Various forms are clinically distinguished, the most important of which are :
Localised cutaneous leishmaniasis: skin ulcers that heal very slowly or nodular lesions, limited in extent and number. These chronic sores have regional names: clou de Biskra in Algeria and Aleppo boil in Syria.
Diffuse cutaneous leishmaniasis: cutaneous nodules and plaques that do not ulcerate but can sometimes spread over the entire body.
Recurrent cutaneous leishmaniasis
A description from 1756 by a certain Alexander Russell is still relevant:
"... After it is cicatrised, it leaves an ugly scar, which remains through life, and for many months has a livid colour. When they are not irritated, they seldom give much pain... It affects the natives when they are children and generally appears in the face, though they also have some on their extremities... In strangers, it commonly appears some months after their arrival. Very few escape having them, but they seldom affect the same person above more than once."
Localised cutaneous leishmaniasis
After a bite by a sandfly infected with L. tropica (mainly urban infection), there is an incubation period of a few weeks or months, occasionally years. There is initially a small papula and usually only a single lesion, though sometimes there are several. This slowly spreads, can remain completely dry, become warty or nodular or develop into a painless, sharply delineated ulcer surrounded by a purplish raised border. Satellite lesions can occur. Spontaneous healing often occurs after 6 to 12 months, resulting in a depressed scar. Recurring cutaneous lesions - possibly with severe disfigurements - occasionally occur. There is usually immunity to any subsequent infection with the same organism. In infection with L. major (mainly rural infections, particularly from a rodent reservoir) the lesions are usually larger and develop more quickly, hence the name. There is a greater tendency to local spreading via the lymphatics and have to be distinguished from sporotrichosis. The lesions will eventually spontaneously heal with scar formation.
In South America the lesions often have their own local names and clinical expressions. Hence in Peru they are called "uta" (a solitary ulcer or a few restricted lesions brought about by L. peruviana, frequently on the face). In Guyana they are known as "bush yaws" or (French) "pian bois" (L. guyanensis) with rasberry-like lesions that resemble yaws. In Yucatan, Mexico an ulcer on the ear (usually caused by L. mexicana) is know as "chiclero" ulcer.
Diffuse cutaneous leishmaniasis
Diffuse cutaneous leishmaniasis is a diffuse affection of the skin with extensive non-ulcerative nodules and is a very chronic disease. It is sometimes followed by chronic lymphoedema of an affected part of the body. This disease is poorly understood, but is probably caused by a diminished resistance to the parasite. This immunosuppression is possibly brought about by the parasite itself. In East Africa diffuse cutaneous leishmaniasis is often caused by L. aethiopica and in the New World frequently by L. mexicana.
If there are generalised cutaneous lesions the condition has to be differentiated from lepromatous leprosy, keloids, neurofibromatosis and post kala azar dermal leishmaniasis (PKDL). Due to the low resistance of the patient very numerous amastigotes are present skin smears are always positive. Treatment is difficult, as the patient’s immune system itself is functioning poorly. Differentiation from PKDL is important, as the latter can still be treated reasonably well. In Sudan 1 case of diffuse cutaneous leishmaniasis is found for every 100 cases of localised cutaneous leishmaniasis. The incidence varies greatly from district to district. It occurs frequently in South America, but in contrast to this it does not occur in India.
Recurring cutaneous leishmaniasis
Recurring cutaneous leishmaniasis seldom occurs (Iraq, Iran). This disease, also known as leishmaniasis recidivans leads to significant tissue damage. Parasites are very difficult to detect in these very chronic lesions. Differentiation from cutaneous tuberculosis is important.
Attempts should be made to detect the parasite microscopically in a biopsy or smear from the edge of the wound. The biopsy will, if possible, be divided up for pathology (seldom available, not very sensitive, is principally used more for exclusion of another cause) and cultures (bacteria, mycobacteria, fungi, Leishmania) and an impression preparation should also be made. Lesions on the face can be injected with 0.1 ml physiological saline and aspirated again while moving the small, thin needle back and forth in the skin. Serology is usually negative. Differential diagnosis includes ulcers due to mycobacteria, cutaneous diphtheria, tertiary syphilis, yaws, cutaneous carcinoma and deep or subcutaneous mycosis. Acid fast bacilli can be made visible using the method of Ziehl-Neelsen. Field sore (cutaneous diphtheria) and tropical ulcers (fusobacteria + Borrelia) are painful, particularly in the early phase.
The response to treatment varies according to the species. Drugs for systemic and topical treatment can be used. There is an urgent need for better and cheaper drugs.
Indications for local treatment
lack of risk of developing mucosal lesions
Old World cutaneous leishmaniasis
small, single lesion
absence of lymph node metastasis
Indications for systemic treatment
presence of mucosal lesion or lymph node metastasis
New World cutaneous leishmaniasis, except localised Leishmania mexicana infection
lesions unresponsive to local treatment
physical methods: cryotherapy (liquid nitrogen) for 15-20", repeated 2-3 times. Blistering will occur.
application of local heat (e.g. infrared lamp). Heat-induced skin bullae are common.
ointment with 15% paromomycin and 12% methylbenzethonium chloride in soft white paraffin (e.g. Leishcutan® ointment). Urea can be added as a keratolytic. Twice daily application is advised, for a duration of 20-30 days.
skin infiltration with pentavalent antimony with a fine gauge needle. Blanching of the lesions should be obtained. Treatment is repeated every 5-7 days, in general 2-5 times, sometimes more.
imiquimod crĆØme (Aldara®). This immunomodulator activates macrophage killing of Leishmania amastigotes, but is best used in combination with systemic meglumine antimonate. Experience with this drug is limited. Local application of imiquimod crĆØme (250 mg, 5% weight/volume), i.e. one individual packet every other day x 20 days is possible.
Pentavalent antimonials (meglumine antimonate [85 mg Sb/ml, IM] or sodium stibogluconate [100 mg/ml, IV]. Duration of treatment is not standarised (e.g. 14 to 28 days).
Pentamidine. First line against L. guyanensis (French Guyana). Check glycaemia. Several treatment schemes exist and the cure rate is dose-dependent. Some short-courses use 1200 mg as a total dose. In Guyana 3 mg/kg/day every other day is often used (4 injections).
Imidazoles, triazoles. Fluconazole promising against L. major. Ketoconazole 600 mg per day x 28 days is moderately effective for L. mexicana, but much lower against L. braziliensis.
Miltefosine. Still experimental.
Amphotericine B and its liposomal formulation
Allopurinol. Not as monotherapy, but associated with e.g. pentavalent antimony for L. panamensis.
Glucantime® (meglumine antimonate) or Pentostam® (stibogluconate) can be injected intralesionally (that is, into the edge of the lesion itself) as a treatment for cutaneous leishmaniasis. These can be given parenterally for extensive lesions. Varying results have also been reported with allopurinol (Zyloric®), which can be given orally. Topical treatments with heating (40C to 42C for 12 hours), freezing with liquid nitrogen and paromomycin ointment (15% aminosidine in methylbenzethonium BD x 15-30 days) have been used with varying success. Itraconazole (Sporanox®) gave good results in initial studies, but is still controversial. Ketoconazole is sometimes used, but is use is often complicated by hepatotoxicity, abdominal pain and nausea. Imiquimod 5% cream (Aldara®) is an immunomodulating substance, initially used for warts caused by papilloma virus. Its use in cutaneous leishmaniasis is still experimental.
Infections caused by Leishmania major can be successfully treated with oral fluconazole 200 mg/day for 6 weeks (cure rate of 80%).
The treatment of diffuse cutaneous leishmaniasis caused by L. aethiopica is problematical, as this parasite is less sensitive to Glucantime®. Pentamidine can be used against L. aethiopica. A dose of 4 mg/kg/week which has to be continued for at least 4 months after disappearance of the parasites from the skin is an acceptable guideline here. Parenteral aminosidine sulphate is another therapeutic possibility. This is an antibiotic that is obtained from Streptomyces chrestomyceticus. It is an aminoglycoside and is thus potentially nephro- and ototoxic. It is chemically identical to paromomycin, which is obtained from a related Streptomyces strain. The compound is not resorbed from the intestine. Recurrences are frequently seen with aminosidine given as monotherapy. Aminosidine is, however, synergistic with stibogluconate and a permanent remission can be obtained with the combination of aminosidine with Glucantime® or Pentostam®. The dose is 14 mg/kg/day IM to be continued for up to 60 days after all parasites have been eliminated. The total treatment period takes 6 months or more. Good results were obtained with amphotericin B.
