Histoplasmosis of the nervous system
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the
Jun. 09, 2021
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Sleeping sickness is a prevalent and serious, yet often ignored and understudied, infectious illness. In this article, the author summarizes the key features of this illness and provides information about promising treatment and prevention methods.
• African sleeping sickness is a devastating but unfortunately forgotten epidemic that affects tens of thousands of sub-Saharan Africans.
• Underdiagnosis remains a major barrier to effective control and diagnosis is usually established by parasite identification, although PCR and other gene tests are being developed.
• The causative agent usually belongs to 1 of 3 species of the Trypanosoma genus and is transmitted to humans through a vector, the tsetse fly.
• Effective vaccination does not exist and most available chemotherapeutic agents have some degree of toxicity although research is ongoing to find an effective, nontoxic alternative.
• Vector control remains an effective yet not often utilized method of prevention.
African sleeping sickness or human African trypanosomiasis (HAT), in French la maladie du sommeil, was described in the last half of the 19th century by European explorers of West Africa who observed patients with enlarged glands and dramatic neurologic symptomatology, often in epidemic settings. Sleeping sickness was an established part of the tribal lore of West Africa, especially in the Congo and Niger basins and the Upper Voltas. Beginning in 1885, the commercial development of the Congo Free State, with soldiers, settlers, and laborers plying the Congo River basin, led to the extensive spread of the disease from "primordial" riverside foci, aided by the clearing of the forests and their replacement with low thicket that favors the tsetse fly (Glossina genus) vector. During the early 1900s, several legendary pioneers of tropical medical science, including D Bruce, A Castellani, JE Dutton, H Koch, A Laveran, P Manson, FW Mott, and E Rouband, elucidated the disease cycle and causative protozoal trypanosomes now known collectively as the Trypanosoma brucei subspecies.
HAT evolves in 2 distinct stages. In the first stage, the illness principally affects the hemolymphatic system with the parasite confined to the blood and lymphatic system. The second or late stage affects the nervous system, causing meningoencephalitis. There have been, however, reports of nervous system involvement in the early stages as well. Neurologic symptoms and CSF inflammatory markers can appear in the first stage of the Trypanosoma brucei rhodesiense variant (37). Depending on the parasite strain, the clinical picture varies as do virulence and degree and rate of progression. Concurrent infections are common. The 2 major groupings are geographical. Trypanosoma brucei rhodesiense characteristically produces an acute course that is fatal in a few months from damage to the heart or viscera; Trypanosoma brucei gambiense frequently results in a chronic infection of several years, leading to the extensive nervous system involvement of classic HAT. Rarely, even the initial symptoms manifest after a long incubation period lasting up to 7 years (75).
In the virulent Trypanosoma brucei rhodesiense variant, a chancre develops at the site of the infective bite of Glossina. In both variants, local lymph gland enlargement occurs near the bite. Fever develops when the parasite invades the blood several hours or weeks after the bite. In the Gambian disease, there may be enlarged cervical lymph nodes (Winterbottom sign). In the Rhodesian form, the adenopathy principally involves the axillary and epitrochlear nodes. Irregular febrile episodes are accompanied by endocrine disorders (sterility, impotence or amenorrhea, and abortion) and moderate splenomegaly and hepatomegaly. Cardiac abnormalities progress from early tachycardia to pericarditis involving all layers, valves, and conducting systems. Anemia is a consistent symptom, probably caused by changes on the red blood cell membranes that lead to erythrophagocytosis during acute stages of the disease (64). A peculiar deep hyperesthesia (Kerandel sign) can occur in a small number of patients. Human African trypanosomiasis can also be considered in cases with anterior uveitis in patients coming from endemic areas (54).
Neurologic manifestations, including headache, altered EEG, mood changes, may occur during the initial febrile period before trypanosomes can be detected in the cerebrospinal fluid and are associated with meningeal inflammation. Nevertheless, neurologic symptoms such as gait ataxia, somnolence, tremor, and abnormal Glasgow Coma Scale score may persist into the late-stages (63). In the Rhodesian variety, the neurologic changes do not always become marked, with only drowsiness, tremors, and unsteadiness, preceding the terminal coma. In the Gambian form, meningitis progresses to encephalitis with serious motor impairment (dyskinesia and choreoathetosis); dysregulation of the circadian clock including reversal of sleep patterns with daytime somnolence interspersed with bouts of delirium, mania, and schizoid and aggressive behavior; and finally permanent sleep, coma, and death. Meningitis and encephalitis are marked by extensive infiltrations of monocytes, lymphocytes, and plasma cells. With Trypanosoma brucei gambiense, the interval between the start of the infection and the encephalitic stage is about 2 years, but an interval of as long as 8 years may elapse. With Trypanosoma brucei rhodesiense, the interval is usually a few months. The prominence of one symptom over the other, the rate of progression, and prognosis vary with geographic location as well (38). Symptoms may also be different among natives of endemic areas and those spending short periods of time in those areas primarily because of a difference in the pathogen. Trypanosoma brucei gambiense is extremely rare among tourists and visitors from nonendemic areas who tend mostly to become infected by Trypanosoma brucei rhodesiense. They, therefore, present with the more acute symptomatology (04).
