Cleveland Clinic Journal of Medicine

Birds are among the most popular pets in the United States, ranking fourth behind dogs, cats, and fish. According to a commercial survey,¹ 6.4 million US households own at least one pet bird—and are therefore at risk of a number of bacterial, protozoal, fungal, viral, or parasitic zoonoses (infectious diseases of animals that are communicable to humans).²

This review focuses on the most common pet bird-associated diseases, with implications for bird-keepers’ health. Unless specifically stated otherwise, these diseases are not routinely transmissible from human to human.

NO NEED TO AVOID OWNING A BIRD

Although one can indeed acquire an infection from a pet bird, this possibility need not discourage people from owning birds.^3,4

The ability of a microorganism to make a person sick varies with the virulence of the organism, the dose to which a person is exposed, and the route of infection. For a bird owner, prevention often involves simple hygiene, handwashing, sanitation, and regular veterinary care for the bird.³ Many of these diseases are transmitted by ingestion of food contaminated by avian fecal matter or inhalation of contaminated dust. Therefore, bird owners should take steps to minimize dander in the environment. Furthermore, wearing a mask during cage cleaning is suggested.⁵ Obtaining pet birds from reputable domestic sources decreases the risk of acquiring a bird with an infectious disease.^4,6

These hygienic measures are especially important for people who are more susceptible to infection, eg, the very young or very old, those in poor health to begin with, and those with compromised immunity.

Most of the illnesses one can acquire from birds are asymptomatic or self-limited in humans, but they should be considered if a bird-keeper has persistent or unusual symptoms of infection or if the pet bird was recently acquired or has been ill or died.

DISEASES PRESENTING WITH FLU-LIKE OR PULMONARY SYMPTOMS

Psittacosis (ornithosis, parrot fever, chlamydiosis)

Psittacosis is caused by Chlamydophila (formerly Chlamydia) psittaci. The organism has been reported to be present in 40% of birds.^4,7 Humans are considered incidental hosts.

Transmission of C psittaci is usually via inhalation of aerosolized particles contaminated with infected bird excreta, nasal secretions, tissue, or feathers. Beak-to-mouth transmission and transmission via bird bites have been reported.⁸ Unlike Chlamydophila pneumoniae, C psittaci has not conclusively been reported to be transmitted from human to human.

Many infected pet birds show no signs of the disease, but others may have conjunctivitis, liver disease, or generalized signs of severe infection such as ruffled feathers, loss of appetite, diarrhea, or lime-green urates (R. Stevenson, personal communication, 2007).^2,5,9,10

Recognizing that the patient has been exposed to birds is clinically useful, as in one study 90% of patients with psittacosis had been exposed to birds as pets or in their occupations.¹¹

Atypical pneumonia is the most common presentation of psittacosis in humans. The symptoms typically begin 7 to 14 days after exposure, with fever, chills, prominent headache, photophobia, and cough. Hepatosplenomegaly is clinically detectable in 10% to 70% of patients. Serious but uncommon presentations include pericarditis, myocarditis, bacterial culture-negative endocarditis, mental status changes, and thrombophlebitis. The combination of pneumonitis and hepatosplenomegaly should prompt consideration of psittacosis.¹¹

Influenza

All known subtypes of influenza A virus can infect birds (influenza B virus cannot). However, there are substantial genetic differences between the subtypes of influenza A that typically infect both people and birds.¹²

Avian influenza viruses affecting birds and humans (H5N1, H7N7, H9N2, and others), commonly called “bird flu,” emerged in 1997 in association with poultry.^13,14 Highly pathogenic H5N1 viral infections have attracted particular attention, as they have killed millions of birds and infected several hundred humans, half of whom have died.¹³ Various avian influenza viruses that can affect humans have been isolated from captive birds such as parrots, canaries, and poultry and from wild waterfowl and migrating birds.¹⁵ To our knowledge, pet birds have not been implicated in transmission, but they are a potential source of infection if they have been in contact with infected birds.

Transmission from bird to human has usually been via inhaled droplets and, less likely, from contaminated environmental sources. According to the US Centers for Disease Control and Prevention, family clusters of H5N1 infection have been observed,¹⁶ but person-to-person transmission has been very rare, limited, and unsustained.¹³

Signs of influenza in birds can range from none to respiratory tract infection, decreased egg production, systemic illness, and death.¹⁵

Avian influenza should be suspected in people with flu symptoms who have been exposed to sick poultry or wild birds, have travelled to an endemic area, or have had direct contact with a person known or suspected to be infected with avian influenza.¹⁷ Information about areas of the world in which avian influenza is endemic or is breaking out is available at the World Health Organization Epidemic and Pandemic Alert and Response Web page (www.who.int/csr/disease/avian_influenza/updates/en/index.html).

Signs and symptoms of avian influenza in humans include fever, upper respiratory tract infection, cough, and gastrointestinal symptoms. With highly pathogenic viruses such as H5N1, the disease can progress very rapidly from onset to death. Less-pathogenic viruses such as H9N2 cause milder symptoms.¹⁶

Histoplasma capsulatum is a fungus that colonizes the gastrointestinal tract of birds and contaminates the soil via bird and bat droppings. The most highly endemic regions of the world are the Ohio and Mississippi River valleys. Typical pet birds such as canaries and parrots are not susceptible to symptomatic infection, but doves and pigeons (often treated as pets by bird-lovers) may become colonized if they contact contaminated birds or excreta (R. Stevenson, personal communication, 2007).^5,18

Humans commonly acquire the organisms when they inhale disrupted soil contaminated with the organism. Human-to-human transmission has not been reported.

The degree of human illness depends on the inoculum size and the immunity of the person infected. In more than 90% of cases, the primary infection is minimally symptomatic or goes unnoticed. The typical incubation time is 7 to 21 days. In patients who become ill, symptoms include fever, chills, headache, nonproductive cough, and adenopathy-mediated chest pain. Disseminated disease generally occurs in immunocompromised patients and presents with fever, weight loss, hepatosplenomegaly, and pancytopenia.¹⁸

Newcastle disease (avian pneumoencephalitis)

The virus that causes Newcastle disease, avian paramyxovirus 1, can affect animals, reptiles, birds, and people. It is most common in wild birds, but parrots are also highly susceptible and can be reservoirs that continue to shed the virus for up to 12 months after the acute illness has subsided. Illegally imported Amazon parrots are the most likely source of infection for US households. The virus is spread through an infected bird’s feces and secretions from the nose, mouth, and eyes and can be carried on a person’s clothing, footwear, and equipment.

Some infected birds show no signs of it; others have respiratory signs, green diarrhea, muscle tremors, circling, paralysis, or swelling of tissues around the eyes and neck. The mortality rate in infected birds can be up to 100%.¹⁹

Human infection most often results in conjunctivitis. Chills, fever, and lethargy are exceptionally rare.¹⁵ Because the virus is prevalent in poultry, poultry workers are at greatest risk of infection. Rapid recovery in humans is common. People with conjunctivitis due to Newcastle disease virus should avoid contact with birds.^2,20

Q fever

Q fever is caused by Coxiella burnetii, a gram-negative pleomorphic bacillus. Ticks and vertebrates (goats, sheep, and, less commonly, birds) are natural reservoirs for the organism. Human infection results from contact with infected animals or inhalation of dust contaminated with infected excreta or placental tissue.² Birds may harbor the infection in experimental and natural settings.^21,22

Symptoms in humans typically include fever, pneumonitis, severe headache, and photophobia. Meningitis, hepatitis, and thromboses are seen in more-severe disease. Infection acquired in pregnancy may lead to prematurity, abortion, or stillbirth.^18,21

West Nile fever and West Nile encephalitis

Wild birds such as corvids and raptors harbor the West Nile virus; pet songbirds (passerines) can harbor it as well.^23,24 The principal means of transmission of West Nile infection from birds to humans is via a mosquito biting an infected bird and then biting a human. Direct bird-to-human transmission has not been described.¹⁸ Infected birds may be asymptomatic or appear ill or reluctant to fly and die of disseminated viral infection.²³

The incubation period in humans is generally 3 to 14 days, followed by the sudden onset of fever, malaise, nausea, vomiting, rash, lymphadenopathy, and retro-orbital pain. Neurologic presentations—ataxia, extrapyramidal signs, cranial nerve abnormalities, myelitis, optical neuritis, and seizures—are quite rare and generally occur in the elderly or immunocompromised. Fewer than 1% of affected people develop more-severe disease, such as acute encephalitis, aseptic meningitis, or Guillain-Barré syndrome.²⁵

Allergic alveolitis

Allergic alveolitis (hypersensitivity pneumonitis, parakeet dander pneumoconiosis, pigeon lung disease, bird-breeder’s lung, bird-fancier’s disease) is not a zoonosis; the term describes diffuse parenchymal lung disease caused by repeated exposure to an inhaled allergen.²⁶ However, it should be considered in patients with pulmonary symptoms and bird exposure. Avian proteins are a known trigger.²⁷

Acute allergic alveolitis is clinically indistinguishable from a respiratory infection. It is characterized by the abrupt onset of an intense nonproductive cough, chest tightness, dyspnea, chills, fever, myalgia, and malaise. Symptoms gradually improve over 24 to 48 hours without antigen exposure but recur with repeated exposure.

Subacute illness presents with similar symptoms, which gradually worsen over weeks to months, and it can be indistinguishable from interstitial lung disease. Many patients with chronic allergic alveolitis are suspected of having tuberculosis or fungal pneumonia or receive a misdiagnosis of idiopathic pulmonary fibrosis.

Patients usually have a favorable outcome if the allergen is removed. If exposure continues, irreversible pulmonary fibrosis may develop.²⁸

DISEASES PRESENTING WITH GASTROINTESTINAL SYMPTOMS

Salmonellosis

Nontyphoidal Salmonella species colonize the gastrointestinal tract of many animals, including birds. Up to 80% of chicken eggs are contaminated with this gram-negative bacterium.

Spread of nontyphoidal Salmonella to humans is much more common from poultry, poultry products, and pet reptiles than from pet birds, although ducks and baby chicks have transmitted infection to humans. Hand-to-mouth spread occurs after contact with pets or pet excreta.^29,30 Infected birds may be healthy carriers, may develop enteritis or hemorrhagic hepatosplenic disease, or may even die.^2,9

Gastroenteritis due to nontyphoidal Salmonella in humans begins with nausea, vomiting, fever, and loose, nonbloody diarrhea about 48 hours after ingestion. Most gastroenteritis infections are self-limited, with resolution of fever within 48 to 72 hours and resolution of diarrhea within 4 to 10 days.³¹

Systemic or severe infection warranting “preemptive” therapy is more likely in immunosuppressed patients, in patients with reduced gastric acid or impaired gastrointestinal mucosal integrity, in infants less than 3 months of age, and in patients with chronic gastrointestinal tract disease, malignant neoplasms, hemoglobinopathies, or infection with the human immunodeficiency virus.³¹ Systemic nontyphoidal Salmonella infection may settle in structurally abnormal sites such as in existing fractures, severe degenerative joint disease, organs affected by stones, or abnormal lung tissue. Large-vessel arteritis due to non-typhoidal Salmonella should be suspected in a person at risk (particularly if the person is elderly) who presents with back, chest, or abdominal pain preceded by gastroenteritis.^31,32

The main reservoirs for Campylobacter jejuni are wild birds and poultry, although this bacterium can also affect other animals and pet birds.² The most commonly affected pet birds are psittaciforms (parrots) and passeriforms (finches and canaries).

