The English sweating sickness (1485-1551) caused by Plasmodium falciparum?
The English sweating sickness (1485-1551) caused by Plasmodium falciparum?
Markus Brummer-Korvenkontio1,2 and Lea Brummer-Korvenkontio2
1 Department of Virology, Faculty of Medicine, University of Helsinki. Helsinki, Finland
2 Tvärminne Zoological Station, University of Helsinki. Finland
Correspondence to markus.brummer@welho.com
Abstract
Background: Sweating sickness occurred in epidemics in England and on the Continent five hundred years ago. The aetiology is still open.
Methods: The data of the English sweat have been documented and described in various reports by the past and subsequent authors. The findings in literary sources have been compared to the current scientific knowledge of malaria falciparum.
Results: The symptoms of the English sweat in the 15th and 16th century were similar to malaria falciparum known at the present. The sudden deaths caused by the sweat could be interpreted as manifestations of malaria falciparum encephalopathy. The areas of the epidemics in England and on the Continent coincide with the regions which were known to be rich in populations of mosquitoes and malaria. The plasmodium had evidently been imported in the blood of the “healthy” carriers with asymptomatic parasitaemia, e.g. the slaves from Africa to Europe. The merchants who landed at English and German ports transmitted parasites to local Anopheles mosquitoes dwelling in the houses. Plasmodium falciparum may have been able to complete sporogony under the favourable weather conditions prevailing during the epidemics. The epidemics of the sweating sickness - like malaria falciparum - did not survive over the winter.
Conclusion: The symptoms and the epidemiological features lend support to the theory of P. falciparum as the causative agent in the rather paradoxical and certainly mysterious circumstances of the sweating sickness epidemics. Afterwards occasional malaria epidemics with high mortality typical for malaria falciparum have occurred in Central Europe.
Keywords: sweating sickness, 16th cent. medicine, fever of unknown origin, Plasmodium falciparum, Anopheles atroparvus, Anopheles plumbeus, asymptomatic malaria, Walheren fever, Picardy sweat, climate warming
Background
Sweating sickness (the English sweat, sudor anglicus) has occurred in epidemics in England in the years 1485, 1508, 1517, 1528, 1551, and in 1529 on the Continent along the coast of the North Sea and the southern Baltic Sea as well as in the hinterlands [1, 2]. The outbreak of 1551 was the final one reported.
The epidemics impressed contemporaries because they were spectacular, sometimes one was killed within twenty-four hours and thousands of people may have died within a few days. Its occurrence was scattered. The victims were mainly the rich and the gentry. The exact nature of the disease has remained mysterious. Numerous theories have been put forward. Most often an unknown arbo- or hantavirus has been suggested as a causative agent [2-6, 8]. Based on our long experience in the field of the research of arboviruses, hantaviruses as well as of mosquito ecology, we see neither the epidemiology nor the pathology of the above-mentioned virus groups, or other candidates presented hitherto, as supporting in the rather mysterious circumstances of the sweating sickness epidemics.
Methods
The characteristic manifestations of the sweating sickness epidemics have been documented in various notes and reports by the early and subsequent authors [1-4, 7-11]. We compare these old descriptions of the disease and the circumstances to the current knowledge of the epidemiology of malaria falciparum, considering environmental, specifically climatic conditions and social factors as prerequisites for the outbursts of the sweat.
Results
Symptoms of the sweating sickness
The disease began suddenly without marked prodromal symptoms. The dominant features were fever, profuse sweating, continuous thirst, violent headache with redness of the face, prostration and syncope, ‘pricking of the brains”. In addition, cardiac palpitation, vomiting, difficulty of breathing, and delirium have been reported. Renal insufficiency was remarkable, urine was dark and occasionally cloudy. [1, 2, 7-11]
In grave cases intense headache and convulsions were followed by coma, and death arrived with incredible speed, well within twenty-four hours of the apparent onset [1-5, 7, 8, 11]. ‘For there were some dancing in the Court at nine o’clock that were dead at eleven’ [1], although it is possible that earlier prodomata passed unremarked[2]. Some were said to have endured two even three attacks in succession [1]. There are no reports on neurological sequels after the sweating sickness.
