Lesson 3, Volume 16–Tropical Lung Diseases

By Arunabh, MD; Aamir Awan, MD; and Alan M. Fein, MD, FCCP

Objectives

1. Review the epidemiology of pulmonary diseases prevalent in tropical countries.
2. Detail the pathophysiologic events leading to eosinophilia in tropical pulmonary disorders.
3. Review the clinical and laboratory techniques currently available for diagnosis.
4. Review treatment of specific disorders.

Key words

eosinophilia; lung; parasite; tropical medicine

Abbreviations

ELISA = enzyme-linked immunosorbent assay; IL = interleukin; TPE = tropical pulmonary eosinophilia

The term "tropics" refers to the region of the earth lying between the Tropic of Cancer and the Tropic of Capricorn. The warm climate and general socioeconomic status in tropical countries provide an ideal environment for pathogenic organisms, their vectors, and intermediate hosts to flourish. Tropical pulmonary infections are the leading cause of infection-attributable morbidity and mortality. These deaths are potentially preventable if appropriate clinical and laboratory tools are in place to facilitate early detection of the pulmonary infections, identification of the pathogen involved, and institution of appropriate therapy. The tools currently available for the diagnosis of acute, lower respiratory tract infections in tropical countries have low sensitivity and are, in any case, grossly underutilized. Consequently, there is a great shortage of the data necessary for implementing potentially effective interventions.

In addition, international travel and changing immigration patterns have made tropical diseases part of the scope of medicine throughout the world.¹ Each year, millions of travelers visit tropical countries and many spend time in the areas where they are at risk for infectious diseases.² Today it is essential for the practicing physician to be aware of the common tropical lung diseases. In particular, when evaluating pulmonary infections in a returned traveler, a thorough understanding of common organisms, their epidemiology, and their modes of presentation is required. Although tuberculosis and malaria are the most common infectious diseases prevalent in tropics, this review of the common tropical pulmonary disorders is necessarily selective, primarily focusing on parasitic diseases (including protozoa; worms such as nematodes, cestodes, trematodes, and pentastomes) affecting the lung (Table 1).

Helminthic parasites are multicellular, metazoan organisms, and infections with a diversity of these organisms elicit eosinophilia and IgE production controlled by cytokines of Th2 lymphocyte cells.³ Although eosinophilia may provide a hematologic clue to the presence of helminthic infection, the sensitivity is < 100% (Table 2). In contrast to infections with multicellular helminthic parasites, infections with single-celled protozoan parasites do not characteristically elicit blood eosinophilia. The increased IgE levels that occur during metazoan parasitic infections seem to correlate with the increasing levels of tissue invasion, probably due to the secretion by parasites of factors that stimulate interleukin (IL)-4. It is also hypothesized that the IgE is at least partially protective against parasites. Total serum IgE falls after successful treatment of the parasitized individual. Definite evidence of pleuropulmonary involvement in parasitic infections requires demonstration of ova or larvae in the sputum, BAL fluid, pleural fluid, or lung tissue, which is not always possible. Thus, considerable emphasis is placed on serologic tests, and major advances have been made in diagnostic parasitic serology, particularly in enzyme-linked immunosorbent assay (ELISA) methods and the use of monoclonal antibodies.⁴

Helminthic parasites may cause pulmonary disease by at least three mechanisms: (1) during obligatory migration of the larvae from the gut through the pulmonary capillaries to the alveoli and back to the gut (eg, ascariasis, strongyloidiasis, and hookworm infections); (2) by passage through the pulmonary vasculature as part of a bloodborne stage of the parasite's life cycle (eg, schistosomiasis, filariasis, trichinosis); and (3) by residence of the adult or cyst form in pulmonary tissue (eg, paragonimiasis, echinococcosis). Plasmodium falciparum and Entamoeba histolytica infections are common protozoans associated with pulmonary involvement.

Protozoa

Amebiasis

Amebiasis is an infection with the protozoan E histolytica. It produces a spectrum of clinical illnesses ranging from dysentery to abscesses of the liver and other organs. The disease has been estimated to affect approximately 10% of the world's population and is the third most important parasitic cause of death (after malaria and schistosomiasis).⁵ E histolytica usually involves the intestine before dissemination to other organs, particularly the liver. Pleuropulmonary involvement, which is reported in 20 to 30% of patients, is the most frequent complication of amebic liver abscess. Common clinical presentations include sterile sympathetic effusions, contiguous spread from the liver, and rupture into the pleural space resulting in amebic empyema. The onset of illness can be acute or subacute, and a history of dysentery may be absent in up to half the patients. Most often cough, fever, and right-sided pleuritic chest pain are the presenting complaints. The chest radiograph may show elevation of the right hemidiaphragm, right pleural effusion, or a basilar atelectasis. An ultrasound scan, liver scan, or CT scan is helpful in confirming the presence of liver abscess (Fig 1).

