toxoplasmosis in hiv-infected patients - springer · most patients with cerebral toxoplasmosis...

Toxoplasmosis in HIV-Infected Patients

Juan Ambrosionia, Míriam J. Alvarez-Martínezb, Joan Berenguerc and José M. Miróa*aInfectious Diseases Service, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, SpainbMicrobiology Service, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, SpaincRadiology Service CDIC, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain

Definition

Toxoplasmosis is the infection caused by Toxoplasma gondii, an obligate intracellular protozoan thatbelongs to the phylum Apicomplexa. In immunocompromised patients, such as AIDS patients with lowCD4 cell count, reactivation of latent disease can cause life-threatening encephalitis. The disease usuallypresents with a focal neurological deficit associated with the formation of multiple Toxoplasma abscesses.Treatment requires combination of anti-toxoplasmic drugs and its continuation as suppressive therapyuntil immune reconstitution occurs.

Biology, Epidemiology, and Transmission

BiologyToxoplasmosis is an endemic infection of worldwide distribution caused by Toxoplasma gondii, anintracellular protozoan of the order Coccidia, phylum Apicomplexa. Toxoplasma can present in threeforms in its life cycle: the oocyst, tissue cyst, and tachyzoite.

The infection is acquired orally by ingestion of contaminated food or water oocysts or by ingestion ofundercooked meat containing tissue cysts. The infection can also be acquired through the vertical route(mother-to-child transmission). Once inside the body, the cysts and oocysts release tachyzoites, whichhave the ability to affect intestinal epithelial cells, to invade the mesenteric lymph nodes, and then via thebloodstream to spread to different tissues. Tachyzoites are responsible for the clinical presentation of acutetoxoplasmosis; they replicate intracellularly, infesting and destroying cells until the immune systemdevelops the appropriate response. Subsequently, the parasites that survive this immune response encystin various tissues, including the brain, the retina, skeletal muscle, the myocardium, and occasionally thelungs, where they can stay in a quiescent form for life. Years later, if T cell-mediated immunity isimpaired, the cysts in tissues may break releasing tachyzoites, which produce a reactivation of theinfection.

Oocysts develop in the cells of the intestinal mucosa of cats, domestic cats, and other wild felines, likethe leopard and lions being the definitive host. Cats become infected by ingesting cysts in the raw meat ofinfected animals or oocysts present in feces eliminated by other felines. After 1–2 weeks, oocyst sheddingceases and rarely restarts. Oocysts must sporulate to become infectious, a process that is favored by heatand humidity, conditions typically found in litter boxes used to deposit cat feces in homes. Sporulatedoocysts can remain infectious for more than 1 year.

Tissue cysts can be found in the cells of almost any organ of the host. Maintaining the cysts in aquiescent state and controlling any breakage to avoid the periodical release of tachyzoites is a processmediated by T cells and cytokines. Thus, in individuals previously infected and with T cell impaired

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*Email: [email protected]

Encyclopedia of AIDSDOI 10.1007/978-1-4614-9610-6_405-1# Springer Science+Business Media New York 2015

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immunity, residual cysts are an important source of tachyzoites that may escape immune control.However, cases of retinal involvement can occur in immunocompetent and immunocompromisedindividuals, which are presumed to be mediated by additional mechanisms to those described.

Epidemiology and TransmissionThe most common route of transmission of T. gondii to humans is the eating of raw or undercooked porkor lamb meat. In theory, any animal that ingests infected oocysts or tissue cysts can become infected withtoxoplasmosis. If the meat is not cooked above 60 �C or frozen below �20 �C, cysts remain viable(Montoya and Liesenfeld 2004).

The three main forms of transmission to humans of T. gondii are:

– Ingestion of oocysts eliminated by cats or eating undercooked meat containing cysts– Transplacental transmission– Infection through blood transfusion or organ transplant

Cats living in a strictly domestic environment have little chance of spreading infection. Congenitalinfection occurs if the mother acquires a toxoplasmic infection during pregnancy (primary infection).However, there have been cases of vertical transmission in HIV-positive womenwith latent toxoplasmosisafter reactivation of the parasite.

Clinical Presentation

Primary infection with T. gondii is asymptomatic in most immunocompetent individuals. Up to a third ofcases, and more frequently in children, may present an adenitis, a flu-like or a mononucleosis-likesyndrome.

