Is the incidence of parasitic lung diseases increasing, and how may this affect modern respiratory medicine?

The improved socio–economic conditions, with associated good hygiene practices, in the last century have resulted in a decline in parasitic infestations in developed countries, leading to a reduction in the occurrence of parasitic lung infestations in these countries. However, the latter part of the last century and the beginning of this century have witnessed the emergence of HIV/AIDS, increasing numbers of organ transplants and increased use of immunosuppressive drugs [1,2]. These circumstances result in immunosuppression in individuals, making them prone to the development of parasitic infections de novo from the environment or the recrudescence of dormant infections [2]. Transmission of the parasitic infection, via the graft, is also a possibility in organ transplant recipients. In addition, the migration and travel of a large number of individuals has resulted in the transmission of parasitic infections from high- to low-prevalence countries. Global climate change has also aggravated this situation [3]. As a result, pulmonary physicians are confronted with many parasitic lung infections, and hence a renewed interest in parasitic lung diseases has been observed in recent times. Many protozoal and helminthic parasites cause clinically significant lung diseases [4]. These diseases can affect all anatomical sites, from the chest wall to the trachea–bronchial tree. As a result, diseases caused by these parasites may mimic many common and uncommon lung diseases, presenting diagnostic and therapeutic challenges to pulmonologists. Some of the parasitic diseases can mimic malignancy and others may present with respiratory failure [5].

Protozoal infections

Important protozoal parasites that cause lung diseases include Entamoeba histolytica, Plasmodium falciparum, Plasmodium vivax, Leishmania donovani and Toxoplasma gondii. Amoebiasis is one of the most common infections in the world. It has been estimated that approximately 50 million cases of invasive E. histolytica disease occur worldwide each year, resulting in up to 100,000 deaths [6]. Pulmonary amoebiasis primarily occurs due to extension of the amoebic liver abscess [7]. An increasing number of invasive amoebiasis have recently been reported in HIV-infected patients [8]. Symptoms of pleuropulmonary amoebiasis are an elevated hemidiaphragm, tender hepatomegaly, pleural effusion and basal pulmonary involvement. Expectoration of ‘anchovy sauce-like’ pus indicates amoebiasis [7]. Diagnosis of pulmonary amoebiasis is a challenge, especially in areas where it is not prevalent, as it has to be differentiated from other common pleural diseases and lung abscesses. This is especially true in immunocompromised states. As amoebiasis is a treatable condition, accurate diagnosis is of utmost importance to save lives. Active trophozoites of E. histolytica can be demonstrated in sputum or pleural pus. The presence of amoeba in the stool does not signify that the disease is due to E. histolytica, as two other nonpathogenic species found in humans (Entamoeba dispar and Entamoeba moshkovskii) are morphologically indistinguishable from E. histolytica[2]. Other diagnostic tests include culture of E. histolytica and serological tests (e.g., indirect hemagglutination test, ELISA and indirect fluorescent antibody test). Metronidazole 750 mg orally three times daily for 7–10 days is the treatment of choice. The most important preventive aspect is the improvement of personal and community hygiene, especially in developing countries.

Malaria continues to be an important public health concern in many parts of the world, especially in Africa and Asia. It is an imported disease in many developed countries owing to increased intercontinental travel [5]. The malarial parasites P. vivax, P. falciparum, Plasmodium malariae and Plasmodium ovale are transmitted primarily by the bite of an infected female Anopheles mosquito. However, pulmonary disease is mainly caused by P. falciparum and occasionally by P. vivax[2,9]. The pulmonary manifestations range from cough to severe and rapidly fatal noncardiogenic pulmonary edema and acute respiratory distress syndrome. Prompt diagnosis and treatment are essential in this condition, as untreated cases are associated with high mortality. Light microscopy of stained thick and thin blood smears is the gold standard for the diagnosis of malaria. Thin smears allow the identification of malarial species. Radiological findings in severe P. falciparum malaria include lobar consolidation, diffuse interstitial edema, pulmonary edema and pleural effusion. PCR detection of P. falciparum in human urine and saliva samples has been described [10]. Intravenous artesunate has been found to be useful for the treatment of severe malaria in adults and children [11]. A systematic review has found that parenteral artemisinin derivatives have a similar safety profile to parenteral quinidine in the treatment of severe malaria in children [12]. Patients with respiratory failure require mechanical ventilation [13]. Travelers to malaria-endemic regions where chloroquine-resistant malaria exist are advised to have primary prophylaxis with atovaquone–proguanil, mefloquine or doxycycline [14]. The best way of preventing malaria has been found to be the use of long-lasting insecticide-treated bed nets [15].

