CHEST

Special Features

Parasites of the Air Passages Danai Khemasuwan, MD, MBA; Carol F. Farver, MD; and Atul C. Mehta, MD, FCCP

Parasitic infestations affect millions of the world’s population. Global immigration and climate change have led to changes in the natural distribution of parasitic diseases far removed from endemic areas. A broad spectrum of helminthic and protozoal parasitic diseases frequently affects the respiratory system. The wide varieties of clinical and radiographic presentations of parasitic diseases make the diagnosis of this entity challenging. Pulmonologists need to become familiar with the epidemiology, clinical presentation, pathophysiologic characteristics, and bronchoscopic findings to provide proper management in a timely fashion. This review provides a comprehensive view of both helminthic and protozoal parasitic diseases that affect the respiratory system, especially the airways. CHEST 2014; 145(4):883–895 Abbreviations: BALF 5 BAL fluid; DEC 5 diethylcarbamazine; ELISA 5 enzyme-linked immunosorbent assay; PAH 5 pulmonary artery hypertension; TPE 5 tropical pulmonary eosinophilia

and protozoal infestations cause signifHelminthic icant morbidity and mortality worldwide. A decline

in parasitic infestations has been observed in the past decade as a result of improved socioeconomic conditions and better hygiene practices. However, the rapid urbanization of cities around the world, global warming, international traveling, and increasing numbers of immunocompromised individuals have increased the vulnerability of the world population to parasitic diseases.1 The diagnosis of parasitic diseases of the respiratory system is challenging because the clinical manifestations and radiologic findings are nonspecific. Thus, a high index of suspicion and detailed interrogation regarding travel history are critical. Most parasitic infestations of the respiratory system either involve the airways or require bronchoscopy for diagnosis. Helminthes can affect the airways during both the larval and the mature adult phases of their life cycle. The larvae can cause airway inflammation (paragonimiasis),

Manuscript received September 1, 2013; revision accepted December 16, 2013. Affiliations: From Pulmonary, Allergy and Critical Care Medicine (Drs Khemasuwan and Mehta), Respiratory Institute, and the Department of Anatomical Pathology (Dr Farver), Cleveland Clinic Foundation, Cleveland OH. Correspondence to: Atul C. Mehta, MD, FCCP, Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, A-90, Cleveland, OH 44195; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2072 journal.publications.chestnet.org

whereas migration of the mature adult worms may cause mechanical obstruction of the airways (ascariasis). This article provides a comprehensive review of both helminthic and protozoal infestations, including clinical, radiographic, bronchoscopic, and pathologic manifestations, that may be helpful to pulmonologists in managing this important entity (Table 1).

Nematodes Nematodes, also known as roundworms, have a symmetrical, tube-like body with an anterior mouth and a longitudinal digestive tract. Ascariasis Ascaris lumbricoides is one of the most common parasitic infestations, affecting . 1 billion of the world’s population and causing . 1,000 deaths annually.1 A lumbricoides is transmitted via the feco-oral route. An Ascaris larva migrates to the lungs through either the lymphatics or the venules of the portal system. Larval ascariasis causes Löffler’s syndrome, a concomitance of wheezing, pulmonary infiltrations, and eosinophilia.2 It can cause alveolar inflammation, necrosis, and hemorrhage. Diagnosis of an ascariasis infestation during its larval phase is difficult. The sputum may show numerous eosinophils; stool examination, however, remains negative for eggs during the larval stage.3 The diagnosis requires a high degree of suspicion. Occasionally, CHEST / 145 / 4 / APRIL 2014

