HIV-1 Associated Opportunistic Infections, Toxoplasmosis


Article Author:
Folusakin Ayoade


Article Editor:
Andrew Stevenson Joel Chandranesan


Editors In Chief:
Donald Kushner
Annabelle Dookie


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
1/19/2019 12:49:48 PM

Introduction

Toxoplasmosis is the commonest central nervous system (CNS) infection in patients with HIV/AIDS who are not on appropriate prophylaxis. The usual manifestation of cerebral toxoplasmosis is typically one or more CNS mass lesions. Other opportunistic conditions seen in AIDS that may present with mass like lesions include primary CNS lymphoma (typically associated with the Epstein-Barr virus) and progressive multifocal leukoencephalopathy (PML) which is caused by JC polyomavirus. [1][2][3]

Etiology

The causative agent is Toxoplasma gondii, an exclusively intracellular, coccidian protozoan parasite with worldwide distribution. Transmission occurs following ingestion of infectious oocysts from contaminated meat, other food, or water. The oocysts are abundant in the soil, cat litter contaminated with feline feces or undercooked meat from an infected animal (especially felines). Felines are the only animals in which T. gondii can complete its reproductive cycle. After ingestion, the organisms encyst in nucleated cells and can lie dormant within the tissues for the life of the host (latent infection). In most scenarios, disease occurs following reactivation of latent infection because of progressive loss of cellular immunity. This can occur in the setting of advanced HIV, following solid or stem cell transplant, prolonged steroids, use of monoclonal antibodies, or chemotherapy.[4][5]

Epidemiology

The incidence of toxoplasmosis infection depends on the seropositivity of Toxoplasma gondii in the population. In the United States, the seropositivity of T. gondii is approximately 10% of the adult population. Seropositivity is higher in Africa and Europe where it can reach up to 80%, and toxoplasma encephalitis could be as high as 25% to 50% of susceptible hosts. The seropositivity in the HIV population mirrors that of the general population.[6][7]

Even though cats and related felines have traditionally been associated with toxoplasmosis, the prevalence of infection is not related to owning a cat. In the HIV Toxoplasma-seropositive patients with CD4 less than 100 who are not on appropriate prophylaxis, the probability of developing reactivated toxoplasmosis is as high as 30%.

Apart from oral transmission, toxoplasmosis can also be transmitted via the placenta from mother to fetus or through transplantation of an infected organ.

Pathophysiology

After ingestion of the infective forms, the organism invades the intestinal epithelium and subsequently disseminates throughout the body. At the tissues, which often is the brain but can affect any tissue, they then encyst and lie dormant until immunity wanes. The dormant forms are called bradyzoites while the actively replicating forms are called tachyzoites. Primary toxoplasmosis is often subclinical but could rarely present symptomatically in an immunocompromised seronegative person who became recently exposed to the infective forms. In this scenario, IgM to a toxoplasma is often positive, but IgG is not, unlike most reactivation cases, when IgG is the only positive serology test. As previously outlined, in most situations, clinical toxoplasmosis in the HIV patient is due to reactivation of latent infection as immunity wanes.[8]

Histopathology

The histology usually reveals diffuse encephalitis, cyst-containing lesions, microglial nodules and a lymphocytic vasculitis.

History and Physical

Cerebral toxoplasmosis (toxoplasmic encephalitis), usually with one or more ring-enhancing brain lesions is the typical presentation in HIV patients. Symptoms are often subacute, ranging from a few days to a month. Common symptoms include a headache, confusion, and lethargy. Fever may be present but often absent. There is some suggestion that chronic Toxoplasma infection state may not be completely asymptomatic and in some patients, behavioral changes and neuropsychiatric disorders are possible. Seizures and focal neurologic deficits are also common occurring in up to 30% and 70% of patients respectively. Mental status changes could range from dull affect to stupor and coma often secondary to global encephalitis and/or increased intracranial pressure. On the other hand, the latent/dormant phase is often asymptomatic.

Extracerebral involvement is typically less common than CNS infection. These include pneumonitis, chorioretinitis and less commonly gut, liver, heart, bladder, spinal cord, bone marrow, and testes. Rarely toxoplasmosis may present as a disseminated disease.

