Enduring Warning: A Holistic Comparison of the Establishment and Spread of P. falciparum Evolutionary Lineage Malaria in Ancient Rome and the Threat of Zoonotic P. knowlesi Malaria in Modern Southeast Asia

Simple Summary

This article utilizes an interdisciplinary overlay of detailed evidence, as well as broader examples and lessons from the ancient and modern histories of malarial outbreaks—drawn from both the zoonotic disease histories of the interconnected ancient Roman Republic and our modern globalized planet. Our purpose is to reveal specific informative analytical parallels and contrasts between ancient and modern malaria disease realities. Our consideration encompasses a variety of factors that combine to shape the timeless interplay amongst zoonotic (and formerly zoonotic) pathogens, environmental and climate factors and human societies.

Abstract

Our article presents a holistic analysis aimed at discerning patterns from ancient–modern comparative contexts of malaria. The article’s interdisciplinary and consilient methodology is drawn from a range of disciplines: the humanities and social sciences, medical knowledge (particularly epidemiology and pathology), molecular phylogenetics, demography, archaeology, paleopathology, numismatics, complex systems theory, etc. The article begins with a detailed exploration of a 463 BCE epidemic event that likely marked the, ultimately transformative, debut of P. falciparum evolutionary lineage malaria for ancient Roman civilization. It is important to note that the concept of evolutionary lineage is defined herein as a sequence of organisms, descended from a common ancestor and culminating, for the present at least, in the form existing currently. An interdisciplinary retrospective diagnosis methodology is utilized to establish, with what we believe to be a high degree of probability, a conclusion that effectively marks the beginning point for the ancient side of our comparative example. The deep interdisciplinary/historical methods used to elucidate the ancient side of the disease equation both lead to a clear conclusion and suggest potential modern analogies or even “prophecies.” These are used to highlight the threats emanating from the current spread of zoonotic P. knowlesi malaria in Southeast Asia. The article also utilizes six broader holistic and interdisciplinary factors in its contextual and comparative analysis: (A) political, military and security contexts; (B) the effects of cultural perceptions; (C) the role of climate and climate change; (D) additional anthropogenic environmental factors; (E) perceptions, practices and capabilities of prevailing medical systems and (F) holistic underlying states of the health of affected populations.

1. Introduction: Lessons from a Transformative Ancient Outbreak

There was a significant epidemic in the city of Rome and surrounding areas beginning in the year 463 BCE. Two later ancient authors highlighted the event in their accounts because of its unusual severity. This epidemic, which both strongly reflected and yet also departed from predictable and annualized patterns of infectious disease, was embedded in a period of the early Roman Republic troubled by social crises and continuous wars among the inhabitants of ancient central Italy. The early Romans were incessantly engaged militarily (whether as enemies or allies) with the peoples settled in the areas surrounding their urbe: such peoples as the Volsci, Aequi, Hernicians, Etruscans, Aurunci, etc. At the same time, class conflict between Roman plebeians and the Republic’s aristocrat-dominated Senate frequently resulted in secessions, betrayals and outright warnings of civil war. Even in the context of such a fraught political and military situation, a seasonally/annually fully predictable (late summer/early fall) epidemic disease outbreak became widespread and severe enough, with high adult mortality, that it merited significant historiographical coverage centuries later. Something about this event was clearly very different from the prevailing and indeed expected seasonal infectious disease pattern.

These two ancient authors, Dionysius of Halicarnassus and Livy (both from the later 1st century CE Augustan early imperial period) produced (apparently relying on earlier sources now lost to time) accounts concerning the 463 BCE epidemic in annalistic format (Year of Rome 291, according to Cato; 293, according to Varro; 463 BCE, as noted above, according to the dating in use today). Both the prevailing ancient sanitary fragility, cultural norms, expectations and the general familiarity with annualized patterns of (particularly malarial) disease would have restrained the mention of a less-than-extraordinary outbreak over four centuries later. This reality argues strongly in support of a relevance for the 463 BCE epidemic above and beyond the ordinary. Indeed, we conclude that this event likely represented the Roman epidemic debut of the most severe form of malaria, caused by the parasite Plasmodium falciparum, or more accurately and inclusively, its evolutionary lineage. Early Republican Rome’s population, despite already living with endemic infections deriving from P. malariae and P. vivax, would have been largely, if not fully, naive to such a new pathogen in 463 BCE. Despite some very limited interspecific cross-reactivity, particularly in relation to the immune systems of pregnant women (whose depressed immune systems can also render them particularly vulnerable to malaria [1]), acquired malaria immunity in humans is distinctly species-specific. The biological mechanics of human immune responses differ as per malaria species, and each plasmodium species infects human blood cells differently. As early as the 1920s, studies conducted by Austrian physician Julius von Wagner Jauregg (for which he was awarded the Nobel Prize in 1927) determined that acquired immunity to malaria was indeed largely “species-specific” though not strain-specific—“immunity to a particular species conferred no protection against challenge with a heterologous species” [2]. Modern science has largely confirmed these earlier conclusions; twenty-first-century vaccine development, for example, also targets each species separately [2]. P. falciparum is understood by modern medicine to be by far the most deadly plasmodium species—currently the cause of 90% of global malaria fatalities (which currently total, annually, around 600,000), with children under five years old accounting for “67% of global malaria deaths” due to the “semi-protected acquired immunity” acquired by adults in biogeographical regions in which the disease is endemic [1,3]. This modern public health significance, effectively, was anticipated (over two millennia beforehand) by the history of ancient Rome. During the following centuries after 463 BCE, significant malaria-related effects and feedback would result for Roman civilization. Considering the potential significance of what possibly started in 463 BCE, excerpts of the two relevant ancient accounts are worth reviewing in greater detail.

