Parasitic. Abstract. Entamoeba histolytica. Introduction

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1 PNEUMONIA / Parasitic 447 Parasitic T B Nutman and K R Talaat, National Institutes of Health, Bethesda, MD, USA & 2006 Elsevier Ltd. All rights reserved. Abstract Parasites are eukaryotic organisms that live within another organism or host. They are broadly divided into two groups: single-celled protozoa and multicellular helminths. Most parasites have complex life cycles with multiple stages, often requiring multiple host species to complete their life cycle. Humans acquire infection with parasitic organisms in a number of different ways. Some are ingested through a fecal-oral spread, others transmitted by insect vectors, still others by penetrating through the skin of the host from contaminated soil or water. This article focuses on the major parasitic infections that affect the lungs. Few parasites specifically go to the lungs as their final target organ, with the exception of Paragonimus, the lung fluke. For the majority of the organisms that cause pulmonary disease, either the lungs are secondary sites of infection (e.g., amebiasis and toxoplasmosis), or the parasites migrate through the lung en route to another organ system (e.g., Strongyloides, Ascaris). In some infections, pulmonary symptoms are due to a hypersensitivity immune response to parasite antigen as seen in the tropical pulmonary eosinophilia syndrome. Introduction Parasites are eukaryotic organisms that live within another organism or host. They are broadly divided into two groups: single-celled protozoa and multicellular helminths. Whereas protozoa are often intracellular, helminths are characteristically extracellular. Most parasites have complex life cycles with multiple stages, often requiring multiple host species to complete their life cycle. These host species could be another mammal (e.g., dogs and sheep for Echinococcus), an invertebrate host (crustaceans for Paragonimus sp.), or an insect vector such as Anopheline mosquitoes for the malaria parasites. For most of the infections being described in this article, humans are the definitive hosts (in which the adult or sexual stage (if there is one) is found). For other infections, humans are the intermediate hosts or the incidental dead-end hosts of a parasite that usually infects other species (e.g., Toxocara). Infection with parasitic organisms is acquired in a number of different ways. Some are ingested and are spread person to person or through fecal/oral or fecal/soil/oral transmission (i.e., Ascaris). Others require an insect vector for transmission. Still others have intermediate species in which they complete part of their life cycles. Some organisms can enter from a contaminated environment by penetrating the skin (e.g., Strongyloides, hookworm). Some of these organisms have worldwide distribution (e.g., Ascaris, Toxoplasma), but most have geographic foci of endemicity. Often, these foci are in regions of the world with limited resources and where free and easy access to clean water and sanitation is not available. In industrialized countries, these infections are most commonly encountered in immigrants or returning travelers. Once thought exotic, parasitic diseases account for an increasing presence in industrialized countries because of returning travelers, immigration, and mass movements of people as a result of political or socioeconomic upheavals. An awareness of the clinical manifestations and management of these diseases is therefore crucial for both primary care physicians and specialists. By no means comprehensive, this article will briefly examine those parasites most likely to cause pulmonary disease. Entamoeba histolytica Entamoeba histolytica, the causative organism of amebiasis, is a ubiquitous protozoan. It is more common in developing countries, especially in areas of low socioeconomic resources where access to adequate sanitation is not available. Cysts are ingested in fecally contaminated food and water. Excystation occurs in the small intestine, where the larvae divide into trophozoites that migrate from the intestine to the liver through the portal circulation. The clinical spectrum of E. histolytica infection is very broad. Only about 10% of people infected with E. histolytica develop disease; others can spontaneously clear their asymptomatic infection within 1 year of infection. The most common site for extraintestinal infection with E. histolytica is the liver. Liver disease occurs in 3 9% of cases of amebiasis. Lung disease occurs in 2 7% of those with invasive amebiasis. Most commonly, lung disease develops from extension of a liver abscess. It occurs by direct extension, insidiously from the liver through the diaphragm; by rupture, involving the pleura (leading to pleurisy, effusion, or empyema); or with development of pulmonary consolidation, lung abscess, or bronchohepatic fistula. Up to 40% of patients with liver abscess develop pulmonary complications. The most common is reactive pleuritis secondary to the hepatic abscess. Clinically, patients can complain of right upper quadrant pain with pleuritic chest pain. They frequently have normal liver enzymes. A pleural rub is common in patients with amoebic liver abscess. The fluid in the pleural space is exudative and sterile. If the abscess extends into the pleural cavity, an amoebic empyema can form. The onset of this can be insidious or acute.

