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Cystinuria

Signs and symptoms

Cystinuria is a cause of persistent kidney stones. It is a disorder involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones. If not treated properly, the disorder could cause serious damage to the kidneys and surrounding organs, and in some rare cases death. The stones may be identified by a positive nitroprusside cyanide test. The crystals are usually hexagonal, translucent, white. Upon removal, the stones may be pink or yellow in color, but later they turn to greenish due to exposure to air.

Genetics

Cystinuria has an autosomal recessive pattern of inheritance.
Cystinuria is an autosomal recessive disorder,[1] which means that the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Cause

Cystinuria is caused by mutations in the SLC3A1 and SLC7A9 genes. These genes encode two parts of a transporter protein that is made primarily in the kidneys. These defects prevent proper reabsorption of basic, or positively charged, amino acids: lysine, ornithine, arginine.[2] Under normal circumstances, this protein allows certain amino acids, including cysteine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, the crystals typical of cystinuria are able to form, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The disorder affects 1 in 10,000 people, making it the most common genetic error of amino acid transport. Cystinuria is inherited in an autosomal recessive pattern.

Pathophysiology

Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidney's glomeruli, thus resulting in an excessive concentration of this amino acid in the urine. Cystine may precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrod's tetrad. The disorder is attributed to deficiency in transport and metabolism of amino acids.

Clinical Features

Cystinuria is usually asymptomatic when no stone is formed. Once a stone is formed, however, the following symptoms may be present:

Investigations

1. Blood: Routine hemogram along with blood sugar, urea, and creatinine.
2. Urine: For cystine crystals, and casts.
3. USG/CT scan to reveal if a stone is present.
4. Genetic analysis to determine which mutation associated with the disorder may be present. Currently genotyping is not available in the United States but might be available in Spain and Italy.

Treatment

Initial treatment is with adequate hydration, alkalinization of the urine with citrate supplementation, and dietary modification to reduce salt and protein intake. If this fails then patients are usually started on chelation therapy with an agent such as penicillamine.[3][4] Once renal stones have formed, however, the first-line treatment is surgery. Both endoscopic surgery and conventional open-abdominal surgery have proven to be effective treatment modalities for patients with more advanced disease.
Jeffrey Rimer of the University of Houston suggested in October 2010 that treatment with L-cystine dimethylester could prevent the formation of these kidney stones.[5]

Occurrence in animals

This disease is known to occur in at least three mammalian species. These are: humans, domestic dogs canines, and a wild canid, the Maned Wolf of South America. Cystine uroliths have been demonstrated, most usually in male dogs, from approximately 70 breeds including the Australian cattle dog, Australian shepherd, Basenji, Basset, Bullmastiff, Chihuahua, Scottish deerhound, Scottish terrier, Staffordshire terrier and Welsh corgi; and in both male and female Newfoundland dogs

 

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Kidney stones

Causes, incidence, and risk factors

Kidney stones can form when urine contains too much of certain substances. These substances can create small crystals that become stones.
The biggest risk factor for kidney stones is dehydration.
Kidney stones may not produce symptoms until they begin to move down the tubes (ureters) through which urine empties into the bladder. When this happens, the stones can block the flow of urine out of the kidneys. This causes swelling of the kidney or kidneys, causing pain. The pain is usually severe.
Kidney stones are common. A person who has had kidney stones often gets them again in the future. Kidney stones often occur in premature infants.
Some types of stones tend to run in families. Certain kinds of stones can occur with bowel disease, ileal bypass for obesity, or renal tubule defects.
There are different types of kidney stones. The exact cause depends on the type of stone.
  • Calcium stones are most common. They occur more often in men than in women, and usually appear between ages 20 - 30. They are likely to come back. Calcium can combine with other substances, such as oxalate (the most common substance), phosphate, or carbonate to form the stone. Oxalate is present in certain foods. Diseases of the small intestine increase the risk of forming calcium oxalate stones.
  • Cystine stones can form in people who have cystinuria. This disorder runs in families and affects both men and women.
  • Struvite stones are mostly found in women who have a urinary tract infection. These stones can grow very large and can block the kidney, ureter, or bladder.
  • Uric acid stones are more common in men than in women. They can occur with gout or chemotherapy.
Other substances also can form stones.

Symptoms

The main symptom is severe pain that starts suddenly and may go away suddenly:
  • Pain may be felt in the belly area or side of the back
  • Pain may move to groin area (groin pain) or testicles (testicle pain)
Other symptoms can include:

Signs and tests

Pain can be severe enough to need narcotic pain relievers. The belly area (abdomen) or back might feel tender to the touch.
Tests for kidney stones include:
Stones or a blockage of the ureter can be seen on:
Tests may show high levels of calcium, oxylate, or uric acid in the urine or blood.

Treatment

The goal of treatment is to relieve symptoms and prevent further symptoms. (Kidney stones that are small enough usually pass on their own.) Treatment varies depending on the type of stone and how severe the symptoms are. People with severe symptoms might need to be hospitalized.
When the stone passes, the urine should be strained and the stone saved and tested to determine the type.
Drink at least 6 - 8 glasses of water per day to produce a large amount of urine. Some people might need to get fluids through a vein (intravenous).
Pain relievers can help control the pain of passing the stones (renal colic). For severe pain, you may need to take narcotic pain killers or nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen.
Depending on the type of stone, your doctor may prescribe medicine to decrease stone formation or help break down and remove the material that is causing the stone. Medications can include:
  • Allopurinol (for uric acid stones)
  • Antibiotics (for struvite stones)
  • Diuretics
  • Phosphate solutions
  • Sodium bicarbonate or sodium citrate (which make the urine more alkaline)
Surgery is usually needed if:
  • The stone is too large to pass on its own
  • The stone is growing
  • The stone is blocking urine flow and causing an infection or kidney damage
Today, most treatments are much less invasive than in the past.
  • Extracorporeal shock-wave lithotripsy is used to remove stones slightly smaller than a half an inch that are located near the kidney. This method uses ultrasonic waves or shock waves to break up stones. Then, the stones leave the body in the urine.
  • Percutaneous nephrolithotomy is used for large stones in or near the kidney, or when the kidneys or surrounding areas are incorrectly formed. The stone is removed with an endoscope that is inserted into the kidney through a small opening.
  • Ureteroscopy may be used for stones in the lower urinary tract.
  • Standard open surgery (nephrolithotomy) may be needed if other methods do not work or are not possible.