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the diagnosis can be confirmed by identifying larvae in the sputum. Solitary pulmonary nodules can also develop if the larva dies causing granulomatous inflammation.4 Adult ascaris has been reported to cause airways obstruction in a child, producing a complete lobar collapse.5 Mebendazole and albendazole are the most effective agents against ascariasis. Ancylostomiasis (Hookworm Disease) The most common hookworms are Ancylostoma duodenale and Necator americanus. The latter is found in parts of the southern United States. Hookworm larvae enter human hosts via the skin, producing itching and local infection. The larvae are also infective via the oral route.6 Hookworm infestations involve larval migration through the lungs via the bloodstream, resulting in a hypersensitivity reaction. Patients usually present with transient eosinophilic pneumonia (Löffler’s syndrome).6 If the patient ingests a large number of larvae, he/she may develop a condition known as “Wakana disease,” characterized by nausea, vomiting, dyspnea, and eosinophilia. This clinical picture represents a severe hypersensitivity-like reaction to A duodenale.6 Larval migration may also cause alveolar hemorrhage.7 Similar to ascariasis, the diagnosis of a hookworm infestation during the larvae phase could be difficult to make. CT scanning of the chest may reveal transient, migratory, patchy alveolar infiltrates.8 Sputum examination may reveal occult blood, eosinophils and, rarely, migrating larvae (Fig 1A).9 Bronchoscopic examination may reveal airway erythema and high eosinophil counts in BAL fluid (BALF).10 Patients can become profoundly anemic and malnourished. These manifestations may provide clinical clues to support the diagnosis. The antiparasitic agents for hookworm are mebendazole and albendazole. Strongyloidiasis Strongyloides stercoralis is a common roundworm that is endemic throughout the tropics but is found worldwide in all climates. Infective filariform larvae can penetrate the skin and infect human hosts. The larvae migrate through the soft tissues and enter the lungs via the bloodstream. A majority of roundworms migrate up the bronchial tree to the pharynx and are swallowed, entering the GI tract.11 The larvae can reenter the circulatory system, returning to the lungs and causing autoinfection.11 The life cycle of Strongyloides can be completed entirely within one host. The term “hyperinfection syndrome” describes the presentation of sepsis from enteric flora, mostly in immunocompromised patients.12 The hallmarks of hyperinfection are an exacerbation of GI and pulmonary symptoms and the detection of more larvae in the stool and sputum.13 Common pulmonary symptoms include wheezing, hoarseness, 884

dyspnea, and hemoptysis. A chest radiograph usually demonstrates focal or bilateral interstitial infiltrates. Pleural effusions are present in 40% of patients, and lung abscess is found in 15%.14 Diffuse alveolar hemorrhage is usually found in patients with disseminated strongyloidiasis. ARDS may result as a reaction to the death of the organisms. Migration of a massive number of larvae through the intestinal wall can result in sepsis, because larvae may convey gram-negative bacteria into the bloodstream.13 The diagnosis can be confirmed by the presence of larvae in the stool, duodenal aspirate, sputum, pleural fluid, or BALF or lung biopsy specimens (Figs 1B, 1C).15 The sensitivity of a stool examination for ova and larvae is 92% when performed on three consecutive samples.16 An enzyme-linked immunosorbent assay (ELISA) measures IgG responses to the Strongyloides antigen. However, false-negative results can occur during acute infection because it takes 4 to 6 weeks to mount the immune response.17 The ELISA is sensitive but nonspecific because of cross-reactivity with filarial infestations.15 Oral ivermectin remains the treatment of choice for uncomplicated Strongyloides infestation.13,18 Syngamosis Nematoda of the genus Mammomonogamus affect the respiratory tract of domestic mammals. Occasionally, however, humans can become infested via the respiratory tract. Most cases of human syngamosis are reported from tropical areas, including South America, the Caribbean, and Southeast Asia.19 Two hypotheses have been proposed regarding its life cycle. One is that humans become infested via the ingestion of food or water contaminated with larvae or embryonated eggs. The larvae complete the life cycle in the pulmonary system, and the adult worms migrate to the central airways as the preferred site of infection.20 An alternative hypothesis is that patients are infected by the adult worms present in contaminated food or water. This mode of transmission is supported by its short incubation period (6-11 days).21 The diagnosis requires flexible bronchoscopy unless the worms are expelled through vigorous coughing (Fig 1D). The removal of parasites through bronchoscopy is sufficient to improve symptoms. To date, no studies have supported the effectiveness of antihelminthic therapy.21,22 Dirofilariasis Dirofilaria immitis is the filarial nematode that primarily infects dogs. Humans are considered accidental hosts because D immitis is unable to mature to an adult form. D immitis is transmitted to humans by mosquitoes harboring infective third-stage larvae. The larva travels to the right ventricle and develops into an immature adult worm. It is then swept into the pulmonary Special Features

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Table 1—Parasitic Infection of Respiratory System Parasite Nematodes Ascariasis (Ascaris lumbricoides)