The organism colonizes the small intestine and colon of birds and can be spread to humans through contact with feces or carcasses of infected animals.^33–35 Birds with campylobacteriosis develop hepatitis, lethargy, loss of appetite, weight loss, and yellow diarrhea and often die of the illness (R. Stevenson, personal communication, 2007).

The most important mode of transmission to humans is through handling or consuming chicken, milk, or other products contaminated with feces of carrier animals. However, in up to 24% of cases, the source of infection is unknown.^33,34

Human infection with C jejuni most commonly leads to an acute, self-limited gastrointestinal illness characterized by fever, diarrhea, and abdominal cramps. The diarrhea is typically watery or bloody and occurs 8 to 10 times a day at peak illness. Fever can persist for up to a week. Most cases resolve within 7 days, but some patients may have a relapsing diarrheal illness lasting several weeks. Between 20% and 40% of cases of Guillain-Barré syndrome are preceded by infection with C jejuni.³⁵

Giardiasis

Giardiasis is an intestinal protozoal infection caused by Giardia species (primarily G lamblia) that affect humans and other mammals. The parasite is found in bird droppings, but the role of birds in transmission to humans is unclear. Most infections are transmitted via contaminated surface water supplies, although person-to-person transmission has been documented.³⁶ Infected pet birds have signs of gastroenteritis and can be treated, but reinfection often occurs.³⁷

Giardia infections in humans are often asymptomatic, but about 50% of patients have diarrhea, abdominal pain, bloating, belching, nausea, and vomiting 3 days to 3 weeks after ingesting the parasite. A clinical clue may be new-onset lactose intolerance. Symptoms usually resolve after a week. Prolonged infection occurs in up to 20% of patients. People with hypochlorhydria or hypogammaglobulinemia, children, and travelers to endemic areas are at higher risk of infection.³⁷

DISEASES PRESENTING WITH SKIN SYMPTOMS

Pasteurellosis

Pasteurellosis is caused by Pasteurella multocida, an inhabitant of the healthy nasopharynx of some birds and also the causative agent of avian cholera.³⁸ Many pet birds that acquire systemic Pasteurella infection from a cat bite die of avian cholera (Stevenson R, personal communication, 2007).

Pasteurella organisms are transmissible to humans via bites or scratches from pet birds. Infected wounds in humans are usually red and painful, but the physical findings may lead one to underestimate the severity of infection. Transmission via respiratory droplets is rare but may cause acute or subacute bronchitis, pneumonia, or septicemia.³⁸

Erysipeloid

Erysipeloid, caused by the bacterium Erysipelothrix rhusiopathiae, is transmissible to humans via contact with domestic or wild fowl. Infection in pet birds can cause sepsis but is rarely seen in veterinary practice (R. Stevenson, personal communication, 2007).^38,39

Human infection typically affects broken skin, causing a dramatic, localized skin infection that is painful and pruritic; at first it is livid-red, then blue-red. The infection can spread to nearby joints. Septicemia and endocarditis in humans are rare complications.⁴⁰

Cryptococcosis

Cryptococcosis, caused by the encapsulated yeast Cryptococcus neoformans, can be harbored and transmitted by asymptomatic pet birds such as cockatoos via colonization of the gastrointestinal tract.^38,41 The organism is found in soil contaminated by feces of colonized birds.

Pulmonary symptoms and meningitis are more typical of cryptococcal disease in general, although when contracted from a pet bird via a break in the skin, cutaneous cryptococcosis usually presents with skin lesions resembling cellulitis, molluscum, herpes, and Kaposi sarcomalike papulonodules.⁴² Infection beyond the skin in immunocompromised patients may involve the lungs and the central nervous system.⁴¹ Prostate and eye infections have also been reported.³⁸

Avian mite dermatitis

Birds carry several kinds of mites: feather or “red” mites (which do not affect humans) and mites that can affect humans such as Ornithonyssus sylviarum (the northern fowl mite) and Dermanyssus gallinae (the poultry mite or chicken mite) (R. Stevenson, personal communication, 2007). O sylviarum and D gallinae are found in the commercial poultry industry, but uncommonly, pet birds can harbor them (R. Stevenson, personal communication, 2007).^42–44

In humans, mites can cause an intensely pruritic, papular-papulovesicular eruption.⁴²

Nontuberculous mycobacteriosis

Nontuberculous mycobacteria (Mycobacterium species chelonae, abscessus, fortuitum, avium, kansasii, ulcerans, and marinum) are ubiquitous in the environment and can colonize animals. M avium subsp avium causes avian tuberculosis.³⁸ Birds may carry mycobacterial organisms on beaks, claws, and talons, facilitating passage to humans (J.M. Gaskin, personal communication, 2006). In one reported case, M chelonae skin infection was probably transmitted in this manner to a bird-keeper via a bird bite.⁴⁵

In symptomatic nontuberculous mycobacterial infections, the site of inoculation usually determines the presenting signs. Mycobacteriosis should be suspected when skin or lung infections fail to improve with empiric treatment. Patients with structurally abnormal lungs or immunosuppression may be at higher risk of pulmonary or disseminated disease from infected birds.^46,47

Acknowledgment: The authors extend special thanks to Jack M. Gaskin, DVM, PhD, Department of Infectious Disease and Pathology, University of Florida, Gainesville, FL; Rhoda Stevenson, DVM, Exotic Bird Hospital, Jacksonville, FL; and Stephanie L. Hines, MD, Section of General Internal Medicine, Mayo Clinic, Jacksonville, FL, for their review of this paper. Editing, proofreading, and reference verification were provided by the Mayo Clinic Section of Scientific Publications.

Birds are among the most popular pets in the United States, ranking fourth behind dogs, cats, and fish. According to a commercial survey,¹ 6.4 million US households own at least one pet bird—and are therefore at risk of a number of bacterial, protozoal, fungal, viral, or parasitic zoonoses (infectious diseases of animals that are communicable to humans).²

This review focuses on the most common pet bird-associated diseases, with implications for bird-keepers’ health. Unless specifically stated otherwise, these diseases are not routinely transmissible from human to human.

NO NEED TO AVOID OWNING A BIRD

Although one can indeed acquire an infection from a pet bird, this possibility need not discourage people from owning birds.^3,4

The ability of a microorganism to make a person sick varies with the virulence of the organism, the dose to which a person is exposed, and the route of infection. For a bird owner, prevention often involves simple hygiene, handwashing, sanitation, and regular veterinary care for the bird.³ Many of these diseases are transmitted by ingestion of food contaminated by avian fecal matter or inhalation of contaminated dust. Therefore, bird owners should take steps to minimize dander in the environment. Furthermore, wearing a mask during cage cleaning is suggested.⁵ Obtaining pet birds from reputable domestic sources decreases the risk of acquiring a bird with an infectious disease.^4,6

These hygienic measures are especially important for people who are more susceptible to infection, eg, the very young or very old, those in poor health to begin with, and those with compromised immunity.

Most of the illnesses one can acquire from birds are asymptomatic or self-limited in humans, but they should be considered if a bird-keeper has persistent or unusual symptoms of infection or if the pet bird was recently acquired or has been ill or died.

DISEASES PRESENTING WITH FLU-LIKE OR PULMONARY SYMPTOMS

Psittacosis (ornithosis, parrot fever, chlamydiosis)

Psittacosis is caused by Chlamydophila (formerly Chlamydia) psittaci. The organism has been reported to be present in 40% of birds.^4,7 Humans are considered incidental hosts.

Transmission of C psittaci is usually via inhalation of aerosolized particles contaminated with infected bird excreta, nasal secretions, tissue, or feathers. Beak-to-mouth transmission and transmission via bird bites have been reported.⁸ Unlike Chlamydophila pneumoniae, C psittaci has not conclusively been reported to be transmitted from human to human.

Many infected pet birds show no signs of the disease, but others may have conjunctivitis, liver disease, or generalized signs of severe infection such as ruffled feathers, loss of appetite, diarrhea, or lime-green urates (R. Stevenson, personal communication, 2007).^2,5,9,10

Recognizing that the patient has been exposed to birds is clinically useful, as in one study 90% of patients with psittacosis had been exposed to birds as pets or in their occupations.¹¹

Atypical pneumonia is the most common presentation of psittacosis in humans. The symptoms typically begin 7 to 14 days after exposure, with fever, chills, prominent headache, photophobia, and cough. Hepatosplenomegaly is clinically detectable in 10% to 70% of patients. Serious but uncommon presentations include pericarditis, myocarditis, bacterial culture-negative endocarditis, mental status changes, and thrombophlebitis. The combination of pneumonitis and hepatosplenomegaly should prompt consideration of psittacosis.¹¹

Influenza

All known subtypes of influenza A virus can infect birds (influenza B virus cannot). However, there are substantial genetic differences between the subtypes of influenza A that typically infect both people and birds.¹²

Avian influenza viruses affecting birds and humans (H5N1, H7N7, H9N2, and others), commonly called “bird flu,” emerged in 1997 in association with poultry.^13,14 Highly pathogenic H5N1 viral infections have attracted particular attention, as they have killed millions of birds and infected several hundred humans, half of whom have died.¹³ Various avian influenza viruses that can affect humans have been isolated from captive birds such as parrots, canaries, and poultry and from wild waterfowl and migrating birds.¹⁵ To our knowledge, pet birds have not been implicated in transmission, but they are a potential source of infection if they have been in contact with infected birds.

Transmission from bird to human has usually been via inhaled droplets and, less likely, from contaminated environmental sources. According to the US Centers for Disease Control and Prevention, family clusters of H5N1 infection have been observed,¹⁶ but person-to-person transmission has been very rare, limited, and unsustained.¹³

Signs of influenza in birds can range from none to respiratory tract infection, decreased egg production, systemic illness, and death.¹⁵

Avian influenza should be suspected in people with flu symptoms who have been exposed to sick poultry or wild birds, have travelled to an endemic area, or have had direct contact with a person known or suspected to be infected with avian influenza.¹⁷ Information about areas of the world in which avian influenza is endemic or is breaking out is available at the World Health Organization Epidemic and Pandemic Alert and Response Web page (www.who.int/csr/disease/avian_influenza/updates/en/index.html).

Signs and symptoms of avian influenza in humans include fever, upper respiratory tract infection, cough, and gastrointestinal symptoms. With highly pathogenic viruses such as H5N1, the disease can progress very rapidly from onset to death. Less-pathogenic viruses such as H9N2 cause milder symptoms.¹⁶

Histoplasma capsulatum is a fungus that colonizes the gastrointestinal tract of birds and contaminates the soil via bird and bat droppings. The most highly endemic regions of the world are the Ohio and Mississippi River valleys. Typical pet birds such as canaries and parrots are not susceptible to symptomatic infection, but doves and pigeons (often treated as pets by bird-lovers) may become colonized if they contact contaminated birds or excreta (R. Stevenson, personal communication, 2007).^5,18

Humans commonly acquire the organisms when they inhale disrupted soil contaminated with the organism. Human-to-human transmission has not been reported.

