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Clinical examples of infections in immunocompromised hosts

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الكلية كلية طب حمورابي     القسم الكلية ذات القسم الواحد     المرحلة 2
أستاذ المادة بشار صاحب خلف الشمري       30/04/2019 22:22:30
Session 10 Lecture 2
Clinical examples of infections in immunocompromised hosts

Toxoplasmosis

Causative parasite: Toxoplasma gondii

-This protozoan parasite infects large number of the vertebrates host including man, mammals, birds and reptile (warm blooded animals).
-Geographical distribution: worldwide distribution.
-Habitat: epithelial cells of small intestine (of the final host) or other tissue neucleated cells (of the intermediate host).
-Disease: Toxoplasmosis

Morphology (infective stages)
Toxoplasma gondii occurs in three forms; tackyzoites, tissue cyst and oocyst. The tackyzoites and tissue cyst represent the stages in asexual multiplication (schizogony) while the oocyst is formed by sexual reproduction (gametogony and sporogony).
1-Tackyzoite (trophozoite): it is crescent or oval shaped. Tackyzoites are found in tissue during the acute stage of infection and invade all mammalian cells (any reticuloendothelial cell or parenchymal cell of man or other mammals), except non-nucleated erythrocytes. It can be seen extra-cellularly (after rupture of the infected cells). So, during the acute infection, an infected host cell that contains the proliferating tackyzoites which enclosed by the host cell membrane is called pseudocyst. Tackyzoites replicate rapidly and their number is few (less than 50) within the host cell (pseudocyst).


Tackyzoites inside cell (Pseudocyst) and outside cell


2-Tissue cysts (true cysts): formed during the chronic phase of infection and can found in any organ of the body more particularly in skeletal muscle, heart muscle, and brain, and may contain thousands of organisms (bradyzoites). The slowly multiplying parasites within the tissue cyst are called bradyzoites. Bradyzoites are similar to tackyzoites in shape but slightly smaller in size and multiply slowly. Tissue cysts remain viable in tissues for years. They are important in transmission of infection (one of the infective stages) and source of recrudescent disseminated infection in immunocompromised individuals (reactivation of toxoplasmosis to acute phase from releasing of bradyzoites of the tissue cyst which transform to tackyzoites and initiating new acute infection).

3-Oocysts: These develop only in the final host (cat and members of feline family include cats, tigers, lions …ext). The oocyst is spherical or ovoid in shape, and contains a sporoblast when it is immature oocyst. Cat sheds millions of immature oocyst per day in feces during early part of infection. The freshly passed immature oocysts are not infective. These become infective after development in soil or water for few days (1-4 days). Thus the mature oocyst containing two sporocysts and eight sporozoites is the infective stage. Oocysts on ingestion release sporozoites in the intestine.
The oocyst is found only in cat family feces, but Tachyzoites within pseudocyst and Bradyzoites within tissue cyst are found in other warm blooded animals including cats also.

Life cycle
T. gondii completes its life cycle in two kinds of hosts:
1- (enteric cycle) intestinal phase: in cat (or any member of cat family).
2-(exoenteric cycle) extra-intestinal phase: in man, sheep, pig, mouse, birds and other animals (including cat and members of cat family)
Development in Cat (enteric cycle)
The sporozoites released from the ingested mature oocyst, or the bradyzoites released from the ingested tissue cyst penetrate the epithelial cells of the small intestine. They round up and grow within the epithelial cells and asexual form of division occurs first (schizogony) leading to the formation of merozoites.
Trophozoite ? Schizont ? merozoites.
After rupture of epithelial cells, some merozoites enter extra-intestinal tissues (initiating exoenteric cycle) resulting in the formation of tissue cysts in other organ of the body. Other merozoites penetrate the epithelial cells and transformed into sexual stages (male and female-gametocytes) ? initiating gametogony ? male and female gametocytes ?
fertilization ? zygote ? immature oocyst ? shed into the lumen of small intestine and go out with feces to outside where maturation take place. An oocyst passes through maturation stages before it becomes infective.
So, the cat and its family considered as complete host (final and intermediate host) because both intestinal and extra-intestinal phases take place in it.
Cat could be infected by eating raw meat or undercooked meat of other animals (especially of mice and birds) containing tissue cyst (with bradizoites) or ingestion of food contaminated with mature occysts.

Development in man (Exoenteric cycle)
Infection occurs after ingestion of oocysts from the cat or by eating improperly cooked meat containing tissue cyst. Only asexual development occurs in man and the occysts are not formed in the intestine. In the small intestine the sporozoites released from {1-oocyst (water or food contaminated with cat feces) or 2-bradyzoites released from tissue cyst (undercooked meat) or 3-tackyzoites released from pseudocyst or extracellular tackyzoites (unpasteurized milk)}, these sporozoites peneterate the intestinal epithelial cells. Merozoites arising from asexual development in the epithelial cells of the small intestine enter the lymphatic and blood vessels and the acute stage started by these merozoites which infect any parenchymal and RE cells (as macrophages), and these merozoites divided to form multiple asexual forms (tachyzoites) inside these cells forming what is called pseudocyst (host cell contain few number of tackyzoites) and tackyzoites after rupture of infected cells again invade other parenchymal or RE cells.
Note: sometimes the tackyzoites transmit directly to human blood by blood transfusion or from mother to fetus and invade any parenchymal or RE cells and start the acute stage without need asexual development in the epithelial cells of the small intestine.
With the development of host immunity, the multiplications of tachyzoites ceased down and form bradyzoites surrounded by cystic wall and contains hundreds bradyzoites forming the tissue cyst in various organs of the body (chronic stage). Mother to fetus transmission can occur through the placenta giving rise to congenital toxoplasmosis.
Man and other animals except cat are called incomplete hosts (intermediate hosts only) because only asexual life cycle occurs. Man is considered as a blind end so not regarded as a source of infection but only if he is eaten by a carnivore in forest (Tigers, lion …ect)

