Pernicious Plasmodium vivax as a Historical Cause of Malarial Cachexia?

ABSTRACT.

Prior to the understanding of malaria as a parasitic disease, malaria cachexia was a loosely defined syndrome consisting of severe anemia and splenomegaly in a chronically wasted individual living in a malarious area. Entire rural populations in diverse areas such as the Thames estuary, Marseilles marshes, and the Mississippi valley were said to have cachexia on the basis of chronic malaria “poisoning,” which accounted for their poor socioeconomic health. Malaria cachexia appeared to disappear as the marshes were drained, agriculture improved, and quinine or iron treatments were administered. Malaria cachexia’s association with plasmodia in the blood was uncertain once blood smears were examined in the twentieth century. Modern studies have raised the question of chronic Plasmodium vivax in the spleen as a possible etiology; historical specimens could be examined to clarify malaria cachexia.

The emaciated limbs are in marked contrast to the big belly, and the features are aged beyond the years. The most pronounced phenomena are the anemia and enlarged spleen. (William Deaderick 1916)¹

Malarial cachexia, described in early medical textbooks as a manifestation of chronic malaria, was a loosely defined syndrome of anemia, splenomegaly, and muscle wasting.^1,2 Chronic malaria infections in those inhabiting swampy areas was supposedly the cause of their population’s poor economic and health status. This supposition was supported by extensive historical studies in the Essex marshes and Provence wetlands.^3,4 Chronic malaria and cachexia was even considered a major health problem in nineteenth century Massachusetts as detailed by Oliver Wendell Holmes, arguably the United States’ first malariologist.^5,6 The US Army Surgeon General’s Report of 1902 described 994 cases of malarial cachexia (11/1,000 soldiers), of whom 14 died and 18 were discharged for debility.⁷ By the time malaria was understood to be a mosquito-borne parasitic disease of the blood in the early twentieth century, much of the chronic public health aspects attributed to malaria had already disappeared in Europe and North America, apparently due to land use changes, improved housing, and possibly medication such as quinine. Understanding these historical public health aspects is important because if chronic malaria was the cause of cachexia, it was due to the relapsing Plasmodium vivax and not the more tropical Plasmodium falciparum, based on geographical distribution outside the tropical region. The mortality affect was large but occurred chronically and indirectly as malaria-associated mortality.³ Understanding how strong the historical connection is between malaria cachexia and P. vivax infection is vital to understanding its pathogenesis as well as providing additional justification for the elimination of all species of malaria.⁸

EPIDEMIOLOGY OF MALARIAL CACHEXIA

Malaria cachexia in the rural southern United States after the US Civil War (1861–1865) was used as an explanation of the region’s poverty and lack of agricultural productivity as well as a possible war-related injury in former Union soldiers.⁹ Because malaria “poisoning” could not be differentiated from hookworm infestation or malnutrition, it was not pathologically specific.^2,9 Whatever caused this syndrome of anemia, splenomegaly, and wasting, it had a poor prognosis, often resulting in deaths from intercurrent infections such as pneumonia (Figure 1).¹⁰ Treatment was uncertain, but the old standbys of quinine and iron salts were often used. A disease of distinct geographic areas such as wetlands, malarial cachexia was of interest not only in the South but in New England as well.^5,11 In New England, tertian malaria, most likely P. vivax, was connected directly to nineteenth century canal construction projects that rearranged the riverine environment as well as the return of soldiers from the southern United States after the Civil War or from Cuba after the Spanish-American War. The manifestations of chronic malaria disappeared over generations and only marginally crossed over into the twentieth century, when medicine could confirm parasites in blood microscopically.

Figure 1.