Babesiosis, caused by hemoprotozoan parasites Babesia microti and Babesia divergens, is transmitted to man by the bite of an infected tick, Ixodes scapularis, and can also be transmitted from a contaminated blood transfusion [16,17]. The parasites attack the red blood cells and can be misdiagnosed as Plasmodium. Specific diagnosis is made by examination of a Giemsa-stained thin blood smear. The demonstration of Maltese cross formations in red blood cells is pathognomonic of babesiosis [18]. Acute respiratory distress syndrome is an important pulmonary manifestation [19]. Treatment is with a combination of clindamycin (600 mg every 6 h) and quinine (650 mg every 8 h), or atovaquone (750 mg every 12 h) and azithromycin (500–600 mg on the first day and 250–600 mg on subsequent days) for 7–10 days [20].

Visceral leishmaniasis is caused by the parasite Leishmania donovani, which is transmitted by various species of Phlebotomus, the sand fly [21]. Pulmonary manifestations in leishmaniasis include pneumonitis, pleural effusion and mediastinal adenopathy, especially in patients coinfected with HIV. Visceral leishmaniasis has also been reported in lung transplant patients [22]. The development of a simple and rapid test for the detection of PCR-amplified Leishmania has been described, and it has been observed that PCR alone provides a marker for infection rather than a diagnostic test for disease [23,24]. The drugs for the treatment of leishmaniasis include pentavalent antimonials, amphotericin B, especially the liposome formulations, and pentamidine. Miltefosine is the first orally administered drug against leishmaniasis [25].

Toxoplasmosis is caused by the protozoan parasite, Toxoplasma gondii and cats are the primary carriers of the organism [26]. Humans get the infection by eating parasitic cyst-contaminated raw or undercooked meat, vegetables or milk products. The symptoms of toxoplasmosis are flu-like, such as enlarged lymph nodes or myalgia. Pulmonary toxoplasmosis has been reported with increasing frequency in HIV-infected patients. Toxoplasma pneumonia can manifest as interstitial pneumonia/diffuse alveolar damage or necrotizing pneumonia [27]. Diagnosis of toxoplasmosis is based on detection of the protozoa in body tissues. Toxoplasmosis can be treated with a combination of pyrimethamine and sulfadiazine.

An increasing number of rare pulmonary protozoal infections are reported in immunocompromised individuals. Free-living Acanthamoeba species can cause systemic disease with pulmonary manifestations of nodular infiltrates, pneumonitis and respiratory failure in immunocompromised patients [28]. Cryptospodium parvum infection has been reported to produce interstitial pulmonary infiltrates and focal areas of consolidation in AIDS patients [29]. Recurrent aspiration secondary to megaesophagus can lead to pneumonitis, lung abscess and bronchieactasis in Trypanosoma cruzi infection (Chaga’s disease). Cardiogenic pulmonary edema, pulmonary hypertension secondary to cardiac failure and dilatory cardiomyopathy have also been reported in Chaga’s disease. East African trypanosomiasis due to Trypanosoma brucei rhodesiense infection has been reported to cause acute-stage noncardiogenic pulmonary edema and acute respiratory distress syndrome. Many other rare pulmonary protozoal infections have been reported in immunocompromised individuals [30].

Helminthic infection

Helminthic parasitic infestation is very common in many parts of the world and some helminthic parasites cause devastating disease in immunocompromised individuals. The important helminthic parasites that cause lung diseases include nematodes (Ascaris lumbricoides, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Toxocara canis or catis, Trichinella spiralis, Wuchereria bancrofti, Brugia malayi, Brugia timori, Dirofilaria immitis and Dirofilaria repens), Cestodes (Echinococcus granulosus and Echinococcus multilocularis) and Trematodes (Schistosoma haematobium, Schistosoma mansoni, Schistosoma japonicum and Paragonimus westermani) [2]. Pulmonary diseases caused by helminthic parasites vary from mild, transient, patchy infiltrates (Loeffler-like syndrome) to serious conditions such as space-occupying lesions, pulmonary hypertension and restrictive lung diseases. Most of the cases of helminthic infections are associated with pulmonary and blood eosinophilia [1]. A. lumbricoides, A. duodenale and N. americanus cause a Loeffler-like syndrome during larval migration through the lungs. Many cases of infection with Strongyloides stercoralis have been reported in immunosuppressed individuals, especially in HIV/AIDS patients. In patients at a high risk for strongyloidiasis, adult respiratory distress syndrome and septicemia owing to intestinal transmural migration of bacteria can occur as a result of hyperinfection or disseminated strongyloidiasis [31]. The diagnosis of strongyloidiasis by examination of a single stool specimen using conventional techniques usually fails to detect larvae in up to 70% of cases [2]. The diagnostic yield can be increased by examination of several stool specimens on consecutive days. In disseminated disease, larvae and adult parasites can be seen in the sputum, urine, bronchoalveolar lavage fluid and other body fluids. Ivermectin, thiabendazole or albendazole can be used for the treatment of strongyloidiasis in immunocompetent individuals without complications. Ivermectin is administered in a dosage of 200 µg/kg orally for 1–2 days. Albendazole 400 mg twice-daily for 5 days has been found to be useful in the treatment of strongyloidiasis. Corticosteroids should not be prescribed in suspected cases of strongyloidiasis to prevent the occurrence of life-threatening hyperinfection syndrome [32].

