• FIV and Toxoplasmosis

  • 1. Introduction

  • 2. Toxoplasmosis and FIV

  • 3. Diagnosis

  • 4. Treatment

  • 5. Protective Measures


  • 1. Introduction

  • Toxoplasma gondii is a protozoan parasite that can infect both humans and cats. Felines are the natural host of the organism, which is propagated by the shedding of “ oocysts” in cat feces during a one to two week period following the phase of active, or “acute,” infection in the cat. Eating the infected tissue of intermediate hosts is the primary means of acquisition for cats.

  • Toxoplasmosis is tied in most people's minds with its effect on people--specifically, pregnant women, because of potential harm to the fetus. Never mind that research has pretty convincingly demonstrated that cats are not a significant source of infection of pregnant women. A study conducted in six large European cities and published in the July 2000 issue of the British Medical Journal found "absolutely no association between toxoplasmosis and having a cat, litterbox cleaning or having a cat that hunts"[1].

  • Toxoplasmosis is a common feline infection. 31.5% of cats in a University of Colorado study representing 12 different regions of the U.S. tested positive for exposure to the parasite. The highest incidence was found in the Northeast, where 43.5% tested positive [2]. Toxoplasmosis is an actual threat only to kittens, because of their underdeveloped immune systems. When it produces symptoms at all in adult cats, they are usually variable and of short duration: transient fever, diarrhea, swollen glands, and/or flu-like symptoms. Healthy cats–and healthy people– quickly fight off acute toxoplasmosis infection. The organism encysts itself within body tissue, where it remains permanently suppressed by the immune system for the rest of an individual’s life. . . .

  • 2. Toxoplasmosis and FIV

  • . . . that is, unless the immune system is seriously dysfunctional and unable to keep it suppressed. Toxoplasmosis that has become inactive is referred to as “chronic.” Toxoplasmosis that breaks out anew in immune-suppressed individuals is referred to as “reactivated.”. Reactivated toxoplasmosis is a life-threatening illness for HIV-infected people. It is estimated that as high as 10% of deaths from HIV are due to toxoplasmosis. No reliable statistics statistics on mortality exist for FIV+ cats. An early study confirmed that innoculation with FIV was sufficient to reactivate chronic infection [14], but it is not known how common reactivated infection is relative to new, first-time infections. Reactivated toxoplasmosis can attack the nervous system, the respiratory tract, the eyes, the liver, the intestines– almost anywhere in the body–producing serious illness that will almost certainly be lethal if left untreated and that may still prove lethal even with treatment. However, research to date indicates that FIV+ cats do not shed oocysts for longer periods or in greater numbers than FIV- cats and that repeat shedding does not occur in reactivated infections[13]. In HIV patients, the CNS is the most common locale of the primary life-threatening pathologic lesion due to reactivated infection; in FIV+ cats, one study found the lungs and bronchii (“interstitial pneumonia”) to be the most common life-threatening target, with hepatic necrosis the other major finding of post-mortem studies [11].

  • It is well-established that FIV+ cats are prone to life-threatening infection with toxoplasmosis. Even cats whose clinical health and bloodwork give an appearance of immune competence and in whom FIV disease is not well advanced handle a new toxoplasmosis infection with much more difficulty than other cats [4][11]. Once T gondii proliferation begins to occur, the parasite actually serves as a cofactor in enhancing the immune deficiency of the infected cat, thereby creating conditions to further its own advancement. One study hypothesized “ that T. gondii may cause . . . production of TNF [tumor necrosis factor-alpha] by feline macrophages and, therefore, an increased activation of FIV within lymphocytes. This begins a cycle wherein T. gondii replication causes increased TNF production that leads to increased FIV activation, which causes the dysfunction of CD4 cells and a resulting immune dysfunction that will allow even greater amounts of T. gondii replication” [12].