Most cases of toxoplasmosis with central nervous system (CNS) involvement associated to AIDS or toother states of severe cellular immunosuppression are the consequences of the reactivation of a previousinfection in seropositive individuals. Clinical manifestations depend on where in the CNS the infection isreactivated and the intensity of the local inflammatory response, which can vary according to the CD4+

T cell count of the patient.The clinical description given below is observed in patients with AIDS, who represent the vast majority

of cases of cerebral toxoplasmosis. Other patients with cellular immunodeficiency (such as stem celltransplant recipients) have extra-neurological forms, such as lung disease (pneumonitis) or disseminateddisease, more often than patients with AIDS, but in the case of brain involvement, the clinical presentationis very similar.

Neurological DiseaseAbout 50 % of patients with intracerebral infection present with headaches, confusion, and alteredconsciousness. The beginning of the disease can be insidious or abrupt. Up to 30 % of patients sufferseizures as the initial manifestation, and 50–60 % show signs of focal neurological deficiency. High feverwith chills, neck stiffness, and other meningeal signs are unusual and should suggest other diagnoses(Miro et al. 2008).

Since cerebral toxoplasmosis is often multifocal, intracerebral masses are very destructive and inflam-matory and can develop in any part of the brain, although the cortical-subcortical union of the cerebralhemispheres is the most frequent site. Virtually, any neurological syndrome can develop and producemotor or sensory deficits, among other focal deficits. The brainstem, the basal ganglia, and the cerebellum


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may also be affected, and patients can present with movement disorders, neuropsychiatric findings, andvarying levels of depression in their level of consciousness, including coma.

Hemiparesis is the most common focal deficit, but there may be cranial nerve injuries, focal seizures,aphasia, visual loss, ataxia, dysmetria, tremors, hemiballismus, and other extrapyramidal signs. Theinvolvement of the spinal cord can produce transverse myelitis or conus syndrome. Hydrocephalus,brain hemorrhage, and choroiditis may also occur less frequently (Antinori et al. 2004).

Extra-neurological Disease (Isolated or Concomitant to Cerebral Involvement)In addition to the CNS, reactivation foci can also be observed in other organs, most frequently the lungs inform of pneumonitis and the eyes as chorioretinitis, concomitantly or not with brain involvement. Sinceparasites may form cysts in any organ, and since recurrent parasitemia can occur in association withreactivations, new parasitic implants may occur in other organs, and thus the clinical manifestations ofextracerebral toxoplasmosis can be quite diverse. In fact, autopsy studies often show unrecognized multi-organic involvement; up to 50 % of patients with no concomitant CNS disease have extracerebral lesions,but these are frequently subclinical (Rabaud et al. 1994).

Ocular DiseaseOcular disease is probably the most common clinical manifestation of extracerebral HIV-associatedtoxoplasmosis. In 30–60 % of chorioretinitis cases, encephalitis is also present. Conversely, relativelyfew patients with encephalitis present concomitant chorioretinitis. Visual symptoms due to Toxoplasmaretinitis include loss of visual acuity and myodesopsia. Funduscopic examination reveals areas of yellow-white-colored necrotizing retinitis, sometimes with hemorrhage and vasculitis. Lesions are predominantlyunilateral. Fluorescein angiography shows hyperfluorescence from the periphery and progressing towardthe center of the lesions. Toxoplasma retinitis must be differentiated from retinitis caused by cytomega-lovirus, varicella zoster virus, syphilis, and fungi, including Pneumocystis jirovecii retinitis.

Pulmonary DiseasePulmonary manifestations of toxoplasmosis represent up to 35 % of extrapulmonary forms. Fever anddyspnea are the most common symptoms, while cough and sputum may be missing. Chest x-rays usuallyshow bilateral diffuse infiltrates in the lungs (similar toPneumocystis jiroveciiRXpattern).Multiple nodularinfiltrates have been also reported. Typically, there is a massive increase in lactate dehydrogenase (LDH).The diagnosis can be established by examining the bronchoalveolar lavage, which reveals T. gondiitrophozoites detected by special staining or by molecular biology, i.e., polymerase chain reaction (PCR).

Other Organ InvolvementAlong with pneumonitis and chorioretinitis, extracerebral manifestations have been reported in virtuallyevery organ and even sepsis-like clinical presentations in severely immunocompromised patients(generally non-AIDS immunosuppressed patients) with elevated massive LDH increases, to whichmolecular biology techniques, such as PCR performed in blood, are highly sensitive and specific inestablishing a diagnosis.