2. Ancient Materials and Methods: The Accounts of Dionysius and Livy

Firstly, from Dionysius of Halicarnassus [4]: So it (the disease) meandered among shepherds and settlers gradually throughout the region, ultimately invading Rome as well. It is not easy to recount how many servants, how many mercenaries, how many of the indigent class perished. At first, their corpses were carried in heaps on chariots: but then those of the less respectable were thrown into the current of the (Tiber) river. Counting, a fourth of the senators perished, and with them two consuls, and most of the tribunes. That disease began around the early part of September. (According to the dating in use, the month of the beginning of the epidemic, indicated by Livy (see below), is August). And continued for a year backward, investing and consuming every month and age [5,6].

Livy reports the same events, in the third book of his Histories, as recorded in the following passage [3,6,7]: It was the sickly season, and chanced to be a year of pestilence both in the City and in the country, for beasts as well as men; and the people increased the virulence of the disease, in their dread of pillage, by receiving flocks and country-folk into the City. This conflux of all kinds of living things distressed the citizens with its strange smells, while the country-people, being packed into narrow quarters, suffered greatly from the heat and want of sleep; and the exchange of ministrations and mere contact spread the infection. The Romans could scarce endure the calamities which pressed hard upon them, when suddenly envoys from the Hernici (a people allied to Rome) appeared, announcing that the Aequi and the Volsci had joined forces and established a camp in their territory, from which base they were devastating their land with an enormous army. Not only did the reduced numbers of the Senate {Dionysius also notes stricken senators too weak or lethargic to stand attempting to carry on the business of the Senate while “barely alive on litters” [2]} show their allies that the (Roman) nation was prostrated by the pestilence, but they also returned a melancholy answer to their suit, that the Hernici, namely, with the help of the (ir allies the…) Latins must defend their own possessions; for the City of Rome, in a sudden visitation of divine displeasure, was being ravaged by disease. If there should come any respite from their suffering, they (the Romans) would help their friends, as they had done the year before and on every other occasion. From that time onward, little by little, both because of the peace obtained from the gods and the gradual exhaustion of the unhealthy season, the bodies in which the course of the disease had run its course began to return to health, while minds turned to the problems of the State.

Notes of caution are in order, of course, in that such ancient sources can be confoundingly challenging to interpret for a series of reasons. Canonical tropes/accounts, of which Thucydides description of the Plague of Athens 430–426 BCE was and is the most well-known relevant example, authorial bias and distortion arising from ancient political, class or religious disputes or (as is the case regarding the Historia Augusta) and an unknown author or authors producing a source where the very purpose and nature of the work are unclear. In ancient descriptions of disease, for example, one must also be wary of the potentially distorting perceptual lens of erroneous Greco-Roman humoral medical theory [8]. In the above passages from Livy and Dionysius, however, none of these cautions seem to strongly apply. The accounts themselves, along with a supporting wealth of consilient interdisciplinary analyses, implicate P. falciparum’s evolutionary lineage in the 463 BCE outbreak. The disease clearly was part of, and in many ways fit well within, an established annualized pattern that was characteristic, then and later, of the late summer/early fall malarial “sickly” or “fever season”. This was something that would have been well understood (as a continuing annualized disease reality) by both Livy and Dionysius centuries later. References to this phenomenon indeed constituted a common signifying trope that formed part of the broader cultural and literary heritage of the ancient Greco-Roman Mediterranean world, with examples ranging from Homer’s Iliad to Roman poetic traditions [9,10]. The more prosaic words of the 1st century CE Roman physician Celsus in his work De Medicina “lethal autumn” also reflect specific awareness of this phenomenon within Greco-Roman medicine [11].

Such annualized outbreaks of sickness in Rome had, however, centered, up until 463 BCE, around malarial fevers caused by the less deadly plasmodium parasites P. vivax and P. malariae [11]. Yet, the epidemic event of 463 BCE was different than the norm; both ancient accounts document large numbers of deaths not confined to children or the elderly but including presumably healthy adults. The high death rates likely indicate an at least partially epidemiologically naive population and a new more virulent form of the annualized disease. As noted, P. falciparum statistically causes 90% of human malaria fatalities [3] and fits the retrospective diagnostic parameters for 463 BCE, in a multifaceted sense, well. Celsus (as well as other Greco-Roman physicians) accurately categorized malarial fever types (which we now know are caused by the plasmodium parasites P. malariae, P. vivax and P. falciparum) with a sound understanding of comparative pathologies, enabling environments and a seasonality peak of August–October [12] if not of underlying (including vector/secondary host epidemiology) causation. Thus, the failure of either Livy or Dionysius to mention any relapse phenomenon, which was well understood by 1st century CE Greco-Roman medicine (and far more common with vivax than falciparum) regarding the 463 BCE, is, in our view, also indicative that the outbreak likely marked a watershed moment for ancient Rome in terms of increased disease impact from, specifically, falciparum lineage malaria [13].

While recitations of the elements of pathology in the accounts regarding the 463 BCE outbreak are limited, descriptions indicative of fatigue/lethargy or weakness (noted above) as a primary symptom and protracted illnesses from which numerous sufferers eventually fully and completely recovered, as well as the disease’s seasonality, are also consistent with likely P. falciparum lineage pathology and epidemiology [3]. The described apparent rural-to-urban epidemiological progression of the outbreak of a seemingly single disease is also consistent with malaria and, notably, inconsistent with several other likely candidate pathogens such as typhus, tuberculosis, dysentery or other gastro-intestinal bacterial disorders. Another initially appealing pathogenic suspect in terms of seasonality, pathology and transmission (in this case through Culex, as opposed to Anopheles mosquitos), West Nile Virus, can be ruled out by molecular phylogenetic evidence indicating far more recent emergence and biogeographical introduction to Europe [14].