2 448 PNEUMONIA / Parasitic Patients have fever, right upper quadrant and chest pain, and a dry cough. Rupture into the pleural cavity is often signaled by abrupt exacerbation of pain with rapidly progressive respiratory distress, possibly sepsis and shock. If invasion into a major bronchus occurs, hemoptysis can develop containing the anchovy paste-like pus coming from the amoebic abscess. Physical examination findings of amoebic lung disease often include hepatic enlargement and tenderness, dullness to percussion at the right base with decreased or absent breath sounds, and a pleural rub with occasional crepitation. If the lung disease is chronic, cachexia and clubbing can sometimes be found. Chest X-ray abnormalities occurred in 57% of patients with amoebic liver disease. Untreated, the mortality of invasive amebiasis is over 80%. The diagnosis of invasive amebiasis is made by identifying the organism, by serology or by polymerase chain reaction (PCR). Treatment is with metronidazole and paromomycin or dioxanide furoate. Toxoplasma gondii Toxoplasma gondii is an obligate intracellular parasite in which humans are the incidental host. It is most frequently acquired by ingestion of cysts excreted in cat feces. Once inside the host, the organism can invade any cell of the body, most commonly the brain, lymph node, heart, and lung. The vast majority of immunocompetent persons who are infected is clinically asymptomatic. Immunosuppressed individuals can have more fulminant toxoplasmosis, either during primary infection or with reactivation of latent infection. In the lung, T. gondii infection can cause a necrotizing pneumonia with nodule formation, diffuse alveolar damage, and interstitial pneumonitis. Edema develops in the alveolar capillary interface with lymphocytic infiltration. AIDS patients with Toxoplasma pneumonia present with cough, dyspnea, and fever. Toxoplasmosis is diagnosed by serology or by identifying tachyzoites in bronchioalveolar lavage (BAL) smears. Pyrimethamine with folinic acid and sulfadiazine is the treatment of choice for Toxoplasma pneumonia. Paragonimus Few helminths specifically go to the lungs as their final target organ, the notable exception being Paragonimus, or the lung fluke. Found throughout the world, but primarily in Asia, paragonimiasis is acquired by ingestion of raw, undercooked or pickled crabs or other crustaceans. Once ingested the larvae penetrate through the intestines and migrate through the diaphragm and pleura into the lungs. There, worm pairs encyst together near bronchial passages and mature into adult worms that lay eggs. Paragonimiasis is rarely a serious or fatal infection. The symptoms depend on the location of the worms and their developmental stage. Shortly after infection, patients may complain of diarrhea or abdominal pain or discomfort, although most people are asymptomatic initially. The initial penetration of the larvae through the diaphragm and pleura can cause pleuritic chest pain and pneumothoraces. Symptoms of paragonimiasis include cough, hemoptysis, and chest pain. The hemoptysis is usually of rusty or chocolate sputum; large amounts of frank bright red blood are unusual. Pleural effusions can form and, if large, can result in dyspnea. Chronic infection is often mistaken for tuberculosis, especially in areas where paragonimiasis is less prevalent; however, in some instances, tuberculosis and paragonimiasis can coexist. The physical exam is usually normal, although rales may be heard. Rarely, clubbing of the fingers is seen. Radiographically, nodules, pneumothoraces and interstitial infiltrates, effusions, cavities, or ring cysts resembling bronchiectasis can be seen. Parenchymal consolidation is seen in the majority of patients. The infiltrates can be transient, especially in acute infection as the worms migrate. CT can show the migration tracks of the worms as linear opacities and later as cysts within the parenchymal consolidations (see Figure 1). The chest X-ray can be normal in 10 20% of cases. Once suspicion of paragonimiasis has been aroused by a history of handling or eating freshwater crabs or crayfish, isolating Paragonimus eggs in the sputum or stool make the diagnosis. Treatment is with praziquantel. Intestinal Roundworms: Ascaris, hookworm, Strongyloides Roundworms or nematodes can be classified broadly into those inhabiting the intestine, which are by far the most common, and those infecting deep tissue. It is estimated that there are more than 1 billion cases of ascariasis worldwide. With the exception of Strongyloides stercoralis, intestinal nematodes do not multiply within humans, and finding either eggs or parasites, usually in the stool, makes the diagnosis. Strongyloides, through its autoinfection cycle, can multiply and disseminate widely in an immunocompromised individual (hyperinfection syndrome). Pulmonary disease in intestinal helminth infections is relatively uncommon but can occur during the stage of larval migration through the lungs en route to the intestine. When apparent in immunocompetent hosts, pulmonary disease usually occurs as

