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    Percentage of patients with A, fever (≥ 101°F), B, parasitemia ≥ 1,000/μl and ≥ 10,000/μl, and C, gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days for 55 patients previously infected with Plasmodium malariae, P. ovale, and/or P. vivax who were reinfected with the McLendon strain of P. falciparum.

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    Percentage of patients with A, fever (≥ 101°F), B, parasitemia ≥ 1,000/μl and ≥ 10,000/μl, and C, gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days for 34 patients previously infected with Plasmodium malariae, P. ovale, and/or P. vivax who were reinfected with the El Limon strain of P. falciparum.

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    Prepatent periods for 32 patients with previous experience with Plasmodium malariae, P. ovale, and/or P. vivax who were infected via sporozoite inoculation.

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    Mean daily percentage of patients with fever ≥ 101°F and ≥ 104°F during the first 20 days of patent parasitemia with Plasmodium falciparum. Group I = 73 sporozoite-induced primary infections modified with subcurative doses of antimalarial drugs; Group II = 104 trophozoite-induced primary infections that were modified; Group III = 40 sporozoite-induced primary infections that were not modified; Group IV = 47 trophozoite-induced primary infections that were not modified; Groups I-IV = 264 primary infections; Group V = 22 infections following infection with P. ovale; Group VI = 16 infections following infection with P. vivax; Group VII = 41 infections following infection with P. malariae.

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    Mean daily percentage of patients with asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 20 days of patent parasitemia with Plasmodium falciparum. Group I = 73 sporozoite-induced primary infections modified with subcurative doses of antimalarial drugs; Group II = 108 trophozoite-induced primary infections that were modified; Group III = 40 sporozoite-induced primary infections that were not modified; Group IV = 47 trophozoite-induced primary infections that were not modified; Groups 1-IV = 268 primary infections; Group V = 22 infections following infection with P. ovale; Group VI = 16 infections following infection with P. vivax; Group VII = 41 infections following infection with P. malariae.

  • 1.

    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity during primary infection. Am J Trop Med Hyg 61 (suppl): 419.

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  • 2.

    Collins WE, Jeffery GM, 1999. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum: development of parasitologic and clinical immunity following secondary infection. Am J Trop Med Hyg 61 (suppl): 2035.

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    Young MD, Hardman NF, Burgess RW, Frohne WC, Sabrosky CW, 1948. The infectivity of native malarias in South Carolina to Anopheles quadrimaculatus. Am J Trop Med Hyg 28: 303311.

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    Jeffery GM, Eyles DE, Young MD, 1950. The comparative susceptibility of Anopheles quadrimaculatus and two strains of Anopheles albimanus to a Panama strain of Plasmodium falciparum. J Natl Malaria Soc 9: 349355.

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    Eyles DE, Young MD, 1950. The comparative susceptibility of Anopheles albimanus and Anopheles quadrimaculatus to a South Carolina strain of Plasmodium falciparum. J Infect Dis 87: 189193.

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    Earle WC, Perez M, 1932. Enumeration o f parasites in the blood of malarial patients. J Lab Clin Med 17: 11241130.

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    Mayne B, Young MD, 1941. The technique of induced malaria as used in the South Carolina State Hospital. Venereal Dis Information 22: 271276.

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A Retrospective Examination of Sporozoite- and Trophozoite-Induced Infections with Plasmodium Falciparum in Patients Previously Infected with Heterologous Species of Plasmodium: Effect on Development of Parasitologic and Clinical Immunity

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  • 1 Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

A retrospective examination was made to determine parasitemia and episodes of fever in 97 patients, previously infected with Plasmodium malariae, P. ovale, and/or P. vivax, who were reinfected with P. falciparum for treatment of neurosyphilis, the standard treatment at the time. Data were collected at the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963. Results were compared with observations recorded for patients following primary infection with P. falciparum. The mean daily percentage of patients with fever ≥ 101°F during the first 20 days of primary infection with P. falciparum was 42.4; the percentage with fever ≥ 104°F was 19.9%. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of fever ≥ 101°F and ≥ 104°F of 39.1% and 14.8%, 39.1% and 19.4%, and 28.4%, and 11.3%, respectively. Previous infection with P. ovale or P. vivax had little, if any, effect on subsequent clinical malaria due to P. falciparum, whereas infection with P. malariae resulted in reduced frequencies of fever. A similar comparison was made for parasite counts ≥ 1,000/μl and > 10,000/μl. The percentages for 268 patients during the first 20 days of primary infection with P. falciparum parasite counts ≥ 1,000/μl and ≥ 10,000/μl were 58.2% and 29.9%, respectively. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of parasitemia ≥ 1,000/μl and ≥ 10,000/μl of 58.0% and 24.3%, 57.3% and 31.1% , and 45.9% and 19.0%, respectively. Previous infection with P. malariae resulted in a reduction in the frequency of high-density parasitemia (≥ 10,000/μl) as well as an asexual parasite count ≥ 1,000/μl. These results suggest that P. falciparum and P. malariae share common antigens that are able to induce parasitologic and clinical protection when infection with P. falciparum follows that with P. malariae. The results did not suggest that protection to P. falciparum is provided by previous infection with P. ovale or P. vivax.