The degree of human illness depends on the inoculum size and the immunity of the person infected. In more than 90% of cases, the primary infection is minimally symptomatic or goes unnoticed. The typical incubation time is 7 to 21 days. In patients who become ill, symptoms include fever, chills, headache, nonproductive cough, and adenopathy-mediated chest pain. Disseminated disease generally occurs in immunocompromised patients and presents with fever, weight loss, hepatosplenomegaly, and pancytopenia.¹⁸

Newcastle disease (avian pneumoencephalitis)

The virus that causes Newcastle disease, avian paramyxovirus 1, can affect animals, reptiles, birds, and people. It is most common in wild birds, but parrots are also highly susceptible and can be reservoirs that continue to shed the virus for up to 12 months after the acute illness has subsided. Illegally imported Amazon parrots are the most likely source of infection for US households. The virus is spread through an infected bird’s feces and secretions from the nose, mouth, and eyes and can be carried on a person’s clothing, footwear, and equipment.

Some infected birds show no signs of it; others have respiratory signs, green diarrhea, muscle tremors, circling, paralysis, or swelling of tissues around the eyes and neck. The mortality rate in infected birds can be up to 100%.¹⁹

Human infection most often results in conjunctivitis. Chills, fever, and lethargy are exceptionally rare.¹⁵ Because the virus is prevalent in poultry, poultry workers are at greatest risk of infection. Rapid recovery in humans is common. People with conjunctivitis due to Newcastle disease virus should avoid contact with birds.^2,20

Q fever

Q fever is caused by Coxiella burnetii, a gram-negative pleomorphic bacillus. Ticks and vertebrates (goats, sheep, and, less commonly, birds) are natural reservoirs for the organism. Human infection results from contact with infected animals or inhalation of dust contaminated with infected excreta or placental tissue.² Birds may harbor the infection in experimental and natural settings.^21,22

Symptoms in humans typically include fever, pneumonitis, severe headache, and photophobia. Meningitis, hepatitis, and thromboses are seen in more-severe disease. Infection acquired in pregnancy may lead to prematurity, abortion, or stillbirth.^18,21

West Nile fever and West Nile encephalitis

Wild birds such as corvids and raptors harbor the West Nile virus; pet songbirds (passerines) can harbor it as well.^23,24 The principal means of transmission of West Nile infection from birds to humans is via a mosquito biting an infected bird and then biting a human. Direct bird-to-human transmission has not been described.¹⁸ Infected birds may be asymptomatic or appear ill or reluctant to fly and die of disseminated viral infection.²³

The incubation period in humans is generally 3 to 14 days, followed by the sudden onset of fever, malaise, nausea, vomiting, rash, lymphadenopathy, and retro-orbital pain. Neurologic presentations—ataxia, extrapyramidal signs, cranial nerve abnormalities, myelitis, optical neuritis, and seizures—are quite rare and generally occur in the elderly or immunocompromised. Fewer than 1% of affected people develop more-severe disease, such as acute encephalitis, aseptic meningitis, or Guillain-Barré syndrome.²⁵

Allergic alveolitis

Allergic alveolitis (hypersensitivity pneumonitis, parakeet dander pneumoconiosis, pigeon lung disease, bird-breeder’s lung, bird-fancier’s disease) is not a zoonosis; the term describes diffuse parenchymal lung disease caused by repeated exposure to an inhaled allergen.²⁶ However, it should be considered in patients with pulmonary symptoms and bird exposure. Avian proteins are a known trigger.²⁷

Acute allergic alveolitis is clinically indistinguishable from a respiratory infection. It is characterized by the abrupt onset of an intense nonproductive cough, chest tightness, dyspnea, chills, fever, myalgia, and malaise. Symptoms gradually improve over 24 to 48 hours without antigen exposure but recur with repeated exposure.

Subacute illness presents with similar symptoms, which gradually worsen over weeks to months, and it can be indistinguishable from interstitial lung disease. Many patients with chronic allergic alveolitis are suspected of having tuberculosis or fungal pneumonia or receive a misdiagnosis of idiopathic pulmonary fibrosis.

Patients usually have a favorable outcome if the allergen is removed. If exposure continues, irreversible pulmonary fibrosis may develop.²⁸

DISEASES PRESENTING WITH GASTROINTESTINAL SYMPTOMS

Salmonellosis

Nontyphoidal Salmonella species colonize the gastrointestinal tract of many animals, including birds. Up to 80% of chicken eggs are contaminated with this gram-negative bacterium.

Spread of nontyphoidal Salmonella to humans is much more common from poultry, poultry products, and pet reptiles than from pet birds, although ducks and baby chicks have transmitted infection to humans. Hand-to-mouth spread occurs after contact with pets or pet excreta.^29,30 Infected birds may be healthy carriers, may develop enteritis or hemorrhagic hepatosplenic disease, or may even die.^2,9

Gastroenteritis due to nontyphoidal Salmonella in humans begins with nausea, vomiting, fever, and loose, nonbloody diarrhea about 48 hours after ingestion. Most gastroenteritis infections are self-limited, with resolution of fever within 48 to 72 hours and resolution of diarrhea within 4 to 10 days.³¹

Systemic or severe infection warranting “preemptive” therapy is more likely in immunosuppressed patients, in patients with reduced gastric acid or impaired gastrointestinal mucosal integrity, in infants less than 3 months of age, and in patients with chronic gastrointestinal tract disease, malignant neoplasms, hemoglobinopathies, or infection with the human immunodeficiency virus.³¹ Systemic nontyphoidal Salmonella infection may settle in structurally abnormal sites such as in existing fractures, severe degenerative joint disease, organs affected by stones, or abnormal lung tissue. Large-vessel arteritis due to non-typhoidal Salmonella should be suspected in a person at risk (particularly if the person is elderly) who presents with back, chest, or abdominal pain preceded by gastroenteritis.^31,32

The main reservoirs for Campylobacter jejuni are wild birds and poultry, although this bacterium can also affect other animals and pet birds.² The most commonly affected pet birds are psittaciforms (parrots) and passeriforms (finches and canaries).

The organism colonizes the small intestine and colon of birds and can be spread to humans through contact with feces or carcasses of infected animals.^33–35 Birds with campylobacteriosis develop hepatitis, lethargy, loss of appetite, weight loss, and yellow diarrhea and often die of the illness (R. Stevenson, personal communication, 2007).

The most important mode of transmission to humans is through handling or consuming chicken, milk, or other products contaminated with feces of carrier animals. However, in up to 24% of cases, the source of infection is unknown.^33,34

Human infection with C jejuni most commonly leads to an acute, self-limited gastrointestinal illness characterized by fever, diarrhea, and abdominal cramps. The diarrhea is typically watery or bloody and occurs 8 to 10 times a day at peak illness. Fever can persist for up to a week. Most cases resolve within 7 days, but some patients may have a relapsing diarrheal illness lasting several weeks. Between 20% and 40% of cases of Guillain-Barré syndrome are preceded by infection with C jejuni.³⁵

Giardiasis

Giardiasis is an intestinal protozoal infection caused by Giardia species (primarily G lamblia) that affect humans and other mammals. The parasite is found in bird droppings, but the role of birds in transmission to humans is unclear. Most infections are transmitted via contaminated surface water supplies, although person-to-person transmission has been documented.³⁶ Infected pet birds have signs of gastroenteritis and can be treated, but reinfection often occurs.³⁷

Giardia infections in humans are often asymptomatic, but about 50% of patients have diarrhea, abdominal pain, bloating, belching, nausea, and vomiting 3 days to 3 weeks after ingesting the parasite. A clinical clue may be new-onset lactose intolerance. Symptoms usually resolve after a week. Prolonged infection occurs in up to 20% of patients. People with hypochlorhydria or hypogammaglobulinemia, children, and travelers to endemic areas are at higher risk of infection.³⁷

DISEASES PRESENTING WITH SKIN SYMPTOMS

Pasteurellosis

Pasteurellosis is caused by Pasteurella multocida, an inhabitant of the healthy nasopharynx of some birds and also the causative agent of avian cholera.³⁸ Many pet birds that acquire systemic Pasteurella infection from a cat bite die of avian cholera (Stevenson R, personal communication, 2007).

Pasteurella organisms are transmissible to humans via bites or scratches from pet birds. Infected wounds in humans are usually red and painful, but the physical findings may lead one to underestimate the severity of infection. Transmission via respiratory droplets is rare but may cause acute or subacute bronchitis, pneumonia, or septicemia.³⁸

Erysipeloid

Erysipeloid, caused by the bacterium Erysipelothrix rhusiopathiae, is transmissible to humans via contact with domestic or wild fowl. Infection in pet birds can cause sepsis but is rarely seen in veterinary practice (R. Stevenson, personal communication, 2007).^38,39

Human infection typically affects broken skin, causing a dramatic, localized skin infection that is painful and pruritic; at first it is livid-red, then blue-red. The infection can spread to nearby joints. Septicemia and endocarditis in humans are rare complications.⁴⁰

Cryptococcosis

Cryptococcosis, caused by the encapsulated yeast Cryptococcus neoformans, can be harbored and transmitted by asymptomatic pet birds such as cockatoos via colonization of the gastrointestinal tract.^38,41 The organism is found in soil contaminated by feces of colonized birds.

Pulmonary symptoms and meningitis are more typical of cryptococcal disease in general, although when contracted from a pet bird via a break in the skin, cutaneous cryptococcosis usually presents with skin lesions resembling cellulitis, molluscum, herpes, and Kaposi sarcomalike papulonodules.⁴² Infection beyond the skin in immunocompromised patients may involve the lungs and the central nervous system.⁴¹ Prostate and eye infections have also been reported.³⁸

Avian mite dermatitis

Birds carry several kinds of mites: feather or “red” mites (which do not affect humans) and mites that can affect humans such as Ornithonyssus sylviarum (the northern fowl mite) and Dermanyssus gallinae (the poultry mite or chicken mite) (R. Stevenson, personal communication, 2007). O sylviarum and D gallinae are found in the commercial poultry industry, but uncommonly, pet birds can harbor them (R. Stevenson, personal communication, 2007).^42–44

In humans, mites can cause an intensely pruritic, papular-papulovesicular eruption.⁴²

Nontuberculous mycobacteriosis

Nontuberculous mycobacteria (Mycobacterium species chelonae, abscessus, fortuitum, avium, kansasii, ulcerans, and marinum) are ubiquitous in the environment and can colonize animals. M avium subsp avium causes avian tuberculosis.³⁸ Birds may carry mycobacterial organisms on beaks, claws, and talons, facilitating passage to humans (J.M. Gaskin, personal communication, 2006). In one reported case, M chelonae skin infection was probably transmitted in this manner to a bird-keeper via a bird bite.⁴⁵

In symptomatic nontuberculous mycobacterial infections, the site of inoculation usually determines the presenting signs. Mycobacteriosis should be suspected when skin or lung infections fail to improve with empiric treatment. Patients with structurally abnormal lungs or immunosuppression may be at higher risk of pulmonary or disseminated disease from infected birds.^46,47

Acknowledgment: The authors extend special thanks to Jack M. Gaskin, DVM, PhD, Department of Infectious Disease and Pathology, University of Florida, Gainesville, FL; Rhoda Stevenson, DVM, Exotic Bird Hospital, Jacksonville, FL; and Stephanie L. Hines, MD, Section of General Internal Medicine, Mayo Clinic, Jacksonville, FL, for their review of this paper. Editing, proofreading, and reference verification were provided by the Mayo Clinic Section of Scientific Publications.