Expectations (prognosis)

Kidney stones are painful but usually can be removed from the body without causing permanent damage. They tend to return, especially if the cause is not found and treated.

Complications

Calling your health care provider

Call your health care provider if you have symptoms of a kidney stone.
Also call if symptoms return, urination becomes painful, urine output decreases, or other new symptoms develop.

Prevention

If you have a history of stones, drink plenty of fluids (6 - 8 glasses of water per day) to produce enough urine. Depending on the type of stone, you might need to take medications or other measures to prevent the stones from returning.
You may need to change your diet to prevent some types of stones from coming back.

References

  1. Cameron MA, Sakhaee K. Uric acid nephrolithiasis. Urol Clin North Am. 2007;34(3):335-346.
  2. Chandhoke PS. Evaluation of the recurrent stone former. Urol Clin North Am. 2007; 34(3):315-322.
  3. Finkielstein VA. Strategies for preventing calcium oxalate stones. CMAJ. 2006;174(10):1407-1409.
  4. Pietrow PK, Preminger GM. Evaluation and medical management of urinary lithiasis. In: Wein AJ, ed. Campbell-Walsh Urology. 9th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 43.
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Urinary Tract Infections in Women

What causes urinary tract infections?

Urinary tract
Bacteria cause most urinary tract infections. The urinary tract includes the kidneys, ureters, bladder and urethra. Any part of your urinary tract can become infected, but bladder and urethra infections are the most common.


Why do women get urinary tract infections more often than men?

Women tend to get urinary tract infections more often than men because bacteria can reach the bladder more easily in women. The urethra is shorter in women than in men, so bacteria have a shorter distance to travel.

The urethra is also located near the rectum in women. Bacteria from the rectum can easily travel up the urethra and cause infections.

Having sex may also cause urinary tract infections in women because bacteria can be pushed into the urethra. Using a diaphragm can lead to infections because diaphragms push against the urethra and make it harder to completely empty the bladder. The urine that stays in the bladder is more likely to grow bacteria and cause infections.


How do I know if I have a urinary tract infection?

The box below lists possible signs of a urinary tract infection. Nausea, lower back pain and fever may be signs of a more serious kidney infection. Call your doctor if you have any of these symptoms.

How are urinary tract infections treated?

If your family doctor thinks you have a urinary tract infection, he or she will probably test a sample of your urine to find out if there are bacteria in it. If you have an infection, your doctor will then prescribe an antibiotic. Usually, symptoms of the infection go away 1 to 2 days after you start taking the medicine. Make sure you take all the medicine, even if you are feeling better.

Your doctor may also suggest a medicine to numb your urinary tract and make you feel better while the antibiotic starts to work. The medicine makes your urine turn bright orange, so don't be alarmed by the color when you urinate.


Possible signs of a urinary tract infection

  • A burning sensation when you urinate
  • Feeling like you need to urinate more often than usual
  • Feeling the urge to urinate but not being able to
  • Leaking a little urine
  • Cloudy, dark, smelly or bloody urine


What can I do if I have frequent infections?

If you have urinary tract infections often, you can try some of the suggestions in the box below. Talk with your family doctor about what changes would be helpful for you.

Your doctor also may give you a low dose of medicine for several months or longer to prevent infections from coming back.

If having sex seems to cause your infections, your doctor may suggest that you take a single low dose antibiotic pill after you have sex to prevent urinary tract infections.


Tips on preventing urinary tract infections

  • Drink plenty of water to flush out bacteria. Drinking cranberry juice may also help prevent urinary tract infections. However, if you're taking warfarin, check with your doctor before using cranberry juice to prevent urinary tract infections. Your doctor may need to adjust your warfarin dose or you may need to have more frequent blood tests.
  • Don't hold your urine. Urinate when you feel like you need to.
  • Wipe from front to back after bowel movements.
  • Urinate after having sex to help wash away bacteria.
  • Use enough lubrication during sex. Try using a small amount of lubricant (such as K-Y Jelly) before sex if you're a little dry.
  • If you get urinary tract infections often, you may want to avoid using a diaphragm as a birth control method. Ask your doctor about other birth control choices.


How serious are urinary tract infections?

Urinary tract infections can be painful. But medicine can keep them from becoming a serious threat to your health.

