Plasmodium vivax Relapse Rates in Allied Soldiers during the Second World War: Importance of Hypnozoite Burden

ABSTRACT.

Allied soldiers suffered repeated relapses of Plasmodium vivax malaria during and immediately after the Second World War. This surprised many military medical officers who had underestimated the huge casualties produced by P. vivax malaria. Tropical (Philippines) strains of P. vivax were known to relapse more frequently than those from temperate regions (the United States). Intense exposure to mosquito infection likely increased the absolute number of hypnozoites in soldiers’ livers. Both quinine and quinacrine were used as chemosuppressive agents, but their inconsistent use until at least 1943 promoted intermittent parasitological failures. Fear of hemolytic reactions after a mass casualty event in 1943 engendered fear and avoidance of the only 8-aminoquinoline pamaquine then available to cure relapses. Variable chemosuppression likely prevented acquisition of effective parasitological immunity. Unexpectedly high relapse rates in soldiers were likely an indirect measure of the high hypnozoite burden and suggest how difficult it will be to eliminate P. vivax malaria from endemic areas.

This will be a long war if for every division I have facing the enemy I must count on a second division in the hospital with malaria and a third division convalescing from this debilitating disease! —Gen. Douglas MacArthur, 1943¹

Plasmodium vivax often does not get the same respect given to Plasmodium falciparum because of a perceived malaria mortality gap, but from a military perspective, P. vivax malaria causes many more casualties due to its ability to relapse from latent liver parasites (hypnozoites) months to a few years after the original infection. This was most graphically demonstrated in the southwest Pacific during the Second World War when nearly 50,000 malaria hospitalizations occurred in the U.S. Army in 1943 alone.² MacArthur’s foregoing remark came when it became apparent that even healthy soldiers would become incapacitated by malaria when removed from chemosuppression with quinacrine. The war against the Japanese Empire in the Pacific simply could not continue without minimizing the huge malaria casualties seen beginning in 1942. Eventually much better drug discipline and many infantry reinforcements turned the tide of battle in the Pacific, but not before many soldiers developed serial relapses—sometimes > 20 episodes, often on a monthly basis. How to manage such a large number of malaria casualties was a pressing military medical problem that was not solved until improved chemotherapy with chloroquine and primaquine became available during the Korean War.³ Examining some of the large and at times conflicting literature generated during the 1940s is useful in understanding the biology of relapsing malaria. Hypnozoite burden largely appears to explain the extraordinary number of P. vivax relapses seen in Allied soldiers who developed malaria in the Pacific Theater during the Second World War. More effective use of current 8-aminoquinolines to destroy this parasite reservoir will be required to eliminate relapsing malaria from large areas of the Indo-Pacific Region and Latin America.⁴

The Allies’ colonial tropical medicine experience in the Philippines, New Guinea, and India should have prepared medical officers as the difference between temperate (United States) and tropical (Philippines) P. vivax malaria relapse patterns were well known from the 1920s.⁵ Temperate P. vivax malaria relapsed once usually 6 to 8 months after the primary infection, whereas tropical P. vivax relapsed much more frequently.⁶ See Figure 1, which shows an estimated quarter of Philippine infections relapsed. An empirically derived chemotherapy combination of 10 to 14 days of quinine plus quinacrine followed by pamaquine (aka QAP) had been standard for P. vivax malaria since the 1930s in the United States, Australian, and British Armies.⁷ QAP was considered successful enough that the Indian treatment center for chronically ill British soldiers with malaria at Kasauli was largely disestablished.⁸ However, colonial era soldiers largely lived in barracks in low endemicity zones with malaria infection occurring mostly during relatively brief field exercises or campaigns. Wartime experience was much longer in duration with more intense exposure.

Figure 1.

Short-term (within a few months) relapse rates of vivax malaria in various military groups infected in the Americas, southeast Asia, or southwest Pacific during 1920–1940s, ranging from 20% to nearly 100%. (A) U.S. soldiers in the continental United States, 1920s after variable quinine prophylaxis.⁵ (B) U.S. soldiers in Panama, 1920s.⁵ (C) U.S. soldiers (white) in the Philippines, 1920s.⁵ (D) U.S. soldiers (native Pilipino) in Philippines, 1920s.⁵ (E) U.S. soldiers from the southwest Pacific during World War II after short exposure (44 days) to quinacrine.¹ (F) U.S. soldiers from the southwest Pacific repatriated to a U.S. hospital after quinacrine suppression.¹⁵ (G) Australian soldiers from the southwest Pacific after > 1 year of exposure after returning to Australia.⁷ (H) U.S. southwest Pacific veterans in a U.S. hospital postwar after quinacrine suppression.¹⁷ (I) Australian and U.K. prisoners of war in southeast Asia in Singapore with variable quinine treatment.¹¹ (J) U.S. soldiers from the southwest Pacific in Fiji off quinacrine suppression prophylaxis.¹²