A secondary outbreak of typhoid fever (which indeed would have been an enhanced R0 threat in the prevailing urban conditions described for Rome in 463 BCE), including medically possible co-infections, contrastingly, cannot entirely be ruled out [15]. Tellingly, however, the 463 BCE outbreak also appears to have occurred firstly outside of the city of Rome and during a time of Roman contact and conflict with the Volsci, whose coastal territories (then and later after their eventual incorporation into the expanding Roman state) constituted one of ancient Italy’s primary malaria outbreak hotspots [12]. The described unusual influx of animals and their herders (as a symptom of the prevailing (A) political, economic and security/military contexts that were characterized by an overall high level of disorder, uncertainty and insecurity, into the city) likely also greatly augmented and concentrated mosquito—including Anopheles vector/secondary host—presence in the city of Rome. This may well have been a key epidemiologically enabling factor that increased the scale of the suspected falciparum lineage outbreak and overcame the formerly countervailing epidemic malarial stochasticity that was linked to certain limitations on Anopheles presence [11]. A 2018 epidemiological study conducted in Indonesia, in fact, strongly “highlights the importance of livestock (presence) for amplified malaria risk (by a factor of 2.8) rather than prophylaxis” in such close-proximity settings [16]. As noted above, another potentially exacerbating factor for the epidemic is that Romans would have been largely naive to P. falciparum pathology. Unlike Africans, they would not have long before developed variants such as the sickle cell trait “which is common in African populations and somewhat protects against fatal P. falciparum malaria.” [17,18]. While a hypothesis of a secondary Roman typhoid outbreak in 463 BCE is certainly possible, the evidence (when holistically considered), does not, in our view, make it very probable but rather favors a single outbreak of disease largely caused by P. falciparum evolutionary lineage malaria.

References in both ancient accounts to a preceding disease outbreak that devastated cattle and other animals in the 5th century BCE also lend at least indirect (if, unfortunately, also somewhat circular) support to the diagnosis of malaria through indirect possible implication of stagnant pools of contaminated water in that preceding outbreak. The now-eradicated single-strand RNA paramyxoviridae rinderpest virus is clearly a possible candidate pathogen in that instance, though the evidence in this regard is somewhat thinner and less compelling. Northern rinderpest strains had an extraordinary morbidity rate of nearly 100% [19], which is, however, consistent with both ancient accounts [4,7]. Rinderpest was ”very fragile” in terms of aerosolization, but that was not its primary path of transmission [20]; stagnant pools (which could also have also been fertile environments for Anopheles mosquitoes that are the secondary host/primary vector of malaria) of contaminated water were. Ancient writers such as Livy, in particular, seem to have erroneously conflated the epidemics [7]; modern science has additionally found no evidence of zoonotic transmission of rinderpest to humans [20], and WGS analysis indicates a later-to-much-later genetic (and zoonotic) emergence of measles from rinderpest, with these genetically linked viruses, however, continuing to co-exist in a temporal sense [21].

According to a relaxed clock Bayesian phylogenetic study with an HPD confidence level of 95%, the eleventh and twelfth centuries are the likely temporal window for measles emergence from rinderpest—the highly relevant early edge of that temporal window would be between 437 and 678 CE [22]. This would be far too late to be the cause of the 5th century BCE epidemic. The described seasonality of the 463 BCE ancient outbreak also does not match that of measles [23], and therefore, that alternative can be fairly firmly ruled out. Rinderpest itself was likely already present in the 5th century BCE in ancient Italy. Rinderpest was more certainly established in the Roman Empire sometime prior to the 4th century CE. The detailed description contained in De mortibus boum (alternatively Carmen bucolicum de virtute signi crucis domini) written by the 4th century CE Roman poet Severus Sanctus Endeleichus strongly indicates fairly regular and long-standing outbreaks of epizootic (and endemic) rinderpest disease in the European territories of the ancient Roman Empire [19,20].

As with typhoid fever, one also cannot wholly eliminate an unusually virulent strain from the evolutionary lineage of P. vivax as the primary (or secondary) cause of the 463 BCE Roman outbreak, but this again appears far less likely, especially in terms of the differentially indicated primary cause, than does the falciparum lineage. Though, in fact, “mixed infections with the two species are (medically) common” [13]. Rome’s population in 463 BCE would likely have acquired some level of immunity to vivax, its’ pathology is also generally less severe (if sometimes harder to clear, or in modern times, eradicate medically) and neither Livy nor Dionysius mention any relapse phenomenon, which is far more medically common with vivax than falciparum infection [13].

Later evidence from Livy regarding a similarly timed (late summer/early fall) episode of pestilence that, in an “unhealthy” marshy locality in Sicily where falciparum’s presence was already likely long endemic, broke out during the Roman siege of the city of Syracuse (214–212 BCE) is also indirectly telling. Livy’s account again describes a particularly widespread, notable and severe pestilential event with heavy adult mortality, “a calamity almost heavy enough to turn them (Greeks, Sicilians, Carthaginians and Romans were all affected) from all thoughts of war.” The generally unsanitary and difficult conditions of the siege may also have played a role, with secondary bacteriological infections a distinct possibility [7,24,25]. Though many Roman soldiers were “carried off by that pestilence” the Carthaginians were, according to Livy, even more heavily affected, and the Sicilians fighting on the Carthaginian side fled the “unhealthy place.” Corpses of the infected were also perceived as dangerous with direct contact such as carrying (though apparently not otherwise), a risk which rather precisely (though far from exclusively in terms of other infectious diseases) applies today (in situations with the bodies of malaria victims and also with malaria contaminated medical waste from procedures such as diagnostic tests) to modern health care workers and requires the use of PPE [7,9,10,11,24,25,26]. Livy attributes this greater resilience to the Roman besiegers’ adaptation to the “climate and water” [7,13,14,24,25]. Modern medical research, however, beginning with German physician and microbiologist Robert Koch at the beginning of the 20th century, indicates that adult acquired immunity comes only slowly through repeated exposure to the malarial plasmodium parasite [2]—differentially suggesting that at least some Roman soldiers had been repeatedly exposed over the longer term (something unlikely to have occurred solely in Sicily). Notably, the infections are clearly also described by Livy as non-relapsing, e.g., “those who had been weakened by sickness were restored by shade and shelter” [7,15,24,25]. More broadly, our proposed timeline and implicated P. falciparum evolutionary lineage pathogen also (while not rising to the level of scientific confirmation) fits very well overall, in terms of a more holistically considered retrospective diagnosis, into what we already know or can reasonably surmise about the history of malaria in ancient Italy.

