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    Parasitemia curves, fever episodes, and peak parasite counts per microliter during recrudescence in patient S-1044 infected with Plasmodium falciparum. Treatments: A = amodiaquine; L = lapadrine; Py = pyrimethamine.

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    Intervals between recrudescences in immunologically naive patients infected with Plasmodium falciparum. A, 40 sporozoite-induced, and B, 67 trophozoite-induced infections. Antimalarial drugs were given to modify the primary attack.

  • View in gallery

    Intervals between recrudescences in immunologically naive patients infected with Plasmodium falciparum. A, 35 sporozoite-induced, and B, 88 trophozoite-induced infections. No treatment was given to modify the primary attack.

  • View in gallery

    Intervals between recrudescences in 44 patients reinfected with Plasmodium falciparum.

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    Intervals between recrudescences in patients infected with Plasmodium falciparum after previous infection with P. malariae and/or P. ovale and P. vivax. A, 39 patients infected with the McLendon strain, and B, 30 patients reinfected with other strains of P. falciparum.

  • 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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    • Export Citation
  • 2.

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

    • Search Google Scholar
    • Export Citation
  • 3.

    Collins WE, Jeffery GM, 1999. 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. Am J Trap Med Hyg 61: (suppl): 3643.

    • Search Google Scholar
    • Export Citation
  • 4.

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

  • 5.

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

    • Search Google Scholar
    • Export Citation
 
 
 

 

 
 
 

 

 

 

 

 

 

A Retrospective Examination of the Patterns of Recrudescence in Patients Infected with Plasmodium Falciparum

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

A retrospective examination was made to determine median intervals between recrudescences of Plasmodium falciparum in 343 neurosyphilitic patients who were given malariatherapy, which was routine care at that time. Data were collected at the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963. The geometric mean days of peak parasite count for the patients were 8, 26.5, 43.5, 62, 78.5, and 95.5 days, respectively. The intervals between these peaks of 18.5, 17, 18.5, 16.5, and 17 days suggest a fixed time frame for the appearance of different dominant parasite populations during the first 100 days of patent infection. When the data from these same patients were examined for mean peak parasite counts, the patterns indicated a consistent decrease in parasite count suggestive of increasing immunity, which was sufficient to reduce but not eliminate subsequent parasite populations. The geometric mean peak parasite counts for the 343 patients during the primary attack and the first 5 recrudescences were 40,350, 6,975, 5,090, 3,820, 3,455, and 2,375/μl, respectively.

Previously, we reported on the parasite densities that developed in patients infected and reinfected with different strains of Plasmodium falciparum for the treatment of neurosyphilis.13 These observations had been recorded by the National Institutes of Health laboratories in Columbia, South Carolina and Milledgeville, Georgia during the period 1940 to 1963.

A consistent pattern of infections with P. falciparum was the sequential appearance of peaks in the parasite count, referred to as recrudescences. Patient S-1044 is an example of this (Figure 1). The patient had been previously infected with P. falciparum; in spite of this, drug treatment was required to modify the primary attack. Following subcurative drug treatment, a series of 4 recrudescences occurred with peak parasite counts of 1,926, 2,536, 690, and 200/μl. Whether these secondary peaks were due to the antigenic polymorphism of the malaria parasites or the appearance of new variant forms, it indicates the appearance of populations of parasites that may be less susceptible to the immune response induced by previous parasite populations. An examination of the records of these infections was made to determine the frequency and spacing of recrudescences and peak parasite densities that developed during each recrudescence.

Materials and Methods

Infections with different strains of P. falciparum, P. vivax, P. ovale, and P. malariae were induced in patients for the treatment of neurosyphilis. Patients were infected either by the inoculation of parasitized blood or via sporozoites. With the latter, inoculation was either by the bites of infected Ano pheles quadrimaculatus, An. albimanus, or An. freeborni 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 were thawed immediately before inoculation into the patient.

Parasitemia. Thick and thin peripheral blood films were made daily by the method of Earle and Perez,4 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 2–3 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, the temperature, pulse, and respiration were checked every 4 hr and hourly during paroxysms. Infections were terminated for these 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.5

Treatment. Treatment with noncurative doses of antimalarial drugs, usually with low dosages of quinine, was often necessary to modify and control the early stages of the infection with P. falciparum. Infections were terminated by the use of drugs appropriate for the different parasites.