Outbreaks in England
The sweating sickness spread over England five times in 1485, 1508, 1517, 1528, and 1551. Some Englishmen were reported having fallen ill in 1528 on the other side of the Channel in Calais, back then a British possession [1, 2]. The outbreaks were widely scattered and characteristically patchy in their geographical distribution affecting predominantly rural areas but also London and the university communities of Oxford and Cambridge [1-3].
Each time the epidemic faded away by winter for years even for decades.
The distinguishing feature of the sweat epidemics was the unique combination of brevity and intensity. During the 1551 epidemic bursts of burials lasted for days rather than weeks, reached the climax very rapidly and fell away just as abruptly. Altogether 90 per cent of the burials in London took place in eleven days. The mortality pattern suggests that groups of inhabitants must have been infected virtually simultaneously. The sweat often seems to have been transmitted through towns on main roads, as the term “posting sweat” suggests. The possibility of infection carried by coasting vessels between ports is a factor, which should be considered in the north. [3]
The victims
The higher risk of the sweat infection stemming from the close contacts of family life is evident [3]. However, according to Hirsch, most of the trustworthy contemporary observers of the sweat have emphasized that the disease was not contagious [11].
The ones that suffered the most of the English sweat were the rich and nobility, the institutionalized clergy and the merchants as well as the students and scholars at the universities, especially during the early epidemics. The common people called the disease the ‘stop-gallant’ [1, 3].
Men appeared to have been affected more frequently than women. Young children, the elderly, and otherwise frail tended to be spared. The mortality was highest among the men and those of ‘the best age’ [2, 3, 7].
The sweat epidemics on the Continent
The sweat emerged in 1529 on the Continent in many parts north of the Alps. There were thousands of victims along the coast of the North and the Baltic Sea: in Denmark, Germany, South Sweden [1, 2, 8, 10, 11] reaching the southwest corner of Finland [12], in the busy ports, frequently visited by Hansa together with Dutch and English merchant ships. Eastern Europe, Poland and Austria suffered as well [1, 2, 8]. In 1529 there was a severe famine in Germany [9], and therefore the food import must have been remarkable, causing extensive shipping traffic.
Hecker [9] favours the view that the outbreaks in 1529 were independent of the English epidemic only one year earlier. (Besides, some German authors have assumed that the sweat was prevalent already in 1528 on the Continent as in England, but this seems to be an error, caused by the one-year discrepancy between the English and the Roman calendars [1]).
On 25 July in 1529 a German ship with a German captain and crew arrived at Hamburg with twelve men already dead. Soon after 1100 inhabitants had died within five weeks in Hamburg [1, 2, 8]. A few days later the disease arrived in Lübeck and one month later in Stettin and Danzig. The sweating sickness affected the inland of Central Europe from the coast of the Baltic Sea along the inundated banks of the great rivers, which created optimal biotope for mosquitoes: via the Elbe to Hamburg (25 Jul), Leipzig (first days in October); via the Isar to Bremen (31 Jul), Hannover (24 Aug); via the Rhine to Cologne (6 Sept) and Frankfurt (7 Sept). As late as at the turn of September/ October the sweat reached Alsace (Strasbourg) and Switzerland (Basel). [8].
In Augsburg 15.000 people fell ill and 800 died in the first five days after the sweat epidemic had struck on 6 September (simultaneously in Cologne and Frankfurt, too [sic]). Then it continued along the flooded margins of the river Danube via Linz to Vienna (Sept 22). At this time Vienna was sieged by the Ottomans and the disease was ravaging the Turkish army, too [8, 9, 10]. During the second wave in Augsburg in November 600 out of 3000 patients died within fourteen days [10].