Central Nervous System Involvement During Acute Toxoplasmic InfectionAlthough it is much less common, the CNS can be affected during the Toxoplasma primary infection.Patients with primary infection and with severe forms of cellular immunosuppression can produce severevisceral manifestations and disseminated infection, including pneumonitis, myositis, myocarditis,orchitis, and encephalitis, manifested in the form of diffuse involvement or intracerebral masses.


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Diagnosis

Clinical Suspicion

Anatomical Neuroimaging (CT/MRI)When cerebral toxoplasmosis is suspected, neuroimaging must be performed urgently. In most clinicalseries, 10–43 % of patients with toxoplasmic encephalitis have a solitary parenchymal injury, demon-strated by computed tomography (CT); the remaining patients have more than one injury. It is unusual tohave a negative CT scan in symptomatic patients (3–10 %).

The most typical presentation of cerebral toxoplasmosis is the presence of multiple focal intracerebrallesions (Fig. 1), which are detected more often with magnetic resonance imaging (MRI), as it is more sensitivethan CT. With MRI, over 80 % of patients are found to have multiple lesions. Therefore, if there is a singlelesion on CT, and this is confirmed byMRI, a lymphoma or other causes of focal injury associated with AIDS(as tuberculoma or histoplasmoma) should be ruled out. In cerebral toxoplasmosis, injuries are more oftenbilateral and present contrast ring enhancement (80–90 % cases) and produce a mass effect and edema. Theyoften develop in the basal ganglia, the thalamus, or the corticomedullary junction of the cerebral hemispheres.

However, no presentation using CTor MRI is considered absolutely diagnostic of cerebral toxoplasmosis.Lymphoma and toxoplasmosis can produce very similar imaging, for example, multifocal disease andcontrast reinforcing ring lesions can be seen in up to 40–50% of AIDS patients with primary CNS lymphoma(PCNSL). Hemorrhage before treatment may sometimes be seen in toxoplasmosis, and this finding can helpdifferentiate toxoplasmosis from lymphoma. Furthermore, a “target sign” (an eccentric nodule inside anenhancing ring) is highly suggestive of toxoplasmosis (Smith et al. 2008). Advanced MRI techniques canalso help differentiate diagnoses. Lymphoma lesions show reduced diffusion in diffusion-weighted imaging,and MR perfusion shows an elevated relative cerebral blood volume. HMR spectroscopy in lymphomaindicates elevated peaks of choline.

Fig. 1 Toxoplasmosis in a 55-year-old female. Panel (a) Post-contrast axial T1-weighted MRI demonstrating multiplehemorrhagic enhancing lesions (nodular and ring enhancing) with edema. Panel (b) Non contrast axial T1-weighted MRItaken 4 months later showing marked decrease in the number, size, and edema of lesions with residual calcified images (greenarrows)


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Functional Neuroimaging (SPECT/PET)In an effort to clarify the noninvasive diagnosis of cerebral toxoplasmosis (which is always presumptive),other imaging techniques have been evaluated, particularly to help to differentiate it from PCNSL. Single-photon emission CT (SPECT) using thallium 201 and positron emission tomography (PET) using marked2-fluorodeoxyglucose are useful techniques. In both techniques, infections (such as cerebral toxoplas-mosis) are observed as cold or hypometabolic lesions, while lymphoma behaves like a hypermetaboliclesion. Both techniques are insensitive to small lesions, less than 8 mm, and, although rare, false positivesand false negatives may occur. Although these techniques are useful to diagnose a PCNSL, they are notnecessary to confirm toxoplasmosis. If cerebrospinal fluid (CSF) is obtained, these functional imagingtechniques can be combined with molecular techniques, such as PCR for toxoplasmosis or the Epstein-Barr virus (EBV), in order to make reliable differential diagnoses between cerebral toxoplasmosis andprimary CNS lymphoma (Antinori et al. 1999).

Therapeutic Trial as a Diagnostic Method and Indication to Brain BiopsyFrom a practical perspective, however, most of these patients undergo an empirical trial of anti-Toxo-plasma therapy for 10–14 days. If after this period there is no clinical or radiological improvement, a brainbiopsy should be performed. Most patients with cerebral toxoplasmosis (65–90 %) respond readily to atreatment of two drugs: pyrimethamine, with either sulfadiazine, or clindamycin, with response rates ofover 90 % within 2–3 weeks (Fig. 2). Brain biopsy has been transformed over the years into a procedurenow only reserved for a limited number of clinical situations, particularly for those patients who do notrespond to empirical treatment or who have an alternative diagnosis suggested by imaging or microbi-ological CSF findings.