Fever among Caucasian visitors is common with both species (Trypanosoma brucei rhodesiense 97.8% and Trypanosoma brucei gambiense 93.3%) as is headache (50% each). Chancres were more common with Trypanosoma brucei rhodesiense (84.4%) than with Trypanosoma brucei gambiense (46.7%). Surprisingly, although sleep symptoms are prevalent in endemic HAT, they are rarely reported in travelers. Insomnia was more common (Trypanosoma brucei rhodesiense 7.1%, Trypanosoma brucei gambiense 21.4%) than daytime sleepiness (Trypanosoma brucei rhodesiense 4.8%, Trypanosoma brucei gambiense none). Jaundice, a symptom never described in endemic HAT, was reported in 24.2% of the Caucasian Trypanosoma brucei rhodesiense patients (69). Neurologic and psychiatric symptoms predominate in the presentation of HAT among Africans from nonendemic areas because the early symptoms are often missed. The common symptoms were daytime sleepiness (46.2%), weakness (64.3%), hyperreflexia (14.3%), hallucinations (21.4%), and depression (21.4%) (69).
With the advent of PCR, the presence of asymptomatic human carriers is now well documented. Treating these seropositive individuals may significantly cut down the risk of transmission, especially in areas of low disease prevalence (25; 27). Spontaneous termination for Trypanosoma brucei rhodesiense, although rarely reported is suspect because of lack of precise diagnosis and long-term follow-up. Such cases are probably due to atypical or anomalous parasite strains. Early detection reduces mortality significantly, even in the second stage. Without chemotherapy, the outcome is inevitably fatal once there is neurologic involvement. A study estimated that survival in stage 1 and stage 2 Trypanosoma brucei gambiense infections was 3 years in the absence of treatment. In both forms of the disease, prognosis is excellent, provided chemotherapy is given early. After the parasite is established in the central nervous system, chemotherapy with toxic drugs is required, and cure rates of around 90% may be obtained. Single or multiple relapses may occur, but the melarsoprol sometimes used in the resistant late stage may itself induce a fatal reactive encephalopathy, which in some studies has been put at 10%. In some patients, the parasites may be resistant to even melarsoprol. Surveillance should continue for up to 4 years in Trypanosoma brucei gambiense infections. If treatment commences when meningoencephalitis is advanced and the parasitic infection is successfully cleared, sequelae may include insomnia or sometimes attacks of violent behavior. Biological markers were developed to assess treatment outcome in late stage Trypanosoma brucei gambiense. Six months after treatment, CSF WBC counts of less than 5 cells/mL were a marker of low risk of relapse. Twelve to 24 months after treatment, the combination of high CSF white blood cell counts and high IgM levels were accurate markers of subsequent treatment failure. Infection by multiple different strains of Trypanosoma brucei gambiense results in a more severe neurologic course and higher mortality (68). Barriers to early treatment include difficulty of detection, logistics of treatment, regional socio-political instability, and cultural stigma (11).
A novel protein marker in the CSF, neopterin, is the most accurate marker to date of response to treatment as well as a predictor of treatment failure. High levels of neopterin in the CSF of those infected with Trypanosoma brucei gambiense were associated with a higher rate of treatment failure. In addition, 6 months after treatment, neopterin discriminated between cured and relapsed S2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers (65). Another biomarker currently being studied for disease staging is CXCL-13. Using both neopterin and CXCL13 in conjunction could prove to be a sturdier predictor of disease than each alone. In addition, those markers could be detected in body fluids other than CSF, thus avoiding excessive lumbar punctures (08).