The kidneys can also be infected, which can be a more serious problem. Kidney infections usually require an antibiotic for a longer period of time and are sometimes treated in the hospital.
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Mycobacterium tuberculosis

From Wikipedia, the free encyclopedia
Mycobacterium tuberculosis
M. tuberculosis bacterial colonies
Scientific classification
Kingdom: Bacteria
Phylum: Actinobacteria
Class: Actinobacteria
Order: Actinomycetales
Suborder: Corynebacterineae
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: M. tuberculosis
Binomial name
Mycobacterium tuberculosis


Mycobacterium tuberculosis (MTB) is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis.[1] First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on the cell surface (primarily mycolic acid), which makes the cells impervious to Gram staining so acid-fast detection techniques are used instead. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, MTB infects the lungs. The most frequently used diagnostic methods for TB are the tuberculin skin test, acid-fast stain, and chest radiographs.[1]
The M. tuberculosis genome was sequenced in 1998.[2][3]
Pathophysiology M. tuberculosis requires oxygen to grow. It does not retain any bacteriological stain due to high lipid content in its wall, and thus is neither Gram positive nor Gram negative; hence Ziehl-Neelsen staining, or acid-fast staining, is used. While mycobacteria do not seem to fit the Gram-positive category from an empirical standpoint (i.e., they do not retain the crystal violet stain), they are classified as acid-fast Gram-positive bacteria due to their lack of an outer cell membrane.[1]
M. tuberculosis divides every 15–20 hours, which is extremely slow compared to other bacteria, which tend to have division times measured in minutes (Escherichia coli can divide roughly every 20 minutes). It is a small bacillus that can withstand weak disinfectants and can survive in a dry state for weeks. Its unusual cell wall, rich in lipids (e.g., mycolic acid), is likely responsible for this resistance and is a key virulence factor.[4]
When in the lungs, M. tuberculosis is taken up by alveolar macrophages, but they are unable to digest the bacterium. Its cell wall prevents the fusion of the phagosome with a lysosome. Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carried the UreC gene, which prevents acidification of the phagosome.[5] The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.
The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced our understanding of the pathogenesis and virulence factors of M. tuberculosis. Many secreted and exported proteins are known to be important in pathogenesis.[6]

Strain variation

M. tuberculosis comes from the genus Mycobacterium, which is composed of approximately 100 recognized and proposed species. The most familiar of the species are Mycobacterium tuberculosis and Mycobacterium leprae (leprosy).[7] M. tuberculosis appears to be genetically diverse, which results in significant phenotypic differences between clinical isolates. M. tuberculosis exhibits a biogeographic population structure and different strain lineages are associated with different geographic regions. Phenotypic studies suggest this strain variation never has implications for the development of new diagnostics and vaccines. Microevolutionary variation affects the relative fitness and transmission dynamics of antibiotic-resistant strains.[8]

Hypervirulent strains

Mycobacterium outbreaks are often caused by hypervirulent strains of M. tuberculosis. In laboratory experiments, these clinical isolates elicit unusual immunopathology, and may be either hyperinflammatory or hypoinflammatory. Studies have shown the majority of hypervirulent mutants have deletions in their cell wall modifying enzymes or regulators that respond to environmental stimuli. Studies of these mutants have indicated the mechanisms that enable M. tuberculosis to mask its full pathogenic potential, inducing a granuloma that provides a protective niche and enables the bacilli to sustain a long-term, persistent infection.[9]
Mycobacterium tuberculosis (stained red) in tissue (blue)

Microscopy

M. tuberculosis is characterized by caseating granulomas containing Langhans giant cells, which have a "horseshoe" pattern of nuclei. Organisms are identified by their red color on acid-fast staining.

Genome

The genome of the H37Rv strain was published in 1998.[10] Its size is 4 million base pairs, with 3959 genes; 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also 6 pseudogenes.
The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating the waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival.
About 10% of the coding capacity is taken up by two clustered gene families that encode acidic, glycine-rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.[11]
Nine noncoding sRNAs have been characterised in M. tuberculosis,[12] with a further 56 predicted in a bioinformatics screen.[13]

Symptoms

Only an estimated 10% of people infected with M. tuberculosis ever develop the disease, and many of those have the disease only for the first few years following infection, even though the bacillus may lie dormant in the body for decades.[14]
The symptoms that patients infected with M. tuberculosis may experience are usually absent until the disease has become more complicated. It may take many months from the time the infection initially gets into the lungs until symptoms develop.[15] Cough is however the first symptom of the infection with M. tuberculosis.[16] The initial symptoms, including loss of appetite, fever, productive cough and loss of energy or loss of weight or night sweats, are not specific and might be easily attributed to another condition.
Primary pulmonary tuberculosis is the first stage of the condition, and it may cause fever, dry cough and some abnormalities that may be noticed on a chest X-ray. In most cases, though, primary infections tend to cause no symptoms that people do not overcome. This condition resolves itself, although it returns in more than half of the cases.
Tuberculosis causing lung disease may result in tuberculous pleuritis, a condition that may cause symptoms such as chest pain, nonproductive cough and fever. Moreover, infection with M. tuberculosis can spread to other parts of the body, especially in patients with a weakened immune system. This condition is referred to as miliary tuberculosis, and people contacting it may experience fever, weight loss, weakness and a poor appetite. In more rare cases, miliary tuberculosis can cause coughing and difficulty breathing.
Dormant (inactive) tuberculosis may return after a certain period of time, and it usually occurs in the upper lungs, causing severe symptoms, such as common cough with a progressive increase in production of mucus and coughing up blood.[14] Most patients also develop fever, loss of appetite, unexplained weight loss and night sweats.
In cases in which the infection spreads to other parts of the body, additional symptoms may occur, depending on the exact site of the spread. If the infection spreads to the abdominal cavity, symptoms such as fatigue, swelling, slight tenderness and appendicitis-like pain are likely to occur. Also, painful urination might be a sign the infection has reached the bladder. In children, M. tuberculosis infections may affect the bones, causing mild swelling and minimal pain. Fever, headache, nausea, drowsiness, and, if untreated, coma and brain damage may occur if the brain has been affected.[16] If the infection affects the pericardium, symptoms and signs such as fever, enlarged neck veins, and shortness of breath may develop. Kidney damage and the symptoms emerging with it, as well as sterility, may occur if the kidney and the reproductive system are affected, respectively.