Previously, we presented a retrospective analysis of the clinical and parasitologic responses in patients being infected with Plasmodium falciparum for the treatment of neurosyphilis,1 and the effect of previous infection with homologous and heterologous strains of the parasite on these responses.2 Here, we report on a similar retrospective analysis of patients reinfected with P. falciparum following previous infection with P. vivax, P. malariae, and/or P. ovale.

Materials and Methods

Strains of Plasmodium. McLendon. The McLendon strain of P. falciparum was isolated in October 1940 from a patient who was admitted to the South Carolina State Hospital with malaria.3

El Limon. The El Limon strain of P. falciparum was isolated from a resident of El Limon, Transisthmian Highway, Panama in 1948.4

Santee-Cooper. The Santee Cooper strain of P. falciparum was isolated during the summer of 1946 from a patient living in the vicinity of the Santee-Cooper water impoundments in South Carolina.5

Methods of inoculation. Patients were infected either by the inoculation of parasitized blood or via sporozoites. Anopheles quadrimaculatus, An. albimanus, and An. freeborni were the mosquito species used for transmission studies. Mosquitoes were fed on patients to induce infection. Mosquitoes were also allowed to feed on patients during periods of gametocytemia to be able to infect mosquitoes for additional transmission studies. Inoculation was either by the bites of infected mosquitoes or by the subcutaneous or intravenous inoculation of sporozoites dissected aseptically from mosquito salivary glands. In some instances, blood parasites or sporozoites were preserved frozen and thawed immediately before inoculation into the patient.

Parasitemia. Thick and thin peripheral blood films were made daily by the method of Earle and Perez,6 stained with Giemsa stain, and examined microscopically for the presence of parasites. Asexual and sexual parasites were recorded per microliter of blood. During the later stages of the infection, when parasite counts were very low and no symptoms of malaria were evident, blood films were usually made two or three times a week.

Patient management. All patients were housed in screened wards of the hospital to prevent infection of local anophelines. While undergoing paroxysms, the patients were treated symptomatically. During infection, temperature, pulse, and respiration were checked every 4 hr and hourly during paroxysms. Infections were terminated for the following reasons: sudden overwhelming infection with parasites, severe anemia, unremitting pyrexia, rapidly enlarged and tender spleen, extreme exhaustion, cardiac disturbances, cyanosis, edema, convulsions, renal disturbances, marked increase in blood urea, development of another infectious disease, severe jaundice, or rapid debilitation involving weight loss.7

Treatment. Treatment with noncurative doses of antimalarial drugs was often necessary to modify and control the early stages of the infection with P. falciparum. When needed, parasitemia was also modified by the administration of bismuth thioglycolate. Infections were terminated by the use of drugs appropriate for the different parasites.

Data presentation. Ninety-seven patients who had previously experienced infection with P. vivax, P. malariae, and/or P. ovale were reinfected with P. falciparum for the treatment of paresis and other mental disorders associated with tertiary syphilis. Parasitologic and medical records obtained during these studies were examined to determine the natural course of infection as immunity developed. Presented here are the records obtained from infections with fever and/or parasitologic data considered adequate for this study.

The following data are presented graphically for each patient: 1) the presence of fever ≥ 101°F and ≥ 104°F, 2) days when asexual parasite counts were ≥ 10,000/μl and ≥ 1,000/μl, and 3) days when gametocyte counts were ≥ 100/μl and ≥ 1,000/μl during the first 20 days of patent asexual parasitemia. In addition, the following data are presented: 1) the frequency of fever ≥ 101°F (number of patients with fever/number of patients remaining in study) for the first 100 days of patent parasitemia, 2) the frequency of parasite counts ≥ 1,000/μl and ≥ 10,000/μl during the first 100 days of patent parasitemia, and 3) the frequency of gametocyte counts ≥ 100/μl and ≥ 1,000/μl during the first 100 days of patent parasitemia.

The days of maximum parasitemia, number of days with fever ≥ 101°F and ≥ 104°F, the length in days of the asexual parasitemia and number of days when the asexual parasite count was ≥ 10,000/μl, and the length in days of gametocytemia are presented in tabular form. In addition, the drugs used for modifying or termination of the infection are listed. For sporozoite-induced infections, the species of mosquito, the route of inoculation (bites or syringe), the number of mosquitoes or the intensity of the salivary gland infection, and the prepatent periods are given. The intensity of infection of the salivary glands was determined by rating the number of sporozoites present at dissection as 1 + (1 - 10 sporozoites), 2+ (11 - 100 sporozoites), 3 + (101 - 1,000 sporozoites), or 4+ (> 1,000 sporozoites). The total number of + ratings was then determined.