Figure 1.A 40-year-old man who had recently immigrated from India presented with increasing nocturnal cough and bilateral wheezing. Chest radiograph showed diffuse bibasilar interstitial infiltrates. His total eosinophil count was > 3,000 cells/mm³ and the antifilarial antibodies were positive (1:512). These findings confirm the diagnosis of tropical pulmonary eosinophilia.

Sterile effusions and contiguous spread usually resolve with medical therapy but frank rupture into pleural space requires surgical drainage. In this situation the pleural effusion is typically described as "chocolate sauce" or "anchovy paste" in appearance. A positive diagnosis can be established by demonstration of trophozoites in the pleural exudates or in material obtained by needle aspiration. Rarely, a hepatobronchial fistula may cause a cough that produces large amounts of necrotic material, which may contain amebae. Pleuropulmonary involvement such as amebic liver abscess occurs predominantly in men. The reported male:female ratio varies from 9:1 to 15:1.⁶ The diagnosis of amebic pleural effusion should be considered in all patients who have traveled to an endemic area and have right-sided pleural effusion for which no other explanation is available. Leukocytosis occurs in about 75% patients, with a left shift; eosinophilia is rare. More than 90% of patients with pleuropulmonary amebiasis have positive antibody titers. A positive serologic test, however, does not distinguish between active tissue invasion and previous infection. Serologic tests may be positive for 2 years or more after effective treatment.

Metronidazole is currently the drug of choice (Table 3). Side effects include nausea, anorexia, metallic taste, dizziness, and a disulfiram-like reaction with alcohol. Metronidazole acts a radiation sensitizer, so it should be used with caution in those receiving radiation treatment. Other imidazole compounds, such as tinidazole and ornidazole, are effective, but are not available in the United States. It is believed that serous pleural effusion should be medically treated, but treatment of amebic empyema requires surgical drainage. The combination of medication and drainage results in clinical cure in the majority of the patients. Bacterial superinfection, which is common in patients with bronchopleural fistula, responds to appropriate antibiotic therapy. After successful treatment of invasive disease, patients should be considered for eradication of the intestinal phase of the disease with a luminal agent (eg, iodoquinol, diloxanide furoate, or paramomycin).⁷

Malaria

Malaria is one of the major world public health problems resulting in more than 1 million deaths worldwide. It is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes (Fig 2). Four species of the genus Plasmodium cause all infections in humans, ie, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and P falciparum. Clinically significant pulmonary involvement is seen in up to 5% of infected patients, ranging from mild cough to respiratory failure due to ARDS.⁸ Fulminant respiratory failure is an often fatal manifestation of P falciparum malaria in adults and is usually associated with cerebral malaria, acute renal failure, high levels of parasitemia, or delayed treatment.⁹ The central pathologic feature of severe falciparum malaria is the sequestration of parasitized erythrocytes in the microvasculature of organs, including the lung.¹⁰ The development of the inflammatory response to these parasites leads to release of mediators, which results in alveolar and endothelial damage and capillary leak. It is suggested that the balance between proinflammatory (tumor necrosis factor-a, interferon-g, IL-6, IL-8) and anti-inflammatory cytokines (IL-4, IL-10) determines the degree of malarial parasitemia, clinical severity, and outcome.¹¹ Many factors seem to contribute to the genesis of hypoxemia in severe malaria, including sequestration of parasitized RBCs in the pulmonary vasculature, aspiration pneumonia, fluid overload, and secondary Gram-negative bacteremia. P vivax malaria has been reported to be associated with bronchiolitis obliterans organizing pneumonia.¹²

Figure 2. Ring forms of malaria parasite.