Paleopathology research has uncovered evidence of thalassemia, a genetic mutation commonly known as Mediterranean anemia and classified by modern medicine as a hereditary blood disorder, that confers (like the sickle cell trait in Africans) some immunity against malaria being present in ancient Greek populations. Ancient skeletons have been unearthed whose “bones show osseous abnormalities suggestive of severe thalassemia disease.” But such scientific confirmation remains “tentative”, as a variety of infectious diseases could have caused similar abnormalities. An extensive study of 49 4000-year-old ancient Minoan (Crete) skeletons, however, failed to produce scientific confirmation of thalassemia presence and concluded that, if present at that earlier stage in the history of the ancient Mediterranean, “it is therefore likely that the frequency of thalassemia mutations among ancient Minoans was relatively low”—suggesting a less intensive or widespread presence of the disease in that earlier time period [24]. Dates for the establishment and spread of malaria as an annualized/endemic (peak late summer/early fall seasonality) ancient disease in Europe do vary in the established scholarship. Such timelines have been particularly disputed, and we hope that our conclusions here help clarify this question, for the evolutionary lineage of P. falciparum—though it seems to have been well on the way to becoming endemic in nearby northern Greece by 500 BCE. General agreement also exists that P. vivax arrived earlier in Italy than P. falciparum [11]. Malaria outbreaks occurred though from the 6th century BCE onwards, with the effects of endemic disease eventually becoming “considerable” in terms of killing or debilitating people (to the extent that malaria) altered the age structure of human populations” in the ancient Mediterranean World [11]. As noted above, we believe that our evidence, when considered holistically and consiliently, likely demonstrates that the epidemic of 463 BCE marked a key moment in this progression. As to any retrospective diagnosis alternatives of more exotic/less common/unlikely/hypothetical or extinct pathogens not known to be biogeographically included that also nonetheless fit the annualized seasonal pattern in 463 BCE (when Roman realities were still far more biogeographically/epidemiologically-localized than they later became during the heyday of empire from the 1st to the 3rd centuries CE), we reference the famous phrase of Dr. Theodore Woodward traditionally used to train medical students: “When you hear hoofbeats behind you, don’t expect to see a zebra” [25].

Based on a highly detailed description of the pathology of quotidian fevers [27] from Celsus in the early 1st century CE, it can also be safely concluded that the evolutionary lineage of P. falciparum had long been endemic in Italy before then [11]. Indeed, a Canadian team from the McMaster University Ancient DNA Centre led by Stephanie Marciniak scientifically confirmed P. falciparum mtDNA fragments from ancient remains unearthed from the Velia and Vagnari regions of Italy, dating to the early to mid-imperial period of the 1st–2nd centuries CE [28]. Less certain, but still telling, ancient literary references to annually escaping, deadly “bad air”, an allusion to the Greco-Roman humoral medical concept of disease-causing miasmas, in the late summer/early fall around the town of Tarquinia (with nearby apparently Anopheles-ridden malarial coastal marshes) indeed date as far back as the 2nd and even 3rd centuries BCE. These are again indicative of the evolutionary lineage of P. falciparum causing endemic disease [11] by that, far earlier, time period. As noted, Roman (B) culture, more broadly, reflected and shaped perceptions and at times outcomes (through inducing changes in behavior). The 1st century BCE famed poet Horace, in his Odes and Epistles, uses the phrase “fever season” not only to describe specific conditions in the late summer–early fall but also to represent periods of difficulty, illness or even historical events that have caused suffering to humanity—a clear signifier of the trope’s cultural recognition and relevance for ancient Rome [29].

Overall, one can conclude that the process of malaria becoming an endemic disease throughout non-alpine Italy was steady and significant but also slow and extended (hindered initially by the lack of consistent/sufficient presence of Anopheles mosquitoes) and took place between 700 and 100 BCE [11]. There was a combination of factors that initially likely limited vector presence. In the spread of P. falciparum to ancient central and southern Italy, Anopheles labranchiae (via North Africa) was the sole species vector. These mosquitos would also have had to seek shelter in human buildings to survive the colder Italian winters [30].

Another relevant factor involves Anopheles vector frequency of human bite selections amongst total bite selections (known as the anthropophilic index). In sub-Saharan Africa, anthropophilic index percentages are as high as 80–100%. But initially, in Italy, as in North Africa, percentages of mosquito bites on humans would have likely been 50% or below [30]. This was likely another limiting reality that the specific circumstances of the events in 463 BCE could well have, according to modern scientific evidence, helped epidemiologically surmount [16]. In fact, malaria reached the Italian north much later, only by around 1000 CE [27], though the colder and drier prevailing climate there likely also inhibited the spread of the disease. The Pontine Marshes near Rome itself, however, were a suitable spot for the disease to become strongly established. By the 1st century BCE, Julius Caesar was making the first of many historical attempts to drain the Pontine Marshes [12]. Horace, like many upper-class Romans, fled Rome during these unpleasant and dangerous months to avoid the muggy climate and the malarial disease that often spread through the city. This was common behavior among the well-to-do, who preferred to take refuge in villas and summer residences in the countryside in drier and cooler locations [29].