Results

Ninety-seven patients, previously infected with P. malariae, P. ovale, and/or P. vivax, were reinfected with P. falciparum. The patients were divided into 3 groups: Group I had 55 patients reinfected with the McLendon strain; Group II, 34 patients reinfected with the El Limon strain; and Group III, 8 patients reinfected with the Santee-Cooper strain of P. falciparum.

Reinoculation with the McLendon strain of P. falciparum. Thirty-five patients with previous history of infection with P. malariae were reinfected with the McLendon strain of P. falciparum via inoculation of parasitized blood (29 patients) or sporozoites (6 patients) (Table 1). The mean length of prior infection with P. malariae was 66.8 days. Maximum parasitemia ranged from 3,325 to 121,600/μl. The mean length of asexual parasitemia during infection with P. falciparum was 61.1 days and the mean length of total parasitemia including gametocytes was 65.7 days. Nine infections were terminated early (after 24 days or less of patent parasitemia), with either chloroquine, chlorguanide, or mepacrine (Table 1); infections in patients S-1034, S-669, S-1042, S-1109, and S-912 were modified with subcurative treatments with chlorguanide or chloroquine during the primary attack. There were 282 episodes of fever ≥ 101°F and 82 episodes ≥ 104°F. Of these, 198 (70.2%) occurred during the first 25 days, 49 (17.4%) during the 26-50-day period, 21 (7.4%) during the 51-75-day period, and 9 (3.2%) during the 76-100-day period. Patient S-912 had fever on days 102, 103, 104, 119, and 121. High-density parasitemia (≥ 10,000/μl) for the 35 patients occurred on 130 days (Table 1). All but 5 of these occurred during the first 25 days.

Seven patients with a history of infection with P. ovale were reinfected with the McLendon strain of P. falciparum via inoculation of parasitized blood (5 patients) or sporozoites (2 patients) (Table 1). The mean length of prior experience with P. ovale was 55 days. Maximum parasitemia ranged from 11,355 to 48,240/μl. The mean length of asexual parasitemia during infection with P. falciparum was 93.9 days and the mean length of total parasitemia including gametocytes was 108.0 days. Patients S-1328 and S-1327 had their primary attacks modified with small doses of quinine. There were 56 fever episodes ≥ 101°F and 23 ≥ 104°F for the 7 patients with previous infection with P. ovale. Of these, 46 (82.1%) occurred during the first 25 days, 7 (12.5%) during the 26-50-day period, 1 (1.8% ) during the 50-75-day period and 2 (3.6%) during the > 100-day period. High-density parasitemia (≥ 10,000/μl) for the 7 patients occurred on 28 days; 26 (92.9%) occurred during the first 25 days.

Seven patients with a history of infection with P. vivax were reinfected with the McLendon strain of P. falciparum via inoculation of parasitized blood (6 patients) or sporozoites 1 patient) (Table 1). The mean length of prior experience with P. vivax was 53 days. Maximum parasitemia ranged from 12,680 to 104,540/μl. The mean length of asexual parasitemia was 34.3 days and the mean length of total parasitemia including gametocytes was 42.6 days. There were 52 episodes of fever ≥ 101°F and 26 ≥ 104°F for the 7 patients with previous infection with P. vivax. Of these, 48 (92.3% ) occurred during the first 25 days. High-density parasitemia (≥ 10,000/μl) for the 7 patients occurred on 37 days; of these, 35 (94.6%) occurred during the first 25 days.

Six patients with a history of infection with two or three of the species P. malariae, P. vivax, and P. ovale were reinfected with the McLendon strain of P. falciparum via inoculation of parasitized blood (Table 1). The mean length of previous plasmodial infection was 123 days. Maximum parasitemia ranged from 3,040 to 96,400/μl. The mean length of asexual parasitemia was 57.0 days and the mean length of total parasitemia including gametocytes was 68.3 days. There were 79 episodes of fever ≥ 101°F and 30 ≥ 104°F for the 6 patients with previous infection with multiple species (P. vivax, P. malariae, and/or P. ovale). Of these, 55 (69.2%) occurred during the first 25 days, 20 (25.6%) during the 26-50-day period, and 4 (5.1%) during the 51-75-day period. High-density asexual parasitemia (≥ 10,000/μl) for the 6 patients occurred 29 times, 26 (89.7%) during the first 25 days.

Summary for patients infected with the McLendon strain of P. falciparum. The frequency of fever (≥ 101°F) during the first 100 days of patent parasitemia for the 55 patients with previous infection with P. malariae, P. ovale, and/or P. vivax who were reinoculated with the McLendon strain of P. falciparum is presented in Figure 1A. The highest percentage with fever occurred on day 6 (69.1%). Fever persisted until day 95. The frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 100 days of patent parasitemia for the 55 patients is presented in Figure 1B. The highest percentage with parasitemia ≥ 10,000/μl occurred on day 7 (50.9%). The frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days of patent parasitemia for 50 patients is presented in Figure 1C. The highest percentage with gametocytemia ≥ 1,000/μl occurred on day 16 (41.2%).