American Trypanosomiasis (Chagas' Disease)

Chagas' disease is an endemic disease in Latin America, from Brazil to Argentina, and is caused by the flagellate protozoan parasite, Trypanosoma cruzi. It is transmitted to humans by reduviid bugs. Metacyclic forms of the parasite eliminated with insect feces penetrate human skin and reach the blood, from where they disseminate to the other tissues. In the acute form, the illness is characterized by fever, inflammation at the portal of entry, acute myocarditis (with or without heart failure), and meningoencephalitis. Chronic disease usually occurs years after the initial infection and results in chronic cardiomyopathy (20 to 30% of patients). GI megasyndromes occur in < 10% and peripheral nerve involvement in < 5%. It is believed that the tracheobronchial tree may be affected by the lesions of the autonomic nervous system resulting in dilatation and eventually in bronchiectasis. Esophageal involvement by the parasite results in megaesophagus, which causes symptoms of dysphagia, odynophagia, regurgitation, heartburn, and coughing. Aspiration of the the liquid fat contents commonly results in pneumonia. Congestive cardiomyopathy may result in pulmonary edema, unilateral or bilateral pleural effusions, or pulmonary thromboembolism. Therapy for Chagas' disease is unsatisfactory, with nifurtimox the only drug available in the United States.

Nematodes (Roundworms)

Simple Pulmonary Eosinophilia (Löffler's Syndrome)

The roundworm Ascaris lumbricoides and the hookworms Ancylostoma duodenale and Necator americanus may cause pulmonary symptoms during their migration through the lung. This acute disorder also known as Löffler's syndrome is most commonly caused by infection with Ascaris spp.¹⁶ It is characterized by migratory pulmonary infiltrates accompanied by peripheral blood eosinophilia and minimal pulmonary symptoms. Ascaris is transmitted by the ingestion of the fertilized eggs, while hookworm transmission occurs via oral or skin penetration by infective larvae. The migration of the parasite larvae from the pulmonary capillaries results in low-grade fever, blood-streaked sputum, cough, wheezing, dyspnea, and substernal chest discomfort. These symptoms are caused by transient allergic pneumonitis in response to parasite antigens. Löffler's syndrome generally tends to occur 1 to 2 weeks after ingestion of the larval eggs.¹⁷ The sputum examination reveals eosinophilia and Charcot-Leyden crystals. The chest radiograph shows fleeting infiltrates that resolve over days. Ascaris or hookworm ova may be absent from stool at the time of pneumonitis, but larvae can often be seen in sputum or gastric lavage. The appearance of Ascaris or hookworm ova in the stool within 3 months of self-limited eosinophilic pneumonitis suggests this diagnosis. Occasionally, Löffler's syndrome may be drug-induced (Table 2), and approximately one third of cases are idiopathic. Although severity of symptoms correlates with larval burden, this disorder is self-limited and tends to resolve spontaneously. Symptomatic patients may be treated with bronchodilators. Prevention of infection and treatment of the intestinal phase are the mainstays of management. The drug of choice for intestinal infestation is mebendazole, although pyrantel pamoate or albendazole can also be used (Table 3). Albendazole is a newer benzimidazole with activity similar to that of mebendazole, but it is used as a single dose. It is not licensed for general use in the United States.

Tropical Pulmonary Eosinophilia

Tropical pulmonary eosinophilia (TPE) results from immunologic hyperresponsiveness to filarial parasites (Wuchereria bancrofti and Brugia malayi).¹⁸ It is seen mostly in the Indian subcontinent, although it has also been reported from other areas of the world. The disease occurs mostly in men and is characterized by persistent cough and wheezing of insidious onset associated with a striking eosinophilia. The cough is often worse at night with nonproductive sputum. Physical examination reveals minimal pulmonary findings, hepatosplenomegaly, and generalized lymphadenopathy. Radiography shows increased bronchovascular markings and diffuse coarse interstitial infiltrates, but the radiograph may be normal in up to 30% of cases. Pulmonary function testing reveals a predominant restrictive pattern together with mild reversible airway obstruction in the majority of patients. The absolute eosinophil count often exceeds 4,000/mm³ with elevation in serum IgE levels (> 1,000 U/mL) and erythrocyte sedimentation rate. BAL often reveals an intense eosinophilic alveolitis¹⁹ and striking elevation of antifilarial IgE.²⁰ While filarial antibodies are typically detected, microfilaria cannot be found in the peripheral blood. This syndrome must be distinguished from other eosinophilic syndromes; this is generally not difficult, given the geographic distribution of the disease and rapid clinical and radiologic response to therapy with diethylcarbamazine.²¹ Cases of TPE have typically been reported to present as "refractory bronchial asthma" usually in nonimmune individuals (visitors to endemic regions). Despite a 3-week course of diethylcarbamazine (Table 3), low-grade alveolitis persists in almost half of such patients and may be the cause of progressive pulmonary fibrosis seen in many inadequately treated patients.²² Relapses can occur and are treated with repeat courses of the same drug. Corticosteroids may be helpful in treating the chronic forms of TPE²³ (Fig 3).