Malaria falciparum
Malaria falciparum is the most pathogenic of malaria species (‘malignant malaria’). Attacks may be uncomplicated or associated with serious and often fatal complications. None of the symptoms and signs is specific, hence it is a great mimic of other diseases. Recrudescence is not uncommon [13, 14].
The fever is usually irregular at first and shows no sign of periodicity, but lassitude is strong and sweating is excessive. There is palpitation of the heart, the face is flushed and the pulse rate is usually rapid and weak. Nausea and vomiting are prominent. The patient complains of severe headache and epigastric discomfort. Acute renal insufficiency is an important complication of severe malaria, urine can be dark with slimy sediment. There is often some involvement of the lungs to signs of bronchopneumonia, notably those found in the Balkan and West Africa. [13, 14].
Cerebral malaria is a severe and common complication in malaria falciparum. There has usually been an insidious prelude; this feature is evidenced by the frequent tendency of the patient to continue his usual activities, though not feeling entirely well. It is possible to see a man in the morning with practically normal temperature and without any symptoms, while twelve hours later he would be in coma. Coma is frequently preceded by delirium. The event usually terminates fatally in untreated cases, sometimes very rapidly [14]. In cerebral malaria a high proportion of survivors have no residual neurological deficit, in striking contrast to unrousable coma from non-malarial sources [15].
In areas where P. vivax and P. falciparum are endemic, double infections exist and may give rise to some diagnostic confusion [14].
Malaria vectors
Malaria occurs in swampy lowlands, the favourite biotope of mosquitoes. The anophelini are seldom the vectors of arboviruses but as the vectors of human malaria they hold the monopoly. The opinion on A. atroparvus asthe most important vector of malaria in the coastal lowlands of western Europe is a classic [16, 17]. The species breeds mainly in brackish waters and is a coastal species found along estuarine marshes and in areas liable to coastal flooding. A. atroparvus is, and malaria has been, found along the coast of the North Sea and the southern Baltic Sea, extending south to the Iberian Peninsula and to Italy, and all the way east to Hungary and the Black Sea. Where A. atroparvus is found inland as in various parts of Germany, Poland, and the Hungarian plains, it is generally associated with salty soil conditions. [17, 18].
The conventional concept above has been challenged. It is unlikely that English A. atroparvus is able to transmit the tropical strains of P. falciparum [19], although the possibility of transmission of Europian strains of P. falciparum during hot summers cannot be ruled out [18].
A. plumbeus is a neglected malaria vector, distributed throughout Europe, the Middle East and in North Africa [20]. Experimental data have shown that British and Swiss females of A. plumbeus are very susceptible to infection with P. falciparum [21, 22]. This mosquito species is considered to be an efficient carrier of Eurasian strains of P. vivax and tropical strains of P. falciparum [22, 23]. Among the anopheline species found in Provence, only it can significantly transmit tropical P. falciparum [24]
A. plumbeus is known to be a particularly aggressive biter, including humans [20]. Some populations have shown strong anthropophilic preference [23]. A. plumbeus has been found breeding in tree holes and artificial containers [20]. Eggs are laid just above the waterline, so the number of generations produced each year depends upon hydrobiological conditions. This species has a longevity up to two months, but in adult stage not over the winter [22, 23].
Anophelines have short flight ranges, usually no more than two to three kilometres [25]. Malaria has a very focal distribution. Since it is quite common for blood feeds of a female mosquito to be interrupted and then to be finished on another person, it is possible for one mosquito to infect several people in a single household. Even a very limited number of anophelines is sufficient to cause a considerable spread of malaria. Thus, an infecting anopheline retained in a room may not only bite repeatedly in several successive nights, but it may attempt to feed upon several persons during the same night when unprotected people sleep in the same room [16]. The “malaria houses” with the malarious families were not found in a section of their own but were distributed throughout the villages in Europe [26].