At present 90% of all mucocutaneous leishmaniasis occurs in Bolivia, Peru and Brazil. Illustrations of skin lesions and disfigurements suggestive of leishmaniasis are encountered on pre-Inca earthenware. These indicate that the disease was already in existence in Peru and Ecuador in the 1st century AD. Texts dating from the 15-16th century Inca period and the Spanish conquest mention the risk of cutaneous ulcers in seasonal farmers. Espundia was also described as "white leprosy".
When skin and mucosae are affected the disease is known as mucocutaneous leishmaniasis. This is very rare in East Africa but frequent in South America, where it is known as "espundia". After an initial skin lesion, that slowly but spontaneously heals, chronic ulcers appear after months or years on the skin, mouth and nose, with destruction of underlying tissue (nasal cartilage, for example). Tissue destruction with disfigurement can be very severe. Parasites are usually rare in the lesions. A substantial part of the disfigurement is possibly due to immunological mechanisms. One hypothesis is a relationship between the occurrence of mucocutaneous lesions and the presence of certain alleles of polymorphic tumour necrosis factor and genes.
The lesions often contain few parasites. Diagnosis is sometimes made solely on a clinical basis. Culture of the parasites is possible, but not really feasible in primitive rural conditions. Serology in espundia can be positive or negative (the quality of the antigen is of crucial importance). A practical problem in South America is whether a certain skin lesion with Leishmania amastigotes is caused by L. braziliensis or not. The geographical origin of the lesion or PCR and/or zymodeme analyses may give an answer here, though these laboratory techniques are not available in rural areas.
Differential diagnosis includes skin cancer, tertiary syphilis and yaws, leprosy, rhinoscleroma (a very chronic granulomatous infection with Klebsiella rhinoscleromatis), rhinosporidiosis, midline granuloma (a form of T-cell lymphoma), Wegener's granulomatosis, sarcoidosis, skin tuberculosis, infection with the free-living amoeba Balamuthia mandrillaris, chronic nasal cocaine abuse, noma, and fungal infections such cryptococcosis, histoplasmosis and South American blastomycosis (paracoccidioidomycosis). With this last disease, which is a very chronic infection, the lungs are frequently affected in a manner that can mimic tuberculosis. The yeast has typical oval cells with ectospores and can be detected in sputum.
Systemic drugs should be given. In South America meglumine antimonate® (20 mg Sb/kg/day for 30 days) is first choice. Beware: the dose is expressed in mg antimony (Sb). Alternatives are amphotericin B (Fungizone®), pentamidine and allopurinol. Ketoconazole can be used in L. mexicana infections. Plastic surgery is sometimes necessary in espundia in case of disfigurement. The use of pentoxyphylline (a xanthine derivative) plus antimony in refractory mucosal leishmaniasis is still in the experimental phase. Pentoxyphylline 400 mg t.i.d. orally for 30 days should have an anti-TNF-Ī± effect. It is better known for its vasodilating effects (use in chronic occlusive diseases of the legs).
arly case-detection, treatment and reporting of the case. Control of leishmaniasis is sometimes restricted to these "minimal control initiatives" owing to, for example, financial reasons.
Vector control with insecticides in and around dwellings. This can be coordinated with malaria and/or Chagas’ disease control.
Use of a fine gauze mosquito net impregnated with permetrine if transmission is taking place via a nocturnal biting vector
Biotope modification: environmental sanitation in order to destroy the sandflies’ breeding sites. An area of 300 metre radius is sometimes cleared of vegetation around villages (Amazonia, French Guyana).
Reservoir control: Sick dogs are treated or killed (L. infantum). Pets can wear a dog-collar impregnated with deltametrine, permetrine of phenthione or be treated with a lotion containing these active compounds. May be combined with rabies and echinococcosis control. Rodents (L. major) are suitably controlled by various methods: poison such as anticoagulants, deep ploughing to destroy their holes and passageways, elimination of their breeding sites (rubbish dumps) and of food plants (such as goosefoot [Chenopodium] for Psammomys obesus ("fat sand rat").
Vaccination with L. major on aesthetically unimportant body sites. This causes a lesion for a varying number of months which sometimes has to be treated. New developments are vaccines based on killed Leishmania organisms mixed with BCG and vaccines based on genetically modified Leishmania parasites and variants of these. The value of vaccination remains disputed and vaccination is not practised routinely.
General
Occurrence of abdominal complaints together with peripheral hypereosinophilia with or without increased IgE values and/or Charcot-Leydig crystals in the faeces is a frequent problem after travel in the (sub)tropics. A problem that occurs during or after a trip does not necessarily need to have a causal connection with that trip. It may be an incidental combination of eosinophilia and abdominal discomfort (no causal relationship). It occasionally is a cosmopolitan condition, though there is often an exotic cause.
Worm infestations are often responable for eosinophilia and abdominal complains. As a rule it can be stated that protozoa do not cause eosinophilia, with the exception of Sarcocystis (eosinophilic enteritis) and Isospora belli, although this is controversial.
Diagnosis
An attempt should be made to identify the parasite. This can sometimes be done via simple examination of the faeces. Concentration methods may be necessary, particularly with species that produce few eggs or larvae. X-rays, ultrasound, endoscopy and biopsies may have to be called upon for other parasites. Diagnosis can sometimes be made only on a surgical excision biopsy.
Faecal examination
Ascaris lumbricoides can usually be detected easily by simple faecal examination. It should be pointed out that eosinophilia will occur principally during the parasite’s migration phase. Once the worm has grown into the adult animal in the lumen of the intestine the eosinophilia usually diminishes or returns to normal.
Hookworms or ancylostomiasis can usually be found in the faeces without problems. If the ova have all eclosed it should be possible to differentiate the larvae from those of Strongyloides stercoralis. Oesophagostomum larvae resemble hookworm larvae.
Schistosomiasis due to both Schistosoma mansoni and S. japonicum and to a lesser extent to S. intercalatum and S. mekongi is a major cause of eosinophilia and abdominal discomfort. One must not forget the acute Katayama syndrome, where initially no ova are found in the faeces.
Strongyloides stercoralis larvae are often difficult to detect with a standard coprological examination, and therefore a Baerman concentration test can be indicated.
It is most important to detect Capillaria philippinenesis as this parasite can have a fatal outcome. Severe abdominal pain, diarrhoea, emaciation and eosinophilia are the most obvious symptoms.
Infestations by liver flukes such as Fasciola hepatica cause abdominal discomfort. After the parasite’s migration phase this is restricted to the liver.
Infestations with intestinal flukes such as Heterophyes heterophyes, Metagonimus yokogawai, Gastrodiscoides hominis, Echinostoma sp, Euparyphium sp. and Fasciolopsis buski are usually asymptomatic, unless they are present in massive numbers. Metorchis conjunctus is a North American liver fluke that can cause acute abdominal pain and eosinophilia (e.g. after the human host has eaten raw fish).
In rare cases it is adult tapeworms (Taenia sp., Diphyllobothrium latum, Hymenolepis sp., Dipylidium caninum, Inermicapsifer, Bertiella sp., Raillietina sp, Diplogonoporus sp.) which are responsible for abdominal discomfort.
Serology
Cross-reactivity is a problem with a number of serological tests for detection of worm infections. Serological testing can lead to suspicion of a visceral migrating larva (toxocariasis). Confirmatory diagnosis can only be made via biopsy. Detecting seroconversion is very important in Katayama syndrome. Initially negative while the patient has fever or thoracic and abdominal discomfort, this will later become positive. Ova of the schistosomes can subsequently be demonstrated in a rectum biopsy or urine sample (e.g. after swimming in Lake Malawi or in visitors of the Dogon plateau).
X-rays
Pentastomiasis (Armillifer armillatus infestation) is a rare cause of abdominal discomfort. Some time afterwards the calcified, comma-shaped larvae can be observed on an X-ray of the abdomen. If there is an infestation with exclusively male Ascaris lumbricoides, there will be no eggs in the stools, but the adult parasite can be detected via X-rays of the small intestine (barium transit). Calcified Echinococcus lesions are likewise detectable by X-ray.