Fig. 2 Cerebral toxoplasmosis. Panel (a) Post-contrast axial CT showing a large deep lesion in the left hemisphere withsignificant edema, mass effect, and contrast ring enhancement. A second smaller lesion seems to be present behind the biggerone. Panel (b) Post-contrast axial T1-weighted MRI taken 3 weeks after anti-Toxoplasma treatment showing a markedreduction in lesion size, mass effect, and edema


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Microbiological DiagnosisThe definitive diagnosis of the cause of toxoplasmosis encephalitis is performed by the demonstration oftachyzoites in the brain tissue (Fig. 3). However, as already mentioned, because of the invasiveness ofbrain biopsies and the lack of experience in many centers, this option is limited to rare cases in whichdiagnosis cannot be confirmed by other techniques or in which there has been no response to therapeutictreatment.

Until the advent of molecular biology techniques, the etiologic diagnosis of toxoplasmosis was madealmost exclusively by serology. However, if the patient presents severe immunodeficiency, serology mayfail or give misleading results, and there have been reports of a lack of Toxoplasma IgG response in serumin HIV-positive patients. However, in Western Europe and the United States, undetectable levels of IgGare very rare in determinations performed in reference laboratories. The presence of IgM anti-Toxo-plasma, however, is difficult to detect in HIV-positive patients; and, since in most cases cerebraltoxoplasmosis is caused by reactivations, it has limited value (Marcos et al. 2008).

Anti-Toxoplasma IgG detection in CSF is positive in 30–70 % of patients with toxoplasmic enceph-alitis, although this alone does not constitute a diagnosis of brain disease. It does, however, have a highspecificity when clinical presentation is also suggestive. Moreover, despite the detection of intrathecalIgG production being very useful, obtaining CSF is not always possible. In many patients with suspectedtoxoplasmosis, CSF extraction is avoided due to the risk of herniation, and in many centers it is not part ofthe routine diagnostic procedures for cerebral toxoplasmosis. If it is obtained, CSF frequently does notshow any significant alteration, since these lesions are frequently not in contact with the subarachnoidspace (Miro and Alvarez-Martinez 2013).

Fig. 3 Toxoplasma encephalitis in humans (AIDS related) – #LSHTM. Panel (a) Tachycyst of T. gondii in brain 100 �(arrows) – hematoxylin and eosin stain. Panel (b) Tachycyst of T. gondii (arrows) at bigger magnification – hematoxylin andeosin stain


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Molecular diagnostic techniques are not exempt from difficulties either. The main problem for theamplification of the toxoplasmic genetic material by PCR techniques is the absence of standardizedprotocols. Various types of PCR have been used: conventional PCR, final-time PCR (semi-nested andnested formats), real-time PCR, and PCR followed by oligochromatography. Likewise, several geneshave been used as T. gondii target amplification. The B1 is the most widely used gene, having 35 copies inthe genome, and also the most stable. Other genes used as targets are the P30 gene, a uni-copy geneencoding the major surface antigen; rRNA, encoding the small subunit ribosomal RNA, with 110 copiesin the genome; the fragment 529 bp with 300 copies per genome, the genes encoding a-tubulin andb-tubulin; and the DNA repetitive noncoding fragment TGR1E.

In addition to CSF, PCR can be also performed in the bronchoalveolar lavage, the vitreous and aqueoushumor, pleural and peritoneal fluid, bone marrow aspirates, peripheral blood, and affected tissues, such asthe brain.

Until the development of PCR-based techniques, brain biopsy was the gold standard for diagnosisconfirmation. Currently, the diagnosis is confirmed by PCR from blood or preferably from CSF,preventing the morbidity of intraoperative biopsy. The sensitivity of PCR blood is 16–86 %, dependingon the type of test used.With CSF, sensitivity is also very variable, from 17% to 100%. For both samples,the sensitivity decreases dramatically if the patient has previously received anti-Toxoplasma treatment.Specificity of CSF PCR is higher than 90 %. Despite the variable sensitivity, the high specificity and thehigh positive predictive value of CSF PCR make it a very useful technique in the diagnosis of focal brainlesions in immunosuppressed patients with clinical and radiological suspicion. It must be remembered,however, that a positive PCR for T. gondii in the blood does not mean that the intracerebral process has thesame etiology. Indeed, multiple opportunistic infections in extremely immunosuppressed AIDS patientsare not unusual.