  • The problem of co-infection of toxoplasmosis and FIV was illustrated in a recent Nigerian study involving a comparable (at least superficially) group of siamese cats. One group was FeLV+. One group was FIV+. One group was uninfected with either. The immunosuppressed groups scored differently on antibody titres, showing poorer initial response with immediate-response antibodies (IgM), but comparable response with longer- term antibodies (IgG). By Day 24, however, the IgG response had fallen off in the immunosuppressed cats but was still on the rise in the negative cats[5]. Another study found that FIV+ cats also had a greater difficulty mounting an effective cell-mediated immune response to T gondii because of the immune imbalance induced by the virus: excessive elevation of the cytokine (immune-signaling protein) Interleuken-10 (IL-10) led to suppression of the cytokines IL-2 and IL-12, which are necessary to maturing and proliferative response of T cells [6].

  • Dr. Michael Lappin, an authority on feline toxoplasmosis, has theorized that the book is perhaps still being written on toxoplasmosis in FIV+ cats. "It has long been hypothesized," he notes, "that FIV-coinfected cats have . . . long-term activated infection . . ." [3]. This activated infection may show itself by degrees over time, as well as by a sudden, violent onset. Because most FIV+ cats who die from causes not clearly understood are not post-mortemed for cause of death, toxoplasmosis may be underdiagnosed and underappreciated as a cause.

  • 3. Diagnosis

  • A number of tests exist for detection of toxoplasmosis, and infected tissue can sometimes be examined microscopically. But the Elisa test for the presence of toxoplasma gondii, familiarly known as a “toxo titer,” is by far the most common. The test determines the host's antibody response to the organism by measuring levels of two toxoplasmosis-specific immunoglobulins, IgG and IgM. While the figures reported by the test are straight forward and simple, establishing a diagnosis is not. As pointed out by Dr. Lappin,“[N]o test can document clinical feline toxoplasmosis” [3].Serological evidence is complicated and ambiguous, requiring thorough knowledge on the part of the interpreter. Clinical signs of disease, exclusion of other causes, and positive response to treatment must be factored in [7]. Yet many practicing veterinarians have never seen toxoplasmosis in a cat with FIV. Although laboratories doing toxo titers commonly offer interpretive models for a variety of findings in their reports, these findings often cover only acute first-time infections and chronic (carrier-state) infections; they do not necessarily offer interpretive criteria for recognizing reactivated infection.

  • The fact is, the serological profile for an immune-suppressed cat with well-advanced FIV infection is different from that of a cat which is not immune-suppressed. The important variables are (1) When the test is given relative to the onset of acute infection; (2) What the IgM and IgG figures are in the absolute and relative to one another. A negative IgM finding does not eliminate an ordinary cat from a diagnosis of acute infection because in ordinary cats the IgM rises and falls back to zero rapidly. If the test is given too long after the onset of infection, the IgM will be negative. In an immunosuppressed cat with reactivated toxoplasmosis, the IgM will almost always be positive because characteristically the spike persists longer than four months. FIV-naive cats with acute toxoplasmosis infection typically have high and rising IgG numbers. However, since that IgG number shows increase only for several weeks and since high numbers may persist for years, diagnosis of acute infection based on IgG alone is unreliable. Conversely, FIV cats tend not to show high or rising IgG numbers characteristic of an FIV-naive cat with acute infection. Evidently, in ordinary cats there is an antibody class-shift from IgM to IgG. In a cat with advanced FIV, the class shift is retarded by immune-suppression. The IgG may not rise at all despite the fact that activated toxoplasmosis exists.

  • In practical terms, a vet inexperienced in working with immune-suppressed animals with toxoplasmosis may force the facts he sees on the lab report to fit the model of chronic or acute disease without realizing that a third model exists for explaining the figures he is seeing–namely reactivated acute infection. He may, for instance, interpret a relatively low IgG as evidence of the absence of active infection. Or he may interpret the presence of IgM as evidence of the presence of active infection.

