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Prolonged and Perplexing Fevers in Antiquity: Malaria and Typhoid Fever
Infect Dis Clin N Am 21 (2007) 857–866
Prolonged and Perplexing Fevers in Antiquity: Malaria and Typhoid Fever Cheston B. Cunha Pennsylvania State University College of Medicine, Pennsylvania, USA
If fever afflicts a person and then it releases him and then, on the third day, it afflicts him and pursues him, he continually has burning fever, severe fever, and lots of sweat, his illness has been prolonged and has knocked him down. –Babylonian medical text.
Fever of unknown origin is a topic that has enduring interest to physicians. The sheer variety of potential etiologies can make it difficult to differentiate a primary cause (eg, infection, tumor, and so forth). Even today, with the great panoply of powerful diagnostic tools at a physician’s disposal, fever of unknown origin can prove to be a challenging medical puzzle. Although this is often the case with the modern clinician, it was even more so with physicians of the Classical world. Within the overarching theme of fever of unknown origin, the prolonged fevers of infectious etiology must have been of particular concern to the ancient physician. As texts of the period reveal, infection was widespread throughout the ancient world; but most of these diseases leave telltale signs of their identity. For example, the classic exanthems, such as smallpox, a likely cause of the second and third century AD Antonine plague, ran a relatively short course, displayed a characteristic set of signs and symptoms, and then resulted in death or complete recovery. Similarly, infection by an organism like Bacillus anthracis, which is well described in Virgil’s Georgics Book III, was easily recognized by ancient physicians. Other diseases, such as measles, endemic typhus, or bubonic plague, the disease responsible for the Justiniac plague of the sixth century AD, elicited specific identifiable symptoms that eventually resolved with cure or death. Malaria or typhoid fever, however, could have presented as a prolonged fever, lasting several weeks or more, with
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few other distinguishing features to the ancient physician. Undoubtedly other conditions, such as occult malignancy, syphilis, and tuberculosis, were responsible for many of these fevers; nevertheless, this study of prolonged fever in antiquity focuses on malaria and typhoid fever as primary infectious causes [1,2]. Although the best way to obtain a definitive diagnosis of an ancient disease is by genetic analysis of surviving tissue, this is not always possible. The difficulty inherent to obtaining such samples from victims of ancient plagues often makes it impossible to use the technique of paleomicrobiology to determine the cause of ancient infection. It is frequently necessary to study literary descriptions of the disease written by the eminent physicians of the era to investigate the pandemics of the ancient world. Indeed, these descriptions are the most available and helpful to the modern investigator. The ancient physicians’ lack of diagnostic and therapeutic tools made them keen observers of the natural course of the diseases they encountered, a fact that works in the modern investigator’s favor when studying the ancient plagues. Essentially having only a history or present illness on which to base a diagnosis, the modern clinician can sharpen their diagnostic skills by attempting to identify these ancient plagues. Despite this often being the best evidence available, however, working with these sorts of documents can prove difficult. The difficulties encountered when translating any foreign text are compounded by the fact that so many words in the Classical languages have a variety of meanings. Additionally, because of the precision required for medical descriptions, words or phrases that are interpreted in ways other than what the original author intended can skew a description toward or away from an accurate diagnosis [3].
Malaria He must not go into the lowlands by the river or an infectious disease will infect him. –Babylonian medical text
Malaria, caused by the Plasmodium organism, has affected humans since ancient times. Originally evolving in Africa, it was only a matter of time before the parasite made its way to the temperate climate of the Mediterranean to plague the early civilizations of that region. Carried by the Anopheles mosquito, the malarial parasite is transmitted to humans by the bite of the female mosquito. Breeding in standing water, malaria was of particular concern in areas with a high concentration of swamps and marshes and demonstrates an increased incidence during the warmer, wet seasons of the year. Once the human host is infected, the organism replicates during an asymptomatic period of 1 to 2 weeks inside the host’s liver before entering the bloodstream. Once in the blood, the parasite infects the red blood cells and as a result of the destruction of blood cells, an intense febrile
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reaction occurs. Characteristically, patients with malarial infection note alternating periods of fever and chills along with periods of profuse sweating, particularly during the night. This can continue, depending on the species of malaria and the health of the host, for several weeks or even months. Of the many species of malarial parasites that infect humans, it is important to differentiate them based on the locations in which they are typically endemic. Plasmodium ovale is seen almost exclusively in West Africa, whereas Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae all are principally found in the Mediterranean. It is these last three species of malaria that were of eminent concern to the ancient Greek, Roman, and Near Eastern cultures. Infection involving P malariae, the least malignant, but most chronic of the malarial species, produces fever peaks every 72 hours (a quartan fever) and would have presented as a prolonged fever. Although death from this form of malaria is uncommon, fatal nephrotic syndrome, characterized by extreme edema, can develop in some cases. P vivax is another relatively benign species of malaria, producing fevers peaking every 48 hours, causing it to be labeled a ‘‘benign tertian fever.’’ The disease course associated with P vivax commonly lasts for several months and is often complicated by relapse following apparent cure, making it a frequent cause of prolonged fevers in antiquity. The more virulent form, P falciparum, is characterized by a tertian fever, occurring every 48 hours for a period of weeks to months. This form has the potential to cause severe complications, such as renal failure (known as ‘‘blackwater fever’’); cerebral malaria; and potentially death. It is important to note that although primary infection with P falciparum frequently causes the characteristic tertian fever, a low-grade fever can persist between peaks in a subtertian fashion. Additionally, concurrent infection with multiple P falciparum subtypes can result in daily fever peaks, mimicking other infectious causes of a quotidian fever [4,5]. Because of the nature of the disease, which leaves no specific pathognomonic findings in the remains of its victims, evidence for the historical presence of malaria lies almost exclusively in the written reports of ancient physicians. References to potential malarial infections are seen in medical texts from the Mesopotamian, Chinese, and Indian civilizations and are usually described as a period of relapsing and remitting fever that is a punishment of the gods. It is, of course, possible that these texts describe infections that can mimic the relapsing nature of malarial fever, such as Borrelia recurrentis, but the meticulousness of the descriptions by these ancient authors is often so precise as to leave little doubt as to malaria being the causative agent. Mesopotamian texts describe an illness that affects those who live near marshland during the summer months. ‘‘If he is sick for six days and on the seventh he gets well, on the eighth day he is sick and on the ninth he gets well, on the tenth day he is sick and on the eleventh he gets well (and) his illness has a turn for the worse, the [asipu] shall not make a prognosis as to his recovery.’’ This classic description of a tertian fever is highly
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suggestive of infection by either P vivax or P ovale. There are even potential descriptions of a serious complication of P falciparum infection, cerebral malaria. The following sections of Babylonian text suggest the potential presence of nystagmus, lethargy, confusion, seizure, and cranial nerve involvement that can characterize cerebral malaria in those afflicted by prolonged fevers [6]. If his face seems continuously to be spinning (and) his head, his hands, and his feet tremble. If.his limbs tremble and twist If when it comes over him, his left/right eye (makes bobbing movements similar to what) a spindle (does) when it spins (and) his right/left eye is full of blood, he continually opens his mouth and he bites [his] tongue. If his right cheek is pale (and) the left one is flushed [.] gives him a piercing pain, he is not [in full] possession of his faculties and [he.] sweat [.] LUGAL.GIR.RA afflicts him. If when it comes over him, his right hand [and] the [left] side of his face [.] he growls like a \dog, [he grinds?] his teeth, [and] his eyes jerk, LUGAL.GIR.RA afflicts him. LUGAL.GIR.RA is an associate of Nergal, the god of pestilence.