Ultrasound
Liver flukes in the bile ducts or an aberrant migration of an adult Ascaris (Wirsung duct, choledocus) can be detected by ultrasound. An ultrasound of the abdomen can show dilated bile ducts. Liver lesions due to Capillaria hepatica are found only very rarely. No ova of this latter parasite appear in the faeces. Echinococcosis also tends to affects the liver. Fibrosis of the liver due to schistosomiasis can be suspected on ultrasound (periportal fibrosis).
Endoscopy
Anisakis worms (anisakiasis) can be diagnosed via gastroscopy and treated by mechanical extraction of the worm.
Biopsy and surgery
Rectum biopsy is a sensitive technique for detection of dead or living Schistosoma ova. Oesophagostoma worms can be found via surgery in intestinal abscesses. A few other rare parasites can also produce eosinophilic intestinal abscesses, namely: Angiostrongylus costaricensis, anisakiasis due to Anisakis simplex, Pseudoterranova decipiens, Phocanema, Contracaecum or Hysterothylacium. Eustrongylides sp. are large, bright red nematodes that elicit severe intestinal lesions. Macracanthorhynchus hirudinaceus is a thornhead worm or acanthocephalus that fortunately only seldom infects humans.
General
There is sometimes an incidental combination of eosinophilia and pruritus (no causal relation). In a traveller to the (sub)tropics, it occasionally concerns a cosmopolitan disease, though there is often an exotic cause. Scabies (Sarcoptes sp.) and pubic lice (Phthirus pubis) are a frequent cause of pruritus, but do not so frequently cause eosinophilia.
Reactions to bites and stings
Reactions to insect bites and stings (Culicoides sp, bedbugs, etc.), trombiculosis (harvest mites), contact dermatitis (e.g. to plants) and allergic reactions to medications taken during a trip sometimes raise diagnostic problems. Itching dermatitis can be elicited by the hairs of caterpillars of certain Lepidoptera. The hairs of certain bird spiders can also cause prolonged, severe pruritus.
Worm infestations
Worm infestations must be considered. Certain infections are obvious at a glance (e.g. typical larva currens, larva cutanea migrans). Other diseases are much more difficult to identify (e.g. gnathostomiasis). It should be borne in mind that a positive parasitological result may confirm the diagnosis, but that a negative result is less conclusive. In filarioses one is often confronted with the difficulty of amicrofilaraemic infections. This latter problem frequently occurs with Loa loa infections. Calabar swellings and subconjunctival migration of the adult worm will suggest the diagnosis in these cases. Note that Onchocerca volvulus microfilariae are only found in dermal fluid (not in blood). Serological tests have only a limited sensitivity and specificity. Ectopic localisations of worms can cause various cutaneous symptoms (e.g. Poikilorchis infestations, sparganosis). Cercarial dermatitis can occur after skin contact with contaminated fresh water. Early after infestation no Schistosoma ova will yet be detectable. If the infection is casued by a parasite species which has an animal (e.g. birds) as its normal host, the cercarial dermatitis will be more pronounced, but no patent infection will ensue. One of the frequent causes of urticaria in travellers is anisakiasis. This condition is frequently misdiagnosed as allergy to fish.
Itching after swimming in seawater
A planula larva dermatitis will occur shortly after bathing in seawater in which these microscopic animals (coelenterata) are present in large numbers. Fire coral dermatitis can cause quite annoying discomfort (irritation due to nematocysts). Contact with jellyfish can cause linear skin lesions. Traditional aquagenic urticaria is not related to travel.
There may be an incidental combination of eosinophilia and respiratory symptoms (no causal relationship). A cosmopolitan disease (e.g. asthma) may occasionally be involved, but there is often an exotic cause in travellers with recent onset respiratory problems and eosinophilia.
Among the exotic causes we mention paragonomiasis (lung flukes), Katayama syndrome (acute schistosomiasis) and occult filariosis (Weingarten syndrome or tropical pulmonary eosinophilia syndrome). Migration of various nematode larvae (Ancylostoma, Strongyloides, Ascaris, Toxocara) through the lung can result in Loeffler's syndrome. Strongyloides infections tend to be very persistent (beware of steroids and HTLV-1 infections). Chronic schistosomiasis can also cause pulmonary lesions and eosinophilia. Pulmonary echinococcosis tends to be asymptomatic although narrowing of a bronchial lumen can occur due to external compression.
Asthma can be triggered by hypersensitivity to cockroaches (Blatta sp, Blatella sp, Periplaneta sp) and other insects. Inhalation of urticarial (stinging) hairs of certain caterpillars can provoke acute airway symptoms.
Know the mechanism of formation of congenital and acquired diverticula. congenital--may be due to a focal failure of development of the normal musculature or to some urinary tract obstruction during fetal development
acquired--seen most often w/prostatic enlargement, producing obstruction to urine outflow & marked muscle thickening of the bladder wall; increased intravesical pressure causes outpouching of bladder wall & formation of diverticula
Know the complications of bladder diverticula: stone and urinary infection.
Know the pathology of bladder extrophy and complications (mucosal metaplasia, development of cancer and urinary infection) of bladder extrophy.
pathology--implies the presence of a developmental failure of the anterior wall of the abdomen and the bladder; bladder can communicate directly through large defect w/ surface of body or can lie as an opened sac
complications--may undergo colonic glandular metaplasia; is subject to development of infections (may spread to upper urinary system) if infections are chronicmucosa often becomes an ulcerated surface of granulation tissue and preserved marginal epithelium becomes transformed into a stratified squamous type; increased tendency later in life to carcinoma (mostly adenocarcinoma)
Know other congenital anomalies: vesicoureteral reflux, fistulas, partial and total persistent urachus. What are the complications of persistent urachus?
vesicoureteral reflux--most common and serious; major contributor to renal infection and scarring.
fistulas--abnormal connections between bladder and vagina, rectum or uterus
total persistent urachus--when totally patent, fistulous urinary tract is created that connects the bladder w/ the umbilicus
partial urachus--umbilical end or bladder end is patent but central region is obliterated. sequestered umbilical epithelial rest or bladder diverticulum is formed (may provide site for infection); central region of urachus may persist => urachal cysts lined by transitional or metaplastic epithelium. carcinomas (mostly glandular) can arise in these cysts--only 0.1-0.3% of bladder CA but 40% of bladder adenocarcinoma.
Know the causes (table 22-1 p.999 Robbins) & consequences of ureteral obstruction. intrinsic: calculi, strictures, tumorous masses, blood clots, neurogenic causes
extrinsic: pregnancy, periureteral inflammation, endometriosis, tumors
Know sites where stones are most frequently impacted in the ureter.
Know the possible causes of retroperitoneal fibrosis.
drugs (ergot derivatives, Ī²-adrenergic, Ī²-blockers), adjacent inflammatory conditions (vasculitis, diverticulitis, Chron's disease), or malignant disease (lymphomas, urinary tract carcinomas)
70% of cases--no obvious cause; considered 1Āŗ or idiopathic
Know the gross pathology of ureteritis cystica (Robbins fig 22-1 p 999).
What is the clinical significance of renal hamartoma?
Which disease is/can be assoc. w/ angiolopoma?
What is oncocytoma?
epithelial tumor thought to arise from intercalated cells of collecting ducts; not uncommon
GROSS: tan or mahogany brown, relatively homogeneous and usually well-encapsulated; up to 12cm
MICRO: large eosinophilic cells w/ small rounded, benign-appearing nuclei; (w/EM--eosinophilic cells have lost of mitochondria)
px: benign
What is the difference between cortical adenoma and renal cell carcinoma?