The spread of the sweat epidemics was probably started when the mosquitoes under the roof became infected during the visits of the carrier merchants to the houses of the rich. The scholars in Cambridge and in Oxford, sleeping in numbers in the dormitories, were easily exposed to mosquitoes. Before the dissolution of the monastic system the monasteries were wealthy, dealing with merchants, but they also functioned as hospitals and inns, providing shelter for travelling traders [2] and during the night mass the mosquitoes were active.
Climatic factors
Mosquito density is a major determinant in the transmission of malaria. It largely depends on the availability of suitable breeding conditions and on the longevity of adult mosquitoes. In the area where malaria instability exists, minor changes in the quantity of rainfall, relative humidity, temperature, and in vector deviation may provoke profound changes in the epidemiological situations. [27]
Seasonal rainfall may increase mosquito breeding sites and also raises the relative humidity leading to longer survival of the anophelines [25]. Malarious years are often characterized by wet springs and hot summers. Rain helps the anophelines whereas the parasites benefit from high temperature [26].
For sporogony P. falciparum requires two to three degrees more than of P. vivax. The threshold of P. falciparum is 16°C to 19°C [25, 28]. The speed of sporogony in a mosquito is not determined by the mean [sic] temperature; it depends only on the accumulated degree hours (time x degrees over the threshold). It could be sufficient when only a part of the summer is exceptionally warm and daily temperature maxima are high enough. Reliable observers have reported malaria falciparum in significant amounts at latitudes and altitudes where the mean summer atmospheric temperature is well below twenty degrees. According to Martini malaria tropica (malaria falciparum) was transmitted by local Anopheles species during the unusual hot summer in 1826 on the North Sea coast of Germany [29]. Sporadic cases of malaria falciparum were occasionally recorded in 1936 in northern Russia as far north as in Archangel (65° N), when exceptionally high summer temperature of up to 35°C were measured [30, 31], showing that the parasite can overcome the outside temperature constraints.
Many summers between 1450-1550 were unusually warm [32, 33]. The sweat epidemics were invariably preceded by heavy rains, and in some areas, considerable flooding, both of which could have dramatically encouraged mosquito proliferation. Many authors have emphasized the significance of exceptionally high humidity and fluvial floods in the years of the sweat. [9-11]. In 1528 and 1551 the antecedent appears to have been an excessive rainfall in England, ‘a soil poisoning’ [1]. (Later it has been put forward an idea that the sweat was not an infectious disease but the result of mass food poisoning by fungi or some other contamination of cereals [34]). In the Balkans the spring rains had been particularly heavy in 1529 causing incredible flooding, and late August was exceptionally warm [9].
Seasonal occurrence
Malaria falciparum is so called ‘aestivo-autumnalis fever’. P. falciparum has no year-to-year maintenance in the north, as P. vivax used to have [26].
Unstable malaria occurs mostly in areas with relatively short transmission seasons and is marked by sudden and very often intense malaria epidemics. The simultaneously infected mosquitoes become simultaneously infectious after the extrinsic incubation time. The malaria falciparum epidemic is mostly sharp. It soon dies out, because the second parasite generation seldom finds time enough, more than three weeks, to complete the sporogony [27]. The epidemic in Augsburg in 1529 took place in two waves, the second outburst was two months after the first one [10]. The local warm late summer climate allowed a new plasmodium generation to develop. P. falciparum cannot bridge the gap from summer to summer, and the possible vector, A. plumbeus does not overwinter as adult stage.
The sweating sickness seldom appeared as early as in June. Most often it arrived in the second half of July, sometimes not until August. Epidemics prevailed normally until the end of August and ceased mostly before the end of October [1-3]. Intermittent fevers (e.g. malaria) in Provence (1745-1850) reached their maximum growth in August-September. The outdoor anopheline maximum presence observed from June to September coincides with the season of intermittent fevers. The relatively high number of endemic intermittent fevers still in October could be explained by the length of the incubation period in humans [35].