Figure 3. A 50-year-old man presented with right pleuritic chest pain, fever, and right pleural effusion. He had returned 1 month earlier from a trip to Mexico. The patient had already been treated with antibiotics on an outpatient basis. Aspiration of the pleural effusion revealed brown-colored fluid with amebic trophozoites identified. A diagnosis of amebic liver abscess with rupture into the pleural space was established.

Dirofilaria immitis

Human pulmonary dirofilariasis is caused by the dog parasite Dirofilaria immitis. Infection occurs when mosquito-borne infective larvae are transmitted to humans. Because humans are not a natural host, the organism does not complete its life cycle and dies before reaching sexual maturity. It is subsequently embolized into the pulmonary arterial circulation, causing thrombosis, infarction, and a granulomatous reaction.²⁴ Most patients are asymptomatic and present with a solitary pulmonary nodule; peripheral eosinophilia is sometimes seen. Surgical resection is both diagnostic and curative.

Visceral Larva Migrans

This disease is also called systemic toxocariasis, a zoonotic disease infecting the human viscera by the migrating larvae of Toxocara canis or Toxocara cati, the common intestinal ascarids of the dog and cat, respectively. Human beings are accidental hosts who acquire this condition by ingesting eggs in contaminated soil or food. Once ingested, the larvae migrate from the intestines via the lymphatics and bloodstream to reach other organs, including the liver and lungs. The host's immune response to this invasion results in increased eosinophils and IgE levels, both in the serum and BAL fluid. Pulmonary involvement is reported in 20 to 80% of cases²⁵ and may vary from dry cough and wheezing (mimicking asthma) to respiratory failure.²⁶ The chest radiographic findings usually demonstrate unilateral or bilateral migratory infiltrates. The diagnosis of visceral larva migrans is established by a positive ELISA for T canis in a patient with history of pica. The condition is usually self-limited and rarely requires treatment. The role of specific antihelminthic drugs mebendazole or albendazole is not established. Preventive measures, like curbing geophagia and deworming the animal hosts, are important in decreasing the incidence of this condition.

Strongyloidiasis

Strongyloides stercoralis is a free-living parasite that is endemic throughout the tropics. The larvae of S stercoralis penetrate the skin and enter the patient's blood, traveling to the lung en route to the small intestine to complete their life cycle. Within the small intestine, they develop into adults and then reenter the bloodstream (without going through a soil cycle), causing autoinfection. The most common respiratory manifestation of S stercoralis infection in normal hosts is Löffler's syndrome, presenting as transient cough and wheeze, eosinophilia and dyspnea during the migration of the larvae through the lungs. The infection in the gut is usually asymptomatic and can remain undetected for decades. Strongyloides is difficult to diagnose because the parasite load is low and the larvae output is irregular.²⁷ Several immunodiagnostic assays have been found ineffective in detecting disseminated infections and show cross reactivity with hookworms, filariae, and schistosomes.

Hyperinfection is seen in patients who are immunosuppressed and receiving corticosteroid therapy, resulting in high mortality rates (approximately 90%). Almost all deaths due to helminths in the United States result from S stercoralis hyperinfection.²⁸ It develops when larva that have hatched from eggs laid by adult worms in the duodenum develop into the infective stage, repenetrate the bowel, and develop into adult forms and spread throughout the body, particularly into the lungs. Patients develop spiking fever, anemia, weight loss, diffuse alveolar infiltrates, and hypoxic respiratory failure resembling ARDS.²⁹ Larvae are present in sputum, BAL fluid, urine, and stool. Gram-negative fecal flora piggybacking onto the parasites may cause sepsis.³⁰

The clinical features alone seldom permit a diagnosis. However, in a patient with multisystem involvement, a history of travel to an endemic region, even in the remote past, is typical. Thiabendazole (25 mg/kg bid for 2 days) has been the drug of choice despite the associated GI side effects and high relapse rate³¹ (Table 3). Ivermectin, a potent macrocyclic lactone, which causes paralysis of the nematodes,³² is found to be the most effective drug in treating disseminated strongyloidiasis.³³

Trematodes (Flatworms)