Diagnosis

Sputum is taken on three successive mornings as the number of organisms could be low, and the specimen is treated with 3% KOH or NaOH for liquefaction and decontamination. Gram stain should never be performed, as the organism is an "acid-fast bacillus" (AFB), meaning that it retains certain stains after being treated with acidic solution. In the most common staining technique, the Ziehl-Neelsen stain, AFB are stained a bright red, which stands out clearly against a blue background; therefore, the bacteria are sometimes called "red snappers".[17] The reason for the acid-fast staining is because of its thick waxy cell wall.[18] The waxy quality of the cell wall is mainly due to the presence of mycolic acids. This waxy cell wall also is responsible for the typical caseous granuloma formation in tuberculosis. The component responsible, trehalose dimycolate, is called the cord factor. A grading system exists for interpretation of the microscopic findings based on the number of organisms observed in each field. Patients of pulmonary tuberculosis show AFB in their sputum in only 50% of cases, which means, even if no organisms are observed, further investigation is still required. AFB can also be visualized by fluorescent microscopy using auramine-rhodamine stain for screening, which makes them appear somewhat golden in color. Also, M. tuberculosis traditionally is grown on a selective medium, Lowenstein-Jensen medium. However, this method is quite slow, as this organism requires six to eight weeks to grow, which delays reporting of results. A faster result can now be obtained using Middlebrook medium or BACTEC.
During an advanced stage of tuberculosis, the organism may infect almost any part of the body, which means the specimen chosen should be appropriate for the symptoms or tissues (e.g. intestinal tuberculosis-stool).
An immunochromatographic serological essay for the diagnosis of M. tuberculosis has also been developed.[19]

Treatment
Treatment is usually administered on an outpatient basis, and consists mainly of medications. Usually, the treatment is given for six to nine months according to a therapy regimen consisting of two months of isoniazid, rifampin, and pyrazinamide, four months of isoniazid and rifampin, and ethambutol or streptomycin until the drug sensitivity is known.[20] The drug treatment schema may be changed according to the laboratory results.
Antibiotics are usually part of therapy in people who have no symptoms and whose germs are in inactive state, because they are helpful in preventing the activation of the infection. The antibiotic used is isoniazid (INH), usually taken for six to 12 months, to prevent future activation.[21] This medicine may not, however, be taken during pregnancy or in people who suffer from liver disease or alcoholism. Moreover, several side effects have been reported; some can be even life-threatening. One of the side effects caused by this drug is peripheral neuropathy, meaning a decreased sensation in the extremities and which is normally prevented or avoided by administering vitamin B6 at the same time with isoniazid.
Patients who have active bacteria are usually treated with a combination of medications; the primary antibiotic, isoniazid, is used in conjunction rifampin, ethambutol and pyrazinamide.
Streptomycin, a drug given by injection, may be used as well, particularly when the disease is extensive and/or the patients do not take their oral medications reliably (termed "poor compliance").[21]
Usually, treatment lasts for few months, but it can even be administered for years in some cases. Mainly, the success rate of the treatment is closely related to the patient's compliance and ability to take the drugs as prescribed.

History

M. tuberculosis, then known as the "tubercle bacillus", was first described on 24 March 1882 by Robert Koch, who subsequently received the Nobel Prize in physiology or medicine for this discovery in 1905; the bacterium is also known as "Koch's bacillus".[22]
Tuberculosis has existed throughout history, but the name has changed frequently over time. In 1720, though, the history of tuberculosis started to take shape into what is known of it today; as the physician Benjamin Marten described in his A Theory of Consumption, tuberculosis may be caused by small living creatures that are transmitted through the air to other patients
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Loa loa filariasis

From Wikipedia, the free encyclopedia
Loa loa
Classification and external resources

Loa loa microfilaria in thin blood smear (Giemsa stain)










Loa loa filariasis (also known as loiasis, loaiasis, Calabar swellings, Fugitive swelling, Tropical swelling[1]:439 and African eyeworm) is a skin and eye disease caused by the nematode worm, loa loa. Humans contract this disease through the bite of a Deer fly or Mango fly (Chrysops spp), the vectors for Loa loa. The adult Loa loa filarial worm migrates throughout the subcutaneous tissues of humans, occasionally crossing into subconjunctival tissues where it can be easily observed. Loa loa does not normally affect one's vision but can be painful when moving about the eyeball or across the bridge of the nose.[2][3] The disease can cause red itchy swellings below the skin called "Calabar swellings". The disease is treated with the drug diethylcarbamazine (DEC), and when appropriate, surgical methods may be employed to remove adult worms from the conjunctiva.
Human loiasis geographical distribution is restricted to the rain forest and swamp forest areas of West Africa, being especially common in Cameroon and on the Ogooué River. Humans are the only known natural reservoir. It is estimated that 12-13 million humans are infected with the Loa loa larvae.
An area of tremendous concern regarding loiasis is its co-endemicity with onchocerciasis in certain areas of west and central Africa, as mass ivermectin treatment of onchocerciasis can lead to serious adverse events (SAEs) in patients who have high Loa loa microfilarial densities, or loads. This fact necessitates the development of more specific diagnostics tests for Loa loa so that areas and individuals at a higher risk for neurologic consequences can be identified prior to microfilaricidal treatment. Additionally, the treatment of choice for loiasis, diethylcarbamazine, can lead to serious complications in and of itself when administered in standard doses to patients with high Loa loa microfilarial loads.

Synonyms


Loa loa in subconjunctival tissues. Source: J.D. McLean, McGill Medicine.
Synonyms for the disease include African eye worm, Loaiasis, Loaina, Loa loa filariasis, Filaria loa, Filaria lacrimalis, Filaria subconjunctivalis, Calabar swellings, Fugitive swellings, Loaina, and Microfilaria diurnal.[4] Loa loa, the scientific name for the infectious agent, is an indigenous term itself and it is likely that there are many other terms used from region to region.

