Correspondence

Central Nervous System Toxoplasmosis in AIDS

N Engl J Med 1993; 328:1352-1354May 6, 1993

Article

To the Editor:

Further clarification of the methods and recognition of potential biases would assist in interpretation of the report of patients with central nervous system toxoplasmosis by Porter and Sande (Dec. 3 issue).1 In their study, “a patient was considered to have toxoplasmosis if there was histologic proof of central nervous system infection at either biopsy or autopsy, in addition to the appearance of brain lesions on CT [computed tomography] or MRI [magnetic resonance imaging] consistent with a diagnosis of toxoplasmosis that improved after specific treatment.” However, it appears that only 29 patients had histologic proof of infection. Therefore patients apparently were included who had either histologic proof of infection or consistent neuroradiologic findings with improvement on therapy.

Thirteen patients had negative assays for serum antitoxoplasma IgG antibodies. One might question the certainty of diagnosis in the nine such persons who did not have histologically proved toxoplasmosis. The finding that four (22 percent) with histologically confirmed disease lacked serum antibodies should be interpreted with the recognition that patients lacking antibodies would be more likely to undergo biopsy, as noted in the introduction. . . .

Robert S. Klein, M.D.
Montefiore Medical Center, Bronx, NY 10467

1 References

1. 1

   Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med 1992;327:1643-1648
   Full Text | Web of Science | Medline

To the Editor:

In the report by Porter and Sande the data on survival rates reflect a heterogeneous group of patients comprising not only those who were treated with zidovudine (AZT) or other antiretroviral agents but also those who were not, particularly if they were given a diagnosis during the first half of the 1980s. Because of the known beneficial effect of zidovudine on the survival of patients with advanced HIV disease,1 it would be helpful to break down the survival data according to whether patients were treated with antiretroviral agents. Otherwise, the relevance of such data to present-day patients with advanced HIV disease who are taking these agents is open to question.

The data on relapse rates need to take into account the concurrent administration of drugs with antitoxoplasma activity, such as trimethoprim-sulfamethoxazole,2 which are also routinely used as prophylaxis against Pneumocystis carinii. An analysis of the adverse effects of antitoxoplasma drugs on the bone marrow should clarify the frequency of the concurrent use of other potentially myelosuppressive agents, such as zidovudine and trimethoprim-sulfamethoxazole.

Farrin A. Manian, M.D.
St. John's Mercy Medical Center, St. Louis, MO 63141

2 References

1. 1

   Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987;317:185-191
   Full Text | Web of Science | Medline

2. 2

   Beaman MH, Luft BJ, Remington JS. Prophylaxis for toxoplasmosis in AIDS. Ann Intern Med 1992;117:163-164
   Web of Science | Medline

To the Editor:

It appears that Porter and Sande reported only the antitoxoplasma antibody titers obtained at presentation. The early identification and serial evaluation of military personnel infected with HIV afford us the opportunity to follow antitoxoplasma antibody titers in individual patients for a period of several years. Our retrospective review suggests that serial measurement of antitoxoplasma antibodies in asymptomatic patients may be useful for predicting clinical toxoplasmosis in patients with increasing immunodeficiency.

Of 1040 patients who were followed at 6-to-12-month intervals beginning in 1986, 202 (19 percent) were positive for antitoxoplasma IgG antibody (titer, >1:16 by immunofluorescence assay; Roche Laboratories). Twenty-two seropositive patients had CD4+ lymphocyte counts of ≤ 200 per cubic millimeter and were therefore considered to be at risk for toxoplasmosis. Central nervous system toxoplasmosis developed in 7 of 10 patients at risk (70 percent) who had either a fourfold rise in antibody titer or at least one titer of ≥ 1:2048. Toxoplasmosis did not develop in any of the 12 patients without these criteria who were at risk. During this period, toxoplasmosis also developed in one patient who was negative for antitoxoplasma antibody. All diagnoses were established either by brain biopsy (three patients) or on the basis of characteristic lesions found on neuroradiologic imaging and a favorable response to therapy (five patients). Thus, a fourfold increase in antibody titer or a single titer of ≥ 1:2048 predicted the development of toxoplasmosis in seven of our eight patients (88 percent).

Previous studies1,2 have detected a significant increase in the antibody titer in only a minority of patients with toxoplasmosis. Since in most instances these antibody measurements were made at the onset of clinical disease, the inability to detect a significant increase in the titer may be attributed either to the sampling of antibody over too short a time or to the presence of advanced immunodeficiency. In most of our patients, a fourfold increase in the titer occurred while CD4+ lymphocyte counts exceeded 200 per cubic millimeter and required a period of one or more years to become apparent.

Although these observations are based on a relatively small number of patients, our data suggest that antitoxoplasma antibody titers measured early in the course of infection with HIV, and at regular intervals thereafter, may help define the subgroup of patients at highest risk for toxoplasmosis. If our data are confirmed by additional studies, serial neuroradiologic imaging or antitoxoplasma prophylaxis may be indicated in these patients.

Anthony LaRocco, Jr., M.D.
John W. Sanders, M.D., M.P.H.T.M.
James W. Myers, M.D.
Naval Hospital, Portsmouth, VA 23708

2 References

1. 1

   Luft BJ, Brooks RG, Conley FK, McCabe RE, Remington JS. Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA 1984;252:913-917
   CrossRef | Web of Science | Medline

2. 2

   Navia BA, Petito CK, Gold JW, Cho ES, Jordan BD, Price RW. Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: clinical and neuropathological findings in 27 patients. Ann Neurol 1986;19:224-238
   CrossRef | Web of Science | Medline

To the Editor:

We share Porter and Sande's surprise at the high rate (16 to 22 percent) of toxoplasmosis in patients with AIDS who have undetectable levels of antitoxoplasma antibodies. If toxoplasmosis is regarded as mainly due to reactivated infection, most of these patients should have substantial antibody levels. We use both enzyme-linked immunosorbent assay (Platelia, Pasteur) and indirect immunofluorescence assay (Toxospot IF, Biomerieux) to assess IgG titers; the results are expressed in International Units per liter.1 Discrepancies between the two methods are unusual.

