Plague and history have always been strongly interrelated since the earliest description of plague pandemic [1]. Excluding the so-called plague of Athens, which could have been caused by typhus or other microorganisms, the first well-authenticated mention of plague dates back to the 6th century: the Justinian Plague, named after the Byzantine emperor. This outbreak took place in Egypt in 542 AD and spread across the Mediterranean basin regions, killing more than 25 million people [2]. Three large pandemics occurred afterward, including a major outbreak during the decline of the Eastern Roman Empire, the rapid weakening of the Persian Empire, and the subsequent tumultuous rise of the Islamic Empire [3]. Another major episode was the Great Plague Pandemic, which began in China in 1333-1334 during a period of famine and spread to Europe by trade causing millions of deaths [4]. The third major outbreak was the Modern Plague Pandemic, which originally occurred in China in 1860, spreading worldwide by rats on trade ships leading to over 10 million deaths across the world [5,6].

This highly infectious zoonotic disease is caused by the bacillus Yersinia pestis, a member of the Enterobacteriaceae family [7]. Transmission of plague occurs when infected rodents’ fleas bite humans. Human-to-human transmission is possible when transmitted by infected air droplets. Three major forms of the disease are known: (1) bubonic plague, the most common form of plague, which is characterized by acute febrile illness accompanied by enlarged and tender lymph nodes; (2) septicemic plague, characterized by sepsis manifested by fever and systemic illness, generally without preceding symptoms; and (3) pneumonic plague, which may be primary when acquired directly by infected air droplets and secondary when it spreads to the lung from other infected sites of the body—both of these forms lead to a highly contagious and lethal disease [8].

Diagnosis of plague is made based on the above-mentioned clinical findings accompanied with suspected history of exposure. Identification by culture as well as increased paired serum titers are suitable diagnostic methods. Plague can be fatal if left untreated. Besides supportive therapy for severely ill patients, treatment is composed of systemic antibiotics of aminoglycoside-based therapy.

Though highly associated with the past, plague still represents a global public health concern. Cases of plague continue to be reported worldwide, especially in Africa but also in Asia, South America, and even in the United States. According to the World Health Organization (WHO), 3248 cases of plague were reported from 2010 until 2015, with 584 deaths [9]. Recently, foci have been described in Libya and Algeria [8]. The highest incidence of plague cases in recent years is reported from Madagascar. In fact, cases of bubonic plague are reported annually in Madagascar since the first case was introduced in 1898; however, recent reports show a large outbreak of pneumonic plague occurring in major urban cities, which is different from what was previously reported (ie, cases concentrated mainly in rural areas). In recent months, we have witnessed the spread of plague to the Seychelles islands, reflecting a further escalation of the current outbreak [10-12].

However, despite such a long-standing and rich history, it is rather difficult to get a comprehensive overview of the general situation. Within the framework of electronic health (eHealth), in which people surf the internet more and more looking for health-related material, new information and communication technologies, such as Web 2.0, portable computers, mobile phones and devices, as well as social media and social networks, could enable researchers to get a wealth of data, which could complement traditional surveillance of infectious diseases.

In this study, we aimed to assess public reaction regarding the recent plague outbreak in Madagascar by quantitatively characterizing this interest and correlating it to epidemiological real-world data, in terms of incidence rate and spread pattern.

Google Trends (GT) is a free open-source tool used to track and observe internet search activity [13]. GT was used to assess recent search activity with regard to the recent plague outbreak in Madagascar. To that end, GT was mined from August 1 to November 17, 2017 [13]. This particular time frame was chosen in order to better capture the temporal dynamics of the plague outbreak, monitoring the internet-related activity before (ie, digital behavior at the baseline) and during the epidemic. During the drafting and production of this study, the latest available WHO situation report, released on November 17, 2017 [14], was utilized.

The GT search tool has two options for searching keywords: searches can be performed by search term or by search topic. While the former enables the user to search for exact keywords, the latter option uses a broader search that finds all Web searches containing the inserted keyword(s) or related terms.

The results given by GT are output as normalized values (ie, relative search volumes [RSVs]) rather than absolute, raw values. Every query is divided by the total searches performed in a given geographic region and time range and normalized to a scale between 0 and 100 based on the topic’s popularity in comparison to all searches carried out in that region and time frame. For further details concerning GT, the reader is referred to Nuti et al’s review of GT and its potential applications in the medical field [15]; the reader is also referred to Mavragani et al’s recent systematic review concerning methods, tools, and statistical approaches and techniques in the field of GT research [16].

In this study, the second search option (ie, searching by topic with related terms) was used. Specifically, we searched for “Plague (Topic).” Searches were geographically limited to Madagascar. In Madagascar, the language spoken is Malagasy, while the second official language is French. English is spoken by less than 20% of the population. It is widely known that the sample when using online queries cannot be representative; however, in our case, searching for “Plague” and selecting the search topic option enabled us to overcome any linguistic issue related to the diffusion of the language. This approach ensured the robustness of our results.

Correlational analysis and multivariate regression models for nowcasting and forecasting, with lags up to 7 days, were performed based on the GT results with the number of confirmed, suspected, and probable cases of plague as reported by the WHO situation report. Different regression models were run, computing the different fitting parameters, including R² and adjusted R², and the best model was chosen according to the Akaike Information Criterion (AIC) values.

Statistical analyses were performed with the commercial software XLSTAT 2017 (Addinsoft). All values with P values less than .05 were considered statistically significant.

Average plague-related search activities, expressed as RSVs, are shown superimposed on the trends of new suspected, probable, and confirmed cases of plague in Figure 1. The searches showed a small burst of activity on September 14, 2017, immediately after the official notification (ie, September 13, 2017) sent to the WHO by the Madagascar Ministry of Public Health of an outbreak of pneumonic plague in Madagascar. This notification followed the death of a young man some days before on September 11, 2017, who suffered from severe respiratory disease confirmed to be caused by plague. A very large spike was noticed during the first week of October 2017. Afterward, RSVs tended to decrease over time to slightly above baseline levels. Similarly, the incidence of suspected, probable, and confirmed cases of plague in Madagascar also exhibited a small spike in the third week of September 2017, and many more cases were confirmed during the recent outbreak starting in the first week of October.

The best nowcasting model in terms of AIC values (see Multimedia Appendix 1) showed that new confirmed cases of plague had a statistically significant association with GT-based RSVs (P<.001, beta coefficient 1.158), as shown in the multivariate regression analyses in Multimedia Appendix 2. Scatterplots of incident cases showed similar and statistically significant positive correlations with GT search data (R²=0.549, P=.001 for the confirmed cases; R²=0.265, P=.005 for the suspected cases; and R²=0.518, P=.001 for the probable cases; see Figure 2). From a geospatial standpoint, plague-related GT queries were concentrated in certain regions of Madagascar, most notably in Toamasina (100%), Toliara (68%), and Antananarivo (65%). A heat map of search density in different regions of Madagascar is shown in Figure 3. Concerning the forecasting models, the 1-day lag model was selected for regression analysis due to optimal AIC values (see Multimedia Appendix 3). This forecasting model shows that we can predict new probable cases up to 1 day in advance with statistically significant certainty (P<.001; see Multimedia Appendix 4).