Evaluation

There are no routine laboratory findings that are specific for toxoplasmosis. Lactate dehydrogenase (LDH) can be increased markedly in patients with disseminated toxoplasmosis and pulmonary disease.[2][9][10]

A presumptive diagnosis of cerebral toxoplasmosis in the HIV patient can be made as follows:

  • CD4 count less than 100 cells/microliter without any effective prophylaxis
  • A compatible clinical syndrome
  • A positive T. gondii IgG antibody (Anti-toxoplasma IgM antibodies are usually absent except rarely in cases of primary infection. Quantitative IgG antibody titers are not helpful in diagnosis.)
  • Brain imaging (preferably MRI) that demonstrates a typical radiographic appearance.

If the above criteria are present, there is at least a 90% probability the diagnosis will be cerebral toxoplasmosis.

It is important to note however that a positive serology does not confirm the diagnosis and a negative serology implies the diagnosis is not likely (though not impossible) to be cerebral toxoplasmosis.

The brain imaging often shows multiple (67%) or single (33%) ring-enhancing brain lesions often associated with edema (See figure). There is a predilection for involvement of the basal ganglia, corticomedullary junction or brain white matter.

A more definitive diagnosis can be made by obtaining lumbar puncture. Cerebrospinal fluid (CSF) analysis will often show mononuclear pleocytosis, elevated protein and sometimes, reduced CSF glucose.  Polymerase chain reaction (PCR) testing for T. gondii in CSF is 100% specific but only 44% to 65% sensitive. This suggests a positive CSF PCR result establishes the diagnosis of cerebral toxoplasmosis but a negative one does not rule it out.

When the diagnosis is in doubt and alternative diagnoses considered, brain biopsy can be obtained. Findings in cerebral toxoplasmosis may show necrotic abscesses with blood vessel thrombosis and necrosis. Cysts containing bradyzoites may often be found coexisting with numerous active tachyzoites. In most cases, brain biopsy is not required for diagnosis.

Treatment / Management

The treatment of toxoplasmosis in HIV-infected patients includes:

  • Antimicrobial therapy directed against T. gondii
  • Antiretroviral therapy for immune recovery

Pyrimethamine and sulfadiazine are most commonly employed in treatment. Both agents synergistically and sequentially block folic acid metabolism which is necessary for the development of the parasite. Folinic acid (leucovorin) is often added to replace folate stores which are non-selectively depleted. Initial treatment is typically for six weeks.[11][12][13][12]

Initial therapy is followed by secondary prophylaxis or maintenance therapy which is continued until CD4 plus T-lymphocyte counts are over 200 cells/microliters for more than three months. In addition to awaiting immune recovery, secondary prophylaxis provides continuous therapy against dormant cystic forms which may rupture and reinitiate the infectious process at any time. Maintenance therapy, therefore, is necessary to prevent relapse.

In patients who are allergic to sulfonamides, treatment options include any of the following: clindamycin; trimethoprim/sulfamethoxazole; pyrimethamine plus atovaquone plus folinic acid; pyrimethamine plus azithromycin plus folinic acid; and atovaquone alone (if unable to tolerate sulfur drugs or pyrimethamine).

Spiramycin is the drug of choice in the first trimester of pregnancy as pyrimethamine may be teratogenic.

Most clinicians often employ the use of steroids (when edema is present), but studies have shown its use to be neither beneficial or harmful. The use of steroids in cerebral toxoplasmosis should probably be limited to impending brain herniation as the diagnosis may be clouded once steroid is started before a definitive diagnosis is made.

Treatment course is often dramatic with half the cases showing neurological improvement by day three and in most cases by day seven of treatment commencement. If there is no significant improvement or worsening symptoms by days ten to 14 of therapy, repeat imaging and possibly brain biopsy should be considered. Persistent neurologic sequelae may remain in 37% of survivors and death rate at one year could vary from 10% to 60%.

An integral part of therapy is starting antiretroviral (ART) agents as soon as feasible, usually within 2 weeks of starting anti-toxoplasma therapy. Immune reconstitution inflammatory syndrome (IRIS) which can present as paradoxical worsening of symptoms as immunity recovers is rarer with toxoplasmosis compared to mycobacterial and cryptococcal infections. Even though there are no studies about the optimal timing of ART in toxoplasmosis, early ART has clear benefits and should not necessarily be delayed beyond 2 weeks. [14][15]

Differential Diagnosis

Complications

Postoperative and Rehabilitation Care

Once antibiotic treatment has started, improvement is gradual and may take several weeks. Imaging studies need to be repeated in 4-6 weeks to determine if the lesion is decreasing in size.