Just as the Assyrians and Babylonians before them, the Greeks too struggled with, and chronicled in their writings, the impact of malaria on their culture. Herodotus describes the annual flooding of the Nile River, which would be highly conducive to mosquito breeding. He also describes the ancient Egyptians’ methods to prevent malarial infection, such as living in elevated houses and sleeping with protective netting. This was not always sufficient, however, and Egyptian mummies provide some of the rare instances where genetic testing has proved the presence of malaria in the population living around the Nile delta around 3200 BC. Even the great poet Homer references malarial infection in Book II of his Iliad, describing times of illness during the ‘‘dog days’’ of summer, a typical time for malarial infection, when Sirius rises in the night sky [5]. Brief descriptions of seasonal fevers that occur near swamps and marshes are found throughout the writings of various other Greek authors, but it is not until Hippocrates that a fully detailed description of acute malaria is documented. His description of the tertian, semitertian, and quartan fevers is found in his Epidemics, Book I [7]: When the paroxysms fall on even days, the crises will be on even days; and when the paroxysms fall on odd days, the crises will be on odd days. Thus the first interval of those with crises on even days is on the fourth day, the sixth day, the eighth day, the tenth day, the fourteenth day, the twentieth day, the twenty-fourth day, the thirtieth day, the fortieth day, the sixtieth day, the eightieth day, and the one hundred and twentieth day. While those with crises on odd days, the first interval is on the third day, the fifth day, the seventh day, the ninth day, the eleventh day, the seventeenth day, the twenty-first day, the twenty-seventh day, and the thirty-first day.
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Furthermore, it is necessary that one know that if the crises fall on days other than those mentioned above, there will be a relapse, and this may be deadly. But it is essential to pay attention and know in which times the crises will lead to death and in which to recovery, or during which is there tendency to fair better or worse. The intervals when crises occur in irregular fevers, quartans, quintans, septans and nonans, should also be considered. –Hippocrates, epidemics, book I, XXVI (translation by Cheston Cunha).
Other texts in the Hippocratic corpus discuss those who live in or near marshland and drink stagnant marsh water developing weight loss, obtunded bellies, and splenomegaly; symptoms that may suggest chronic malaria. These individuals were noted to suffer prolonged, relapsing fevers along with profuse sweating during the course of their disease. It is impossible to say conclusively that this could only be a sign of chronic malaria, because such conditions as schistosomiasis (bilharzia), visceral leishmaniasis (kala-azar), or other parasitic infection could also present in this fashion. By studying these descriptions in isolation, it is not always possible truly to understand the impact malaria and other infections had on the Ancient Greeks. There are numerous instances where disease has directly impacted the course of Greek history, however, the most obvious of which was the Peloponnesian War, lasting from 431 to 404 BC. In 430 BC, the city of Athens was decimated by plague, likely caused by epidemic typhus, greatly hindering their ability to wage war, and depriving them of the great leader Pericles. As ancient authors have described, when the Athenians under Alcibiades chose to open a second front in Sicily in the summer of 413 BC, the Syracusan forces were able to confine the Athenians to marshy areas that had long been known to be rampant with prolonged fevers. It is highly likely that malaria played a key role in the eventual Athenian defeat in Sicily. These texts clearly show that not only was malaria a recognizable condition in ancient Greece, but that the disease itself had a significant impact on Greek civilization [5]. Although Greece was certainly affected by malaria, it was the Romans who truly had to contend with malaria as a constant influencing force. It was the Roman author Frontinus who first referenced the ‘‘bad air’’ for which malaria gets its name, in his first century AD text. Beginning with Rome’s founding, malaria and other infections played a critical role in the city’s history and development. Arguably, the most important factor that determines the placement of cities and the nature of their development is water. The quantity of, and proximity to, this critical element can often decide whether a city thrives or perishes. Indeed, the ancient Romans went to great lengths to ensure that ample amounts of fresh water were brought to their capital and that a sufficient distribution network was constructed to allow most, if not all, of its citizens’ access to this water supply. In the 10th century BC, when settlements first appeared on the hills overlooking what would later become the forum, the land between the Capitaline and