cortical adenoma (renal papillary adenoma): benign, usually papillary; commonly found at autopsy; histo. criteria--do not differ from low-grade papillary renal cell adenocarcinoma and share some immunohistochemical and cytogenic features (trisomies 7 &17) w/ papillary CAs; px--no real reliable marker for benignity so usually treat small tumors as early CAs
renal cell carcinoma: see table for complete info; malignant; may be either clear cell (nonpapillary) carcinoma, papillary carcinoma, or chromophobe renal carinoma
Know the incidence, sex distribution, possible causes and clinical manifestations of renal cell carcinoma
85% of renal CA in adults; 30,000 new cases/yr; 12,000 deaths/yr; usually in 6th or 7th decade of life
male > female (2-3:1)
possible causes: smoking; obesity (esp. in females); HTN; unopposed estrogen tx; exposure to asbestos, petroleum products, and heavy metals; increased incidence in pts w/chronic renal failure, acquired cystic disease, and tuberous sclerosis; assoc. w/Von Hippel-Lindau syndrome; some rare familial forms
clinical manifestations: 3 classic signs--costovertebral pain, palpable mass, and hematuria, this triad of sx only appears in about 10% of cases. the most reliable sx is hematuria but may be intermittent and microscopic so may not be obvious until tumor is large. other sx may be fever, malaise, weakness, and weight loss
Know the cytogenetic aspects of clear cell, papillary and chromophobe carcinoma
Know that in asymptomatic hematuria in elderly pts the dx of renal cell carcinoma should be seriously considered
Know the prognosis of renal cell carcinoma
Know the incidence, possible causes and px of urothelial carcinomas
5-10% of 1Āŗ renal tumors; range from benign papillomas to frank papillary carcinomas (benign are difficult to distinguish from low-grade papillary CAs); usually small when discovered b/c of locationfragmentation causes noticeable hematuria; may be multifocal; in 50%, have preexisting or concomitant bladder urothelial tumor
possible causes: increased incidence in pts w/ analgesic nephropathy
px: 50-70% 5 yr survival for low-grade superficial lesions to 10% w/high-grade infiltrating tumors
Know the pathogenesis of type I and type II MPGN Granular deposits of IgG and C3 in subendothelial and mesangial distributions
Activation of classic complement pathway
Presence of cryoglobulins and circulating Igs
Similar lesions produced in animal studies utilizing foreign serum proteins
NOT an immune complex disease
Probably due to abnormality in complement metabolism
C3 nephritic factor present in the serum
Know the LM, IF, and EM findings of type I and type II MPGN - Type I
- Light Microscopy
- Diffuse, proliferative GN
- Thickening of glomerular capillary walls due to subendothelial immune deposits and interposition of mesangial matrix and cells between layers of GBM
- Seen on silver stain as double contour, splitting, or train track appearance of capillary walls.
- Increase in mesangial cells and matrix
- Glomerulus appears lobulated
- Crescents rare
- Immuno Fluorescence – Coarsely granular deposits of C3 and often IgG, IgM, C4, properdin, and fibrin in mesangium and peripheral capillary loops
- Electron Microscopy
- Dense subendothelial and mesangial deposits
- Mesangial matrix interposition w/ capillary wall thickening and narrowing of capillary lumen
- Type II
- LM
- Similar to Type I, although crescents are more common
- Dense deposits seen as PAS+, ribbon-like deposits w/in the capillary wall (i.e., intamembranous) as well as along Bowman’s capsule and tubular membrane.
- IF – C3 present in deposits, IgG much less commonly found
- EM – extensive replacement of lamina densa with “very dense deposits”
Know the clinical manifestations and prognosis of MPGN
- Mainly a disease of children/young adults
- Exception – association of type I with Hepatitis B infection
- Nephrotic Syndrome (80%)
- Acute nephritic syndrome (20%) more common in type I
- Type II associated with partial lipodystrophy in some patients
- Poor prognostic signs include
- Reduced GFR at onset
- Presence of nephrotic syndrome
- Early HTN
- Gross hematuria
- Presence of crescents or sclerosis on biopsy
- Recurs in about 25% of transplants, but rarely interferes with function
Know the urinary sediment and renal function of MPGN
Shows nephrotic range proteinuria along with nephritic syndromes such as hematuria
About 33% develop end-stage renal disease w/in 10 years (type II) or 15-20 years (type I)
About 33% have persistent nephrotic syndrome with relatively stable renal function
About 33% have persistent non-nephrotic proteinuria and/or hematuria
Less than 5% experience spontaneous remission
Know the pathology, clinical manifestations, classification, and prognosis of lupus nephritis
- Class I – normal kidney
- Class II –Minimal/Mesangial Lupus Nephritis
- Earliest and mildest form of renal involvement
- Characterized by mesangial deposits of Ig and C3
- Proteinuria and hematuria present
- Nephrotic syndrome and renal insufficiency are very uncommon
- EM – IC deposits in mesangium
- IF – appears similar to IgA
- Class IIA – mesangial proliferative change
- Class IIB – no proliferative change
Class III – Focal proliferative Lupus Nephritis
- Proliferative changes present in <50%>
- ALL glomeruli have immune deposits of IgG, IgA, C3, and often IgM and fibrin-related Ags – seen on IF
- Mainly mesangial deposits with occasional subendothelial deposits (seen on EM – most reliable predictor of progression)
- All patients show proteinuria, but nephrotic syndrome and renal insufficiency are rare
- Hypocomplementemia more severe
- Long-term prognosis is good, but there is a high incidence of transformation to class IV
Class IV – Diffuse Proliferative Lupus Nephritis
- Most common and most severe form
- Proliferation seen in >50% of glomeruli, with crescent formation and necrosis common
- Extensive mesangial and subendothelial deposits
- Nephrotic range proteinuria
- Renal function decreased in 75% of patients at presentation
- Hypocomplementemia, high levels of anti-DNA Ab, and circulating Igs present in most patients
- Long-term survival rate is ~75% past five years
- Best prognosis is with those who show remission of nephrotic syndrome and normalization of serologic parameters achieved w/in 1 year of starting therapy
Class V
- Occurs in ~15% of SLE patients – hard to distinguish from idiopathic MN on LM
- IF – all sorts of Ig – contrast to idiopathic MN
- EM – other deposit sites in addition to those normally associated w/ MN
- May have undetectable levels of anti-DNA Ab at presentation
- Long-term prognosis about the same as with II (good)
What is ANCA?
Where are ANCA antigens in normal conditions and after activation of neutrophils?
Detected in serum using IF – 2 types
C-ANCA (cytoplasmic) – most commonly seen in Wegener’s
P-ANCA (perinuclear) – specificity for myeloperoxidase and reacts w/ neutophil elastase, seen in renal-limited disease
- With activation of neutrophils, granules are present at surface of cells, and circulating ANCA may cause respiratory burst and degranulation
-
Know the clinical presentation of polyarteritis nodosa, Wegener’s granulomatosis, and pauci-immune necrotizing glomerulonephritis
- Polyarteritis nodosa (PAN)
- Mean age of onset is ~45-58 years (w/ superadded GN, it’s a little earlier)
- Fever, myalgia, weight loss, and arthralgia are common
- Other symptoms depend on organ systems involved
- Main laboratory findings include plasma ANCA, elevation of C-reactive protein, positive rheumatoid factor, and circulating immune complexes
Mean age of onset is 36-54 years
Initial signs involve the upper airway, lung, and kidney
Upper airways: rhinitis, sinusitis, epistaxis, deafness and ulcers
Lung: dyspnea, cough, hemoptisis, and radiologic signs such as infiltrates, nodules, and cavitation
Renal: oliguria, hematuria, proteinuria, and raised serum creatinine
Renal symptoms are usually the last presenting signs, but may precede lung symptoms in some cases
Pauci-immune necrotizing GN (PINGN)
- Renal-limited variant of systemic vasculitis
Know the vascular lesions in PAN and Wegener’s granulomatosis
- Mainly affects arteries of arcuate size
- Acute, healing, and healed lesions may be present at same time in a specimen
- Acute lesions – whole circumference or a portion is replaced by fibrin-like material (fibrinoid necrosis) and infiltrated by neutrophils, monocytes, and eosinophils. Elastic lamina is destroyed. Cellular reaction spreads to surrounding tissue and forms a layer that may encircle the vessel. Aneurysm formation if only part of vessel wall affected.
- Healing – Inflammatory cells decrease in #, necrotic areas invaded by smooth muscle cells, which may cause intimal thickening and lumen narrowing
- Healed – No inflammatory cells, destroyed part of arterial wall replaced with fibrous tissue. Hemosiderin deposits may be present.
Know the glomerular lesions in PAN, Wegener’s granulomatosis, and pauci-immune necrotizing glomerulonephritis
May occur w/o GN infarcts and aneurysms seen
Focal segmental necrotizing glomerulonephritis
Fibrinoid necrosis associated with eosinophillic areas
Segmental or diffuse proliferative change
Granulomatous changes are less common than in WG
Tubules show atrophy/necrosis
Focal segmental necrotizing glomerulonephritis
Mesangial hypercellularity
Granulomatous glomerulonephritis more common
Know the mechanism of tissue injury in ANCA-associated disease
Circulating ANCA interacts with primed neutrophils to cause a respiratory burst and degranulation
Respiratory burst releases toxic oxygen
Degranulation releases lytic enzymes
Know the glomerular lesions in DM. Which one is the most characteristic of diabetic nephropathy?