Immunologic hyper-responsiveness to human filarial parasites, W. bancrofti and B. malayi results in an occult form of filariasis, termed tropical pulmonary eosinophilia (TPE) [1,33]. It is prevalent in filarial endemic regions of the world, especially in southeast Asia [1]. TPE should be considered in the differential diagnosis of a patient traveling from a filarial endemic region to nonendemic areas who presents with asthma-like symptoms [34]. TPE patients usually present with paroxysmal cough, breathlessness, wheezing and chest pain. Absolute eosinophil counts are usually more than 3000 cells/mm3 and may range from 5000 to 80000 cells/mm3 [35]. The chest radiological features of TPE include reticulonodular shadows, predominantly seen in mid and lower zones, and miliary mottling from 1 to 3 mm in diameter, and are often indistinguishable from miliary TB. Treatment is with oral diethylcarbamazine citrate at a dosage of 6 mg/kg daily for 3 weeks [33]. A chronic, mild, interstitial lung disease has been found to persist in TPE, despite treatment [33,36].

Pulmonary dirofilariasis is a zoonotic infection caused by filarial nematodes, D. immitis and D. repens. Clinical symptoms are chest pain, cough, fever, hemoptysis and dyspnea. CT scan may show a well-defined nodule with a smooth margin connected to an arterial branch [37], and this may mimic lung cancer. A definitive histopathological diagnosis of pulmonary dirofilariasis can be made in tissue specimens obtained by wedge biopsy, video-assisted thoracoscopy or rarely by fine-needle biopsy [38]. There is no specific treatment for human dirofilariasis.

The parasites that cause visceral larva migrans and eosinophilic lung disease in humans are a dog ascarid (Toxocara canis), and less commonly a cat ascarid (Toxocara catis). Pulmonary manifestations are reported in 80% of cases and patients may present with severe asthma and intense blood eosinophilia. Skiagram chest may reveal focal patchy infiltrates. In some cases, severe eosinophilic pneumonia may lead to respiratory distress. Other clinical features include generalized lymph node enlargement, hepatomegaly and splenomegaly. Migratory nodular shadows with halos on chest CT scans have been described in toxocariasis [39].

Humans contract Trichinella spiralis infection from raw and partially cooked pork, when infected pork muscle containing larval trichinellae is consumed. Pulmonary involvement includes shortness of breath, dyspnea and pulmonary infiltrates. Dyspnea results from parasite invasion of the diaphragm and the accessory muscles of respiration [40]. A definitive diagnosis can be made by muscle biopsy (usually deltoid muscle), which may demonstrate larvae of T. spiralis. An ELISA using excretory/secretory antigens to detect anti-Trichinella IgG antibodies in human sera has been validated for the diagnosis of human trichinellosis [41]. Symptomatic treatment includes analgesics and corticosteroids. Specific treatment is with mebendazole 200–400 mg three-times daily for 3 days followed by 400–500 mg three-times daily for 10 days. Trichinellosis can be prevented by consuming properly cooked pork.

The parasite species that cause hydatid disease in man are E. granulosus and E. multilocularis. Pulmonary symptoms include cough, fever, dyspnea and chest pain. Signs and symptoms can occur owing to the compression of adjacent tissue by cysts. Rupture of the cysts into a bronchus may result in hemoptysis and the expectoration of cystic fluid containing parasite membrane, and can cause anaphylactic shock, respiratory distress, asthma-like symptoms, persistent pneumonia and sepsis [42,43]. Rupture into the pleural space results in pneumothorax, pleural effusion and empyema. Chest radiographs show solitary or multiple round opacities mimicking lung tumors. Treatment of a hydatid cyst is primarily surgical. Parenchyma-preserving surgery (cystotomy alone, or cystotomy and capitonnage) is the preferred treatment [44]. Radical surgery including pneumonectomy, lobectomy and segmentectomy should be avoided. Pharmacotherapy with albendazole or mebendazole has also been found to be useful, especially in recurrent and multiple cysts. The efficacy of treatment can be improved by combining albendazole with praziquantel [45]. The treatment of alveolar ecchinococcosis caused by E. multilocularis is radical surgical resection of the entire parasitic lesion. Pharmacotherapy with mebendazole, albendazole or praziquantel involves continuous administration for many years in inoperable cases [46].