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Palatine hills and throughout areas of Rome was primarily marshland. It was only after the Etruscan king Tarquinius Priscus installed a system of drainage canals in the sixth century BC, the most notable of which was the large Cloaca Maxima, that the first manmade water-related structures were constructed. The Romans covered this drain during the second century BC and it remains in use to this day, feeding into the Tiber River. Until this drainage system was complete, the local population was unable to travel far from their protected houses in the, as Livy describes them, ‘‘very healthy hills’’ of Rome without risk of contracting a prolonged fever. Indeed, throughout Italy, areas of marsh and swampland frequently interfered with urban development, as was chronicled by many Roman authors. The author Pausanius describes one instance where the city of Myous actually had to be abandoned because of the malaria spread by mosquitoes from nearby swamps. Columella’s writings advise against building houses in areas near marshes, whereas Varo describes the transmission of prolonged fevers by small insects from ‘‘unhealthy marshes.’’ It is interesting to note that, although Varo was never actually able to make the direct connection between the mosquito vector and the disease (he and his contemporaries believed it was the air from the marshes itself that caused fever) this was the closest the Classical world would come to determining the etiology of any of the prolonged fevers [8,9]. Perhaps the clearest and most meticulous of the Roman descriptions of the prolonged fevers that affected those living near marshland in the summer and fall months is that of Celsus. His classic description, found next, from the first century AD is highly suggestive of the course of malarial infection [10]. But quartans are simpler. The fevers begin with shivering, then a heat erupts, and then, the fever having ended, the next two days are free of it. On the fourth day it returns. However, tertian fevers surely have two types. The one type beginning and ending in the same manner as a quartan, the other with only this difference; that it allows one day to be free of it, and returns on the third. The other type is far more insidious, for it always returns on the third day, and out of forty-eight hours, thirty-six of them (although sometimes less or more) are occupied by the paroxysm. Neither does it completely halt during remission, but only takes a lighter course. This type most physicians call semitertian. Quotidians, on the other hand, are surely varied and have many parts. For some begin immediately with a heat, others with a coldness, and still others with shivering. I call it coldness when the extremities of the body are cold; I call it shivering when the entire body trembles. Again, some end with that, and a period free of symptoms follows; others end thusly, so that the fever diminishes somewhat, but nevertheless, some remnants of disease remain, until another paroxysm occurs; and some often have no remission, and continue on. I say again, some have an intense fever, others a more tolerable one: some are the same everyday, other are different and, alternating,
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the fever is milder one day, more severe the next. Some return at the same time the next day, others either later or sooner; some take a day and a night to have paroxysm and remission, some take less time, others more. Some, when they remit, cause a sweat, others do not; and from the sweat some are free of their disease, but in others the body is only made weaker by it. And the paroxysms sometimes occur only once during a single day, sometimes two or more times. Thus it often happens that everyday there are multiple paroxysms and remissions, as though each of the two answers its predecessor. –Celsus, de medicina, liber III (translation by Cheston Cunha).
Additionally, the great physician Galen clearly describes the characteristic fevers of malaria in many of his writings. Stating that Rome and the area surrounding it demonstrated a high prevalence of prolonged fever, he noted that, in some cases, these episodic fevers would resolve and return repeatedly for as many as 2 years, ultimately resulting in nephrotic syndrome and death. Other Roman authors provide very detailed descriptions of individual cases of malarial infection, the most notable of which is Cicero’s writing concerning the infection of Atticus. He chronicles the course of the disease from the original high fever in the fall, through periods of recurrence after intervals when Atticus was free of fever, ultimately resulting in complete resolution after many months. Martial also provides a somewhat briefer example of epistle writings involving what is almost certainly malaria [5,11]. But, Maximus, nothing more scandalous was ever done by Carus than his dying of fever, for it too committed an outrage. The cruel, deadly fever should have, at least, been a quartan! At least that disease should have been reserved for its own physician. (Carus was a physician who specialized in the diagnosis and treatment of quartan fevers) –Martial, epigrams X LXXVII. For his old friend, Maro, sick with a severe, burning, semi-tertian fever, vowed, and he did this aloud, that if the sick man were not sent down to the Stygian shades, a victim, welcome to mighty Jove, should die. The physicians begin to promise a definite recovery. Maro now makes vows not to pay his vow. –Martial, epigrams X XII XC (translation and parenthetical by Cheston Cunha).
The historical impact of malaria on ancient Roman civilization is not completely understood but is potentially underestimated. Although efforts to drain marshland and provide freshwater to cities and towns were largely successful, much of the Roman and Mediterranean region continued to be plagued by malaria well into the medieval and Renaissance periods. This ultimately meant that much of the Roman population constantly had to deal with chronic malarial infection. There are reports from ancient writers that Julius Caesar, while on campaign against Pompey, contracted a quartan fever for a time from which he recovered fully. Although other infections,
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such as bubonic plague or smallpox, inflicted enormous damage on the Roman Empire during the Antonine and Justiniac plagues, the constant presence of prolonged fevers of malarial infection must have been a force acting against Roman society.
Typhoid fever If [setu] burns him and sometimes he is hot, sometimes he is cold, he has [li’bu] but he does not have a sweat, that person has been sick for a month. –Babylonian medical text.