Infective Form

Endemic Area

Mode of Transmission

CHEST / 145 / 4 / APRIL 2014

Eggs and larva

Asia, Africa, and South America

Ingestion

Hookworm (Ancyclostoma duodenale) (Necator americanus)

Larva

Tropical and subtropical areas

Skin penetration

Strongyloidiasis (Strongyloides stercoralis)

Filariform larvae

Tropical and subtropical areas

Skin penetration

Syngamosis (Mammomonogamus laryngeus)

Eggs or adult worms

Asia, Africa, and South America

Ingestion

Dirofilariasis (Dirofilaria immitis)

Larva

Tropical and subtropical areas

Mosquito-borne infection

Tropical pulmonary eosinophilia (Brugia malayi) (Wuchereria bancrofti)

Larva

Tropical and subtropical areas (South and Southeast Asia)

Mosquito-borne infection

Visceral larva migrans (Toxocara canis) (Toxocara catis) Trichinella infection (Trichinella spiralis)

Larva

Worldwide

Ingestion

Larva

Worldwide

Ingestion

Cercarial larvae

East Asia, South America, Sub-Saharan Africa

Skin penetration

Trematodes Schistosomiasis (Schistosoma species)

Pulmonary Presentation Eosinophilic pneumonia, cough, wheezing, dyspnea Eosinophilic pneumonia, cough, wheezing, dyspnea, alveolar hemorrhage

Bronchoscopic Evaluation

Treatment

Presence of parasite in the airways

Mebendazole and albendazole

Presence of hookworm in sputum, a marked eosinophil predominance from BAL Bloody BAL and presence of parasite from BAL under microscopic examination Presence of parasite in the airways

Mebendazole and albendazole

Surgical lung biopsy

None (self-limited)

BAL shows eosinophils more than 50% of the total cells

Diethylcarbamazine

N/A

Diethylcarbamazine

Cough, pulmonary infiltrates, dyspnea due to respiratory muscles involvement

N/A

Mebendazole

Pulmonary hypertension and Katayama fever

An eosinophil predominance from BAL in the absences of parasites

Praziquantel

Eosinophilic pneumonia, cough, wheezing, dyspnea, hyperinfection syndrome Foreign body-like lesion in bronchus, nocturnal cough Cough, chest pain, fever, dyspnea, mild eosinophilia, and lung nodules Eosinophilic pneumonia, cough, wheezing, dyspnea, restrictive pattern on spirometry, decreased diffusion lung capacity Eosinophilic pneumonia, episodic wheezing

Ivermectin and albendazole

Removal through bronchoscopy

(Continued)

885

Therapeutic bronchoscopy and dapsone Bronchoscopy revealed pinkish mulberry-like rhinosporidiosis mass in the airway

Tropical Pulmonary Eosinophilia Tropical pulmonary eosinophilia (TPE) is a syndrome of immunologic reaction to microfilaria of the lymphaticdwelling organisms Brugia malayi and Wuchereria bancrofti. It is a mosquito-borne infestation. The larvae reside in the lymphatics and develop into mature adult worms. The microfilariae are released into the circulation and may be trapped in the pulmonary circulation.28 Trapped microfilariae demonstrate a strong immunogenicity and trigger antimicrofilarial antibodies, resulting in asthma-like symptoms. The hallmark of TPE is a high absolute eosinophil count (5,00080,000/mm3).29 The radiologic features include reticulonodular opacities, predominantly in the middle and the lower lung zones; miliary mottling; and predominant hila with increased vascular markings at the bases.30 Chest CT scanning may demonstrate bronchiectasis, air trapping, calcification, and mediastinal lymphadenopathy.31 Pulmonary functions indicate a restrictive defect with mild airways obstruction.29 BALF may contain numerous eosinophils. Occasionally, microfilaria can be identified on brushings or needle biopsy specimens.32 The chronic phase of TPE may lead to progressive and irreversible pulmonary fibrosis.28 The standard treatment of TPE is diethylcarbamazine (DEC). Patients usually show improvement within 3 weeks. However, a mild form of interstitial lung disease with diffusion impairment may remain.33 Toxocariasis N/A 5 not available.