The immunity
The immune response to malaria species is very complex. The immunity is species- and strain specific. It is also dependent upon the presence of repeated infections, loss of immunity results from loss of exposure. [25] A person immune to P. vivax exhibits no heterologous immunity to P. falciparum [36]. It has even been reported that enhanced infectivity of P. falciparum occurred in Aotus monkeys previously infected with P. vivax [37].
The persistence of some level of protection against falciparum malaria seems to last almost thirty years [38]. Between the first and the second English sweat 23 years did pass (one generation) as between the fourth and the fifth, but the middle ones were separated only by 9 and 11 years. The fourth epidemic in England in 1528 was not as bad as the third one eleven years earlier; deaths were few [1]. In the last sweat epidemic in 1551 nothing of the deaths of the mayors of cities or of the infection of ministers and courtiers was reported as in earlier epidemics. Instead, the clustering of younger victims would support an interpretation dependent on the importance of immunity derived from previous exposure. The concentration of heavy mortality on out-of-the-way villages would be due to their isolation from previous exposure [3].
The acquisition of broad antimalaria immunity requires that an individual be habitually subjected to a succession of inoculations of parasites that are genetically and antigenically distinct. Only when a sufficiently wide spectrum of such parasite strains has been experienced is effective immunity achieved against all the parasites within a locality where an infection is endemic [39]. Repeated P. falciparum infections result in immune responses that do not eliminate parasites from the carriers, but decrease malaria-related morbidity, especially in lethal cerebral malaria [38].Patients with asymptomatic parasitaemia may occur with great frequency [14, 25].
Malaria has spread over long distances to non-endemic areas with residents of warm regions or by the transport of for example slaves and infected mosquitoes on crowded ships [25]. Infected anophelines of temperate regions create epidemics around themselves during visits in particularly warm years. Epidemic malaria, unlike the endemic, is evidenced by obvious morbidity and usually by obvious mortality [40].
Introduction to England
The epidemiology of sweating sickness in England suggests that the outbreaks were caused by the movements of parasitemic carriers from the south to the non-endemic north. The English sweat reports point to the great significance of trade routes in the spread. Merchants landing on foreign ships in the ports of southern England may well have been the carriers of P. falciparum. The diary of a London citizen tells that ’there died in London many merchants and great rich men and women’ [1]. The merchants and the rich have been mentioned repeatedly in the reports. During the third sweat outbreak, in 1517, the Venetian envoy in London wrote: ‘The citizens in London have a turbulent mood against the foreign traders’ [sic] [1].
In the Tudor period the overseas trade especially from Portugal was at its highest climax. The Portuguese were in close contact with Africa transporting freight and slaves from African coast already in the 15th century [5]. The area of the malarious territory in Portugal was estimated to cover nearly half of the total area of the country [30]. The years 1528 and 1551 in England stand out in the annals as years of scarcity following bad harvests, the price of corn was unusually high [1] and the import apparently remarkable.
There may have been other possible ways as well. In the late medieval period, there were regular contacts between England and Rome: soldiers, merchants, students, administrators and pilgrims travelled back and forth. The Tudor period witnessed intense foreign activity. Creighton [1] claims that suspicion falls upon the foreign mercenaries who landed with Henry Tudor at Milford Haven on 6 August in 1485 [41]. During the first epidemic the coronation of Henry VII took place, during the second sweat Henry VII was in the last months of his life, and during the third sweat Henry VIII was a candidate for Holy Roman Emperor [5]. These events brought a lot of visitors and entailed many contacts with foreigners. Visitors from northern Europe to Rome contracted ‘Roman fever’ and brought parasites along when returning back home [42].
Four sharp epidemic outbursts began in London and the fifth one in Shrewsbury, which was at its height of commercial importance. The problems of tracing the course of the fifth sweating sickness during early weeks are considerable [3]. The epidemic started already on 22 March according to the manuscript chronicle of that town [1], or in the middle of April according to Caius [7]. Thereafter, the disease did not necessarily spread from parish to neighbouring parish, but was capable of jumping to attack London, where it erupted on 7 July [3].
