Lymphatic and Hematologic infections

Diseases with hematological and lymphatic manifestations: malaria, visceral leishmaniasis, trypanosomiasis (Chagas Disease).

Ana María Gómez J. MD. Msc. PhD(c)Tropical Medicine Faculty of Medicine UDLA

index

1. Introduction (terms)

2. Malaria: pathogenesis/clinical manifestations

3. Visceral Leishmaniasis: pathogenesis / clinical manifestations

4. Chagas Disease: pathogenesis / clinical manifestations

Introduction (terms)

Lymphatic and hematologic infections

1. Introduction (terms)

Hematologic infection of parasites involves diferent mechanisms in order to the pathogen to arise the circulatory system, the red blood cells (ej) and the involved solid organs (hematopoyetic tissues as liver) And then, as a consequence, can be generalized during a systemic infection.

Mandell, 2020

1. Introduction (terms)

Lymphadenitis is an acute or chronic inflammation of the lymphnodes. It may be restricted to a solitary node or to a localized group of nodes draining an anatomic area (regional lymphadenitis), or the involvement can be generalized during a systemic infection. The gross features may reflect nonsuppurative, suppurative, necrotizing, or caseous inflammation, depending on the nature of the infecting microorganism, or noninfectious inflammatory or neoplastic processes.

Mandell, 2020

malaria (hematologic parasite infection)

parasite Lyfe cycle

(1) Plasmodium-infected Anopheles bites a human and transmits sporozoites into the bloodstream. (2) Sporozoites migrate through the liver where they invade hepatocytes and divide to form multinucleated schizonts (preerythrocytic stage). (3) Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. This liver stage does not cause clinical symptoms. (reactivation).

Lyfe cycle

(4) The schizonts rupture and release merozoites into the circulation where they invade red blood cells. Within red cells, merozoites mature from ring forms to trophozoites to multinucleated schizonts (erythrocytic stage). (5) Some merozoites differentiate into male or female gametocytes. These cells are ingested by the Anopheles mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary glands of the mosquito. The mosquito completes the cycle of transmission by biting another host.

pathophysiology

Microvascular disease and sequestration

Coagulation

Parasite biomass

Nitric Oxide

Cytoquines

pathophysiology

Microvascular disease and sequestration

All species of Plasmodium in human infections are likely cytoadherent to cell surfaces. P. falciparum, this period of sequestration is very short it is more than half of the 48-hour life cycle. As P. falciparum parasites mature from rings to trophozoites within red blood cells, they induce the formation of sticky knobs on the surface of erythrocytes, composed of a combination of parasite-produced proteins including P. falciparum erythrocyte membrane protein-1 (PfEMP-1), KAHRP, PfEMP-2, and RESA. The knobs bind to receptors on a variety of cell types in capillaries and venules, including endothelial cells. Notable human receptors include ICAM-1 and ePCR (vascular endothelium), CD36 (on endothelium and platelets), and CSA (in the placenta); a variety of other binding interactions have also been elucidated.

pathophysiology

Microvascular disease and sequestration

Endothelial binding leads to sequestration of infected red cells within these small vessels (thereby removing parasites from the peripheral circulation during a prolonged period of the life cycle). This leads to partial blood flow obstruction, endothelial barrier breakdown, and inflammation. Sequestration can be demonstrated in any organ, the most catastrophic clinical manifestation is cerebral malaria, and renal failure. Clearance of infected red cells by macrophages in the spleen through antibody-mediated mechanisms is a crucial control point for preventing severe disease.

pathophysiology

Parasite biomass

Vascular beds harboring sequestered parasites allow accumulation of high levels of parasite biomass in the host. HRP-2 (a secreted P. falciparum antigen expressed on the erythrocyte membrane) can be used as an indirect measure of parasite biomass both in the circulation and sequestered in the microvasculature. The concentration of this antigen has been observed to correlate with severity of clinical disease

pathophysiology

cytoquines

• The interaction between host endothelium and immune cells with malaria parasites is complex.
• The "cytokine storm" hypothesis suggests that, in the setting of severe malaria, damaging cytokines and small molecules become unregulated and lead to a systemic inflammatory response syndrome (SIRS)-like state with high circulating levels of tumor necrosis factor (TNF) and nitric oxide.
• However, evidence of direct correlation between severe malaria and the activity of these markers is limited. Some markers, such as the acute phase reactant C-reactive protein (CRP), correlate directly with parasitemia.
• Cytokines TNF, lymphotoxin, interleukin (IL)-6, IL-10, IL-12, IL-18, and macrophage inflammatory protein (MIP)-1 are consistently elevated in the setting of malaria.

pathophysiology

pathophysiology

coagulation

• The initiation of tissue factor production in the coagulation cascade has been proposed as a unifying mechanism of pathogenesis in severe malaria, based on the following observations.
• Thrombocytopenia is a common feature of severe malaria; it may also be observed in uncomplicated malaria.
• Activation of the coagulation cascade in the absence of overt bleeding (eg, elevated D-dimer and thrombin-antithrombin complexes with normal prothrombin time and thromboplastin time) is also common.
• Autopsies of patients with cerebral malaria frequently demonstrate fibrin microthrombi admixed with platelets in the cerebral vasculature (as well as other organs).