A 58-year-old man presented to an emergency room with lethargy and fever in Düsseldorf, Germany. He had just returned home from a 15-day vacation at a Lusaka game reserve in Zambia. Three days earlier he had noticed painful swelling on his right leg. During the examination he was drowsy, had slurred speech, and was febrile. He was mildly tachypneic and tachycardic with a Glasgow coma scale of 12/15. He was also noted to have facial swelling, a macular rash, 2 indurated skin chancres on his leg, and hepatosplenomegaly. Blood smears detected Trypanosoma brucei rhodesiense. Treatment was initiated first with pentamidine, but the patient failed to respond and his condition deteriorated until he ended up in the intensive care unit, intubated. He then received intravenous suramin with 6 weekly doses of 20 mg/kg. After the second dose, the patient improved clinically, and both CSF and blood analyses showed no evidence of Trypanosoma. The patient recovered completely and was discharged after the last treatment. He was followed for 18 months after discharge and had no residual sequelae (58).
The disease is caused by a subspecies of the flagellated protozoa Trypanosoma brucei (order Kinetoplastida) transmitted to humans by the bite of the tsetse fly, Glossina. The acute Trypanosoma brucei rhodesiense is transmitted by flies of the G mortisans group, and the chronic Trypanosoma brucei gambiense is transmitted by the G palpalis group, but all 23 species of Glossina appear capable of acting as vectors. Although the terminology Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are adhered to, application of isoenzyme electrophoresis and DNA analysis is leading to more accurate understanding of strain and zymogene groups, which correlate with clinical features and geographical distribution. Human blood, unlike the blood of other mammals, has efficient trypanolytic activity due to apolipoprotein L1, an ionic-pore-forming apolipoprotein. Among mammals, pigs are the most common reservoir followed by humans, wild animals, and lastly goats. In areas where there are larger herds of pigs, there is a lower infection rate among humans (53).
The parasites are acquired by the tsetse's feeding on infected animal reservoirs, including domestic animals and cattle, game, and sometimes humans. According to a study from Cameroon, 3.88% of domestic animals harbored Trypanosoma brucei gambiense (52). A complex developmental cycle in the fly leads to infective metacyclic trypanosomes that are extruded during the probing and feeding process. The parasites spread to the hemolymphatic system and also occupy perivascular and connective tissue spaces. There is a general increase in inflammatory perivascular cellularity (lymphocytes and plasma cells). Waves of parasitemia are controlled by specific antibodies, but some parasites escape immune lysis by the mechanism of antigenic variation, which is an innate genetic switching process that enables the parasite to produce an antigenically different surface coat (46). A new multiplication cycle is then initiated. The result is a fluctuating parasitemia with progressive immunosuppression and multisystem pathology, which vary in intensity according to parasite strain, population, and individual characteristics.
Immunology. Another mechanism by which the trypanosomes evade the immune response and, in addition, divert the host reactions to their benefit is the release of a specific substance termed trypanosome lymphocyte-triggering factor (TLTF). This substance binds to CD8+ T-cells and activates them to produce interferon-gamma, which in turn triggers proliferation of the parasite. This contributes to the Th-1-type immunological response triggered by stimulation of Toll-like receptor 9 on macrophages by parasite CpG DNA (40). The causes of the pathology are multifactorial and thought to result from direct parasite damage, toxic parasite products, and altered immune function and cytokine production. Stage progression in human African trypanosomiasis has been associated with high CSF levels of IL-6, IL-10, and INF-gamma (63). Rather than clearing the parasites, tumor necrosis factor-alpha may act as agents of host pathology. TNF-alpha-mediated inflammatory pathology is associated with rapid disease progression. The different severities observed in different populations may result either from differing virulence phenotypes trypanosomes or from immune response polymorphisms in the different host populations. CSF levels of CD19+ B cell increase with disease severity, whereas in the serum, CD19+ B cells are consistently high. Activated CD8+ T cells, on the other hand, are not elevated, and memory CD8 T-cell levels are suppressed (06).
High levels of endotoxins and antibodies to endotoxins from gram-negative bacteria occur in the blood of the chronic patient. There is good evidence from studies on animal models and research realized in Uganda that Trypanosoma brucei rhodesiense is associated with low-grade parasite-independent endotoxemia. Plasma endotoxin concentration has been correlated to the occurrence of splenomegaly and lymphadenopathy. The source of endotoxin in this disease comes from increased intestinal leakage initiated by the parasite; elevated endotoxins in turn correlate with the alterations in nitric oxide and other proinflammatory cytokines such as IFN-γ and TGF-β (36).