Discussion
The great similarity between the symptoms of the sweating sickness and those of malaria lend among others support to the presumption that P. falciparum was the etiological agent of the English sweat. The symptoms are alike, profuse sweating, prostration, vomiting, acute renal insufficiency and disturbances in CNS, in grave cases delirium and coma. The death may arrive with incredible speed in both diseases. There are no reports whether the survivors had any neurological deficit after the sweat. After cerebral malaria they are very rare [14].
All contemporary chronicles stress the special vulnerability of the rich people to the English sweat [1, 11]. It was not only that the early reporters emphasized the disease among the rich and had less interest in poor people. The sweat obviously spared the lower classes because the poor had fewer contacts with foreign merchants. The poor lived in cellars or garrets, where the temperature was insufficient for sporogony of P. falciparum. In addition, they suffered malnutrition which is antagonistic to malaria [43].
The age curves of the sweat and malaria falciparum mortalities are similar, highest in the age group of twenty to forty years [1, 2, 7]. The evidence for cytokine theory has increasingly explained the dangerous outcomes in cerebral malaria in younger patients [15, 44].
There seems to be no special mention of a high incidence of the sweat in children [2]. In the old reports the children’s proportion has probably been underestimated. Formerly doctors by and large showed relatively little interest in the diseases of infants. The registers of christenings and burials, which had first been ordered in 1538, were kept only partially from that date, but generally from 1558 onwards, some years after the last sweat epidemic [1, 3]. Some of those who appeared to be adults were in fact children and the provincial evidence does not support the assertion that young children were generally spared by the sweat in 1551 [3]. In malaria, cerebral symptoms rarely, if ever, occur in children with severe malnutrition [45].
The English sweat occurred in the lowland regions typical for malaria. The sweat was reported in Kent Essex near the estuary of the Thames, in the Fens of Cambridgeshire and Lincolnshire in Somerset, Lancashire, and the borders of Scotland [30]. The sweat seems to have spared Wales, Ireland and Scotland [2]. The first mentioned was less-suitable for mosquito breeding, as the Scottish Highlands, whereas Ireland was protected by a channel to be leapt over. In France, malaria has been generally absent at altitudes higher than 400–500 meters [35].
Malaria diagnosis by identification of Plasmodium species using microscopic examination of blood films dates from the end of the 19th century and, therefore, before this period historical retrospective diagnosis is difficult. However, if data in the old literary sources are sufficiently pertinent, thorough analyses can give support to the strong arguments in favor of the involvement of malaria, even for very old times [35].
P. falciparum seems to be the best candidate for the aetiological agent of the sweating sickness – and according to data presented above, the only probable one. For the sporogony it requires higher temperature than P. vivax, the malaria parasite in the north [28]. Interior temperature high enough, rendered the past occurrence of malaria vivax in Finland up to 68°N [46]. The mean temperature is no threshold, the sporogony depends only on the cumulative degree-hours. At the cooler fringes of malaria, fluctuation of temperature makes transmission possible at lower mean temperatures than currently predicted [28, 47]. Even the effects of small temperature changes could be most significant in the periphery of the distribution of P. falciparum [42]. Warm summers were prevalent during the sweat epidemics [32, 33], and the sweat years were many times very rainy according to the chronicles [1, 8, 9-11]. The longevity of A. plumbeus up to two months enables the completion of parasite development to the sporozoite stage under cooler conditions [22].
Data of the past might help to evaluate retrospectively the status of anopheline populations, but extrapolations are uncertain for many reasons. The first information about Anopheles collections was obtained more than a century after the last great malarial epidemics. The literature on malaria vectors, especially in southern Europe, must be evaluated with caution; for example, in the past, the taxonomic relationships of species complexes were not understood. Great faunistic changes may occur over time, such as those observed within this genus during the 20thcentury [35].