Birds are among the most popular pets in the United States, ranking fourth behind dogs, cats, and fish. According to a commercial survey,¹ 6.4 million US households own at least one pet bird—and are therefore at risk of a number of bacterial, protozoal, fungal, viral, or parasitic zoonoses (infectious diseases of animals that are communicable to humans).²

This review focuses on the most common pet bird-associated diseases, with implications for bird-keepers’ health. Unless specifically stated otherwise, these diseases are not routinely transmissible from human to human.

NO NEED TO AVOID OWNING A BIRD

Although one can indeed acquire an infection from a pet bird, this possibility need not discourage people from owning birds.^3,4

The ability of a microorganism to make a person sick varies with the virulence of the organism, the dose to which a person is exposed, and the route of infection. For a bird owner, prevention often involves simple hygiene, handwashing, sanitation, and regular veterinary care for the bird.³ Many of these diseases are transmitted by ingestion of food contaminated by avian fecal matter or inhalation of contaminated dust. Therefore, bird owners should take steps to minimize dander in the environment. Furthermore, wearing a mask during cage cleaning is suggested.⁵ Obtaining pet birds from reputable domestic sources decreases the risk of acquiring a bird with an infectious disease.^4,6

These hygienic measures are especially important for people who are more susceptible to infection, eg, the very young or very old, those in poor health to begin with, and those with compromised immunity.

Most of the illnesses one can acquire from birds are asymptomatic or self-limited in humans, but they should be considered if a bird-keeper has persistent or unusual symptoms of infection or if the pet bird was recently acquired or has been ill or died.

DISEASES PRESENTING WITH FLU-LIKE OR PULMONARY SYMPTOMS

Psittacosis (ornithosis, parrot fever, chlamydiosis)

Psittacosis is caused by Chlamydophila (formerly Chlamydia) psittaci. The organism has been reported to be present in 40% of birds.^4,7 Humans are considered incidental hosts.

Transmission of C psittaci is usually via inhalation of aerosolized particles contaminated with infected bird excreta, nasal secretions, tissue, or feathers. Beak-to-mouth transmission and transmission via bird bites have been reported.⁸ Unlike Chlamydophila pneumoniae, C psittaci has not conclusively been reported to be transmitted from human to human.

Many infected pet birds show no signs of the disease, but others may have conjunctivitis, liver disease, or generalized signs of severe infection such as ruffled feathers, loss of appetite, diarrhea, or lime-green urates (R. Stevenson, personal communication, 2007).^2,5,9,10

Recognizing that the patient has been exposed to birds is clinically useful, as in one study 90% of patients with psittacosis had been exposed to birds as pets or in their occupations.¹¹

Atypical pneumonia is the most common presentation of psittacosis in humans. The symptoms typically begin 7 to 14 days after exposure, with fever, chills, prominent headache, photophobia, and cough. Hepatosplenomegaly is clinically detectable in 10% to 70% of patients. Serious but uncommon presentations include pericarditis, myocarditis, bacterial culture-negative endocarditis, mental status changes, and thrombophlebitis. The combination of pneumonitis and hepatosplenomegaly should prompt consideration of psittacosis.¹¹

Influenza

All known subtypes of influenza A virus can infect birds (influenza B virus cannot). However, there are substantial genetic differences between the subtypes of influenza A that typically infect both people and birds.¹²

Avian influenza viruses affecting birds and humans (H5N1, H7N7, H9N2, and others), commonly called “bird flu,” emerged in 1997 in association with poultry.^13,14 Highly pathogenic H5N1 viral infections have attracted particular attention, as they have killed millions of birds and infected several hundred humans, half of whom have died.¹³ Various avian influenza viruses that can affect humans have been isolated from captive birds such as parrots, canaries, and poultry and from wild waterfowl and migrating birds.¹⁵ To our knowledge, pet birds have not been implicated in transmission, but they are a potential source of infection if they have been in contact with infected birds.

Transmission from bird to human has usually been via inhaled droplets and, less likely, from contaminated environmental sources. According to the US Centers for Disease Control and Prevention, family clusters of H5N1 infection have been observed,¹⁶ but person-to-person transmission has been very rare, limited, and unsustained.¹³

Signs of influenza in birds can range from none to respiratory tract infection, decreased egg production, systemic illness, and death.¹⁵

Avian influenza should be suspected in people with flu symptoms who have been exposed to sick poultry or wild birds, have travelled to an endemic area, or have had direct contact with a person known or suspected to be infected with avian influenza.¹⁷ Information about areas of the world in which avian influenza is endemic or is breaking out is available at the World Health Organization Epidemic and Pandemic Alert and Response Web page (www.who.int/csr/disease/avian_influenza/updates/en/index.html).

Signs and symptoms of avian influenza in humans include fever, upper respiratory tract infection, cough, and gastrointestinal symptoms. With highly pathogenic viruses such as H5N1, the disease can progress very rapidly from onset to death. Less-pathogenic viruses such as H9N2 cause milder symptoms.¹⁶

Histoplasma capsulatum is a fungus that colonizes the gastrointestinal tract of birds and contaminates the soil via bird and bat droppings. The most highly endemic regions of the world are the Ohio and Mississippi River valleys. Typical pet birds such as canaries and parrots are not susceptible to symptomatic infection, but doves and pigeons (often treated as pets by bird-lovers) may become colonized if they contact contaminated birds or excreta (R. Stevenson, personal communication, 2007).^5,18

Humans commonly acquire the organisms when they inhale disrupted soil contaminated with the organism. Human-to-human transmission has not been reported.

The degree of human illness depends on the inoculum size and the immunity of the person infected. In more than 90% of cases, the primary infection is minimally symptomatic or goes unnoticed. The typical incubation time is 7 to 21 days. In patients who become ill, symptoms include fever, chills, headache, nonproductive cough, and adenopathy-mediated chest pain. Disseminated disease generally occurs in immunocompromised patients and presents with fever, weight loss, hepatosplenomegaly, and pancytopenia.¹⁸

Newcastle disease (avian pneumoencephalitis)

The virus that causes Newcastle disease, avian paramyxovirus 1, can affect animals, reptiles, birds, and people. It is most common in wild birds, but parrots are also highly susceptible and can be reservoirs that continue to shed the virus for up to 12 months after the acute illness has subsided. Illegally imported Amazon parrots are the most likely source of infection for US households. The virus is spread through an infected bird’s feces and secretions from the nose, mouth, and eyes and can be carried on a person’s clothing, footwear, and equipment.

Some infected birds show no signs of it; others have respiratory signs, green diarrhea, muscle tremors, circling, paralysis, or swelling of tissues around the eyes and neck. The mortality rate in infected birds can be up to 100%.¹⁹

Human infection most often results in conjunctivitis. Chills, fever, and lethargy are exceptionally rare.¹⁵ Because the virus is prevalent in poultry, poultry workers are at greatest risk of infection. Rapid recovery in humans is common. People with conjunctivitis due to Newcastle disease virus should avoid contact with birds.^2,20

Q fever

Q fever is caused by Coxiella burnetii, a gram-negative pleomorphic bacillus. Ticks and vertebrates (goats, sheep, and, less commonly, birds) are natural reservoirs for the organism. Human infection results from contact with infected animals or inhalation of dust contaminated with infected excreta or placental tissue.² Birds may harbor the infection in experimental and natural settings.^21,22

Symptoms in humans typically include fever, pneumonitis, severe headache, and photophobia. Meningitis, hepatitis, and thromboses are seen in more-severe disease. Infection acquired in pregnancy may lead to prematurity, abortion, or stillbirth.^18,21

West Nile fever and West Nile encephalitis

Wild birds such as corvids and raptors harbor the West Nile virus; pet songbirds (passerines) can harbor it as well.^23,24 The principal means of transmission of West Nile infection from birds to humans is via a mosquito biting an infected bird and then biting a human. Direct bird-to-human transmission has not been described.¹⁸ Infected birds may be asymptomatic or appear ill or reluctant to fly and die of disseminated viral infection.²³

The incubation period in humans is generally 3 to 14 days, followed by the sudden onset of fever, malaise, nausea, vomiting, rash, lymphadenopathy, and retro-orbital pain. Neurologic presentations—ataxia, extrapyramidal signs, cranial nerve abnormalities, myelitis, optical neuritis, and seizures—are quite rare and generally occur in the elderly or immunocompromised. Fewer than 1% of affected people develop more-severe disease, such as acute encephalitis, aseptic meningitis, or Guillain-Barré syndrome.²⁵

Allergic alveolitis

Allergic alveolitis (hypersensitivity pneumonitis, parakeet dander pneumoconiosis, pigeon lung disease, bird-breeder’s lung, bird-fancier’s disease) is not a zoonosis; the term describes diffuse parenchymal lung disease caused by repeated exposure to an inhaled allergen.²⁶ However, it should be considered in patients with pulmonary symptoms and bird exposure. Avian proteins are a known trigger.²⁷

Acute allergic alveolitis is clinically indistinguishable from a respiratory infection. It is characterized by the abrupt onset of an intense nonproductive cough, chest tightness, dyspnea, chills, fever, myalgia, and malaise. Symptoms gradually improve over 24 to 48 hours without antigen exposure but recur with repeated exposure.

Subacute illness presents with similar symptoms, which gradually worsen over weeks to months, and it can be indistinguishable from interstitial lung disease. Many patients with chronic allergic alveolitis are suspected of having tuberculosis or fungal pneumonia or receive a misdiagnosis of idiopathic pulmonary fibrosis.

Patients usually have a favorable outcome if the allergen is removed. If exposure continues, irreversible pulmonary fibrosis may develop.²⁸

DISEASES PRESENTING WITH GASTROINTESTINAL SYMPTOMS

Salmonellosis

Nontyphoidal Salmonella species colonize the gastrointestinal tract of many animals, including birds. Up to 80% of chicken eggs are contaminated with this gram-negative bacterium.