Many studies have focused on the mechanisms underlying the changes in the CNS, especially those associated with alterations in sleep that accompany the late disease stages. Most information has been obtained from the animal models. The neuropathology has many components; these include a meningeal and generalized perivascular inflammation, with the infiltrations consisting chiefly of lymphocytes and plasma cells. There is breakdown of the choroids and compromise of the blood-brain barrier. Throughout the brain, there is activation of astrocytes and microglia, with alterations in cytokine and mediator expression and production. However, with the exception of the periventricular organs, the trypanosomes do not penetrate the brain parenchyma. Studies in mouse models suggest that parasites gain entry to the brain parenchyma by capitalizing on the translocation of T cells across the blood-brain barrier. Release of TNF-alpha is necessary for their penetration of the endothelial tight junctions, and IFN-gamma activation of the chemokine CXCL10 is required for crossing the astrocyte basement membrane (40). Glial fibrillary acidic protein (GFAp), light subunit neurofilament protein, autoantibodies against cerebrosides, gangliosides, and myelin basic proteins as well as immune complexes and bacterial endotoxins can be detected in the CSF.
Pathophysiology. The oscillatory activities and circadian timing capacities of the suprachiasmatic nuclei of the hypothalamus become dysregulated. CSF hypocretin-1 levels were found to be significantly higher in HAT (423.2 +/- 119.7 pg/mL) than in narcoleptic patients (40.16 +/- 60.18 pg/mL) but lower than in neurologic controls (517.32 +/- 194.5 pg/mL). No differences were found in CSF hypocretin levels between patients with stage 1 or stage 2 HAT; however, the presence of major sleep-wake cycle disruptions was significantly associated with lower CSF hypocretin-1 level (15). CSF tryptophan and kynurenine concentrations were found to be elevated in early and late stages of the disease. Kynurenine pathway activation was associated with increased neuroinflammatory markers; however, a relationship with neurologic symptoms was not established (63). Recent animal (mouse) studies suggest that trypanosomes shorten the period of the circadian clock in infected mice, most likely secondary to a secreted substance, as the effect precedes the detection of parasites in the brain parenchyma (59). This period shortening accumulates over time and leads to significant disruption of the mouse activity cycle. Such a disruption would be consistent with the observation that patients with HAT sleep the same amount during the day as controls, but that sleep occurs at irregular intervals.
HAT is only endemic in areas where Glossina species are found. This is in turn determined by climate through its effect on vegetation. The ecological range of Glossina is bound approximately by a line commencing 14 degrees north from Senegal in the West to 10 degrees north in Somalia in the East, and 20 degrees south corresponding to the northern fringes of the Kalahari and Namibian deserts. The area is about 11 million square km or one third of the African continent. The disease is endemic in 36 countries, an area of approximately 10 million square kilometers. The annual incidence of the disease used to be approximately 300,000 cases; however, thanks to new chemotherapeutic agents, awareness campaigns, and the World Health Organization’s efforts of controlling transmission, the number of reported cases over the first decade of the 21st century dropped to only 10,000 in 2009, an all-time 50-year low (62). That number further dropped to 1420 cases in 2017 (16). High-risk foci (foyers) of Trypanosoma brucei gambiens remain, however, in Chad, Central African Republic, Democratic Republic of Congo, Equatorial Guinea, and Gabon with incidences of 0.1% to 1% per year (60). Outbreaks of Trypanosoma brucei rhodesiense sickness commonly occur in foci ("foyers") historically recognized as sites of high prevalence, with increased transmission at the end of the dry season when contact between humans and fly is intense. Trypanosoma brucei rhodesiense is endemic in woodland savanna, where the game animal reservoir and Glossina are prevalent, HAT foci seem to have moved from the North to the South of West Africa. Endemic HAT presently appears to be limited to areas where annual rainfall exceeds 1200 mm. Currently, the most severely affected countries are the Democratic Republic of the Congo, Guinea, and Côte D’Ivoire whereas the northern countries seem less affected. There are 21 million people who live in areas classified as moderate to very high risk, where more than 1 HAT case per 10,000 inhabitants per annum is reported (61). The prevalence in Democratic Republic of the Congo for example, was estimated in 2011 to be 30 out of 100,000 almost twice the 2007 reported prevalence. This increase was due to better reporting that led to discovery of cases that were previously missed (45). According to the World Health Organization, Democratic Republic of Congo is the only country that currently reports more than 1000 cases per year and accounts for 84% of the cases reported in 2015. Overall number of fatalities in 2010 (although greatly underdocumented) was 9100, with an incidence of 0.1 out of 100,000 per year (33).