It is not decisive for our theory which Anopheles species might have been the vector. Nowadays it is impossible to know what was the vector capacity of for example A. atroparvus five hundred years ago. Traditionally A. atroparvus has been nominated for the main vector of malaria in Central Europe. Its distribution in the 1930’s [26 fig. 6] seems to coincide with the sweat. However, according to the recent studies, A. atroparvus appears to be incapable to spread P. falciparum - at least nowadays. Instead, A. plumbeus is a good candidate for a vector. The species is aggressive biter of humans, being most active during the crepuscular period but also a massive biting nuisance during the day [48]. A. plumbeus is suspected of having contributed to malaria transmission in the past and has been shown to be a competent vector of both tropical and Eurasian strains of malaria. Its occurrence depends on flooding. It is present in urban, rural, natural and importation-risk habitats: harbours, airports, and importation company premises [49]. The intense malaria episode in southern Europe, apparently in large part of the severe falciparum type, rose to its peak in late summer [26]. The sweat epidemics occurred in late summers as well. Overwintering of A. plumbeus takes place in the egg or larval stage, the adults do not hibernate [23]. P. falciparum cannot live over the winter unlike P. vivax [26]. Likewise, the epidemics of the English sweat never continued to the next year.
The key Anopheles/Plasmodium-related traits that together determine malaria transmission intensity (i.e., parasite infection, parasite growth and development, immature mosquito development and survival, length of the gonotrophic cycle and adult survival) are all sensitive to daily variations in temperature [50]. During the sweat epidemics European climate was warm, and therefore the ‘tropical’ P. falciparum may have had a chance to complete sporogony as north as in England up to the border of Scotland. Populations in which P. vivax and P. falciparum coexist, immunity seems to be acquired faster to the former and this is commonly interpreted as indicating greater antigenic diversity of P. falciparum [28].
In 1529 the outbreak on the Continent had an enormous range of fatality, but by then the sweat was already absent in England. However, right at the opposite side of the Channel the disease occurred in a mild form, lasting only five days in Amsterdam [10]. Apparently, people in Amsterdam had developed a relative immunity during the fourth English sweat one year earlier.
A stable malaria forms when repeated bouts of malaria in a relatively short period of time occur, causing a non-sterilizing immunity that does not prevent parasites from developing and circulating in the blood, but may suppress the development of severe clinical symptoms [14, 36, 50]. These asymptomatic ‘patients’ may carry P. falciparum from Africa and South Europe to the north, P. vivax immunity is no hindrance. There are several proofs, both experimentally and in the field, indicating that healthy human carriers arriving from endemic area are a source of anopheline infection [35]. It has been noted that the immigrant travellers have P. falciparum infections over two months after leaving the endemic area [51].
Maritime transportation has been responsible for some disastrous worldwide epidemics. The introduction of P. falciparum from Africa to South America with the Spanish and Portuguese invaders bringing African slaves, and its transmission to humans since the 16th century constitute one of the best examples of historical parasite-vector co-adaptation of tropical Plasmodium strains to local anophelines [27, 52, 53]. The sweat epidemic outbursts began in the ports (e.g., London, Hamburg) and spread evidently ‘postal’ with the merchants. In England the outbreaks began four times out of five in London and once in Shrewsbury, on the Continent in Hamburg.
The fifth sweat epidemic in 1551 was the last one reported. After the middle of the 16th century the temperature declined and effectively cut down the breakthrough of southern pathogens such as P. falciparum into the northern territories.
There was an incredibly savage sea of pestilence continually washing over England. In the 16th century bubonic plague, smallpox and measles all coexisted [1, 5]. The differential diagnosis between the sweating sickness and for example influenza must have been sometimes problematic. So it is confusing to read that while the sweating sickness was flying about in England in 1551, the same year influenza (‘coqueluche’) was flying about in France [1].