  • 4. Treatment

  • The antibiotics clindamycin or the combination of pyrimethamine and sulfadiazine are customarily used to treat people with acute toxoplasmosis, whether an original or reactivated infection. Clindamycin is also effective against toxoplasmosis infection in cats, although in one study of ocular toxoplasmosis, clindamycin actually hindered recovery, possibly by inhibiting natural phagocyte function [8]. While pyrimethamine and sulfadiazine are a highly effective combination in cats too, pyrimethamine magnifies the effect of the sulfa drug and creates a possibility of severe sulfa drug reaction. For this reason a combination of trimethoprim and sulfadiazine is used, although clindamycin is usually the drug of choice. Other drugs may be prescribed in addition or instead to target particular sites of infection. Particularly disturbing about the previously mentioned Nigerian study is that the FIV+ cats did not respond effectively to standard clindamycin therapy; the FIV- cats did. Is this because a suboptimal immune system is unable to provide a needed assist, or is it because clindamycin depresses priming of phagocytes (macrophages) with interferon-gamma by already impaired helper T cells [8]? Whatever the explanation, the failure of clindamycin to affect mortality in FIV+ cats was also established by an earlier study[11]. Whether a riskier, more aggressive treatment regimen of pyrimethamine and sulfadiazine would have made a difference is an intriguing but unanswerable question..
  • It is standard medical practice for people with HIV to go on anti-toxoplasmosis drugs once their count of CD4+ lymphocytes (the immune cell whose loss to FIV infection accounts most directly for loss of immune function) falls below 100/mm3. They stay on medication for life or until their CD4 + count improves sufficiently. Clindamycin alone is not an effective suppressor drug. Instead, pyrimethamine and sulfadiazine are administered–at 50% the dosage level used against acute infection. If sulfa drugs cannot be tolerated, clindamycin is substituted, but in combination with the pyrimethamine.
  • Published research is silent on the question of whether a similar strategy involving trimethoprim and sulfadiazine is workable in the case of severely immune deficient cats who are known to harbor toxoplasmosis as chronic carriers. The point is anything but academic. 50% of the human population are estimated to be chronic carriers; there is no reason to think that the figure is less in cats–it may be higher. (Studies have produced figures ranging from 30 to 80%.) Since specialized CD4+ lymphocyte testing is done at only a handful of university-associated veterinary schools, CD4+ counts cannot be widely used as a trigger. And it is doubtful that experimental work has even been done to establish the efficacy of a suppressor dosage. As a practical matter, many pet owners are not looking to put their pets on antibiotics for life to guard against a hypothetical threat; and sulfa drugs do have possible short- and long-term side effects, though the long-term effects are not life-threatening.

  • 5. Protective Measures

  • Things an owner can do:
  • --He can keep a known FIV+ cat, especially one with advanced disease, indoors and feed a quality cooked diet to minimize the possibility of exposure.
  • --Bovine lactoferrin has shown some ability to exert a protective effect against toxoplasma gondii[9][10]. Regular supplementation might have value.
  • --He can, if he wishes, invest in a one-time toxo titer to ascertain whether his cat is a chronic carrier. Forewarned is forearmed.
  • --He can monitor his cat’s condition thoughtfully for clues that significant immune deficiency has set in: e.g., stomatitis, ocular disease, recurrent URI, fungal infections, and the like.
  • --He can ask for a copy of any lab reports on toxoplasmosis testing so that he has a permanent record of what his vet was basing the diagnosis on.
  • --In conjunction with his veterinarian, he could at least discuss the possibility of initiating antibiotic therapy specific to toxoplasmosis while waiting for test results to arrive–which may take several weeks.
  • --In an FIV+ cat, toxoplasmosis is not a mild illness; it is a severe one producing severe symptoms. A severe infection that is unresponsive to an initial therapeutic program should immediately bring to mind the possibility of toxoplasmosis.
  • --He can sound out his veterinarian to find out whether he has knowledge of or experience dealing with toxoplasmosis in immune-suppressed cats and whether he is confident of his ability to interpret laboratory results in that light. If not, the owner might suggest a consult with someone more knowledgeable–for instance a veterinary internist.
  • --If a given illness responds to therapy specific to toxoplasmosis, he can discuss with his veterinarian whether to initiate half-dosage maintenance therapy on an experimental basis once (or if) the toxoplasmosis has been effectively controlled

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  • References

  • [1] Cook AJ, Gilbert RE, Buffolano W, Zufferey J, Petersen E, Jenum PA, Foulon W, Semprini AE, Dunn DT. Sources of toxoplasma infection in pregnant women: European multicentre case-control study. European Research Network on Congenital Toxoplasmosis. BMJ. 2000 Jul 15;321(7254):142-7.
  • http://www.ncbi.nlm.nih.gov/pubmed/10894691?