Spores Mesomycetozoea Rhinosporidiosis (Rhinosporidium seeberi)

South Asia

Ingestion of contaminated water

Strawberry-like, nasopharyngeal polyps, epitasis, nasal congestion

Surgical removal of cysts, followed by mebendazole and albendazole Bronchoscopic examination reveals sac-like cyst in the airway Chest pain, cough, hemoptysis, pleural lesion, expectoration of cyst contents, and hypersensitivity reaction Ingestion Worldwide (especially Middle East) Eggs Cestodes Hydatid disease (Echinococcus granulosus)

Treatment

Praziquantel and triclabendazole Bronchial stenosis due to mucosal edema and mucosal nodularity Fever, cough, hemoptysis, chest pain, and pleural effusion Ingestion of infested crustaceans Southeast Asia, South America, Africa Metacercaria (infective larvae) Paragonimiasis (Paragonimus species)

Bronchoscopic Evaluation Pulmonary Presentation Mode of Transmission Parasite

Infective Form

Endemic Area

Table 1—Continued 886

arteries. The worm dies as a result of the inflammatory response and evokes granuloma formation.23 A majority of patients with pulmonary dirofilariasis are asymptomatic. However, some patients (about 5%) may develop cough, hemoptysis, chest pain, fever, dyspnea, and mild eosinophilia.24 A peripheral or a pleural-based solitary pulmonary nodule is a typical presentation. The nodule may show increased fluorodeoxyglucose avidity on a PET scan25,26 and is often confused with malignancy. Calcification occurs within only 10% of these nodules. CT scanning may show a branch of the pulmonary artery entering the nodule.27 Serology has poor specificity because of cross-reactivity with other helminths. The diagnosis is established by identifying the worm in the excised lung tissue (Fig 1E). Needle biopsy and brushings are usually nondiagnostic because of the small sample size. The condition does not require any specific treatment because it is a self-limiting condition.24

Toxocara canis and cati are roundworms that affect the dog and cat, respectively. These roundworms are common parasites that cause visceral larva migrans and eosinophilic lung disease in humans. Toxocariasis is transmitted to humans via ingestion of food that is contaminated with parasite eggs. The larvae can migrate Special Features

Figure 1. A, Hookworm larva in the sputum sample (wet smear, original magnification 3 88). Morphologically, hookworm larvae have long buccal cavities, whereas Strongyloides larvae have short buccal cavities. (Reprinted with permission from Beigel et al.9) B, Bloody aliquot from BAL sample and Strongyloides larvae from BAL (hematoxylin and eosin [H&E], original magnification 3 200). Note: short buccal cavity distinguishes Strongyloides from the hookworm (inset) (H&E, original magnification 3 400). C, Strongyloides larvae (arrow) present in alveolar space in lung with diffuse alveolar damage (H&E, original magnification 3 400). D, Bronchoscopic findings in anterior basal segment of right lower lobe. The syngamosis male is smaller and attached to the copulatory bursa of the female body (arrow). The parasite can be seen in bronchoscopy because they reside in the bronchial mucosa. (Reprinted with permission from Kim et al.19) E, Cross-sections of coiled Dirofilaria worms within involved artery causing surrounding infarction of lung tissue. Note the smooth cuticle at the external layer (Movat stain, original magnification 3 200). F, Schistosomal ova in the lung biopsy specimen. The arrow points to ova within the granulomatous reaction (H&E, original magnification 3 100).

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Figure 2. A, Bronchoscopic findings showed mucosal nodularity on the right upper lobe (RUL). (Reprinted with permission from Jeon et al.51) B, Microscopic examination of bronchial tissue obtained from the RUL bronchus showing thickening of the basement membrane and chronic inflammation with eosinophilic infiltration (H&E, original magnification 3 200). (Reprinted with permission from Jeon et al.51) Inset: Paragonimus kellicotti egg in a BAL sample. The arrow points to the operculum ridges of the egg (Papanicolaou, original magnification 3 400). (Image courtesy by Gary Procop, MD.) C, Granulomas in the pleura in a patient with paragonimiasis. The arrow points to a light brown egg within the granuloma (H&E, original magnification 3 100). (Image courtesy by Gary Procop, MD.) D, Protruded hydatid cyst from left lower lobe bronchus. (Image courtesy by Farid Rashidi, MD.) E, Echinococcus cyst fragments in lung biopsy specimen. The arrows highlight the collapsed chitinous layer of a death hydatid cyst (H&E, original magnification 3 44). F, Echinococcus cyst fragments in lung biopsy specimen. The fragmented ecchinococus cyst with collapsed chitinous layer resides within the granulomatous reaction (H&E, original magnification 3 200). See Figure 1 legend for expansion of other abbreviation.