Paragonimiasis

Paragonimiasis is caused by trematodes of the genus Paragonimus, which are prevalent in Southeast Asia and in Central and South America. Paragonimus westermani is the most common cause of this disease in humans. The infection is caused by ingesting freshwater crabs that harbor the metacercarial parasite. Excystation of the organisms occurs in the duodenum, and then they move into the peritoneal cavity to enter the abdominal wall or liver, ultimately reaching the lung by penetrating the diaphragm and pleura. In the lung they mature into adult forms that deposit eggs in the lung parenchyma, leading to hemorrhage, necrosis that may present as bronchopneumonia, interstitial pneumonia, bronchitis, bronchiectasis, collapse, fibrosis, pleural thickening, or pleural effusions. The right lung is more commonly affected than the left lung. Most patients are asymptomatic, but fever, malaise, weight loss, and dry cough with rusty, blood-flecked sputum may occur. Chest radiographs show poorly defined pulmonary infiltrates that are either localized or multisegmental.³⁴ Pleural effusions, which are characteristically eosinophilic, are characterized by low glucose, low pH, and elevated IgE. IL-5 is particularly important in mediating eosinophilia in both peripheral blood and pleural fluid.³⁵

The diagnosis is established by demonstrating ova in the stool, sputum, and BAL or biopsy specimens. ELISA and immunoblot serologic tests may also be helpful.³⁶ Paragonimiasis needs to be differentiated from tuberculosis because both show similar radiologic features and occasionally coexist.³⁷ Praziquantel is the drug of choice at a dose of 25 mg/kg tid for 2 to 3 days (Table 3). For heavy infections, a second course may be required. Bithionol is an alternative drug (30 to 50 mg/kg on alternate days for 10 to 15 doses). Paragonimiasis is rarely fatal and cure rates approach 100%.

Schistosomiasis

Schistosomiasis is a parasite that is carried by freshwater snails in tropical countries around the world. Eggs are passed in human excrement, hatch in water into mericidia, and are ingested by the snails. The cercarial form is released into water from snails and rapidly penetrates the skin to localize in various organs. There are two common forms: urinary schistosomiasis (Schistosoma haematobium) seen commonly in Africa and intestinal schistosomiasis (Schistosoma mansoni, Schistosoma japonicum) seen commonly in the Middle East, Central Africa, South America, and parts of Southeast Asia.

Acute schistosomiasis (Katayama fever) is a febrile response to the parasite in nonimmune persons 6 to 8 weeks after a heavy first infection. Pulmonary involvement in acute schistosomiasis includes ill-defined nodular pulmonary infiltrates, which are believed to be immunologically mediated,³⁸ along with associated eosinophilia. This is usually self-limited and resolves over 1 to 2 months. The natural history can be abbreviated by steroids and praziquantel.

In the chronic stage, granulomatous inflammation of the lung results in pulmonary hypertension. Approximately 25% of patients with schistosomal hepatosplenomegaly have clinical evidence of pulmonary disease, but < 5% progress to true cor pulmonale.³⁹ Pulmonary hypertension results from abnormal migration of eggs of S mansoni from either the portal system through portocaval shunts or from vesicle veins in S haematobium to pulmonary vascular beds⁴⁰ with granuloma formation around the eggs. Dyspnea on exertion, decreased lung volume, and impaired diffusion are common. Fine nodules combined with dilatation of pulmonary arteries are the most common radiographic pattern. Eggs may be detected at times in BAL or transbronchial biopsy. Usually ova can be detected in urine (S haematobium), stool (S mansoni or S japonicum), or in bladder or rectal biopsy specimens.

Praziquantel is the drug of choice for the treatment of all forms of schistosomiasis⁴¹ (Table 3). S mansoni is also sensitive to oxamniquine.⁴² Praziquantel (single dose) also appears to be more effective than metrifonate in terms of parasitologic cure of S haematobium, but the reinfection rate is high with both drugs.⁴³ Initiation of antischistosomal therapy may result in coughing and wheezing accompanied by new infiltrates on chest radiograph, as well as eosinophilia due to an immunologic response to antigens from dead worms.⁴⁴

Cestodes (Tapeworms)

Echinococcosis (Hydatid Disease of the Lung)