Typhoid fever, caused by the organism Salmonella typhi, is the other potentially undiagnosed, prolonged fever that affected the classical world. Because of its nature, it is often difficult to differentiate from malaria using history alone as a diagnostic tool. Indeed, until Sir William Osler analyzed the precise fever patterns of each disease, malaria and typhoid fever were often misdiagnosed as one another or as a combined entity. Although certain cardinal features stand out in each disease (eg, chills are nearly always present in malaria, but are rare in typhoid) it is, nevertheless, often difficult to distinguish between the two, particularly when using ancient texts as a primary source, which may not include findings helpful to a clinician in discriminating between the two diseases [12]. There is relatively few classical descriptions that can be specifically ascribed to typhoid fever. Indeed, without precise ways of measuring the exact temperatures of patients, ancient physicians may not have been aware of the classic stepwise progression of fever so characteristic of typhoid. Instead, typhoid would likely present to them as an insidious, prolonged fever, very similar in nature to the daily fevers seen with some malarial infections. Only in cases where a distinguishing feature presents itself, such as the intestinal bleeding or peritonitis of typhoid, is it possible to differentiate the ancient descriptions of persistent, lingering fever. In several sources, Babylonian medical writings allude to potential typhoid infection with intestinal bleeding. ‘‘If he has been sick for a long time and red liquid flows from his anus, his illness will let up. He burns with fever, he will get well. His days will be long.’’ [6]. It has been suggested that Alexander the Great ultimately died as a result of infection from typhoid fever, and this remains one of the great historical and medical mysteries. The descriptions of Alexander’s last days, provided by Arrian and Plutarch, are fairly detailed, and clearly indicate a prolonged fever was responsible for Alexander’s death, but, unfortunately, they do not provide an obvious diagnosis. Depending on how certain elements of the description are translated, a diagnosis of malaria or typhoid could be supported. Immediately after returning to Babylon in 324 BC, Alexander decided to inspect the swampy marshland surrounding the city, despite
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the advice of seers and priests to stay out of Babylon. It is likely that at this point he became infected with the organism (either typhoid or malaria) that was endemic to the swamps of Mesopotamia, and which ultimately killed him. Several days later, as the royal diaries relate, he became severely ill [13]: On the 29th May he slept in the bathroom because he was feverish. Next day, after taking a bath, he moved into the bedchamber and spent the day playing dice with Medius. He took a bath late in the evening, offered sacrifice to the gods, dined, and remained feverish throughout the night. On the 31st of May, he again bathed and sacrificed as usual and while he was lying down in the bathroom he was entertained by listening to Nearchus’ account of his voyage and his exploration of the great sea. On June 1st, the fever grew more intense: He had a bad night and all through the next day his fever was very high. He had his bed moved and lay in it by the side of the great plunge bath; there he discussed with his commanders the vacant posts in the army and how to fill them with top caliber officers. On the 4th of June his fever was still worse and he had to be turned on his side to perform the sacrifice. He then gave orders to his senior commanders to spend the night outside. On June 5th he was moved to the palace on the other side of the Euphrates, and there slept a little, but the fever did not abate. When his commanders entered the room he was speechless and remained so through June 6th. The Macedonians now believed he was dead and crowded the doors of the palace; they began to shout and threaten the Companions, who at length were forced to let them in. When the doors had been thrown open they all slowly filed past his bedside one by one, wearing neither cloak nor armor. Nothing could keep them from seeing him one last time and they were moved, in almost every heart was grief and a sort of helpless bewilderment at the thought of losing their king. Lying speechless as the men filed by, he struggled to raise his head, and in his eye there was a look of recognition for each individual as he passed. Python and Seleucus were sent to the temple of Serapis to ask whether Alexander should be moved there. The god replied that they should leave him where he was. On the 28th day of the month of Daisios (10 June, 323 BC) toward evening he died. Alexander was not yet thirty-three.
Based on this description, it seems as though the fever afflicting Alexander was constant and gradually increased in intensity over the initial few days after the onset of symptoms. The characteristic sweats and chills of malaria are not mentioned in this account, suggesting typhoid as the likely cause. Later in his disease, it is quite possible that Alexander entered a ‘‘typhoid state’’ manifested by his apathetic appearance. Indeed, the only element of typhoid fever that seems to be lacking from this description is the characteristic intestinal symptoms. As such, it is highly likely that the chronicle of Alexander’s final days is actually one of the few specific descriptions of the course of typhoid fever in the Classical world. The impact of Alexander’s death from typhoid fever cannot be understated. For those who believe, as the ancients did, that great individuals
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shape history, the death of Alexander from an unknown fever demonstrates than an infectious disease shaped the history of humankind. Although it is impossible to predict what might have happened had Alexander lived past 33 years, it is certain that his death, at the height of his power, allowed the collapse of one of the greatest, unifying empires the world has ever seen. It is for this reason that the prolonged fevers of antiquity have incredible significance and enduring interest.
Summary It can be said that infectious diseases have shaped the way the world has developed. Particularly in the Classical world, infection has influenced the creation of empires and wars, and has contributed to the fall of some of the greatest dynasties in human history. As many texts of the period reveal, the prolonged fevers, particularly those caused by malaria and typhoid fever, had a particularly powerful impact on the course of history. These diseases proved to be a constant, powerful force against which the Mesopotamians, Egyptians, Greeks, Romans, and others were forced to struggle with to thrive as cultures. The impact of malaria on the Peloponnesian War and the development of Rome, along with the death of Alexander the Great to typhoid fever, illustrate the importance of examining these ancient fevers of unknown origin.
References [1] Cunha CB, Cunha BA. The great plagues of the past: remaining questions. In: Drancourt M, Raoult D, editors. Paleomicrobiology: past human infections. New York: Elsevier; 2007. [2] Cunha CB. Anthrax: ancient plague, persistent problem. Infect Dis Pract 1999;23(4):35–9. [3] Cunha CB, Cunha BA. Impact of plague on human history. Infect Dis Clin North Am 2006; 20:253–72. [4] Warrell DA, Gilles HM. Essential malariology. 4th edition. New York: Arnold Publishing; 2002. [5] Retief F, Cilliers L. Malaria in Graeco-Roman times. Acta Cl 2004;XLVII:127–9. [6] Scurlock J, Anderson BR. Diagnoses in Assyrian and Babylonian medicine. Chicago: University of Illinois Press; 2005. p. 38. [7] Hippocrates, epidemics, book I, XXVI Loeb Classical Library. Harvard University Press; 1995. [8] Aicher PJ. Guide to the aqueducts of ancient Rome. Wauconda (IL): Bolchazy-Charducci Publishers, Inc; 1995. [9] Sallares R. Malaria and Rome. New York: Oxford University Press; 2002. p. 200–4. [10] Celsus, De Medicina, Liber III. Loeb Classical Library. Harvard University Press; 1997. [11] Martial, Epigrams. Loeb Classical Library. Harvard University Press; 1997. [12] Christie AB. Infectious diseases: epidemiology and clinical practice. Edinburgh (Scotland): Churchill Livingsone; 1987. p. 100–6. [13] Cunha BA. The death of Alexander the Great: malaria or typhoid fever? Infect Dis Clin North Am 2004;18:53–63.