3 PNEUMONIA / Parasitic 449 Figure 1 Computed tomography image of Paragonimus westermani infection in a 46 year Korean man showing a cystic lesion within an infiltrate. The patient also developed a pulmonary effusion. Courtesy of Myoung-don Oh, Seoul National University College of Medicine, South Korea. a Loeffler s syndrome with cough, asthma, fever, patchy pulmonary infiltrates on chest radiographs, and eosinophilia. Ascaris, hookworm, and Strongyloides are the most common causes of this syndrome among the intestinal helminths. Ascariasis is the most common cause worldwide of transient eosinophilic pulmonary infiltrates. In some areas, the pneumonitis occurs at specific times of the year depending on the climate. Infection is acquired by ingestion of eggs on contaminated foods or from soil. Symptoms develop 9 12 days after ingestion of the eggs and can last from 2 to 3 weeks. Larval migration through the lungs leads to pneumonitis, which can manifest as a nonproductive cough, asthma, burning substernal pain that is pleuritic in nature, dyspnea, and occasionally mild hemoptysis, rales, or wheezes. These may be associated with an urticarial rash or low-grade fever. Rarely, an adult worm can ectopically migrate into the lungs or other viscera and get lost. Human hookworm disease is caused primarily by either Ancylostoma duodenale or Necator americanus. Larvae enter the skin and then migrate to the lungs. From there, they crawl up the bronchial tree to the epiglottis, where they are swallowed. Once in the small intestine, the adult worm develops and starts shedding eggs. The migration of the larvae through the lungs may cause a Loeffler s syndrome similar to that in ascariasis. Patients may have a mild cough, or the symptoms may be more severe, with associated dyspnea and wheezing. Symptoms generally last B2 weeks; in heavy infections, they can last up to 3 months. Chest X-ray can show transient, migratory opacities, especially in the hilar areas, with spontaneous clearing. Strongyloides infection is also acquired when larvae penetrate through skin on contact with fecally contaminated soil or water. In strongyloidiasis, the pulmonary symptoms are predominantly cough, dyspnea, and bronchospasm during the migratory phase, although persistent asthma due to Strongyloides infection has been reported. Patients with chronic lung disease may retain the larvae in the lungs, where they molt into adults and complete their entire life cycle, leading to worsening lung disease with chronic cough and bronchospasm. In disseminated disease, intense worm burdens or inflammatory response can cause acute respiratory distress syndrome (ARDS), alveolar hemorrhage, or bacterial superinfection of the lungs. During the initial, pulmonary phase of infection, intestinal roundworm infections are difficult to diagnose. Once the mature worms have started shedding eggs in the intestines, these eggs (for Ascaris and hookworm), or larvae (for Strongyloides), can be identified in the stool. Anthelmintic treatment of intestinal infections probably has no effect on larval stages in the lungs; however, pulmonary disease is usually self-limited and does not require specific treatment, except for symptomatic relief. To treat intestinal disease, albendazole or mebendazole can be used for ascariasis and hookworm, and ivermectin is the treatment of choice for strongyloidiasis. Lymphatic Filariasis Filariae are a family of tissue-dwelling roundworms that infect adults in the tropics and subtropics. The major pulmonary manifestation of these organisms is tropical pulmonary eosinophilia (TPE) seen in

4 450 PNEUMONIA / Parasitic infection with the lymphatic filariae, Wuchereria bancrofti and Brugia malayi. TPE is felt to be secondary to increased immune responsiveness to the parasites, and is really a systemic syndrome, with the pulmonary component being the most significant. Initially, patients complain of vague systemic symptoms, including low-grade fevers and myalgias. Then pulmonary symptoms start, and these include cough (which can be paroxysmal) and wheezing, both being worse at night, dyspnea, and occasionally chest pain. This can often be mistaken for asthma, and patients may be incorrectly treated for more common disorders. Pulmonary function is abnormal in these patients. As the disease progresses, the symptoms can spontaneously remit and recur and gradually worsen, with a decrease in the wheezing but an increase in dyspnea. This