Table 1

Maximum parasitemia, episodes of fever, and length of parasitemia for 55 infections with the McLendon strain of Plasmodium falciparum in patients with a previous history of infection with P. malaria (Pm), P. ovale (Po), and/or P. vivax (PV)

Days of parasitemia

Previous infectionDays of feverAsexualGametocytes




Patient no.Spp.Days positiveMaximum para.*Day≥101°F≥104°F≥1,000/μl≥10,000/μl≥10/μl≥1,000/μlTreatment
S-103Pm  17                36,800                  5    3      1      7      2        0      0                 Ca
S-1020Pm  70                96,960                  6    7      3      10      3        0      0                 Pa, Ca
S-1037Pm§68                3,325                  8    11      3      10      0        28      0                 Ca
S-927Pm  81                113,250                  9    4      3      12      5        36      0                 Ca
S-766Pm  69                83,500                  9    5      0      17      9        0      0                 Ma
S-1014Pm  31                121,600                  13    3      2      15      8        55      23                 Pa
S-1006Pm  45                86,200                  8    9      4      17      9        19+    11+               Ca
S-806Pm§113                43,520                  7    7      6      21      4        32      0                 Pa
S-1194Pm  28                3,520                  20    1      0      23      0        48      0                 Ca
S-828Pm  65                121,033                  7    5      2      24      8        23      0        
S-816Pm  12                15,730                  5    0      0      33      2        34      0        
S-818Pm  27                25,760                  4    0      0      34      2        29      0        
S-871Pm§30                6,150                  8    9      2      37      0        42      0        
S-498Pm  280                10,500                  4    4      1      38      1        28      0        
S-456Pm§53                20,600                  7    4      0      40      5        39      0        
S-1054Pm  47                58,944                  6    4      0      40      2        40      19        
S-1044Pm§47                7,640                  4    3      0      41      0        29      0        
S-682Pm  112                106,200                  7    8      3      43      2        45      0        
S-829Pm  32                63,825                  7    5      0      46      6        38      0        
S-907Pm§25                114,000                  7    13      6      60      5        60      13        
S-1138Pm  50                34,350                  7    10      3      67      3        58      1                 Ca
S-1041Pm  121                60,350                  6    7      4      69      2        64      12                 Ca
S-1034Pm  26                34,100                  5    7      3      69      4        90      9                 Pb
S-738Pm  27                20,800                  11    22      0      85      6        83      0        
S-715Pm  73                82,400                  8    8      4      90      6        82      0        
S-875Pm  123                70,950                  9    11      4      98      7        87      12                 Ca
S-1053Pm  14                13,100                  4    4      4      98      1        103      12        
S-674Pm  36                43,920                  8    6      1      100      6        32      0        
S-801Pm  34                34,075                  11    4      2      106      3        50      0        
S-669Pm  66                21,250                  7    13      4      108      1        114      11                 Pb, Ca
Pm  44                
S-948Pm  65                15,640                  6    11      4      125      2        139      19        
S-1042Pm  160                9,080                  7    17      3      132      0        143      4                 Pb, Ca
S-1109Pm  103                46,700                  11    8      4      137      4        112      9                 Cb
S-861Pm§92                88,200                  6    23      4      138      8        127      4        
S-912Pm  51                99,200                  3    26      2      149      4        167      21                 Pb
S-1110Po  63                12,100                  5    4      3      7      1        20      0        
S-1260Po  30                11,355                  9    2      0      13      1        43      10                 Ca
S-1086Po  43                43,264                  13    7      4      47      9        56      10                 Ca
S-1280Po  40                12,241                  4    7      4      114      1        128      7                 Ca
S-1269Po  54                20,150                  9    15      5      139      2        136      7        
S-1328Po  79                20,901                  5    12      2      152      4        176      0                 Qb
S-1327Po  76                48,240                  6    9      5      185      10        194      0                 Qb, Ca
S-599Pv  58                17,500                  4    2      2      8      1        0      0                 Ma
Pv  78                
S-1117Pv  20                12,680                  7    3      2      10      2        22      0                 Ca
S-864Pv  49                31,196                  5    10      10      14      6        30      4                 Ma, Ca
S-836Pv  3                65,840                  7    13      6      28      8        27      0                 Ca
Pv  36                
S-826Pv  47                28,720                  5    5      1      43      6        0      0        
S-1325Pv  44                31,190                  11    6      2      58      4        79      16                 Prc
S-1237Pv  36                104,540                  6    13      3      79      10        88      15                 Cb, Ca
S-1172Pm  37                3,040                  3    3      2      45      0        35      1                 Ca
Po  23                
S-1121Pm  171                17,650                  12    22      3      86      4        89      12                 Ca
Po§
S-783Pm  114                7,660                  9    12      3      26      0        46      19                 Pb,a
Pm  38                
Po§
S-1057Pv  33                54,405                  24    30      16      45      14        73      2                 Qb, Prc, Aa
Pv  29                
Po  41                
S-1060Pv  24                80,548                  15    6      4      82      7        109      11                 Qb, Cc, Ac, Ca
Po  25                
Pv  32                
S-542Pm  99                96,400                  3    6      2      58      4        20      0        
Pv  69                
Pm  3                

Parasites/μl.

a = treatment to cure infection; b = subcurative treatment to modify primary attack; c = subcurative treatment after primary attack; C = chloroquine; P = chlorguanide; M = mepacrine; Q = quinine; Pr = primaquine; A = amodiaquine.