Photo of three inhabitants of the southern United States circa late-nineteenth century showing wasting and splenomegaly consistent with malarial cachexia. Reproduced from a 1916 medical textbook.¹

In Europe, malarial cachexia was largely gone by the twentieth century, leaving questions about its actual causes and relationship to P. vivax.^3,4 The Essex and Kentish fens or swamplands were infamously unhealthy places whose markedly increased mortality rates from the sixteenth to nineteenth centuries were documented in the Anglican Church burial registers. Dobson’s observations on the medical geography of the Thames estuary left little doubt that a location-specific infectious disease was involved.³ Communities only 100 m higher in elevation and a few miles apart had very different mortality rates; few pathogens other than P. vivax dependent on brackish water breeding Anopheles atroparvus are consistent with such a pattern. Essex “marsh fever” was characterized as “severe agues which the inhabitants are very rarely without, whose complexions from those distempers become of a dingy yellow colour, and if they survive, are generally afflicted with them till summer.”¹² In the early twentieth century, some cases of marsh fever were shown to be caused by P. vivax parasites.³ Provence in France also had wetlands in the Rhone delta and the brackish lagoon of Etang de Berre that were historically known for chronic malarial fevers and cachexia.⁴ Descriptions of the inhabitants said they were recognized by “his pale complexion, his drawn-out emaciated of puffy features, his flabby muscles, his slow step, a certain indolence in all his movements, and his swollen belly.”¹³ In the infamous Pontine Marshes near Rome, malaria cachexia was described as “a condition of complete exhaustion of the natural power of resistance to the infection.”¹⁴ Once the Pontine Marshes were eliminated by a Mussolini-era drainage project, Sardinia remained the most malarious area of Italy. Sardinia’s chronically ill population was largely reversed after the Second World War by a dichlorodiphenyltrichloroethane spray program in the late 1940s that eventually eliminated malaria.¹³ The elimination of endemic malaria in North America and Europe in the first half of the twentieth century was co-incident with the elimination of endemic cachexia in those regions.

EXCLUSIONS AND MODERN POPULATIONS

Once stools could be tested for hookworm eggs and tissues tested for leishmania as well as plasmodia, it became easier to say what was not malaria cachexia. Leonard Rogers eventually showed that epidemics of lethal cachexia in Northeast India were not due to malaria as originally thought but caused by infection by Leishmania donovani producing kala-azar.¹⁵ Later some persons with particularly large malarial spleens were grouped into a relatively rare disease, hyper-reactive malaria splenomegaly (HMS), defined as marked splenomegaly (> 10 cm), immunological evidence of antibody to malaria, IgM concentrations > 2 SD above locally obtained mean IgM concentrations, response to antimalarial drugs, and exclusion of alternative pathologies.¹⁶ These restrictive diagnostic criteria made HMS rare but do not indicate if malaria cachexia might have been part of a larger malaria-associated syndrome. Classically HMS was associated mostly with Plasmodium malariae, but a population-based study in Papua New Guinea showed that P. vivax could also cause HMS.¹⁷

There are a few populations that, due to historical transpositions, have recreated pre-modern malaria conditions while still having malariometric indices that may be informative regarding malaria-associated mortality. Allied prisoners of war (POWs) on the Thai-Burma railway suffered huge casualties due to a combination of malnutrition, injury, and infection with tropical diseases.¹⁸ Malaria was nearly universal in the POWs working in the Thai jungles, and the parasites were only variably suppressed with irregularly supplied quinine. Direct malaria mortality, largely from acute P. falciparum, caused < 5% of POW deaths.¹⁸ Two to three times as many POW died of malaria-associated mortality that was largely due to multiple relapses of P. vivax causing severe anemia. Interestingly, whole blood transfusion administered by the captured Allied medical officers was life saving, indicating that much of the problem was a subacute effect on the bone marrow.¹⁸ Modern studies in Indonesia confirm that vivax mortality is subacute and largely causes severe anemia.¹⁹

ROLE OF P. VIVAX?