Data presentation. The results of the observations conducted at Milledgeville and Columbia have been combined. The data presented are based on those records we consider sufficiently complete to be useful. Parasitologic and clinical records obtained during these observations were examined to determine the natural course of infection as immunity developed. Signs and symptoms of immunity in untreated patients were taken to be the lessening of episodes of fever and decreases in the parasite count.

For this particular study, the following data were considered: 1) the intervals between the peak parasite count occurring during the primary attack and subsequent recrudescent peaks in the parasite count, and 2) the peak parasite counts associated with each recrudescence.

Results

Three-hundred forty-three patients inoculated with P. falciparum had one or more recrudescences. These were considered in seven groups: Group I-40 patients infected with sporozoites and treated with antimalarial drugs to modify the primary attack; Group II-67 patients infected with trophozoites and treated to modify the primary attack; Group III-35 patients infected with sporozoites and not treated to modify their primary attack; Group IV-88 patients infected with trophozoites and not treated to modify the primary attack; Group V-44 patients reinfected with homologous and heterologous strains of P. falciparum (some patients also had been previously infected with P. malariae, P. ovale, and/or P. vivax). Group VI-39 patients infected with the McLendon strain of P. falciparum after previous infection with P. vivax, P. ovale, and/or P. malariae; Group VII-30 patients reinfected with strains of P. falciparum other than the McLendon strain after previous infection with P. vivax and/or P. ovale.

Figure 1.
Figure 1.

Parasitemia curves, fever episodes, and peak parasite counts per microliter during recrudescence in patient S-1044 infected with Plasmodium falciparum. Treatments: A = amodiaquine; L = lapadrine; Py = pyrimethamine.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-044

The intervals and ranges varied among the different groups of patients (Table 1). Forty sporozoite-induced infections in malaria naive patients in which drugs were given to modify the infection (Group I) exhibited 1 or more recrudescences; 36 patients had 2 recrudescences, 31 patients had 3 recrudescences, 30 patients had 4 recrudescences, and 29 patients had 5 recrudescences (Figure 2A). The median day of the primary peak parasite count was day 9; the median days of peak parasite count for the first 5 recrudescences were days 26.5, 44, 5 8 , 77, and 92.5. The median intervals between peaks in the parasitemia were determined for each recrudescence. The intervals between the median peak days for Group I were 17.5 , 17.5, 14, 19 , and 15.5 days. Sixty-seven trophozoite-induced infections in malaria naive patients in whom treatment was given to modify the infection (Group II) recrudesced one or more times (Figure 2B). The median days of peak parasite count were 8, 28.5 , 46.5, 64.5, 82.5, and 96; the intervals between the peaks in parasite count were 20.5, 18, 18, 18, and 13.5 days.

Thirty-five sporozoite-induced infections in malaria naive patients in whom no treatment was given (Group Ill) recrudesced (Figure 3A). The median days of peak parasite count were 8, 31.5 , 51, 70.5 , 85.5, and 108; the intervals between peaks in the parasitemia were 23.5, 19.5, 19.5, 15, and 22.5 days. Eighty-eight trophozoite-induced infections in malaria-naive patients in whom no treatment was given (Group IV) recrudesced (Figure 3B). The median days of peak parasite count were 8, 27, 43.5, 65, 78, and 98; the intervals between peaks in the parasitemia were 19, 16.5, 21.5, 13, and 20 days.

Table 1

Days of peak Plasmodium falciparum parasitemia during the primary attack and the first 5 recrudescences in 343 patients in whom recrudescences were recorded

Group*Peak 1Peak 2Peak 3Peak 4Peak 5Peak 6
INo.404036313028
Range5–2010–5521–9333–9047–11259–132
Median926.544587792.5
IINo.676751443827
Range4–1912–5328–16440–11556–17367–192
Median828.546.564.582.596
IIINo.353531282213
Range8–1715–4832–9543–9858–12673–132
Median828.546.564.582.596
IVNo.888871553923
Range3–2214–9024–14736–15350–16663–169
Median82743.5657898
VNo.44443224149
Range4–1518–6028–8350–12064–15375–152
Median724.544.56583108
VINo.39392619148
Range3–1417–5327–8542–10652–11473–185
Median724.5395270.585
VIINo.303025171513
Range3–1513–5321–8541–7748–10956–129
Median72337556994
Totalno.343343272218172121
Range3–2210–9021–16433–15347–17356–192
Median826.543.56278.595.5