pathophysiology

coagulation

pathophysiology

coagulation

• Low nitric oxide, low arginine (the precursor of nitric oxide), and elevated arginase activity in peripheral blood have been observed in severe malaria.
• The parasite's arginase enzyme (which converts arginine to ornithine) may contribute to hypoargininemia in severely ill patients, shutting down nitric oxide production.
• Children with nitric oxide depletion due to intravascular hemolysis in the setting of malaria subsequently develop pulmonary hypertension and myocardial wall stress.
• Replenishment of nitric oxide via peripheral arginine has been suggested as a possible treatment.

pathophysiology

pathophysiology

host factors - pathophysiology

Genetic factors Hemoglobin and red cells antigens

Inmmunity Humoral and Cellular response

TNF Factor

pathophysiology

genetic factors

pathophysiology

genetic factors: hemoglobin and red cell antigens

• Several genetic polymorphisms and mutations appear to influence the severity of malaria infection
• Hemoglobin and red cell antigens can confer variable protection against malaria.
• A classic example is the Duffy blood group factor, a red cell antigen necessary for invasion by P. vivax. Absence of the Duffy antigen on red cells is protective for P. vivax malaria.
• There is strong evidence that sickle cell genetic alterations evolved in part because of the survival advantage against lethal P. falciparum infections. Children with HbAS have a significantly lower risk of P. falciparum malaria, lower parasite densities, and lower rates of hospital admissions than children with HbAA. The potential protective effect of sickle hemoglobin against malaria may be augmented in malaria-endemic areas; individuals outside endemic areas may have a lesser degree of protection.

pathophysiology

genetic factors: hemoglobin and red cell antigens

• Red blood cells in individuals with thalassemia appear to be susceptible to P. falciparum invasion but are associated with significantly reduced parasite multiplication.
• This may be due to the variable degree of persistence of hemoglobin F.
• Ovalocytosis in Southeast Asia appears to confer protection against malarial infection. Possible mechanisms include diminished invasion, poor intraerythrocytic growth, or diminished cytoadherence of infected erythrocytes
• Hereditary elliptocytosis appears to confer protection against malaria.
• The haptoglobin (Hp) genotype determines the efficiency of hemoglobin clearance after malaria-induced hemolysis (polymorphism genotype (Hp2/2) has been associated with a reduction in the number of clinical malarial episodes.
• Pyruvate kinase deficiency appears to be protective against infection and replication of P. falciparum in human erythrocytes.

pathophysiology

immunity: humoral and cellular response

• Individuals living in endemic areas appear to develop partial immunity to clinical episodes of malaria following repeated infections; the degree of protective immunity appears to be proportional to transmission intensity and increases with age.
• Individuals in highly endemic areas (eg, sub-Saharan Africa) acquire nearly complete protection from clinical disease by early adulthood.
• Individuals in low transmission areas (eg, Southeast Asia) remain at risk for clinical disease and fatal disease into adulthood; these individuals are referred to as "semi-immune." Individuals not living in endemic areas (eg, travelers) infected with malaria form a detectable antibody response (which can be measured by ELISA).

pathophysiology

immunity: humoral and cellular response

• The humoral immune response to malaria appears to correlate with severity of clinical infection
• Elevated levels of immunoglobulin (Ig)G4, IgE, and IgM are associated with severe disease in individuals with ≤5 previous clinical episodes of malaria, while elevated levels of IgG (IgG, IgG1, IgG2, and IgG3) are associated with mild disease in individuals with >5 previous clinical episodes.
• In addition, individuals who leave endemic areas appear to lose some humoral protection; these individuals are "semi-immune"

pathophysiology

TNF

• Polymorphisms in tumor necrosis factor (TNF) genes appear to influence the severity of P. falciparum infection (homozygous for a polymorphism in the promoter region of the TNF gene (TNF2 allele)).
• Severe anemia was associated with a different TNF allele, suggesting that different genetic factors affect susceptibility to these two disease manifestations.

CLINICAL MANIFESTATIONS OF MALARIA IN NON PREGNANT ADULTS

LYFE CYCLE

SEVERITY, diagnosis

CEREBRAL MALARIA

UNCOMPLICATED MALARIA

COMPLICATED MALARIA - SEVERE MALARIA

DIAGNOSIS

UNCOMPLICATED MALARIA

COMPLICATED MALARIA (falciparum)

DIAGNOSIS OF MALARIA

TREATMENT OF MALARIA

Visceral Leishmaniasis: pathogenesis / clinical manifestations

pathogenesis and clinic

DIAGNOSIS

PATHOGENESIS

CLINICAL MANIFESTATIONS AND COMPLICATIONS

TREATMENT

PATHOGENESIS

• Leishmania invade and replicate within host macrophages, evading innate and cell-mediated immune responses.
• Infection generally appears to persist after clinical cure of the primary infection.
• Evasion and persistence are achieved through a combination of strategies including neutralization of complement components, preventing release of macrophage superoxide and nitric oxide, and suppressing induction of antigen-specific CD4+ T helper lymphocytes.
• Spontaneous recovery is rare, although some relatively mild, self-limited cases of VL have been reported in a cohort of Brazilian children