With increased awareness of the illness and increased travel to endemic areas, there has been an increase in the number of HAT reported among European and other nonendemic expatriates. A comprehensive study reported 244 cases of HAT in people from nonendemic countries over a period of 110 years. The 2 peaks of incidence were from 1902 to 1920 (110 cases) and 2000 to 2012 (125 cases). Of the former group, 74.3% were missionaries and soldiers and Trypanosoma brucei gambiense accounted for 78% of cases. Of the latter group, 73% were short-term tourists to game reserves and Trypanosoma brucei rhodesiense was the more prevalent infection, accounting for 76.4% of all HAT cases in this cohort (50).
The Food and Agriculture Organization of the United Nations is developing a geographic database to track the distribution of the illness for future monitoring, control, and research activities (12). In 2012 a targeted door-to-door survey that focused on former HAT patients was performed in Bonon (Côte d’Ivoire), but no new cases of HAT were detected; however, when testing 1058 individuals from the immediate neighborhood of 72 former HAT patients, 4 new HAT cases were detected with 0.4% prevalence (29).
Intensive campaigns have been shown to be effective in eliminating trypanosomiasis in certain areas. Tsetse fly bites are reduced by protective clothing. Trypanosoma brucei rhodesiense transmission is "site associated," with up to 10-fold higher prevalence at sites near riverine vegetation, crossings, villages, sacred sites, and water collection and washing sites. Trypanosoma brucei rhodesiense is considered to place at greatest risk those whose occupations bring them into more frequent contact with savanna Glossina: honey gatherers, fishermen, game wardens, poachers, and firewood collectors. Some campaigns to control tsetse flies have proven to be counterproductive. Although some lead to a decrease in tsetse fly population densities, they allow for the emergence of treatment resistant flies (14). Because cattle can serve as a reservoir as well, particularly for the Trypanosoma brucei rhodesiense disease variant, livestock markets play a role in the transmission of the illness; transmission can be prevented if the animals are treated at the point of sale as required by the government of Uganda (73). This is not as common for the Gambiense variant as a study failed to find any Trypanosoma brucei gambiense in blood samples from cattle and pigs, making them unlikely reservoirs of the disease (14). In addition, there has been some evidence that infected humans can remain asymptomatic for long period of times, thus becoming cryptic reservoirs of the disease themselves. This issue needs to be further studied with proper diagnostic tools developed to aid in eliminating HAT (14). Large-scale screening of affected individuals has also been difficult because of lack of privacy and associated stigma and misconceptions about treatment and the toxicity of the drugs used to treat HAT (42). In addition, the diagnosis of HAT is more complex than a simple screening, whereby positive screening should be followed by a parasitological confirmation. This proves to be difficult on the logistic and resources level (43). Using insecticide treated traps in the shape of humans and cattle, vector control is another method of prevention that has been proven somewhat successful (71), especially when integrated with other screening strategies (28). Political turbulence and resulting armed conflict, however, has made this type of prevention increasingly difficult (02). A single intervention with trypanocidal chemoprophylaxis targeted at cattle in Eastern Uganda was highly effective at removing Trypanosoma brucei rhodesiense parasites from cattle reservoir and significantly decreased cases of the disease in that area (21). Alternatively, for Trypanosoma brucei gambiense, where wild animal reservoirs play a larger role in transmission, vector control has also been shown to be effective. New, more cost-effective methods include using smaller electrified nets and small, inexpensive, insecticide-impregnated targets (19; 66). A study has shown that in order to achieve g-HAT elimination, a combination of vector control and medical intervention has to be pursued (48). Vector control has to be tailored towards identifying, targeting, and monitoring local tsetse migration corridors and migration rates. Models implemented in Chad, Uganda, and Guinea have proven that medical interventions combined with vector control lead to a significant decrease in Trypanosoma brucei gambiense transmission. Continued use of this strategy is predicted to result in elimination of a public health problem by 2018 and zero transmission in 2020 (39).
Vaccination is theoretically, the most viable and complete option for prevention. It has thus far been unsuccessful because of the difficulty of finding an effective antigen and dearth of research projects. Partially effective trials have been conducted with the following antigens: actin, tubulin, sialidase microtubule-associated protein, surface glycoproteins, and other enzymes (30). Variant surface glycoprotein-derived peptides (VSG) hold some promise as the target for vaccines as they are relatively conserved among strains (03).
Lastly, recognizing that the tsetse fly often infects hosts while they are indoors may lead to better methods of “fly proofing” individual houses (70).