Prolonged and Perplexing Fevers in Antiquity: Malaria and Typhoid Fever Cheston B. Cunha Pennsylvania State University College of Medicine, Pennsylvania, USA
If fever afflicts a person and then it releases him and then, on the third day, it afflicts him and pursues him, he continually has burning fever, severe fever, and lots of sweat, his illness has been prolonged and has knocked him down. –Babylonian medical text.
Fever of unknown origin is a topic that has enduring interest to physicians. The sheer variety of potential etiologies can make it difficult to differentiate a primary cause (eg, infection, tumor, and so forth). Even today, with the great panoply of powerful diagnostic tools at a physician’s disposal, fever of unknown origin can prove to be a challenging medical puzzle. Although this is often the case with the modern clinician, it was even more so with physicians of the Classical world. Within the overarching theme of fever of unknown origin, the prolonged fevers of infectious etiology must have been of particular concern to the ancient physician. As texts of the period reveal, infection was widespread throughout the ancient world; but most of these diseases leave telltale signs of their identity. For example, the classic exanthems, such as smallpox, a likely cause of the second and third century AD Antonine plague, ran a relatively short course, displayed a characteristic set of signs and symptoms, and then resulted in death or complete recovery. Similarly, infection by an organism like Bacillus anthracis, which is well described in Virgil’s Georgics Book III, was easily recognized by ancient physicians. Other diseases, such as measles, endemic typhus, or bubonic plague, the disease responsible for the Justiniac plague of the sixth century AD, elicited specific identifiable symptoms that eventually resolved with cure or death. Malaria or typhoid fever, however, could have presented as a prolonged fever, lasting several weeks or more, with
E-mail address: [email protected] 0891-5520/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.08.010
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few other distinguishing features to the ancient physician. Undoubtedly other conditions, such as occult malignancy, syphilis, and tuberculosis, were responsible for many of these fevers; nevertheless, this study of prolonged fever in antiquity focuses on malaria and typhoid fever as primary infectious causes [1,2]. Although the best way to obtain a definitive diagnosis of an ancient disease is by genetic analysis of surviving tissue, this is not always possible. The difficulty inherent to obtaining such samples from victims of ancient plagues often makes it impossible to use the technique of paleomicrobiology to determine the cause of ancient infection. It is frequently necessary to study literary descriptions of the disease written by the eminent physicians of the era to investigate the pandemics of the ancient world. Indeed, these descriptions are the most available and helpful to the modern investigator. The ancient physicians’ lack of diagnostic and therapeutic tools made them keen observers of the natural course of the diseases they encountered, a fact that works in the modern investigator’s favor when studying the ancient plagues. Essentially having only a history or present illness on which to base a diagnosis, the modern clinician can sharpen their diagnostic skills by attempting to identify these ancient plagues. Despite this often being the best evidence available, however, working with these sorts of documents can prove difficult. The difficulties encountered when translating any foreign text are compounded by the fact that so many words in the Classical languages have a variety of meanings. Additionally, because of the precision required for medical descriptions, words or phrases that are interpreted in ways other than what the original author intended can skew a description toward or away from an accurate diagnosis [3].
Malaria He must not go into the lowlands by the river or an infectious disease will infect him. –Babylonian medical text
Malaria, caused by the Plasmodium organism, has affected humans since ancient times. Originally evolving in Africa, it was only a matter of time before the parasite made its way to the temperate climate of the Mediterranean to plague the early civilizations of that region. Carried by the Anopheles mosquito, the malarial parasite is transmitted to humans by the bite of the female mosquito. Breeding in standing water, malaria was of particular concern in areas with a high concentration of swamps and marshes and demonstrates an increased incidence during the warmer, wet seasons of the year. Once the human host is infected, the organism replicates during an asymptomatic period of 1 to 2 weeks inside the host’s liver before entering the bloodstream. Once in the blood, the parasite infects the red blood cells and as a result of the destruction of blood cells, an intense febrile
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reaction occurs. Characteristically, patients with malarial infection note alternating periods of fever and chills along with periods of profuse sweating, particularly during the night. This can continue, depending on the species of malaria and the health of the host, for several weeks or even months. Of the many species of malarial parasites that infect humans, it is important to differentiate them based on the locations in which they are typically endemic. Plasmodium ovale is seen almost exclusively in West Africa, whereas Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae all are principally found in the Mediterranean. It is these last three species of malaria that were of eminent concern to the ancient Greek, Roman, and Near Eastern cultures. Infection involving P malariae, the least malignant, but most chronic of the malarial species, produces fever peaks every 72 hours (a quartan fever) and would have presented as a prolonged fever. Although death from this form of malaria is uncommon, fatal nephrotic syndrome, characterized by extreme edema, can develop in some cases. P vivax is another relatively benign species of malaria, producing fevers peaking every 48 hours, causing it to be labeled a ‘‘benign tertian fever.’’ The disease course associated with P vivax commonly lasts for several months and is often complicated by relapse following apparent cure, making it a frequent cause of prolonged fevers in antiquity. The more virulent form, P falciparum, is characterized by a tertian fever, occurring every 48 hours for a period of weeks to months. This form has the potential to cause severe complications, such as renal failure (known as ‘‘blackwater fever’’); cerebral malaria; and potentially death. It is important to note that although primary infection with P falciparum frequently causes the characteristic tertian fever, a low-grade fever can persist between peaks in a subtertian fashion. Additionally, concurrent infection with multiple P falciparum subtypes can result in daily fever peaks, mimicking other infectious causes of a quotidian fever [4,5]. Because of the nature of the disease, which leaves no specific pathognomonic findings in the remains of its victims, evidence for the historical presence of malaria lies almost exclusively in the written reports of ancient physicians. References to potential malarial infections are seen in medical texts from the Mesopotamian, Chinese, and Indian civilizations and are usually described as a period of relapsing and remitting fever that is a punishment of the gods. It is, of course, possible that these texts describe infections that can mimic the relapsing nature of malarial fever, such as Borrelia recurrentis, but the meticulousness of the descriptions by these ancient authors is often so precise as to leave little doubt as to malaria being the causative agent. Mesopotamian texts describe an illness that affects those who live near marshland during the summer months. ‘‘If he is sick for six days and on the seventh he gets well, on the eighth day he is sick and on the ninth he gets well, on the tenth day he is sick and on the eleventh he gets well (and) his illness has a turn for the worse, the [asipu] shall not make a prognosis as to his recovery.’’ This classic description of a tertian fever is highly
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suggestive of infection by either P vivax or P ovale. There are even potential descriptions of a serious complication of P falciparum infection, cerebral malaria. The following sections of Babylonian text suggest the potential presence of nystagmus, lethargy, confusion, seizure, and cranial nerve involvement that can characterize cerebral malaria in those afflicted by prolonged fevers [6]. If his face seems continuously to be spinning (and) his head, his hands, and his feet tremble. If.his limbs tremble and twist If when it comes over him, his left/right eye (makes bobbing movements similar to what) a spindle (does) when it spins (and) his right/left eye is full of blood, he continually opens his mouth and he bites [his] tongue. If his right cheek is pale (and) the left one is flushed [.] gives him a piercing pain, he is not [in full] possession of his faculties and [he.] sweat [.] LUGAL.GIR.RA afflicts him. If when it comes over him, his right hand [and] the [left] side of his face [.] he growls like a \dog, [he grinds?] his teeth, [and] his eyes jerk, LUGAL.GIR.RA afflicts him. LUGAL.GIR.RA is an associate of Nergal, the god of pestilence.