Daily quinine was standard malaria chemosuppression in the Allied Armies of 1940, but the Pacific War began with the Japanese capture of the global supply of quinine in the cinchona plantations of Java.⁷ The only alternative was quinacrine, which was in limited supply in 1942. Quinacrine dosage was initially insufficient to suppress malaria parasites and had to be increased to 100 mg daily to achieve consistent suppression. The yellow skin staining of quinacrine, along with its nonexistent but widely rumored induction of sexual impotency, caused both epidemic quinacrine avoidance as well as malaria infection.² Eighty percent of the U.S. First Marine Division was hospitalized for malaria during or immediately after fighting on Guadalcanal, rendering the unit combat ineffective.⁹ Combat as well as many other physical stressors (e.g., heat, hunger, exercise) were empirically felt to cause the many malaria relapses observed, and it was not until careful clinical studies were done by U.S. and Australian medical officers under controlled conditions that these widely held beliefs could be debunked.^1,7 If soldiers took their quinacrine every day, it suppressed even intense malaria infection, but it took nearly 2 years for the military to understand this and then put robust disciplinary measures in place to enforce drug compliance.

One naval construction unit was prospectively observed during the Solomon Islands campaign while taking suboptimal amounts of quinacrine¹⁰ (see Figure 2). Initial high infection rates with falciparum malaria were followed by P. vivax malaria, which then became the dominant species, a pattern repeated in many other units including prisoners of war (POWs) camps in Thailand.¹¹ Soldiers who successfully suppressed malaria with quinacrine often quickly developed P. vivax relapses once the medication was discontinued. If exposure was relatively short (44 days), then relapse rates resembled those seen pre-1940, as shown in Figure 1.¹ Soldiers exposed for up to 1 year and then removed from chemosuppression had higher relapse rates (> 80%) which started from 4 weeks off medication and then plateaued after 12 weeks. Relapses often reoccurred on nearly a monthly basis.¹² These results in entire infantry divisions forced medical authorities to mandate continued quinacrine chemosuppression indefinitely, even when combat forces moved to nonendemic areas of the Pacific.¹² One unit removed from quinacrine after 17 months of enforced, continuous chemosuppression, having left the endemic area 20 months earlier, still experienced limited numbers of relapses, suggesting that at least some hypnozoites had been eliminated in the interim.² POWs with limited access to any antimalarial drugs and intense, continuing exposure had perhaps the highest relapse rates, which could exceed 20 episodes¹¹ (Figure 1).

Figure 2.

Malaria experience of a U.S. Naval engineering battalion (Seabees, maximum number = 1,000) that was closely followed for 1 year in the Solomon Islands with heavy malaria infection pressure that was inadequately suppressed by daily quinacrine. (A) Epidemic curve of all malaria cases with secondary cases are most likely relapses and the line shows the malaria rates for all units on the same island (likely New Georgia).¹⁰ (B) Species diagnoses over time showing the progression toward nearly all late infections consisting of Plasmodium vivax.

The treatment of relapsing malaria has for nearly a century involved clearing the blood parasitemia with schizonticidal drugs (quinine, quinacrine, chloroquine) and then destroying the exo-erythrocytic parasites (hypnozoites) with 8-aminoquinolines (pamaquine aka plasmochin, primaquine). The definite synergy produced against relapses when both types of drugs are given together rather than sequentially has been known since the 1930s but never mechanistically explained.⁸ Unfortunately, a mass casualty event in 1943 involving several thousand healthy Panama Canal workers, some (10%) of whom hemolyzed on receiving quinacrine and pamaquine, made the U.S. Army Surgeon General determine that pamaquine was a dangerous drug that should not be used in soldiers.¹³ This event preceded the discovery of glucose-6-phosphate dehydrogenase deficiency, which likely explains the pamaquine-induced hemolysis. Therefore, pamaquine was either not used or used in subtherapeutic regimens during the Second World War despite it being part of standard QAP malaria treatment before the war.¹²

Soldiers with repeated P. vivax relapses were judged to be combat ineffective, and many thousands from the Solomon Islands and New Guinea campaigns were repatriated to tropical disease hospitals (e.g., Klamath Falls, OR, and Longview, TX) for extended treatment as invalids^14,15 (Figure 3). Detailed observations on these chronically infected men with multiple relapses showed that except during a febrile paroxysm, they were not acutely ill with only a small minority having anemia or splenomegaly.¹⁶ Acute attacks were rapidly treated with quinine/quinacrine, resulting in > 90% having cleared their parasites by the fourth day of illness.¹⁵ A wide variety of chemotherapeutic trials were initiated but in the absence of 8-aminoquinolines, relapses continued with decreasing frequency (“burned out”) over time. Military medical officers debated how much ancillary symptoms (e.g., fatigue, weakness) were associated with infection versus neuropsychiatric causes.¹⁵

Figure 3.

Harmon General Hospital of the U.S. Army in Longview, TX, where many returned infantrymen from the southwest Pacific Theater were treated for Plasmodium vivax relapses, 1943–1945. Harmon General Hospital was the geographic source of the original Chesson strain of P. vivax from a U.S. Army sergeant who relapsed after serving in New Guinea.¹⁵ Photo from National Library of Medicine, in the public domain. http://resource.nlm.nih.gov/101402382.