Overall, as Roman civilization grew and expanded over the centuries, the feedbacking combination of the continuing warmer climate and the greater scale and intensification of agricultural practices created an environment that led to a steadily strengthening amplification of the epidemiology of malarial infection in ancient southern and central Italy [30]. Besides the evidence from a multitude of literary sources, paleopathology research has also scientifically confirmed, in addition to the aforementioned 1st–2nd century CE finds, (through PCR/DNA analysis] ancient Roman P. falciparum malaria infections and deaths—from corpses found at the Umbrian so-called “Infant Cemetery” from the 5th century CE (occurring against the later backdrop of the Western Roman Empire’s collapse) at the archaeological site of Lugnano [11].

That same 5th century CE outbreak also relevantly highlighted the differences in terms of epidemiology and pathology for a naive population (in this case, Attila’s invading Huns whom the outbreak affected so severely as to likely drive them from Italy) and one that had been living with P. falciparum for nearly a millennium. The local victims at Lugnano were (typically) children who lacked immune responses fully attuned through prior exposure [31]. Lacking basic germ theory and modern blood tests to confirm and identify parasite species [32], a wide range of antimalarial drugs, ACT therapies used by modern medicine to treat uncomplicated forms of P. falciparum lineage infection or the parenteral antimalarial therapies used to combat more severe cases [1], surviving adults at Lugnano desperately turned to magical remedies involving ravens’ talons, “stones in the mouths of the small children’s corpses” and pots of ash [31]. The intensification of malaria with the onset of Italian P. falciparum lineage infections that seems to have begun in 463 BCE indeed thus had significant and enduring civilizational-level consequences for ancient Rome.

More broadly, (C) changing climatic conditions clearly also seem to have played a role in the expanding epidemiological footprint of a variety of types of malaria in ancient Italy. It is notable, however, that direct correlations between climate (and climate change) and infectious disease presence can be difficult to scientifically prove conclusively, and according to a 2001 report of the Committee on Climate, Ecosystems, Infectious Disease and Human Health of the National Academy of Sciences, “ultimately these climatic impacts must be placed in the context of all the other factors that can influence infectious disease (presence and) transmission rates” [33]. This is precisely the holistic approach that we have tried to follow here. Yet, a combination of written records and a range of consilient scientific data makes deducing relevant ancient Roman climate trends generally reliable from the 5th century BCE onward. This was the early part of the era often characterized by historians as the Roman Warm Period (RWP), or alternatively, the Roman Climate Optimum (RCO). There are strong signs of warmer and wetter climate trends from around the 6th Century BCE onwards [34]. The Tiber river, for example, seems to have changed course by the 6th Century BCE due to, amongst other factors, steadily warmer temperatures. Wetter conditions also prevailed more generally, in a partially overlapping manner, between 800 to 400 BCE across the non-alpine regions of Italy [34].

The overall picture though is complex in more than one sense, often regionally varied and at times strongly interrupted. In 426 BCE, for example, an unknown stratospheric volcanic eruption took place that led to sharply cooler temperatures for the following three years. More consistent “warmer, wetter or more stable” climate conditions began to prevail again around 200 BCE [34]. In a feedbacking manner with climate change, malaria’s arrival and expanding presence in ancient Italy was also likely enabled and exacerbated by additional (D) anthropogenic environmental factors: increasing deforestation, interrelated practices of agriculture, increasing urbanization and other forms of human activity. The water table also rose in Italy by a meter between the 6th and 4th centuries BCE [12]. Over time, under these changed climate and environmental realities, malaria became more widespread and significant as an endemic disease in the emerging Roman Empire. Indeed, malaria (in all its three present lineage species—P. malariae, P. vivax and P. falciparum), tuberculosis and many forms of dysentery were the most prominent diseases in ancient Rome. Chickenpox, diphtheria, mumps and whooping cough also occurred in childhood, with less frequent attacks on adults [35].

Yet, it was malaria, augmented by the more deadly P. falciparum lineage legacy that likely began in 463 BCE that was the most significant infectious disease threat for ancient Rome. Historian Robert Sallares noted that ancient Rome’s holistic interaction with malaria (particularly P. falciparum) shows that “Malaria has an awesome power as a determinant of demographic patterns” [12]. Anthropologist Stephanie Marciniak of Toronto Metropolitan University Centre noted that “the historical record attests to the devastation that malaria exacted on ancient civilizations, particularly the Roman Empire” [28]. There were significant effects on population health, structure and life expectancy, and in Rome’s case, malaria (particularly P. falciparum) was also a contributor to an extremely high rate of early childhood (2–5 years old) mortality. Especially if we agree with the complex systems theory-based analysis of the Club of Rome’s Ugo Bardi that the Roman Empire of the 1st through 3rd centuries was “larger, better organized and better managed than anything that had existed before” [36], malaria and its destructive demographic consequences (particularly those caused by P. falciparum), [12], constituted a key and ever-present feedbacking flaw in the complex holistic functioning of the Roman Republic and later empire. More broadly, malarial disease impacts human populations at a deep biological level; “variants in the human genome that are associated with resistance to Plasmodium infection disease are estimated to be thousands of years old” in Africa [37]. Our supporting evidence for Section 1 is summarized, holistically, in

Table 1. Lessons from a Transformative Outbreak.