History of discovery

The first case of Loa loa infection was noted in the Caribbean (Santo Domingo) in 1770. A French surgeon named Mongin tried but failed to remove a worm passing across a woman's eye. A few years later, in 1778, the surgeon François Guyot noted worms in the eyes of West African slaves on a French ship to America; he successfully removed a worm from one man's eye.
The identification of microfilaria was made in 1890 by the ophthalmologist Stephen McKenzie. Localized angioedema, a common clinical presentation of loiasis, was observed in 1895 in the coastal Nigerian town of Calabar—hence the name, "Calabar" swellings. This observation was made by a Scottish ophthalmologist named Douglas Argyll-Robertson, but the association between Loa loa and Calabar swellings was not realized until 1910 (by Dr. Patrick Manson). The determination of vector—Chrysops spp.—was made in 1912 by the British parasitologist Robert Thomson Leiper.[5]

Clinical Presentation in Humans

Filariasis such as loiasis most often consists of asymptomatic microfilaremia. Some patients develop lymphatic dysfunction causing lymphedema. Episodic angioedema (Calabar swellings) in the arms and legs, caused by immune reactions are common. When chronic, they can form cyst-like enlargements of the connective tissue around the sheaths of muscle tendons, becoming very painful when moved. The swellings may last for 1–3 days, and may be accompanied by localized urticaria (skin eruptions) and pruritus (itching). Subconjunctival migration of an adult worm to the eyes can also occur frequently, and this is the reason Loa loa is also called the "African eye worm." The passage over the eyeball can be sensed, but it usually takes less than 15 min. Gender incidence of eyeworms have approximately the same frequency, but it tends to increase with age. Eosinophilia is often prominent in filarial infections. Dead worms may cause chronic abscesses, which may lead to the formation of granulomatous reactions and fibrosis.

Transmission

Loa loa microfilariae are transmitted to humans by the mango (also, mangrove) or deerfly vectors, Chrysops silicea and C. dimidiata. The vectors are blood-sucking and day-biting, and they are found in rainforest-like environments in west and central Africa. Microfilaria mature to adults in the subcutaneous tissues of the human host, after which the adult worms—assuming presence of a male and female worm—mate and produce more microfilaria. The cycle of infection continues when a non-infected mango or deerfly takes a blood meal from a microfilaremic human host, and this stage of the transmission is possible due to the combination of the diurnal periodicity of microfilaria and the day-biting tendencies of the Chrysops spp.[6]

Reservoir

Humans are the primary reservoir for Loa loa. Other minor potential reservoirs have been indicated in various fly biting habit studies: hippopotamus, wild ruminants (e.g., buffalo), rodents, and lizards. A simian type of loiasis exists in monkeys and apes but it is transmitted by Chrysops langi. There is no cross-over between the human and simian types of the disease.[7]

Vector

Microfilaria of Loa loa are transmitted by several species of tabanid flies (Order: Diptera; Class: Tabanidae). Although horseflies of the Tabanus genus are often mentioned as Loa vectors, the two prominent vector are from the Chrysops genus of tabanids—C. silicea and C. dimidiata. These species exist only in Africa and are popularly known as deerflies and mango, or mangrove, flies.[8]
Chrysops spp are small (5–20 mm long) with a large head and downward pointing mouthparts.[6][8] Their wings are clear or speckled brown. They are hematophagous and typically live in forested and muddy habitats like swamps, streams, reservoirs, and in rotting vegetation. Female mango and deerflies require a blood meal for production of a second batch of eggs. This batch is deposited near water, where the eggs hatch in 5–7 days. The larvae mature in water or soil,[6] where they feed on organic material such as decaying animal and vegetable products. Fly larvae are 1–6 cm long and take 1–3 years to mature from egg to adult.[8] When fully mature, C. silacea and C. dimidiata assume the day-biting tendencies of all tabanids.[6]

Loa loa vector. Source: J.D. McLean. McGill Medicine
The bite of the mango fly can be very painful, possibly due to the laceration style employed; rather than puncturing the skin like a mosquito does, the mango (and deerfly) make a laceration in the skin and subsequently lap up blood. Female flies require a fair amount of blood for their aforementioned reproductive purposes and thus may take multiple blood meals from the same host if disturbed during the first one.[6]
Interestingly, although Chrysops silacea and C. dimidiata are attracted to canopied rainforests, they do not do their biting there. Instead, they leave the forest and take most blood meals in open areas. The flies are attracted to smoke from wood fires and they use visual cues and sensation of carbon dioxide plumes to find their preferred host, humans.[7]
A study of Chrysops spp biting habits showed that C. silacea and C. dimidiata take human blood meals approximately 90% of the time, with hippopatomus, wild ruminant, rodent, and lizard blood meals making up the other 10%. The fact that no simian (ex: monkeys or apes) blood meals were taken suggests that there is no crossover between the human and simian types of Loa loa. A related fly, Chrysops langi, has been isolated as a vector of simian loiasis, but this variant hunts within the forest and has not as yet been associated with human infection.[7]

Incubation Period

In the human host, Loa loa larvae migrate to the subcutaneous tissue where they mature to adult worms in approximately one year, but sometimes up to four years. Adult worms migrate in the subcutaneous tissues, mating and producing more microfilaria. The adult worms can live up to 17 years in the human host.[6]

Morphology

Adult Loa worms are sexual, with males considerably smaller than females at 30–34 mm long and 0.35-0.42 mm wide compared to 40–70 mm long and 0.5 mm wide. Adults live in the subcutaneous tissues of humans, where they mate and produce worm-like eggs called microfilaria. These microfilariae are 250-300μm long, 6-8μm wide, and can be distinguished morphologically from other filariae—they are sheathed and contain body nuclei that extend to the tip of the tail.[3]