Spread of nontyphoidal Salmonella to humans is much more common from poultry, poultry products, and pet reptiles than from pet birds, although ducks and baby chicks have transmitted infection to humans. Hand-to-mouth spread occurs after contact with pets or pet excreta.^29,30 Infected birds may be healthy carriers, may develop enteritis or hemorrhagic hepatosplenic disease, or may even die.^2,9

Gastroenteritis due to nontyphoidal Salmonella in humans begins with nausea, vomiting, fever, and loose, nonbloody diarrhea about 48 hours after ingestion. Most gastroenteritis infections are self-limited, with resolution of fever within 48 to 72 hours and resolution of diarrhea within 4 to 10 days.³¹

Systemic or severe infection warranting “preemptive” therapy is more likely in immunosuppressed patients, in patients with reduced gastric acid or impaired gastrointestinal mucosal integrity, in infants less than 3 months of age, and in patients with chronic gastrointestinal tract disease, malignant neoplasms, hemoglobinopathies, or infection with the human immunodeficiency virus.³¹ Systemic nontyphoidal Salmonella infection may settle in structurally abnormal sites such as in existing fractures, severe degenerative joint disease, organs affected by stones, or abnormal lung tissue. Large-vessel arteritis due to non-typhoidal Salmonella should be suspected in a person at risk (particularly if the person is elderly) who presents with back, chest, or abdominal pain preceded by gastroenteritis.^31,32

The main reservoirs for Campylobacter jejuni are wild birds and poultry, although this bacterium can also affect other animals and pet birds.² The most commonly affected pet birds are psittaciforms (parrots) and passeriforms (finches and canaries).

The organism colonizes the small intestine and colon of birds and can be spread to humans through contact with feces or carcasses of infected animals.^33–35 Birds with campylobacteriosis develop hepatitis, lethargy, loss of appetite, weight loss, and yellow diarrhea and often die of the illness (R. Stevenson, personal communication, 2007).

The most important mode of transmission to humans is through handling or consuming chicken, milk, or other products contaminated with feces of carrier animals. However, in up to 24% of cases, the source of infection is unknown.^33,34

Human infection with C jejuni most commonly leads to an acute, self-limited gastrointestinal illness characterized by fever, diarrhea, and abdominal cramps. The diarrhea is typically watery or bloody and occurs 8 to 10 times a day at peak illness. Fever can persist for up to a week. Most cases resolve within 7 days, but some patients may have a relapsing diarrheal illness lasting several weeks. Between 20% and 40% of cases of Guillain-Barré syndrome are preceded by infection with C jejuni.³⁵

Giardiasis

Giardiasis is an intestinal protozoal infection caused by Giardia species (primarily G lamblia) that affect humans and other mammals. The parasite is found in bird droppings, but the role of birds in transmission to humans is unclear. Most infections are transmitted via contaminated surface water supplies, although person-to-person transmission has been documented.³⁶ Infected pet birds have signs of gastroenteritis and can be treated, but reinfection often occurs.³⁷

Giardia infections in humans are often asymptomatic, but about 50% of patients have diarrhea, abdominal pain, bloating, belching, nausea, and vomiting 3 days to 3 weeks after ingesting the parasite. A clinical clue may be new-onset lactose intolerance. Symptoms usually resolve after a week. Prolonged infection occurs in up to 20% of patients. People with hypochlorhydria or hypogammaglobulinemia, children, and travelers to endemic areas are at higher risk of infection.³⁷

DISEASES PRESENTING WITH SKIN SYMPTOMS

Pasteurellosis

Pasteurellosis is caused by Pasteurella multocida, an inhabitant of the healthy nasopharynx of some birds and also the causative agent of avian cholera.³⁸ Many pet birds that acquire systemic Pasteurella infection from a cat bite die of avian cholera (Stevenson R, personal communication, 2007).

Pasteurella organisms are transmissible to humans via bites or scratches from pet birds. Infected wounds in humans are usually red and painful, but the physical findings may lead one to underestimate the severity of infection. Transmission via respiratory droplets is rare but may cause acute or subacute bronchitis, pneumonia, or septicemia.³⁸

Erysipeloid

Erysipeloid, caused by the bacterium Erysipelothrix rhusiopathiae, is transmissible to humans via contact with domestic or wild fowl. Infection in pet birds can cause sepsis but is rarely seen in veterinary practice (R. Stevenson, personal communication, 2007).^38,39

Human infection typically affects broken skin, causing a dramatic, localized skin infection that is painful and pruritic; at first it is livid-red, then blue-red. The infection can spread to nearby joints. Septicemia and endocarditis in humans are rare complications.⁴⁰

Cryptococcosis

Cryptococcosis, caused by the encapsulated yeast Cryptococcus neoformans, can be harbored and transmitted by asymptomatic pet birds such as cockatoos via colonization of the gastrointestinal tract.^38,41 The organism is found in soil contaminated by feces of colonized birds.

Pulmonary symptoms and meningitis are more typical of cryptococcal disease in general, although when contracted from a pet bird via a break in the skin, cutaneous cryptococcosis usually presents with skin lesions resembling cellulitis, molluscum, herpes, and Kaposi sarcomalike papulonodules.⁴² Infection beyond the skin in immunocompromised patients may involve the lungs and the central nervous system.⁴¹ Prostate and eye infections have also been reported.³⁸

Avian mite dermatitis

Birds carry several kinds of mites: feather or “red” mites (which do not affect humans) and mites that can affect humans such as Ornithonyssus sylviarum (the northern fowl mite) and Dermanyssus gallinae (the poultry mite or chicken mite) (R. Stevenson, personal communication, 2007). O sylviarum and D gallinae are found in the commercial poultry industry, but uncommonly, pet birds can harbor them (R. Stevenson, personal communication, 2007).^42–44

In humans, mites can cause an intensely pruritic, papular-papulovesicular eruption.⁴²

Nontuberculous mycobacteriosis

Nontuberculous mycobacteria (Mycobacterium species chelonae, abscessus, fortuitum, avium, kansasii, ulcerans, and marinum) are ubiquitous in the environment and can colonize animals. M avium subsp avium causes avian tuberculosis.³⁸ Birds may carry mycobacterial organisms on beaks, claws, and talons, facilitating passage to humans (J.M. Gaskin, personal communication, 2006). In one reported case, M chelonae skin infection was probably transmitted in this manner to a bird-keeper via a bird bite.⁴⁵

In symptomatic nontuberculous mycobacterial infections, the site of inoculation usually determines the presenting signs. Mycobacteriosis should be suspected when skin or lung infections fail to improve with empiric treatment. Patients with structurally abnormal lungs or immunosuppression may be at higher risk of pulmonary or disseminated disease from infected birds.^46,47

Acknowledgment: The authors extend special thanks to Jack M. Gaskin, DVM, PhD, Department of Infectious Disease and Pathology, University of Florida, Gainesville, FL; Rhoda Stevenson, DVM, Exotic Bird Hospital, Jacksonville, FL; and Stephanie L. Hines, MD, Section of General Internal Medicine, Mayo Clinic, Jacksonville, FL, for their review of this paper. Editing, proofreading, and reference verification were provided by the Mayo Clinic Section of Scientific Publications.

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS

Recurrent acute pancreatitis is defined as more than one episode of acute pancreatitis.¹ In clinical practice, it is important to distinguish between the first and recurrent episodes of acute pancreatitis.

Most patients who have one episode of acute pancreatitis never have another one.^2,3 Therefore, for patients having an initial attack, we recommend a limited workup that includes a detailed history, laboratory evaluation, and a noninvasive imaging study such as transcutaneous ultrasonography or computed tomography.

On the other hand, people who have a second attack are at higher risk of more recurrences. Therefore, patients having recurrent attacks need a more extensive workup to determine the underlying cause. We recommend referring them to a gastroenterologist for further evaluation.

WHICH CAUSES CAN BE MANAGED ENDOSCOPICALLY?

In the Western world, 70% to 80% of cases of recurrent pancreatitis are due to either alcohol abuse or gallstone disease.^2,4 The rest are related to:

• Autoimmune disorders
• Cancer, including occult malignancies and premalignant conditions such as intraductal papillary mucinous neoplasm
• Chronic pancreatitis
• Drugs
• Heredity
• Metabolic abnormalities (hypertriglyceridemia, hypercalcemia)
• Sphincter of Oddi dysfunction
• Structural or congenital abnormalities (pancreas divisum)
• Trauma.

• Gallstone disease, including biliary microlithiasis and sludge (in patients with or without a gallbladder)
• Sphincter of Oddi dysfunction
• Pancreas divisum
• Obstruction to flow of pancreatic juice.

Endoscopy is not completely benign

Although endoscopic procedures are less invasive than surgery, they are not completely benign. They can cause anxiety and are associated with risks such as bleeding, perforation, and pancreatitis.⁵ The risks, benefits, and alternatives to these procedures should be discussed with the patient, and informed consent should be obtained before any endoscopic procedure.⁶

STONES (LARGE OR SMALL) OR SLUDGE IN PATIENTS WITH A GALLBLADDER

Gallstones can be large, but small stones (microlithiasis) and sludge are more common and therefore account for more cases of pancreatitis.

Strictly defined, microlithiasis refers to stones smaller than 2 mm in diameter in the biliary tract, whereas sludge is a suspension of biliary crystals, mucin, and cellular debris in the gallbladder or bile ducts.⁷ The terms are often used interchangeably, since the conditions often coexist and their treatment is similar.

Theories differ as to how microlithiasis or sludge can cause recurrent pancreatitis. According to one theory, the debris blocks the common channel, increasing the pancreatic intraductal pressure and leading to pancreatitis.⁸ A second theory is that small stones or biliary crystals passing through the sphincter of Oddi cause inflammation, and that repeated inflammation eventually leads to stenosis or dyskinesia of the sphincter, both of which have been associated with pancreatitis.⁹

Studies suggest that microlithiasis and sludge are common causes of recurrent pancreatitis, accounting for about two-thirds of cases according to estimates by Ros et al¹⁰ and Lee et al.¹¹

Detecting small stones and sludge

The diagnosis of microlithiasis and biliary sludge in patients with a gallbladder is based on imaging studies and bile microscopy.¹²

Transabdominal ultrasonography is the imaging study most often used for diagnosing microlithiasis. The technology and expertise for this test are widely available, and it is relatively inexpensive.

Endoscopic ultrasonography is more sensitive for detecting microlithiasis and can examine the distal common bile duct.

Bile microscopy involves obtaining bile from the second portion of the duodenum (via an endoscope or a duodenal tube) or from the bile ducts (by cannulating the common bile duct and stimulating the gallbladder with cholecystokinin). The bile sample is centrifuged and inspected microscopically under plain light and polarized light (which aids the visualization of biliary crystals). The crystals can be cholesterol monohydrate, calcium bilirubinate, or calcium carbonate.^7,13,14

Removing the gallbladder is the treatment of choice for small stones and sludge

Treatments to prevent recurrent attacks of acute pancreatitis due to microlithiasis and sludge include cholecystectomy, biliary sphincterotomy, and ursodioxycholic acid.^10,11,15

In prospective observational studies by Ros et al¹⁰ and Lee et al,¹¹ about half of the patients with recurrent pancreatitis were treated with cholecystectomy, endoscopic sphincterotomy, or ursodioxycholic acid in a nonrandomized fashion. The choice of therapy was based on the patient’s medical status and the preferences of the patient and the physician. Half the patients received no treatment. In both studies the median follow-up was 4 years. Treated patients had a significantly lower rate of recurrent attacks of pancreatitis during follow-up: less than 20% with therapy compared with more than 60% without therapy. Unfortunately, no published study has compared these three treatments head to head.