Evidence for P. falciparum Malaria	Evidentiary Presence and Source(s) Cited for Table 1 Row #
1. Relevant notice in ancient accounts	1. Present (Fully) [4,7]
2. Matching seasonality	2. Present (Fully) [4,7]
3. Matching pathology indicators	3. Present (Partially) [4,7]
4. Lethality in hypothetically naive population	4. Present (Fully) [2,4,7]
5. Rural–urban epidemiological spread	5. Present (Fully) [4,7]
6. Pattern not matching other likely pathogens	6. Present (Partially) [3,7,13,14,15,17]
7. Contemporaneous regional presence	7. Present (Fully) [11]
8. Factor(s) indicating R0 enhancement	8. Present (Fully) [4,7,16]
9. Literary/scientific evidence—later presence	9. Present (Fully) [28] and ([8])
10. Conflict linked to malarial environments	10. Present (Fully) [12]
11. Evidence vector enhancing conditions	11. Present (Fully) [4,7,19]

#: number.

(below).

During the late 19th century, however, the areas around Rome contributed to the foundational modern medical understanding of malaria (through the pioneering work of 19th–20th Century French physician Alphonse Laveran) and also saw efforts in the use of engineering to eradicate malaria through the successful draining of the Pontine Marshes [12]. The influx of a new and deadlier form of malaria in 463 BCE had also occurred against the developing (E) perceptions, practices, knowledge and capabilities of the prevailing medical system and (F) the existing holistic underlying state of the health of the affected population. Largely urban-based ancient Greco-Roman physicians associated the epidemiology/presence of malaria generally with miasmas emanating from unhealthy marshes but not specifically with mosquito bites. Though, contrastingly, rurally based Roman agricultural experts such as Varro (2nd Century BCE) and Columella (1st Century CE) do seem to have been at least vaguely aware of the mosquito vector for the various malarial fevers [27]. The likely reason for this oversight by the physicians, along with the prevailing and distorting lens of Greco-Roman medicine’s humoral theory (e.g., the famed second century CE physician Galen believed that quotidian fever was caused by an excess of phlegm [38]), is that the Anopheles secondary host/vector is complex and highly species-dependent. Many of the relevant species are indistinguishable without the modern technology of a microscope [12]. Thus, the prevalence of situations characterized by “lots of mosquitos but no malaria” likely explains why “ancient Greek and Roman physicians failed to notice the connection between the periodic intermittent fevers of malaria and mosquito bites” [12]. The dangers of P. falciparum, a modern transdisciplinary combination of archaeology and medicine informs us, were also likely exacerbated “by (underlying) moderate degrees of malnutrition” amongst the Roman lower classes during both the Republican and Imperial periods [12].

Greco-Roman medicine also lacked a consistently applied or effective remedy for severe malaria that extended beyond basic palliative care. The resulting intermixing of mystical elements within (noticeable indeed in the accounts of the 463 BCE outbreak) Greco-Roman medicine—conceptualization of malaria as a demon, magic, cults of Dea Febris (Goddess of Fevers) and amulets—also did not help matters. In regard to pathology, Greco-Roman physicians such as Celsus and Galen were on somewhat firmer ground, correctly classifying the intermittent (at times recurring over months or even years and also associated with gastro-intestinal disorders and miscarriages) but generally non-fatal milder “quartan” or somewhat more serious “tertian” fevers (those which we know today are caused, respectively, by P. malariae and P. vivax) as different from the more dangerous quotidian fevers associated, we know now, with P. falciparum [12]. Malaria seems to have depressed life expectancy overall in a way at least somewhat, if not exactly, analogous to the Yersinia pestis infection to during the later Middle Ages [12]. The physician Asclepiades of Bithnya described more severe fevers associated (descriptions recognizably associated by modern medicine) with P. falciparum (“semitertian” (archaic) and/or quotidian) and P. vivax (tertian) as fairly “common” in ancient Italy by the 3rd to 2nd centuries BCE [12]. One of the main symptoms of the more severe types of fevers was lethargy. The brilliant Galen, in the 2nd century CE, also inferred the concept of acquired immunity, noting the vulnerability of children and newcomers to these fevers [12]. He thus indirectly anticipated the modern medical conclusion that, “In low transmission areas, all ages are at risk due to low immunity” [3]. The Romans also had enough engineering capability and understanding of the importance of the very serious threat from malaria to build, at the empire’s height in the 2nd century CE, mitigating drainage systems in the Campagna around Rome that helped limit the impact of the disease in the city itself for centuries. These complex mitigation/control systems, however, collapsed completely along with the Western Roman Empire during the 5th century CE [27].

However, “during the 20th Century, malaria was eradicated from many temperate areas including the whole of Europe” [39]. Sophisticated detection and eradication methods have proved effective, and in today’s Europe, malaria is largely a disease of travelers, though some autochthonous cases of human-to-human transmission do occur [39]. While, as in ancient times, climate change (now more exclusively anthropogenic as opposed to naturally cyclic and anthropogenic) may mean that vector-borne malaria may once again become endemic to southern Europe [40], modern medical understanding and continued diligent use of a wide variety of prophylactic measures are likely to mitigate against renewed expansion of non-zoonotic malaria in the southern European lands it once haunted in ancient Roman times. Such expansion of mosquito-vector-borne disease threats in Europe during an era of anthropogenic climate change and environmental disturbance is also not limited to Anopheles-vector malaria; invasive Aedes albopictus mosquitoes, linked to the spread of tropical diseases such as dengue fever, chikungunya and the Zika virus have now been found in no less than 18 European countries. Aedes aegypti mosquitoes, linked to the spread of yellow fever, have recently become established in Cyprus [41].