The prevalence of other tropical diseases in areas where HAT is endemic together with the high incidence of intercurrent infections in patients makes accurate diagnosis essential. The early chancre may be confused with infected bites from insects other than tsetse. Among the many causes of fever in a HAT area are malaria, relapsing fever, typhoid, and kala azar. Hodgkin disease, with characteristic temperature fluctuations and adenopathy, infectious mononucleosis, and brucellosis are other alternatives. The enlarged glands may be due to tuberculosis or in some patients from pediculosis, scabies, or other skin lesions. The varied nervous manifestations of the chronic Gambian disease may result from meningovascular syphilis, tuberculous or viral meningitis, parkinsonism, or HIV-1 disease. The wasting may be associated also with HIV-1 or hookworm infections. The likelihood of double infection, in particular with hookworm, malaria, or HIV-1, is high. Differential diagnosis also includes autoimmune disorders such as systemic lupus erythematosus. Differential diagnosis has posed particular problems for emigrants or visitors returning from Africa, where the insidious and often long latent period of the Gambian disease, which can be up to 4 years, has resulted in misdiagnosis and unnecessary death (69). Additionally, American physicians may lack familiarity with the disease, and the initial symptoms can be vague. HAT diagnosis should not be overlooked in patients coming from endemic areas, especially if they have a clinical presentation consistent with subacute encephalitis (18; 11).
As mentioned previously, diagnosis of sleeping sickness requires screening with a rapid diagnostic test followed by parasitological confirmation (43).The traditional mainstay of diagnosis has been the positive identification of trypanosomes in fluids or tissue from patients. Blood films may be examined directly under the microscope, but the major problem with both forms of the disease is that parasites may only be present in small numbers for periods of weeks or more. Sensitivity is increased by concentrating the parasites using either thick blood films or microhematocrit triple centrifugation followed by examination under dark-ground/phase contrast microscopy. Quantitative buffy coat technique combines centrifugation with acridine orange fluorescent trypanosome detection. Parasites may also be separated by passing through a miniature anion exchange column (mAECT) and then visualized under a microscope. The main limitation of direct visualization is the inability to differentiate between the 2 types of trypanosomes. Aspirates of lymph fluid or, occasionally, bone marrow are also valuable.
Several serological methods are available that are based on direct agglutination, hemagglutination, gel precipitation, immunofluorescence, and enzyme-linked immunosorbent assays. Because antibody production against the surface glycoproteins of Trypanosoma brucei rhodesiense is relatively limited regardless of geographical location, their detection provides a fairly reliable marker. The card agglutination test (CATT) is the most practical and in widespread use. Unfortunately, it has many limitations, including poor sensitivity and specificity. The immune trypanolysis test improves the accuracy of the card agglutination test in endemic areas (26), as does the ELISA test (22) and the latex agglutination. The use of these tests, however, applies primarily for the detection of Trypanosoma brucei gambiense. CATT remains the best serological screen Trypanosoma brucei rhodesiense (74). Since 2010, rapid diagnostic tests (RDT) have been used as a complement of CATT. SD BIOLINE® HAT is a new RDT that has shown higher sensitivity and slightly lower specificity than CATT, which means that the need for a test with better performance persists (34). A test using similar technology, HAT Sero-K-SeT, was shown to have excellent sensitivity and specificity (100% and 97%, respectively) in a phase III diagnostic accuracy trial for use in passive screening, although the study was limited by its small size (07). It also remains quite expensive due to use of native antigens. In contrast, SD BIOLINE® HAT 2.0, which is considerably cheaper due to use of recombinant antigens, was assayed against the CATT and the original SD BIOLINE® HAT in a much larger trial that looked at both active and passive screening. In this trial, SD BIOLINE® HAT 2.0 had a sensitivity of 98.4% in passive screening and 83% in active screening. There was some evidence suggesting that a test incorporating multiple antigens may be more sensitive and specific to account for parasite variation (35).
The advent of real-time PCR for the detection of Trypanosoma brucei in human blood samples has increased the accuracy of diagnosis whenever it is available and may eventually replace microscopy (44). Moreover, PCR is helpful in differentiating between different Trypanosoma species. There is, however, a limitation to PCR use in the follow-up of treated patients as 20% of cases, despite successful cure, continue to have PCR positivity for up to 2 years (17). Two other techniques that have been developed and require fewer resources than PCR are loop-mediated isothermal amplification (LAMP) and nucleic acid sequence-based amplification (NASBA). Neither is commercially widely available nor have they been compared directly to PCR (74).
Polysomnography can demonstrate normalization of sleep-wake patterns after treatment is instituted. Actigraphy, a simpler and less costly sleep diagnostic tool shows promise in evaluating sleep-wake disturbances in patients with HAT. Although actigraphic changes do not mirror white blood cell counts in the CSF, they do correspond to polysomnographic changes and may demonstrate clear sleep-wake improvement once treatment is instituted (51).