Nodular intercapillary glomerulosclerosis
Most characteristic, but not diagnostic (amyloidosis)
Acellular
Located in mesangial/intercapillary regions of glomerular tufts
Laminated appearance and are eosinophilic on H&E stain
PAS+ and argyrophillic
Almost always seen with diffuse intercapillary glomerulosclerosis
Know the characteristic vascular lesion in diabetic nephropathy
Know the clinical presentation of diabetic nephropathy
Know the definition of microalbuminuria
Abnormal, but subclinical albuminuria
-
20 mcg/min, but < 200 mcg/min
Know the mechanism of thickening of the glomerular basement membrane and alteration of glomerular filtration barrier
Know the hemodynamic change in diabetic nephropathy and its mechanisms
Larger glomeruli and attendant microvasculature could reduce vascular resistance and increase the surface area for filtration
Some hormonal aspects (elevated glucagons/growth hormone levels) could cause relaxation of renal vasculature
Enhanced renal production of prostaglandin occurs
ECF volume expansion is common in DM
Atrial peptides contribute to renal vasodilation/hyperfiltration
Elevated kinin
Increased dietary protein intake may influence
Know the characteristics of HIVAN at the level of light microscopy
FSG w/ hyalinosis
Collapse of capillaries around mesangia
Swelling of epithelial cells w/ accumulation of hyaline droplets in cytoplasm
Dilation of capsular space containing cast-like material
Dilation, flattening of epithelium, hyaline droplets, necrosis
Eosinophillic casts containing IgA, IgG, IgM, complement, albumin, kappa, and lambda, No Tamm-Horsfall protein. Scalloped appearance at periphery of casts
Interstitial nephritis
Both HAN and HIVAN show focal segmental glomerulosclerosis. What are the differences between HAN and HIVAN clinically and at the level of electonmicroscopy?
Tubular reticular inclusions are commonly seen in endothelial cells
Cylindrical confronting cysternae in lymphocytes, macrophages, and endothelial cells
Know the prevalence of HIVAN in different groups of patients
Know the age and gender of patients with essential mixed cryoglobulinemia
Know the systemic symptoms associated with essential mixed cryoglobulinemia
Know the LM, IF, and EM findings
Diffuse, proliferative, and exudative GN, sometimes accompanied by vasculitis
Large PAS+ proteinaceous deposits present in capillaries
Subendothelial capillary deposits composed predominantly of IgG, IgM, and lesser amounts of C3 and fibrin
In 1907 the physician Carlos Chagas (1879-1934) was working in Lassance, a small poverty-stricken town on the Sao Francisco river in the state of Minas Gerais, Brazil. The town had been built along the railway from Rio de Janeiro to Belem. Chagas treated the workmen for injuries, syphilis, malaria etc. He noticed that cardiac arrhythmias occurred frequently. One day an engineer brought him an insect, of the type which was known to often suck the blood of humans at night. Chagas wondered if this creature could also transmit malaria, like the Anopheles mosquitoes. In the bug he discovered a unicellular parasite. In April 1908 he found the same parasite in a sick cat. Two weeks later, in the same house, the parasite was found in the blood of a 3-year-old child (Rita), who was ill with fever. Her face, liver, spleen and lymph nodes were swollen and the child died shortly afterwards. In the house there were countless bugs which tested positive for the parasite. He sent bugs to Rio, to Oswaldo Cruz, his former teacher (Brazilian physician 1872-1917). In the laboratory the parasite caused an infection in marmoset monkeys (Callithrix sp.), rodents and puppies. The disease caused by this parasite, American trypanosomiasis, was named after Chagas. The parasite was given the name Trypanosoma cruzi. The parasite did not always trigger disease, however. In 1908 Chagas also discovered the parasite in another person (Bernice). This woman died in 1989, still infected, but without signs of organ involvement.
The infection apparently already existed before contact with the West. In 1985, 22 mummies were found in the Andes mountains. These were 1500 years old. In approximately half of them the heart, colon and/or oesophagus were clearly enlarged (lesions typical for Chagas’ disease). Trypanosoma cruzi DNA was found in 1999 in a 4000 year-old mummy in Northern Chile. In one of his books Charles Darwin describes how in 1835 in South America he was bitten by the bugs. It is possible that he incurred infection and later developed a chronic form of the disease.
The infection only occurs in America in endemic regions. It is a disease associated directly with poverty. The severity varies from region to region. In the South of Texas there are very few cases. Infections occur in Central America sporadically. Although the disease is endemic in large areas of South America, the majority of those infected have no symptoms. Until recently it was thought that approximately 16 million persons were infected, but these figures are under review (see Prevention). The disease is transmitted via the faeces of an infected bug. These are blood-sucking insects which are widely distributed. The illness is characterised by an acute and a chronic phase. Not all infections lead to disease. Untreated, the infection can lead to a great deal of suffering.
The parasite, Trypanosoma cruzi, occurs in more than 100 species of mammal (opossums, guinea pigs, goats, dogs, cats, rats, mice, and so on). There are several known (and probably also some unknown) subtypes, each of which has its own distribution and probably also its own pathogenic features. In view of the extent of the animal reservoir, eradication of the parasite will not be possible. This does not mean that the disease and the transmission cannot themselves be controlled. At present the strains are divided into two groups. Trypanosoma cruzi I has an extensive sylvatic reservoir, of which opossums appear the most important. This group is not very common in the “Southern Cone” countries (Argentina, Brazil, Chile, Paraguay, Uruguay), but it is virtually the only form which occurs north of the Amazon region. T. cruzi II seems to be chiefly associated with rodents and is common in the Southern Cone.
Transmission occurs chiefly via infected bugs. These large insects like to bite sleeping humans at night (a mosquito net gives protection). They have a sharp proboscis which at rest is folded below the head like a jack-knife. When biting they inject anticoagulants and an anaesthetic substance into the wound. Since this makes their bite quite painless (kissing bugs), people seldom wake up and several bites may take place unnoticed in the course of one night. The parasite is not inoculated directly by the bite, as Chagas initially thought. In 1913 Brumpt showed that the parasite is found in the faeces of the insect. While the animals suck blood, they defecate. By scratching, a bitten person can bring the faeces into the bite wound or rub them into the conjunctiva. The parasites multiply in humans and appear in the blood. The cycle is completed when a subsequent bug drinks infected blood. In the bug the parasite undergoes further changes and after 2 to 3 weeks is excreted with the faeces during a subsequent bite. It is estimated that the risk per bite by an infected Triatoma is one in a thousand. The existence of a totally different infection route was demonstrated in animals and is assumed in some human cases. Food or drink infected with the faeces of infected bugs or containing dead bugs may lead to infection in experimental animals. It is not known whether this also occurs in humans, and how common oral transmission then is. Congenital infection (1 to 2 % risk) and transmission via blood transfusion also occur (poor people often sell their blood). Transmission via transfusion is particularly important in urban zones. The risk of infection after an infected blood transfusion is estimated at one in five. There are sporadic cases of accidental contamination of laboratory staff (finger prick, aerosol) and after organ transplantation.
The bugs are also known locally as “vinchucas” or “barbeiros”. The latter common name refers to the blood-sucking (since in the olden days the barber carried out blood letting as well as shaving). Of the approximately 120 vector species only about 7 are important. Each species has its own region of distribution:
Central America and northern South America: Triatoma dimidiata and Rhodnius prolixus
South America (south of 5 S): T. infestans, T. braziliensis, T. sordida, Panstrongylus megistus
The bugs mentioned here are the main vectors. Other bugs also play a part (Triatoma barberi [Mexico], Rhodnius pallescens [Panama and Colombia], T. phyllosoma group [Mexico] and T. protracta. Twelve species of triatomines are known to occur in the United States, the most important being Triatoma sanguisuga in the Eastern United States, Triatoma gerstaeckeri in the region of Texas and New Mexico, and Triatoma rubida and Triatoma protracta in Arizona and California. The bugs each have their own preferred biotopes. T. dimidiata, for example, is often found inside houses on the floor or the lower 150 cm of the walls or immediately outside in dung heaps, hollow trees, etc. In contrast, R. prolixus prefers to live in palm leaves either in the roof of the house or in the tree itself. In and around the house the bugs can feed on animals (e.g. dogs are important because they sleep at night, when the bugs are active). The vectors often live in chicken runs, but chickens themselves are not infected (they do eat bugs). During the day the insects hide in all kinds of cracks and crannies (importance of earthen or adobe walls) and in the roofing (straw, wood, etc). It can be seen immediately that the key word in Chagas’ disease is "poverty". These are insects which reproduce slowly and whose geographical spread is slow. Migration of bugs, by migrating birds for example, still needs to be studied. In view of these characteristics and the fact that the important vectors live around houses, they can easily be reached by eradication campaigns.