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Special Features

throughout the host’s body, including the lungs.34 The pathology of visceral larva migrans is a hypersensitivity response to the migrating larvae. Visceral larva migrans can present with fever, cough, wheezing, seizures, and anemia. Leukocytosis and severe eosinophilia are demonstrated in a peripheral smear. A chest radiograph reveals pulmonary infiltrates with hilar and mediastinal lymphadenopathy. Bilateral pleural effusion can occur.35 Noncavitating pulmonary nodules have also been reported.36 The diagnosis of toxocariasis is established by an ELISA for the larval antigens.37 The treatment of choice is DEC; however, it may exacerbate the inflammatory reaction because of the resulting death of the larvae. It is advisable to combine DEC with corticosteroids.34 Trichinella Infection Trichinella spiralis is the most common Trichinella species that infects humans. Trichinella is a foodborne disease from undercooked pork containing larval trichinellae. In addition to the pork meat, meat from wild animals such as bear may contain T spiralis.38 The larvae migrate and reside in the GI tract until they develop into an adult form. Fertilized female worms release first-stage larvae into the bloodstream and the lymphatics.39 Pulmonary involvement, although uncommon, produces shortness of breath and pulmonary infiltrates. Dyspnea is caused by parasitic invasion of the diaphragm and the accessory respiratory muscles.39 The diagnosis is confirmed by muscle biopsy, which may demonstrate T spiralis larvae. An ELISA using anti-Trichinella IgG antibodies can confirm the diagnosis in humans.40 A 2-week course of mebendazole, along with analgesics and corticosteroids, is the recommended treatment.39 Trematodes Trematodes (flatworms) have a flat body with a sucker near the mouth that is used for attachment to the host. Most flatworms are hermaphrodites, except Schistosoma species, which have separate sexes.

tive larva). After the cercarias have penetrated the skin, they migrate to the lung and the liver. There are several case reports of a high incidence of acute schistosomiasis (Katayama fever) among travelers with a history of swimming in Lake Malawi and rafting in sub-Saharan Africa.41 In acute schistosomiasis, patients present with dyspnea, wheezing, dry cough, abdominal pain, hepatosplenomegaly, myalgia, and eosinophilia.42 Patients experience shortness of breath because of an immunologic reaction to antigens released by the worms. The level of circulating immune complexes correlates with the symptoms and with the intensity of infection. In chronic schistosomiasis, embolization of the eggs in the portal system causes periportal fibrosis and portal hypertension. Pulmonary involvement can occur as a result of the systemic migration of parasitic eggs from the portal system. The eggs trigger an inflammatory response that leads to pulmonary arterial hypertension (PAH) and subsequent development of cor pulmonale in 2% to 6% of patients.43 Apoptosis of the endothelial cells in the pulmonary vasculature plays a role in the pathogenesis of schistosomal-associated cor pulmonale.44 Chest radiographs and CT scanning may show a diffuse reticulonodular pattern or ground-glass opacities.45 In the acute phase, BALF may reveal eosinophilia in the absence of parasites. The diagnosis is confirmed by microscopic examination of stool and urine or by rectal biopsy. However, the sensitivity of these tests is low for an early infection. ELISA can be used as a screening test and is confirmed by enzyme-linked immuneelectrotransfer blot. These tests become positive within 2 weeks after the infestation. Schistosomal ova can be found in the lung biopsy specimen (Fig 1F). Acute schistosomiasis is treated with praziquantel. The treatment is repeated within several weeks because it has no antihelminthic effect on the juvenile stages of the parasites.46 Acute pneumonitis, which is believed to be related to lung embolization by adult worms in the pelvic veins, can be observed 2 weeks after the treatment.47 Patients with schistosomal-associated PAH can be treated with PAH-specific therapy along with antiparasitic medications.47