The most common form of extracerebral and extraocular toxoplasmosis in immunocompromisedincluding HIV-infected patients is lung infection. Detection of T. gondii by PCR in lung tissue samplesor bronchoalveolar lavage has a sensitivity and specificity of 100 % in these cases. In the diagnosis ofdisseminated forms, detection by PCR in blood has a sensitivity and specificity of close to 100 %. Inocular toxoplasmosis, DNA detection of the parasite in the aqueous humor is less sensitive than localantibody detection; indeed, PCR has a sensitivity of 18–37%. However, when the diagnosis is made in thevitreous humor, the sensitivity approaches 100 %.

Therefore, despite the lack of standardization for molecular diagnostic methods for toxoplasmosis, theyshould still be considered to supplement or confirm a clinical, radiological, and serological diagnosis inimmunocompromised patients as well as to be useful in monitoring the progress of patients with, or at riskof, toxoplasmosis.

Antimicrobial Treatment

Cerebral ToxoplasmosisTreatment of cerebral toxoplasmosis includes treating the clinically active infection, followed by main-tenance therapy to suppress recurrent disease in patients with CD4+ T cell count below 200 cells/mm3.The recommendations for treatment almost always involve drug combination (Table 1).

The standard treatment for toxoplasmosis includes an association of pyrimethamine (loading dose of100 or 200 mg followed by 75 or 50 mg/day) and sulfadiazine 1,000 mg (<60 kg) or 1,500 mg (>60 kg)every 6 h. In the outpatient setting, the sulfadiazine daily dose can also be given twice daily taking intoaccount the serum half-life of 7–12 h. Intravenous trimethoprim-sulfamethoxazole is a recommendedtherapy for patients unable to receive oral therapy.


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For patients with intolerance to sulfonamides, pyrimethamine plus clindamycin (600 mg four timesdaily, intravenously or orally) has shown comparable or slightly lower effectiveness in most studies(Katlama et al. 1996). Clindamycin has the advantage of an IV formulation. Clindamycin/pyrimethaminedoes not prevent Pneumocystis jirovecii pneumonia; therefore, a pneumocystis prophylactic regimenmust be added. Patients with pneumonitis, chorioretinitis, the involvement of other organs, or a

Table 1 Prophylaxis and treatment of cerebral toxoplasmosis in patients with AIDSa

Primary prophylaxis

Indication Preferred Alternatives Suspension/reinitiation

Positive IgG anti-ToxoplasmaAb and CD4 < 100/mcl(US) (AII) or <200/mcl(Europe)All the regimens recommendedfor 1ry prophylaxis areeffective against P. jiroveciiPrevention of exposure

Eat cooked enough(or previously frozen at�20 �C) meat, wash fruits andvegetables, and wear gloves ifclose contact with raw meat orgardening activities (BIII)

Wear gloves and applyhygiene measures if closecontact with domestic animals(cats) and their droppings

Ensure that cats stay at homeand avoid eating raw orundercooked meat (BIII)

Co-trimoxazole 1 compDD (trimethoprim/sulfamethoxazole160/800 mg) PO/d (AII)

Co-trimoxazole 1 comp DD�3/sem PO (BIII)Co-trimoxazole 1 comp(trimethoprim/sulfamethoxazole80/400 mg)/d PO (BIII)Dapsone 50 mg/d VO +pyrimethamine 25 mg +folinic acid 25 mg �2/semPO (BI)Dapsone 200 mg +pyrimethamine 75 mg +folinic acid 25 mg/sem PO(BI)Atovaquone 1,500 mg with/without pyrimethamine25 mg + folinic acid 15 mg/dPO (CIII)

Stop prophylaxis after �6 months of ART, ifCD4 > 200 cel/mcl and VLundetectable during �3 months (AI)Resume prophylaxis ifCD4 < 100–200 cells/mcl(AIII)

Treatment of acute episode

Disease Preferred Alternatives Comments

Focal abscesses in CNS orretinochoroiditis

Pyrimethamine 200 mgPO (loading dose),followed by:

Pyrimethamine50 mg/d PO +sulfadiazine1,000 mg/6 h PO(<60 kg)

Pyrimethamine75 mg/dPO + sulfadiazine1,500 mg/6 h PO(�60 kg)+ folinic acid 15 mg/dVO (AI)

Pyrimethamine 50–75 mg/dPO + clindamycin600 mg/6 h IVo PO + folinicacid 15 mg/d PO (AI)Co-trimoxazole(trimethoprim/sulfamethoxazole,�trimethoprim 10 mg/kg/d-)IVo VO (BI)Atovaquone 1,500 mg/12 hPO + pyrimethamine50–75 mg/d PO (and folinicacid 15 mg/d PO) or +sulfadiazine1,000–1,500 mg/6 h (BII)Pyrimethamine 50–75 mg/dVO + azithromycin900–1,200 mg/d PO + folinicacid 15 mg/d PO (CII)

Minimum duration: 6 weeks(prolong it if growinglesions of incompleteresponse) (BII)Clindamycin regimens donot protect againstPneumocystis jirovecii; addspecific prophylaxis (AII)If intracranial hypertension,add dexamethasone (BIII)If seizures, add antiepilepticdrugs (not as prophylaxis)(AIII)

(continued)


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disseminated infection should receive the same treatment. Folinic acid (leucovorin calcium,10–20 mg/day orally, although this dose can be increased to 50 mg/day or more) must be associatedwith a regimen containing pyrimethamine to reduce toxicity to bone marrow.

The clinical and radiological response of patients depends on the level of neuronal destruction and thetiming of the initiation of therapy and of the immune response, but it should be evident during the first3 weeks, at least clinically. Resistance of T. gondii to drugs used for therapy has not been documented.Most patients with chorioretinitis also respond and show an improvement in visual acuity within 6 weeks.Mortality rates in the acute phase of Toxoplasma encephalitis ranged between 5 % and 20 % in publishedseries. Death usually occurs due to very advanced illness at the time therapy was initiated and is often dueto other simultaneous opportunistic diseases. The prognosis for medium and long-term recovery dependson the state of immunosuppression. Patients with pneumonia or disseminated infection have a poorprognosis, often associated to the base state of immunosuppression.

Treatment of cerebral toxoplasmosis should continue for at least 6 weeks. Most clinicians continuetherapy longer if the clinical manifestations do not improve or if lesions on MRI remain stable or do notsignificantly decrease in size for many weeks. Imaging studies should be repeated within 2 weeks toensure that toxoplasmosis was the correct and only cause of the injury (Fig. 3). If the lesions have notimproved, a biopsy (or a repeat biopsy) should be considered to determine whether more than one processwas present. If toxoplasmosis is the only proven diagnostic and neurological symptoms have notimproved after 2 weeks, an alternative regimen could be used, but there is no evidence that this strategymay improve the prognosis. Although serial scans during the following months can demonstrate thecomplete or nearly complete resolution of the localized and multifocal disease, no repeat studies are

Table 1 (continued)

Suppressive therapy (secondary prophylaxis)

Indication Preferred Alternatives Suspension/reinitiation

All the patients who havecompleted the acute phase oftherapy

Pyrimethamine25–50 mg/d PO +sulfadiazine1,000 mg/6–12 h VO +folinic acid 15 mg/d VO(AI)

Pyrimethamine 25–50 mg/dVO + clindamycin600 mg/8 h VO + folinic acid15 mg/d VO (BI)Co-trimoxazole 1 compDD/12 h VO (BII)Atovaquone750–1,500 mg/12 h PO +pyrimethamine 25 mg/d PO(+ folinic acid 15 mg/d VO)or + sulfadiazine1,000 mg/6–12 h (BII)Pyrimethamine 25–50 mg/dPO + azithromycin500–1,000 mg/d PO + folinicacid 15 mg/d PO

Stop if CD4 > 200 cells/mcland ART > 6 months andviral load undetectable (BI)Resume prophylaxis ifCD4 < 200 cel/mcl (AIII)

aThe level of recommendation (A, B, C and I, II, III) corresponds to the Infectious Diseases Society of America (IDSA)Adapted from Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents, GESIDA and National AIDS PlanExpert Panel (2008), Guidelines of the AIDS Study Group (GESIDA), and National AIDS Plan (2008)


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required in a patient with clinical improvement receiving standard treatment. The initial diagnosisalgorithm in a patient with suspected cerebral toxoplasmosis can be seen in Fig. 4.