PATHOGENESIS

CLINICAL MANIFESTATIONS

CLINICAL MANIFESTATIONS

CLINICAL complications

diagnosis

diagnosis

diagnosis

• Histopathologic demonstration of parasite requires needle aspiration or biopsy of affected organs. Usually, bone marrow or spleen aspirations are performed (sensitivity 70 and 96 percent in one comparative analysis)
• Lymph node aspiration can also be performed, although sensitivity is lower than at the other sites (sensitivity 58 percent)

diagnosis

differential diagnosis

• Malaria
• Tuberculosis
• Histoplasmosis
• Amebic liver abscess
• Schistosomiasis
• Lymphoma

treatment

principles of treatment

Agents with efficacy against VL include:

• amphotericin B, pentavalent antimonial drugs,
• paromomycin (a parenteral aminoglycoside),
• and miltefosine (the first oral drug for treatment of VL

main treatment

TRYPANOSOMA SPP. / CHAGAS DISEASE: pathogenesis / clinical manifestations

pathogenesis and clinic

DIAGNOSIS

EPIDEMIOLOGY - TRANSMISSION AND PATHOGENESIS (RISK GROUPS)

CLINICAL MANIFESTATIONS Acute and Chronic Infection

TREATMENT

epidemiology - transmission - pathogenesis

epidemiology

other transmission routes

• Vertical: 22% - breastfeedng: 1 - 10%
• Blood Transfusion: the risk of transmission via blood transfusion has diminished greatly but has not been eliminated; in such regions, the risk of transmission is estimated to be 1:200,000 units
• Organ Transplantation:
• kidney recipients (0 to 19 percent)
• liver recipients (0 to 29 percent)
• heart recipients (75 to 100 percent)
• Oral transmission: Vehicles of oral transmission have included açaí palm fruit, guava juice, and juice prepared from sugarcane. However, ingestion of T. cruzi amastigotes via consumption of raw meat is an unlikely mode of transmission
• Laboratory accidents: rarely

PATHOGENESIS - NATURAL HISTORY

CLINICAL MANIFESTATIONSACUTE AND CHRONIC INFECTION

ACUTE INFECTION

ACUTE INFECTION

chronic INFECTION

• When the host immune response succeeds in decreasing parasite replication, parasitemia falls below levels detectable by microscopy, acute symptoms resolve, and the patient passes into the chronic phase.
• In the absence of successful antitrypanosomal therapy, this usually occurs 8 to 12 weeks after the onset of infection, and the chronic phase lasts for the life of the patient.
• Nearly all T. cruzi-infected persons have the indeterminate (asymptomatic) form during the first one to three decades of the chronic phase; an estimated 20 to 40 % will subsequently develop cardiac and/or gastrointestinal forms of the disease.

indeterminate form

• Patients with the indeterminate form of the chronic phase of T. cruzi infection have positive serology but no symptoms or signs of cardiomyopathy or gastrointestinal disease
• The indeterminate form may persist for decades.
• About 20 to 30 % with the indeterminate form develop cardiomyopathy after a latent period ranging from 5 to 30 years.
• Approximately 10 to 15 % of patients with the indeterminate form develop gastrointestinal disease, and a subset of patients develop both cardiac and gastrointestinal (cardiodigestive) disease

risk factors - clinical manifestations

risk factors - clinical manifestations

risk factors - clinical manifestations

DIAGNOSIS

diagnosis

diagnosis

DIAGNOSIS CRITERIA: indeterminate form

• The approach to identification of determinate forms of Chagas disease is controversial.
• Classical criteria:
• The indeterminate (or latent) form of Chagas disease is classically diagnosed in patients with serologic and/or parasitologic evidence of chronic T. cruzi infection who lack all of the following:
• Symptoms or physical signs of heart failure, arrhythmia, or thromboembolism
• Abnormalities on 12-lead-ECG with 30-second lead II rhythm strip
• Any radiographic evidence (on chest radiograph or barium-contrast esophageal or colon radiographs) of cardiac or gastrointestinal involvement

treatment

treatment: principles

• The only drugs with proven efficacy against Chagas disease in human trials are benznidazole and nifurtimox. In general, benznidazole is better tolerated as the first-line treatment for Chagas disease.
• In addition, compared with nifurtimox, there are more recent clinical trial data for the use of benznidazole.
• However, some patients tolerate nifurtimox better than benznidazole; when treatment with one drug must be discontinued, the other can be used as an alternative.
• Both benznidazole and nifurtimox are contraindicated in pregnancy.
• Antitrypanosomal agents are contraindicated in patients with severe renal or hepatic dysfunction

treatment

treatment

treatment

treatment: adverse effects

thanks!