Long-term therapy is continued at low doses. If the CD4 count improves and the lesion is resolving then one may consider discontinuing the therapy.

Deterrence and Patient Education

Avoid eating raw or undercooked meat

Wash hands thoroughly after handling cat litter or soil

Pearls and Other Issues

Prophylaxis against reactivation of T. gondii in seropositive patients with CD4 lymphocyte counts less than 100 cells/microliter is recommended. Mostly used is trimethoprim/sulfamethoxazole. Other options include dapsone plus pyrimethamine and folinic acid or atovaquone with or without pyrimethamine/leucovorin.

In conclusion, toxoplasmosis should always be included in the differential diagnosis of CNS lesions in advanced HIV/AIDS. Diagnosis is a combination of clinical symptoms and signs, serology and imaging. CSF may further support the diagnosis. Brain biopsy is often reserved for difficult cases. Treatment is often dramatic, and most patients have a favorable clinical outcome. 

Enhancing Healthcare Team Outcomes

Besides physicians, the role of the nurse and pharmacist cannot be overemphasized in the management of HIV patients with CNS toxoplasmosis. The nurse should emphasize safe sex practices and counsel both partners on sex education. Washing hands after contact with cat litter is highly recommended. In addition, walking bare feet in contaminated soil is not recommended. Patients should be cautioned against the use of intravenous drugs. One should wash hands after coming into contact with raw meat and wear gloves when gardening. Because these patients are on many medications including HAART, the pharmacist is in the ideal position to encourage compliance. HIV patients with CNS toxoplasmosis require life long prophylaxis with trimethoprim-sulfamethoxazole and the pharmacist should educate the patient on potential complications if one does not comply with therapy. Finally, these individuals should be told to avoid travel to areas where toxoplasmosis is endemic. Only through an established integrative approach can the morbidity and mortality of CNS toxoplasmosis be lowered in HIV patients.  [16][17](Level V)

Evidence-based Outcomes

The prognosis of CNS toxoplasmosis in HIV is guarded. Relapses are very common if the treatment is discontinued. Ongoing treatment can lower the risk of recurrent infection. If the disorder is not treated adequately, complications like deafness, seizures, and blindness can occur. Infants with congenitally acquired toxoplasmosis generally have a better outcome than HIV adults.[18][19] (level V)


  • Image 5683 Not availableImage 5683 Not available
    Contributed by Folusakin Ayoade, MD
Attributed To: Contributed by Folusakin Ayoade, MD

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

HIV-1 Associated Opportunistic Infections, Toxoplasmosis - Questions

Take a quiz of the questions on this article.

Take Quiz
Which drug is effective in the prevention of toxoplasmic encephalitis in patients with HIV?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is least likely in patients with AIDS that develop subacute toxoplasmosis infections?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which symptom is least likely secondary to Toxoplasmosis infection in HIV?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A male patient presents to the emergency department with a generalized seizure. He has HIV but has refused care up to this point. This is his first seizure. His physical exam is essentially unremarkable. CT shows ring-enhancing lesions in the left temporal lobe with edema but no mass effect. Cerebrospinal fluid is negative for WBCs, RBC, Gram stain, and cryptococcal antigen. Serum Toxoplasma IgG is positive. Select the appropriate next step.



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient with AIDS presented with a seizure and had a ring-enhancing lesion with edema but no mass effect on CT scan. He was treated for toxoplasmosis for 3 weeks and a follow-up CT is unchanged. Cerebrospinal fluid was negative at the time of the lumbar puncture, and all cultures for viruses, bacteria, and fungus were negative. The patient has had no further seizures. What is the appropriate management of this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which central nervous system opportunistic infection is most common in AIDS?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following will not be an adequate prophylaxis against toxoplasmosis and Pneumocystis in a patient with HIV and a CD4 count of 80 cells/microliter?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