Adverse Effects of Treatment and Alternative RegimensRashes and other adverse inflammatory reactions to sulfonamides are well recognized in HIV-infectedpatients. Additionally, patients treated with sulfadiazine can develop crystalluria, hematuria, renal colic,and occasionally some degree of kidney failure. Adequate fluid intake should be guaranteed to minimizetubular crystal formation.

Blood count should bemonitored since pyrimethamine is associated with pancytopenia, especially withneutropenia. This effect may be more pronounced if pyrimethamine is combined with sulfa drugs thanwith clindamycin.

The main adverse effect of clindamycin is diarrhea. In patients to whom no orally drugs can be given,trimethoprim-sulfamethoxazole has shown comparable activity in some small clinical trials and can beadministered intravenously. Some authors consider trimethoprim-sulfamethoxazole as one of the pre-ferred regimens.

Atovaquone is also an antimicrobial with anti-toxoplasmic activity and may be associated with bothpyrimethamine and sulfadiazine. It can also be used as monotherapy in patients unable to tolerate either ofthese drugs, but its effectiveness is reduced compared to the previously discussed regimens. Macrolides(azithromycin and clarithromycin) are also active molecules against Toxoplasma, but should be used incombination with pyrimethamine.

Fig. 4 Neuroimaging work-up plan in AIDS patients with CNS lesions. A cerebrospinal fluid sample should be obtained whenpossible for viral (CMV, EBV, JCV), parasitic (T. gondii), and mycobacterial molecular diagnosis. CT computed tomography,MRI magnetic resonance image, 201Tl SPECT 201 thallium single-photon emission computed tomography, PML progressivemultifocal leukoencephalopathy, PCNSL primary central nervous system lymphoma, CMV cytomegalovirus, EBV Epstein-Barr virus, JCV JC virus. 201Tl SPECT: useful to differentiate from PCNSL, but not necessary to confirm toxoplasmosis


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Adjuvant Use of Corticosteroids and AnticonvulsantsAdjunctive corticosteroids (e.g., dexamethasone) should not be administered routinely but only if aclinical evaluation indicates the need to reduce intracerebral pressure where there is considerable masseffect from focal lesions or when seizures are intractable. Patients receiving corticosteroids must beclosely monitored to prevent the development of other opportunistic infections such as cytomegalovirusretinitis, disseminated cryptococcosis, and tuberculosis.

Anticonvulsants should be given to patients with proven seizures but not routinely to all patients withToxoplasma encephalitis. Phenobarbital or phenytoin sodium is not recommended due to potential druginteractions with many antiretroviral drugs. Sodium valproate is preferred. There is no clear evidence ofhow long they should be continued after an initial convulsive attack. Anticonvulsants should probably becontinued for at least the duration of the acute treatment.

Suppressive Therapy (Secondary Prophylaxis) After the Acute EpisodeAfter at least 6 weeks of treatment, with clinical and radiographical response, patients should maintaintreatment for life (secondary prophylaxis or suppressive therapy), unless there is effective immunereconstitution in response to antiretroviral therapy with an increase in CD4+ T cells to above 200 cells/ml. Maintenance therapy should only be discontinued once CNS lesions show no contrast enhancement onCT/MRI. Without prophylaxis, rates of relapse for Toxoplasma encephalitis are 50–80 % at 6–12 monthsin patients without effective immune reconstitution.

For maintenance therapy, most clinicians maintain the oral dosing regimen at a half dosage. Recur-rences (10–40 %) may occur and, as already mentioned, are due to nonadherence either to drug treatmentor to serious immunodeficiency. Drug resistance is thought to be a rare event. In patients who were treatedwith trimethoprim-sulfamethoxazole, a reduction of the dose to a daily double-dose tablet seems areasonable alternative to secondary prophylaxis.

Suppressive treatment can be stopped with immune reconstitution and is generally accepted aftermeasurements of CD4> 200 cells//mL in patients whose viral loads of HIV-1 remain undetectable for 3–6months and who are adherent to treatment. In this situation, discontinuation is considered without risk ofrecurrence (Miro et al. 2006). The summary of the recommendations of treatment of acute episodes andprimary and secondary prophylaxis are shown in the table.