3. Modern Materials and Methods: The Spread of Zoonotic Malaria

On our 21st century globalized planet, the non-zoonotic and zoonotic malaria goal for many countries is to meet the WHO’s standard of “zero indigenous malaria cases for three years and a programme for prevention of reestablishment of transmission” [42]. Globally, there are four main human non-zoonotic malaria-causing parasites: P. falciparum (with its more severe pathology), P. vivax, P. ovale and P. malariae. Six main types infect humans—P. falciparum, P. vivax, P. malariae, P. ovale, P. knowlesi (zoonotic and hosted by macaques) and P. cynomolgi (basically zoonotic and hosted primarily by chimps). Other malaria-causing plasmodium parasites from simians, in particular, (could) be transmitted to humans in the future” [43]. Particularly notable in this context is P. cynomolgi, which is an African plasmodium parasite that is hosted by chimpanzees but has also infected humans [43]. Indeed, in Africa today, patterns of spillover potentially blur lines between zoonotic and non-zoonotic forms of malaria, as the human forms (P. vivax and P. falciparum), which seem to have been the products of zoonoses from African apes, have now been genetically documented to spill over into wildlife populations from humans and then spill back over into humans [42]. Two-way spillovers of the African plasmodium parasite P. ovale between humans and chimpanzees have also occurred [43]. P. knowlesi is a sixth specifically and (so far at least) exclusively zoonotic form of malaria that spills over to humans from macaques in Southeast Asia. Such complex epidemiological realities are also revelatory of malaria’s complex, varied and “deep time” biological history as a simultaneously zoonotic and human-to-human transmitted disease [42]. For example, highly pathological P. falciparum, according to WGS-based molecular phylogenetic analysis, seems to have diverged from the primate-based P. reichenowi around 50,000 to as little as 10,000 years ago; P. vivax is far older—having emerged around 2 million years ago ([1,43]).

Today, amid broader concerns that global warming/climate change will lead to a broader “resurgence of malaria”, there is the interconnected (through the epidemiological feedback associated with the annual monsoon) and more acute problem of emerging P. knowlesi-caused zoonotic malaria, though often not fully understood and still often misdiagnosed (perceptions, practices, knowledge and capabilities of the prevailing medical system), and it is becoming quite widespread in Malaysia and Malaysian Borneo [1,44]. Both climate change and anthropogenic environmental factors have, as in ancient Italy, been likely strong contributors toward P. knowlesi’s rapid biogeographical–epidemiological expansion, with cases now detected quite far apart: with a western biogeographical boundary of India’s Andaman Islands and an eastern boundary of the Philippines [44]. Indeed, “despite the ongoing reduction in the number of cases of human malaria throughout the world, the incidence rate of knowlesi malaria is continuing to rise, especially in Southeast Asia” [45]. Expanded testing now shows a rapidly growing problem that is far “more prevalent than (had been) suspected.” Thus, appropriate strategies need to be developed for the prevention, diagnosis and treatment of zoonotic malaria [44]. In yet another unfortunate ancient–modern parallel, regional national (e.g., Thailand–Cambodia) and internal conflicts (e.g., Myanmar) and security threats in the region are also currently increasing (political, economic and security/military contexts). While conventional prophylactic measures will likely provide “some protection”, “innovative” modern medical strategies tailored towards the specific threat of P. knowlesi need to be developed and deployed. Such strategies should include deployment of “personal-level protection, vector control and environmental control” [45]. In a clear contrast to the helpless and baffled 5th century CE Romans at Lugnano, such modern preventive measures should also both acknowledge and build upon existing levels of local knowledge (culture, more broadly, reflects and shapes perceptions and at times outcomes), which recent research concerning the perceptions about zoonotic P. knowlesi malaria from indigenous hunter–gatherers in Orang Asli in Malaysia, for example, revealed to be fairly accurate [1].

Though an evolution to human-to-human transmission has not yet been documented for P. knowlesi, such an emergence (which would worsen an already concerning situation considerably in an epidemiological sense) certainly seems a distinct future possibility given the evolutionary history noted above. The case of 5th century BCE Rome, where malarial disease realities strongly evolved with profound longer-term effects, thus serves as a highly cautionary tale. Indeed, as noted above on an even “deeper time” biological history scale, PCR and high-throughput DNA sequencing confirm that what we today consider non-zoonotic human malaria is, in fact, a zoonotic disease in terms of “deep time” origins. “Presently available data are… compatible with a hypothesis that human P. malariae and P. ovale, like P. falciparum and P. vivax, also originated by cross-species transfer from African apes and then spread worldwide” [44]. This constitutes an enduring warning far older than even that offered by the experience of ancient Rome.

Macaque-hosted zoonotic P. knowlesi is now the most rapidly growing “challenge” for the worldwide goal of malaria elimination; it has now spread to seven countries [43]. P. knowlesi, while somewhat less severe (similar in manifestations of pathology but sans coma) than P. falciparum, still causes severe malaria in up to 10% of adult cases [46]. The Anopheles secondary host/vector is identical. The asexual stage of infection in humans is similar to that of P. falciparum but with a 24 h erythrocytic cycle. Unlike ovale, cynomolgi and vivax, relapses are not characteristic of knowlesi’s pathology [46]. A total of 90% of cases occur in adults “mostly living in forest edge areas undergoing intensive land use change (anthropogenic human disturbance).” High-risk groups include farmers and plantation workers [46]. Knowlesi is also “unique among zoonotic malarias in being able to cause severe and fatal disease, and is now the most common cause of death from malaria in (the nation of) Malaysia” [46]. As noted above, future mutations could certainly both make the disease directly transmissible between humans and therefore effectively non-zoonotic and more widespread (this has already been demonstrated in a laboratory setting but not yet conclusively in nature) and make it more dangerous to vulnerable populations—such as children that have not been exposed frequently so far due to environmental/epidemiological factors and among whom no fatalities have yet been recorded (the existing holistic underlying state of the health of the affected population). Indeed, P. knowlesi already demonstrates more genetic diversity than either P. falciparum or P. vivax [46]. The rapid spread of the disease has outrun the perceptions and capabilities of regional and local medical systems, and much about the true extent of P. knowlesi’s spread in Southeast Asia is not totally clear, with the “true burden of clinical disease outside Malaysia not well characterized” [46]. Yet, it is quite clear that while the human-hosted plasmodium species continue their decline in these regions, “the burden of clinical disease from P. knowlesi will likely increase” [46]. As in ancient Rome in 463 BCE, the threat from a new form of malaria in modern Southeast Asia is clearly evolving, spreading and deepening in multifaceted ways that highlight the key role played by certain shared contexts.