Life cycle


Loa loa life cycle. Source: CDC
The vector for Loa loa filariasis are flies from two hematophagous species of the genus Chrysops, C. silacea and C. dimidiata. During a blood meal, an infected fly (genus Chrysops, day-biting flies) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound. The larvae develop into adults that commonly reside in subcutaneous tissue. The female worms measure 40 to 70 mm in length and 0.5 mm in diameter, while the males measure 30 to 34 mm in length and 0.35 to 0.43 mm in diameter. Adults produce microfilariae measuring 250 to 300 μm by 6 to 8 μm, which are sheathed and have diurnal periodicity. Microfilariae have been recovered from spinal fluids, urine, and sputum. During the day they are found in peripheral blood, but during the noncirculation phase, they are found in the lungs. The fly ingests microfilariae during a blood meal. After ingestion, the microfilariae lose their sheaths and migrate from the fly's midgut through the hemocoel to the thoracic muscles of the arthropod. There the microfilariae develop into first-stage larvae and subsequently into third-stage infective larvae. The third-stage infective larvae migrate to the fly's proboscis and can infect another human when the fly takes a blood meal.

Diagnosis

Identification of microfilariae by microscopic examination is a practical diagnostic procedure. Examination of blood samples will allow identification of microfilariae of Loa loa. It is important to time the blood collection with the known periodicity of the microfilariae. The blood sample can be a thick smear, stained with Giemsa or hematoxylin and eosin (see staining (biology)). For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knott's technique), or filtration through a Nucleopore membrane.
Antigen detection using an immunoassay for circulating filarial antigens constitutes a useful diagnostic approach, because microfilaremia can be low and variable. Interestingly, the Institute for Tropical Medicine reports that no serologic diagnostics are available.[9] While this was once true, and many of recently developed methods of Antibody detection are of limited value—because substantial antigenic cross reactivity exists between filaria and other helminths, and a positive serologic test does not necessarily distinguish between infections—up and coming serologic tests that are highly specific to Loa loa were furthered in 2008. They have not gone point-of-care yet, but show promise for highlighting high-risk areas and individuals with co-endemic loiasis and onchocerciasis. Specifically, Dr. Thomas Nutman and colleagues at the National Institutes of Health have described the a luciferase immunoprecipitation assay (LIPS) and the related QLIPS (quick version). Whereas a previously described LISXP-1 ELISA test had a poor sensitivity (55%), the QLIPS test is both practical, as it requires only a 15 minutes incubation, and has high sensitivity and specificity (97% and 100%, respectively).[10] No report on the distribution status of LIPS or QLIPS testing is available, but these tests would help to limit complications derived from mass ivermectin treatment for onchocerciasis or dangerous strong doses of diethylcarbamazine for loiasis alone (as pertains to individual with high Loa loa microfilarial loads).
Physically, Calabar swellings (see image) are the primary tool for diagnosis. Identification of adult worms is possible from tissue samples collected during subcutaneous biopsies. Adult worms migrating across the eye are another potential diagnostic, but the short timeframe for the worm's passage through the conjunctiva makes this observation less common.
In the past, health care providers use a provocative injection of Dirofilaria iminitis as a skin test antigen for filariasis diagnosis. If the patient was infected, the extract would cause an artificial allergic reaction and associated Calabar swelling similar to that caused, in theory, by metabolic products of the worm or dead worms .
Blood tests to reveal microfilaremia are useful in many, but not all cases, as one third of loiasis patients are amicrofilaremic. By contrast, eosinophilia is almost guaranteed in cases of loiasis, and blood testing for eosinophile fraction may be useful.[3]

Treatment

Treatment of loiasis involves chemotherapy or, in some cases, surgical removal of adult worms followed by systemic treatment. The current drug of choice for therapy is diethylcarbamazine (DEC), though ivermectin use is not unwarranted. The recommend dosage of DEC is 6 mg/kg/d taken three times daily for 12 days. The pediatric dose is the same. DEC is effective against microfilariae and somewhat effective against macrofilariae (adult worms).[11]
In patients with high microfilaria load, however, treatment with DEC may be contraindicated, as the rapid microfilaricidal actions of the drug can provoke encephalopathy. In these cases, albendazole administration has proved helpful, and superior to ivermectin, which can also be risky despite is slower-acting microfilaricidal effects.[11]
Management of Loa loa infection in some instances can involve surgery, though the timeframe during which surgical removal of the worm must be carried out is very short. A detailed surgical strategy to remove an adult worm is as follows (from a real case in New York City). The 2007 procedure to remove an adult worm from a male Gabonian immigrant employed proparacaine and povidone-iodine drops, a wire eyelid speculum, and 0.5ml 2% lidocaine with epinephrine 1:100,000, injected superiorly. A 2-mm incision was made and the immobile worm was removed with forceps. Gatifloxacin drops and an eye-patch over ointment were utilized post surgery and there were no complications (unfortunately, the patient did not return for DEC therapy to manage the additional worm—and microfilaria—present in his body).[12]