The schistosomes that cause human disease are S. haematobium, S. mansoni and S. japonicum. Schistosome eggs are passed in the urine (S. haematobium) or in the feces (S. mansoni and S. japonicum) by infected humans. Urinary bladder vesicle beds are the final habitat of S. haematobium and the mesenteric beds are the final habitat of S. mansoni and S. japonicum. Pulmonary schistosomiasis can manifest clinically as an acute or a chronic form. The acute form, also known as Katayama syndrome, presents with fever, chills, weight loss, diarrhea, abdominal pain, myalgia, urticaria, shortness of breath, wheezing and dry cough, and is observed in nonimmune patients [47]. Diffuse pulmonary infiltrates are seen radiologically in Katayama syndrome and almost all patients suffer from eosinophilia [48]. Patients with chronic schistosomiasis present with features of pulmonary hypertension and pulmonary heart disease [49]. Diagnosis of chronic schistosomiasis is based on the demonstration of eggs in the stools or urine by direct microscopy or rectal/bladder biopsy. Acute schistosomiasis can be treated with praziquantel 40 mg/kg for 3 days (for S. mansoni or S. haematobium) and 60 mg/kg for 6 days (for S. japonicum), with or without steroids [2,48]. Praziquantel can be repeated several weeks later to eradicate adult flukes. Artemisinin has been found to be useful in the early stages after exposure, as the drug has been found to act on juvenile forms of the schistosomes and may reduce the risk of Katayama syndrome [50]. Chronic schistosomiasis can also be treated with the same dosage of praziquantel as is used for acute schistosomiasis. Biennial treatment with praziquantel in school-age children in sub-Saharan Africa has resulted in a significant and sustained reduction in S. haematobium infection, suggesting that this can be a cost-effective treatment strategy for control programs in resource-limited countries [51].

Of the cases of paragonimiasis, 90% occur in Asia, where nearly 20 million people are infected [52]. The main species that causes paragonimiasis in humans is Paragonimus westermani. Adult worms live in the lungs and the eggs are voided in the sputum or feces. The miracidia produced from the eggs penetrate the soft tissues of the first intermediate host, the snail, and develop into free-swimming cercariae. Cercariae invade the second intermediate host, a crustacean such as a crab or crayfish, and produce metacercariae, which are the infective stage for the mammalian host. Humans are infected when raw or undercooked crabs or crayfishes infected with infective metacercariae are ingested. The metacercariae ex-cyst in the duodenum penetrates the intestinal wall into the peritoneal cavity, then through the abdominal wall and diaphragm into the lungs. In the lungs they become encapsulated and develop into adults. Pulmonary paragonimiasis manifests as fever, chest pain, chronic cough and hemoptysis [2]. Chest radiographs may show infiltrative, nodular and cavitating shadows. Pleural effusion or pneumothorax is an important finding in paragonimiasis. Eggs can be demonstrated in sputum samples, bronchoalveolar lavage fluid or lung biopsy specimens. Peripheral blood eosinophilia and elevated serum IgE levels are seen in more than 80% of patients with paragonimiasis [2]. Paragonimiasis can be treated with praziquantel (75 mg/kg daily for 3 days), bithionol (30–40 mg/kg over 10 days on alternate days), niclofolan (2 mg/kg as a single dose) or triclabendazole (20 mg/kg in two equal doses) [53].

Parasitic lung diseases are now increasingly being reported in many parts of the world owing to globalization and climate change. In addition, the resurgence of parasitic lung diseases has been noted due to the increasing number of organ transplants and the frequent use of immunosuppressive drugs. Pulmonary disease due to parasites may range from asymptomatic disease to severe life-threatening conditions. The availability of new molecular diagnostic methods and antiparasitic drugs enables us to detect parasitic lung infections early and to treat them successfully. Many patients under the care of pulmonologists, especially in respiratory intensive care units, are being treated empirically with antibiotics. In this era of globalization and increasing occurrence of immunosuppression, some of these patients may be infected with parasites. A high index of suspicion of parasitic lung infections is, therefore, essential for prompt early diagnosis and treatment to avoid the morbidity and mortality associated with these conditions.

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