Cholecystectomy, however, is the most definitive therapy and is generally considered the treatment of choice.

Biliary sphincterotomy is an endoscopic procedure that involves cutting the sphincter of Oddi to allow the stones and sludge to pass more freely. It is as effective as cholecystectomy in preventing recurrent attacks but does not eliminate the risk of cholecystitis and cholangitis (Figure 1). For this reason, it is usually reserved for patients who cannot tolerate surgery due to comorbidities, those who refuse surgery, or those who are pregnant.¹⁶

Ursodeoxycholic acid is a reasonable alternative in patients who cannot tolerate surgical or endoscopic biliary sphincterotomy.^1,17–20 The dosage is 10 mg/kg/day, which can be in two or three divided doses. The optimal duration of treatment is not known; however, since this drug works slowly, it may need to be taken for 2 years or more. Ursodeoxycholic acid is more effective in patients with cholesterol-based stones and crystals. It is not effective for large stones (> 1 cm in diameter) or calcified stones.

STONES AFTER CHOLECYSTECTOMY

Bile duct stones can be classified as primary or secondary. A primary stone is one that remains where it was formed, whereas a secondary stone is one that has migrated from its site of formation.²¹

Some suggest that bile duct stones that are detected within 2 years of cholecystectomy originated in the gallbladder and were missed when the gallbladder was removed (and therefore are considered secondary stones), and that stones that present more than 2 years after cholecystectomy are de novo (ie, primary) stones.^22,23

In any event, stones have been found in the common bile duct in 4% to 24% of patients up to 15 years after cholecystectomy.^24–26 A fair number of these patients have no symptoms.²⁷ Risk factors for stone recurrence are lithogenic bile (ie, high concentration of cholesterol, low concentration of bile salts), biliary stasis, strictures, dilated bile ducts, and advanced age.^28–30

No role for crystal analysis after cholecystectomy

Biliary crystal analysis does not seem to have diagnostic value in patients with recurrent acute pancreatitis after cholecystectomy,³¹ because removing the gallbladder eliminates the crystals and sludge. Imaging studies are therefore the cornerstone of diagnosis.

Transabdominal ultrasonography is the most commonly used initial imaging test. However, abdominal fat and gas in the duodenum can obscure the distal common bile duct and decrease the sensitivity of this test.³²

Endoscopic ultrasonography involves positioning the transducer in the second part of the duodenum, where it can show the adjacent biliary tree without interference from digestive gas or abdominal fat.

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography are both highly sensitive for detecting common bile duct stones and are recommended if they can be done without delay.

Endoscopic retrograde cholangiopancreatography (ERCP). As a rule, patients who are very likely to have gallstones are best served by proceeding directly to ERCP, a procedure that enables both imaging and treatment. However, ERCP exposes the patient to radiation and the risk of pancreatitis, so in some patients (eg, pregnant women, people who recently had acute pancreatitis), one may want to do ultrasonography first.

ERCP is the treatment of choice after cholecystectomy

The treatment of choice in patients with choledocholithiasis is ERCP with biliary sphincterotomy and stone extraction. Success at clearing the biliary tree of all stones depends on the size, number, and location of the stones, the anatomy of the digestive tract and the bile duct, and the experience of the endoscopist. At specialized centers, the rate of successful clearance with subsequent procedures is close to 100%. Large stones may require fragmentation inside the bile duct to aid their removal.³³

SPHINCTER OF ODDI DYSFUNCTION

The sphincter of Oddi, located where the bile and pancreatic ducts penetrate the wall of the duodenum, actually consists of three sphincters: the common, the biliary, and the pancreatic. Its physiologic role is to regulate the flow of bile and pancreatic juice into the duodenum and to prevent reflux into the ducts from the duodenum.³⁴ Its basal pressure is the main regulating mechanism for pancreatic and biliary secretions into the intestine, and its phasic contractile activity is closely associated with duodenal motility.

Sphincter dysfunction: Stenosis, dyskinesia

The sphincter of Oddi can obstruct the flow of bile and pancreatic juice owing either to stenosis or to dyskinesia.^35,36 Stenosis refers to structural alteration of the sphincter, probably from inflammation and subsequent fibrosis. In contrast, dyskinesia refers to a motor abnormality of the sphincter that makes it hypertonic.

Stenosis or dyskinesia can occur in the biliary sphincter, the pancreatic sphincter, the common sphincter, or any combination of the three. For example, dysfunction of the biliary sphincter can cause abnormalities in liver-associated enzyme levels and biliary-type pain, whereas pancreatic sphincter dysfunction can cause recurrent attacks of pancreatitis and pancreatic-type pain.³⁷ Elevated pancreatic sphincter pressure has been shown to correlate with increased pancreatic ductal pressure, suggesting that the sphincter plays a role in the pathogenesis of acute pancreatitis.^23,38

Sphincter pressure can be measured during ERCP, but ERCP is risky

The gold standard for the diagnosis of sphincter of Oddi dysfunction is manometry,^23,35 ie, direct measurement of sphincter pressure via a thin catheter placed inside the pancreatic or biliary sphincter during ERCP (Figure 1).

However, in patients with suspected sphincter of Oddi dysfunction, ERCP with or without manometry is associated with a high rate of complications, with pancreatitis occurring in up to 25% of cases.^39–41 Therefore, several noninvasive and provocative tests have been designed in an attempt to identify patients with this disorder. Unfortunately, none of them seems to be as sensitive and specific as manometry for diagnosing sphincter of Oddi dysfunction, and so they have not gained widespread use.

Opening the sphincter of Oddi with drugs, endoscopy, or surgery

Drug treatment of sphincter of Oddi dysfunction is based on drugs that relax smooth muscle, such as calcium channel blockers and nitrates. The treatment must be lifelong. Also, it does not improve sphincter stenosis, and only half of patients with sphincter dyskinesia respond to it. For these reasons, drug treatment of sphincter of Oddi dysfunction has not gained widespread acceptance.^36,42

Endoscopic sphincterotomy is the current standard endoscopic therapy for sphincter of Oddi dysfunction. This procedure is performed during ERCP and involves cutting the sphincter with electrocautery.

Endoscopic pancreatic sphincterotomy prevents recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction in more than 60% of cases.^23,43–46 A potential complication is pancreatitis, which occurs more often in patients with pancreatic sphincter dyskinesia. Placing a stent in the pancreatic duct after pancreatic sphincterotomy reduces the risk of pancreatitis after ERCP.^37,47,48

Surgery. Pancreatic sphincterotomy can also be done surgically, most commonly via transduodenal pancreatic sphincteroplasty. Surgical sphincteroplasty is as effective as endoscopic sphincterotomy for preventing recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction.⁴⁹ However, endoscopic therapy is much less invasive and remains the preferred treatment for sphincter of Oddi dysfunction in most centers with experience in this technique.⁵⁰

PANCREAS DIVISUM

Pancreas divisum is the most common congenital anomaly of the pancreatic duct. Autopsy studies show it occurs in 5% to 10% of the population.^51–53

At approximately the 5th week of gestation, there are two pancreatic buds: a ventral and a dorsal bud. The ventral bud eventually gives rise to part of the pancreatic head and uncinate process of the pancreas in the adult. The dorsal bud eventually gives rise to the rest of the pancreatic head, the pancreatic body, and the pancreatic tail. At 6 to 7 weeks of gestation, the ventral bud rotates clockwise and lies posterior to the dorsal bud. At this stage, both the dorsal and ventral pancreata have their own ducts, which do not communicate with each other. Normally, the ventral and dorsal pancreas and their ducts fuse together at 8 weeks of gestation; in people with pancreas divisum, this ductal fusion does not occur.⁵¹

The pancreas secretes 1.5 L of fluid per day. Normally, 90% to 95% of this volume drains through the major papilla. In people with pancreas divisum, 90% to 95% of the fluid drains through the minor papilla.

People with pancreas divisum are a heterogeneous group. Most have no symptoms, and their ductal anatomy is diagnosed only incidentally. However, a subgroup is prone to develop acute pancreatitis. The cause is thought to be the small diameter of the minor papilla, which poses a relative obstruction to the flow of pancreatic juice.⁵⁴ Direct support for this theory comes from a study in which investigators measured pancreatic ductal pressures in eight people with normal anatomy and six people with pancreas divisum. The pressure in the main pancreatic duct in those with pancreas divisum was significantly higher than in those with normal anatomy.⁵⁵ Additional evidence in favor of this theory is the effectiveness of treatment, which involves widening the minor papillary opening (minor papillary sphincterotomy).

Diagnosis of pancreas divisum

The diagnosis of pancreas divisum is based on imaging studies, and ERCP remains the gold standard for patients with equivocal results on noninvasive imaging. However, MRCP, especially secretin-enhanced MRCP, is as accurate as ERCP. In most cases, MRCP has replaced ERCP for the diagnosis of this condition, although a recent study suggests that MRCP is inferior to ERCP in the diagnosis of pancreas divisum.⁵⁶ We recommend secretin-enhanced MRCP for this purpose.

Computed tomography and endoscopic ultrasonography can also diagnose pancreas divisum, but their diagnostic accuracy is lower than that of ERCP and MRCP.

Minor papillary sphincterotomy

Treating recurrent pancreatitis due to pancreas divisum involves relieving the relative obstruction of the minor papilla by minor papillary sphincterotomy. This can be done surgically or endoscopically (Figure 1).

Surgery. No randomized, controlled study has yet assessed the efficacy of surgical sphincteroplasty for recurrent pancreatitis in patients with pancreas divisum. However, retrospective studies and one prospective study have been published.^57,58

In the retrospective study with the largest number of patients, Warshaw et al⁵⁷ reported their experience in 49 patients who had recurrent pancreatitis due to pancreas divisum. After surgical sphincteroplasty, the patients were followed for a mean of 53 months; 40 (82%) of the 49 patients had no further episodes of acute pancreatitis during this time.

Bradley and Stephan⁵⁸ studied 37 patients with pancreas divisum and recurrent pancreatitis.⁵⁸ After surgical sphincteroplasty, the patients were followed for a mean of 60 months; 31 of the 37 patients had no further attacks, a success rate of 84%.

Endoscopic therapy. As with surgical therapy trials, most trials of endoscopic therapy of recurrent pancreatitis in patients with pancreas divisum are small case series. In a retrospective study with one of the largest number of patients, Heyries et al⁵⁹ reported their experience with 24 patients with pancreas divisum and recurrent pancreatitis. After undergoing endoscopic minor papillary sphincterotomy, all patients were followed for a mean of 39 months, during which 22 (92%) did not have further episodes of acute pancreatitis.

In the only randomized controlled trial available, 19 patients with recurrent pancreatitis and pancreas divisum underwent either no treatment or endoscopic minor papillary sphincterotomy.⁶⁰ In the treatment group, 9 of 10 patients had no further episodes of acute pancreatitis during the 3 years of follow-up, while 6 of 9 patients who were randomized to no treatment had at least one episode.⁶⁰

Although surgical and endoscopic minor papillary sphincterotomy are equally effective, endoscopic therapy is preferred since it is less invasive, is associated with less morbidity, and costs less. It is also more convenient for patients, since it is an outpatient procedure. Surgical treatment is usually reserved for those in whom endoscopic treatment has failed or is not technically possible.