The adult insects measure 2-3 cm. The front wings (hemi-elytra or hemelytra: "half wing sheath"[Gr. elytron = cover]), consist of a hardened foremost part (divided into corium and clavus) and a rearmost membranous part. This order is named "Hemi-ptera": "half-wings"[Gr. pteron = wing]) after their wing construction. The name Heteroptera is used for the suborder which includes the bugs, while the other Hemiptera are classified in the suborder Homoptera. Each species has a typical morphology and colour pattern which includes connexival markings. The latter are markings (red, orange, yellow) of the lateral edges of the abdominal tergites [Lat. “tergum” = back; tergite = sclerosed dorsal segment]. They are visible because the wings are folded over each other so that the back is not fully covered. Naturally the identification of bugs is very important in the evaluation of vector control programmes. Differentiation between re-infestation from neighbouring areas or insufficient local control can be made by genetic analysis of the bugs.
A fertilised female lays several hundred eggs in her lifetime. From the egg comes a nymph which always needs a blood meal for its subsequent development stages (both sexes suck blood). The last instar will develop into an adult insect. During a blood meal they suck more than their own weight in blood. This takes 10-25 minutes. The insects may live for up to 2 years (5 years for T. barberi). Rhodnius prolixus has a relatively short generation time (3-5 months), while for T. dimidiata this time is quite long (1 year or longer). Long generation times make the development of resistance to insecticides difficult.
In stained blood preparations the parasites are C- or S-shaped with a prominent kinetoplast towards the rear (trypomastigotes). The nucleus is elongated and the undulating membrane is usually not clearly visible. After infection, multiplication of the parasite in the human is solely intracellular. They form microscopic pseudocysts in the tissues (similar to toxoplasmosis and sarcocytosis). This occurs mainly in the heart, muscle cells, some nerve cells and the lymphatic system. In the cell the parasite is small and rounded, with no flagellum (amastigote). When the infected cell ruptures, the parasites are released into the blood circulation where they become elongated and develop a flagellum. These forms can then infect other cells or be ingested by a bug.
An important protease for the parasite is lysosomal cruzipain (cruzain), a substance related to papain. This is being investigated as a possible therapeutic target. An unusual parasite-derived proline racemase was identified as a B-cell mitogen, resulting in polyclonal B-cell activation. The surface of the parasite is covered by mucin-type glycoproteins that attach to the membrane by glycosylphosphatidylinositol (GPI) anchors, similar to those of the variant surface glycoproteins in African trypanosomes. Mucins are recipients of the sialic acid transferred by surface trans-sialidase. T. cruzi has several hundreds of such mucin genes. The exposed N-terminal moiety of the molecules is hypervariable. It is postulated that this might play a role in immune evasion.
If the parasites penetrate via the conjunctiva, there is unilateral redness and oedema of the upper and lower eyelids after 4 to 12 days. This is RomaƱa’s sign, named after the Argentinean physician Cecilio RomaƱa, who described the oedema in 1935. This swelling may last for weeks. Sometimes there is also swelling of the ipsilateral lymph nodes (including the pre-auricular lymph nodes). Trypanosomes may be found in the tears at this stage. If inoculation is in the skin there is local oedema and redness (chagoma) in 75% of cases. This remains for 1 to 4 months. From these sites the infections spreads. In the case of an infected blood transfusion, the incubation time may be 20 to 40 days.
Most infections are initially asymptomatic. Acute symptoms occur more frequently in children than in adults. Dissemination of the parasite from the inoculation site may go unnoticed but may also give rise to acute illness with muscle pain, local or generalised oedema, swollen liver, spleen and lymph nodes. Moderate fever is almost always present in symptomatic cases and may persist for a long time, two or even four months. Sometimes there is also acute inflammation of the heart (myocarditis) with arrythmias, decreased blood pressure, and heart failure. As with other forms of myocarditis the echocardiogram is frequently abnormal. There is low QRS-voltage, prolonged PR- and/or QT-interval, T-wave abnormalities. Rarely there are ventricular extrasystoles or atrial fibrillation (the prognosis is poor if this occurs). Acute inflammation of the brain and meninges (meningo-encephalitis) occurs, chiefly in young children. Inflammation of the heart and brain may be fatal. There is pronounced lymphocytosis and monocytosis. It is at this stage that therapy with nifurtimox or benznidazole is generally still capable of destroying the parasite.
If the patient survives the initial phase (which is usually the case), a latent period occurs of indeterminate duration. The patient is asymptomatic, seropositive and the parasitaemia is very low. Focal lesions are found in 60% of endomyocardial biopsies from patients in the latent phase. A positive xenodiagnosis can be obtained in 50% to 100% of these patients. For xenodiagnosis 10 to 40 non-infected bugs (e.g. Dipetalogaster maxima or Triatoma infestans) feed on blood from the patient. The faeces from these animals are investigated after 30, 60 and 90 days. In the event of immunosuppression there may be an acute flare-up, including meningo-encephalitis associated with AIDS or heart transplantation.
Gradually the patient develops symptoms. These vary greatly from region to region. Lesions of the heart, oesophagus and colon are the most common.
Chronic heart problems
Chronic damage to the heart muscle cells and the cardiac conduction system (including that caused by auto-immune mechanisms) leads to heart failure. There is dyspnoea during exertion, orthopnoea and sometimes paroxysmal nightly dyspnoea, oedema of the feet and ankles, congestion of the neck veins, enlarged liver, crepitations over the base of the lungs. Cheyne-Stokes respiration may occur in advanced heart failure. This phenomenon is characterised by periodic respiration in which apnoea episodes alternate with hyperventilation. It is assumed that the prolonged lung-to-brain circulation time plays a role in Cheyne-Stokes with a long cycle (e.g. 3 minutes) [Other causes of this phenomenon are for example brain stem lesions or compression]. Sometimes there is pulsus alternans: the peripheral arterial pulsations are alternately strong and weak.
The precise physiopathological mechanism is not fully known. The apex of the heart, which is normally situated on the midclavicular line, is displaced to the left. The heart sometimes becomes enormous, which may lead to clot formation in the heart. If blood clots break loose, there may be embolic complications: CVA, ischaemia of limbs, renal infarction. Apical lesions in the left ventricle (wall thinning, intramural bleeding, aneurysms) are typical and occur in approximately 50% of patients. Unlike arteriosclerotic post-infarction aneurysms, in Chagas’ disease the apical cardiac tissue does not consist of scar tissue, the wall is simply thinned. Right ventricular lesions occur in 10 to 20%. Cardiac arrhythmias may cause palpitations, dizziness, syncope and sudden death. On the electrocardiogram a right bundle branch block is often seen, together with a left anterior hemiblock, ventricular extrasystoles, abnormal Q-waves and/or AV-conduction disturbances.
The coronary arteries are normal. A complete left bundle branch block is exceptional, unlike in idiopathic dilated cardiomyopathy. Sudden death is common in people with Chagas’ disease. Probably this is due to ventricular tachycardia which changes suddenly into ventricular fibrillation.
In advanced heart failure, typical radiographic signs may be observed on a chest X-ray: cardiomegaly, prominent hili and distended pulmonary veins in the upper fields, pleural fluid, interstitial pulmonary oedema (fluid in the interlobular septa with Kerley B lines), peribronchial cuffing and finally alveolar pulmonary oedema ("butterfly oedema").
Oesophagus and colon problems
Due to involvement of the small nerves in the oesophagus and colon, peristalsis is reduced and these organs are distended. This occurs in 5 to 10% of seropositive people south of the Amazon, and is virtually absent further north. Trypanosoma cruzi I and II are both associated with cardiac lesions, but apparently intestinal lesions only occur in infection with T. cruzi II (the southern area).