Occurring against a similar background of enabling climate change and increased anthropogenic environmental disturbance, it is indeed the growing epidemiological footprint of zoonotic P. knowlesi that most strongly echoes ancient Roman malaria realities today. ”Zoonotic malaria transmissions (more broadly, however,) are (also) widespread and growing, which poses a threat to public health” [43]. A total of 368,000 cases were recorded in 87 malaria-endemic countries in 2019 [43]. Rodent- and avian-based plasmodium parasites have no record of zoonoses, but non-human primates, as noted, are another story. An additional, to P. knowlesi in Southeast Asia, current additional zoonotic malaria risk (though considerably less severe than knowlesi in terms of human pathology) involves the New World monkey-hosted forms P. simium (genetically similar to P. vivax) and P. brasilianum (indeed, nearly “genetically identical” to P. malariae) [43]. The Atlantic Forest near Rio de Janeiro has been one hotspot for P. simium transmission. Anopheles mosquitoes remain the common secondary host/vector across all relevant malaria plasmodium parasite types. P. brasilianum and P. simium have both now caused malaria in humans [47,48]. Our overall findings and evidence supporting them are summarized in

Table 2. Comparative Materials and Methods: Ancient Rome and the Spread of Zoonotic Malaria in Modern Southeast Asia.

Malarial Disease Outbreak Features	Ancient	Modern
Outbreak location	Republican and Imperial Rome	Modern SE Asia [4,7,44]
Plasmodium parasite	P. falciparum	P. knowlesi [8,44]
Biogeographically novel	Likely yes	Yes [11,44]
Zoonotic malaria	No	Yes (macaque reservoir) [11,44]
Human–human transmission	Yes	No (possible with pathogen mutation) [3,44]
Severe pathology adults	Yes	Yes [3,4,7,44]
Anopheles vector	Yes	Yes [3,44]
Endemic footprint widening	Yes	Yes [11,44]
Associated warming climate	Yes	Yes [11,44]
Children particularly affected	Yes	No (possible with pathogen mutation) ([8]) and [46]
Anthropogenic causation/R0 Enhancement	Yes	Yes [11,44,45]
Significant demographic impact	Yes	Not so far, but potentially [11,12,45]
Treatment/mitigation available	No (limited)	Yes, but not fully deployed so far [44]

(below).

4. Conclusions

Ancient Greco-Roman culture’s understanding of the threat posed by infectious disease and interrelated social disorder was perhaps best embodied by Thucydides’ canonical account of the Plague of Athens (430 BCE) in his The History of Peloponnesian War [49]. While lacking modern scientific knowledge about zoonosis or microbial genesis, ancient Greeks and Romans nevertheless developed foundational concepts concerning public health. Such discourse was also of contemporary socio-political importance; the 1st century BCE Roman Republican dictator Lucius Cornelius Sulla Felix, for example, claimed the ability to master the epidemic fulgors with which the god Apollo Pythios could disseminate deadly plagues among humans [50]. Sulla thus used the widely feared threat of infectious disease to bolster his own political authority.

Writing in 2025, biologist Gwen Robbins-Schug of the University of North Carolina Greensboro and bioarcheologist Jane Buikstra of Arizona State University and the National Academy of Sciences called for the application of a comprehensive and interdisciplinary paleopathology perspective, one that “incorporates human, animal, environmental and planetary health into a deep time perspective that could be instrumental in addressing contemporary health challenges in the face of climate change” [51]. This is, in a more delimited way, what we have tried to achieve in this article. More broadly, the 21st century world faces increased threats from a wide range of zoonotic diseases. “Most of the new pathogens are zoonotic in origin” [52]. “Zoonotic outbreaks are also becoming more frequent”, with some emerging diseases displaying pandemic potential in terms of moving with an epidemiological speed (particularly in our globalized age) and a feedbacking epidemiological pathogenic impact that could potentially overwhelm our defenses [52]. Such failures, despite the historically unprecedented recent advances in medical knowledge, indeed clearly occurred during the COVID-19 pandemic. In addition to the potentially zoonotic pathogen enhancement threats implicit in the operation of mass-production commercial CAFOs, zoonoses derived from spillover from wildlife have also “seen a drastic increase in the emergence and re-emergence of viral zoonotic disease” [53]. There is also a clear modern historical precedent for such concern regarding malaria. After much progress in the early twentieth century in Europe in regard to malaria eradication, the chaos of WWI unexpectedly brought malaria “roaring back” to such an extent that it, at times, disrupted military operations [30].

Yet, resources are also not unlimited; fine-tuning in relation to expense, as well as in terms of planning and response, are practical and necessary. Against such a reality, a focused holistic awareness of the capabilities and limitations of our medical systems, gaining an understanding of the likely effects of complex feedbacks from existing population health as well as cultural perceptions, the influences of climate change and anthropogenic environmental disruption, as well as careful consideration of the possible political and military implications of zoonotic disease outbreaks, are all factors that a comparative overlay of the zoonotic disease history of the ancient and modern worlds demonstrates to be worthy of our consideration. Such interdisciplinary analyses, in our view, constitute a useful component in attempting to analyze and predict the complex future parameters of the timeless human struggle with zoonotic disease [54]. History thus can, we assert, serve as a kind of informative prophecy and symbiotic guide for a range of future scientific–medical adaptations and policy considerations to more holistically and effectively meet the increasing challenges likely arising from zoonotic disease for humanity in the future.