Just as the Assyrians and Babylonians before them, the Greeks too struggled with, and chronicled in their writings, the impact of malaria on their culture. Herodotus describes the annual flooding of the Nile River, which would be highly conducive to mosquito breeding. He also describes the ancient Egyptians’ methods to prevent malarial infection, such as living in elevated houses and sleeping with protective netting. This was not always sufficient, however, and Egyptian mummies provide some of the rare instances where genetic testing has proved the presence of malaria in the population living around the Nile delta around 3200 BC. Even the great poet Homer references malarial infection in Book II of his Iliad, describing times of illness during the ‘‘dog days’’ of summer, a typical time for malarial infection, when Sirius rises in the night sky [5]. Brief descriptions of seasonal fevers that occur near swamps and marshes are found throughout the writings of various other Greek authors, but it is not until Hippocrates that a fully detailed description of acute malaria is documented. His description of the tertian, semitertian, and quartan fevers is found in his Epidemics, Book I [7]: When the paroxysms fall on even days, the crises will be on even days; and when the paroxysms fall on odd days, the crises will be on odd days. Thus the first interval of those with crises on even days is on the fourth day, the sixth day, the eighth day, the tenth day, the fourteenth day, the twentieth day, the twenty-fourth day, the thirtieth day, the fortieth day, the sixtieth day, the eightieth day, and the one hundred and twentieth day. While those with crises on odd days, the first interval is on the third day, the fifth day, the seventh day, the ninth day, the eleventh day, the seventeenth day, the twenty-first day, the twenty-seventh day, and the thirty-first day.
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Furthermore, it is necessary that one know that if the crises fall on days other than those mentioned above, there will be a relapse, and this may be deadly. But it is essential to pay attention and know in which times the crises will lead to death and in which to recovery, or during which is there tendency to fair better or worse. The intervals when crises occur in irregular fevers, quartans, quintans, septans and nonans, should also be considered. –Hippocrates, epidemics, book I, XXVI (translation by Cheston Cunha).
Other texts in the Hippocratic corpus discuss those who live in or near marshland and drink stagnant marsh water developing weight loss, obtunded bellies, and splenomegaly; symptoms that may suggest chronic malaria. These individuals were noted to suffer prolonged, relapsing fevers along with profuse sweating during the course of their disease. It is impossible to say conclusively that this could only be a sign of chronic malaria, because such conditions as schistosomiasis (bilharzia), visceral leishmaniasis (kala-azar), or other parasitic infection could also present in this fashion. By studying these descriptions in isolation, it is not always possible truly to understand the impact malaria and other infections had on the Ancient Greeks. There are numerous instances where disease has directly impacted the course of Greek history, however, the most obvious of which was the Peloponnesian War, lasting from 431 to 404 BC. In 430 BC, the city of Athens was decimated by plague, likely caused by epidemic typhus, greatly hindering their ability to wage war, and depriving them of the great leader Pericles. As ancient authors have described, when the Athenians under Alcibiades chose to open a second front in Sicily in the summer of 413 BC, the Syracusan forces were able to confine the Athenians to marshy areas that had long been known to be rampant with prolonged fevers. It is highly likely that malaria played a key role in the eventual Athenian defeat in Sicily. These texts clearly show that not only was malaria a recognizable condition in ancient Greece, but that the disease itself had a significant impact on Greek civilization [5]. Although Greece was certainly affected by malaria, it was the Romans who truly had to contend with malaria as a constant influencing force. It was the Roman author Frontinus who first referenced the ‘‘bad air’’ for which malaria gets its name, in his first century AD text. Beginning with Rome’s founding, malaria and other infections played a critical role in the city’s history and development. Arguably, the most important factor that determines the placement of cities and the nature of their development is water. The quantity of, and proximity to, this critical element can often decide whether a city thrives or perishes. Indeed, the ancient Romans went to great lengths to ensure that ample amounts of fresh water were brought to their capital and that a sufficient distribution network was constructed to allow most, if not all, of its citizens’ access to this water supply. In the 10th century BC, when settlements first appeared on the hills overlooking what would later become the forum, the land between the Capitaline and