We confirmed the presence of cerebral toxoplasmosis at autopsy in 43 of 91 patients with AIDS. We identified parasites by histologic or immunocytochemical methods using polyclonal antibody (ICN). All 43 patients were part of a subgroup with antitoxoplasma antibody levels of ≥ 9 IU per liter (80 of 91 patients; 88 percent). Parasites were never found in the 11 seronegative patients. In each case, a minimum of 21 blocks of tissue were sampled plus additional blocks depending on clinical data and the results of computed tomography, so very few cases should have been missed. We also amplified Toxoplasma gondii DNA using the polymerase chain reaction in bronchoalveolar-lavage samples from patients with AIDS. All positive samples (6 of 42) were from patients with measurable antitoxoplasma titers (28 of 42).

We agree that some patients with AIDS can have toxoplasmosis without detectable levels of antitoxoplasma antibodies. Porter and Sande suggested some explanations for this phenomenon. We suggest another -- a decrease in antibodies in patients with advanced AIDS. Early serologic testing might enable us to identify patients at risk for toxoplasmosis.

Our finding that seronegativity has a high predictive value is partly due to the low sensitivity threshold of our serologic methods. Although false positive results can occur, our approach identifies patients who are at very low risk for toxoplasmosis. This is important, since seronegative patients do not require prophylaxis. They need follow-up to monitor for primary toxoplasmosis.

Stephane Bretagne, M.D.
Francoise Gray, M.D., Ph.D.
Universite Paris XII, 94010 Creteil, France

Jean-Marc Costa, M.D.
Institut de Puericulture, 75014 Paris, France

1 References

1. 1

   Niel G, Desmonts G, Gentilini M. Immunofluorescence quantitative et diagnostic serologique de la toxoplasmose: introduction des unites internationales dans l'expression des positivites. Pathol Biol (Paris) 1973;21:157-161
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Klein correctly points out an inconsistency that appears in the Methods section: the study included patients who had histologically proved infection as well as patients who had consistent radiographic findings that subsequently improved with therapy. It was impossible for us to confirm the diagnosis definitively in patients who did not undergo histologic examination. All the patients with negative antibody assays who were tested, however, had the most typical findings of toxoplasmosis seen in our study (multiple lesions on magnetic resonance imaging that improved and a CD4+ cell count of less than 200 per cubic millimeter). Although it is true that patients who lack detectable antibodies are more likely to undergo biopsy, we believe that the results nevertheless demonstrate that the absence of detectable antibodies on immunofluorescence assay does not rule out the disease.

Dr. Manian's remarks about the influence of other concomitantly administered drugs on survival, relapse, and toxicity are valid. At diagnosis, only 17 and 2 patients were taking zidovudine and trimethoprim-sulfamethoxazole, respectively. Many more received these and other potentially toxic medications at various times, but analysis of their long-term effects was impossible in our retrospective report. Since patients with symptomatic AIDS receive an average of more than five prescription medications,1 it is unusual for antitoxoplasma therapy to be administered alone. Therefore, although the rates of adverse drug reactions that we reported no doubt had many causes, they probably accurately reflect the situation faced by physicians treating patients with advanced HIV infection and toxoplasmosis.

Both LaRocco et al. and Bretagne et al. present interesting results. Fifteen patients in our study had follow-up antibody titers after diagnosis, but no consistent increase was observed. The theory of Bretagne et al. that antitoxoplasma antibodies may decrease in advanced HIV infection may explain both the small number of seronegative patients and the lack of consistent increase in titer when measured only at the time of diagnosis. Despite this, it remains true that the majority of patients with AIDS and detectable antitoxoplasma antibodies do not have active disease2. We hope that improving diagnostic methods3-5 will decrease our reliance on traditional serologic methods for the diagnosis of toxoplasmic encephalitis in AIDS.

Steven B. Porter, M.D., Ph.D.
Merle A. Sande, M.D.
San Francisco General Hospital, San Francisco, CA 94110

5 References

1. 1

   Greenblatt RM, Hollander H, McMaster JR, Henke CJ. Polypharmacy among patients attending an AIDS clinic: utilization of prescribed, unorthodox, and investigational treatments. J Acquir Immune Defic Syndr 1991;4:136-143
   Web of Science | Medline

2. 2

   Grant IH, Gold JWM, Rosenblum M, Niedzwiecki D, Armstrong D. Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS. AIDS 1990;4:519-521
   CrossRef | Web of Science | Medline

3. 3

   Parmley SF, Goebel FD, Remington JS. Detection of Toxoplasma gondii in cerebrospinal fluid from AIDS patients by polymerase chain reaction. J Clin Microbiol 1992;30:3000-3002
   Web of Science | Medline

4. 4

   Hitt JA, Filice GA. Detection of Toxoplasma gondii parasitemia by gene amplification, cell culture, and mouse inoculation. J Clin Microbiol 1992;30:3181-3184
   Web of Science | Medline

5. 5

   Angel S, Maero E, Blanco JC, et al. Early diagnosis of toxoplasmic encephalitis in AIDS patients by dot blot hybridization analysis. J Clin Microbiol 1992;30:3286-3287
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Stuart Brody. (1996) Continued lack of evidence for transmission of human immunodeficiency virus through vaginal intercourse: A reply to Carey and Kalichman. Archives of Sexual Behavior 25:3, 329-337
   CrossRef