Sporozoite-induced infection.

Currently infected with heterologous species at time of inoculation with P. falciparum.

Reinoculation with the El Limon strain of P. falciparum. Thirty-four patients with a history of infection with P. ovale, P. vivax, and/or P. malariae were reinfected with the El Limon strain of P. falciparum via inoculation of parasitized blood (15 patients) or sporozoites (19 patients) (Table 2). Maximum parasitemia ranged from 3,060 to 551,960/μl. The mean length of asexual parasitemia was 76.8 days and the mean length of total parasitemia including gametocytes was 90.6 days.

Figure 1.
Figure 1.

Percentage of patients with A, fever (≥ 101°F), B, parasitemia ≥ 1,000/μl and ≥ 10,000/μl, and C, gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days for 55 patients previously infected with Plasmodium malariae, P. ovale, and/or P. vivax who were reinfected with the McLendon strain of P. falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-036

Thirteen patients previously infected with P. ovale were reinfected with the El Limon strain. The mean length of their previous infection with P. ovale was 93.6 days. Five of the patients had their primary attacks modified with subcurative doses of chlorguanide or quinine. There were 156 fever episodes ≥ 101°F and 40 episodes ≥ 104°F for the 13 patients. Of these, 124 (79.5%) occurred during the first 25 days, 19 (12.2%) during the 26-50-day period, 10 (6.4%) during the 51-75-day period, and 3 (1.9%) during the 76-100-day period. High-density parasitemia (≥ 10,000/μl) occurred on 106 days. Of these, 88 (83.0%) occurred during the first 25 days, 10 (9.4%) during the 26-50-day period, 6 (5.7%) during the 51-75-day period, and 2 (1.9%) during the 76-100-day period.

Nine patients previously infected with P. vivax were infected with the El Limon strain. The mean length of previous infection was 176.4 days. There were 107 fever episodes ≥ 101°F and 35 episodes ≥ 104°F; of these, 82 (82.8%) occurred during the first 25 days, 20 (18.7% ) during the 26-50-day period, and 5 (4.7%) during the 51-75-day period. High-density parasitemia (≥ 10,000/μl) occurred on 104 days; of these, 70 (67.3%) occurred during the first 25 days, 20 (19.2%) during the 26-50-day period, 8 (7.7%) during the 51-75-day period, and 6 (5.8%) during the 76-100-day period.

Twelve patients were previously infected with P. malariae alone (2 patients) or with several combinations of P. malariae, P. vivax, and/or P. ovale before reinfection with the El Limon strain of P. falciparum. The mean length of the previous infections was 171.9 days. There were 127 episodes of fever ≥ 101°F and 40 episodes ≥ 104°F; of these, 112 (88.2 %) occurred during the first 25 days, 14 (11.0%) during the 26-50-day period, and 1 (0.8%) during the 51-75-day period. High-density parasitemia (≥ 10,000/μl) occurred on 123 days; of these, 108 (87.8%) occurred during the first 25 days, 14 (11.4%) during the 26-50-day period, and 1 (0.8%) during the 51-75-day period.

Summary for patients inoculated with El Limon strain of P. falciparum. The frequency of fever (≥ 101°F) during the first 100 days of patent parasitemia for the 34 patients with previous infection with P. malariae, P. ovale, and/or P. vivax who were reinoculated with the El Limon strain of P. falciparum is presented in Figure 2A. The highest percentage with fever occurred on day 7 (91.2%). The frequency of asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 100 days of patent parasitemia for the 34 patients is presented in Figure 2B. The highest percentage with parasitemia ≥ 10,000/μl occurred on day 6 (67.6%). The frequency of gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days of patent parasitemia is presented in Figure 2C. The highest percentage with gametocytemia ≥ 1,000/μl occurred on day 18 (45.5%).