eventually leads to chronic lung disease with dyspnea and hypoxia at rest, which in later stages is indistinguishable from any cause of interstitial pulmonary fibrosis. Rarely, TPE can present as cor pulmonale. The diagnosis of TPE requires that a patient meets both clinical and laboratory criteria with marked elevations of peripheral eosinophil and IgE levels. Most patients respond dramatically to treatment with diethylcarbamazine. Toxocara Visceral larva migrans (VLM) or toxocariasis is a zoonotic infection usually caused by dog or cat ascarids of the Toxocara genus. The eggs are ingested and then hatch into larvae, which penetrate the intestine and start migrating. Because humans are not the definitive host, the larvae cannot mature, and so continue migrating for months or years. Most people who are infected with Toxocara spp. are asymptomatic. Symptoms depend on the extent and frequency of infection, the distribution of larvae in tissues, and the inflammatory response of the host. There are two clinical syndromes of infection: VLM and ocular larval migrans (OLM). The symptoms of VLM are related to the organ invaded, most commonly the liver, lung, or other thoracic or abdominal organ. VLM usually affects children o5 years old, although it can affect adults. In children with VLM 33 86% had pulmonary symptoms: most commonly, chronic cough, which may be paroxysmal and worse at night, wheezing, and pulmonary infiltrates. On exam, 65% had hepatomegaly, 43% had an abnormal lung exam (wheezes or rales). VLM is diagnosed by serology and treated with albendazole. Echinococcus Humans can develop lung disease after being incidentally infected with Echinococcus sp., which are usually parasites of canines, sheep, and other domestic ungulates. Infection with Echinococcus is always asymptomatic for months to decades. Cysts are commonly found when symptoms develop or on routine or screening imaging. Symptoms develop because of one or more of three processes: (1) mechanical pressure or deformation of tissues, or nearby vascular structures; (2) rupture or leakage of the cyst; or (3) superinfection. The liver is the organ most commonly affected in 60% of cases, and the lungs are affected in 20 30% of cases. Pulmonary symptoms have been reported in 67 89% of patients with lung cysts. Most commonly, symptoms are cough, fever, and chest pain. Occasionally, hemoptysis can occur, and rarely, biliptysis, pneumothorax, or pleuritis. With rupture of the cyst into a bronchus, hydatid vomica of cystic contents can occur: clear, salty/peppery fluid with or without hemoptysis. The fluid can be purulent if superinfected. With dissemination of the antigenic fluid, respiratory failure or anaphylaxis can occur. One-third of diagnosed cases of pulmonary hydatid cyst show ruptured or infected cysts. Diagnosis is made by clinical history and radiologic findings. Early surgical intervention promptly after diagnosis can help prevent complications. Perioperatively, or for unresectable lesions, medical therapy with anthelmintics (albendazole) should also be used. See also: Allergy: Allergic Reactions. Asthma: Overview. Human Immunodeficiency Virus. Leukocytes: Eosinophils. Pneumonia: Overview and Epidemiology; The Immunocompromised Host. Systemic Disease: Eosinophilic Lung Diseases. Further Reading Chu E, Whitlock WL, and Dietrich RA (1990) Pulmonary hyperinfection syndrome with Strongyloides stercoralis. Chest 97: DeFrain M and Hooker R (2002) North American paragonimiasis: case report of a severe clinical infection. Chest 121(4): Dogan R, Yuksel M, Cetin G, et al. (1989) Surgical treatment of hydatid cysts of the lung: report on 1055 patients. Thorax 44(3): Gottstein B and Reichen J (2002) Hydatid lung disease (echinococcosis/hydatidosis). Clinics in Chest Medicine 23(2): ix. Huntley CC, Costas MC, and Lyerly A (1965) Visceral larva migrans syndrome: clinical characteristics and immunologic studies in 51 patients. Pediatrics 36: Ibarra-Perez C (1981) Thoracic complications of amebic abscess of the liver. Report of 501 cases. Chest 79: Mandell GL, Bennett JE, and Dolin R (eds.) (2000) Principles and Practice of Infectious Diseases, 5th edn. Philadelphia: Churchill Livingstone. Meehan AM, Virk A, Swanson K, and Poeschla EM (2002) Severe pleuropulmonary paragonimiasis 8 years after emigration from