I = trophozoite-induced infections with no treatment of primary attack; no previous malaria; II = = trophozoite-induced infections with treatment of primary attack; no previolls malaria; III = sporozoite-induced infections with no treatment of primary attack; no previous malaria; IV = sporozoite-induced infections with treatment of primary attack: no previous malaria; V = reinfections with Plasmodium falciparum; previous infection with P. falciparum: VI = reinfections with the McLendon strain of Plasmodium falciparum; previous infection with P. malariae, P. ovale, and/or P. vivax: VII = reinfections with heterologous strains of Plasmodium falciparum; previous infection with P. malariae, P. ovale, and/or P. vivax.

Figure 2.
Figure 2.

Intervals between recrudescences in immunologically naive patients infected with Plasmodium falciparum. A, 40 sporozoite-induced, and B, 67 trophozoite-induced infections. Antimalarial drugs were given to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-044

Forty-four reinfections with P. falciparum after previous infection with homologous or heterologous strains of P. falciparum (Group V) recrudesced (Figure 4). The median days of peak parasite count were 7, 24.5, 44.5, 65, 83, and 108 ; the intervals between peaks in the parasitemia were 17.5, 20, 20.5, 18, and 25 days.

Thirty-nine infections with the McLendon strain of P. falciparum after previous infection with P. malariae (24 patients) or P. ovale (5 patients), P. vivax (4 patients), and multiple infections of P. malariae, P. ovale, and/or P. vivax (6 patients) (Group VI) recrudesced (Figure 5A). The median days of peak parasite count were 7, 24.5, 39, 52. 70.5, and 85; the intervals between peaks in the parasitemia were 17.5, 14.5, 13, 18.5, and 14.5 days.

Finally, 30 infections with P. falciparum after previous infection with P. ovale (18 patients) or P. ovale and/or P. vivax (12 patients) (Group VII) recrudesced (Figure 5B). The median days of peak parasite count were 7, 23, 37, 55, 69, and 94; the intervals between peaks in the parasitemia were 16, 14, 18, 14, and 15 days. The overall phenomenon was evident in both sporozoite and blood-induced infections, and whether or not the patients had been previous infected.

Figure 3.
Figure 3.

Intervals between recrudescences in immunologically naive patients infected with Plasmodium falciparum. A, 35 sporozoite-induced, and B, 88 trophozoite-induced infections. No treatment was given to modify the primary attack.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-044

The geometric mean days of peak parasite count for all 343 patients (Table 1) who had one or more recrudescences were 8, 26.5, 43.5, 62, 78.5, and 95.5 days, respectively. The intervals between these peaks of 18.5, 17, 18.5, 16.5, and 17 days suggest a fixed time frame for the appearance of different dominant parasite populations during the first 100 days of patent infection.

Figure 4.
Figure 4.

Intervals between recrudescences in 44 patients reinfected with Plasmodium falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-044

Figure 5.
Figure 5.

Intervals between recrudescences in patients infected with Plasmodium falciparum after previous infection with P. malariae and/or P. ovale and P. vivax. A, 39 patients infected with the McLendon strain, and B, 30 patients reinfected with other strains of P. falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 61, 1_Supplement; 10.4269/tropmed.1999.61-044

When the data from these same patients were examined for mean peak parasite counts, the patterns indicate a consistent decrease in parasite count suggestive of increasing immunity that was sufficient to reduce, but not eliminate subsequent parasite populations. The geometric mean peak parasite counts for the primary attack and the recrudescences are presented in Table 2.

Forty sporozoite-induced infections in malaria-naive patients in whom drugs were given to modify the infection (Group I) recrudesced with mean maximum parasite counts of 78,900, 22,900, 11,300, 9,090, 7,590, and 4,91O/µl. Sixty-seven trophozoite-induced infections in malaria-naive patients in whom treatment was given to modify the infection (Group II) recrudesced with mean maximum parasite counts of 74,900, 18,500, 7,580, 4,950, 4,625 , and 1,820/µl.