HIV-1 Associated Opportunistic Infections, Toxoplasmosis - References

References

Giovane RA,Lavender PD, Central Nervous System Infections. Primary care. 2018 Sep     [PubMed]
Paquet C,Yudin MH, No. 285-Toxoplasmosis in Pregnancy: Prevention, Screening, and Treatment. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2018 Aug     [PubMed]
Mendez OA,Koshy AA, Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system. PLoS pathogens. 2017 Jul     [PubMed]
Rapalino O,Mullins ME, Intracranial Infectious and Inflammatory Diseases Presenting as Neurosurgical Pathologies. Neurosurgery. 2017 Jul 1     [PubMed]
Sonneville R,Magalhaes E,Meyfroidt G, Central nervous system infections in immunocompromised patients. Current opinion in critical care. 2017 Apr     [PubMed]
Crabtree-Ramírez B,Caro-Vega Y,Shepherd BE,Grinsztejn B,Wolff M,Cortes CP,Padgett D,Carriquiry G,Fink V,Jayathilake K,Person AK,McGowan C,Sierra-Madero J, Time to HAART Initiation after Diagnosis and Treatment of Opportunistic Infections in Patients with AIDS in Latin America. PloS one. 2016     [PubMed]
Miura Y,Kishida S, [Neurological complications with HIV infection]. Brain and nerve = Shinkei kenkyu no shinpo. 2013 Mar     [PubMed]
Ho YC,Sun HY,Chen MY,Hsieh SM,Sheng WH,Chang SC, Clinical presentation and outcome of toxoplasmic encephalitis in patients with human immunodeficiency virus type 1 infection. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi. 2008 Oct     [PubMed]
Brandsma D,Bromberg JEC, Primary CNS lymphoma in HIV infection. Handbook of clinical neurology. 2018     [PubMed]
Christo PP,Vilela Mde C,Bretas TL,Domingues RB,Greco DB,Livramento JA,Teixeira AL, Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system. Journal of the neurological sciences. 2009 Dec 15     [PubMed]
Okome-Nkoumou M,Guiyedi V,Ondounda M,Efire N,Clevenbergh P,Dibo M,Dzeing-Ella A, Opportunistic diseases in HIV-infected patients in Gabon following the administration of highly active antiretroviral therapy: a retrospective study. The American journal of tropical medicine and hygiene. 2014 Feb     [PubMed]
Thoden J,Potthoff A,Bogner JR,Brockmeyer NH,Esser S,Grabmeier-Pfistershammer K,Haas B,Hahn K,Härter G,Hartmann M,Herzmann C,Hutterer J,Jordan AR,Lange C,Mauss S,Meyer-Olson D,Mosthaf F,Oette M,Reuter S,Rieger A,Rosenkranz T,Ruhnke M,Schaaf B,Schwarze S,Stellbrink HJ,Stocker H,Stoehr A,Stoll M,Träder C,Vogel M,Wagner D,Wyen C,Hoffmann C, Therapy and prophylaxis of opportunistic infections in HIV-infected patients: a guideline by the German and Austrian AIDS societies (DAIG/ÖAG) (AWMF 055/066). Infection. 2013 Sep     [PubMed]
Low A,Gavriilidis G,Larke N,B-Lajoie MR,Drouin O,Stover J,Muhe L,Easterbrook P, Incidence of Opportunistic Infections and the Impact of Antiretroviral Therapy Among HIV-Infected Adults in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Jun 15     [PubMed]
Tan IL,McArthur JC, HIV-associated neurological disorders: a guide to pharmacotherapy. CNS drugs. 2012 Feb 1     [PubMed]
Masur H,Kaplan JE,Holmes KK, Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Annals of internal medicine. 2002 Sep 3     [PubMed]
Kaplan JE,Masur H,Holmes KK, Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2002 Jun 14     [PubMed]
Kirk O,Lundgren JD,Pedersen C,Nielsen H,Gerstoft J, Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS (London, England). 1999 Sep 10     [PubMed]
Robert-Gangneux F,Meroni V,Dupont D,Botterel F,Garcia JMA,Brenier-Pinchart MP,Accoceberry I,Akan H,Abbate I,Boggian K,Bruschi F,Carratalà J,David M,Drgona L,Djurković-Djaković O,Farinas MC,Genco F,Gkrania-Klotsas E,Groll AH,Guy E,Hirzel C,Khanna N,Kurt Ö,Junie LM,Lazzarotto T,Len O,Mueller NJ,Munoz P,Pana ZD,Roilides E,Stajner T,van Delden C,Villena I,Pelloux H,Manuel O, Toxoplasmosis in Transplant Recipients, Europe, 2010-2014. Emerging infectious diseases. 2018 Aug     [PubMed]
Halonen SK,Weiss LM, Toxoplasmosis. Handbook of clinical neurology. 2013     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Podiatry APMLE Part 3. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Podiatry APMLE Part 3, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Podiatry APMLE Part 3, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Podiatry APMLE Part 3. When it is time for the Surgery-Podiatry APMLE Part 3 board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Podiatry APMLE Part 3.