5 PNEUMONIA / Mycobacterial 451 a region of endemicity. Clinical Infectious Diseases 35(1): O Lorcain P and Holland CV (2000) The public health importance of Ascaris lumbricoides. Parasitology 121(supplement): S51 S71. Ottesen EA and Nutman TB (1992) Tropical pulmonary eosinophilia. Annual Review of Medicine 43: Sarinas PSA and Chitkara RK (1997) Ascariasis and hookworm. Seminars in Respiratory Infections 12(2): Shamsuzzaman SM and Hashiguchi Y (2002) Thoracic amebiasis. Clinics in Chest Medicine 23(2): Stanley SL Jr (2003) Amoebiasis. Lancet 361(9362): Talaat KR and Nutman TB (2005) Parasitic infections. In: Murray JF, Nadel JA, Mason RJ, and Broaddus VC (eds.) Textbook of Respiratory Medicine, 4th edn. Philadelphia: Elsevier. Tor M, Atasalihi A, Altunas N, et al. (2000) Review of cases with cystic hydatid lung disease in a tertiary referral hospital located in an endemic region: a 10 years experience. Respiration 67(5): Mycobacterial N W Schluger, Columbia University College of Physicians and Surgeons, New York, NY, USA J Burzynski, New York City Department of Health, New York, NY, USA & 2006 Elsevier Ltd. All rights reserved. Abstract Tuberculosis has probably been the cause of more deaths than any other infectious disease. Although the disease is almost always treatable with a handful of antibiotics taken once a day, it continues to cause tremendous suffering and is a leading cause of death. Despite the recent attention and efforts at control in the short term, rates are likely to increase. In many parts of the world, current tuberculosis control programs are ineffective and the number of tuberculosis cases is rising. A program of directly observed therapy short (DOTS) course has been widely accepted as a standard of care but less than half of all persons with tuberculosis receive treatment with directly observed therapy. In many countries with high disease burden, coinfection with human immunodeficiency virus (HIV) has contributed to increasing rates of tuberculosis. Tuberculosis is the leading cause of death from an opportunistic infection in persons with acquired immunodeficiency syndrome (AIDS) worldwide. Epidemiology One-third of the world s population is infected with tuberculosis and infection leads to over eight million cases of active disease and two million deaths per year. Case rates of active disease vary greatly by geographic region and by country and are influenced by many factors including varying case definitions and completeness of reporting. The highest incidence rates are in sub-saharan Africa; China and India have the highest number of total cases. Case rates in the US and Western Europe trended downwards for most of the twentieth century and are currently at the lowest rate in recorded history. A thorough understanding of the epidemiology of tuberculosis is essential in establishing effective public health control measures. Clinicians understanding of the epidemiology and the ability to suspect and establish the diagnosis is heavily influenced by an understanding of a patient s epidemiologic risk factors. Case rates are highest in young adults as a result of increased social interaction and an initial opportunity for exposure to someone else with an infectious form of the disease. At the extremes of age, young children and the elderly are also especially prone to developing active disease. Children who are infected after an exposure to an active case have a much higher rate of progression to active disease. While overall, 5 10% of infected contacts progress to active disease after an exposure to an active case, 43% of infants under 1 year of age and 24% of children 1 5 years old develop active disease after recent infection. The elderly have a higher case rate as a result of reactivation disease. With the advances of age, a weakened immune system can no longer control dormant bacteria from a previous infection and active disease develops. In low incidence countries like the US and most of the countries of Western Europe, tuberculosis cases are more common in men than in women but now in some countries with high rates of HIV infection, tuberculosis case rates are higher in women than in men. Certain host characteristics are associated with disease progression. Clinicians have long noticed more cases of pulmonary disease associated with tall, lean persons. Poor nutrition and being underweight are also risk factors. Certain medical conditions in the host are associated with an increased risk of tuberculosis disease, including HIV infection, diabetes mellitus (particularly when poorly controlled), end-stage renal disease, and silicosis. These conditions that have an effect on the response of the immune system all have well-documented associations with active tuberculosis disease. The use of certain medications that affect host defenses including corticosteroids, blockers of tumor necrosis factor (TNF), and immunosuppressive medications used for patients with organ transplantation also pose significant risks for developing active tuberculosis. Nothing has had more impact on tuberculosis epidemiology than HIV. HIV coinfection is the greatest risk factor for reactivation of latent infection into clinical tuberculosis disease. HIV-positive persons