Differential DiagnosesAs previously explained, PCNSL represents the most important diagnosis to exclude. PCNSL presentsmore frequently as a single lesion, hypermetabolic in SPECT or PET. If a lumbar puncture is notcontraindicated, PCR for EBV is frequently positive. Indeed, the association of a single lesion inCT/MRI, a positive PET/SPECT, and a positive PCR for EBV has extremely high specificity and positivepredictive value for PCNSL (Fig. 4).

In single lesions, with negative SPECT/PETand negative T. gondii IgG serology and no anti-Toxoplasmaresponse, alternative diagnoses such as cryptococcoma or tuberculoma should be considered (Fig. 4). BothCryptococcus and M. tuberculosis present more frequently as chronic meningitis, but they can producesingle or multiple intracerebral masses, which are normally hypometabolic in functional imaging tech-niques. PCR for M. tuberculosis or capsular Ag for Cryptococcus is usually positive in CSF. However, insome cases, confirmation may require the aspiration of material or a biopsy (Skiest 2002).

Other causes of multiple cerebral abscesses, such as a Nocardia infection or other bacterial and fungaldiseases, may also be considered.


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ART InitiationIn AIDS patients with opportunistic diseases, the early initiation of antiretroviral therapy (ART) within2 weeks of the diagnosis of an opportunistic infection improves prognosis (reduces the risk of clinicalprogression to new AIDS events and death), with the exception of cryptococcal meningitis and probablyof tuberculous meningitis. Therefore, the initiation of ARTshould not be delayed, although this entails anadditional burden given the number of tablets and the risk of interactions. For toxoplasmosis, druginteractions do not represent a major problem, and there is no preferred antiretroviral regimen. Someclinicians prefer an antiretroviral combination with good penetration into the CNS, although it has notbeen shown that this is associated with a better prognosis. As with most opportunistic infections inpatients with AIDS, there is a risk of worsening clinical manifestations when patients improve theirimmune status, a phenomenon known as immune reconstitution inflammatory syndrome (IRIS). How-ever, it is rarely seen in cerebral toxoplasmosis, even if steroids are not used. Nevertheless, there should bevery close monitoring of neurologic outcomes in patients during the first weeks of ART treatment. If IRISis suspected, other concomitant neurological processes should be excluded. Treating IRIS involves theuse of anti-inflammatory drugs such as corticosteroids.

Antimicrobial Treatment of Extracerebral ToxoplasmosisData on the outcome of treatment of AIDS patients with toxoplasmosis outside the CNS are limited;available information on the therapy of ocular and pulmonary involvement indicates that these forms oftoxoplasmosis are also responsive to treatment. Therapeutic combinations are the same used for toxo-plasmic encephalitis, although duration of therapy is less well established.

Prevention

Primary ProphylaxisPrimary prophylaxis is indicated in patients with a positive serology for T. gondiiwith CD4< 100 cells/mL according to the US guidelines and in patients with CD4< 200 according to some European experts. Inpractice, the patients should receive trimethoprim-sulfamethoxazole where CD4 < 200 cells/mL toprevent P. jirovecii pneumonia, typically a double-dose tablet (160/800 mg) three times a week. Thisregimen protects very effectively against toxoplasmosis. Pyrimethamine alternative schemes are associ-ated with dapsone, sulfadoxine, or atovaquone or also atovaquone alone (Table 1).

HIV-Infected Patients Seronegative for T. gondiiIn severely immunocompromised patients who are seronegative for T. gondii, primary infection withT. gondii should be avoided (by not eating raw meat or poorly washed vegetables).

Conclusions

Cerebral toxoplasmosis continues to be a major problem with high morbidity and mortality in severelyimmunocompromised HIV-positive patients and, less frequently, in other patients with depressed cellularimmunity. The diagnostic approach, treatment, and prognosis have remained relatively unchanged inrecent years. Neurological Toxoplasma involvement is still prevalent in patients with late diagnosis ofHIV infection, so detailed knowledge is essential for specialists in neurology, infectious diseases, clinicalmicrobiology, and internal medicine.


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Cross-References

▶AIDS-Related Primary Central Nervous System Lymphoma▶Antiretroviral Medications, Adult Care and Treatment▶Co-morbidity: Opportunistic Infections▶Cryptococcosis and HIV▶ Immune Reconstitution Inflammatory Syndrome in NeuroAIDS: Treatment Considerations▶Tuberculosis and HIV

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toxoplasmosis in hiv-infected patients - springer · most patients with cerebral toxoplasmosis...

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