Epidemiology

As of 2009, loiasis is endemic to 11 countries, all in western or central Africa, and an estimated 12-13 million people have the disease. The highest incidence is seen in the following countries:
The rates of Loa loa infection are lower but still felt in Benin, Chad, Uganda, and Angola. The disease was once endemic to the western African countries of Ghana, Ivory Coast, Mali, Guinea, and Guinea Bissau but has since disappeared.[4]
Throughout Loa loa-endemic regions, infection rates vary from 9% to 70% of the population.[3] Areas at high risk of severe adverse reactions to mass treatment (with Ivermectin) are at current determined by the prevalence in a population of >20% microfilaremia, which has been recently shown in eastern Cameroon (2007 study), for example, among other locales in the region.[4]
Endemicity is closely linked to the habitats of the two known human loiasis veetors, Chrysops silicea and C. dimidiata.
Cases have been reported on occasion in the United States but are restricted to travelers who have returned from endemic regions.[12][13]
onchocerca co-endemicity map. Source: Gilbert M. Burnham. Ivermectin where loa is endemic]] In the 1990s, the only method of determining Loa loa intensity was with microscopic examination of standardized blood smears, which is not practical in endemic regions. Because mass diagnostic methods were not available, complications started to surface once mass ivermectin treatment programs started being carried out for Onchocerciasis, another filariasis. Ivermectin, which is a microfilaricidal drug, can be contraindicated in patients who are co-infection with loiasis and have associated high microfilarial loads. The theory is that the killing of massive numbers of microfilaria, some of which may be near the ocular and brain region, can lead to encephalopathy. Indeed cases of this have been documented so frequently over the last decade that a term has been given for this set of complication: neurologic serious adverse events (SAEs).[14]
Advanced diagnostic methods have been developed since the appearance the SAEs, but more specific diagnostic tests that have been or are currently being development (see: Diagnostics) must to be supported and distributed if adequate loiasis surveillance is to be achieved.
The righthand image is the result of a geo-mapping study that has overlaid the endemicity of onchocerciasis with loiasis. As one can see, there is much overlap between the endemicity of the two distinct filariases, which complicates mass treatment programs for onchocerciasis and necessitates the development of greater diagnostics for loiasis.
In Central and West Africa, initiatives to control onchocerciasis involve mass treatment with Ivermectin. However, these regions typically have high rates of co-infection with both L. loa and O. volvulus, and mass treatment with Ivermectin can have severe adverse effects (SAE). These include hemorrhage of the conjunctiva and retina, heamaturia, and other encephalopathies that are all attributed to the initial L. loa microfilarial load in the patient prior to treatment. Studies have sought to delineate the sequence of events following Ivermectin treatment that lead to neurologic SAE and sometimes death, while also trying to understand the mechanisms of adverse reactions to develop more appropriate treatments.
In a study looking at mass Ivermectin treatment in Cameroon, one of the greatest endemic regions for both onchocerciasis and loiasis, a sequence of events in the clinical manifestation of adverse effects was outlined. It was noted that the patients used in this study had a L. loa microfilarial load of greater than 3,000 per ml of blood. Within 12–24 hours post-Ivermectin treatment (D1), individuals complained of fatigue, anorexia, and headache, joint and lumbar pain—a bent forward walk was characteristic during this initial stage accompanied by fever. Stomach pain and diarrhea were also reported in several individuals. By day 2 (D2), many patients experienced confusion, agitation, dysarthria, mutism and incontinence. Some cases of coma were reported as early as D2. The severity of adverse effects increased with higher microfilarial loads. Hemorrhaging of the eye, particularly the retinal and conjunctiva regions, is another common sign associated with SAE of Ivermectin treatment in patients with L. loa infections and is observed between D2 and D5 post-treatment. This can be visible for up to 5 weeks following treatment and has increased severity with higher microfilarial loads. Haematuria and proteinuria have also been observed following Ivermectin treatment, but this is common when using Ivermectin to treat onchocerciasis. The effect is exacerbated when there are high L. loa microfilarial loads however, and microfilaria can be observed in the urine occasionally. Generally, patients recovered from SAE within 6–7 months post-Ivermectin treatment; however, when their complications were unmanaged and patients were left bed-ridden, death resulted due to gastrointestinal bleeding, septic shock, and large abscesses ([15]). Mechanisms for SAE have been proposed. Though microfilarial load is a major risk factor to post-Ivermectin SAE, three main hypotheses have been proposed for the mechanisms. The first mechanism suggests that Ivermectin causes immobility in microfilariae, which then obstructs microcirculation in cerebral regions. This is supported by the retinal hemorrhaging seen in some patients, and is possibly responsible for the neurologic SAE reported. The second hypothesis suggests that microfilaria may try to escape drug treatment by migrating to brain capillaries and further into brain tissue; this is supported by pathology reports demonstrating a microfilarial presence in brain tissue post-Ivermectin treatment. Lastly, the third hypothesis attributes hypersensitivity and inflammation at the cerebral level to post-Ivermectin treatment complications, and perhaps the release of bacteria from L. loa after treatment to SAE. This has been observed with the bacteria Wolbachia that lives inside O. volvulus. More research into the mechanisms of post-Ivermectin treatment SAE is needed to develop drugs that are appropriate to individuals suffering from multiple parasitic infections ([16]). One drug that has been proposed for the treatment of onchocerciasis is Doxycycline. This drug has been shown to be effective in killing both the adult worm of O. volvulus and the Wolbachia, the bacteria believed to play a major role in the onset of onchocerciasis, while having no effect on the microfilaria of L. loa. In a study done at 5 different co-endemic regions for onchocerciasis and loiasis, Doxycycline was shown to be effective in treating over 12,000 individuals infected with both parasites with very minimal complications. Drawbacks to using Doxycycline include bacterial resistance and patient compliance because of a longer treatment regimen and emergence of Doxycycline-resistant Wolbachia. However, in the study over 97% of the patients complied with treatment, so it does pose as a promising treatment for onchocerciasis, while avoiding complications associated with L. loa co-infections ([17]).