Mega-oesophagus is characterised by difficulty in swallowing (dysphagia), choking, hiccups, nocturnal cough. This often leads to under-nourishment and loss of weight. A clinical aid for detecting delayed oesophageal emptying is to measure the time between swallowing a mouthful of water, and observing the abdominal noises (stethoscope on the epigastrium). Normally this is less than 10 seconds. A distended oesophagus may also be shown on X-ray. The parotid gland may hypertrophy and lead to so-called “cat’s face”.
Mega-colon can lead to pronounced constipation, meteorism, abdominal pain and functional intestinal obstruction (involvement of Auerbach’s myenteric plexus). The abdomen is often distended. Faecaloma, volvulus and peritonitis are complications.
The nervous system
In no other infectious disease is the involvement of the autonomous nervous system so important as in Chagas’ disease. Denervation of the parasympathetic nervous system is better documented and is much more pronounced than denervation of the orthosympathetic system. There can be sensorimotor polyneuritis. There is some hypoaesthesia and paresthesia, but chiefly a reduction or loss of tendon reflexes. The EMG is disturbed. In the central nervous system there is meningo-encephalitis in the acute phase, but the abnormalities in the chronic phase need to be better defined. In flare-up (e.g. AIDS) there may be intracranial hypertension, lesions of the cerebral nerves, paresis, plegia, stupor and convulsions.
The cerebrospinal fluid exhibits a normal number of cells or pleocytosis with predominant lymphocytes and an elevated protein content. At times T. cruzi may even be detected in the cerebrospinal fluid. A CT scan of the brain shows one or more necrotising lesions which may or may not be ring-shaped, with haemorrhages, usually subcortical in the brain hemispheres and occasionally in the cerebellum or the brain stem. T. cruzi lesions rarely occur in the basal nuclei. These clinical pictures should be differentiated from cerebral toxoplasmosis, abscesses, mycoses, tuberculomata or other mycobacterial lesions, metastases or lymphoma.
About 1 to 2 % of babies born to seropositive mothers are infected. They may be asymptomatic (rarely) or may develop hepatosplenomegaly, neurological involvement, myocarditis, oedema and a bleeding tendency. The babies may be dysmature and/or premature. Fever is rare in these children. The mortality may be as high as 50% and they tend to die within a week. Those who survive will generally have permanent residual neurological damage.
In the acute stage the parasite may be found in the blood via a thin blood smear, thick smear or buffy coat. As a concentration technique an anion-exchange minicolumn may be used (Woo’s technique similar to Lanham’s column, but with a different buffer, see African sleeping sickness). Strout’s concentration technique includes the double centrifugation of serum (from 10-20 ml of blood), after which the motile trypanosomes can be detected in the sediment. PCR techniques for T. cruzi exist, but can only be carried out in better equipped laboratories. The serology is positive from the fourth week. To know whether the neonate from a seropositive mother is infected, PCR is performed and IgM antibodies in its blood are determined. A positive serology (IgG) 6 months after birth also indicates infection. In-vitro and in-vivo culture is possible, but usually not available. Biopsies of lymph nodes, heart and muscles sometimes show parasitic pseudocysts (amastigotes in the cells). This is quite an aggressive technique, however, and not very sensitive. Several chronic cases have been described where the parasites were seen on a blood smear, the PCR was positive, but the classical serological tests (ELISA, IFA, HAI) as well as anti-cruzipain antibodies were negative. How frequent this situation is, is not clear at present.
In the latent and chronic phases the serology is positive but only seldom will a positive parasitaemia be found. Parasites may be detected via culture (NNN-medium [Novy-Nicolle-McNeal agar] or inoculation of a test animal) and via xenodiagnosis.
Chagas’ cardiomyopathy. Differentiation from ischaemic, hypertensive or idiopathic cardiomyopathy is not always easy. The differential diagnosis includes high-output heart failure (anaemia, beriberi, hyperthyroidism, large AV-fistula and Paget’s disease of the bone), postpartum heart failure, acute rheumatic fever, valvular disease, congenital abnormalities, pericardial disorders and the sequelae of acute myocarditis (e.g. Coxsackie virus). A cor pulmonale is usually obvious. It is useful to have an electrocardiogram available and if possible an ultrasound evaluation.
Mega-oesophagus: Achalasia of the oesophagus may be very similar to Chagas’ oesophageal dilation. Strictures, benign and malignant tumours should be ruled out.
Megacolon may also occur in Hirschsprung’s disease [congenital megacolon] [aganglionosis of a rectal segment, frequency 1/5000], diabetic neuropathy, psychogenic (mainly in psychosis, schizophrenia), after stricture (e.g. upon ischaemic insult of the colon or rectal stricture due to schistosomiasis or lymphogranuloma venereum), chronic severe laxative misuse (senna, cascara, aloe), neurological diseases (Parkinson’s disease, myotonic dystrophy), chronic use of morphine analogues, chronic lead intoxication, Fabry’s disease (glycolipid accumulation), systemic sclerosis (scleroderma), severe hypothyroidism and amyloidosis.
In an endemic region an asymptomatic person with positive serology is probably a carrier (xenodiagnosis positive in 50 to 100 % of cases). The percentage of seropositive persons who develop symptoms is highly dependent on the geographical region (e.g. 10 to 30%). Asymptomatic mega-organs occur. If the ECG is abnormal, the mortality is 40% after 10 years.
Acute phase
The acute phase lasts up to 60 days. All patients who are in this phase should be treated.
Congenital infection
All infected children should be treated. The earlier therapy is begun, the better the results.
Chronic phase
Aetiological drug treatment is indicated for "recent" chronic infections (a few years). In practice all children younger than 10 years are treated. If mega-oesophagus is already present, the dysphagia should be treated (the passage and absorption of oral medication may be severely impeded). Aetiological treatment in these latter patients was not advised formerly, but more recent data have brought this into question. In a study in Argentina, 131 patients with chronic Chagas’ disease were treated with benznidazole. After an average follow up of 8 years, 4.2% exhibited ECG changes compared to 30% in the untreated group. There was also considerably less clinical deterioration in the treated group (2.1% compared to 17%).
Accidental infection
This may occur, for example in laboratory staff. A serum specimen should be frozen before beginning treatment and a second blood sample taken 4 weeks later. Serology is performed on these paired sera. Benznidazole 7-10 mg/kg/day x 10 days is the usual treatment regimen in this situation.
Transplant patients
There are two possible situations: transplantation of an infected organ into a non-infected patient and transplantation of a healthy organ into an infected patient. A donor may be infected so that the recipient becomes infected. Normally the donor is tested beforehand, and positive donors are refused, but nevertheless these situations sometimes occur. Alternatively, a transplantation may be carried out on a patient who is a chronic carrier. The immune suppression that these patients undergo [steroids, azathioprine (Imuran®) and cyclosporin (Sandimmun®)], may lead to reactivation of Chagas’ disease. In both cases treatment with benznidazole 5 mg/kg/day x 60 days, is indicated.
HIV patients
Infection with HIV may lead to significant flare-up of Chagas’ disease. In endemic regions all HIV patients should be monitored for Chagas’ disease. If positive, benznidazole is recommended. There are insufficient data concerning chemoprophylaxis.
Pregnancy
Treatment during pregnancy is not recommended.
There are several problems. The drugs have an unsatisfactory cure rate. The chronic lesions may be caused by auto-immune mechanisms and might not be improved by eradicating parasites. [Nevertheless the role of auto-immune mechanisms should not be exaggerated: the disease worsens during immune suppression as in transplantation and in HIV]. The drugs should be given long term. Results vary from country to country, possibly due to a difference in sensitivity of the parasites. Side effects occur, more often in adults than in children. It is best to avoid steroids and possibly tetracyclines, since these may exacerbate the infection.
Nifurtimox (Lampit®) 5 mg/kg/day orally, slowly increased to 15 mg/kg/day (divided over 3 doses) for 2 to 4 months. The drug is no longer produced. Side effects: neurotoxicity (insomnia, tremor, polyneuritis), nausea, leukopaenia, thrombocytopaenia or hypersensitivity. May cause haemolysis in G6PD deficiency [glucose-6-phosphate dehydrogenase]. In the acute phase the parasites disappear from the blood in 80 % to almost 100 % of cases. The actual cure rate is 50-60%.
Benznidazole (syn. benzonidazole: Radanil®, Ragonil®, Rochagan®), 5-10 mg/kg/day orally for 1 to 2 months. Administration (generally 100 mg tablets) is twice daily. The same side effects as nifurtimox, but less frequent and less pronounced, although skin rash occurs relatively frequently (up to 30% of patients), sometimes accompanied by swollen lymph nodes. The pharmaceutical company Roche has donated all commercial rights and the technology to manufacture benznidazole to the Brazilian government.