Schistosomiasis Five schistosomes species cause disease in humans: Haematobium, Mansoni, Japonicum, Intercalatum, and Mekongi.7 After malaria, schistosomiasis is the most common cause of mortality among parasitic infections, annually affecting 200 million individuals worldwide.1 Schistosoma haematobium resides in the urinary bladder, whereas Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric beds.34 Humans become infested through the skin from contact with fresh water containing Schistosomal cercaria (infecjournal.publications.chestnet.org

Paragonimiasis Paragonimus species, including westernmani, cause paragonimiasis that usually involves the lungs. The mode of transmission is ingestion of the metacercaria (infective larvae) from undercooked crustaceans. Undercooked meat of crab-eating mammals (wild boars, rats) can infect humans as an indirect route of transmission.48 The larvae penetrate the intestinal wall and migrate through the diaphragm and the pleura into the bronchioles.49 The eggs are produced by the mature adult CHEST / 145 / 4 / APRIL 2014

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worms, which are expelled in the sputum or swallowed and passed with the stool. Typically acute symptoms include fever, chest pain, and chronic cough with hemoptysis.50 Pleural effusion and pneumothorax may be the first manifestation during the migration of the juvenile worms through the pleura. A chest radiograph demonstrates patchy infiltrates, nodular opacities, pleural effusion, and fluid-filled cysts with ring shadows.34 Chest CT scans may reveal a band-like opacity abutting the visceral pleura (worm migration tracks), bronchial wall thickening, and centrilobular nodules. Bronchoscopic examination may reveal airway narrowing from mucosal edema (Fig 2A).51 A lung biopsy specimen may show chronic eosinophilic inflammation (Fig 2B). The diagnosis is confirmed by the presence of eggs or larvae in the sputum sample or BALF (Fig 2C). The pleural fluid, when present, is an acidic exudate with eosinophilia, mostly sterile, without the presence of any organisms.52 Eosinophilia and elevated serum IgE levels are also observed in more than 80% of infected patients.34 Serologic tests with ELISA and a direct fluorescent antibody are highly sensitive and specific for establishing the diagnosis.53 Praziquantel and triclabendazole are the treatments of choice, with a cure rate of 90% and 98.5%, respectively.34 Cestodes Cestodes are a subclass of tapeworms; parasites in this group have no digestive system. These parasites live in the digestive tract of mammals. The body is composed of multiple, successive segments (proglottids). Tapeworms are exclusively hermaphrodites with both male and female reproductive systems in their body.

include cough, fever, dyspnea, and chest pain. The cyst may rupture into a bronchus and cause hemoptysis and/or expectoration of cystic fluid containing parasitic components (hydatoptysis), which is considered a pathognomonic finding of cystic rupture.55 The patients may present with hydropneumothorax or empyema. Occasionally, a ruptured cyst can cause an anaphylactic-like reaction and pneumonia.8 Cystic hydatidosis is diagnosed by chest radiography, which demonstrates a well-defined, homogenous, fluid-filled, round opacity. Ruptured cysts may have characteristic features, including air crescent, pneumocyst, floating membrane (“water lily sign”) (Fig 3), or completely empty cavity images.56 A “meniscus” or “crescent” sign or Cumbo’s sign (onion peel) have also been described. Thoracic ultrasonography may be useful to confirm the cystic structure, demonstrating the characteristic double-contour (pericyst and parasitic membrane endocyst) of intact cysts. However, daughter cysts are also observed occasionally in pulmonary hydatidosis.56 Bronchoscopic examination reveals sac-like cysts in the airway (Fig 2D). A surgical lung biopsy may reveal echinococcus cyst fragments (Figs 2E, 2F). Bronchoscopic extraction of the hydatid cyst is possible; however, because of the risk of cyst rupture, it should be considered on a case-by-case basis. Serologic tests are more sensitive in patients with liver involvement (80%-94%) than in those with lung hydatidosis (65%).34 Hydatid cyst rupture can increase the sensitivity of serologic tests to . 90%.55 Cystic hydatidosis is the only infestation that needs surgical treatment. Complete resection of the cyst is the cornerstone of the management of pulmonary hydatidosis: to remove the intact cyst, preserve as much viable lung tissue as possible, and treat the associated