  • [2] Vollaire MR, Radecki SV, Lappin MR. Seroprevalence of Toxoplasma gondii antibodies in clinically ill cats in the United States. Am J Vet Res. 2005 May;66(5):874-7.
  • http://www.ncbi.nlm.nih.gov/pubmed/15934615?.

  • [3] Lappin M. CVT update: Feline toxoplasmosis. In Bonagura JD, Kirk RW, editors. Kirk's Current Veterinary Therapy. XII Small Animal Practice. Philadelphia: Saunders, 1995:309-14.

  • [4] Lappin MR, George JW, Pedersen NC, Barlough JE, Murphy CJ, Morse LS. Primary and secondary Toxoplasma gondii infection in normal and feline immunodeficiency virus-infected cats. J Parasitol. 1996 Oct;82(5):733-42.
  • http://www.ncbi.nlm.nih.gov/pubmed/8885881?

  • [5] E. A. Okewole, and M. O. Akpan. Clinical feline toxoplasmosis: parasitological, haematological and serological findings in retroviral infected and uninfected. VETERINARSKI ARHIV 72 (2), 67-79, 2002.
  • http://www.vef.hr/vetarhiv/papers/72-2/okewole.pdf.

  • [6] Levy, J. K., Liang, Y. H., Ritchey, J. W., Davidson, M. G., Tompkins, W. A., Tompkins, M. B. Failure of FIV-infected cats to control Toxoplasma gondii correlates with reduced IL2, IL6, and IL12 and elevated IL10 expression by lymph node T cells. Veterinary Immunology and Immunopathology, 2004 (Vol. 98) (No. 1/2) 101-111.
  • http://www.cababstractsplus.org/google/abstract.asp?AcNo=20043031672

  • [7] Lappin MR. Feline toxoplasmosis: interpretation of diagnostic test results. Semin Vet Med Surg (Small Anim). 1996 Aug;11(3):154-60.
  • http://www.ncbi.nlm.nih.gov/pubmed/8942211?

  • [8] Davidson M, Lappin M, Rottman J, Tompkins M, English R, Bruce A, Jayawickrama J. Paradoxical Effect of Clindamycin in Experimental, Acute Toxoplasmosis in Cats. Antimicrobial Agents & Chemotherapy, June 1996, p. 1352–1359 Vol. 40, No. 6.
  • http://aac.asm,org/cgi/reprint/40/6/1352.pdf

  • [9] Omata Y, Satake M, Maeda R, Saito A, Shimazaki K, Yamauchi K, Uzuka Y, Tanabe S, Sarashina T, Mikami T. Reduction of the infectivity of Toxoplasma gondii and Eimeria stiedai sporozoites by treatment with bovine lactoferricin. J Vet Med Sci. 2001 Feb;63(2):187-90.
  • http://www.ncbi.nlm.nih.gov/pubmed/11258458?

  • [10] Isamida T, Tanaka T, Omata Y, Yamauchi K, Shimazaki K, Saito A. Protective effect of lactoferricin against Toxoplasma gondii infection in mice. J Vet Med Sci. 1998. Feb;60(2):241-4.
  • http://www.ncbi.nlm.nih.gov/pubmed/9524950?

  • [11] Davidson MG, Rottman JB, English RV, Lappin MR, and Tompkins MB. Feline Immunodeficiency Virus Predisposes Cats to Acute Generalized Toxoplasmosis. American Journal of Pathology, Vol. 143, No. 5, November 1993: 1486-97.
  • http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1887187&pageindex=1

  • [12] Lin DS, Bowman DD, Jacobson RH. Immunological changes in cats with concurrent Toxoplasma gondii and feline immunodeficiency virus infections. J Clin Microbiol 1992, 30:17-24.
  • http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1346403

  • [13] Lappin MR. Pet Ownership by Immunocompromised People. Clinical Suppl Compend Contin Educ Pract Vet Vol. 24, No. 5(A), 2002 (Bayer Zoonosis Symposium, 2002 TNAVC).

  • [14] Lappin MR, Gasper PW, Rose BJ, Powell CC. Effect of primary phase feline immunodeficiency virus infection on cats with chronic toxoplasmosis. Vet Immunol Immunopathol. 1992 Dec;35(1-2):121-31.
  • http://www.ncbi.nlm.nih.gov/pubmed/1363007?

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