OTHER PROCESSES OBSTRUCTING THE FLOW OF PANCREATIC JUICE

Any process preventing free flow of pancreatic juice can lead to acute pancreatitis. The cause of the blockage can be around the ampulla, in the ampulla, or in the duct.⁶¹

Periampullary lesions, tumors, or polyps can press on the ampulla and cause complete or relative obstruction of the pancreatic duct with a subsequent increase in intraductal pressure and, thus, acute pancreatitis.⁶² Tumors or polyps of the ampulla, such as ampullary adenoma or carcinoma, can cause pancreatitis by directly obstructing the pancreatic duct where it opens into the duodenum.^63–66 Intraductal processes such as ductal adenocarcinoma, intraductal papillary mucinous tumor, pancreatic duct stone, and intraductal stricture due to cancer, chronic pancreatitis, or trauma can also cause pancreatitis by preventing free flow of pancreatic juice.^67–71

Although it is well known that sequelae of severe chronic pancreatitis such as ductal strictures or intraductal stones can lead to recurrent attacks of acute pancreatitis by preventing the free flow of pancreatic juice, a relationship also seems to exist between early chronic pancreatitis and recurrent acute pancreatitis.⁷² Several studies have shown that up to 50% of patients with idiopathic recurrent pancreatitis have evidence of chronic pancreatitis.^72–74 However, it is still unclear whether early chronic pancreatitis is the underlying cause of the recurrent attacks of acute pancreatitis or whether recurrent attacks of acute pancreatitis might have led to the development of chronic pancreatitis.

Diagnosis

Ampullary and periampullary neoplasms can be diagnosed endoscopically. Intraductal lesions such as strictures can be diagnosed by MRCP, especially secretin-enhanced MRCP, or by ERCP. ERCP has the additional advantage of being able to deliver treatment, ie, balloon dilation and stenting. In the case of ductal strictures, upsizing of the stents or placement of multiple stents during subsequent procedures is usually needed. Pancreatic ductal calcifications associated with chronic pancreatitis are usually radiopaque and are easily visible on plain films or computed tomography of the abdomen. Parenchymal and ductal changes of chronic pancreatitis can be diagnosed by endoscopic ultrasonography.

Treatment

The treatment is to relieve the obstruction and re-establish the free flow of pancreatic juice.

Periampullary tumors or polyps can be resected surgically or, if they involve only the mucosa, by endoscopic mucosal resection. Ampullary adenomas can be resected endoscopically. Ampullary carcinomas usually require surgical resection.

Small, nonobstructive stones in the pancreatic duct can be removed during ERCP.⁷⁵ Larger stones may need to be fragmented by extracorporeal shock wave lithotripsy to facilitate removal by ERCP.⁷⁵

Intraductal strictures should raise the suspicion of pancreatic adenocarcinoma, especially in older patients.⁶¹ In these cases, relief of the obstruction by placement of a pancreatic stent can prevent further attacks of pancreatitis until a diagnosis can be established and a more definitive treatment can be offered.

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS

Recurrent acute pancreatitis is defined as more than one episode of acute pancreatitis.¹ In clinical practice, it is important to distinguish between the first and recurrent episodes of acute pancreatitis.

Most patients who have one episode of acute pancreatitis never have another one.^2,3 Therefore, for patients having an initial attack, we recommend a limited workup that includes a detailed history, laboratory evaluation, and a noninvasive imaging study such as transcutaneous ultrasonography or computed tomography.

On the other hand, people who have a second attack are at higher risk of more recurrences. Therefore, patients having recurrent attacks need a more extensive workup to determine the underlying cause. We recommend referring them to a gastroenterologist for further evaluation.

WHICH CAUSES CAN BE MANAGED ENDOSCOPICALLY?

In the Western world, 70% to 80% of cases of recurrent pancreatitis are due to either alcohol abuse or gallstone disease.^2,4 The rest are related to:

• Autoimmune disorders
• Cancer, including occult malignancies and premalignant conditions such as intraductal papillary mucinous neoplasm
• Chronic pancreatitis
• Drugs
• Heredity
• Metabolic abnormalities (hypertriglyceridemia, hypercalcemia)
• Sphincter of Oddi dysfunction
• Structural or congenital abnormalities (pancreas divisum)
• Trauma.

• Gallstone disease, including biliary microlithiasis and sludge (in patients with or without a gallbladder)
• Sphincter of Oddi dysfunction
• Pancreas divisum
• Obstruction to flow of pancreatic juice.

Endoscopy is not completely benign

Although endoscopic procedures are less invasive than surgery, they are not completely benign. They can cause anxiety and are associated with risks such as bleeding, perforation, and pancreatitis.⁵ The risks, benefits, and alternatives to these procedures should be discussed with the patient, and informed consent should be obtained before any endoscopic procedure.⁶

STONES (LARGE OR SMALL) OR SLUDGE IN PATIENTS WITH A GALLBLADDER

Gallstones can be large, but small stones (microlithiasis) and sludge are more common and therefore account for more cases of pancreatitis.

Strictly defined, microlithiasis refers to stones smaller than 2 mm in diameter in the biliary tract, whereas sludge is a suspension of biliary crystals, mucin, and cellular debris in the gallbladder or bile ducts.⁷ The terms are often used interchangeably, since the conditions often coexist and their treatment is similar.

Theories differ as to how microlithiasis or sludge can cause recurrent pancreatitis. According to one theory, the debris blocks the common channel, increasing the pancreatic intraductal pressure and leading to pancreatitis.⁸ A second theory is that small stones or biliary crystals passing through the sphincter of Oddi cause inflammation, and that repeated inflammation eventually leads to stenosis or dyskinesia of the sphincter, both of which have been associated with pancreatitis.⁹

Studies suggest that microlithiasis and sludge are common causes of recurrent pancreatitis, accounting for about two-thirds of cases according to estimates by Ros et al¹⁰ and Lee et al.¹¹

Detecting small stones and sludge

The diagnosis of microlithiasis and biliary sludge in patients with a gallbladder is based on imaging studies and bile microscopy.¹²

Transabdominal ultrasonography is the imaging study most often used for diagnosing microlithiasis. The technology and expertise for this test are widely available, and it is relatively inexpensive.

Endoscopic ultrasonography is more sensitive for detecting microlithiasis and can examine the distal common bile duct.

Bile microscopy involves obtaining bile from the second portion of the duodenum (via an endoscope or a duodenal tube) or from the bile ducts (by cannulating the common bile duct and stimulating the gallbladder with cholecystokinin). The bile sample is centrifuged and inspected microscopically under plain light and polarized light (which aids the visualization of biliary crystals). The crystals can be cholesterol monohydrate, calcium bilirubinate, or calcium carbonate.^7,13,14

Removing the gallbladder is the treatment of choice for small stones and sludge

Treatments to prevent recurrent attacks of acute pancreatitis due to microlithiasis and sludge include cholecystectomy, biliary sphincterotomy, and ursodioxycholic acid.^10,11,15

In prospective observational studies by Ros et al¹⁰ and Lee et al,¹¹ about half of the patients with recurrent pancreatitis were treated with cholecystectomy, endoscopic sphincterotomy, or ursodioxycholic acid in a nonrandomized fashion. The choice of therapy was based on the patient’s medical status and the preferences of the patient and the physician. Half the patients received no treatment. In both studies the median follow-up was 4 years. Treated patients had a significantly lower rate of recurrent attacks of pancreatitis during follow-up: less than 20% with therapy compared with more than 60% without therapy. Unfortunately, no published study has compared these three treatments head to head.

Cholecystectomy, however, is the most definitive therapy and is generally considered the treatment of choice.

Biliary sphincterotomy is an endoscopic procedure that involves cutting the sphincter of Oddi to allow the stones and sludge to pass more freely. It is as effective as cholecystectomy in preventing recurrent attacks but does not eliminate the risk of cholecystitis and cholangitis (Figure 1). For this reason, it is usually reserved for patients who cannot tolerate surgery due to comorbidities, those who refuse surgery, or those who are pregnant.¹⁶

Ursodeoxycholic acid is a reasonable alternative in patients who cannot tolerate surgical or endoscopic biliary sphincterotomy.^1,17–20 The dosage is 10 mg/kg/day, which can be in two or three divided doses. The optimal duration of treatment is not known; however, since this drug works slowly, it may need to be taken for 2 years or more. Ursodeoxycholic acid is more effective in patients with cholesterol-based stones and crystals. It is not effective for large stones (> 1 cm in diameter) or calcified stones.

STONES AFTER CHOLECYSTECTOMY

Bile duct stones can be classified as primary or secondary. A primary stone is one that remains where it was formed, whereas a secondary stone is one that has migrated from its site of formation.²¹

Some suggest that bile duct stones that are detected within 2 years of cholecystectomy originated in the gallbladder and were missed when the gallbladder was removed (and therefore are considered secondary stones), and that stones that present more than 2 years after cholecystectomy are de novo (ie, primary) stones.^22,23

In any event, stones have been found in the common bile duct in 4% to 24% of patients up to 15 years after cholecystectomy.^24–26 A fair number of these patients have no symptoms.²⁷ Risk factors for stone recurrence are lithogenic bile (ie, high concentration of cholesterol, low concentration of bile salts), biliary stasis, strictures, dilated bile ducts, and advanced age.^28–30

No role for crystal analysis after cholecystectomy

Biliary crystal analysis does not seem to have diagnostic value in patients with recurrent acute pancreatitis after cholecystectomy,³¹ because removing the gallbladder eliminates the crystals and sludge. Imaging studies are therefore the cornerstone of diagnosis.

Transabdominal ultrasonography is the most commonly used initial imaging test. However, abdominal fat and gas in the duodenum can obscure the distal common bile duct and decrease the sensitivity of this test.³²

Endoscopic ultrasonography involves positioning the transducer in the second part of the duodenum, where it can show the adjacent biliary tree without interference from digestive gas or abdominal fat.

Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography are both highly sensitive for detecting common bile duct stones and are recommended if they can be done without delay.

Endoscopic retrograde cholangiopancreatography (ERCP). As a rule, patients who are very likely to have gallstones are best served by proceeding directly to ERCP, a procedure that enables both imaging and treatment. However, ERCP exposes the patient to radiation and the risk of pancreatitis, so in some patients (eg, pregnant women, people who recently had acute pancreatitis), one may want to do ultrasonography first.

ERCP is the treatment of choice after cholecystectomy

The treatment of choice in patients with choledocholithiasis is ERCP with biliary sphincterotomy and stone extraction. Success at clearing the biliary tree of all stones depends on the size, number, and location of the stones, the anatomy of the digestive tract and the bile duct, and the experience of the endoscopist. At specialized centers, the rate of successful clearance with subsequent procedures is close to 100%. Large stones may require fragmentation inside the bile duct to aid their removal.³³

SPHINCTER OF ODDI DYSFUNCTION

The sphincter of Oddi, located where the bile and pancreatic ducts penetrate the wall of the duodenum, actually consists of three sphincters: the common, the biliary, and the pancreatic. Its physiologic role is to regulate the flow of bile and pancreatic juice into the duodenum and to prevent reflux into the ducts from the duodenum.³⁴ Its basal pressure is the main regulating mechanism for pancreatic and biliary secretions into the intestine, and its phasic contractile activity is closely associated with duodenal motility.