Public Health and Prevention Strategies/Vaccines

Diethylcarbamazine has been shown as an effective prophylaxis for Loa loa infection. A study of Peace Corps volunteers in the highly Loa—endemic Gabon, for example, had the following results: 6 of 20 individuals in a placebo group contracted the disease, compared to 0 of 16 in the DEC-treated group. Seropositivity for antifilarial IgG antibody was also much higher in the placebo group. The recommended prophylactic dose is 300 mg DEC given orally once weekly. The only associated symptom in the Peace Corps study was nausea.[4][18]
Researchers believe that geo-mapping of appropriate habitat and human settlement patterns may, with the use of predictor variables such as forest, land cover, rainfall, temperature, and soil type, allow for estimation of Loa loa transmission in the absence of point-of-care diagnostic tests.[19] In addition to geo-mapping and chemoprophylaxis, the same preventative strategies used for malaria should be undertaken to avoid contraction of loiasis. Specifically, DEET-containing insect repellent, permethrin-soaked clothing, and thick, long-sleeved and long-legged clothing ought to be worn to decreased susceptibility to the bite of the mango or deerfly vector. Because the vector is day-biting, mosquito (bed) nets do not increase protection against loiasis.
Vector elimination strategies are an interesting consideration. It has been shown that the Chrysops vector has a limited fly range,[20] but vector elimination efforts are not common, likely because the insects bite outdoors and have a diverse, if not long, range, living in the forest and biting in the open, as mentioned in the vector section.
No vaccine has been developed for loiasis and there is little report on this possibility.

References

  1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
  2. ^ Osuntokun O, Olurin O (March 1975). "Filarial worm (Loa loa) in the anterior chamber. Report of two cases". Br J Ophthalmol 59 (3): 166–7. doi:10.1136/bjo.59.3.166. PMC 1017374. PMID 1131358.
  3. ^ a b c d e John, David T. and William A. Petri, Jr. Markell and Voge's Medical Parasitology. 9th ed. 2006.
  4. ^ a b c d The Gideon Online. Available online at: http://web.gideononline.com/web/epidemiology/index.php?disease=11340&country=&view=General
  5. ^ Cox FE (October 2002). "History of human parasitology". Clin. Microbiol. Rev. 15 (4): 595–612. doi:10.1128/CMR.15.4.595-612.2002. PMC 126866. PMID 12364371.
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  7. ^ a b c Gouteux JP, Noireau F, Staak C (April 1989). "The host preferences of Chrysops silacea and C. dimidiata (Diptera: Tabanidae) in an endemic area of Loa loa in the Congo". Ann Trop Med Parasitol 83 (2): 167–72. PMID 2604456.
  8. ^ a b c World Health Organization (WHO). Vector Control – Horseflies and deerflies (tabanids). 1997. Available online at: http://www.who.int/docstore/water_sanitation_health/vectcontrol/ch06.htm#b6-Horseflies%20and%20deerflies%20%28tabanids%29.
  9. ^ "Loiasis." 2009. The Institute of Tropical Medicine. Available online at: http://www.itg.be/itg/distancelearning/lecturenotesvandenendene/41_Filariasisp5.htm.
  10. ^ Burbelo PD, Ramanathan R, Klion AD, Iadarola MJ, Nutman TB (July 2008). "Rapid, novel, specific, high-throughput assay for diagnosis of Loa loa infection". J. Clin. Microbiol. 46 (7): 2298–304. doi:10.1128/JCM.00490-08. PMC 2446928. PMID 18508942.
  11. ^ a b The Medical Letter – Filariasis. Available online at: http://www.dpd.cdc.gov/dpdx/HTML/PDF_Files/MedLetter/Filariasis.pdf.
  12. ^ a b Nam, Julie N., Shanian Reddy, and Norman C. Charles. "Surgical Management of Conjunctival Loiasis." Ophthal Plastic Reconstr Surg. (2008). Vol 24(4): 316-317.
  13. ^ Grigsby, Margaret E. and Donald H. Keller. "Loa-loa in the District of Columbia." J Narl Med Assoc. (1971), Vol 63(3): 198-201.
  14. ^ Kamgno J, Boussinesq M, Labrousse F, Nkegoum B, Thylefors BI, Mackenzie CD (April 2008). "Encephalopathy after ivermectin treatment in a patient infected with Loa loa and Plasmodium spp". Am. J. Trop. Med. Hyg. 78 (4): 546–51. PMID 18385346.
  15. ^ 1.Boussinesq, M., Gardon, J., Gardon-Wendel, N., and J. Chippaux. 2003. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria Journal 2: 1-13.
  16. ^ 1. Boussinesq, M., Gardon, J., Gardon-Wendel, N., and J. Chippaux. 2003. Clinical picture, epidemiology and outcome of Loa-associated serious adverse events related to mass ivermectin treatment of onchocerciasis in Cameroon. Filaria Journal 2: 1-13.
  17. ^ 2. Wanji, S., Tendongfor, N., Nji, T., Esum, M., Che, J. N., Nkwescheu, A., Alassa, F., Kamnang, G., Enyong, P. A., Taylor, M. J., Hoerauf, A., and D. W. Taylor. 2009. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon. Parasites & Vectors. 2(39): 1-10.
  18. ^ Nutman, TB, KD Miller, M Mulligan, GN Reinhardt, BJ currie, C Steel, and EA Ottesen. "Diethylcarbamazine prophylaxis for human loiasis. Results of a double-blind study."New Eng J Med. (1988), 319: 752-756.
  19. ^ Thomson MC, Obsomer V, Dunne M, Connor SJ, Molyneux DH (September 2000). "Satellite mapping of Loa loa prevalence in relation to ivermectin use in west and central Africa". Lancet 356 (9235): 1077–8. doi:10.1016/S0140-6736(00)02733-1. PMID 11009145.
  20. ^ Chippaux J-P, Bouchité B, Demanou M, Morlais I, Le Goff G (September 2000). "Density and dispersal of the loaiasis vector Chrysops dimidiata in southern Cameroon". Med. Vet. Entomol. 14 (3): 339–44. doi:10.1046/j.1365-2915.2000.00249.x. PMID 11016443.
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