Echinococcosis Echinococcus granulosus and multilocularis are the parasite species that cause hydatid disease in humans. E granulosus is endemic in sheep-herding areas of the Mediterranean, Eastern Europe, the Middle East, and Australia. An estimated 65 million individuals in these areas are infected.1 Humans become accidental hosts either by direct contact with the primary hosts (usually dogs) or by the ingestion of food contaminated with feces, containing parasite eggs.34 The larvae reach the lymphatics of the intestines and the bloodstream and then migrate to the liver, the main habitat in human hosts. Two different presentations of echinococcosis are noted: (1) cystic hydatidosis and (2) alveolar echinococcosis. An ecchinococcal infection becomes symptomatic after 5 to 15 years, secondary to local compression or dysfunction of the affected organ. Pulmonary cysts expand at a rate of 1 to 5 cm/y, and calcification is less common.54 Pulmonary symptoms from the intact cyst 890

Figure 3. Water lily sign. CT scan obtained at level of right middle lobe shows ruptured hydatid cyst. After rupture and discharge of cyst fluid into pleural cavity, endocyst collapses, sediments, and floats in remaining fluid at bottom of original cyst. (Image courtesy by Farid Rashidi, MD.) Special Features

Figure 4. A, Bronchoscopy revealed pinkish mulberry-like rhinosporidiosis mass in the right main stem bronchus. (Reprint with permission from Singh et al.64) B, Microscopic examination of the resected specimen shows bronchial subepithelium with sporangia of Rhinosporodium; filled with small round endospores (H&E, original magnification 3 100). (Reprint with permission from Singh et al.64) C, Amebic lung abscess from lung biopsy specimen. The arrows point to trophozoites of Entamoeba histolytica (H&E, original magnification 3 200). D, Transbronchial needle biopsy specimen of a mediastinal lymph node shows histiocytes containing abundant Leishmania amastigotes (arrows) (H&E, original magnification 3 1,000). Inset shows a close-up view of an amastigote. Its ovoid shape, eccentric nucleus, and kinetoplast are discerned (same magnification as image). (Reprint with permission from Kotsifas et al.68) E, Lung infected with Toxoplasmosis gondii (arrow) with diffuse alveolar damage (H&E, original magnification 3 100). Inset shows bradyzoites of T gondii present in cytoplasm of alveolar macrophage (H&E, original magnification 3 1,000). See Figure 1 legend for expansion of abbreviation.

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parenchymal and bronchial disease. The lung parenchyma around a hydatid cyst is often affected by the lesion and may exhibit chronic congestion, hemorrhage, and interstitial pneumonia, which often resolve after the surgery.57 Spillage of hydatid fluid must be avoided to prevent secondary hydatidosis. Medical therapy may have a role in poor surgical candidates and in intraoperative spillage of fluid from a hydatid cyst. Antihelminthic agents, such as mebendazole or albendazole, have shown only 25% to 34% cure rates.58 The drawback of antihelminthic therapy is that it weakens the cyst wall and increases the risk of rupture. In addition, if the parasite dies because of the drug, the cyst membrane may remain within the cavity and lead to secondary complications, including infections.59 Percutaneous treatment by puncture-aspiration-injectionreaspiration has rarely been used in pulmonary cysts because of the risk of anaphylactic shock, pneumothorax, pleural spillage, and bronchopleural fistulae.60 Pulmonary alveolar echinococcosis is a rare but severe and potentially fatal form of echinococcosis but it is restricted to the Northern Hemisphere. The liver is the first target for the parasite, with a long, silent incubation period. Pulmonary involvement results from either dissemination or the direct extension of the hepatic echinococcosis with intrathoracic rupture through the diaphragm into the bronchial tree, pleural cavity, or mediastinum. Chest radiograph or CT scanning may aid in the diagnosis. ELISAs and indirect hemagglutination assay are available and offer early detection in endemic areas. Radical resection of localized lesions is the only curative treatment yet, is rarely possible in invasive and disseminated disease. Mebendazole and albendazole can be used, but the required treatment duration need is a minimum of 2 years after the radical surgery.61

Mesomycetozoea Mesomycetozoea is a group of organisms at the border of the animal-fungal kingdom.62 They appear in host tissues as sphere-shaped spores. Rhinosporidiosis Rhinosporidiosis is a chronic granulomatous infectious disease caused by Rhinosporidium seeberi. This condition has a high prevalence in South Asia, especially Sri Lanka.63 Patients usually present with recurrent polypoidal, friable, hemorrhagic, lesions. The common sites of involvement are the nose and nasopharynx. However, lesions can involve the tracheobronchial tree, leading to partial or complete airway obstruction (Figs 4A, 4B).64 CT imaging is the preferred study because it defines the extent of disease. Therapeutic bronchoscopy plays a major role in bronchial rhinosporidiosis. Dapsone is the only medication to arrest the maturation of the sporangia, but the lesions may recur after months or years.65 Follow-up bronchoscopy is recommended to monitor signs of recurrence.