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Palatine hills and throughout areas of Rome was primarily marshland. It was only after the Etruscan king Tarquinius Priscus installed a system of drainage canals in the sixth century BC, the most notable of which was the large Cloaca Maxima, that the first manmade water-related structures were constructed. The Romans covered this drain during the second century BC and it remains in use to this day, feeding into the Tiber River. Until this drainage system was complete, the local population was unable to travel far from their protected houses in the, as Livy describes them, ‘‘very healthy hills’’ of Rome without risk of contracting a prolonged fever. Indeed, throughout Italy, areas of marsh and swampland frequently interfered with urban development, as was chronicled by many Roman authors. The author Pausanius describes one instance where the city of Myous actually had to be abandoned because of the malaria spread by mosquitoes from nearby swamps. Columella’s writings advise against building houses in areas near marshes, whereas Varo describes the transmission of prolonged fevers by small insects from ‘‘unhealthy marshes.’’ It is interesting to note that, although Varo was never actually able to make the direct connection between the mosquito vector and the disease (he and his contemporaries believed it was the air from the marshes itself that caused fever) this was the closest the Classical world would come to determining the etiology of any of the prolonged fevers [8,9]. Perhaps the clearest and most meticulous of the Roman descriptions of the prolonged fevers that affected those living near marshland in the summer and fall months is that of Celsus. His classic description, found next, from the first century AD is highly suggestive of the course of malarial infection [10]. But quartans are simpler. The fevers begin with shivering, then a heat erupts, and then, the fever having ended, the next two days are free of it. On the fourth day it returns. However, tertian fevers surely have two types. The one type beginning and ending in the same manner as a quartan, the other with only this difference; that it allows one day to be free of it, and returns on the third. The other type is far more insidious, for it always returns on the third day, and out of forty-eight hours, thirty-six of them (although sometimes less or more) are occupied by the paroxysm. Neither does it completely halt during remission, but only takes a lighter course. This type most physicians call semitertian. Quotidians, on the other hand, are surely varied and have many parts. For some begin immediately with a heat, others with a coldness, and still others with shivering. I call it coldness when the extremities of the body are cold; I call it shivering when the entire body trembles. Again, some end with that, and a period free of symptoms follows; others end thusly, so that the fever diminishes somewhat, but nevertheless, some remnants of disease remain, until another paroxysm occurs; and some often have no remission, and continue on. I say again, some have an intense fever, others a more tolerable one: some are the same everyday, other are different and, alternating,
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the fever is milder one day, more severe the next. Some return at the same time the next day, others either later or sooner; some take a day and a night to have paroxysm and remission, some take less time, others more. Some, when they remit, cause a sweat, others do not; and from the sweat some are free of their disease, but in others the body is only made weaker by it. And the paroxysms sometimes occur only once during a single day, sometimes two or more times. Thus it often happens that everyday there are multiple paroxysms and remissions, as though each of the two answers its predecessor. –Celsus, de medicina, liber III (translation by Cheston Cunha).
Additionally, the great physician Galen clearly describes the characteristic fevers of malaria in many of his writings. Stating that Rome and the area surrounding it demonstrated a high prevalence of prolonged fever, he noted that, in some cases, these episodic fevers would resolve and return repeatedly for as many as 2 years, ultimately resulting in nephrotic syndrome and death. Other Roman authors provide very detailed descriptions of individual cases of malarial infection, the most notable of which is Cicero’s writing concerning the infection of Atticus. He chronicles the course of the disease from the original high fever in the fall, through periods of recurrence after intervals when Atticus was free of fever, ultimately resulting in complete resolution after many months. Martial also provides a somewhat briefer example of epistle writings involving what is almost certainly malaria [5,11]. But, Maximus, nothing more scandalous was ever done by Carus than his dying of fever, for it too committed an outrage. The cruel, deadly fever should have, at least, been a quartan! At least that disease should have been reserved for its own physician. (Carus was a physician who specialized in the diagnosis and treatment of quartan fevers) –Martial, epigrams X LXXVII. For his old friend, Maro, sick with a severe, burning, semi-tertian fever, vowed, and he did this aloud, that if the sick man were not sent down to the Stygian shades, a victim, welcome to mighty Jove, should die. The physicians begin to promise a definite recovery. Maro now makes vows not to pay his vow. –Martial, epigrams X XII XC (translation and parenthetical by Cheston Cunha).
The historical impact of malaria on ancient Roman civilization is not completely understood but is potentially underestimated. Although efforts to drain marshland and provide freshwater to cities and towns were largely successful, much of the Roman and Mediterranean region continued to be plagued by malaria well into the medieval and Renaissance periods. This ultimately meant that much of the Roman population constantly had to deal with chronic malarial infection. There are reports from ancient writers that Julius Caesar, while on campaign against Pompey, contracted a quartan fever for a time from which he recovered fully. Although other infections,
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such as bubonic plague or smallpox, inflicted enormous damage on the Roman Empire during the Antonine and Justiniac plagues, the constant presence of prolonged fevers of malarial infection must have been a force acting against Roman society.
Typhoid fever If [setu] burns him and sometimes he is hot, sometimes he is cold, he has [li’bu] but he does not have a sweat, that person has been sick for a month. –Babylonian medical text.