Recently it has become apparent that P. vivax has a large, previously unappreciated tissue phase in the spleen and bone marrow, indicating that chronic pathology might be due to disruption of the reticuloendothelial system in the absence of parasitemia detectable by practical means.²⁰ Among 22 spleens surgically removed from patients living in eastern Indonesia and not showing signs of acute malaria, 21 were infected by plasmodia (eight of those by P. vivax). The infection of the extravascular spaces of deep organs without detectable parasitemia may be a natural and common state of infection by P. vivax. This may be analogous to P. falciparum’s ability to cytoadhere in the deep vasculature and cause severe disease, separate from what can be visualized in the peripheral blood. How might such latent and inapparent disease due to vivax malaria manifest itself and could that be consistent with historical descriptions of malarial cachexia? If disruption of the reticuloendothelial system is the focus, then one would expect to see increased mortality due to common bacterial infections such as pneumococcal pneumonia and possibly tuberculosis. Although this is credable as a hypothesis of malaria-associated mortality, it is not very useful differentially because there are few ways to confirm or deny malaria disruption of the reticuloendothelial system. Anemia is a common association with chronic malaria, both P. vivax and P. falciparum, and severe malarial anemia remains poorly defined as having multiple elements besides parasite rupture of erythrocytes. What role the spleen plays in severe malaria anemia remains uncertain.²¹

Therefore, if malaria cachexia was a historical expression of pernicious P. vivax infection, how might this be expressed in modern populations? Plasmodium vivax is a very wide-ranging parasite, and its dismissal as a cause of disease from sub-Saharan Africa on the basis of blood surveys may be premature, especially if one focuses on parasites in the reticuloendothelial system and not the peripheral blood.²² Duffy antigen/chemokine (DARC receptor) negativity is a very common genetic polymorphism that likely minimizes P. vivax circulation in the blood without actually preventing infection, as demonstrated by the parasite’s ability to maintain transmission in Africa.²² If P. vivax infection of the reticuloendothelial system without parasitemia was widespread in a modern population, how might this be expressed? Chronic anemia from disruption of the bone marrow would be the most obvious manifestation, and this fits well with longitudinal observations from Papua in Indonesia showing that chronic P. vivax is expressed primarily as severe anemia.¹⁹ Plasmodium vivax in the spleen is harder to predict, but if there was a functional disruption of this vital immune organ, chronic P. vivax infection might manifest itself as increased morbidity and mortality from common bacterial infections, such as pneumococcal pneumonia, typhoid fever, and tuberculosis. Given the difficulties in measuring baseline values for these important infections in developing countries, it is possible that a synergistic contribution by cryptic vivax infections might have been missed. One possible explanation of malaria-associated mortality is seen when malaria-specific interventions, such as extensive residual insecticide house spraying, reduce infectious disease mortality not only due to malaria but for other lethal infectious diseases.²³ Tropical infections are rarely singular, such that malarial cachexia historically and modern malaria-associated mortality may both be the cumulative product of several chronic infections that are exacerbated by P. vivax. Increased mortality results when the host’s ability to cope is eventually exceeded by sequential P. vivax infections, as demonstrated in POWs during the Second World War.¹⁸

Although malaria cachexia may have been a pre-modern way to describe malaria-associated mortality, the historical connections are weak largely due to a lack of direct pathological evidence of parasites in chronically ill persons from areas of known vivax malaria endemicity. Is there any realistic opportunity to strengthen the connections using archival material? Despite the vast number of historical medical papers that are only briefly mentioned in this review, they largely pre-dated our understanding of malaria as a parasitic disease and cannot directly link to plasmodia. Pathological material exists in a few collections from the early twentieth century that might be of use particularly those from military forces with soldiers deployed to or recruited from the tropics. Autopsy material consisting of formalin-fixed, paraffin-embedded tissue blocks from the Armed Forces Institute of Pathology (previously the Army Medical Museum) have been preserved at the National Pathology Center in Washington, DC. Their historical usefulness was most dramatically demonstrated by the recovery of 1918 influenza virus genomic material from soldiers who died in US recruit camps.²⁴ Whether similar historical retrievals can be done regarding relapsing malaria remains to be seen, but certainly spleens were routinely sampled and saved during military autopsies. If splenic material can be shown to give reliable plasmodial genomic signatures after decades of storage, it may then be possible to see if an association can be constructed between increased infectious disease mortality and impaired splenic function due to parasitic infection. This hypothesis might seem improbable to some, but the implications of finding P. vivax genomic material in historical pathology specimens such as spleens is potentially profound in its implications for the large numbers of people suffering from P. vivax–induced pathology and for malaria elimination.⁸