Thereafter
It was as late as in 1717/8, while the English sweat had been long forgotten, that a similar type of disease began to emerge in France [1, 5, 6]. According to Hirsch, the Picardy Sweat (Suette des Picards, Frieselfieber), the first febris miliaris, coincides in time and place with the sweat epidemics [11]. However, the same author reports that a half of 184 febris miliaris epidemics with variable disease patterns occurred in winter or in spring but only 9 of them in autumn, so P. falciparum could not have been the causative agent, at least not the main one. According to Heyman, Picardy sweat is a later appearance of the English sweating sickness, both most likely being caused by a hantavirus (‘pre-Puumala’) [6]. However, other researchers agree with us that the Picardy sweat could be differentiated from the English sweat. It was a milder sickness of a week or two, largely on the basis of intense itching exanthema. It was without violent cerebral symptoms and less fatal [1, 41].
A disease may be endemic in one country and produce a widespread immunity with a minimum of visible symptoms, while in another, where such immunization has not occurred, its introduction results in outbreaks of serious and often fatal disease. A well-known example is the catastrophe of Walcheren in 1809. The English army of 40.000 men was sent over the sea to Walcheren (Holland) in August and within a few weeks the army was almost entirely destroyed by diseases. The Walcheren fever had the propensity to relapse. A review of contemporary sources suggests that Walcheren fever was due to a lethal combination of malaria, typhus, typhoid, and dysentery. There is enough evidence to implicate malaria as a major component of Walcheren fever. The high mortality in such a short period is not compatible with the types of malaria known to have affected Holland at this time. Only virulent falciparum malaria could have caused such decimation, despite the notion that ‘this was restricted to the tropics’ [sic]. [54].
The role and the significance of P. falciparum in severe malaria epidemics north of the Alps needs to be considered [55]. Throughout the 17th and 18th centuries, ‘agues’ appeared to have been prevalent in England and were imported by soldiers and sailors returning from overseas [53]. The mortality in untreated malaria falciparum can reach 25 percent, while in malaria vivax infections it is under 5 percent [18]. The warmest decades of the 17th century were accompanied by the highest mortality in the marshland parishes in England [18]. In 1768 it was noted in Holland that malaria was most violent after hot summers, the months of September and October were those in which malaria was most fatal in Zeeland (Holland) [30]. In addition, a variety of elements suggest the plausible implication of P. falciparum in the Provencal epidemics in 1745-1850 [35].
Conclusions
The symptoms and the circumstances of the sweating sickness with many similarities to malaria falciparum led us to consider them as aetiologically connected. In the 15th and 16th centuries warm and rainy summers favored the invasion of Plasmodium falciparum to the north and the concurrent increase of close trade contacts with Africa and European countries enhanced the spread of the disease by anopheline mosquitoes. The apparent climate warming trend today is alerting and should raise the awareness of the probable risk of malaria falciparum in the northern regions.
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Declarations
Ethics approval and consent to participate
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Availability of data and materials
All data generated or analysed during this study are included in this published article
Competing interests
The authors declare that they have no competing interest.
Funding
The authors received no specific funding for this work.
Authors' contributions
MBK (MSc in zoology, MD, PhD) wrote the manuscript based on his expertise on infectious diseases, and mosquitoes. The biologist LBK (MSc) completed the manuscript with entomological remarks. Both authors contributed to the interpretations of the study findings. Both authors have read and approved the final manuscript
Acknowledgements
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Authors’ information
MBK: Prof. h.c., MSc (zoology), MD, PhD, has participated as a leader in many research projects promoting epidemiology, laboratory diagnostics, and clinical picture of zoonoses, especially of arbo- and hantaviruses. He has been a member of the Intern. Committee on Arctic Arboviruses, and of the Intern. Adv. Board Hemorrhagic Fevers with Renal Syndrome [Hantaviruses].
LBK: MSc (biology), has acted as a senior lecturer at the Laurea University of Applied Sciences. Her topic is mosquito ecology.
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