Sphincter dysfunction: Stenosis, dyskinesia

The sphincter of Oddi can obstruct the flow of bile and pancreatic juice owing either to stenosis or to dyskinesia.^35,36 Stenosis refers to structural alteration of the sphincter, probably from inflammation and subsequent fibrosis. In contrast, dyskinesia refers to a motor abnormality of the sphincter that makes it hypertonic.

Stenosis or dyskinesia can occur in the biliary sphincter, the pancreatic sphincter, the common sphincter, or any combination of the three. For example, dysfunction of the biliary sphincter can cause abnormalities in liver-associated enzyme levels and biliary-type pain, whereas pancreatic sphincter dysfunction can cause recurrent attacks of pancreatitis and pancreatic-type pain.³⁷ Elevated pancreatic sphincter pressure has been shown to correlate with increased pancreatic ductal pressure, suggesting that the sphincter plays a role in the pathogenesis of acute pancreatitis.^23,38

Sphincter pressure can be measured during ERCP, but ERCP is risky

The gold standard for the diagnosis of sphincter of Oddi dysfunction is manometry,^23,35 ie, direct measurement of sphincter pressure via a thin catheter placed inside the pancreatic or biliary sphincter during ERCP (Figure 1).

However, in patients with suspected sphincter of Oddi dysfunction, ERCP with or without manometry is associated with a high rate of complications, with pancreatitis occurring in up to 25% of cases.^39–41 Therefore, several noninvasive and provocative tests have been designed in an attempt to identify patients with this disorder. Unfortunately, none of them seems to be as sensitive and specific as manometry for diagnosing sphincter of Oddi dysfunction, and so they have not gained widespread use.

Opening the sphincter of Oddi with drugs, endoscopy, or surgery

Drug treatment of sphincter of Oddi dysfunction is based on drugs that relax smooth muscle, such as calcium channel blockers and nitrates. The treatment must be lifelong. Also, it does not improve sphincter stenosis, and only half of patients with sphincter dyskinesia respond to it. For these reasons, drug treatment of sphincter of Oddi dysfunction has not gained widespread acceptance.^36,42

Endoscopic sphincterotomy is the current standard endoscopic therapy for sphincter of Oddi dysfunction. This procedure is performed during ERCP and involves cutting the sphincter with electrocautery.

Endoscopic pancreatic sphincterotomy prevents recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction in more than 60% of cases.^23,43–46 A potential complication is pancreatitis, which occurs more often in patients with pancreatic sphincter dyskinesia. Placing a stent in the pancreatic duct after pancreatic sphincterotomy reduces the risk of pancreatitis after ERCP.^37,47,48

Surgery. Pancreatic sphincterotomy can also be done surgically, most commonly via transduodenal pancreatic sphincteroplasty. Surgical sphincteroplasty is as effective as endoscopic sphincterotomy for preventing recurrent attacks of pancreatitis in patients with pancreatic sphincter dysfunction.⁴⁹ However, endoscopic therapy is much less invasive and remains the preferred treatment for sphincter of Oddi dysfunction in most centers with experience in this technique.⁵⁰

PANCREAS DIVISUM

Pancreas divisum is the most common congenital anomaly of the pancreatic duct. Autopsy studies show it occurs in 5% to 10% of the population.^51–53

At approximately the 5th week of gestation, there are two pancreatic buds: a ventral and a dorsal bud. The ventral bud eventually gives rise to part of the pancreatic head and uncinate process of the pancreas in the adult. The dorsal bud eventually gives rise to the rest of the pancreatic head, the pancreatic body, and the pancreatic tail. At 6 to 7 weeks of gestation, the ventral bud rotates clockwise and lies posterior to the dorsal bud. At this stage, both the dorsal and ventral pancreata have their own ducts, which do not communicate with each other. Normally, the ventral and dorsal pancreas and their ducts fuse together at 8 weeks of gestation; in people with pancreas divisum, this ductal fusion does not occur.⁵¹

The pancreas secretes 1.5 L of fluid per day. Normally, 90% to 95% of this volume drains through the major papilla. In people with pancreas divisum, 90% to 95% of the fluid drains through the minor papilla.

People with pancreas divisum are a heterogeneous group. Most have no symptoms, and their ductal anatomy is diagnosed only incidentally. However, a subgroup is prone to develop acute pancreatitis. The cause is thought to be the small diameter of the minor papilla, which poses a relative obstruction to the flow of pancreatic juice.⁵⁴ Direct support for this theory comes from a study in which investigators measured pancreatic ductal pressures in eight people with normal anatomy and six people with pancreas divisum. The pressure in the main pancreatic duct in those with pancreas divisum was significantly higher than in those with normal anatomy.⁵⁵ Additional evidence in favor of this theory is the effectiveness of treatment, which involves widening the minor papillary opening (minor papillary sphincterotomy).

Diagnosis of pancreas divisum

The diagnosis of pancreas divisum is based on imaging studies, and ERCP remains the gold standard for patients with equivocal results on noninvasive imaging. However, MRCP, especially secretin-enhanced MRCP, is as accurate as ERCP. In most cases, MRCP has replaced ERCP for the diagnosis of this condition, although a recent study suggests that MRCP is inferior to ERCP in the diagnosis of pancreas divisum.⁵⁶ We recommend secretin-enhanced MRCP for this purpose.

Computed tomography and endoscopic ultrasonography can also diagnose pancreas divisum, but their diagnostic accuracy is lower than that of ERCP and MRCP.

Minor papillary sphincterotomy

Treating recurrent pancreatitis due to pancreas divisum involves relieving the relative obstruction of the minor papilla by minor papillary sphincterotomy. This can be done surgically or endoscopically (Figure 1).

Surgery. No randomized, controlled study has yet assessed the efficacy of surgical sphincteroplasty for recurrent pancreatitis in patients with pancreas divisum. However, retrospective studies and one prospective study have been published.^57,58

In the retrospective study with the largest number of patients, Warshaw et al⁵⁷ reported their experience in 49 patients who had recurrent pancreatitis due to pancreas divisum. After surgical sphincteroplasty, the patients were followed for a mean of 53 months; 40 (82%) of the 49 patients had no further episodes of acute pancreatitis during this time.

Bradley and Stephan⁵⁸ studied 37 patients with pancreas divisum and recurrent pancreatitis.⁵⁸ After surgical sphincteroplasty, the patients were followed for a mean of 60 months; 31 of the 37 patients had no further attacks, a success rate of 84%.

Endoscopic therapy. As with surgical therapy trials, most trials of endoscopic therapy of recurrent pancreatitis in patients with pancreas divisum are small case series. In a retrospective study with one of the largest number of patients, Heyries et al⁵⁹ reported their experience with 24 patients with pancreas divisum and recurrent pancreatitis. After undergoing endoscopic minor papillary sphincterotomy, all patients were followed for a mean of 39 months, during which 22 (92%) did not have further episodes of acute pancreatitis.

In the only randomized controlled trial available, 19 patients with recurrent pancreatitis and pancreas divisum underwent either no treatment or endoscopic minor papillary sphincterotomy.⁶⁰ In the treatment group, 9 of 10 patients had no further episodes of acute pancreatitis during the 3 years of follow-up, while 6 of 9 patients who were randomized to no treatment had at least one episode.⁶⁰

Although surgical and endoscopic minor papillary sphincterotomy are equally effective, endoscopic therapy is preferred since it is less invasive, is associated with less morbidity, and costs less. It is also more convenient for patients, since it is an outpatient procedure. Surgical treatment is usually reserved for those in whom endoscopic treatment has failed or is not technically possible.

OTHER PROCESSES OBSTRUCTING THE FLOW OF PANCREATIC JUICE

Any process preventing free flow of pancreatic juice can lead to acute pancreatitis. The cause of the blockage can be around the ampulla, in the ampulla, or in the duct.⁶¹

Periampullary lesions, tumors, or polyps can press on the ampulla and cause complete or relative obstruction of the pancreatic duct with a subsequent increase in intraductal pressure and, thus, acute pancreatitis.⁶² Tumors or polyps of the ampulla, such as ampullary adenoma or carcinoma, can cause pancreatitis by directly obstructing the pancreatic duct where it opens into the duodenum.^63–66 Intraductal processes such as ductal adenocarcinoma, intraductal papillary mucinous tumor, pancreatic duct stone, and intraductal stricture due to cancer, chronic pancreatitis, or trauma can also cause pancreatitis by preventing free flow of pancreatic juice.^67–71

Although it is well known that sequelae of severe chronic pancreatitis such as ductal strictures or intraductal stones can lead to recurrent attacks of acute pancreatitis by preventing the free flow of pancreatic juice, a relationship also seems to exist between early chronic pancreatitis and recurrent acute pancreatitis.⁷² Several studies have shown that up to 50% of patients with idiopathic recurrent pancreatitis have evidence of chronic pancreatitis.^72–74 However, it is still unclear whether early chronic pancreatitis is the underlying cause of the recurrent attacks of acute pancreatitis or whether recurrent attacks of acute pancreatitis might have led to the development of chronic pancreatitis.

Diagnosis

Ampullary and periampullary neoplasms can be diagnosed endoscopically. Intraductal lesions such as strictures can be diagnosed by MRCP, especially secretin-enhanced MRCP, or by ERCP. ERCP has the additional advantage of being able to deliver treatment, ie, balloon dilation and stenting. In the case of ductal strictures, upsizing of the stents or placement of multiple stents during subsequent procedures is usually needed. Pancreatic ductal calcifications associated with chronic pancreatitis are usually radiopaque and are easily visible on plain films or computed tomography of the abdomen. Parenchymal and ductal changes of chronic pancreatitis can be diagnosed by endoscopic ultrasonography.

Treatment

The treatment is to relieve the obstruction and re-establish the free flow of pancreatic juice.

Periampullary tumors or polyps can be resected surgically or, if they involve only the mucosa, by endoscopic mucosal resection. Ampullary adenomas can be resected endoscopically. Ampullary carcinomas usually require surgical resection.

Small, nonobstructive stones in the pancreatic duct can be removed during ERCP.⁷⁵ Larger stones may need to be fragmented by extracorporeal shock wave lithotripsy to facilitate removal by ERCP.⁷⁵

Intraductal strictures should raise the suspicion of pancreatic adenocarcinoma, especially in older patients.⁶¹ In these cases, relief of the obstruction by placement of a pancreatic stent can prevent further attacks of pancreatitis until a diagnosis can be established and a more definitive treatment can be offered.

Endoscopic therapy has become an alternative to surgery for some patients with acute recurrent pancreatitis, ie, those whose disease is caused by gallstones or other mechanical processes that can obstruct the outflow from the pancreas.

In this paper, we review the specific situations in which endoscopic therapy might be useful in patients with acute recurrent pancreatitis.

ACUTE PANCREATITIS IS MANAGED DIFFERENTLY IF IT RECURS