Table 2

Maximum parasitemia and length of parasitemia for 34 infections with the El Limon strain of Plasmodium falciparum in patients with a previous history of infection with Plasmodium malaria (Pm), P. ovale (Po), and/or P. vivax (Pv)

Days of parasitemia

Previous infectionDays of feverAsexualGametocytes




Patient no.Spp.Days (+)Maximum para.*Day≥101°F≥104°FDays≥10,000/μlDays≥1,000/μlTreatment
G-455      Po11           68,760                7    3+    0      16        2            48    8                        Pb, Ca
      Po10           
G-488      Po45           20,340                12    11    7      19        4            28    0                        Pra, Ca
G-481      Po112           118,800                7    11    5      36        5            60    2                        Pb, Qb, Ca
G-480      Po36           57,960                7    8    4      42        5            69    2                        Qb, Ca
G-362      Po42           34,080                7    23    7      53        16            58    0                        Pb, Qb, Ca, Pra
G-451      Po95           45,000                7    24    4      103        15            144    7                        Pb, Qb, Ca, Pra
      Po69           
S-1310      Po85           16,100                5    6    0      111        4            107    0                        Prc
G-381      Po55           44,280                7    10    0      120        10            197    11         
      Po7           
G-469      Po57           64,440                11    11    3      128        9            131    2                        Ca
      Po13           
G-441      Po31           72,720                4    6    1      144        8            138    19         
G-449      Po282           24,480                8    16    5      163        11            188    0                        Ca
      Po69           
G-417      Po103           77,040                12    17    2      174        17            154    22                        Ca
      Po11           
S-1311      Po84           3,060                12    10    2      176        0            197    4                        Prc
G-349      Pv50           56,520                6    5    3      10        2            0    0                        Pa, Qa, Ca
      Pv34           
G-191      Pv19           92,520                9    10    7      15        11            33    0                        Tb, Qb, Ca
      Pv49           
G-432      Pv121           216,720                6    9    3      17        3            44    0                        Qb, Pb,a
      Po25           
G-266      Pv543           133,920                7    14    3      29        18            36    8                       Pb, Qb,a, Pra
G-400      Pv129           189,360                5    14    6      31        13            33    5                        Pb, Qb, Ca, Pra
      Pv36           
G-213       Pv419           344,160                6    13    1      34        19            48    2                        Pb, Ca
G-353      Pv116           99,360                6    17    3      38        16            39    10                        Pb, Qb, Ca, Pra
G-231      Pv18           29,520                9    11    7      47        3            61    0                        Ca
G-100      Pv12           551,960                8    14    2      84        19            87    20                        Pb,c, Cb,a, Qc, Pra
      Pv17           
S-878      Pm85           19,750                5    13    3      139        3            143    3                        Ca
G-225      Pm>26           102,240                7    8    6      193        6            184    0         
S-1287      Pm264           3,913                8    5    1      16        0            50    1                        Pya
      Po133           
S-1322      Pm11           21,423                14    9    5      90        7            107    16                        Prc
      Po32           
S-1293      Po25           12,830                3    7    2      139        2            154    2         
      Pm182           
G-108      Pv12           39,240                21    19    2      31        19            49    0                        Qb, Ca
      Pv17           
      Pv8           
      Po104           
G-185      Pv17           49,680                6    0    0      33        16            37    11                        Pb, Qb,a, Pra
      Pv145           
      Po84           
G-440      Pv152           94,320                7    12    2      67        3            40    0                        Qb, Pb, Cc,a, Pra
      Pv21           
      Po26           
G-406      Pv189           281,520                5    10    2      182        15            172    12                        Pb,c, Qb, Pyc, Ca
      Pv16           
      Pv11           
      Po180           
G-302      Pm>23           120,960                9    16    4      22        16            49    16                        Ca
      Pv256           
G-352      Pv30           74,160                6    15    6      48        15            48    11                        Qa, Pra
S-1305      Po71           90,831                14    13    7      60        21            51    21                        Prb,c, Qb,c, Ac, Ca
      Pm19           
      Pv39           

Parasites/μl.

a = treatment to cure infection; b = subcurative treatment to modify primary attack; c = subcurative treatment after primary attack; P = chlorguanide; C = chloroquine; Pr = primaquine; Q = quinine; T = bismuth thioglycolate; Py = pyrimethamine; A = amodiaquine.

Sporozoite-induced infection.

Figure 2.
Figure 2.

Percentage of patients with A, fever (≥ 101°F), B, parasitemia ≥ 1,000/μl and ≥ 10,000/μl, and C, gametocytemia ≥ 100/μl and ≥ 1,000/μl during the first 100 days for 34 patients previously infected with Plasmodium malariae, P. ovale, and/or P. vivax who were reinfected with the El Limon strain of P. falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-036

Table 3

Maximum parasitemia and length of parasitemia for 8 infections with the Santee-Cooper strain of Plasmodium falciparum in patients with a previous history of infection with Plasmodium malariae (Pm), and P. ovale (Po)

Days of Parasitemia

Previous infectionDays of feverAsexualGametocytes




Patient no.Spp.Days (+)Maximum para.*Day≥101°F≥104°FDays≥10,000/μlDays≥1,000/μlTreatment
G-77      Pm113                43,200                9    ?      ?      10    2            31    0                    Ca
G-25      Pm73                118,080                7    ?      ?      11    4            0    0                    Ca
S-778Pm§7,120                11    6      1      38    0            27    0           
S-791Pm§12,750                12    8      4      48    2            44    0           
S-734      Pm172                660                8    1      0      55    0            39    0           
G-6      Pm30                494,640                8    ?      ?      271    16            231    10                    Qb
G-320Po60                167,000                9    22      9      130    10            –    –                   Pb,c, Ca
G-321Po78                146,160                7    12      2      180    10           –    –                   Pb,c, Ca

Parasites/μl.

a = treatment to cure infection; b = subcurative treatment to modify primary attack; c = subcurative treatment after primary attack; C = chloroquine; Q = quinine; P = chlorguanide.