Typhoid fever, caused by the organism Salmonella typhi, is the other potentially undiagnosed, prolonged fever that affected the classical world. Because of its nature, it is often difficult to differentiate from malaria using history alone as a diagnostic tool. Indeed, until Sir William Osler analyzed the precise fever patterns of each disease, malaria and typhoid fever were often misdiagnosed as one another or as a combined entity. Although certain cardinal features stand out in each disease (eg, chills are nearly always present in malaria, but are rare in typhoid) it is, nevertheless, often difficult to distinguish between the two, particularly when using ancient texts as a primary source, which may not include findings helpful to a clinician in discriminating between the two diseases [12]. There is relatively few classical descriptions that can be specifically ascribed to typhoid fever. Indeed, without precise ways of measuring the exact temperatures of patients, ancient physicians may not have been aware of the classic stepwise progression of fever so characteristic of typhoid. Instead, typhoid would likely present to them as an insidious, prolonged fever, very similar in nature to the daily fevers seen with some malarial infections. Only in cases where a distinguishing feature presents itself, such as the intestinal bleeding or peritonitis of typhoid, is it possible to differentiate the ancient descriptions of persistent, lingering fever. In several sources, Babylonian medical writings allude to potential typhoid infection with intestinal bleeding. ‘‘If he has been sick for a long time and red liquid flows from his anus, his illness will let up. He burns with fever, he will get well. His days will be long.’’ [6]. It has been suggested that Alexander the Great ultimately died as a result of infection from typhoid fever, and this remains one of the great historical and medical mysteries. The descriptions of Alexander’s last days, provided by Arrian and Plutarch, are fairly detailed, and clearly indicate a prolonged fever was responsible for Alexander’s death, but, unfortunately, they do not provide an obvious diagnosis. Depending on how certain elements of the description are translated, a diagnosis of malaria or typhoid could be supported. Immediately after returning to Babylon in 324 BC, Alexander decided to inspect the swampy marshland surrounding the city, despite
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the advice of seers and priests to stay out of Babylon. It is likely that at this point he became infected with the organism (either typhoid or malaria) that was endemic to the swamps of Mesopotamia, and which ultimately killed him. Several days later, as the royal diaries relate, he became severely ill [13]: On the 29th May he slept in the bathroom because he was feverish. Next day, after taking a bath, he moved into the bedchamber and spent the day playing dice with Medius. He took a bath late in the evening, offered sacrifice to the gods, dined, and remained feverish throughout the night. On the 31st of May, he again bathed and sacrificed as usual and while he was lying down in the bathroom he was entertained by listening to Nearchus’ account of his voyage and his exploration of the great sea. On June 1st, the fever grew more intense: He had a bad night and all through the next day his fever was very high. He had his bed moved and lay in it by the side of the great plunge bath; there he discussed with his commanders the vacant posts in the army and how to fill them with top caliber officers. On the 4th of June his fever was still worse and he had to be turned on his side to perform the sacrifice. He then gave orders to his senior commanders to spend the night outside. On June 5th he was moved to the palace on the other side of the Euphrates, and there slept a little, but the fever did not abate. When his commanders entered the room he was speechless and remained so through June 6th. The Macedonians now believed he was dead and crowded the doors of the palace; they began to shout and threaten the Companions, who at length were forced to let them in. When the doors had been thrown open they all slowly filed past his bedside one by one, wearing neither cloak nor armor. Nothing could keep them from seeing him one last time and they were moved, in almost every heart was grief and a sort of helpless bewilderment at the thought of losing their king. Lying speechless as the men filed by, he struggled to raise his head, and in his eye there was a look of recognition for each individual as he passed. Python and Seleucus were sent to the temple of Serapis to ask whether Alexander should be moved there. The god replied that they should leave him where he was. On the 28th day of the month of Daisios (10 June, 323 BC) toward evening he died. Alexander was not yet thirty-three.
Based on this description, it seems as though the fever afflicting Alexander was constant and gradually increased in intensity over the initial few days after the onset of symptoms. The characteristic sweats and chills of malaria are not mentioned in this account, suggesting typhoid as the likely cause. Later in his disease, it is quite possible that Alexander entered a ‘‘typhoid state’’ manifested by his apathetic appearance. Indeed, the only element of typhoid fever that seems to be lacking from this description is the characteristic intestinal symptoms. As such, it is highly likely that the chronicle of Alexander’s final days is actually one of the few specific descriptions of the course of typhoid fever in the Classical world. The impact of Alexander’s death from typhoid fever cannot be understated. For those who believe, as the ancients did, that great individuals
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shape history, the death of Alexander from an unknown fever demonstrates than an infectious disease shaped the history of humankind. Although it is impossible to predict what might have happened had Alexander lived past 33 years, it is certain that his death, at the height of his power, allowed the collapse of one of the greatest, unifying empires the world has ever seen. It is for this reason that the prolonged fevers of antiquity have incredible significance and enduring interest.
Summary It can be said that infectious diseases have shaped the way the world has developed. Particularly in the Classical world, infection has influenced the creation of empires and wars, and has contributed to the fall of some of the greatest dynasties in human history. As many texts of the period reveal, the prolonged fevers, particularly those caused by malaria and typhoid fever, had a particularly powerful impact on the course of history. These diseases proved to be a constant, powerful force against which the Mesopotamians, Egyptians, Greeks, Romans, and others were forced to struggle with to thrive as cultures. The impact of malaria on the Peloponnesian War and the development of Rome, along with the death of Alexander the Great to typhoid fever, illustrate the importance of examining these ancient fevers of unknown origin.
References [1] Cunha CB, Cunha BA. The great plagues of the past: remaining questions. In: Drancourt M, Raoult D, editors. Paleomicrobiology: past human infections. New York: Elsevier; 2007. [2] Cunha CB. Anthrax: ancient plague, persistent problem. Infect Dis Pract 1999;23(4):35–9. [3] Cunha CB, Cunha BA. Impact of plague on human history. Infect Dis Clin North Am 2006; 20:253–72. [4] Warrell DA, Gilles HM. Essential malariology. 4th edition. New York: Arnold Publishing; 2002. [5] Retief F, Cilliers L. Malaria in Graeco-Roman times. Acta Cl 2004;XLVII:127–9. [6] Scurlock J, Anderson BR. Diagnoses in Assyrian and Babylonian medicine. Chicago: University of Illinois Press; 2005. p. 38. [7] Hippocrates, epidemics, book I, XXVI Loeb Classical Library. Harvard University Press; 1995. [8] Aicher PJ. Guide to the aqueducts of ancient Rome. Wauconda (IL): Bolchazy-Charducci Publishers, Inc; 1995. [9] Sallares R. Malaria and Rome. New York: Oxford University Press; 2002. p. 200–4. [10] Celsus, De Medicina, Liber III. Loeb Classical Library. Harvard University Press; 1997. [11] Martial, Epigrams. Loeb Classical Library. Harvard University Press; 1997. [12] Christie AB. Infectious diseases: epidemiology and clinical practice. Edinburgh (Scotland): Churchill Livingsone; 1987. p. 100–6. [13] Cunha BA. The death of Alexander the Great: malaria or typhoid fever? Infect Dis Clin North Am 2004;18:53–63.