Allopurinol (Zyloric®): 600 mg/day orally for 2 months (adult dose). The place of this therapy has not yet been determined, but it is currently used following flare-ups after heart transplantation.
Experimental: D0870 (a bis-triazole derivative), posaconazole, squalene oxidase inhibitors such as terbinafine, proteasome inhibitors, trans-sialidase inhibitors.
T. cruzi is auxotrophic for polyamine biosynthesis, since it does not have ornithine decarboxylase, and is thus naturally refractory to the effects of eflornithine.
In the chronic phase the usefulness of these drugs is doubtful, but the tendency is more and more towards treatment. Symptomatic therapy is indicated: oesophageal sphincter dilation, extramucosal cardiotomy (Heller’s operation), colon surgery. An experimental treatment is the endoscopic injection of botulin toxin into the distal oesophageal sphincter (e.g. 20 U into each quadrant).
In heart failure, diuretics, ACE-inhibitors and antiarrhythmic drugs may be beneficial. Beta-blockers are best avoided in view of the AV-conduction problems and bradyarrhythmias. Anticoagulants are indicated for patients with atrial fibrillation, previous embolic phenomena and apical aneurysms. Amiodarone (Cordarone®) is effective in more than 50% of patients who develop ventricular extrasystoles or ventricular tachycardia. A bifascicular or trifascicular conduction block, also a second or third degree AV-block are contra-indications. Amiodarone is an iodine-containing Vaughan-Williams class III antiarrhythmic drug. It may cause thyroid problems (either hypothyroidism or hyperthyroidism). Reversible deposits in the cornea, pulmonary toxicity, neuropathy, photosensitivity and grey discoloration of the skin may occur. The elimination half-life varies greatly from individual to individual (20 to 100 days). A high incidence of "torsades de pointes" has been observed during use of quinidine, disopyramide and other class I antiarrhythmic drugs. Patients with cardiac problems are generally very sensitive to digitalis (lower dose necessary). Pacemakers and cardiac surgery are reserved in practice for those with financial means and these persons have an inherently low risk of infection. Pacemakers can be used in cases of severe bradyarrhythmia. Implantation of an automatic defibrillator is indicated for patients with recurrent ventricular tachycardia or a history of cardiac arrest.
The animal reservoir of Trypanosoma cruzi cannot be eradicated. There is no vaccine. Chagas’ disease is typically a disease of poverty. Improvements in housing (brick or plaster walls, corrugated iron roofs, long-acting insecticides on house walls) diminish the insect population. A mosquito net has also proved its usefulness here. Serological testing of the blood used for transfusion is very helpful. In 1953 it was discovered that adding gentian violet kills the trypanosomes in 24 hours (0.25 g/litre of blood = 1/4000). This colours the blood purple, however. If 2 mg/ml of ascorbic acid (vitamin C) is also added and the blood is illuminated with a 75 Watt fluorescent lamp, the time necessary to sterilise the blood is greatly shortened (30'). To date the various biological methods of eradication of the vectors which have been tested (increasing natural enemies) have not been effective because a new ecological balance is very quickly achieved.
This programme was begun in Brazil in 1975. The intention was to reach the whole country and the strategy included spraying houses with insecticides. In Sao Paulo the vector Triatoma infestans was eliminated in 1982. Between 1983 and 1993 reductions of house infestation, ranging between 100% (Mato Grosso) and 80% (Goias) were observed in 8 of the 11 endemic states. In the states Bahia, Tocantins and Rio Grande do Sul the results were less spectacular. Nevertheless further successes are expected in the coming years. The total incidence of seropositivity in children from 7-14 years fell by 96% between 1980 and 1994. In 1998 there was still one T. infestans per 10,000 houses. A much higher frequency would be required to maintain transmission of T. cruzi. It is reasonable to expect the transmission will be interrupted.
In 1991-92 the "Southern Cone Initiative" project was launched by Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay, with the objective of stopping the transmission of Chagas’ disease. In 1997 Peru joined the project. After an initial phase for preparation (charting the foci, programming the activities, calculating the costs), there was an attack phase with insecticides, repeated after 3 to 6 months. Insecticide-containing paint is cheaper than the traditional insecticides which are applied by spraying. Insecticides dispersed by fumigant canisters were also used. These are locally produced, e.g. in Argentina, are cheap, effective and also active against Aedes aegypti, the important dengue vector. At present there are effective colourless long acting insecticides. The fact that people see the bugs, cockroaches, etc. lying dead after spraying, is a bonus which makes it easier to accept the spraying procedure. In the Southern Cone Initiative, 1,800,000 houses were treated with pyrethroids (deltametrine, lambda-cyhalotrine, cyflutrine) by the year 2000.
Since then there has been further selective treatment of the houses which still exhibited infestation with triatomes. Simple "sensor boxes" of cardboard (traps for the bugs) were placed in the rooms and the occupants themselves could simply ascertain the presence of triatomes. The last phase is surveillance for the detection of residual foci. This is decentralised and involves the population. The effectiveness of the control programme has been demonstrated by the very pronounced drop in seropositivity among young children. The surveillance phase has been reached in 6 countries of the Southern Cone. At present there are several South American countries (Colombia, Ecuador, Venezuela) which have a national control programme. Similar programmes were begun in Central America in 1997: Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Mexico and Panama. These programmes can only be successful if there is participation of the population and if they can be continued for long enough. The latter is a political decision.
The Southern Cone Initiative began in 1991-92. Many countries have now been declared free from transmission by the PAHO [Pan-American Health Organization].
The Central American Initiative was begun in 1997-98 in Guatemala, Honduras, Nicaragua, El Salvador, Panama.
The Andean Pact Initiative was set up in 1997-98 in Venezuela, Colombia, Ecuador. Northern Peru began surveys during the same period.
The Mexican Initiative was begun in 2000-1. In 2001 this was still at a very early stage.
In 2001 there was still no control or surveillance in the Guyanas, Surinam and Costa Rica.
Trypanosoma cruzi, only in the New World
Transmission via bugs, blood transfusion and congenitally, rarely orally
Importance of poverty (housing)
Acute (especially children): chancre, RomaƱa’s sign, fever, lymphadenophathy, myocarditis, hepatosplenomegaly
Chronic: cardiac arrhythmias, heart failure, emboli, apical aneurysms
Chronic: dysphagia, constipation (mega-syndrome)
Diagnosis: clinical + thick smear/buffy coat (early), serology, xenodiagnosis, ECG, X-ray (late), PCR
Treatment in the early phase still reasonably successful with medication; in the late phase difficult
Benznidazole: problems with bone marrow toxicity, hypersensitivity, peripheral neuropathy.
Prevention: much progress in recent years via vector control and control of blood banks.
Microangiopathic hemolytic anemia
Thrombocytopenia
Increased numbers of reticulocytes
Elevated bilirubin levels
Reduced haptoglobin levels
Elevated level of fibrin split products – less elevated in TTP
What are the causes of HUS in children and adults?
Adults
Associated with complications of pregnancy or post-partum period
Use of contraceptives / chemotherapeutic / immunosuppressive drugs
Systemic diseases such as scleroderma, SLE, and malignant HTN
Probably involves glomerular endothelial cell injury with subsequent fibrin deposition and thrombosis
Decreased endothelial cell production of prostaglandin I2 and NO
Release of endothelin
Activation of endothelial cells, increasing their adhesiveness to leukocytes, contributing to thrombosis
More common occurrence of TTP in young adults
Fever is a more frequent manifestation of TTP
Neurologic abnormalities that tend to predominate and cause death in TTP
Lesser degree if renal involvement in TTP
TTP has a worse prognosis than HUS
Concentric cellular thickening of intima of arterioles and interlobular arteries
Thickening of glomerular capillary walls by endothelial swelling
Deposits of fibrin-related material in the capillary lumina, subendothelially, and in the mesangium.
Intracapillary fibrin thrombi
Sometimes cortical necrosis
Type I Surface pili ® adhesin molecules bind to mannose on uroepithelium ® UTI ® stimulation of T-helper cells ® stimulation of phagocytes ® scarring and release of lysozyme
Type P Surface pili ® adhesin molecules bind galactose ® pyelonephritis