Veterans of the southwest Pacific campaigns became a natural experiment in how long P. vivax malaria could continue without further mosquito infection. P. vivax relapse patients (N = 328), who had discontinued quinacrine suppression on return to the United States, were studied in Minnesota.¹⁷ Twenty-five percent of relapses terminated within 1 year, 53% in the second year, and 18% in the third year, with very infrequent relapses occurring out to 4 years.¹⁷ No P. vivax relapses were being seen in U.S. military veterans of the Second World War by the time the next wave of malaria relapses arrived during the Korean War in 1950.⁹ Veterans’ widely repeated statement that they were permanently infected with malaria due to war service was useful for compensation claims but had no biological basis. The current understanding of hypnozoites, which must reside within a hepatocyte whose mean lifespan is estimated to be approximately 1 year, implies that malaria parasites may have some means of either selecting long-lived hepatocytes or delaying their host cell’s eventual apoptosis. Alternatively, relapses after 1 year’s duration may simply be a reflection of the total number of hypnozoites in some heavily infected individuals. Heterogeneity of sequential P. vivax relapses in a single soldier was shown by serial human inoculation experiments, demonstrating that mixed populations of hypnozoites were likely a reflection of a heavy burden of infection.¹⁸

The prewar malaria experts were mostly physicians who used malariotherapy with induced P. vivax to treat syphilis. The goal was to induce as many febrile episodes as possible to kill bacteria and thus cure neurosyphilis. Although using temperate (lower relapsing) strains, their experience was that patients adapted relatively quickly to single infections becoming tolerant (few symptoms) after a few paroxysms and then immune (resistant to reinfection).⁶ The suggestion was that if one let the soldiers become ill without suppressive treatment, they would soon develop natural immunity and thus tolerate the infection that they could not occupationally avoid. This was formally tested in returned soldiers at Hammond General Hospital, Modesto, CA, in 72 P. vivax patients who had a mean of six previous relapses.¹⁹ The average duration of 113 untreated attacks was 5.5 days. Although strongly suggesting that the medical officer’s habit of rapidly treating all febrile episodes in the tropics with quinacrine was likely suppressing the soldier’s acquisition of tolerance and subsequent immunity, this naturalistic approach conflicted with the military necessity of having as many fit soldiers as possible. Quinacrine chemosuppression worked despite its unwanted adverse events and requirement for strict discipline. Further studies in Australian soldier volunteers who were serially infected indicated that although tolerance was not strain-specific, resistance to reinfection did appear to be largely limited to individual strains of P. vivax.²⁰

Malaria was one of the greatest causes of medical casualties during the Second World War not only in the southwest Pacific but also in India, Burma, and Italy.⁹ Entire infantry divisions were turned into invalids requiring long-term rehabilitation and suppressive medication largely because of the propensity of P. vivax to frequently relapse.¹² Despite a great military tradition of clinical tropical medicine carried over from various colonial wars, military medical officers were surprised by the problems produced by relapsing malaria and took several years to devise temporary countermeasures. These problems all hinged on the yet to be discovered and still poorly understood hypnozoite, a latent parasite in the liver that reactivates long after the original mosquito bite. It is likely that the apparent differences between temperate P. vivax malaria (with few relapses) used to treat syphilis patients and tropical P. vivax malaria (with many relapses) seen in veterans from New Guinea are largely explained by the total burden of hypnozoites. Tropical P. vivax does not have any seasonal constraints on its relapse pattern such that it can reenter the blood at nearly anytime and still have a reasonable chance of having its gametocytes picked by mosquitoes. Temperate P. vivax has to time its reentry (usually 6–8 months after primary infection, with fall infections relapsing during the subsequent spring) to have any hope finding vector mosquitoes to carry it to the next human host. Total exposure likely determines the hypnozoite burden, with longer term exposures such as in POWs leading to more latent parasites in the liver. One can reverse this process by either maintaining chemosuppression for many months or by using 8-aminoquinolines, such as pamaquine or the more modern drugs such as primaquine or tafenoquine, to eliminate the hypnozoite burden. How this happens mechanistically is still unclear, but it now appears certain that the same metabolic redox stress that results in hemolysis in those with glucose-6-phosphate dehydrogenase deficiency is essential if 8-aminoquinolines are to kill hypnozoites.¹³ Nonhemolytic 8-aminoquinolines do not stop relapses. Nonmetabolizers of primaquine due to cytochrome polymorphisms also do not kill hypnozoites.⁴ Interrupting the survival strategy of P. vivax malaria requires killing hypnozoites. Until we learn to use more effectively our only real pharmacological tool in the 8-aminoquinolines, we will be stuck in the same futile cycle faced by the medical officers of the Second World War, treating soldiers repeatedly for the same parasitic infection. Malaria elimination will require 8-aminoquinolines.