The late, or second-stage, disease with central nervous system involvement is determined by cerebrospinal fluid analysis. The fresh cerebrospinal fluid must be centrifuged and quickly analyzed because the parasites are rendered more fragile than in blood. Multiple centrifugation procedures may be employed. Parasites may be absent from the cerebrospinal fluid sample even though the blood-cerebrospinal fluid barrier has been breached and meningoencephalitis is established. More precise criteria for accurate staging of the blood, lymph, or CNS involvement are required. At present, the combination of lymph fluid and CSF examination by miniature anion exchange and modified single centrifugation analysis provides the most suitable routine procedure for detection in the field. The widely accepted criteria for CNS involvement following cerebrospinal fluid analysis are (1) presence of trypanosomes, (2) white blood cells greater than 5 cells per mm2, or (3) protein greater than 40 mg. If HAT has already been diagnosed, the lymphocyte pleocytosis and elevated protein, which in some cases may be high, may be considered strong indication of central nervous system involvement or relapse (67). New research has been directed to the identification of biomarkers of disease in blood that will enable to discriminate between stage 1 and 2, removing the need for lumbar puncture from HAT staging algorithms (72).
There have been attempts in creating algorithms for early detection and disease staging. These incorporate clinical findings, CATT, and other serological testing in blood, CSF, and lymph. Five regional algorithms exist with a sensitivity ranging from75% to 90% and a maximum positive predictive value of 75% at 1% prevalence. Approximately 50% of stage 1 cases were misclassified as stage 2 (13).
A specific marker of cure is spliced leader RNA. When compared to DNA detection in serum, its specificities were 98.4% to 100% as compared to only 77% for DNA detection (24).
A study using brain MRI imaging in HAT demonstrated unique high FLAIR signals in the midbrain, pons, medulla, corona radiata, caudate nuclei, hypothalamus, and cerebellar white matter (09). These changes were not reported before in humans. The uniqueness of these findings and the correlation with clinical findings may be an important area to explore in order to further enhance the ability to diagnose HAT.
The treatment of gambiense HAT varies with the stage of the disease. Traditionally, pentamidine used to be given for the early stages of infection with Trypanosoma brucei gambiense. However, clinical trials with fexinidazole were successfully completed, and fexinidazole was hence introduced to the therapeutic protocols (20). Fexinidazole has replaced pentamidine as first-line treatment in patients with first-stage gambiense HAT (31). Pentamidine is given at 4 mg/kg intramuscularly every 24 hours for 7 days. Fexinidazole on the other hand is administered as oral medication once a day for 10 days. If the patient is an adult weighing more than 35 kgs, the patient should receive a loading dose of 3 tablets (1800 mg) each day for 4 days and a maintenance dose of 2 tablets (1200 mg) each day for the remaining 6 days. If the patient is a child aged more than 6 years and weighs more than 20 kg and less than 35 kg, the patient should receive 2 tablets (1200 mg) each day as a loading dose for 4 days and then 600 mg (1 tablet) each day as a maintenance dose for the remaining 6 days (31; 49).
For late stage infection with Trypanosoma brucei gambiense, the traditional first line of treatment has been a combination of eflornithine and nifurtimox or NECT. The dosing is usually eflornithine 200 mg/kg every 12 hours intravenously for 7 days and oral nifurtimox 15 mg/kg orally per day in 3 divided doses for a duration of 10 days (57). Compared to eflornithine alone at the same total daily amount divided into 4 doses but for 14 days, NECT was equally effective and was less toxic (57). Third-line treatment would be intravenous melarsoprol 2.2 mg/kg daily for 10 days.
Head-to-head comparison has also shown that eflornithine saves more lives than melarsoprol, but melarsoprol is slightly more cost effective. Switching from melarsoprol to eflornithine can be considered a cost-effective option according to the WHO choice criteria.
Lately however, the recommendation has evolved to using fexinidazole instead of nifurtimox-elfornithine combination therapy in patients with second-stage gambiense HAT and less than 100/μL cerebrospinal fluid white blood counts. The recommendation remains to use nifurtimox-elfornithine in patients with more than 100/μL cerebrospinal fluid white blood counts (31).