Pathogenesis and clinical features
In acute infection, the proliferation of tachyzoites in the extra-intestinal sites, cause disruption and death of cells, resulting in the foci of necrosis. The development of both the humoral and cell mediated immunities in the immunocompetent hosts, resolve the acute infection. It is associated with the disappearance of tachyzoites from various tissues, especially from the extra-neural tissues and the formation of tissue cysts.
Toxoplasmosis in man occurs as congenital, ocular, acquired infections in the immunocompetent hosts or an infection in the immunocompromised host.



1-Congenital toxoplasmosis
Congenital toxoplasmosis results from an acute primary infection acquired by the mother during pregnancy (transmission can occur only if infection, symptomatic or asymptomatic is acquired by mother during pregnancy), a women who acquired toxoplasma infection at any time before gestation will not deliver an infected infant (mother having suffered (in the past, before pregnancy) from acute toxoplasmosis once shall not give birth to a child infected with T. gondii). Transplacental transmission from a chronic infection does not occur.
Infection in early pregnancy is less common but more severe than that occur in late pregnancy. Infection of the fetus during last trimester of pregnancy is more likely to be mild or asymptomatic at birth.
In pregnancy, abortion, death in utero, or severe neurological/ocular manifestations may result (hydrocephaly, microcephaly, brain calcification, chorioretinitis). Asymptomatic infection at birth is common, other may develop chorioretinitis, blindness, epilepsy, mental retardation weeks, months or years after birth.

2-Acquired toxoplasmosis
Acquired infection with Toxoplasma in immunocompetent persons is generally an asymptomatic infection. However, 10% to 20% of patients with acute infection may develop cervical lymphadenopathy and/or a flu-like illness. The clinical course is benign and self-limited. Rarely presents as maculopapular rash, pneumonia and myocarditis.

3-Occular Toxoplasmosis
Chorioretinitis is the major manifestation of ocular toxoplasmosis.

4-Infection in the immunocompromised host
The infection is more serious in immunosuppressed patients receiving immuno-suppressive therapy for malignancies; or persons receiving organ transplantations and AIDS. Immunodeficient patients often have central nervous system (CNS) disease (encephalitis, meningitis) but may have chorioretinitis, or pneumonitis.

Laboratory diagnosis
1)Microscopic detection: Tachyzoites occasionally may be demonstrated microscopically in the smears of lymph node, bone marrow, brain and other specimen (as CSF or amniotic fluid).



3)Serological diagnosis
a)Antibody detection:
The detection of Toxoplasma-specific antibodies is the primary diagnostic method to determine infection with Toxoplasma. It is considered positive test if:
1-detection of IgM antibodies.
2-rising titers of total antibodies (IgM & IgG).
b)Antigen detection
The detection of circulating Toxoplasma antigen in the serum is a recent method. It has the potential for diagnosis of toxoplasmosis in the immunocompromised hosts. This also offers the possibility of detection of antigen in the amniotic fluid to diagnose congenital toxoplasmosis but still is at experiment stage.

4)Molecular diagnosis
Detection of parasite genetic material by PCR, especially in detecting congenital infections in utero.

Modes of transmission
1)Oral transmission:
T. gondii infection is acquired by eating raw or undercooked meat (chicken, pork and goat meat) containing the tissue cyst and ingesting food and water contaminated with mature oocysts from cat feces.
2) Congenital transmission:
The infection is transmitted from the infected pregnant mother to the fetus, by the tachyzoits passing through the placenta.
3) Other modes of transmission:
Laboratory infection is caused by accidental self-inoculation of tachyzoites. It is less common. The infection may be transmitted by blood transfusion, drinking unpasteurized milk, eating egg and organ transplantation.


Treatment
The combined therapy with sulfonamide and pyrimethamine are widely used in the treatment of toxoplasmosis. They are synergistic in combination and are effective against tachyzoites but not against tissue cysts of T. gondii.
Treatment is not needed for a healthy person who is not pregnant. Symptoms will usually go away within a few weeks. For pregnant women or persons who have weakened immune systems, pyrimethamine plus sulfadiazine with leucovorin are the drugs of choice.

Prevention and control
-For high risk individuals such as immunodeficient patients and pregnant women, avoidance of contact with cat feces containing oocysts and eating meat adequately cooked are important measures for prevention of acquired and congenital toxoplasmosis.
-Adequate cooking kills all the cysts in the meat.
-Proper hand washing is important.
-Fruits and vegetables that may be contaminated with oocysts should be washed adequately before eating.
-blood and blood products from persons with positive test for toxoplsmosis should not be given to immunocompromised patients.
-Pasteurization of milk kills the tackyzoites.




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