Hydatid cyst is caused by the larval stage of the tapeworm Echinococcus granulosus (dog tapeworm) or Echinococcus multilocularis. Although hydatid disease is worldwide in its distribution, it is most commonly found in regions where sheep and cattle raising constitute important industries, eg, Australia, the Middle East, and South America. The larvae develop in these animals and give rise to the echinococcal cyst. Humans are an accidental host and are usually infected by the intimate handling of an infected dog. The liver (60 to 70%) and the lungs (20 to 30%) are the most frequently involved organs. Pulmonary disease, in particular, appears to be more common in younger individuals.⁴⁵ Monocytes, macrophages, giant cells, and eosinophils result in a defensive reaction that destroys a large number of parasites. Embryos that escape destruction develop into hydatid cysts. The cellular reaction slowly gives rise to fibrosis and a calcified cyst known as the pericyst. Diagnosis is established when typical radiographic features are present, which include well-defined solitary or multiple lesions. While most patients are asymptomatic, some may occasionally expectorate the contents of the cyst, or develop symptoms related to compression of the surrounding structures. The cyst may erode into the bronchi, mediastinum, or pleural cavity. An air leak between the adventitious and laminated layer of the cyst may give rise to a crescent, or "water lily" appearance. MRI, CT scan, and ultrasound reveal a well-defined cyst with thick or thin walls. The cysts are characteristically seen as solitary circumscribed or oval masses, but up to 30% of cases may involve multiple cysts. Detection of antibody to specific echinococcal antigens by immunoblotting has the highest degree of specificity. Surgical excision of the cyst is the treatment of choice whenever feasible.⁴⁶ Albendazole, given at a dose of 400 mg bid for 12 weeks, is most efficacious, although multiple courses may be necessary (Table 3; Fig 2).

Pentastomiasis

Pentastomiasis is a parasitic zoonosis of humans caused by several species of bloodsucking invertebrate parasites, the larvae of which occasionally infest humans. Most of the human infections are caused by Armillifer armillatus, a parasite that normally inhabits the nasopharynx of carnivorous mammals, and Linguatula serrata, which is found in the lungs of reptiles and carnivorous mammals.⁴⁷ Humans acquire disease by ingesting eggs in contaminated food or water. In humans, larvae are commonly found in the abdomen; rarely, the lungs also may be involved. In a great majority of cases, infestation does not produce symptoms and is discovered only at autopsy.

Others

A number of zoonotic infections also may involve the lung, including melioidosis and Leptospira spp. It is also important to consider such zoonotic infections while managing patients with pneumonia in the tropics.

Melioidosis

Melioidosis is an infectious disease of humans and animals caused by Burkholderia pseudomallei. This is a Gram-negative rod organism widely distributed in the soil of rice and in stagnant water throughout the tropics. Although it is a major public health problem in Southeast Asia and northern Australia, melioidosis occurs sporadically throughout the world (often in patients with a history of residence in these areas). Humans are usually infected by traumatic inoculation of the organism from the soil or, rarely, by inhalation or ingestion. The symptoms are mostly referable to the upper respiratory tract and include cough, sputum, transient bronchitis, or vague chest pain.⁴⁸ In these cases the chest radiograph is normal. Complications include localized abscess, severe community-acquired pneumonia, and fatal septicemia. Progressive upper-lobe infiltrates mimic tuberculosis.

Diagnosis is based on a combination of clinical features, epidemiologic evidence, culture, and serologic tests. The definitive diagnosis is established by recovering the organism in culture, seroconversion with a fourfold increase in titer, or the presence of high titers. b-Lactam antibiotics have dramatically reduced the risk of death, but mortality still remains high. Regimens for the acute phase of illness should contain ceftazidime or imipenem.⁴⁹ For oral therapy after the acute phase of treatment, a switch can be made to an oral agent such as trimethoprim-sulfamethoxazole or amoxicillin/clavulanate. Antibiotic therapy for 60 to 150 days is usually necessary.

Leptospirosis

Leptospirosis is an infectious disease caused by the Leptospira interrogans complex. Rodents, particularly rats, are the major reservoirs of the disease all over the world. It is characterized by a spectrum of clinical manifestations including fever, chills, headache, conjunctivitis, muscular pain, hemorrhagic diathesis, and hepatic and renal dysfunction. Pulmonary manifestations occur in a high percentage of patients and include a nonspecific cough, hemoptysis, and pleural effusion. ARDS and profuse hemoptysis can occur rarely. The radiographic abnormalities are more common at the bases and lung periphery. Cigarette smoking is a risk factor for the development of pulmonary involvement in human leptospirosis.⁵⁰ Variables that are independently associated with mortality include hemodynamic disturbance, progressive renal failure, and hyperkalemia.⁵¹ Serologic testing is very helpful for the diagnosis of leptospirosis. Penicillin G is the treatment of choice with streptomycin, tetracycline, and erythromycin medications as alternatives.

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