definitions.
As inferred from these definitions, Zika can be easily mistaken for any other unspecific febrile disease unless confirmation laboratory tests are performed. However, the capability of conducting such and thus confirming a diagnosis is, in so many areas of the Americas, and even worse, in Asia and Africa, far from guaranteed. The same applies to other viral and parasitical illness.
ZIKV has now attracted a focused effort, but what about similar diseases? Dengue and Chikungunya are almost identical in terms of clinical presentation.11–14
In March 2015, Brazil reported to the WHO a cluster of patients presenting an illness characterised by a skin rash and other unspecific mild symptoms in its north-eastern states. What demanded attention was the clustering of the cases and the rapid dissemination of the disease in the area. Initial investigations of a few cases showed most to be negative for Dengue and other endemic viruses. 15 At that stage, ZIKV was not even suspected. Only in May did Brazil’s National Reference Laboratory confirm the presence of ZIKV in blood samples by polymerase chain reaction (PCR). This was the first evidence of locally acquired ZIKV circulating in the Americas, and led the WHO/PAHO to issue an epidemiological alert. 16 PAHO recommended its Member States establish the capacity for ZIKV detection.
In July 2015, certain neurological disorders, mainly variations of Guillain-Barré syndrome, were noted in one of the states where ZIKV was first detected. By October 2015, neighbouring countries began to confirm locally acquired ZIKV, Colombia among them. This country included ZIKV in its epidemiological bulletin corresponding to their 43rd epidemiological week (25–31 October 2015). 17 PAHO already issued an alert in May 2015. At the end of 2015, Colombia had reported a total of 11,712 confirmed and suspected cases establishing the epidemic phase of Zika at their 40th epidemiological week (4–10 October 2015); of these cases, only 746 (6.36 %) had been confirmed by laboratory tests. 18
In the meantime, in the same 40th week, according to the epidemiological bulletin, 339,006 cases of Chikungunya disease had been reported, but only 1982 laboratory confirmed (0.58 %). 19
Temporal distribution of epidemiological data available on Dengue.
CFR, case fatality rate (of DHF&DSS cases); D, Dengue; DHF, Dengue Haemorrhagic Fever; DSS, Dengue Shock Syndrome (previously known as Complicated Dengue); IR, Incidence rate (×100,000 population).
When empty cells, no data available.
Source: PAHO, Dengue: Datos estadísticos y epidemiología; http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=3274&Itemid=40734&lang=es
When this information is displayed in a graphical manner, the figures eloquently display low confirmation capabilities (Figures 1 and 2).
Temporal series of total Dengue cases reported and confirmed by laboratory and the rate of confirmation in Brazil. Temporal series of total Dengue cases reported and confirmed by laboratory and the rate of confirmation in Colombia.
Thus, in Brazil the percentage of confirmed cases has never surpassed 50%, with ratios as low as 8% during the year when the second highest number of cases was recorded. In Colombia, the situation is slightly better but nothing to be proud of. Importantly, though, in both countries, even when the reported case number rises, the confirmation rate drops, resulting in a widening and worsening breach between reported and confirmed cases.
It is obviously difficult to issue alerts and to establish policies and strategies with these intervals; and, in the presence of high numbers of co-incidental similar illnesses, such wide variation in figures is quite worrying. It implies there may be many cases of ZIKV hiding as Dengue or Chikungunya. Poor rates of confirmation of Dengue in hyper-endemic areas has an opposite effect in other countries, mainly in Africa, where it is not considered as a likely differential diagnosis, despite the fact that many studies confirm its presence and spread.20–22 Like ZIKV, Dengue, particularly, is no inconsequential infection, considering the potential fatality of its complications (Dengue haemorrhagic fever and Dengue shock syndrome).
The sad fact is that reliable confirmation rates may be even worse in many parts of Africa and Asia. Thus the data for many parasitic diseases may be hugely under-estimated.
Discussion
Despite of the assumption of the genetic evolution of ZIKV as a plausible explanation for the changes in its behaviour, another hypothesis is that it has actually been circulating unnoticed through countries unable to detect, identify and diagnose it. Adverse outcomes and complications may have been existent but never attributed to ZIKV. The results from retrospective studies (in French Polynesia and the Americas) prove that there is longstanding evidence for ZIKV. If this is the case where health systems are reasonably functional, access to health infrastructure moderately well guaranteed and the population is induced to seek medical attention even for mild ailments, it is logical to infer that in poor-resourced areas knowledge about the true state of affairs regarding the incidence and prevalence of neglected diseases may be much worse.
The huge number of suspected cases and more formally ‘clinically’ confirmed cases, among illnesses with almost identical presentation, poses a huge diagnostic burden. Where health personnel are untrained and the means are lacking to effect reliable diagnoses, a vast risk exists for the dissemination of emerging pathogens. Thus the lack of attention to neglected diseases may itself mask their endemicity. Where new pathogens, resembling others already present, do not greatly worsen already poor clinical outcomes of disease, no great efforts are likely to be made for their detection and control.
Sadly, it is only when an alarm trigger is a severe complication coming from a previously unnoticed infection and the causal agent could spread rapidly to the rich world that the international community begins to fear a maximal risk. Then, and only then, do global health authorities gather resources for developing new laboratory methods, expensive treatments and new vaccines within a few months.
Neglected diseases, affecting and killing millions of people around the world, are a huge burden for LMICs. They should also be a burden of guilt and cause of humiliation for the international community. While these diseases are confined to LMICs, the efforts of the rich consist mainly in protecting travellers going on holiday to paradisiacal private, safe resorts where the complete elimination of disturbing mosquitoes and other vectors is not quite complete.
It is only when fatal diseases, such as Ebola, threaten the comfort and security zones of the rich that help is made available to keep these illnesses confined to where it is assumed they belong.
ZIKV and its dissemination and behavioural change is another example of how neglected diseases, despite that they are a protracted problem for >80% of the population living in many poor-resource settings, can bring new issues concerning new pathogens. Indeed, it is virtually certain that many other hidden pathogens with unknown effects remain to be discovered.
To wait until these neglected diseases emerge to wreak havoc is like applying Sellotape to a large abscess or aneurysm about to explode. The only way to prevent catastrophic deleterious effects of these emerging pathogens is for the rich world to invest in effective healthcare in LMICs, even if this demands much effort and cost. Such altruism may well prove worthwhile for global health, the rich as well as the poor!
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.