Protozoal Parasites Protozoa parasites are single-celled organisms that are mostly intracellular in humans (Table 2). Pulmonary amebiasis is caused by Entamoeba histolytica trophozoites invading the intestinal mucosa and entering the bloodstream, effecting systemic infection. Pleuropulmonary amebiasis occurs mainly by local extension from the amoebic liver abscess. Patients usually present with fever, right-upper-quadrant abdominal pain, and cough. Sterile pleural effusion, lung abscess, hepatobronchial

Table 2—Protozoal Infection of Respiratory System Mode of Transmission

Protozoal Parasites

Endemic Area

Pulmonary amebiasis

Worldwide

Ingestion

Pulmonary leishmaniasis

Asia, Africa, Central and South America

Sand fly-borne infection

Pulmonary toxoplasmosis

Worldwide

Ingestion

892

Presentation Fever, right upper quadrant abdominal pain, lung abscess, hepatobronchial fistula Pneumonitis, pleural effusion, mediastinal lymphadenopathy

Generalized lymphadenopathy, interstitial pneumonia, diffuse alveolar damage

Bronchoscopic Evaluation

Treatment

Surgical lung biopsy specimen shows Entamoeba histolytica trophozoites

Metronidazole

Transbronchial needle biopsy specimen of a mediastinal lymph node showing histiocytes containing Leishmania donovani organisms Histologic examination of lung biopsy specimen can identify Toxoplasma gondii tachyzoites in necrotic area

Pentavalent antimonials and liposomal amphotericin B

Pyrimethamine and sulfadiazine

Special Features

fistula, empyema, and pyopneumothorax have also been reported.1 Live trophozoites of E histolytica can be demonstrated in sputum, pleural pus, or lung biopsy specimens (Fig 4C). The presence of amoeba in the stool does not indicate an active E histolytica infection because two other nonpathologic Entamoeba species are found in humans.66 Metronidazole is the treatment of choice for invasive amoebiasis. Leishmania causes visceral leishmaniasis, which has been reported in patients who have undergone lung transplants.67 Pulmonary manifestations include pneumonitis, pleural effusion, and mediastinal lymphadenopathy.34 Leishmania organisms can also be found in the alveoli (Fig 4D)68 and the BALF.69 The diagnosis of leishmaniasis is confirmed by the presence of the parasites in bone marrow aspirates or by polymerase chain reaction identification in tissue biopsy specimens. Treatments of choice include pentavalent antimonials and liposomal amphotericin B. Miltefosine can be used as an oral agent against visceral leishmaniasis.70 Toxoplasmosis is caused by the protozoan, Toxoplasma gondii. Cats are the primary hosts of T gondii.71 Humans become infected by consuming contaminated undercooked food. Pulmonary toxoplasmosis has been reported with increasing frequency in HIV-infected patients. Pulmonary manifestations include interstitial pneumonia, diffuse alveolar damage, or necrotizing pneumonia.72 Histologic examination of lung biopsy specimens can identify T gondii tachyzoites in necrotic areas in both intracellular and extracellular forms (Fig 4E).73 The diagnosis of toxoplasmosis is based on the detection of the protozoa in bodily tissues. Diagnostic real-time polymerase chain reaction-based assays of BALF have been reported for HIV-positive patients. Toxoplasmosis can be treated with a combination of pyrimethamine and sulfadiazine for 3 to 4 weeks.74 Conclusions Although helminthic and protozoal parasitic infestations are dominant mainly in tropical and subtropical areas, global warming, immigration, and an increasing use of immunosupressives have changed their distribution. To manage these challenging clinical scenarios, pulmonologists must understand the epidemiology, life cycles, and clinical presentation of these infestations, as well as the bronchoscopic and laboratory findings and treatment options. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Gary Procop, MD, and Farid Rashidi, MD, for contribution of figures. journal.publications.chestnet.org

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