Sporozoite-induced infection.

Currently infected with heterologous species at time of inoculation with P. falciparum.

Reinoculation with the Santee-Cooper strain of P. falciparum. Eight patients with a history of infection with P. malariae or P. ovale were reinfected with the Santee-Cooper strain of P. falciparum via inoculation of parasitized blood (5 patients) or sporozoites (3 patients) (Table 3). Maximum parasitemia ranged from 660 to 494,640/μl. Two patients (S-778 and S-791) were currently infected with P. malariae when infected with P. falciparum. The mean length of the previous infection for the patients whose infections had been terminated was 87.7 days. The mean length of asexual parasitemia was 90.8 days and the mean length of total parasitemia including gametocytes was 93.5 days. There were 49 fever episodes ≥ 101°F and 16 ≥ 104°F for the 5 patients for whom fever data was available; of these, 35 (71.4%) occurred during the first 25 days, 7 (14.3%) during the 26-50-day period, and 7 (14.3%) during the 51-75-day period. No fever charts were available for patients G-77, G-25, and G-6. High-density parasitemia (≥ 10,000/μl) for the 8 patients occurred on 44 days; of these, 38 (86.4%) occurred during the first 25 days, 5 (11.4%) during the 26-50-day period, and 1 (2.3%) during the 51-75 -day period.

Prepatent periods for sporozoite-induced infections. Thirty-two patients previously infected with P. malariae, P. ovale, and/or P. vivax were infected via sporozoite inoculation. The prepatent periods, mosquito vectors, and inocula for 10 patients infected with the McLendon strain, 19 patients infected with the El Limon strain, and 3 patients infected with the Santee-Cooper strain of P. falciparum (Table 4 and Figure 3) indicated a mean prepatent period of 10.8 days (median 10 days) with a range from 8 to 20 days.

Discussion

Ninety-seven patients previously infected with P. malariae, P. ovale, and/or P. vivax were shown to be susceptible to reinfection with different strains of P. falciparum. Prepatent periods for sporozoite-induced infections were in the same range as those reported previously for patients following primary challenge.1

Our goal was to document the effect of previous malarial experience with heterologous species of Plasmodium on secondary parasitologic and clinical responses. Most of the clinical activity following infection with P. falciparum occurred during the first 20 days of patent parasitemia. If previous experience with P. ovale, P. vivax, or P. malariae had a marked effect on asexual parasitemia or clinical malaria, it should have been evident during this period. Thus, the daily percentages of patients with fever ≥ 101°F and ≥ 104°F and asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl were determined for the first 20 days of patent parasitemia for patients with primary infections with P. falciparum,1 and those patients with secondary infections following infection with P. ovale, P. vivax, and/or P. malariae.

Table 4

Prepatent periods for 32 sporozoite-induced infections with the McLendon (10), El Limon (19) and Santee-Cooper (3) strains of Plasmodium falciparum in patients with a previous history of infection with P. malariae (Pm), P. ovale (Po), and/or P. vivax (Pv)

Patient no.Previous malariaSpecies of AnophelesRoute of inoculation*No. of mosquitoesNo. of +sPrepatent period
McLendon strain
   S-1086               Po               quadrimaculatus           Bites/253         9                  
           Glands/IV34?         
   S-1328               Po               quadrimaculatus           Glands/IV14?         11                  
   S-836               Pv               freeborni           Bites1035         11                  
   S-1138               Pm               freeborni           Bites  28         11                  
   S-1034               Pm               quadrimaculatus           Bites1542         11                  
   S-1031               Pm               quadrimaculatus           Bites49         13                  
   S-682               Pm               freeborni           Bites1248         13                  
   S-1194               Pm               quadrimaculatus           Bites  813         14                  
   S-912               Pm               quadrimaculatus           Bites1220         15                  
   S-1044               Pm               quadrimaculatus           Bites1130         20                  
El Limon strain
   G-349               Pv               albimanus           Bites1543         8                  
   G-440               Pv, Po               albimanus           Glands/IV  6?         9                  
   G-266               Pv               albimanus           Bites  616         9                  
   G-400               Pv               albimanus           Bites1862         9                  
   G-362               Po               albimanus           Bites1852         9                  
   G-451               Po               albimanus           Glands/IV      2.7?         9                  
   G-449               Po               albimanus           Glands/IV15?         9                  
   G-488               Po               albimanus           Glands/IV10?         9                  
   G-480               Po               albimanus           Glands/IV  8?         10                  
   G-455               Po               albimanus           Bites1736         10                  
   G-191               Pv               albimanus           Bites1646         10                  
   G-231               Pv               albimanus           Bites  414         10                  
   G-213               Pv               albimanus           Bites  826         10                  
   G-225               Pm               albimanus           Bites1653         11                  
   G-352               Pm, Pv               albimanus           Bites1128         11                  
   G-481               Po               quadrimaculatus           Glands/IV10?         11                  
   G-108               Pv, Po               albimanus           Bites1334         11                  
   G-406               Pv, Po               quadrimaculatus, albimanus           Bites  610         11                  
   G-302               Pm, Pv               albimanus           Bites1863         16                  
Santee-Cooper strain
   G-77               Pm               quadrimaculatus           Bites110389         8                  
   G-25               Pm               quadrimaculatus           Bites110389         8                  
   G-6               Pm               quadrimaculatus           Bites110389         10                  