The approval for the usage of fexinidazole is a milestone because it is the first oral drug approved for the treatment of HAT. This eliminates the need for injectable treatment, which has been a hurdle in the elimination of HAT because it is more accessible. Fexinidazole has a relatively safe side effect’s profile when compared to other drugs. The side effects are mainly gastrointestinal such as nausea and vomiting, and they may also include headache, insomnia, tremor, and dizziness. Fexinidazole should always be taken with a meal because of a low bioavailability in the fasting state. In addition, fexinidazole has not been approved for usage in children younger than 6 years of age or those who weigh less than 20 kg, whereby pentamidine is still the preferred drug in that population. There is an ongoing clinical trial (DNDiFEX09HAT) assessing the safety and efficacy of fexinidazole in vulnerable populations such as pregnant women, breastfeeding women, and patients with a poor nutritional status (31; 49).
It is important to note that there have been no clinical trials comparing fexinadazole and pentamidine. However, based on the benefits and side effects of both drugs in different studies, fexinidazole seems to be the likely superior drug and is, therefore, now recommended as first line.
For Trypanosoma brucei rhodesiense, suramin is given. For adults in a reasonable state of health, a test dose of intravenous suramin 200 mg is followed by 20 mg/kg intravenously on days 1, 3, 7, 14, and 21. Children should receive lower doses proportional to weight and health.
For the late stage of Trypanosoma brucei rhodesiense, melarsoprol is given by intravenous injection at 2.2 mg/kg/day for 10 days. If melarsoprol fails, then a pretreatment with a single 4 to 5 mg/kg of suramin is recommended followed by a repeat course of intravenous melarsoprol 2.2 mg/kg/day for 10 days. In fact, most experts recommend pretreatment with suramin to treat the parasitemia and avoid a Jarisch-Herxheimer reaction that is a severe inflammatory reaction associated with a sudden release of endotoxins (04).
Because melarsoprol is a highly toxic drug and fexinidazole has shown promise of killing Trypanosoma brucei rhodesiense in vivo and in vitro, a clinical trial assessing the efficacy of fexinidazole in the treatment of rhodesiense HAT has started (NCT03974178) (31).
In all late-stage cases, careful assessment of any intercurrent infections must be made. Preliminary treatment with antimalarials, antibiotics, and anthelminthics is routine in order to avoid the potential toxic effects of currently available medications and to address the issue of drug resistance.
A substance that has shown in vitro trypanocidal activity is the antihelminthic drug niclosamide. This agent has been shown to be noninferior for treatment of stage II Trypanosoma brucei gambiense HAT in a phase III clinical trial (41). Its oral delivery route is a distinct advantage over NECT. It is currently scheduled for testing in children and pregnant women, but low numbers of HAT cases are making it difficult to adequately study it for this purpose (01). Another oral antitrypanosomal that has shown promise is the oxaborole SCYX-7158 (01). Acoziborole is yet another drug being studied that may offer a new perspective because it is a single dose oral treatment (20).
In phase III trials, the first state of Trypanosoma brucei gambiense responded to the experimental antihelminthic pafuramidine. The cure rates 3 months posttreatment were 79% in the 5-day pafuramidine group, 100% in the 7-day pentamidine group, and 93% in the 10-day pafuramidine group (10). When directly compared to pentamidine, the overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group (56).
Finally, a promising class of medications is the selective tubulin inhibitor group, which holds great promise in animal studies because they inhibit the growth of trypanosome cells, sparing viability of mammalian cells (47; 05).
Despite all of these efforts, underdiagnosis, underdetection, and poor compliance with treatment and clinic follow-ups remain huge problems in the fight against trypanosomiasis (23). WHO states that the successful elimination of the illness requires the participation of existing health systems for surveillance and control sustainability; the development of new diagnostic tools and drugs is crucial to guarantee the effective participation of existing health structures, and the maintenance of a specialized central structure at national level is necessary to ensure the coordination and overall technical assistance needed. Training of nonspecialist health-care workers has been shown to improve the rate of syndromic referrals to hospitals for HAT diagnosis and management (55). Furthermore, despite the recent decline in reported cases, the high level of underreporting and increased socioeconomic instability in endemic regions create significant obstacles to the eradication of HAT (66; 01).
Vertical transmission, although uncommon, is well documented for both forms of the disease. The overall risk is unknown, but screening women in HAT endemic areas and testing newborns to mothers infected with Trypanosoma is highly recommended (32).
Ali Karaki MD
Dr. Karaki of Lebanese American University Medical Center has no relevant financial relationships to disclose.See Profile
Hrayr P Attarian MD
Dr. Attarian, Director of the Northwestern University Sleep Disorders Program, received honorariums from Clearview and GLG for consulting work, honorariums from Pre Med for speaking engagements, and royalties from Flo for authorship.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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