Thirty-five sporozoite-induced infections in malaria-naive patients in whom no treatment was given (Group III) had mean parasite counts for the first 5 recrudescences of 36,400, 5,260, 5,200, 3,270, 2,450, and 2,025/µl. Eighty-eight trophozoite-induced infections in malaria-naive patients in whom no treatment was given (Group IV) recrudesced with mean maximum parasite counts of 36,470, 5,625, 3,560, 3,120, 2,920, and 1,875/µl.

Forty-four reinfections with P. falciparum after previous infection with P. falciparum (Group V) recrudesced with mean maximum parasite counts of 16,370, 4,200, 2,890, 1,550, 1,280, and 1,170/µl.

Table 2

Mean peak Plasmodium falciparum parasitemia during the primary attack and the first 5 recrudescences in 343 patients in whom recrudescences were recorded

Group*Peak 1Peak 2Peak 3Peak 4Peak 5Peak 6
INo.404036313028
Mean78,90022,90011,3009,0907,5904,910
IINo.676751443827
Mean74,90018,5007,5804,9504,6251,820
IIINo.353531282213
Mean36,4005,2605,2003,2702,4502,025
IVNo.888871553923
Mean36,4705,6253,5603,1202,9201,875
VNo.44443224149
Mean16,3704,2002,8901,5501,2801,170
VINo.39392619158
Mean28,6303,4402,8002,4902,2202,920
VIINo.303025171513
Mean36,8509,8507,3305,8002,2802,200
Totalno.343343272218173121
Mean40,3506,9755,0903,8203,4552,375

For definitions of groups. see Table 1.

Thirty-nine infections with the McLendon strain of P. falciparum after previous infection with P. malariae (24 patients) or P. ovale (5 patients), P. vivax (4 patients), and multiple infections of P. malariae, P. ovale, and/or P. vivax (6 patients) (Group VI) recrudesced with mean maximum parasite counts of 28,630, 3,440, 2,800, 2,490, 2,220, and 2,920/µl. Finally, 30 infections with heterologous strains of P. falciparum after previous infection with P. ovale (18 patients) or P. ovale and/or P vivax (12 patients) (Group VII) recrudesced with mean maximum parasite counts of 36,850, 9,850, 7,330, 5,800, 2,280, and 2,200/µl.

The geometric mean peak parasite counts for the 343 patients who had infections that recrudesced were 40,350, 6,975, 5,090, 3,820, 3,455, and 2,375/µl, respectively.

Discussion

Infections with P. falciparum are characterized by secondary peak asexual parasite counts. Recrudescence may or may not be followed by an increase in gametocytemia. It was believed that as the infection progresses, the interval between peak parasite counts would be extended. Despite marked variation from patient to patient, when the patterns of recrudescence were examined for this relatively large number of patients, in each of the groups, the intervals between peak parasite counts were remarkably constant. It suggests that the primary population of parasites is controlled by the immune response of the host, and that this population of parasites is supplanted by a new one. This second population is in turn controlled to be replaced by another, and so on. At approximately 3-week intervals, each population of parasites is supplanted by another, regardless of the malarial experience of the host.

Each succeeding population evolving from a single challenge is usually only able to increase to a fraction of the density of the parasite populations before it, indicating a level of conserved immunity that becomes more and more effective against each succeeding parasite population. However, the introduction of a heterologous strain of parasite was usually followed by an increased parasite count greater than that observed in the latter stages of the initial infection.

A long-term chronic infection would be characterized by a succession of peaks in the parasite count that occur at a relatively constant interval of about every 3 weeks; after 5 or more recrudescences, the parasite count becomes barely detectable. Following a rechallenge or superinfection, the cycles are again repeated. Thus, only after multiple challenges will the host develop universal parasitologic immunity. Whether or not a patient can develop sterile immunity to all potential parasite variants is unknown.

REFERENCES

  • 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.

    • Search Google Scholar
    • Export Citation
  • 2.

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

    • Search Google Scholar
    • Export Citation
  • 3.

    Collins WE, Jeffery GM, 1999. 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. Am J Trap Med Hyg 61: (suppl): 3643.

    • Search Google Scholar
    • Export Citation
  • 4.

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

  • 5.

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

    • Search Google Scholar
    • Export Citation

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 S ervice, retired), 1093 Blackshear Drive, Decatur, Ga 30033.

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