IV = intravenous.

Glands were rated 1 + to 4 +.

Days to detectable parasitemia.

Figure 3.
Figure 3.

Prepatent periods for 32 patients with previous experience with Plasmodium malariae, P. ovale, and/or P. vivax who were infected via sporozoite inoculation.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-036

The mean daily percentages of patients with fever ≥ 101°F and ≥ 104°F and asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 20 days of patent parasitemia with P. falciparum were determined for 73 sporozoite-induced primary infections modified with subcurative doses of antimalarial drugs (Group I), 104 trophozoite-induced primary infections that were modified (Group II), 40 sporozoite-induced primary infections not modified (Group III), 47 trophozoite-induced primary infections not modified (Group IV); 22 infections preceded by infection with P. ovale (Group V), 16 infections preceded by infection with P. vivax (Group VI), and 41 infections preceded by infection with P. malariae (Group VII).

Figure 4.
Figure 4.

Mean daily percentage of patients with fever ≥ 101°F and ≥ 104°F during the first 20 days of patent parasitemia with Plasmodium falciparum. Group I = 73 sporozoite-induced primary infections modified with subcurative doses of antimalarial drugs; Group II = 104 trophozoite-induced primary infections that were modified; Group III = 40 sporozoite-induced primary infections that were not modified; Group IV = 47 trophozoite-induced primary infections that were not modified; Groups I-IV = 264 primary infections; Group V = 22 infections following infection with P. ovale; Group VI = 16 infections following infection with P. vivax; Group VII = 41 infections following infection with P. malariae.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-036

The mean daily percentage of patients with fever ≥ 101°F during the first 20 days of primary infection with P. falciparum was 42.4; the percentage with fever ≥ 104°F was 19.9%. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of fever ≥ 101°F and ≥ 104°F of 39.1% and 14.8%, 39.1% and 19.4%, and 28.4% and 11.3% , respectively (Figure 4). Previous infection with P. ovale or P. vivax had little, if any, effect on subsequent clinical malaria due to P. falciparum, whereas infection with P. malariae resulted in reduced frequencies of fever.

A similar comparison was made for parasite counts ≥ 1,000/μl and ≥ 10,000/μl. The percentages for 268 patients during the first 20 days of primary infection with P. falciparum were 58.2% and 29.9%, respectively. Those previously infected with P. ovale, P. vivax, and P. malariae had mean daily percentages of parasitemia ≥ 1,000/μl and ≥ 10,000/μl of 58.0% and 24.3%, 57.3% and 31.1%, and 45.9% and 19.0%, respectively (Figure 5). Previous infection with P. malariae resulted in a reduction in the frequency of high-density parasitemia (≥ 10,000/μl) as well as an asexual parasite count ≥ 1,000/μl.

These results suggest that P. falciparum and P. malariae share common antigens that are able to induce parasitologic and clinical protection when infection with P. falciparum follows that with P. malariae. Whether or not previous infection with P. falciparum will provide protection against subsequent infection with P. malariae remains to be determined. Further analysis of the records of induced malaria should provide these data. The results of this present analysis did not suggest that protection to P. falciparum is provided by previous infection with P. ovale or P. vivax.

Figure 5.
Figure 5.

Mean daily percentage of patients with asexual parasitemia ≥ 1,000/μl and ≥ 10,000/μl during the first 20 days of patent parasitemia with Plasmodium falciparum. Group I = 73 sporozoite-induced primary infections modified with subcurative doses of antimalarial drugs; Group II = 108 trophozoite-induced primary infections that were modified; Group III = 40 sporozoite-induced primary infections that were not modified; Group IV = 47 trophozoite-induced primary infections that were not modified; Groups 1-IV = 268 primary infections; Group V = 22 infections following infection with P. ovale; Group VI = 16 infections following infection with P. vivax; Group VII = 41 infections following infection with P. malariae.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-036

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Author Notes

Authors' addresses: William E. Collins, Division of Parasitic Diseases, Centers for Disease Control and Prevention, Mailstop F-12, 4770 Buford Highway, Atlanta, GA 30341-3724. Geoffrey M. Jeffery (Public Health Service, retired), 1093 Blackshear Drive, Decatur, GA 30033.

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